Full Guideline Sogc 2005 2016 531s6x

CLINICAL PRACTICE GUIDELINE No. 334 (Replaces No. #121, November 2002)

Diabetes in Pregnancy This Clinical Practice Guideline has been prepared by the Maternal Fetal Medicine Committee; reviewed by the Family Physicians Advisory, Aboriginal Health Initiative, and Clinical Practice e Obstetrics Guideline Committees and the Canadian Diabetes Association; endorsed by the Canadian Diabetes Association; and approved by the Board of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Howard Berger, MD, Toronto ON Robert Gagnon, MD, Montreal QC Mathew Sermer, MD, Toronto ON MATERNAL FETAL MEDICINE COMMITTEE Melanie Basso, RN, Vancouver BC Hayley Bos, MD, Victoria BC Richard N. Brown, MD, Beaconsfield QC Emmanuel Bujold, MD, Quebec QC Stephanie L. Cooper, MD, Calgary AB Robert Gagnon, MD, Montreal QC Katy Gouin, MD, Quebec QC N. Lynne McLeod, MD, Halifax NS Savas M. Menticoglou, MD, Winnipeg MB William R. Mundle, MD, Windsor ON Anne Roggensack, MD, Calgary AB Frank L. Sanderson, MD, Saint John NL Jennifer D. Walsh, MD, Rothesay NB Disclosure statements have been received from all of the committee(s).

Key Words: Diabetes, pregnancy, stillbirth http://dx.doi.org/10.1016/j.jogc.2016.04.002

J Obstet Gynaecol Can 2016;-(-):1e13 Copyright ª 2016 by the The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada

Abstract Objective: This guideline reviews the evidence relating to the diagnosis and obstetrical management of diabetes in pregnancy. Outcomes: The outcomes evaluated were short- and long-term maternal outcomes, including preeclampsia, Caesarean section, future diabetes, and other cardiovascular complications, and fetal outcomes, including congenital anomalies, stillbirth, macrosomia, birth trauma, hypoglycemia, and long-term effects. Evidence: Published literature was retrieved through searches of PubMed and the Cochrane Library using appropriate controlled vocabulary (MeSH “diabetes” and “pregnancy”). Where appropriate, results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date limits, but results were limited to English or French language materials. Values: The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). Summary Statements 1. The adverse outcomes associated with diabetes in pregnancy are substantially associated with hyperglycemia and the coexisting metabolic environment. Women with preexisting diabetes should receive preconception care to optimize blood sugar control and other comorbidities. Outcomes for the fetus/neonate and the mother in both pre-gestational diabetes mellitus and gestational diabetes mellitus pregnancies are improved by multidisciplinary management in which the goal is achieving optimal blood sugar control and appropriate fetal surveillance. (II-2) 2. Retrospective studies indicate that women with pre-gestational diabetes mellitus have an increased risk of stillbirth before 40 weeks’ gestation compared with the general obstetrical population. Similarly, large recent cohort and simulation studies of women with gestational diabetes mellitus pregnancies also indicate a higher risk of stillbirth between 36 to 39 weeks’ gestation. (II-2) 3. Women with gestational diabetes mellitus have a higher risk of preeclampsia, shoulder dystocia, Caesarean section, and large for gestational age infants. (II-2) 4. Treatment of women with gestational diabetes mellitus and optimization of glycemic control reduce the risk of preeclampsia, shoulder dystocia, and large for gestational age infants. (I) 5. The occurrence of gestational diabetes mellitus increases the risk of developing type 2 diabetes in the future for the mother. (II-2)

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

-

JOGC

-

2016

l

1

CLINICAL PRACTICE GUIDELINE

Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventative Health Care Quality of evidence assessment* I Evidence obtained from at least one properly randomized controlled trial II-1 Evidence from well-designed controlled trials without randomization II-2 Evidence from well-designed cohort (prospective or retrospective) or case-control studies, preferably from more than one centre or research group II-3 Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in the category III Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

Classification of recommendations† A. There is good evidence to recommend the clinical preventive action B. There is fair evidence to recommend the clinical preventive action C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making D. There is fair evidence to recommend against the clinical preventive action E. There is good evidence to recommend against the clinical preventive action F. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decisionmaking

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care. †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in The Canadian Task Force on Preventive Health Care. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207e8.

Recommendations 1. The “preferred screening and diagnostic 2-step” approach for gestational diabetes mellitus of the Canadian Diabetes Association 2013 guidelines is endorsed. All pregnant women should be offered screening between 24 to 28 weeks using a standardized non-fasting 50-g glucose challenge screening test with plasma glucose measured 1 hour later. (III-B) 1.1. If the value is < 7.8 mmol/L, no further testing is required. 1.2. If the value of the glucose challenge screening test is 7.8 to 11.0, a 2-hour 75-g oral glucose tolerance test with fasting plasma glucose, 1-hour plasma glucose, and 2-hour plasma glucose should be performed.

ABBREVIATIONS

Gestational diabetes mellitus is diagnosed if 1 value is met or exceeded: i. Fasting plasma glucose 5.3 mmol/L ii. 1-hour plasma glucose 10.6 mmol/L iii. 2-hour plasma glucose 9.0 mmol/L 1.3. If the value of the glucose challenge screening test is 11.1 mmol/L, gestational diabetes mellitus is diagnosed. 2. The “alternative 1-step diagnostic” approach of the Canadian Diabetes Association 2013 guidelines is acceptable. In this strategy pregnant women should be offered testing between 24 to 28 weeks using a standardized 2-hour 75-g oral glucose tolerance test with fasting plasma glucose, 1-hour plasma glucose, and 2-hour plasma glucose. (III-B) Gestational diabetes mellitus is diagnosed if 1 value is met or exceeded:

ACOG

American College of Obstetricians and Gynecologists

BMI

body mass index

CDA

Canadian Diabetes Association

ii. 1-hour plasma glucose 10.0 mmol/L

DM

diabetes mellitus

FPG

fasting plasma glucose

GCT

glucose challenge screening test

GDM

gestational diabetes mellitus

HAPO

Hyperglycemia and Adverse Pregnancy Outcome

iii. 2-hour plasma glucose 8.5 mmol/L It is recognized that the use of different diagnostic thresholds for the “preferred” and “alternative” strategies could cause confusion in certain settings. Despite this, the committee has identified the importance of remaining aligned with the current Canadian Diabetes Association 2013 guidelines as being a priority. It is thus recommended that each care centre strategically align with 1 of the 2 strategies and implement protocols to ensure consistent and uniform reporting of test results.

IADPSG International Association of Diabetes and Pregnancy Study Groups LGA

large for gestational age

NST

non-stress test

OGTT

oral glucose tolerance test

PG

plasma glucose

PGDM

pre-gestational diabetes mellitus

RR

relative risk

SMBG

self-monitored blood glucose

2

l

-

JOGC

-

2016

i. Fasting plasma glucose 5.1 mmol/L

3. If there is a high risk of gestational diabetes mellitus based on multiple risk factors, screening or testing should be offered during the first half of the pregnancy and repeated at 24 to 28 weeks’ gestation if initially normal. If for any reason it was missed or if there is a clinical suspicion of later onset of gestational diabetes, a screening or diagnostic test should be performed. (II-2B) 4. Women with preexisting or gestational diabetes mellitus should be provided with care by a multidisciplinary team aimed at attaining and then maintaining euglycemia. (II-2B)

Diabetes in Pregnancy

5. For patients with pre-gestational diabetes mellitus or gestational diabetes mellitus, starting at 28 weeks as a baseline, with subsequent serial assessment of fetal growth, every 3 to 4 weeks is suggested to assess the effect of maternal glycemic control on fetal growth rate and amniotic fluid volume. (II-2B) 6. Initiation of weekly assessment of fetal well-being at 36 weeks is recommended in pre-gestational diabetes mellitus and gestational diabetes mellitus. It is also reasonable to consider weekly fetal assessment for women with diet controlled gestational diabetes mellitus beginning at 36 weeks. Acceptable methods of assessment of fetal well-being near term can include the non-stress test, non-stress test þ amniotic fluid index, biophysical profile, or a combination of these. (III-A) 7. If comorbid factors are present, such as obesity, evidence of suboptimal glycemic control, large for gestational age (> 90%), previous stillbirth, hypertension, or small for gestational age (< 10%), earlier onset and/or more frequent fetal health surveillance is recommended. In specific cases in which fetal growth restriction is suspected, the addition of umbilical artery and fetal middle cerebral artery Doppler assessment may be helpful. (II-2A)

indicated. When istered, close maternal glycemic surveillance is recommended. (I-A) 10. If not previously done, in women with threatened preterm labour requiring betamethasone, a screening for gestational diabetes mellitus should be performed either before or at least 7 days after the istration of betamethasone. (III-B) 11. Women with gestational diabetes mellitus should be offered testing with a 75-g oral glucose tolerance test between 6 weeks and 6 months postpartum to detect prediabetes and diabetes.1 (II-2A) 11.1. Normal i. Fasting plasma glucose < 6.1 mmol/L ii. 2-hour plasma glucose < 7.8 mmol/L iii. Glycated hemoglobin < 6.0% 11.2. Pre-diabetic i. Fasting plasma glucose 6.1 to 6.9 mmol/L or ii. 2-hour plasma glucose 7.8 to 11.0 mmol/L or iii. Glycated hemoglobin 6.0% to 6.4% 11.3. Type 2 diabetes mellitus

8. Pregnant women with gestational diabetes mellitus or pregestational diabetes mellitus should be offered induction between 38 to 40 weeks’ gestation depending on their glycemic control and other comorbidity factors. (II-2B)

ii. Random plasma glucose or 2-hour plasma glucose 11.1 mmol/L

9. The istration of betamethasone to pregnant women with gestational diabetes mellitus should be restricted to the routine obstetric indications related to the risk of preterm and late preterm delivery between 24 to 36 weeks’ gestation, when clinically

12. Breastfeeding is strongly recommended after delivery for all women with pre-gestational diabetes mellitus or gestational diabetes mellitus. (II-2A)

i. FPG 7.0 mmol/L

iii. Glycated hemoglobin 6.5%

-

JOGC

-

2016

l

3

CLINICAL PRACTICE GUIDELINE

INTRODUCTION

but can be found in the 2013 CDA Clinical Practice Guidelines, available at: http://guidelines.diabetes.ca/ browse/chapter36.

A

large population-based study in Ontario demonstrated that between 1996 and 2010 the incidence of both GDM and PGDM, which includes both type 1 and type 2 DM, doubled from 2.7% to 5.6% for GDM and from 0.7% to 1.5% for PGDM.2 When compared with non-diabetic pregnant women, the risk of both congenital anomalies (OR 1.86, 95% CI 1.49 to 2.33) and perinatal mortality (OR 2.33 [1.59 to 3.43]) remained higher in PGDM pregnant women.2 Similarly, in a Swedish population-based cohort of over 1.2 million pregnancies with singleton gestations, women with GDM had a higher risk of adverse maternal outcomes (OR 1.81 [1.64 to 2.00]; for shoulder dystocia of (OR 2.74 [2.04 to 3.68]); and for Caesarean section (OR 1.46 [1.38 to 1.54]).3 In addition, with GDM, a higher risk of adverse neonatal outcomes has been reported, including LGA (OR 3.43 [3.21 to 3.67]), Erb’s palsy (OR 2.56 [1.96 to 3.32]), prematurity (OR 1.71 [1.58 to 1.86]), and major malformations (OR 1.19 [1.02 to 1.39]).3 It is of interest that no statistically significant improvement in maternal and neonatal outcome was seen over time in either study, with the exception of a decline in the rate of congenital anomalies by 23%.2,3

IMPACT OF DIABETES MELLITUS ON PERINATAL MORTALITY

Table 2 summarizes the RR or OR for stillbirth in pregnancies with GDM in different populations studied compared with non-GDM pregnancies. A wide range of absolute stillbirth rate (per 1000 pregnancies) has been reported, from as low as 0.32 to 4.2 per 1000 pregnancies, depending on the population studied and the gestational age cutoff used to define stillbirth (see Table 2). Some studies11 have confirmed that GDM may be diagnosed before 24 weeks’ gestation approximately 22% to 27% of the time. Almost one third (or 8% of the total diagnosed with GDM) of these patients will have type 2 diabetes when tested postpartum.12 This is particularly true in the presence of the following risk factors: maternal age > 35 years; obesity (BMI > 30); ethnicity (Aboriginal, African, Asian, Hispanic, South Asian); family history of diabetes; polycystic ovary syndrome; acanthosis nigricans; corticosteroid use; previous pregnancy complicated with GDM; or previous macrosomic infant.1 Hutcheon et al.6 have suggested that only stillbirths greater than 28 weeks’ gestation should be included to determine the risk of stillbirth associated with GDM. Including women with an earlier diagnosis may not represent the risk associated with GDM but rather a mix of GDM and other causes of stillbirths, leading to the introduction of a bias by including a period of follow-up during which, by design, death or the study outcome cannot occur. Because GDM is usually diagnosed after 24 to 28 weeks’ gestation, it would be more appropriate to include only late stillbirth occurring after 28 weeks. Table 2 illustrates this phenomenon. When defining stillbirth occurring at > 20 weeks, the risk of stillbirth attributable to GDM is reduced or insignificant.6e9 This is because more than 30% of stillbirths

Even though the benefits of specialized management of pregnancies complicated by PGDM is well-known, we now have data from RCTs that document a reduction in certain perinatal morbidities after diagnosis and management of GDM.4,5 The primary goal of this management is to attain and then maintain euglycemia. This is best done by a multidisciplinary team with attention to diet and exercise; glucose monitoring; and, as appropriate, medical management with insulin and/or oral hypoglycemic agents. The purpose of these guidelines is to review the diagnostic criteria and issues related to the obstetrical management of GDM and PGDM. Specific recommendations regarding glycemic control are beyond the scope of this document Table 2. Risk of Stillbirth (GDM vs. No GDM)

Population (n)

Absolute stillbirth rate in GDM (per 1000 pregnancies)

RR or OR (95% CI)

2 001 749

4.2

0.88 (0.79 to 0.99)

Not available

20 weeks

120 604

2.0

0.31 (0.11 to 0.67)

Induction rate: 38% vs 24%

20 weeks

184 256

4.0

0.5 (0.4 to 0.7)

Gestational age cutoff

Hutcheon et al.6

20 weeks

Peticca et al.7 Karmon et al.8

Author

Policy management

Routine induction at 40 weeks

Ohana et al.

20 weeks

228 293

0.32

0.7 (0.5 to 0.8)

Not available

Fadl et al.3

> 28 weeks

1 260 297

4.0

1.18 (0.87 to 1.60)

Not available

> 28 weeks

1 988 320

3.5

1.25 (1.11 to 1.41)

Not available

36 weeks

4 190 953

1.71

1.34 (1.2 to 1.5)

9

Hutcheon et al.6 10

Rosenstein et al.

4

l

-

JOGC

-

2016

At > 39 weeks risk higher if expectant management

Diabetes in Pregnancy

occur at 20 to 23 weeks, before GDM is usually diagnosed.13 When including only stillbirths occurring after 28 weeks, many studies to date have shown a trend or a statistically significant increased risk of stillbirth attributable to GDM.3,6,10 The specific excess risk of stillbirth in relation to week of gestation has recently been shown in a cohort10 and simulation study derived from this cohort.14 This retrospective analysis14 of population-based data from California showed that the overall risk of stillbirth from 36 to 42 weeks’ gestation was higher in women with GDM compared with women without GDM (17.1 vs. 12.7/10 000 deliveries; RR 1.34; 95% CI 1.2 to 1.5). Stillbirth rates were also examined at each gestational age, and from 36 to 39 weeks, women with GDM had a statistically significant elevated RR of stillbirth compared with women without GDM, ranging from RR 1.45 (95% CI 1.1 to 1.9) at 36 weeks to RR 1.84 (95% CI 1.5 to 2.3) at 37 weeks.14 This increased risk of stillbirth remained statistically significant at 39 weeks with a RR of 1.56 (95% CI 1.2 to 2.0) but not at 40 and 41 weeks’ gestation. The loss of significance at 40 to 41 weeks’ gestation was either due to the increase in stillbirths in non-GDM pregnancies15 or due to the relatively low number of patients after 39 weeks’ gestation in GDM pregnancies compared with non-GDM pregnancies. In addition, the risk of expectant management in women with GDM carried a higher risk of perinatal mortality than the risk of delivery at 39 and 40 weeks’ gestation.10,14 The number of women with GDM needed to be delivered at 39 and 40 weeks to prevent 1 excess death was 1518 and 1311, respectively.13 This is comparable with the number needed to be delivered of 1299 at 40 weeks for women without GDM and 40 years at the time of delivery.15 The retrospective nature of this study and the inability to control for glycemic control and insulin treatment presented limitations. A retrospective cohort study from a center with a policy of induction by 40 weeks’ gestation for all pregnant women with diet-controlled GDM suggested that it is protective against stillbirth compared with the general obstetrical population (OR 0.5 [0.4 to 0.7]).8 The impact of this policy of induction on Caesarean section rates and neonatal morbidity is controversial. However, a small RCT in mainly non-diabetic women by Nicholson et al.16 demonstrated a lower neonatal intensive care unit ission rate, a higher uncomplicated vaginal birth rate, and a lower mean adverse outcome index score (better pregnancy outcomes) among women who were actively managed using elective labour induction based on a unique management of risk scoring system. There is good evidence that PGDM is associated with a 3- to 5-fold increased risk in stillbirths compared with non-diabetic pregnant women.17 Further prospective research is needed on the optimization of timing of

delivery in both GDM and PGDM pregnancies with specific attention to stratification by adequacy of glycemic control; the impact on maternal, fetal and neonatal outcomes; and economic analysis of different management strategies. Summary Statements

1. The adverse outcomes associated with diabetes in pregnancy are substantially associated with hyperglycemia and the coexisting metabolic environment. Women with preexisting diabetes should receive preconception care to optimize blood sugar control and other comorbidities. Outcomes for the fetus/neonate and the mother in both pregestational diabetes mellitus and gestational diabetes mellitus pregnancies are improved by multidisciplinary management in which the goal is achieving optimal blood sugar control and appropriate fetal surveillance. (II-2) 2. Retrospective studies indicate that women with pregestational diabetes mellitus have an increased risk of stillbirth before 40 weeks’ gestation compared with the general obstetrical population. Similarly, large recent cohort and simulation studies of women with gestational diabetes mellitus pregnancies also indicate a higher risk of stillbirth between 36 to 39 weeks’ gestation. (II-2)

Screening for GDM (Appendix A)

Despite not meeting many of the criteria for a program of population-based screening,18 screening for GDM has been accepted widely and is almost universally practiced among health care professionals in North America.19,20 Methods for screening for GDM include the following: 1. Screening with a 1-hour 50-g glucose load (or alternative) 2. Risk factor based screening 3. One-step testing with a diagnostic 2-hour 75-g OGTT (this does not in fact constitute a screening test but rather universal testing) 4. Screening with alternative biochemical tests: FPG, glycated hemoglobin, random plasma glucose There have been no RCTs comparing screening for GDM with no screening,20 thus the decision to perform screening is based on the recent RCTs that have shown certain health benefits for treatment of GDM.4,5 Because GDM is an asymptomatic condition, logic dictates that some form of screening would need to be performed to diagnose cases

-

JOGC

-

2016

l

5

CLINICAL PRACTICE GUIDELINE

that might benefit from treatment and management. The Toronto Tri Hospital study established that adverse outcomes associated with GDM increase along a continuum of increasing glucose thresholds.21 More recently, the Hyperglycemia and Adverse Pregnancy Outcome study22 confirmed these findings in a large, prospective, observational study but was unable to define outcome-based thresholds for the diagnosis of GDM. Despite this, the International Association of Diabetes and Pregnancy Study Group published recommendations for new thresholds for the diagnosis of GDM based on statistical re-analysis of the HAPO data.23 The thresholds for the 2-hour 75-g OGTT used were calculated by defining glucose concentrations at which the OR of the 4 HAPO primary outcomes (birthweight > 90%, primary Caesarean section rate, neonatal hypoglycemia, and cord C-peptide levels > 90%) reached 1.75. These thresholds, when applied to the HAPO cohort, led to an average GDM incidence of 17% across all HAPO sites. In addition the IADPSG recommended abandoning the 1-hour 50-g glucose load in favour of a 1-step testing strategy. Table 3 provides a summary of the glucose thresholds, screening, and diagnostic strategies used worldwide. In North America, either a 2-step or a 1-step approach is believed to be acceptable because there is no demonstrated difference in outcome using either strategy.1,24,25

The CDA guidelines, in which SOGC was represented in an attempt to achieve consensus between obstetricians and endocrinologists, were updated in 2013.1 Guiding the decisions of the committee were the realization that: (1) women with 1 abnormal value on the OGTT (previously classified as intolerance to glucose of pregnancy) have similar outcomes of women with 2 abnormal values and are routinely managed in the same manner12,29e33; (2) the HAPO trial22 provided data that could be used to help formulate outcome-based diagnostic thresholds for GDM; and (3) there is a need to achieve some degree of uniformity with regard to screening methodology and diagnostic criteria in Canada. The CDA 2013 guidelines recommend a universal screening for GDM for all pregnant women between 24 and 28 weeks’ gestation followed by a 2-hour 75-g OGTT if the 1-hour PG after a 50-g glucose load value is 7.8 mmol.1 This is referred to as the “preferred 2-step” approach, with diagnostic criteria thresholds corresponding to an OR of 2.0 for the 4 main HAPO outcomes.22 An “alternative 1-step” approach with diagnostic criteria thresholds with an OR of 1.7522 for adverse perinatal outcome is also acceptable.1 The 2014 American Diabetes Association guidelines25 endorsed an approach similar to those of the CDA 2013 guidelines, although the second step differs with the diagnostic test remaining the 100-g OGTT.25 These guidelines are also more in line with

Table 3. Universal Screening and Diagnostic Criteria for GDM (mmol/L)

Gestational age at screening* Steps

ACOG 201324 ADA 201425 Carpenter and Coustan

ACOG 2013 ADA 201425 National Diabetes Data Group

24 to 28 weeks

24 to 28 weeks

24

CDA 2013 “preferred approach”

CDA 20131 “alternative approach,” IADPSG 2010,26 ADIPS 2014,27 ADA 201425

WHO 201328

24 to 28 weeks

24 to 28 weeks

Any time

1-step

1-step

1

2-step

2-step

2-step

Step 2 if value 7.8 No diagnostic cutoff for GDM

Step 2 if value 7.8 No diagnostic cutoff for GDM

GDM if 11.1 Step 2 if value 7.8 to 11.0

Loading dose

100 g

100 g

75 g

75 g

75 g

Fasting

5.3

5.8

5.3‡

5.1†

5.1† 10.0†

Step 1 Screening 1-hour 50-g glucose challenge Step 2

1 hour

10.0

10.6

10.6‡

10.0†

2 hours

8.6

9.2

9.0‡

8.5†

8.5†

3 hours

7.8

8.0

Not needed

Not needed

Not needed

2 abnormal values

2 abnormal values

1 abnormal value

1 abnormal value

1 abnormal value

4.8

3.2

7.0

16.1

16.1

GDM if Prevalence of GDM (%)

ADA: American Diabetes Association; ADIPS, Australasian Diabetes in Pregnancy Society. *Screening offered at any stage in the pregnancy if multiple risk factors. †OR 1.75 for adverse perinatal outcome based on HAPO study. ‡OR of 2.00 for adverse perinatal outcome based on HAPO study.

6

l

-

JOGC

-

2016

Diabetes in Pregnancy

the ACOG 2013 guidelines.25 It is of note that the Australasian Diabetes in Pregnancy Society and the World Health Organization have both adopted the IADPSG criteria in their 2013 guidelines.27,28 The incidence of GDM varies between 3.2% and 16.1%, depending of the thresholds used and the composition of the screened population. Table 3 summarizes the different screening and diagnostic criteria used for GDM. THE 1-HOUR 50-G GCT

It is recognized that there is controversy regarding the use of a 1-hour 50-g non-fasting GCT as a screening test for GDM. Criticism is focused on the following issues: (1) the inability to identify women with isolated elevated FPG, (2) limited reproducibility, (3) incomplete uptake of the diagnostic test in those whose screening result is positive, (4) delay in diagnosis of GDM, and (5) test sensitivity of only 76.6%.34 In contrast, this test is widely practiced in North America and has high acceptance in both patients and caregivers. Until data emerge that significant superior outcomes with a 1-step diagnostic test, the SOGC has decided to recommend the continued use of the 50-g OGTT as the primary screening tool in women without high-risk characteristics. There are no established criteria for the diagnosis of GDM based on the 1-hour 50-g post-load value, but it is recognized that there are results of this test that indicate a very high chance of diagnosing GDM on the confirmatory test. Cheng et al.,35 in a cohort of 14 771 pregnancies with GDM, showed that there is an increase in Caesarean section (OR 4.18 [1.15 to 15.2]) and an increase in shoulder dystocia (OR 15.14 [1.64 to 140]) in women who had a screening 1-hour 50-g glucose post-load value above 11.1 mmol/L. When the outcome 1-hour 50-g glucose post-load is defined by an abnormal OGTT only, the cutoff value that can reliably diagnose GDM is probably > 12.2 mmol/L.35,36 For these reasons, the t CDA-SOGC 2013 committee on diabetes in pregnancy decided that if a value of 11.1 mmol/L after a 1-hour 50-g glucose post-load is obtained, a 2-hour 75-g OGTT is unnecessary. When the a priori risk of diagnosing GDM or overt DM is high based on clinical, demographic, or historical risk factors, it will be prudent to offer either screening or testing earlier in gestation. This is mainly to facilitate the diagnosis of unrecognized type 2 DM that will benefit from earlier interventions to ensure adequate glycemic control. In the presence of the following risk factorsdmaternal age > 35 years; obesity (pre-pregnancy BMI > 30); ethnicity

(Aboriginal, African, Asian, Hispanic, South Asian); family history of diabetes; polycystic ovary syndrome; acanthosis nigricans; corticosteroid use; previous pregnancy complicated with GDM; or previous macrosomic infantdeither a 1-hour 50-g GCT or a diagnostic 75-g OGTT can be offered in the first half of the pregnancy and repeated at 24 to 28 weeks’ gestation if the result is negative.1 Until there is evidence to alternative thresholds for the early 50-g GCT or 75-g OGTT, we suggest using the same criteria that is used for the standard 24 to 28 weeks’ gestation test. Pregnancy after bariatric surgery is becoming more common. GDM diagnostic testing, when applied to women who have undergone Roux-en-Y gastric by, increases the GDM diagnosis without changing pregnancy outcome.37 In addition, a high incidence of 58% of reactive hypoglycemia is encountered during OGTT. Therefore, studies are needed to provide alternative screening and diagnostic criteria for GDM in women who have undergone bariatric surgery. Due to a lack of evidence ing different thresholds for screening for GDM, it is not possible to define alternative thresholds. Until then, it is reasonable to order fasting and 1-hour postprandial blood glucose in addition to the glycated hemoglobin level in these women to rule out abnormalities in carbohydrate metabolism (see Appendix A). Recommendations

1. The “preferred screening and diagnostic 2-step” approach for gestational diabetes mellitus of the Canadian Diabetes Association 2013 guidelines is endorsed. All pregnant women should be offered screening between 24 to 28 weeks using a standardized non-fasting 50-g glucose challenge screening test with plasma glucose measured 1 hour later. (III-B) 1.1. If the value is < 7.8 mmol/L, no further testing is required. 1.2. If the value of the glucose challenge screening test is 7.8 to 11.0, a 2-hour 75-g oral glucose tolerance test with fasting plasma glucose, 1-hour plasma glucose, and 2-hour plasma glucose should be performed. Gestational diabetes mellitus is diagnosed if 1 value is met or exceeded: i. Fasting plasma glucose 5.3 mmol/L ii. 1-hour plasma glucose 10.6 mmol/L iii. 2-hour plasma glucose 9.0 mmol/L 1.3. If the value of the glucose challenge screening test is 11.1 mmol/L, gestational diabetes mellitus is diagnosed.

-

JOGC

-

2016

l

7

CLINICAL PRACTICE GUIDELINE

2. The “alternative 1-step diagnostic” approach of the Canadian Diabetes Association 2013 guidelines is acceptable. In this strategy pregnant women should be offered testing between 24 to 28 weeks using a standardized 2-hour 75-g oral glucose tolerance test with fasting plasma glucose, 1-hour plasma glucose, and 2hour plasma glucose. (III-B) Gestational diabetes mellitus is diagnosed if 1 value is met or exceeded: i. Fasting plasma glucose 5.1 mmol/L ii. 1-hour plasma glucose 10.0 mmol/L iii. 2-hour plasma glucose 8.5 mmol/L It is recognized that the use of different diagnostic thresholds for the “preferred” and “alternative” strategies could cause confusion in certain settings. Despite this, the committee has identified the importance of remaining aligned with the current Canadian Diabetes Association 2013 guidelines as being a priority. It is thus recommended that each care centre strategically align with 1 of the 2 strategies and implement protocols to ensure consistent and uniform reporting of test results. 3. If there is a high risk of gestational diabetes mellitus based on multiple risk factors, screening or testing should be offered during the first half of the pregnancy and repeated at 24 to 28 weeks’ gestation if initially normal. If for any reason it was missed or if there is a clinical suspicion of later onset of gestational diabetes, a screening or diagnostic test should be performed. (II-2B)

ANTEPARTUM MANAGEMENT OF GDM

The benefits of treating GDM are now generally accepted.4,5 There is also an association between the presence of GDM and hypertensive disorders of pregnancy.22,38 The goals of treatment are: (1) optimizing fetal growth and preventing macrosomia, (2) reducing the risk of intrauterine fetal death, (3) reducing the risk of preeclampsia,39 (4) reducing the risk of Caesarean section, and (5) reducing the risk of neonatal complications, including shoulder dystocia, birth trauma, and neonatal hypoglycemia. Summary Statements

3. Women with gestational diabetes mellitus have a higher risk of preeclampsia, shoulder dystocia, Caesarean section, and large for gestational age infants. (II-2)

8

l

-

JOGC

-

2016

4. Treatment of women with gestational diabetes mellitus and optimization of glycemic control reduce the risk of preeclampsia, shoulder dystocia, and largefor-gestational-age infants. (I) 5. The occurrence of gestational diabetes mellitus increases the risk of developing type 2 diabetes in the future for the mother. (II-2)

Optimizing Fetal Growth and Preventing Macrosomia

Fetal macrosomia may occur without gestational diabetes. However, the incidence of macrosomia in pregnancies complicated with maternal hyperglycemia is a function of maternal glycemic control.22,32,33,38,40e42 There is an association between excessive fetal weight and certain perinatal complications, including shoulder dystocia and birth trauma,43,44 perinatal mortality,45 and Caesarean delivery.21,46e49 Landon et al.5 have shown that the treatment of mild gestational diabetes results in a significant reduction compared with usual care in several prespecified secondary outcomes, including mean birth weight (3302 vs. 3408 g), neonatal fat mass (427 vs. 464 g), the frequency of LGA infants (7.1% vs. 14.5%), birth weight greater than 4000 g (5.9% vs. 14.3%), shoulder dystocia (1.5% vs. 4.0%), and Caesarean delivery (26.9% vs. 33.8%). In a secondary analysis the Maternal Fetal Medicine Network RCT for the treatment of mild GDM demonstrated that induction of labour between 37 to 40 weeks’ gestation in women did not increase the rate of Caesarean delivery.50 Treatment of GDM compared with usual care was also associated with reduced rates of preeclampsia and gestational hypertension (combined rates for the 2 conditions, 8.6% vs. 13.6%; P ¼ 0.01). Current CDA 2013 guidelines for maternal glycemic control suggest striving for the following targets on selfmonitored blood glucose: fasting SMBG < 5.3 mmol/L; 1-hour postprandial < 7.8 mmol/L; or 2 hours postprandial < 6.7 mmol/L. This often can be achieved with nutritional counselling and modification of physical activity level. When treatment with non-medical interventions is unsuccessful after 1 to 2 weeks, medical therapy should be initiated.1 Optimizing maternal glycemic control in women with GDM decreases the risk of preeclampsia, fetal macrosomia, shoulder dystocia, and Caesarean section.5 An SGA fetus can also be a complication of overtreatment of GDM or a complication of associated risk factors.50 An RCT comparing insulin therapy based on “tight” maternal glycemic control (keeping fasting SMBG < 5.0 mmol/L and 2-hour postprandial at < 6.7 mmol/L) alone versus

Diabetes in Pregnancy

ultrasound-based measurement of fetal abdominal circumference percentile and more “relaxed” maternal glycemic control (fasting SMBG < 6.6 mmol/L and 2hour postprandial < 11.1 mmol/L) demonstrated that both methods resulted in an equivalent perinatal outcome.51 The addition of measuring the abdominal circumference every 3 to 4 weeks helped guide the decision to treat some pregnant women more aggressively with tighter glycemic control to prevent macrosomia but using a more “relaxed” control if the abdominal circumference was low to prevent the development of an SGA fetus.51e53 If a SGA fetus is suspected, umbilical artery and middle cerebral artery Doppler (if available) should be performed as part of the assessment of placental function and fetal well-being. In the presence of fetal macrosomia or poor glycemic control, polyhydramnios may also develop. Therefore, the measurement of the amniotic fluid volume can be another tool used to assess maternal glycemic control in the context of GDM.54 Reducing the Risk of Intrauterine Fetal Death

The most important factor to minimize fetal death is optimizing maternal glycemic control to optimize fetal growth. The 2007 SOGC guidelines on antenatal fetal surveillance55 lists pre-pregnancy diabetes and insulinrequiring GDM as conditions associated with increased perinatal morbidity/mortality and conditions in which antenatal fetal surveillance may be beneficial. In the light of more recent evidence that diet-controlled GDM might also be associated with an increase in perinatal mortality,6,10,14 particularly after 38 weeks’ gestation, these patients should not be excluded from a protocol for antenatal fetal surveillance applicable to high-risk pregnancies. Landon and Vickers56 previously questioned whether patients with diet-controlled GDM should have any fetal health surveillance prior to 40 weeks’ gestation because the risk of fetal death is low. In contrast, they advocated twice per week fetal health surveillance starting at 32 weeks for all insulin-treated GDM patients. Most published protocols for antenatal fetal surveillance for diet-controlled GDM include ultrasound for fetal growth every 3 to 4 weeks starting at 28 weeks’ gestation and delivery no later than 40 weeks’ gestation.8,51,53,57 The ACOG 2013 guidelines24 state that for women with GDM and poor glycemic control, fetal surveillance may be beneficial. A retrospective study of 2134 women with pregnancies complicated by diabetes reported that an antepartum fetal surveillance program using a twice-weekly non-stress test and fluid index assessment was successful in preventing stillbirth.58 The role of the biophysical profile in antenatal surveillance of diabetic pregnancies has not been studied in a large population, but one can logically extrapolate from the

known value of the biophysical profile in non-diabetic pregnancies59,60 to a diabetic pregnancy surveillance protocol. The use of pre-delivery weight estimation to detect the presence of fetal macrosomia is problematic due to the poor performance of all methods of pre-delivery fetal weight estimation.61e63 Previous evidence has suggested that in the context of suspected fetal macrosomia there is no proven benefit of induction of labour compared with expectant management.64 However, more recently, Boulvain et al.65 demonstrated in a large randomized clinical trial that induction of labour for suspected large-for-date fetuses is associated with a reduced risk of shoulder dystocia and associated morbidity compared with expectant management. Induction of labour did not increase the risk of Caesarean delivery and improved the likelihood of spontaneous vaginal delivery. There is only 1 randomized clinical trial comparing elective induction with expectant management in GDM pregnancies.66 In a mixed group of women with uncomplicated insulin-requiring GDM or PGDM, expectant management of pregnancy after 38 weeks’ gestation did not reduce or increase the incidence of Caesarean delivery. However, there was an increased prevalence of LGA infants (23% vs. 10%) and shoulder dystocia (3% vs. 0% [not significant]) in the expectant group. Recommendations

4. Women with preexisting or gestational diabetes mellitus should be provided with care by a multidisciplinary team aimed at attaining and then maintaining euglycemia. (II-2B) 5. For patients with pre-gestational diabetes mellitus or gestational diabetes mellitus, starting at 28 weeks as a baseline, with subsequent serial assessment of fetal growth, every 3 to 4 weeks is suggested to assess the effect of maternal glycemic control on fetal growth rate and amniotic fluid volume. (II-2B) 6. Initiation of weekly assessment of fetal well-being at 36 weeks is recommended in pre-gestational diabetes mellitus and gestational diabetes mellitus. It is also reasonable to consider weekly fetal assessment for women with diet controlled gestational diabetes mellitus beginning at 36 weeks. Acceptable methods of assessment of fetal well-being near term can include the non-stress test, non-stress test þ amniotic fluid index, biophysical profile, or a combination of these. (III-A) 7. If comorbid factors are present, such as obesity, evidence of suboptimal glycemic control, large for

-

JOGC

-

2016

l

9

CLINICAL PRACTICE GUIDELINE

gestational age (> 90%), previous stillbirth, hypertension, or small for gestational age (< 10%), earlier onset and/or more frequent fetal health surveillance is recommended. In specific cases in which fetal growth restriction is suspected, the addition of umbilical artery and fetal middle cerebral artery Doppler assessment may be helpful. (II-2A) TIMING OF DELIVERY

A recent systematic review demonstrated a reduction in the rate of fetal macrosomia with active rather than expectant management.67 Due to the significant heterogeneity in the studies analyzed, the authors were limited in their ability to draw conclusions and provide recommendations for management. Due to the small number of patients, these studies were not powered to address the impact of induction or expectant management on perinatal mortality. In the view that the risk of intrauterine fetal death appears to outweigh the risk of infant death after 39 weeks’ gestation,10 induction of labour at 39 weeks could be considered in insulin-treated GDM patients. Because retrospective studies suggest that a policy of induction by no later than 40 weeks is associated with a decreased rate of stillbirth in women with dietcontrolled GDM compared with the general obstetrical population (OR 0.5 [0.4 to 0.7]),8 induction by 40 weeks maybe beneficial in this population. It is also reassuring that a recent study including all randomized clinical trials comparing induction of labour at term or post-term with expectant management for high- and low-risk pregnancies showed a reduced risk of fetal death (RR 0.50 [0.25 to 0.99]) and neonatal intensive care unit ission (RR 0.86 [0.79 to 0.94]) and no increase in the Caesarean section rate with labour induction,68 findings that have been replicated in other studies.69,70 Recommendation

8. Pregnant women with gestational diabetes mellitus or pre-gestational diabetes mellitus should be offered induction between 38 to 40 weeks’ gestation depending on their glycemic control and other comorbidity factors. (II-2B) SPECIAL CONSIDERATIONS GDM and the Use of Betamethasone

The widespread use of corticosteroids in patients at risk of preterm delivery, often istered at the same gestational age for which screening and diagnosis of GDM is usually performed, can make interpretation of screening

10

l

-

JOGC

-

2016

for GDM difficult. Fisher et al.71 have demonstrated that abnormal screening tests can be present for more than 1 week after the istration of betamethasone in 48% of patients. For this reason, they suggested that a 1-step diagnostic procedure is more appropriate. The overall incidence of GDM was 14% in women who received betamethasone compared with 4% in control patients using a 3-hour 100-g OGTT using the National Diabetes Data Group criteria (see Table 3).71 Therefore, a 2-hour OGTT should be performed no less than 7 days postistration of the last dose of betamethasone. Because ketoacidosis in the pregnant diabetic individual is a potential cause of fetal demise,72e74 it is also recommended to closely monitor maternal glycaemia after betamethasone istration in women with poorly controlled diabetes, particularly during the first 12 hours after istration. istration of betamethasone in the late preterm period at 34 to 36 weeks’ gestation is associated with a significant reduction in major respiratory morbidity.75 Although pre-gestational diabetic women were excluded from this recent trial, GDM was not. Until such benefit is proven in women with PGDM, the istration of betamethasone in the late preterm period should be limited to women with GDM only. Randomized and quasi-randomized controlled trials comparing prophylactic antenatal corticosteroid istration with placebo or with no treatment given before elective Caesarean section at or after 37 weeks’ gestation resulted in a significant reduction in the risk of ission to the neonatal intensive care unit for respiratory morbidity (OR 0.15 [0.03 to 0.64]).76 However, no significant reduction in respiratory distress syndrome, transient tachypnea of the newborn, need for mechanical ventilation, or length of stay in the neonatal intensive care unit was found.76 The only randomized trial identified77 included only 6 diabetic pregnant women and therefore could not assess its safety in diabetic pregnant women. It also systematically excluded women with severe hypertension, severe fetal rhesus sensitization, and evidence of intrauterine infection. Long-term follow-up of the infants did not show any adverse outcomes or reduction in asthma.78 In light of the marginal short-term benefits for the newborn and the potential side effects of betamethasone on glycemic control, its use in pregnancies with diabetes at 37 to 39 weeks’ gestation scheduled for elective Caesarean section is not recommended. Recommendations

9. The istration of betamethasone to pregnant women with gestational diabetes mellitus should be

Diabetes in Pregnancy

restricted to the routine obstetric indications related to the risk of preterm and late preterm delivery between 24 to 36 weeks’ gestation, when clinically indicated. When istered, close maternal glycemic surveillance is recommended. (I-A) 10. If not previously done, in women with threatened preterm labour requiring betamethasone, a screening for gestational diabetes mellitus should be performed either before or at least 7 days after the istration of betamethasone. (III-B)

Counseling Postpartum (Appendix B)

Women should be encouraged to breastfeed immediately after delivery to avoid neonatal hypoglycemia and to continue for at least 6 months postpartum to reduce the risk of childhood obesity and maternal hyperglycemia.79e82 Up to one third of affected women will have diabetes or impaired glucose tolerance at postpartum screening. It has also been estimated that 15% to 50% will develop type 2 diabetes later in life.24,25,83e87 Recent data from a prospective observational study have shown that after a pregnancy complicated by GDM, higher lactation intensity and longer duration are independently associated with lower 2-year incidences of type 2 diabetes.43,88 Recommendations

11. Women with gestational diabetes mellitus should be offered testing with a 75-g oral glucose tolerance test between 6 weeks and 6 months postpartum to detect prediabetes and diabetes.1 (II-2A) 11.1. Normal i. Fasting plasma glucose < 6.1 mmol/L ii. 2-hour plasma glucose < 7.8 mmol/L iii. Glycated hemoglobin < 6.0% 11.2. Pre-diabetic i. Fasting plasma glucose 6.1 to 6.9 mmol/L or ii. 2-hour plasma glucose 7.8 to 11.0 mmol/L or iii. Glycated hemoglobin 6.0% to 6.4% 11.3. Type 2 diabetes mellitus i. FPG > 7.0 mmol/L ii. Random plasma glucose or 2-hour plasma glucose > 11.1 mmol/L iii. Glycated hemoglobin 6.5% 12. Breastfeeding is strongly recommended after delivery for all women with pre-gestational diabetes mellitus or gestational diabetes mellitus. (II-2A)

REFERENCES 1. Thompson D, Berger H, Feig D, Gagnon R, Kader T, Keely E, et al. Diabetes and pregnancy. Can J Diabetes 2013;37(Suppl 1):S168e83. 2. Feig DS, Hwee J, Shah BR, Booth GL, Bierman AS, Lipscombe LL. Trends in incidence of diabetes in pregnancy and serious perinatal outcomes: a large, population-based study in Ontario, Canada, 1996-2010. Diabetes Care 2014;37:1590e6. 3. Fadl HE, Ostlund IK, Magnuson AF, Hanson US. Maternal and neonatal outcomes and time trends of gestational diabetes mellitus in Sweden from 1991 to 2003. Diabet Med 2010;27:436e41. 4. Crowther CA, Hiller JE, Moss JR, Mhee AJ, Jeffries WS, Robinson JS, et al. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med 2005;352:2477e86. 5. Landon MB, Spong CY, Thom E, Carpenter MW, Ramin SM, Casey B, et al. A multicenter, randomized trial of treatment for mild gestational diabetes. N Engl J Med 2009;361:1339e48. 6. Hutcheon JA, Kuret V, Joseph KS, Sabr Y, Lim K. Immortal time bias in the study of stillbirth risk factors: the example of gestational diabetes. Epidemiology 2013;24:787e90. 7. Peticca P, Keely EJ, Walker MC, Yang Q, Bottomley J. Pregnancy outcomes in diabetes subtypes: how do they compare? A province-based study of Ontario, 2005-2006. J Obstet Gynaecol Can 2009;31:487e96. 8. Karmon A, Levy A, Holcberg G, Wiznitzer A, Mazor M, Sheiner E. Decreased perinatal mortality among women with diet-controlled gestational diabetes mellitus. Int J Gynaecol Obstet 2009;104:199e202. 9. Ohana O, Holcberg G, Sergienko R, Sheiner E. Risk factors for intrauterine fetal death (1988-2009). J Matern Fetal Neonatal Med 2011;24:1079e83. 10. Rosenstein MG, Cheng YW, Snowden JM, Nicholson JM, Doss AE, Caughey AB. The risk of stillbirth and infant death stratified by gestational age in women with gestational diabetes. Am J Obstet Gynecol 2012;206:309.e1e7. 11. Hawkins JS, Lo JY, Casey BM, McIntire DD, Leveno KJ. Diet-treated gestational diabetes mellitus: comparison of early vs routine diagnosis. Am J Obstet Gynecol 2008;198:287.e1e6. 12. Retnakaran R, Zinman B, Connelly PW, Sermer M, Hanley AJ. Impaired glucose tolerance of pregnancy is a heterogeneous metabolic disorder as defined by the glycemic response to the oral glucose tolerance test. Diabetes Care 2006;29:57e62. 13. Liu S, Joseph KS, Hutcheon JA, Bartholomew S, Leon JA, Walker M, et al. Gestational age-specific severe maternal morbidity associated with labor induction. Am J Obstet Gynecol 2013;209:209.e1e8. 14. Niu B, Lee VR, Cheng YW, Frias AE, Nicholson JM, Caughey AB. What is the optimal gestational age for women with gestational diabetes type A1 to deliver? Am J Obstet Gynecol 2014;211:418.e1e6. 15. Page JM, Snowden JM, Cheng YW, Doss AE, Rosenstein MG, Caughey AB. The risk of stillbirth and infant death by each additional week of expectant management stratified by maternal age. Am J Obstet Gynecol 2013;209:375.e1e7. 16. Nicholson JM, Parry S, Caughey AB, Rosen S, Keen A, Macones GA. The impact of the active management of risk in pregnancy at term on birth outcomes: a randomized clinical trial. Am J Obstet Gynecol 2008;198:511. e1e511.e15. 17. Mathiesen ER, Ringholm L, Damm P. Stillbirth in diabetic pregnancies. Best Pract Res Clin Obstet Gynaecol 2011;25:105e11. 18. Grimes DA, Schulz KF. Uses and abuses of screening tests. Lancet 2002;359:881e4. 19. Hillier TA, Vesco KK, Pedula KL, Beil TL, Whitlock EP, Pettitt DJ. Screening for gestational diabetes mellitus: a systematic review for the U. S. Preventive Services Task Force. Ann Intern Med 2008;148:766e75. 20. Ogunyemi DA, Fong A, Rad S, Fong S, Kjos SL. Attitudes and practices of healthcare providers regarding gestational diabetes: results of a survey

-

JOGC

-

2016

l

11

CLINICAL PRACTICE GUIDELINE

conducted at the 2010 meeting of the International Association of Diabetes in Pregnancy Study Group (IADPSG). Diabet Med 2011;28:976e86. 21. Sermer M, Naylor CD, Gare DJ, Kenshole AB, Ritchie JW, Farine D, et al. Impact of increasing carbohydrate intolerance on maternal-fetal outcomes in 3637 women without gestational diabetes. The Toronto Tri-Hospital Gestational Diabetes Project. Am J Obstet Gynecol 1995;173:146e56. 22. HAPO Study Cooperative Research Group, Metzger BE, Lowe LP, Dyer AR, Trimble ER, Chaovarindr U, et al. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 2008;358:1991e2002.

40. Berkus MD, Langer O. Glucose tolerance test: degree of glucose abnormality correlates with neonatal outcome. Obstet Gynecol 1993;81:344e8. 41. Landon MB, Langer O, Gabbe SG, Schick C, Brustman L. Fetal surveillance in pregnancies complicated by insulin-dependent diabetes mellitus. Am J Obstet Gynecol 1992;167:617e21. 42. Langer O, Kozlowski S, Brustman L. Abnormal growth patterns in diabetes in pregnancy: a longitudinal study. Isr J Med Sci 1991;27:516e23.

in

43. Gilbert WM, Nesbitt TS, Danielsen B. Associated factors in 1611 cases of brachial plexus injury. Obstet Gynecol 1999;93:536e40.

24. Committee on Obstetric Practice. Practice Bulletin No. 137: gestational diabetes mellitus. Obstet Gynecol 2013;122:406e16.

44. Nesbitt TS, Gilbert WM, Herrchen B. Shoulder dystocia and associated risk factors with macrosomic infants born in California. Am J Obstet Gynecol 1998;179:476e80.

23. American Diabetes Association. Standards diabetesd2012. Diabetes Care 2012;35:S11.

of

medical

care

25. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2014;37:S81. 26. International Association of Diabetes, Pregnancy Study Groups Consensus , Metzger BE, Gabbe SG, Persson B, Buchanan TA, et al. International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care 2010;33:676e82. 27. Nankervis A, McIntyre HD, Moses R, Ross GP, Callaway I, Porter C, et al., Australasian Diabetes in Pregnancy Society. ADIPS Consensus Guidelines for the Testing and Diagnosis of Gestational Diabetes Mellitus in Australia. Australasian Diabetes in Pregnancy Society; 2014. Available at: http://adips.org/s/ADIPSConsensusGuidelinesGDM-03. 05.13VersionACCEPTEDFINAL.pdf. Accessed on April 12, 2016.

45. Mondestin MA, Ananth CV, Smulian JC, Vintzileos AM. Birth weight and fetal death in the United States: the effect of maternal diabetes during pregnancy. Am J Obstet Gynecol 2002;187:922e6. 46. Boulet SL, Alexander GR, Salihu HM, M. Macrosomic births in the United States: determinants, outcomes, and proposed grades of risk. Am J Obstet Gynecol 2003;188:1372e8. 47. Gregory KD, Henry OA, Ramicone E, Chan LS, Platt LD. Maternal and infant complications in high and normal weight infants by method of delivery. Obstet Gynecol 1998;92:507e13. 48. Lepercq J, Le Meaux JP, Agman A, Timsit J. Factors associated with cesarean delivery in nulliparous women with type 1 diabetes. Obstet Gynecol 2010;115:1014e20.

28. World Health Organization. Diagnostic criteria and classification of hyperglycaemia first detected in pregnancy. Available at: http://apps.who. int/iris/bitstream/10665/85975/1/WHO_NMH_MND_13.2_eng.pdf? ua¼1. Accessed on April 12, 2016.

49. Naylor CD, Sermer M, Chen E, Sykora K. Cesarean delivery in relation to birth weight and gestational glucose tolerance: pathophysiology or practice style? Toronto Trihospital Gestational Diabetes Investigators. JAMA 1996;275:1165e70.

29. Berger H, Crane J, Farine D, Armson A, De La Ronde S, KeenanLindsay L, et al. Screening for gestational diabetes mellitus. J Obstet Gynaecol Can 2002;24:894e912.

50. Sutton AL, Mele L, Landon MB, Ramin SM, Varner MW, Thorp Jr JM, et al. Delivery timing and cesarean delivery risk in women with mild gestational diabetes mellitus. Am J Obstet Gynecol 2014;211:244.e1e7.

30. Ergin T, Lembet A, Duran H, Kuscu E, Bagis T, Saygili E, et al. Does insulin secretion in patients with one abnormal glucose tolerance test value mimic gestational diabetes mellitus? Am J Obstet Gynecol 2002;186:204e9.

51. Schaefer-Graf UM, Kjos SL, Fauzan OH, Buhling KJ, Siebert G, Buhrer C, et al. A randomized trial evaluating a predominantly fetal growth-based strategy to guide management of gestational diabetes in Caucasian women. Diabetes Care 2004;27:297e302.

31. Landon MB, Gabbe SG. Gestational diabetes mellitus. Obstet Gynecol 2011;118:1379e93.

52. Bonomo M, Cetin I, Pisoni MP, Faden D, Mion E, Taricco E, et al. Flexible treatment of gestational diabetes modulated on ultrasound evaluation of intrauterine growth: a controlled randomized clinical trial. Diabetes Metab 2004;30:237e44.

32. Landon MB, Mele L, Spong CY, Carpenter MW, Ramin SM, Casey B, et al. The relationship between maternal glycemia and perinatal outcome. Obstet Gynecol 2011;117:218e24. 33. Langer O, Brustman L, Anyaegbunam A, Mazze R. The significance of one abnormal glucose tolerance test value on adverse outcome in pregnancy. Am J Obstet Gynecol 1987;157:758e63. 34. Simmons D, Moses RG. Gestational diabetes mellitus: to screen or not to screen?: Is this really still a question? Diabetes Care 2013;36:2877e8. 35. Cheng YW, Esakoff TF, Block-Kurbisch I, Ustinov A, Shafer S, Caughey AB. Screening or diagnostic: markedly elevated glucose loading test and perinatal outcomes. J Matern Fetal Neonatal Med 2006;19:729e34. 36. Cheng YW, Block-Kurbisch I, Caughey AB. Carpenter-Coustan criteria compared with the national diabetes data group thresholds for gestational diabetes mellitus. Obstet Gynecol 2009;114:326e32. 37. Freitas C, Araujo C, Caldas R, Lopes DS, Nora M, Monteiro MP. Effect of new criteria on the diagnosis of gestational diabetes in women submitted to gastric by. Surg Obes Relat Dis 2014;10:1041e6. 38. Bauman WA, Maimen M, Langer O. An association between hyperinsulinemia and hypertension during the third trimester of pregnancy. Am J Obstet Gynecol 1988;159:446e50. 39. Magee LA, Pels A, Helewa M, Rey E, von Dadelszen P, Canadian Hypertensive Disorders of Pregnancy Working Group. Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy: executive summary. J Obstet Gynaecol Can 2014;36:416e41.

12

l

-

JOGC

-

2016

53. Kjos SL, Schaefer-Graf UM. Modified therapy for gestational diabetes using high-risk and low-risk fetal abdominal circumference growth to select strict versus relaxed maternal glycemic targets. Diabetes Care 2007;30(Suppl 2):S200e5. 54. Karcaaltincaba D, Yalvac S, Kandemir O, Altun S. Glycosylated hemoglobin level in the second trimester predicts birth weight and amniotic fluid volume in non-diabetic pregnancies with abnormal screening test. J Matern Fetal Neonatal Med 2010;23:1193e9. 55. Liston R, Sawchuck D, Young D. Society of Obstetrics and Gynaecologists of Canada; British Columbia Perinatal Health Program. Fetal health surveillance: antepartum and intrapartum consensus guideline. J Obstet Gynaecol Can 2007;29:S3e56. 56. Landon MB, Vickers S. Fetal surveillance in pregnancy complicated by diabetes mellitus: is it necessary? J Matern Fetal Neonatal Med 2002;12:413e6. 57. Graves CR. Antepartum fetal surveillance and timing of delivery in the pregnancy complicated by diabetes mellitus. Clin Obstet Gynecol 2007;50:1007e13. 58. Johnson JM, Lange IR, Harman CR, Torchia MG, Manning FA. Biophysical profile scoring in the management of the diabetic pregnancy. Obstet Gynecol 1988;72:841e6. 59. Manning FA, Bondagji N, Harman CR, Casiro O, Menticoglou S, Morrison I. Fetal assessment based on the fetal biophysical profile score:

Diabetes in Pregnancy

relationship of last BPS result to subsequent cerebral palsy. J Gynecol Obstet Biol Reprod (Paris) 1997;26:720e9.

74. Sinha N, Venkatram S, Diaz-Fuentes G. Starvation ketoacidosis: a cause of severe anion gap metabolic acidosis in pregnancy. Case Rep Crit Care 2014;2014:906283.

60. Manning FA, Bondaji N, Harman CR, Casiro O, Menticoglou S, Morrison I, et al. Fetal assessment based on fetal biophysical profile scoring. VIII. The incidence of cerebral palsy in tested and untested perinates. Am J Obstet Gynecol 1998;178:696e706.

75. Gyamfi-Bannerman C, Thom EA, Blackwell SC, Tita AT, Reddy UM, Saade GR, et al. Antenatal betamethasone for women at risk for late preterm delivery. N Engl J Med 2016;374:1311e20.

61. Melamed N, Yogev Y, Meizner I, Mashiach R, Bardin R, Ben-Haroush A. Sonographic fetal weight estimation: which model should be used? J Ultrasound Med 2009;28:617e29.

76. Sotiriadis A, Makrydimas G, Papatheodorou S, Ioannidis JP. Corticosteroids for preventing neonatal respiratory morbidity after elective caesarean section at term. Cochrane Database Syst Rev 2009:CD006614.

62. Melamed N, Yogev Y, Meizner I, Mashiach R, Ben-Haroush A. Sonographic prediction of fetal macrosomia: the consequences of false diagnosis. J Ultrasound Med 2010;29:225e30.

77. Stutchfield P, Whitaker R, Russell I. Antenatal Steroids for Term Elective Caesarean Section Research Team. Antenatal betamethasone and incidence of neonatal respiratory distress after elective caesarean section: pragmatic randomised trial. BMJ 2005;331:662.

63. Melamed N, Yogev Y, Meizner I, Mashiach R, Pardo J, Ben-Haroush A. Prediction of fetal macrosomia: effect of sonographic fetal weightestimation model and threshold used. Ultrasound Obstet Gynecol 2011;38:74e81. 64. Vendittelli F, Riviere O, Neveu B, Lemery D, Audipog Sentinel N. Does induction of labor for constitutionally large-for-gestational-age fetuses identified in utero reduce maternal morbidity? BMC Pregnancy Childbirth 2014;14:156. 65. Boulvain M, Senat MV, Perrotin F, Winer N, Beucher G, Subtil D, et al. Induction of labour versus expectant management for large-for-date fetuses: a randomised controlled trial. Lancet 2015;385:2600e5. 66. Kjos SL, Henry OA, Montoro M, Buchanan TA, Mestman JH. Insulinrequiring diabetes in pregnancy: a randomized trial of active induction of labor and expectant management. Am J Obstet Gynecol 1993;169:611e5. 67. Witkop CT, Neale D, Wilson LM, Bass EB, Nicholson WK. Active compared with expectant delivery management in women with gestational diabetes: a systematic review. Obstet Gynecol 2009;113:206e17. 68. Mishanina E, Rogozinska E, Thatthi T, Uddin-Khan R, Khan KS, Meads C. Use of labour induction and risk of cesarean delivery: a systematic review and meta-analysis. CMAJ 2014;186:665e73. 69. Gulmezoglu AM, Crowther CA, Middleton P, Heatley E. Induction of labour for improving birth outcomes for women at or beyond term. Cochrane Database Syst Rev 2012;6:CD004945. 70. Melamed N, Ray JG, Geary M, Bedard D, Yang C, Sprague A, et al. Induction of labor before 40 weeks is associated with lower rate of cesarean delivery in women with gestational diabetes mellitus. Am J Obstet Gynecol 2016;214:364.e1e8. 71. Fisher JE, Smith RS, Lagrandeur R, Lorenz RP. Gestational diabetes mellitus in women receiving beta-adrenergics and corticosteroids for threatened preterm delivery. Obstet Gynecol 1997;90:880e3. 72. Bhagwanjee S, Muckart DJ, Hodgson RE, Naidoo J. Fatal foetal outcome from diabetic ketoacidosis in pregnancy. Anaesth Intensive Care 1995;23:234e7. 73. Montoro MN, Myers VP, Mestman JH, Xu Y, Anderson BG, Golde SH. Outcome of pregnancy in diabetic ketoacidosis. Am J Perinatol 1993;10:17e20.

78. Stutchfield PR, Whitaker R, Gliddon AE, Hobson L, Kotecha S, Doull IJ. Behavioural, educational and respiratory outcomes of antenatal betamethasone for term caesarean section (ASTECS trial). Arch Dis Child Fetal Neonatal Ed 2013;98:F195e200. 79. Chertok IR, Raz I, Shoham I, Haddad H, Wiznitzer A. Effects of early breastfeeding on neonatal glucose levels of term infants born to women with gestational diabetes. J Hum Nutr Diet 2009;22:166e9. 80. Critch JN. Canadian Paediatric Society and Nutrition and Gastroenterology Committee. Nutrition for healthy term infants, birth to six months: An overview. Paediatr Child Health 2013;18:206e9. 81. Gunderson EP, Hedderson MM, Chiang V, Crites Y, Walton D, Azevedo RA, et al. Lactation intensity and postpartum maternal glucose tolerance and insulin resistance in women with recent GDM: the SWIFT cohort. Diabetes Care 2012;35:50e6. 82. Schaefer-Graf UM, Hartmann R, Pawliczak J, ow D, Abou-Dakn M, Vetter K, et al. Association of breast-feeding and early childhood overweight in children from mothers with gestational diabetes mellitus. Diabetes Care 2006;29:1105e7. 83. Buchanan TA, Xiang AH. Gestational diabetes mellitus. J Clin Invest 2005;115:485e91. 84. Chodick G, Elchalal U, Sella T, Heymann AD, Porath A, Kokia E, et al. The risk of overt diabetes mellitus among women with gestational diabetes: a population-based study. Diabet Med 2010;27:779e85. 85. Kaaja RJ, Greer IA. Manifestations of chronic disease during pregnancy. JAMA 2005;294:2751e7. 86. Kim C, Newton KM, Knopp RH. Gestational diabetes and the incidence of type 2 diabetes: a systematic review. Diabetes Care 2002;25:1862e8. 87. Russell MA, Phipps MG, Olson CL, Welch HG, Carpenter MW. Rates of postpartum glucose testing after gestational diabetes mellitus. Obstet Gynecol 2006;108:1456e62. 88. Gunderson EP, Hurston SR, Ning X, Lo JC, Crites Y, Walton D, et al. Lactation and progression to type 2 diabetes mellitus after gestational diabetes mellitus: a prospective cohort study. Ann Intern Med 2015;163:889e98.

-

JOGC

-

2016

l

13

CLINICAL PRACTICE GUIDELINE

APPENDIX A: GESTATIONAL DIABETES MELLITUS

APPENDIX B: GESTATIONAL DIABETES MELLITUS

13.e1

l

-

JOGC

-

2016

SOGC CLINICAL PRACTICE GUIDELINE No. 337, October 2016 (replaces no. 161, June 2005)

Ultrasound Evaluation of First Trimester Complications of Pregnancy This Clinical Practice Guideline has been prepared by the Diagnostic Imaging committee, reviewed by Clinical PracticeObstetrics and approved by the Board of the Society of Obstetricians and Gynaecologists of Canada.

Abstract

PRINCIPAL AUTHORS

2. To identify sonographic features of ectopic pregnancy, and

Lucie Morin, MD, Outremont QC Yvonne M. Cargill, MD, Ottawa ON

3. To provide a diagnostic algorithm leading to improve clinical safety of management decision.

Phyllis Glanc, MD, Toronto ON

Outcomes:

DIAGNOSTIC IMAGING COMMITTEE

1. Accuracy and improved safety in the diagnosis of early pregnancy loss, and

Kimberly Butt, MD, Fredericton NB Yvonne M. Cargill, MD, Ottawa ON Nanette Denis, RDMS, Saskatoon SK Johanne Dubé, MD, Mont-Royal QC Phyllis Glanc, MD, Toronto ON Kenneth I. Lim (Co-chair), MD, Vancouver BC Lucie Morin (Co-chair), MD, Outremont QC Kentia Naud, MD, Edmonton AB Mila Smithies, MD, Halifax ON Disclosure statements have been received from all of the committee.

Key Words: Missed abortion, anembryonic pregnancy, ectopic pregnancy, ultrasound, threatened abortion http://dx.doi.org/10.1016/j.jogc.2016.06.001

Objective: 1. To identify sonographic features suggestive of early pregnancy loss,

2. Accuracy and improved safety in the diagnosis of ectopic pregnancy. Evidence: A MEDLINE search and review of bibliographies identified articles was conducted. Values: The evidence collected was reviewed by the Diagnostic Imaging Committee of the Society of Obstetricians and Gynaecologists of Canada. The recommendations were made according to the guidelines developed by The Canadian Task Force on Preventive Health Care (Table 1). Benefits, Harms, and Costs: Women presenting with first trimester bleeding may be incorrectly diagnosed with a missed abortion, may have an ectopic pregnancy overlooked, or may be inappropriately reassured about viability. Improvement in the identification of the sonographic landmarks of normal embryonic development and awareness of the sonographic risk factors of pregnancy failure may lead to more case-specific management strategies. Diagnosis of suspected ectopic pregnancy often involves an assessment of both hormonal markers and sonographic features. Maternal morbidity and mortality can be reduced with an early diagnosis of ectopic pregnancy. Recommendations

J Obstet Gynaecol Can 2016;38(10):982e988

1. Embryonic demise can be diagnosed when ultrasound imaging documents the following features: intrauterine gestational sac, embryonic crown-rump length 7 mm, no cardiac activity. (II-2A)

Copyright ª 2016 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.

2. Anembryonic pregnancy can be diagnosed when ultrasound imaging documents the following features: no embryo and mean sac diameter 25 mm. (II-2A)

This document reflects emerging clinical and scientific advances on the date issued, and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the publisher.

982

l

OCTOBER JOGC OCTOBRE 2016

Ultrasound Evaluation of First Trimester Complications of Pregnancy

Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventative Health Care Quality of evidence assessment* I: Evidence obtained from at least one properly randomized controlled trial II-1: Evidence from well-designed controlled trials without randomization II-2: Evidence from well-designed cohort (prospective or retrospective) or case-control studies, preferably from more than one centre or research group II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in the category III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

Classification of recommendations† A. There is good evidence to recommend the clinical preventive action B. There is fair evidence to recommend the clinical preventive action C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making D. There is fair evidence to recommend against the clinical preventive action E. There is good evidence to recommend against the clinical preventive action L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care. †Recommendations included in these guidelines have been adapted from the Classification of recommendations criteria described in The Canadian Task Force on Preventive Health Care.

3. In clinically stable or asymptomatic patients, when a suspicion of early pregnancy loss is being considered, a follow-up ultrasound scan should be booked after an additional 7e10 days. (III-A)

nancy. With a complex adnexal mass, a tubal ring, or complex fluid in the pelvis the probability of tubal ectopic pregnancy is high, while a live extrauterine embryo is diagnostic of an ectopic pregnancy. (II-2A)

4. Failure to detect an intrauterine gestational sac, by transvaginal ultrasound, when the b-hCG value exceeds a discriminatory level of 2000e3000 mIU/mL indicates an increased risk for ectopic preg-

5. b-hCG values in a viable pregnancy rise at least 55% over 48 hours. Deviation from this before 7 weeks is indicative of a nonviable pregnancy, intrauterine or ectopic. (II-2A)

ABBREVIATIONS b-hCG

beta human chorionic gonadotropin

CRL

crown-rump length

CS

Caesarean section

OCTOBER JOGC OCTOBRE 2016

l

983

SOGC CLINICAL PRACTICE GUIDELINE

INTRODUCTION

R

ecently published clinical evidence demonstrates that caution must be emphasized when diagnosing early pregnancy complications to avoid misdiagnosis.1 As such, this clinical practice guideline is an update and replaces guidelines No. 161 published in 2005.2 The criteria for establishing definitive pregnancy loss have been further clarified; erroneous diagnosis of miscarriage/intrauterine pregnancy loss can lead to interventions that will disrupt a normal intrauterine pregnancy. Studies published in the early 1990s, which included the introductory use of vaginal ultrasound, allowed for acceptance of new biometry parameters used to define early pregnancy loss. The 2005 SOGC guidelines reflected that knowledge and, as such, a CRL of 5 mm without cardiac activity or an empty gestational sac measuring 16 mm (mean gestational sac diameter) were reported diagnostic criteria to confirm early pregnancy loss.2 More recently, in 2011, two large prospective studies have challenged these previous cut-offs. In a prospective series of 1060 women with pregnancies of uncertain viability, which were followed up to 11e14 weeks gestation, 55.4% received a diagnosis of nonviable gestation during the observation period. In that study, a CRL cut-off of 5 mm was associated with an 8.3% falsepositive rate for early pregnancy loss. A CRL cut-off of 5.3 mm was required to achieve a false-positive rate of 0%.3 In addition, the authors reported a 4.4% false-positive rate for early pregnancy loss when using a mean gestational sac diameter cut-off of 16 mm. A mean gestational sac diameter of 21 mm without an embryo and with or without a yolk sac on the first ultrasound examination was required to achieve 100% specificity for early pregnancy loss.3 In the second study using 359 women from the first study group, the authors concluded that growth rates for the gestational sac and the embryo could not predict viability accurately. They demonstrated that the absence of a visible yolk sac or embryo on second scan performed 7 days or more after the first scan was always associated with pregnancy loss.4 Based on these studies, the Multispecialty on Early First Trimester Diagnosis of Miscarriage and Exclusion of a Viable Intrauterine Pregnancy from the Society of Radiologists in Ultrasound published guidelines that were

984

l

OCTOBER JOGC OCTOBRE 2016

more conservative than previous recommendations resulting in less possibility of error than the previous studies.1,3,4 The American College of Obstetricians and Gynecologists has recently published clinical management guidelines for early pregnancy loss that uses the Society of Radiologist in Ultrasound’s diagnostic criteria.5 Embryonic Period and b-hCG Levels

b-hCG is a very sensitive and specific test for pregnancy. It becomes positive as implantation begins day 21 or 22 after last menstrual period or 8 days post-ovulation. A single bhCG value does not differentiate a viable from a nonviable pregnancy. In a normal, early pregnancy, the b-hCG doubling time is 1.4e2.1 days.6 The slowest rise in a viable pregnancy over 48 hours observed was 55%.7 If a pregnancy is not visible in the uterus or adnexa on ultrasound and the b-hCG is falling or plateaus, the pregnancy is not viable. Embryonic Period: Sonographic Landmarks

The embryonic period is defined as 8 weeks after conception or 10 weeks after the last menstrual period. The first ultrasound evidence of an intrauterine pregnancy is the gestational sac within the thickened deciduas.8 This sac, which represents the chorionic cavity, is a small anechoic fluid collection surrounded by an echogenic ring that represents trophoblasts and decidual reaction.9 It is possible to identify the sac by 4 weeks and 3 days gestation when the mean diameter is 2e3 mm.8,10 The yolk sac is the first structure seen within the gestational sac and, when seen, confirms an intrauterine pregnancy.9 The yolk sac can be identified when the mean gestational sac diameter is as small as 5e6 mm and is generally visualized when the mean gestational sac diameter is greater than or equal to 8 mm.10 Table 2. Typical embryonic chronological landmarks in the development of the embryo, as seen on transvaginal ultrasound examination (conception to 8 weeks development) 5 þ 0 weeks

Empty gestational sac (mean diameter 10 mm)

5 þ 4 weeks

Gestational sac with yolk sac visible

6 þ 0 weeks

Gestational sac (mean diameter 16 mm) and yolk sac with adjacent heart beat but small embryo (3mm)

8 þ 0 weeks

Embryo with CRL of 16 mm with separate amniotic sac and celomic cavity with yolk sac Embryo body movements visible, heart rate 175 bpm

Ultrasound Evaluation of First Trimester Complications of Pregnancy

Table 3. Diagnosis of asymptomatic tubal ectopic pregnancy Possible ectopic pregnancy

Serum b-hCG level > 2000 mIU/mL Absence of intrauterine pregnancy on transvaginal ultrasound

Probable ectopic pregnancy

Serum b-hCG level > 2000 mIU/mL Absence of intrauterine pregnancy on transvaginal ultrasound Adnexal mass on transvaginal ultrasound

Diagnosis of Gestational sac inside fallopian tube on ectopic pregnancy transvaginal ultrasound

The amnion is a thin, rounded membrane surrounding the embryo and is completely enveloped by the thick echogenic chorion. The yolk sac is situated between the amnion and the chorion. The amnion is thin, difficult to visualize, and best seen when the amnion membrane is perpendicular to the ultrasound beam. The amnion grows rapidly during pregnancy and fuses with the chorion between 12 and 16 weeks of gestation.8,10 The embryo can be visualized when as small as 1e2 mm in CRL length. Cardiac activity immediately adjacent to the yolk sac indicates a live embryo but may not be seen until the embryo CRL measures 7 mm. From 5.5e6.5 weeks, an embryonic heart rate of less than 100 beats per minute is normal. During the following 3 weeks, there is a rapid increase up to 180 beats per minute.11,12 Table 2 summarizes the sonographic features of normal early pregnancy. Other Ultrasound Features of Early Pregnancy Loss

Certain ultrasound features are associated with early pregnancy loss including bradycardia (heart rate less than 85 beats per minute) at greater than 7 weeks of gestation,12e15 a small sac size relative to the embryo (difference of less than 5 mm between gestational sac and CRL),16 enlarged (greater than or equal to 5e6 mm),17 or abnormally shaped (crenelated) yolk sac and subchorionic hematoma.18,19 Early Pregnancy Loss

Early pregnancy loss may have occurred with findings of vaginal bleeding and/or abdominal pain. A pregnancy of unknown viability may incidentally be found at the time of a dating or prenatal screening ultrasound. It is important in clinical diagnosis to rule out ectopic pregnancy, gestational trophoblastic disease, and spontaneous abortion. When assessing intrauterine pregnancy, the differential diagnosis would include a developing pregnancy, a missed abortion, or an ectopic pregnancy.

If the viability and location of a pregnancy needs to be decided at a single point in time, such as an emergency visit by a pregnant woman with symptoms of bleeding and pain, the most useful single test to differentiate a viable from a nonviable pregnancy is a progesterone level. Progesterone less than 20 nmol/L have a sensitivity of 75% and specificity of 98% in predicting nonviable pregnancy.20 The most useful single test to differentiate an intrauterine from an ectopic pregnancy is an ultrasound. An ultrasound diagnosis of an embryonic demise can be made when there is no cardiac activity in an embryo with a CRL greater than or equal to 7 mm.1 Ultrasound diagnosis of an anembryonic pregnancy can be made when the mean gestational sac diameter is greater than or equal to 25 mm but without a yolk sac or an embryo. Transvaginal ultrasound is the method of choice for early first trimester pregnancy complications although transabdominal or transvaginal ultrasound may be used for patients with first trimester bleeding. In the absence of cardiac activity, if the gestational sac or the embryo is smaller than expected by menstrual dating, the possibility of incorrect dates should always be considered, especially when there is no pain or bleeding. Under these circumstances, a repeat ultrasound scan should be arranged after an additional 7e10 days.1,5 Single or serial b-hCG values may be used to add to a diagnosis of a nonviable pregnancy. b-hCG values that are falling or not rising appropriately would confirm a nonviable pregnancy. Figure 1. First trimester pregnancy ultrasound: intrauterine pregnancy identified Intrauterine

No cardiac ac vity

CRL > 7 mm

CRL < 7 mm

Cardiac ac vity present

Normal intrauterine

Repeat ultrasound in 7-10 days and/or Serial β-hCG.

If β-hCG not rising appropriately or absent FHR

Non-viable intrauterine pregnancy

OCTOBER JOGC OCTOBRE 2016

l

985

SOGC CLINICAL PRACTICE GUIDELINE

Figure 2. First trimester pregnancy ultrasound No intrauterine pregnancy and β-hCG available

Ultrasound signs of an ectopic?

No

Yes

β-hCG greater than 2000-3000

If β-hCG greater than 2000-3000 or not rising appropriately

No Yes

Likely, an ectopic pregnancy (Consider a complete abor on if β-hCG falling)

Ectopic Pregnancy

The initial diagnostic test in women with suspected ectopic pregnancy is measurement of the serum b-hCG. A negative test rules out pregnancy, including ectopic pregnancy. An ultrasound that demonstrates an intrauterine pregnancy is reassuring because a heterotopic pregnancy occurs in only 1:7000e1:30 000 of spontaneously conceived pregnancies.21 The suspicion of a possible heterotopic pregnancy should be higher with the use of assisted reproduction techniques because of the incidence in this circumstance is up to 1%.22,23 The diagnosis of an intrauterine pregnancy involves visualizing a gestational sac, within the endometrial cavity, and showing an embryo or yolk sac.24 Although an intrauterine fluid collection without these characteristics may be a pseudogestational sac, the likelihood is much higher that this represents an intrauterine pregnancy. Doubilet et al. have demonstrated that any intrauterine fluid collection is associated with a 99.5% chance that the pregnancy is intrauterine.25 The appearance of an ectopic pregnancy is varied. The first ultrasound in ectopic pregnancies is reported as normal i.e., empty uterus, no adnexal mass, and no free fluid in 15% to 25% of cases.26,27 The most common ectopic pregnancy is tubal, thus the findings may include an empty uterus, simple adnexal cyst, complex adnexal mass, solid adnexal mass, tubal ring, free fluid in the adnexa-cul de sac area, or complex fluid in the pelvis. Other ectopic pregnancy locations would include cornual, cervical,

986

l

OCTOBER JOGC OCTOBRE 2016

(1) empty uterus, (2) simple adnexal cyst, (3) complex adnexal mass, (4) solid adnexal mass, (5) tubal ring,( 6) free fluid in the adnexa-cul de sac area, or (7) complex fluid in the pelvis .

Repeat β-hCG every 48 hours

If β-hCG rises not appropriately, β-hCG reaches 2000-3000, or symptoms increase Repeat ultrasound

within the cesarean section scar, intraovarian or an intraabdominal ectopic pregnancy.26,28 With the clinical suspicion of an ectopic pregnancy, a normal scan (no signs of an intrauterine or extrauterine pregnancy), or the presence of a simple adnexal cyst carries a low probability of ectopic pregnancy (5%), whereas the probability is above 90% with a solid or complex adnexal mass separate from the ovary or a tubal ring.28 A live pregnancy that is not implanted within the endometrial cavity is diagnostic of an ectopic pregnancy. Isolated free fluid in the pelvis is rarely the only sonographic finding.28 Colour Doppler waveforms from the peri-trophoblast have been shown to demonstrate low impedance flow. Colour Doppler may demonstrate an ectopic pregnancy as a ringlike structure. Colour Doppler may add useful information when other ultrasound findings lead to a diagnostic dilemma or uncertainty. For example, with a complex adnexal mass, the finding of low impedance colour Doppler waveform or a ring of colour Doppler may more strongly suggest an ectopic pregnancy.29 Nonetheless, it is important to recognize that the corpus luteum, including an exophytic corpus luteum, may present with similar colour Doppler findings. Quantitative level of maternal serum b-hCG and highresolution ultrasound imaging are complementary. The

Ultrasound Evaluation of First Trimester Complications of Pregnancy

b-hCG level of an ectopic pregnancy can be above or below the discriminatory zone. Rupture of ectopic pregnancy can occur at any b-hCG level. Failure to detect an intrauterine gestational sac when the b-hCG values exceed a discriminatory level indicates a high risk of ectopic pregnancy.30 Although intrauterine pregnancy can be documented on transvaginal ultrasound when b-hCG level is as low as 1500 UI/L, current literature review s the use of a discriminatory level of b-hCG from 2000 UI/L up to 3000 UI/L especially when measured before 7 weeks of gestation.1 In the absence of an intrauterine pregnancy a b-hCG level greater than 2500 has an 11% sensitivity and a 95% specificity for an ectopic pregnancy.31 As such, in asymptomatic patient and in the absence of ultrasound features suggestive of ectopic pregnancy, expectant management when serum b-hCG level is less than that cut-off at less than 7 weeks gestation is not associated increased morbidity. A b-hCG not rising appropriately over 48 hours is diagnostic of a nonviable pregnancy intrauterine or ectopic. A single b-hCG level cannot be used to diagnose an ectopic pregnancy without considering the patient’s clinical presentation, physical examination, and ultrasound findings. A complete spontaneous abortion can take place at a b-hCG level above or below 3000. Table 3 simplifies the diagnosis of nonruptured ectopic pregnancy. Figures 1 and 2 propose decision trees for the diagnostic evaluation of first trimester pregnancy complications. Recommendations:

1. Embryonic demise can be diagnosed when ultrasound imaging documents the following features: intrauterine gestational sac, embryonic crown-rump length 7 mm, no cardiac activity. (II-2A) 2. Anembryonic pregnancy can be diagnosed when ultrasound imaging documents the following features: no embryo and mean gestational sac diameter 25 mm. (II-2A) 3. In clinically stable or asymptomatic patients, and when a suspicion of early pregnancy loss is being considered, a follow-up ultrasound scan should be booked after an additional 7e10 days. (III-A) 4. Failure to detect an intrauterine gestational sac, by transvaginal ultrasound, when the b-hCG value exceeds a discriminatory level of 2000e3000 mIU/mL indicates an increased risk for ectopic pregnancy. With a complex adnexal mass or a tubal ring, the probability of tubal ectopic pregnancy is high, while identification of a live extrauterine embryo is diagnostic of an ectopic pregnancy. (II-2A)

5. b-hCG values in a viable pregnancy rise at least 55% over 48 hours. Deviation from this before 7 weeks is indicative of a nonviable pregnancy, intrauterine or ectopic. (II-2A)

REFERENCES 1. Doubilet PM, Benson CB, Bourne T, Blaivas M, Barnhart KT, Benacerraf BR, et al. Diagnostic criteria for nonviable pregnancy early in the first trimester. Society of Radiologists in Ultrasound Multispecialty on Early First Trimester Diagnosis of Miscarriage and Exclusion of a Viable Intrauterine Pregnancy. N Engl J Med 2013;369:1442e51. 2. Morin L, Van den Hof M, Bly S, Farquharson D, Lewthaite B, et al. Ultrasound evaluation of first trimester pregnancy complications. J Obstet Gynaecol Can 2005;27(6):581e5. 3. Abdallah Y, Daemen A, Kirk E, Pexsters A, Naji O, Stalder C, et al. Limitations of current definitions of miscarriage using mean gestational sac diameter and crown-rump length measurements: a multicenter observational study. Ultrasound Obstet Gynecol 2011;38:497e502. 4. Abdallah Y, Daemen A, Guha S, Syed S, Naji O, Pexsters A, et al. Gestational sac and embryonic growth are not useful as criteria to define miscarriage: a multicenter observational study. Ultrasound Obstet Gynecol 2011;38:503e9. 5. Prager S, Dalton VK, Allen RH. ACOG. Practice Bulletin No 150: Early pregnancy loss. Obstet Gynecol 2015;125:1258e67. 6. Daya S. Human chorionic gonadotropin increase in normal early pregnancy. Am J Obstet Gynecol 1987;156:286e90. 7. Barnhart KT, Sammel MD, Rinaudo PF, Zhou L, Hummel AC, Guo W. Symptomatic patients with an early viable intrauterine pregnancy: hCG curves redefined. Obstet Gynecol 2004;104:50e5. 8. Goldstein S. Early detection of pathologic pregnancy by transvaginal sonography. J Clin Ultrasound 1990;18:262e73. 9. Sauerbrei E, Coooperberg PL, Poland JB. Ultrasound demonstration of the normal fetal yolk sac. J Clin Ultrasound 1980;8:217. 10. Timor-Tritsch IE, Farine D, Rosen MG. A close look at early embryonic development with the high-frequency transvaginal transducer. Am J Obstet Gynecol 1988;159:166e81. 11. Merchiers EH, Dhont M, De Sutter PA, Beghin CJ, Vandekerchove DA. Predictive value of early embryonic cardiac activity for pregnancy outcome. Am J Obstet Gynecol 1991;165:11e4. 12. Achiron R, Tor O, Mashiach S. Heart rate as a predictor of first trimester spontaneous abortion after ultrasound-proven viability. Obstet Gynecol 1991;78:330e4. 13. Laboda LA, Estroff JA, Benacerraf BR. First trimester bradycardia a sign of impending fetal loss. J Ultrasound Med 1989;8:561e3. 14. Howe RS, Isaacson KJ, Albert JL, Coutifaris CB. Embryonic heart rate in human pregnancy. J Ultrasound Med 1991;19:367e71. 15. Falco P, Milano V, Pilu C, Grisolia DG, Rizzo N, Bovicelli L. Sonography of pregnancies with first-trimester bleeding and a viable embryo: a study of prognostic indicators by logistic regression analysis. Ultrasound Obstet Gynecol 1996;7:165e9. 16. Bromley B, Harlow BL, Laboda LA, Benacerraf BR. Small sac size in the first trimester: a predictor of poor fetal outcome. Radiology 1991;178:375e7. 17. Hurwitz SR. Yolk sac sign: sonographic appearance of the fetal yolk sac in missed abortion. J Ultrasound Med 1986;5:435e8.

OCTOBER JOGC OCTOBRE 2016

l

987

SOGC CLINICAL PRACTICE GUIDELINE

18. Ferrazzi E, Brambati B, Lanzani A, Oldrini A, Stripparo L, Guerneri S, et al. The yolk sac in early pregnancy failure. Am J Obstet Gynecol 1988;158:137e42.

25. Doubilet PM, Benson CB. First, do no harm.to early. J Ultrasound Med 2010;29:685e9.

19. Mantoni M, Pedersen JF. Intrauterine haematoma an ultrasonic study of threatened abortion. British J Obstet Gynecol 1981;88:47e51.

26. Fleischer AC, Pennell RG, McKee MS, Worrell JA, Keefe B, Herbert CM, et al. Ectopic pregnancy: features transvaginal sonography. Radiology 1990;174:375e8.

20. Verhaegen J, Gallos ID, van Mello NM, Abdel-Aziz M, Takwoingi Y, et al. Accuracy of single progesterone test to predict early pregnancy outcome in women with pain or bleeding: meta-analysis of cohort studies. BMJ 2012;345:e6077.

27. Richardson A, Gallos I, Dobson S, Campbell BK, Coomarasam A, RaineFenning N. Accuracy of first trimester ultrasound diagnosis of tubal pregnancy in the absence of an obvious extrauterine embryo: systematic review and meta analysis. Ultrasound Obstet Gynecol 2016;477:28e37.

21. DeVoe RW, Pratt JH. Simultaneous intra- and extrauterine pregnancy. Am J Obstet Gynecol 1948;56:1119.

28. De Crespigny LC. Demonstration of ectopic pregnancy by transvaginal ultrasound. British J Obstet Gynaecol 1988;95:1253e6.

22. Dimitry ES, Subak-Sharpe R, Mills M, Maragara R, Winston R. Nine cases of heterotopic pregnancies in 4 years of in vitro fertilization. Fertil Steril 1990;53:107e10.

29. Jurkovic D, Bourne TH, Jauniaux E. Transvaginal colour Doppler study of blood flows in ectopic pregnancies. Fertil Steril 1992;57:68e72.

23. Gamberdella FR, Marrs RP. Heterotopic pregnancy associated with assisted reproductive technology. Am J Obstet Gynecol 1989;160:1520e4.

30. Kadar N, DeVore G, Romero R. Discriminatory hCG zone: its use in the sonographic evaluation for ectopic pregnancy. Obstet Gynecol 1981;58:156e61.

24. Nyberg DA, Laing FC, Filly RA, Uri-Simmons M, Jeffrey RB. Ultrasonographic differentiation of the gestational sac of early intrauterine pregnancy from the pseudogestational sac of ectopic pregnancy. Radiology 1983;146:755e9.

31. Condous G, Kirk E, Lu C, Van Huffel S, Gevaert O, de Moor B, et al. Diagnostic accuracy of varying discriminatory zones for the prediction of ectopic pregnancy in women with a pregnancy of unknown location. Ultrasound Obstet Gynecol 2005;26:770e5.

988

l

OCTOBER JOGC OCTOBRE 2016

SOGC CLINICAL PRACTICE GUIDELINE No. 327, August 2015

Adolescent Pregnancy Guidelines This Clinical Practice Guideline has been prepared by the Canadian Paediatric and Adolescent Gynaecology and Obstetricians (CANPAGO) committee, reviewed by the Family Physician Advisory, Aboriginal Health Initiative, Maternal Fetal Medicine, and the Clinical Practice— Obstetrics Committees, and approved by the Executive and Board of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Nathalie Fleming, MD, Ottawa ON Teresa O’Driscoll, MD, Sioux Lookout ON Gisela Becker, RM, Calgary AB Rachel F. Spitzer, MD, Toronto ON CANPAGO COMMITTEE Lisa Allen, MD (Co-chair), Toronto ON Debra Millar, MD (Co-chair), Vancouver BC Philippa Brain, MD, Calgary AB Nancy Dalziel, RN, Ottawa ON Elise Dubuc, MD, Montreal QC Julie Hakim, MD, Ottawa ON Deanna Murphy, MD, St. John’s NL Rachel Spitzer, MD, Toronto ON Disclosure statements have been received from all contributors. The literature searches and bibliographic for this guideline were undertaken by Becky Skidmore, Medical Research Analyst, Society of Obstetricians and Gynaecologists of Canada.

Key Words: Pregnancy, adolescent, teen, teenager, youth

J Obstet Gynaecol Can 2015;37(8):740–756

Abstract Objective: To describe the needs and evidence-based practice specific to care of the pregnant adolescent in Canada, including special populations. Outcomes: Healthy pregnancies for adolescent women in Canada, with culturally sensitive and age-appropriate care to ensure the best possible outcomes for these young women and their infants and young families, and to reduce repeat pregnancy rates. Evidence: Published literature was retrieved through searches of PubMed and The Cochrane Library on May 23, 2012 using appropriate controlled vocabulary (e.g., Pregnancy in Adolescence) and key words (e.g., pregnancy, teen, youth). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. Results were limited to English or French language materials published in or after 1990. Searches were updated on a regular basis and incorporated in the guideline to July 6, 2013. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, national and international medical specialty societies, and clinical practice guideline collections. Values: The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). Benefits/Harms/Costs: These guidelines are designed to help practitioners caring for adolescent women during pregnancy in Canada and allow them to take the best care of these young women in a manner appropriate for their age, cultural backgrounds, and risk profiles. Recommendations   1. Health care providers should adapt their prenatal care for adolescents and offer multidisciplinary care that is easily accessible to the adolescent early in the pregnancy, recognizing that adolescents often present to care later than their adult counterparts. A model that provides an opportunity to address all of these needs at one site may be the preferred model of care for pregnant adolescents. (II-1A)   2. Health care providers should be sensitive to the unique developmental needs of adolescents through all stages of pregnancy and during intrapartum and postpartum care. (III-B)   3. Adolescents have high-risk pregnancies and should be managed accordingly within programs that have the capacity to manage their care. The unique physical risks of adolescent pregnancy should be recognized and the care provided must address these. (II-1A)

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

740 l AUGUST JOGC AOÛT 2015

Adolescent Pregnancy Guidelines

Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.119 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care.119

  4. Fathers and partners should be included as much as possible in pregnancy care and prenatal/infant care education. (III-B)   5. A first-trimester ultrasound is recommended not only for the usual reasons for properly dating the pregnancy, but also for assessing the increased risks of preterm birth. (I-A)   6. Counselling about all available pregnancy outcome options (abortion, adoption, and parenting) should be provided to any adolescent with a confirmed intrauterine gestation. (III-A)   7. Testing for sexually transmitted infections (STI) (II-2A) and bacterial vaginosis (III-B) should be performed routinely upon presentation for pregnancy care and again in the third trimester; STI testing should also be performed postpartum and when needed symptomatically.

a. Because pregnant adolescents are inherently at increased risk for preterm labour, preterm birth, and preterm pre-labour rupture of membranes, screening and management of bacterial vaginosis is recommended. (III-B)



b. After treatment for a positive test, a test of cure is needed 3 to 4 weeks after completion of treatment. Refer partner for screening and treatment. Take the opportunity to discuss condom use. (III-A)

  8. Routine and repeated screening for alcohol use, substance abuse, and violence in pregnancy is recommended because of their increased rates in this population. (II-2A)   9. Routine and repeated screening for and treatment of mood disorders in pregnancy is recommended because of their increased rates in this population. The Edinburgh Postnatal Depression Scale istered in each trimester and postpartum, and more frequently if deemed necessary, is one option for such screening. (II-2A) 10. Pregnant adolescents should have a nutritional assessment, vitamins and food supplementation if needed, and access to a strategy to reduce anemia and low birth weight and to optimize weight gain in pregnancy. (II-2A) 11. Conflicting evidence s and refutes differences in gestational hypertension in the adolescent population; therefore,

the care usual for adult populations is ed for pregnant adolescents at this time. (II-2A) 12. Practitioners should consult gestational diabetes mellitus (GDM) guidelines. In theory, testing all patients is appropriate, although rates of GDM are generally lower in adolescent populations. Practitioners should be aware, however, that certain ethnic groups including Aboriginal populations are at high risk of GDM. (II-2A) 13. An ultrasound anatomical assessment at 16 to 20 weeks is recommended because of increased rates of congenital anomalies in this population. (II-2A) 14. As in other populations at risk of intrauterine growth restriction (IUGR) and low birth weight, an ultrasound to assess fetal wellbeing and estimated fetal weight at 32 to 34 weeks gestational age is suggested to screen for IUGR. (III-A) 15. Visits in the second or third trimester should be more frequent to address the increased risk of preterm labour and preterm birth and to assess fetal well-being. All caregivers should be aware of the signs and symptoms of preterm labour and should educate their patients to recognize them. (III-A) 16. It should be recognized that adolescents have improved vaginal delivery rates and a concomitantly lower Caesarean section rate than their adult counterparts. (II-2A) As with antenatal care, peripartum care in hospital should be multidisciplinary, involving social care, for breastfeeding and lactation, and the involvement of children’s aid services when warranted. (III-B) 17. Postpartum care should include a focus on contraceptive methods, especially long-acting reversible contraception methods, as a means to decrease the high rates of repeat pregnancy in this population; discussion of contraception should begin before delivery. (III-A) 18. Breastfeeding should be recommended and sufficient given to this population at high risk for discontinuation. (II-2A) 19. Postpartum care programs should be available to adolescent parents and their children, to improve the mothers’ knowledge of parenting, to increase breastfeeding rates, to screen for and manage postpartum depression, to increase birth intervals, and to decrease repeated unintended pregnancy rates. (III-B)

AUGUST JOGC AOÛT 2015 l 741

SOGC clinical practice guideline

20. Adolescent women in rural, remote, northern, and Aboriginal communities should be ed to give birth as close to home as possible. (II-2A) 21. Adolescent pregnant women who need to be evacuated from a remote community should be able to have a family member or other person accompany them to provide and encouragement. (II-2A) 22. Culturally safe prenatal care including emotional, educational, and clinical to assist adolescent parents in leading healthier lives should be available, especially in northern and Aboriginal communities. (II-3A) 23. Cultural beliefs around miscarriage and pregnancy issues, and special considerations in the handling of fetal remains, placental tissue, and the umbilical cord, must be respected. (III)

INTRODUCTION

A

dolescence is a distinct and unique physical and developmental stage in a woman’s life. Consequently, the diagnosis and management of pregnancy during this time, before the age of 20, deserves acknowledgement of its distinctive inherent risks and an understanding of the relevant elements of care required for successful outcomes for the mother, the infant, and their surrounding social circle. The SOGC represents a wide variety of practitioners and disciplines involved in maternity care and is therefore well placed to present guidelines on the care of the pregnant adolescent, of which multidisciplinary care is a key feature. Adolescent pregnancy is a subject relevant to practices in Canada and around the world, and it bears mentioning that not all adolescent pregnancies are unplanned or unwanted. Annually, 14 million 14- to 19-year-olds deliver babies globally. Births to adolescent mothers represent 10% of ABBREVIATIONS aRR

adjusted relative risk

BV

bacterial vaginosis

CS

Caesarean section

DMPA

depot medroxyprogesterone acetate

GA

gestational age

GDM

gestational diabetes mellitus

IPV

intimate partner violence

IUD

intrauterine device

IUGR

intrauterine growth restriction

LARC

long-acting reversible contraception

LBW

low birth weight

NICU

neonatal intensive care unit

PPROM preterm pre-labour rupture of membranes PTB

preterm birth

PTL

preterm labour

SGA

small for gestational age

STI

sexually transmitted infection

SVD

spontaneous vaginal delivery

742 l AUGUST JOGC AOÛT 2015

births worldwide, but 23% of maternal morbidity and mortality.1 Adolescent pregnancy is the leading cause of mortality in girls aged 15 to 19 worldwide; 90% of these deaths occur in resource-poor countries and most of them are preventable.1,2 Adolescent pregnancy is also a cause for concern worldwide because of high rates of unsafe abortion and poor knowledge-seeking behaviours, prenatal care, and .1 In Canada, the fertility rate for adolescents aged 15 to 19 in 2009 was 14.2 births per 1000 women; 15 638 babies were born to women under 20 that year, up slightly from the alltime low reached in 2005 (13.4), though still significantly lower than the rates seen in the 1980s.3 Across the country, adolescent pregnancy rates are highest in Nunavut and the Northwest Territories and lowest in Prince Edward Island and Ontario. Between 1996 and 2006, adolescent birth rates in Canada decreased in a continuous downward trend from 22.1/1000 to 13.7/1000 and abortion rates decreased from 22.1/1000 to 14.2/1000. The birth rate is higher in older adolescents (23.3, age 18–19) than in younger (6.5, age 15–17). In Canada, younger adolescents are more likely to have an induced abortion than to give birth, whereas the majority of pregnancies among older adolescents end in a live birth. In 2010, abortion was the most common outcome of adolescent pregnancies in Canada.4 Worldwide, poverty and lower educational attainment are risk factors for adolescent pregnancy.1 Once pregnant, an adolescent becomes more likely than her non-pregnant peers to have lower educational attainment, to drop out of school, and to have lower socioeconomic status and lower social capital. Children of an adolescent parent are similarly more likely than their peers to have lower educational achievement, grow up in a single-mother household, be involved in alcohol and drugs, and to become a single adolescent parent themselves.5–7 Adolescent pregnancies worldwide are noted to have higher maternal, obstetrical, and neonatal risks, with those in women aged ≤ 15 having risks noted to be even higher than those in adolescents aged ≥ 16. Adolescent pregnancies should therefore be managed as high risk in programs that can accommodate their unique risks and concerns.8–10 Consent and Confidentiality in Caring for Adolescent Patients in Canada

In caring for pregnant adolescents, their ability to consent within their relationship should be considered, as should the possible need to report the relationship to child protection authorities if it violates or violated the law. In Canada, by law, the general age of consent for sexual activity is 16, with

Adolescent Pregnancy Guidelines

age-related exceptions for adolescents aged 12 to 16 with partners ranging from up to 2 years older to 5 years older depending on their own age. For exploitive sexual activity, the age of consent is 18. See Appendix A for a detailed outline of consent for different ages and the definition of exploitive sex.11 Respecting the autonomy and confidentiality of the adolescent patient may at times be complicated by the care setting and the surrounding environment. Issues of confidentiality are likely to arise with care of very young adolescents, care in a small community, and care of other family in the clinic and potentially even within team care. Child protection agencies, although not actively involved and part of the circle of care until after the birth of the baby in cases of newborn apprehension, may be able to provide for counselling, parenting, and financial assistance. When considering options for pregnant adolescents in our country, it is important to that there is no specific age of consent for medical treatment in Canada. As long as individuals are deemed to have the capacity to provide consent (i.e. to understand the nature of the procedure as well as its risks and alternatives), they do not need to have reached a particular age in order to provide consent. (By law in Quebec, however, parents have the right to access the medical records of children under the age of 14).12 ANTEPARTUM CARE Prenatal Care and Multidisciplinary Care Programs

Unfortunately, adolescents have a significantly lower attendance of prenatal classes (aRR 0.87, 95% CI 0.85 to 0.91) and first-trimester antenatal visits (aRR 0.53, 95% CI 0.51 to 0.55) than adult women.6,13,14 Reasons for delay in seeking care are multifactorial: lack of knowledge about the importance of prenatal care and lack of understanding of the consequences of its absence; history as a victim of violence, desire to hide pregnancy, fear of potential apprehension of the baby, contemplation of abortion services; concerns about lack of privacy or judgemental attitudes from health care providers or adults; and financial barriers.14 Lack of, or delayed, adolescent prenatal care is associated with adverse maternal, obstetrical, and neonatal outcomes.9,13,15–17 Standard prenatal care improves outcomes in adolescent pregnancy18–21; adequate prenatal care has been shown to be protective against fetal and infant mortality in this population.9 However, studies suggest that standard care misses psychosocial vulnerabilities, STI screening,22 and

postpartum issues such as breastfeeding, contraception, and school return.23 Multidisciplinary adolescent-focused prenatal care leads to better outcomes than standard prenatal care in adolescents,8,10,24 including reductions in PTB,8,10 LBW,10,25 and NICU issions,26 increased SVD,10,26 and reduction in operative delivery.8,10 Major cost savings related to infant and paediatric health could be realized by preventing preterm births. Adolescent-centred multidisciplinary comprehensive care with a goal to improving outcomes for mothers and their infants is considered the gold standard for management of the myriad problems that present in an adolescent pregnancy (Appendix B).8 Elements of care are aimed at reducing adverse maternal and neonatal outcomes. Teaching strategies and topics are important considerations when providing health information for pregnant adolescents. The adolescent should have easy access to care based on a philosophy of providing care in a welcoming environment with multidisciplinary teams to meet the many health care needs of the adolescent. It is also important to encourage early enrollment into prenatal care and participation in community programs.8 Two cohort studies demonstrated a significant reduction in PTB and LBW when adolescents attended specialized multidisciplinary antenatal care. An Australian cohort showed that screening for and treating STIs resulted in a significant reduction in PTB in a general antenatal clinic (OR 0.4; 95% CI 0.25 to 0.62),27 and the Canadian cohort demonstrated that dedicated multidisciplinary care provided in an adolescent-friendly community outreach program led to a 53% reduction in PTB (OR 0.47, 95% CI 0.22 to 1.00).10 This Canadian study observed a 59% reduction in LBW babies (95% CI 0.18 to 0.95).10 It is important to address nutritional requirements and maternal weight gain when caring for pregnant adolescents; useful strategies may include dietary assessments, a comprehensive prenatal nutrition program, and a community food donation program in addition to access to prenatal care.10 Multidisciplinary adolescentfocused antenatal care therefore has tremendous potential to reduce the significant health care costs associated with PTB and LBW infants. A number of models of multidisciplinary care have been described that achieve the aforementioned desired objectives. Successful models have been implemented in hospitals, schools, clinics, and community facilities.10 Multidisciplinary care is usually provided in one place at one time,10 and further study should continue to evaluate this mode of AUGUST JOGC AOÛT 2015 l 743

SOGC clinical practice guideline

care. Where possible “one-stop shopping” and easy visits work best for the adolescent.10 Home visiting programs by health care professionals and trained lay visitors have also been assessed; though this model may impact a particular outcome, it does not appear to contribute to the overall desired outcomes.28–31 Helping the pregnant adolescent to navigate the system is an important function for all team to be aware of and participate in, including being aware of the roles of other team , the services available, and in particular client-centred issues, to assist patients to access needed services.32 Antenatal opportunities to develop parenting skills that continue in the postpartum period are likely to improve birth outcomes, increase maternal school attendance, and reduce rapid repeat pregnancy.33 Assistance with varied parenting structures to reduce parenting stress and child dysfunction can also be helpful. The family system and the intergenerational dynamics within a multigenerational caregiving structure are critical to the health and well-being of both mothers and their children.34 Decisions about including families of origin and fathers when appropriate in the parenting process are often complex and require special consideration of their risks and benefits. Many fathers struggle to stay involved in the lives of their children, and prenatal and young family programs seek to find opportunities to engage young fathers in the programs and ultimately in their children’s lives.35 Adolescents who participate in such and education in adolescentcentred care models are more likely to continue their education during the pregnancy and the postpartum year than peers who do not participate in such programs. Recommendations

1. Health care professionals should adapt their prenatal care for adolescents and offer multidisciplinary care that is easily accessible to the adolescent early in the pregnancy, recognizing that adolescents often present to care later than their adult counterparts. A model that provides an opportunity to address all of these needs at one site may be the preferred model of care for pregnant adolescents. (II-1A) 2. Health care providers should be sensitive to the unique developmental needs of adolescents through all stages of pregnancy and during intrapartum and postpartum care. (III-B) 3. Adolescents are high-risk pregnancies and should be managed accordingly within programs that have the capacity to manage their care. The unique physical risks of adolescent pregnancy should be recognized and the care provided must address these. (II-1A) 744 l AUGUST JOGC AOÛT 2015

4. Fathers and partners should be included as much as possible in pregnancy care and prenatal/infant care education. (III-B) 5. A first-trimester ultrasound is recommended not only for the usual reasons for properly dating the pregnancy, but also for assessing the increased risks of preterm birth. (III-A) Choice in Pregnancy

Upon diagnosis of intrauterine pregnancy, adolescents can and should be counselled, without specific consideration of their age, about their options for continuation with the intent to parent, adoption, or termination. They should be offered with the participation of the person(s) of their choice. Canada has no abortion law, and thus abortion remains an option for the patient so long as access permits. Access to abortion, however, varies greatly in different jurisdictions and provinces across the country.36 Recommendation

6. Counselling about all available pregnancy outcome options (abortion, adoption, and parenting) should be provided to any adolescent with a confirmed intrauterine gestation. (III-A) Sexually Transmitted Infections

Adolescents are at greater risk for STIs because they frequently have multiple partners, have unprotected intercourse, are biologically more vulnerable to sexually acquired infections and face multiple obstacles to utilization of health care.37 Pregnant adolescents may be at further risk because they are less likely to use condoms with intercourse during their pregnancy than non-pregnant adolescents.21,38 In pregnancy, STIs have been associated with preterm delivery, chorioamnionitis, and postpartum infections.39 Adolescents with an STI have a higher risk of PPROM leading to PTB.10,27,40 Vertical transmission of chlamydia during vaginal delivery ranges from 30% to 50% and may result in pneumonia and ophthalmia neonatorum.39 Screening and treatment is associated with a significant decrease in the incidence of newborn febrile morbidity (10% vs. 25%, P = 0.02).41 These infections can also increase the risk of HIV acquisition and transmission.41 Adolescent women are at heightened risk because of the physiologic immaturity of their cervix and the consequent susceptibility of the tissues to infection.42 Prevalence of chlamydia in adolescent pregnancy is high. At initial prenatal visit, infection rates range from 11.8% to 31%.41,43–47 The recurrence rate throughout the pregnancy is also high among adolescents. A Canadian retrospective study reported

Adolescent Pregnancy Guidelines

an infection rate of 22.1% in routine third trimester screening.44 A prospective cohort of 125 adolescents with chlamydia or gonorrhoea in pregnancy who were retested in third trimester reported a reinfection rate of 11%; 7% had a new infection, while 3% had recurrent gonorrhoea.45 Repeated testing between 3 and 4 weeks later to ensure treatment success and lack of reinfection is recommended in this population.48 BV in pregnancy has also been associated with adverse outcomes including PPROM, PTL, PTB, and postpartum endometritis. There is evidence to screening and treatment at 12 to 16 weeks in high-risk (those with previous PTL, PTB, or PPROM) or symptomatic pregnancies, although it is not recommended in low-risk or asymptomatic pregnancies.48 Because of their inherently increased risks of PPROM, PTL, and PTB, adolescent pregnancies are all considered to be high-risk. Recommendation

7. Testing for sexually transmitted infection (II-2A) and bacterial vaginosis (III-B) should be performed routinely upon presentation for pregnancy care and again in the third trimester; testing for sexually transmitted infection should also be performed postpartum and when needed symptomatically. a. Because pregnant adolescents are inherently at increased risk for preterm labour, preterm birth, and preterm pre-labour rupture of membranes, they are a high-risk group and therefore screening and management of bacterial vaginosis is recommended. (III-B) b. After treatment for a positive test, a test of cure is needed 3 to 4 weeks after completion of treatment. Refer partner for screening and treatment. Take the opportunity to discuss condom use. (III-A) Smoking, Substance Abuse, and Alcohol Abuse

Adolescents who are pregnant have higher rates of smoking (38.8% vs. 11.9%, P < 0.001) and substance abuse (11.7% vs. 5.1%, P < 0.0001) than their adult counterparts.13 An Australian retrospective study revealed 20.3% of adolescents used marijuana during pregnancy, of which 33.5% were multidrug s. Of adolescents who were non-s, 50% were previous s who ceased drug use immediately before or early during pregnancy. Illegal drug use was associated with concomitant cigarette and alcohol use.49 However, pregnancy is a powerful incentive for many adolescents to reduce tobacco, alcohol, and drug use; previous studies have shown cessation rates of up to 60% to 75%.49 A critical component of the care of this pregnant population should therefore be aimed at reducing the effects of smoking and substance abuse, including

alcohol. For general recommendations concerning alcohol and substance use in pregnancy, see the SOGC Alcohol Use and Pregnancy Consensus Clinical Guidelines50 and Substance Use in Pregnancy.51 Violence and Coercion

Violence in adolescent pregnancy is unfortunately quite common, with an odds ratio of 1.8 in one study.52 Violence in pregnancy is associated with late engagement in prenatal care and an increased risk of adverse perinatal outcomes such as LBW, PTB, and fetal death,53 and postpartum depression.54,55 Rates of IPV in pregnant adolescents, at 26% to 31%, are higher than in their adult counterparts. Violence often begins in the first trimester and is usually committed by the partner. A history of abuse within the last year is predictive of violence in pregnancy.56 In addition, 26% of pregnant adolescents known to be victims of IPV also reported sexual coercion from their partner.57 A history of past physical abuse at any point is strongly associated with adolescent pregnancy.58 See the SOGC Intimate Partner Violence Consensus Statement59 for recommendations concerning IPV in pregnancy and Appendix C60 for a short screening tool for IPV. Exploring pregnancy intentions and the behaviours of partners of sexually active adolescents may help to identify youth experiencing IPV57; questions about all types of abuse should routinely be asked of adolescent patients.59 Recommendation

8. Routine and repeated screening for alcohol use, substance abuse, and violence in pregnancy is recommended because of their increased rates in this population. (II-2A) Mood Disorders

Depression is diagnosed in 4% to 8% of adolescents. In pregnancy, the rate varies from 16% to 44%, almost twice as high as among adult pregnant women and nonpregnant adolescents. Depressive symptoms among pregnant adolescents become more severe between the second and third trimesters,61 and half of adolescent mothers experience symptoms of depression in the early postpartum period.62 Adolescent mothers are twice as likely to experience depression than adult mothers.16 Factors significantly associated with depressive symptoms in pregnancy include antenatal depressive symptoms and IPV.55,63 Untreated maternal depression is associated with adverse maternal, neonatal, and childhood outcomes, as well as with postpartum depression16,61 and increased frequency of subsequent pregnancies. Untreated maternal depression AUGUST JOGC AOÛT 2015 l 745

SOGC clinical practice guideline

is also associated with preterm delivery and SGA infants. Finally, untreated depression is associated with unresponsive mothering and behavioural and cognitive problems in children.64 The risk of postpartum depression is significant in adolescent mothers. Indeed, 47% of adolescent mothers had significant symptoms of depression at 4 to 6 weeks postpartum, and the depressive symptoms continued at 12 months postpartum.62 Of particular concern, by 12 months postpartum, none of the adolescent mothers in this study with symptoms of depression had pursued referrals for mental health evaluation and treatment.62 It is therefore crucial to promote improved maternal mental health in the adolescent population including early recognition and management of psychiatric disorders and treatment of depression and suicidal ideation and intent.61,62,64 The Edinburgh Postnatal Depression Scale is one option for routine screening.65 Recommendation

9. Routine and repeated screening for and treatment of mood disorders in pregnancy is recommended because of their increased rates in this population. The Edinburgh Postnatal Depression Scale istered in each trimester and postpartum, and more frequently if deemed necessary, is one option for such screening. (II-2A) Anemia and Nutritional Care

Anemia (hemoglobin < 105 g/L) is a very common complication in pregnant adolescents, with a reported prevalence of from 50% to 66%27,66 and an increased relative risk of 1.27 (95% CI 1.15 to 1.4),67 usually attributed to inadequate replacement or nutrition. In addition, a prospective study demonstrated that low body iron stores and low ferritin were significantly more common in pregnant adolescents than in pregnant adults.68 Smoking status was an important risk factor for LBW and anemia.69 Care for the pregnant adolescent should therefore incorporate nutritional care to both optimize weight gain and manage potential nutritional deficiencies. Recommendation

10. Pregnant adolescents should have a nutritional assessment, vitamin and food supplementation if needed, and access to a strategy to reduce anemia and low birth weight and to optimize weight gain in pregnancy. (II-2A) Hypertensive Disorders of Pregnancy

There is conflicting evidence regarding the risk of preeclampsia and gestational hypertension in adolescents. 746 l AUGUST JOGC AOÛT 2015

Some studies demonstrate a higher rate of hypertensive disorders in adolescent pregnancies than in adults.70,71 Other studies, however, do not demonstrate a difference in gestational hypertension between adolescents and adults of the same parity.6,13 While the methodologies of the studies differ, it is also important to control for potential confounders such as parity, smoking, and substance use. When adjusted for these factors, a decreased risk of gestational hypertension was seen in a Canadian cohort (aRR 0.73, 95% CI 0.68 to 0.79).13 Recommendation

11. Conflicting evidence s and refutes differences in gestational hypertension in the adolescent population; therefore, the care usual for adult populations is ed for pregnant adolescents at this time. (II-2A) Gestational Diabetes

In Canada, the prevalence of GDM in all pregnancies is higher than previously thought, varying from 3.7% in the non-Aboriginal population to 8% to 18% in Aboriginal populations.72 However, recent retrospective studies indicate that non-Aboriginal adolescents have lower rates of GDM (OR 0.04; 95% CI 0.01 to 0.29),73 (aRR 0.34; 95% CI 0.30 to 0.39)13 than adult women. However, at this time, screening of pregnant adolescents should follow the same guidelines and management for GDM as for adult women.71 Recommendation

12. Practitioners should consult gestational diabetes mellitus (GDM) guidelines. In theory, testing all patients is appropriate, although rates of GDM are generally lower in adolescent populations. Practitioners should be aware, however, that certain ethnic groups including Aboriginal populations are at high risk of GDM. (II-2A) Prevention of Adverse Maternal and Neonatal Outcomes: PTB, LBW, and IUGR

Adolescent pregnancies have a higher risk of adverse outcomes such as PTB (< 37 weeks),9,15,18,66,74,75 very PTB, (< 32 weeks),9,13,18,74,75 and extremely PTB (< 28 weeks),9,76 LBW (< 2500 g),9,15,66,74,75 very LBW (< 1500 g),9,74 IUGR (< 3rd centile for GA) and stillbirths,9,67,70,76 and NICU issions and neonatal deaths.9,13,17,74–77 In addition, congenital anomalies are more common in adolescent pregnancies. These include central nervous system anomalies (anencephaly, spina bifida, hydrocephaly, microcephaly), gastrointestinal anomalies (gastroschisis, omphalocele), and musculoskeletal anomalies (cleft lip, cleft palate, polydactaly, syndactaly).74,75,78

Adolescent Pregnancy Guidelines

Since a significant proportion of pregnant adolescents have a low socioeconomic status, it has been assumed that the high risk nature of these pregnancies is due to their environment.79,80 However, 2 large retrospective cohort studies challenge this assumption.

14. As in other populations at risk of intrauterine growth restriction (IUGR) and low birth weight, an ultrasound to assess fetal well-being and estimated fetal weight at 32 to 34 weeks’ gestational age is suggested to screen for IUGR. (III-A) 15. Visits in the second or third trimester should be more frequent to address the increased risks of preterm labour and preterm birth and to assess fetal well-being. All caregivers should be aware of the signs and symptoms of preterm labour and should educate their patients to recognize them. (III-A)

The first is a retrospective cohort study of almost 2 million adolescent births in the United States adjusted for potential confounders such as state, race, marital status, smoking, alcohol use, and prenatal care.74 In this cohort, even after adjusting for those confounders, adolescent pregnancy was independently associated with increased risk of PTB (RR = 1.2), very PTB (RR = 1.26), LBW (RR = 1.14), very LBW (RR = 1.11), SGA (RR = 1.07), and neonatal mortality (RR = 1.15). The effect of adolescent pregnancy on neonatal mortality disappeared after adjustment of birth weight and gestational age; this suggests that neonatal mortality may be explained by the higher rate of PTB and LBW infants in adolescent mothers.74 Other studies have found similar results, proposing that increased NICU ission rates are likely a result of increased preterm deliveries.9,17,75

INTRAPARTUM CARE

The second study is a recent retrospective cohort study with data adjusted for race, twins, and number of prior births in 37 million births in the United States, of which over 300 000 were to adolescent mothers ≤ 15 years of age. These young adolescents were at significantly increased risk of PTB (OR = 1.76), very PTB (OR = 2.4), extremely PTB (OR = 2.48), LBW (OR = 1.37), very LBW (OR = 1.47), SGA (OR = 1.14), IUGR (OR = 1.21), stillbirth (OR = 1.31), and infant death (OR = 1.87). Adequate prenatal care was protective against fetal and infant mortality.9

Two large retrospective studies found a higher rate of vaginal deliveries in adolescents than in adult women (aRR 1.76; 95% CI 1.70 to 1.82),13 while their rates of assisted vaginal deliveries (aRR = 0.62 to 0.76) and CS (aRR 0.57 to 0.79) were lower.13,18,84 The adolescent group also had lower epidural use.13,86 However, when adolescents required a CS, unlike adult women, it was most often in an emergency.13,84 The most common indications for emergency CS in the adolescent group in one study were non-reassuring fetal status and labour dystocia.13

When reviewing the fetal and infant outcomes of Canadian adolescent pregnancies, similar adverse outcomes are seen. A recent retrospective study comparing almost 24 000 adolescents with adults in Ontario revealed that neonates born to adolescent mothers have a significantly higher risk of ission to NICU (aRR = 1.08) and very PTB (aRR = 1.16). The risk of having a large for gestational age infant was significantly lower in the adolescent group (aRR = 0.92). There were no significant differences in SGA (aRR = 1.00), LBW (aRR = 1.05), PTB (aRR = 1.04), and fetal death (aRR = 1.02).13 In another study, Canadian adolescents had a 3-fold increase in the risk of delivery before 34 weeks, with a subsequent increase in NICU issions.75 This is a concerning finding, because preterm birth is an important indicator of neonatal well-being that has been associated with severe morbidity and mortality.80–83 Recommendation

13. An ultrasound anatomical assessment at 16 to 20 weeks is recommended because of increased rates of congenital anomalies in this population. (II-2A)

Many retrospective studies in high income countries have demonstrated a higher rate of vaginal deliveries in adolescents than in adults, along with a shorter active phase of labour, similar length of second stage, and a lower rate of assisted vaginal delivery and CS varying from 2% to 14%.6,10,18,67,74,84,85

Recommendation

16. It should be recognized that adolescents have improved vaginal delivery rates and a concomitantly lower Caesarean section rate than their adult counterparts. (II-2A). As with antenatal care, peripartum care in hospital should be multidisciplinary, involving social care, for breastfeeding and lactation, and the involvement of children’s aid services when warranted. (III-B) POSTPARTUM CARE Contraception

Adolescent mothers are at significant risk for repeat pregnancy, with 25% becoming pregnant again within 2 years of delivery.87 However, not all adolescent pregnancies are undesired, and a significant number of them are in fact planned. A prospective cohort study of adolescents in a multidisciplinary care setting demonstrated that over 50% of adolescents idealized pregnancy as the “single most exciting and positive event to have occurred.”30 In a Canadian AUGUST JOGC AOÛT 2015 l 747

SOGC clinical practice guideline

retrospective study, one third desired their pregnancy. Efforts to promote awareness and the availability of contraception would not have prevented these pregnancies.88 Protective factors against repeat pregnancy include use of LARC, school attendance, and living alone or with a parent as opposed to with a partner.89 Postpartum care and the provision of options for contraception are therefore crucial elements of pregnancy care for the adolescent. Evidence in the postpartum adolescent population specifically suggests that LARCs such as DMPA and IUDs are far better at preventing repeat pregnancies than are shorter-term methods such as oral contraception, contraceptive patch, or barrier methods.90 In one study, 14.2% of adolescents on DMPA were pregnant again one year later compared with 29.7% and 31.8% of oral contraception and patch s.91 LARCs are specifically endorsed for adolescents by the American Congress of Obstetricians and Gynecologists.92 Educational encounters with health care providers and education + contraception programs have shown protective outcomes,93 while behavioural interventions alone have not shown consistent results.94 Provision of emergency contraception in addition to the usual contraceptive methods has been associated with a higher likelihood of its use, although these adolescents may also be more likely to engage in unprotected intercourse.95 Immediate postpartum contraception, with initiation of DMPA postpartum, placement of IUD at the time of delivery, or placement of contraceptive implant before hospital discharge have also shown significantly decreased repeat pregnancy rates.96 However, expulsion rates of IUDs are noted to be higher with immediate postpartum placement.97 Other novel techniques to decrease repeat pregnancy rates include peer-led educational models, varied educational modalities, and the use of cell phones and social media to promote participation and follow-up. More investigation of such options is required. Pregnancy prevention and contraception counselling in this population require extra time and energy to improve knowledge,33,98,99 uptake, and management of sociodemographic risk factors. Recommendation

17. Postpartum care should include a focus on contraceptive methods, especially long-acting reversible contraception methods, as a means to decrease the high rates of repeat pregnancy in this population; discussion of contraception should begin before delivery. Breastfeeding and Postpartum

The t WHO/UNICEF global recommendations for optimal infant feeding is exclusive breastfeeding during the first 6 months.100 In Canada, a t statement by Health Canada, the Canadian Paediatric Society, Dieticians of 748 l AUGUST JOGC AOÛT 2015

Canada, and the Breastfeeding Committee for Canada also states that exclusive breastfeeding for the first 6 months is important for the nutrition, immunologic protection, growth, and development of infants and toddlers.101 In Canada, breastfeeding initiation rates have increased significantly in the last decades. In 1965, fewer than 25% of mothers breastfed compared with 88.4% in 2011.101 However, in 2011 only 27.8% continued to breastfeed their infants to 6 months.2,3 Adolescent mothers have an even lower initiation and continuation rate of breastfeeding than adult women.102–105 Published data for breastfeeding rates among adolescent mothers is sparse.102 An American study indicated that 42.8% of adolescent women initiated breastfeeding, but only 9.1% continued to breastfeed to 6 months compared with 15% to 34% of mothers from all other age groups.102 Adolescent mothers and their infants are at greater risk for many health and socioeconomic issues such as anemia and depressive disorders in the mother; LBW, PTB, developmental problems, and learning difficulties in the infants, and rapid repeat pregnancy. Breastfeeding could greatly benefit these young mothers and their infants by ameliorating some of these outcomes. Studies in the adolescent population have suggested multiple sociodemographic factors are associated with lower rates of breastfeeding including age, race, educational level, marital status, and socioeconomic status.102,103,105 Other studies have suggested that lack of knowledge, a negative opinion about pregnancy, and lack of breastfeeding from family, friends, and partner could affect breastfeeding rates.102,103 Programs should be available during pregnancy and postpartum to breastfeeding, enhance parenting skills, reduce rapid repeat pregnancies and improve continuation of maternal education. These may be continuations of an adolescent pregnancy program or specific early-years parenting programs provided through public health agencies and other locally available s. Increased breastfeeding rates can be achieved and ed by adolescent mothers’ involvement in antenatal classes and proactive breastfeeding from a lactation consultant, physician, midwife, or nurse with consideration of specific adolescent concerns such as privacy, body image, and pumping. Recommendation

18. Breastfeeding should be recommended and sufficient given to this population at high risk for discontinuation. (II-2A)

Adolescent Pregnancy Guidelines

19. Postpartum care programs should be available to adolescent parents and their children, to improve the mothers’ knowledge of parenting, to increase breastfeeding rates, to screen for and manage postpartum depression, to increase birth intervals, and to decrease repeated unintended pregnancy rates. (III-B) SPECIAL CONSIDERATIONS IN ABORIGINAL ADOLESCENT POPULATIONS

Culturally, adolescent pregnancies have been accepted in most Aboriginal communities. By tradition, babies are regarded as a gift from the Creator and children are welcomed into the families regardless of the mother’s age. Most of the young mothers keep their babies and are well ed by their own mothers, extended families, and communities.106 At the same time it appears that there is some stigma attached to adolescent childbearing in Aboriginal communities, especially when the mother is very young.107 Currently, concerns about adolescent pregnancies in Aboriginal communities are growing for a number of reasons. While recent Canadian statistics show a steady decline in adolescent pregnancy and birth rates since the 1990s, adolescent pregnancy rates in Aboriginal and northern communities continue to be up to 4 times higher than the national average.108 Among women who reported an Aboriginal background, 24% were adolescent mothers compared with just 10% of non-Aboriginal women. The prevalence of current smoking among Aboriginal youth is more than double that among non-Aboriginal youth (24.9% vs. 10.4%).109 Aboriginal youth also had a higher prevalence of regular exposure to second-hand smoke at home (37.3% vs. 19.7%) and in cars (51.0% vs. 30.3%). Aboriginal youth were more likely than nonAboriginal youth to have tried marijuana and other illicit drugs and to engage in binge drinking; it is also suggested that fetal alcohol spectrum disorder rates are higher in this population than in other populations in Canada.110 Aboriginal youth were less likely than non-Aboriginal youth to have tried to quit smoking.109 Although alcohol and substance abuse have been frequently reported as influencing factors in becoming pregnant, they are generally not an ongoing lifestyle choice for most Aboriginal adolescents. The responsibility of motherhood is a powerful motivator for many of the young women to stop harmful behaviours and to start planning for their futures.111 Access to culturally safe maternity care for adolescents may not always be available in Aboriginal and

northern communities. Young mothers and fathers require emotional, educational, medical, and potentially financial to lead healthier lives without drugs and alcohol and to become positive role models for their children, younger siblings, and the community. Management of diabetes, including GDM, in Aboriginal people should follow the same clinical practice guidelines as those for the general population with recognition of, respect for, and sensitivity to the unique language, cultural, and geographic issues relating to diabetes care and education in Aboriginal communities across Canada and the increased rates of diabetes mellitus in this population.72 Aboriginal adolescent mothers in remote northern communities face additional challenges around birthplace choices and locations. Local maternity care programs do not exist in many communities and frequently young mothers are required to travel weeks in advance to a regional centre to give birth. This practice leads to separation and isolation from family and the home community and has an even greater impact on adolescent mothers who require additional during the labour and birth process.112 The loss of indigenous knowledge and medicine in Aboriginal cultures has been described by many leaders and Elders as the root of many contemporary health and well-being issues faced by Aboriginal peoples today.113 ing existing traditional practices (such as the inclusion of Elders in prenatal care, the use of herbal medicines, specific diet recommendations, the young woman’s desire to give birth on traditional territory) and the use of traditional birthing practices (such as Aboriginal midwifery, smudging, naming ceremony, and retention of placental tissue, and umbilical cord remnants) are important when caring for adolescent pregnant women in northern and Aboriginal communities.113,114 Recognizing and acknowledging the importance and the wide variety of community-specific practices both across the country and within a region are important, as is the acceptance of those practices by the pregnant adolescent.115,116 Custom adoption, the cultural practices of Aboriginal peoples to raise a child by a person who is not the child’s parent, according to the custom of the First Nations and/ or Aboriginal community of the child, is a common form of adoption in Aboriginal communities; it is recognized in the Indian Act of 1985117 and in most Canadian jurisdictions, for example in the 1990 Aboriginal Custom Adoption Recognition Act of the Northwest Territories.118 Custom adoption ensures that Aboriginal children maintain their cultural, linguistic, and spiritual identity. AUGUST JOGC AOÛT 2015 l 749

SOGC clinical practice guideline

Aboriginal custom adoption takes place usually between 2 families who know each other or have connected with one another through word of mouth in the community and often includes a custom adoption ceremony. Statistics on custom adoptions are difficult to obtain. Recommendations

20. Adolescent women in rural, remote, northern, and Aboriginal communities should be ed to give birth as close to home as possible. (II-2A) Adolescent women in rural, remote, northern, and Aboriginal communities should be ed to give birth as close to home as possible. (II-2A) 21. Adolescent pregnant women who need to be evacuated from a remote community should be able to have a family member or other person accompany them to provide and encouragement. (II-2A) 22. Culturally safe prenatal care including emotional, educational, and clinical to assist adolescent parents in leading healthier lives should be available, especially in northern and Aboriginal communities. (II-3A) 23. Cultural beliefs around miscarriage and pregnancy issues, and special considerations in the handling of fetal remains, placental tissue, and the umbilical cord, must be respected. (III) SUMMARY

Adolescence is a unique stage of the life cycle, and adolescent pregnancy, while perhaps slowly on a decline in North America, remains a uniquely high-risk pregnancy situation requiring multidisciplinary care adapted specifically to meet the physical and emotional needs of the adolescent. Special populations within the Canadian population with high rates of adolescent pregnancy, such as Aboriginal populations, demand culturally appropriate care. Appropriate contraception and education also needs to be provided to reduce rapid repeat pregnancy rates in this high risk population. REFERENCES 1. United Nations Population Fund. UNFPA annual report 2007. Available at http://www.unfpa.org/publications/unfpa-annualreport-2007. Accessed on May 30, 2015. 2. Hawkins L, Spitzer RF, Christoffersen-Deb A, Leah J, Mabeya H. Characteristics and surgical success of patients presenting for repair of obstetric fistula in western Kenya. Int J Gynaecol Obstet 2012;120:178–82. 3. Ontario Ministry of Health and Long-Term Care. Initial report on public health. Toronto (ON): Ontario Ministry of Health and Long-Term

750 l AUGUST JOGC AOÛT 2015

Care; 2009. Available at: http://www.health.gov.on.ca/en/public/ publications/pubhealth/init_report. Accessed on June 7, 2012. 4. McKay A. Trends in Canadian national and provincial/territorial teen pregnancy rates 2001-2010. Can J Hum Sex 2012;21:3–4. 5. United Nations Population Fund. State of the world population 2011. New York (NY): UNFPA; 2011. Available at http://foweb.unfpa.org/ SWP2011/reports/EN-SWOP2011-FINAL.pdf. Accessed May 30, 2014. 6. World Health Organization (WHO). Issues in adolescent health and development: adolescent pregnancy. Geneva (CH): WHO, Department of Child and Adolescent Health and Development; 2004. 7. Paranjothy S, Broughton H, Adappa R, Fone D. Teenage pregnancy: who suffers? Arch Dis Child 2009;94:239–45. 8. Quinlivan JA, Evans SF. Teenage antenatal clinics may reduce the rate of preterm birth: a prospective study. BJOG 2004;111:57–8. 9. Malabarey OT, Balayla J, Klam SL, Shrim A, Abenhaim HA. Pregnancies in young adolescent mothers: a population-based study on 37 million births. J Pediatr Adolesc Gynecol 2012;25:98–102. 10. Fleming NA, Tu X, Black AY. Improved obstetrical outcomes for adolescents in a community-based outreach program: a matched cohort study. J Obstet Gynaecol Can 2012;34:1134–40. 11. Department of Justice. Age of consent to sexual activity. Frequently asked questions. Ottawa (ON): Government of Canada; 2015. Available at: http://www.justice.gc.ca/eng/rp-pr/other-autre/clp/ faq.html. Accessed on June 7, 2015. 12. Canadian Medical Protective Association. Age of consent for sexual activity and duty to report. Ottawa (ON): CMPA; 2010. Available at: https://www.cmpa-am.ca/-/age-of-consent-for-sexual-activityand-duty-to-report. Accessed on May 14, 2015. 13. Fleming N, Ng N, Osborne C, Biederman S, Yasseen AS 3rd, Dy J, et al. Adolescent pregnancy outcomes in the province of Ontario: a cohort study. J Obstet Gynaecol Can 2013;35:234–45. 14. Lena SM, Marko E, Nimrod C, Merritt L, Poirier G, Shein E. Birthing experience of adolescents at the Ottawa General Hospital Perinatal Centre. CMAJ 1993;148:2149–54. 15. Loto OM, Ezechi OC, Kalu BK, Loto A, Ezechi L, Ogunniyi SO. Poor obstetric performance of teenagers: is it age- or quality of care-related? J Obstet Gynaecol 2004;24:395–8. 16. Barnet B, Liu J, Devoe M. Double jeopardy: depressive symptoms and rapid subsequent pregnancy in adolescent mothers. Arch Pediatr Adolesc Med 2008;162:246–52. 17. Sandal G, Erdeve O, Oguz SS, Uras N, Akar M, Dilmen U. The ission rate in neonatal intensive care units of newborns born to adolescent mothers. J Matern Fetal Neonatal Med 2011;24:1019–21. 18. Lao TT, Suen SS, Sahota DS, Wa Law L, Yeung Leung T. Has improved health care provision impacted on the obstetric outcome in teenage women? J Matern Fetal Neonatal Med 2012;25:1358–62. 19. Lao TT, Ho LF. Obstetric outcome of teenage pregnancies. Hum Reprod 1998;13:3228–32. 20. Scholl TO, Hediger ML, Belsky DH. Prenatal care and maternal health during adolescent pregnancy: a review and meta-analysis. J Adolesc Health 1994;15:444–56. 21. Niccolai LM, Ethier KA, Kershaw TS, Lewis JB, Ickovics JR. Pregnant adolescents at risk: sexual behaviors and sexually transmitted disease prevalence. Am J Obstet Gynecol 2003;188:63–70. 22. Quinlivan JA, Petersen RW, Gurrin LC. Adolescent pregnancy: psychopathology missed. Aust N Z J Psychiatry 1999;33:864–8. 23. Bensussen-Walls W, Saewyc EM. Teen-focused care versus adult-focused care for the high-risk pregnant adolescent: an outcomes evaluation. Public Health Nurs 2001;18:424–35.

Adolescent Pregnancy Guidelines

24. Ukil D, Esen UI. Early teenage pregnancy outcome: a comparison between a standard and a dedicated teenage antenatal clinic. J Obstet Gynaecol 2002;22:270–2.

43. Oh MK, Cloud GA, Baker SL, MA, Mulchahey K, RF. Chlamydial infection and sexual behavior in young pregnant teenagers. Sex Transm Dis 1993;20:45–50.

25. Barnet B, Duggan AK, Devoe M. Reduced low birth weight for teenagers receiving prenatal care at a school-based health center: effect of access and comprehensive care. J Adolesc Health 2003;33:349–58.

44. Aggarwal A, Spitzer RF, Caccia N, Stephens D, Johnstone J, Allen L. Repeat screening for sexually transmitted infection in adolescent obstetric patients. J Obstet Gynaecol Can 2010;32:956–61.

26. Das S, Dhulkotia JS, Brook J, Amu O. The impact of a dedicated antenatal clinic on the obstetric and neonatal outcomes in adolescent pregnant women. J Obstet Gynaecol 2007;27:464–6.

45. Borges-Costa J, Matos C, Pereira F. Sexually transmitted infections in pregnant adolescents: prevalence and association with maternal and foetal morbidity. J Eur Acad Dermatol Venereol 2012;26:972–5.

27. Quinlivan JA, Petersen RW, Davy M, Evans SF. Abnormal pap smears in teenage mothers and the association with domestic violence, homelessness, and chlamydia. J Low Genit Tract Dis 2004;8:112–7.

46. Quinlivan JA, Petersen RW, Gurrin LC. High prevalence of chlamydia and Pap-smear abnormalities in pregnant adolescents warrants routine screening. Aust N Z J Obstet Gynaecol 1998;38:254–7.

28. Quinlivan JA, Box H, Evans SF. Postnatal home visits in teenage mothers: a randomised controlled trial. Lancet 2003;361:893–900.

47. Berggren EK, Patchen L. Prevalence of Chlamydia trachomatis and Neisseria gonorrhoeae and repeat infection among pregnant urban adolescents. Sex Transm Dis 2011;38:172–4.

29. Nguyen JD, Carson ML, Parris KM, Place P. A comparison pilot study of public health field nursing home visitation program interventions for pregnant Hispanic adolescents. Public Health Nurs 2003;20:412–8. 30. Quinlivan JA. Teenagers who plan parenthood. Sex Health 2004;1:201–8. 31. Gray S, Sheeder J, O’Brien R, Stevens-Simon C. Having the best intentions is necessary but not sufficient: what would increase the efficacy of home visiting for preventing second teen pregnancies? Prev Sci 2006;7:389–95. 32. Brownell MD, Chartier M, Au W, Schultz J. Program for expectant and new mothers: a population-based study of participation. BMC Public Health 2011;11:691.

48. Public Health Agency of Canada. Canadian guidelines on sexually transmitted infections 2013. Ottawa (ON): PHAC; 2013. Available at: http://www.phac-aspc.gc.ca/std-mts/sti-its/cgsti-ldcits/ section-6-4-eng.php. Accessed on August 15, 2014. 49. Quinlivan JA, Evans SF. The impact of continuing illegal drug use on teenage pregnancy outcomes—a prospective cohort study. BJOG 2002;109:1148–53. 50. Carson G, Cox LV, Crane J, Croteau P, Graves L, Kluka S, et al.; Society of Obstetricians and Gynaecologists of Canada. Alcohol use and pregnancy consensus clinical guidelines. SOGC Clinical Practice Guidelines, No. 245, August 2010. J Obstet Gynaecol Can 2010;32(8 Suppl 3):S1–S31.

33. Ford K, Weglicki L, Kershaw T, Schram C, Hoyer PJ, Jacobson ML. Effects of a prenatal care intervention for adolescent mothers on birth weight, repeat pregnancy, and educational outcomes at one year postpartum. J Perinat Educ 2002;11:35–8.

51. Wong S, Ordean A, Kahan M; Society of Obstetricians and Gynaecologists Of Canada Maternal Fetal Medicine, Family Physicians Advisory, and Medico-Legal Committees. Substance use in pregnancy. SOGC Clinical Practice Guidelines, No. 256, April 2011. J Obstet Gynaecol Can 2011;33:367–84.

34. Arnold A, Lewis J, Maximovich A, Ickovics J, Kershaw T. Antecedents and consequences of caregiving structure on young mothers and their infants. Matern Child Health J 2011;15:1037–45.

52. Silverman J, Raj A, Clements K. Dating violence and associated sexual risk and pregnancy among adolescent girls in the United States. Pediatrics 2004;114:e220–e225.

35. Klein JD. Adolescent pregnancy: current trends and issues. Pediatrics 2005;116:281–6.

53. Coker AL, Garcia LS, Williams CM, Crawford TN, Clear ER, McFarlane J, et al. Universal psychosocial screening and adverse pregnancy outcomes in an academic obstetric clinic. Obstet Gynecol 2012;119:1180–9.

36. National Abortion Federation. Abortion coverage by region. Victoria (BC): National Abortion Federation; 2015. Available at: http://www.nafcanada.org/access-region.html. Accessed on June 7, 2015. 37. Workowski KA, Levine WC, Wasserheit JN. U.S. Centers for Disease Control and Prevention guidelines for the treatment of sexually transmitted diseases: an opportunity to unify clinical and public health practice. Ann Intern Med 2002;137:255–62. 38. Crosby R, DiClemente RJ, Wingood GM, Sionean C, Harrington K, Davies SL, et al. Pregnant African-American teens are less likely than their non-pregnant peers to use condoms. Prev Med 2002;34:524–8. 39. Rouse DJ, Spong CY. Chapter 29: categories and causes of fetal death in diseases and injuries of the fetus and newborn. In: Cunningham FG, Leveno KJ, Bloom SL, Hauth JC (eds). Williams obstetrics, 23rd ed. New York (NY): McGraw Medical; 2010, p. 631. 40. Butt K, Lim K; Society of Obstetricians and Gynaecologists of Canada Diagnostic Imaging Committee. Determination of gestational age by ultrasound. SOGC Clinical Practice Guideline, No. 303, February 2014. J Obstet Gynaecol Can 2014;36:171–81.

54. Urquia ML, O’Campo PJ, Heaman MI, Janssen PA, Thiessen KR. Experiences of violence before and during pregnancy and adverse pregnancy outcomes: an analysis of the Canadian Maternity Experiences Survey. BMC Pregnancy Childbirth 2011;11:42. 55. Woolhouse H, Gartland D, Hegarty K, Donath S, Brown SJ. Depressive symptoms and intimate partner violence in the 12 months after childbirth: a prospective pregnancy cohort study. BJOG 2012;119:315–23. 56. Parker B, McFarlane J, Soeken K. Abuse during pregnancy: effects on maternal complications and birth weight in adult and teenage women. Obstet Gynecol 1994;84:323–8. 57. Miller E, Decker MR, Reed E, Raj A, Hathaway JE, Silverman JG. Male partner pregnancy-promoting behaviors and adolescent partner violence: findings from a qualitative study with adolescent females. Ambul Pediatr 2007;7:360–6. 58. Adams JA, East PL. Past physical abuse is significantly correlated with pregnancy as an adolescent. J Pediatr Adolesc Gynecol 1999;12:133–8.

41. Public Health Agency of Canada. Report on sexually transmitted infections in Canada 2009. Ottawa (ON): PHAC; 2008. Available at: http://www.phac-aspc.gc.ca/std-mts/report/sti-its2008/PDF/ 10-047-STI_report_eng-r1.pdf. Accessed on June 7, 2015.

59. Cherniak D, Grant L, Mason R, Moore B, Pellizzari R; Society of Obstetricians and Gynaecologists of Canada Social Sexual Issues Committee. Intimate partner violence consensus statement. SOGC Clinical Practice Guidelines, No 157, April 2005. J Obstet Gynaecol Can 2005;27:365–88.

42. Berman SM, Hein K. Adolescents and STDs. In: Holmes KK, Sparling PF, Mardh P-A, Lemon SM, Stamm WE, Piot P, et al., eds. Sexually transmitted diseases. New York (NY): McGraw-Hill; 1999. pp. 129–42.

60. Quinlivan JA, Evans S. A prospective cohort study of the impact of domestic violence on young teenage pregnancy outcomes. J Pediatr Adolesc Gynecol 2001;14:17–23.

AUGUST JOGC AOÛT 2015 l 751

SOGC clinical practice guideline

61. McClanahan KK. Depression in pregnant adolescents: considerations for treatment. J Pediatr Adolesc Gynecol 2009;22:59–64. 62. Logsdon MC, Foltz MP, Stein B, Usui W, Josephson A. Adapting and testing telephone-based depression care management intervention for adolescent mothers. Arch Womens Ment Health 2010;13:307–17. 63. Gavin AR, Lindhorst T, Lohr MJ. The prevalence and correlates of depressive symptoms among adolescent mothers: results from a 17-year longitudinal study. Women Health 2011;51:525–45.

81. Draper ES, Manktelow B, Field DJ, James D. Prediction of survival for preterm births by weight and gestational age: retrospective population based study. BMJ 1999;319:1093–7. 82. Jolly MC, Sebire N, Harris J, Robinson S, Regan L. Obstetric risks of pregnancy in women less than 18 years old. Obstet Gynecol 2000;96:962–6. 83. Murphy DJ. Epidemiology and environmental factors in preterm labour. Best Pract Res Clin Obstet Gynaecol 2007;21:773–89.

64. Thomas DV, Looney SW. Effectiveness of a comprehensive psychoeducational intervention with pregnant and parenting adolescents: a pilot study. J Child Adolesc Psychiatr Nurs 2004;17:66–77.

84. Jivraj S, Nazzal Z, Davies P, Selby K. Obstetric outcome of teenage pregnancies from 2002 to 2008: the Sheffield experience. J Obstet Gynaecol 2010;30:253–6.

65. Black Dog Institute. Edinburgh Postnatal Depression Scale. Black Dog Institute; 2015. Available at: http://www.blackdoginstitute.org.au. Accessed on May 19, 2015.

85. Black AY, Fleming NA, Rome ES. Pregnancy in adolescents. Adolesc Med State Art Rev 2012;23:123–38, xi.

66. Chang SC, O’Brien KO, Nathanson MS, Mancini J, Witter FR. Hemoglobin concentrations influence birth outcomes in pregnant African-American adolescents. J Nutr 2003;133:2348–55. 67. de Vienne CM, Creveuil C, Dreyfus M. Does young maternal age increase the risk of adverse obstetric, fetal and neonatal outcomes: a cohort study. Eur J Obstet Gynecol Reprod Biol 2009;147:151–6. 68. Soares NN, Mattar R, Camano L, Torloni MR. Iron deficiency anemia and iron stores in adult and adolescent women in pregnancy. Acta Obstet Gynecol Scand 2010;89:343–9. 69. Briggs MM, Hopman WM, Jamieson MA. Comparing pregnancy in adolescents and adults: obstetric outcomes and prevalence of anemia. J Obstet Gynaecol Can 2007;29:546–55. 70. Aliyu MH, Luke S, Kristensen S, Alio AP, Salihu HM. t effect of obesity and teenage pregnancy on the risk of preeclampsia: a populationbased study. J Adolesc Health 2010;46:77–82. 71. Usta IM, Zoorob D, Abu-Musa A, Naassan G, Nassar AH. Obstetric outcome of teenage pregnancies compared with adult pregnancies. Acta Obstet Gynecol Scand 2008;87:178–83. 72. Canadian Diabetes Association; 2008. Clinical practice guidelines for the prevention and management of diabetes in Canada. Can J Diabetes 2008;32(Suppl 1):S1–S201. 73. Chantrapanichkul P, Chawanpaiboon S. Adverse pregnancy outcomes in cases involving extremely young maternal age. Int J Gynaecol Obstet 2013;120:160–4. 74. Chen XK, Wen SW, Fleming N, Demissie K, Rhoads GG, Walker M. Teenage pregnancy and adverse birth outcomes: a large population based retrospective cohort study. Int J Epidemiol 2007;36:368–73. 75. Shrim A, Ates S, Mallozzi A, Brown R, Ponette V, Levin I, et al. Is young maternal age really a risk factor for adverse pregnancy outcome in a Canadian tertiary referral hospital? J Pediatr Adolesc Gynecol 2011;24:218–22. 76. Gilbert W, Jandial D, Field N, Bigelow P, Danielsen B. Birth outcomes in teenage pregnancies. J Matern Fetal Neonatal Med 2004;16:265–70. 77. Chen XK, Wen SW, Fleming N, Yang Q, Walker MC. Increased risks of neonatal and postneonatal mortality associated with teenage pregnancy had different explanations. J Clin Epidemiol 2008;61:688–94. 78. Van den Hof MC, Wilson RD; Society of Obstetricians and Gynaecologists of Canada Diagnostic Imaging and Genetics Committees. Fetal soft markers in obstetric ultrasound. SOGC Clinical Practice Guidelines, No 162, June 2005. J Obstet Gynaecol Can 2005;27:592–612.

86. Thurman AR, Hulsey TC. Pregnant adolescents’ preferences for labor pain management. South Med J 2004;97:964–7. 87. Schelar EE, Manlove J. Repeat teen childbearing: differences across state and by race and ethnicity. Child Trends 2007. Report. Publication #2007-23. Bethesda (MD): Child Trends; 2007. Available at: http://www.childtrends.org/?publications=repeat-teenchildbearing-differences-across-states-and-by-race-and-ethnicity. Accessed on June 7, 2015. 88. Kives S, Jamieson MA. Desire for pregnancy among adolescents in an antenatal clinic. J Pediatr Adolesc Gynecol 2001;14:150. 89. Cavalier YA, Boss-Victoria RG, Hossain MB, Nanda JP. Protective factors to prevent repeat teen pregnancy. American Public Health Association 133rd Annual Meeting & Exposition, December 10-14, 2005, Philadelphia, PA. 90. Tocce K, Sheeder J, Python J, Teal SB. Long acting reversible contraception in postpartum adolescents: early initiation of etonogestrel implant is superior to IUDs in the outpatient setting. J Pediatr Adolesc Gynecol 2012;25:59–63. 91. Thurman AR, Hammond N, Brown HE, Roddy ME. Preventing repeat teen pregnancy: postpartum depot medroxyprogesterone acetate, oral contraceptive pills, or the patch? J Pediatr Adolesc Gynecol 2007;20:61–5. 92. Committee on Adolescent Health Care Long-Acting Reversible Contraception Working Group, American College of Obstetricians and Gynecologists. Committee opinion no. 539: adolescents and long-acting reversible contraception: implants and intrauterine devices. Obstet Gynecol 2012;120:983–8. 93. Stevens-Simon C, Kelly L, Kulick R. A village would be nice but ... it takes a long-acting contraceptive to prevent repeat adolescent pregnancies. Am J Prev Med 2001;21:60–5. 94. Oringanje C, Meremikwu MM, Eko H, Esu E, Meremikwu A, Ehiri JE. Interventions for preventing unintended pregnancies among adolescents. Cochrane Database Syst Rev 2009(4):CD005215. 95. Belzer M, Sanchez K, Olson J, Jacobs AM, Tucker D. Advance supply of emergency contraception: a randomized trial in adolescent mothers. J Pediatr Adolesc Gynecol 2005;18:347–54. 96. Tocce KM, Sheeder JL, Teal SB. Rapid repeat pregnancy in adolescents: do immediate postpartum contraceptive implants make a difference? Am J Obstet Gynecol 2012;206:481 e1–7.

79. Elfenbein DS, Felice ME. Adolescent pregnancy. Pediatr Clin North Am 2003;50:781–800, viii.

97. Eroglu K, Akkuzu G, Vural G, Dilbaz B, Akin A, Taskin L, et al. Comparison of efficacy and complications of IUD insertion in immediate postplacental/early postpartum period with interval period: 1 year followup. Contraception 2006;74:376–81.

80. Beeckman K, van De Putte S, Putman K, Louckx F. Predictive social factors in relation to preterm birth in a metropolitan region. Acta Obstet Gynecol Scand 2009;88:787–92.

98. Smith PB, Weinman M, Mumford DM. Adolescent mothers and postpartum compliance factors associated with patient return. J Pediatr Adolesc Gynecol 1994;7:81–5.

752 l AUGUST JOGC AOÛT 2015

Adolescent Pregnancy Guidelines

99. Katz KS, Rodan M, Milligan R, Tan S, Courtney L, Gantz M, et al. Efficacy of a randomized cell phone-based counseling intervention in postponing subsequent pregnancy among teen mothers. Matern Child Health J 2011;15(Suppl 1):S42–S53. 100. World Health Organization. Infant and young child feeding. Geneva (CH): WHO; 2014. Available at: http://www.who.int/mediacentre/factsheets/ fs342/en. Accessed on June 7, 2015. 101. Health Canada. Nutrition for healthy term infants: recommendations from birth to six months. Ottawa (ON): Health Canada; 2014. Available at: http://www.hc-sc.gc.ca/fn-an/nutrition/infant-nourisson/ recom/index-eng.php. Accessed on June 7, 2015. 102. Wambach KA, Cole C. Breastfeeding and adolescents. J Obstet Gynecol Neonatal Nurs 2000;29:282–94. 103. Park YK, Meier ER, Song WO. Characteristics of teenage mothers and predictors of breastfeeding initiation in the Michigan WIC Program in 1995. Women, infants, and children. J Hum Lact 2003;19:50–6. 104. Nelson A, Sethi S. The breastfeeding experiences of Canadian teenage mothers. J Obstet Gynecol Neonatal Nurs 2005;34:615–24. 105. Mossman M, Heaman M, Dennis CL, Morris M. The influence of adolescent mothers’ breastfeeding confidence and attitudes on breastfeeding initiation and duration. J Hum Lact 2008;24:268–77. 106. Aboriginal Nurses Association of Canada and Planned Parenthood Federation of Canada. Finding our way: a sexual and reproductive health sourcebook for Aboriginal communities. Ottawa (ON); 2002. 107. Devries KM, Free CJ. “It’s not something you have to be scared about”: attitudes towards pregnancy and fertility among Canadian Aboriginal young people. J Aborig Health 2011(3):8–15. 108. O’Donnell V, Wallace S; Statistics Canada. First Nations, Métis, and Aboriginal women. Component of Statistics Canada Catalogue no. 89-503-X, July 2011. Ottawa (ON): Statistics Canada; 2011. Available at: http://www.statcan.gc.ca/pub/89-503-x/2010001/ article/11442-eng.pdf. Accessed on June 7, 2015. 109. Elton-Marshall T, Leatherdale ST, Burkhalter R. Tobacco, alcohol and illicit drug use among Aboriginal youth living off-reserve: results from the Youth Smoking Survey. CMAJ 2011;183:e480–6.

110. Canadian Pediatric Society. Position statement (Ii 2002-01): fetal alcohol syndrome. Ottawa (ON): S; 2002. Available at: http://www.s.ca/ documents/fetal-alcohol-syndrome.pdf. Accessed on January 21, 2014. 111. Best Start: Ontario’s Maternal, Newborn and Early Child Development Resource Centre; Sex Information and Education Council of Canada. Update report on teen pregnancy prevention. Toronto (ON): Best Start; 2007. Available at: http://www.beststart.org/resources/rep_health/pdf/ teen_pregnancy.pdf. Accessed on June 7, 2015. 112. O’Driscoll T, Kelly L, Payne L, St Pierre-Hansen N, Cromarty H, Minty B, et al. Delivering away from home: the perinatal experiences of First Nations women in Northwestern Ontario. Can J Rural Med 2011;16:126–30. 113. Skye A. Aboriginal midwifery: a model for change. Toronto (ON): Department of Public Health Sciences, University of Toronto; 2010. 114. Carroll D, Benoit C. Chapter 13: Aboriginal midwifery in Canada: merging traditional practices and modern science. In: Bourgeault IL, Benoit C, Davis-Floyd R, eds. Reconceiving midwifery. Montreal (QC) and Kingston (ON): McGill-Queen’s Press; 2004, pp. 263–86. 115. O’Driscoll T, Payne L, Kelly L, Cromarty H, St Pierre-Hansen N, Terry C. Traditional First Nations birthing practices: interviews with Elders in Northwestern Ontario. J Obstet Gynaecol Can 2011;33:24–9. 116. Wilson D, Sandra de la Ronde S, Brascoupé S, Apale AN, Barney L, Guthrie B; Society of Obstetricians and Gynaecologists of Canada Aboriginal Health Initiative Committee. Health professionals working with First Nations, Inuit, and Métis consensus guideline. SOGC Clinical Practice Guidelines, No. 293, June 2013. J Obstet Gynaecol Can 2013;35(6eSuppl):S1–S52. 117. Government of Canada. Indian Act (R.S.C., 1985, c. I-5). Available at: http://laws-lois.justice.gc.ca/eng/acts/i-5/page-1.html#h-1. Accessed on June 7, 2015. 118. Department of Justice of the Northwest Territories. Aboriginal custom adoption recognition regulations, NWT Reg 085-95 1990. Ottawa (ON): Canadian Legal Information Institute; 2013. Available at: https://www.canlii.org/en/nt/laws/regu/nwt-reg-085-95/latest/ nwt-reg-085-95.html. Accessed on June 7, 2015. 119. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canad ian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

Appendix begins on next page

AUGUST JOGC AOÛT 2015 l 753

SOGC clinical practice guideline

APPENDIX A What is Canada’s age of consent? The age of consent for sexual activity is 16 years. It was raised from 14 years on May 1, 2008 by the Tackling Violent Crime Act. However, the age of consent is 18 years where the sexual activity “exploits” the young person—when it involves prostitution, pornography, or occurs in a relationship of authority, trust, or dependency (e.g., with a teacher, coach, or babysitter). Sexual activity can also be considered exploitative based on the nature and circumstances of the relationship, e.g., the young person’s age, the age difference between the young person and their partner, how the relationship developed (quickly, secretly, or over the Internet) and how the partner may have controlled or influenced the young person. Are there any exceptions to this? The Criminal Code provides “close-in-age” or “peer group” exceptions. For example, a 14- or 15-year-old can consent to sexual activity with a partner as long as the partner is less than five years older and there is no relationship of trust, authority or dependency or any other exploitation of the young person. This means that if the partner is 5 years or older than the 14- or 15-year-old, any sexual activity will be considered a criminal offence unless it occurs after they are married to each other (in accordance with the “solemnization” of marriage requirements that are established in each province and territory, governing how and when a marriage can be performed, including the minimum age at which someone may marry). There is also a “close-in-age” exception for 12- and 13-year-olds: a 12- or 13-year-old can consent to sexual activity with another young person who is less than two years older and with whom there is no relationship of trust, authority or dependency or other exploitation of the young person. Are 16 and 17 year olds also protected against sexual exploitation? The Criminal Code protects 16- and 17-year-olds against sexual exploitation, where the sexual activity occurs within a relationship of trust, authority, dependency, or where there is other exploitation. Whether a relationship is considered to be exploiting the 16- or 17-year-old will depend upon the nature and circumstances of the relationship, e.g., the age of the young person, the age difference between the young person and their partner, how the relationship developed and how the partner may have controlled or influenced the young person. As well, 16- and 17-year-olds cannot consent to sexual activity that involves prostitution or pornography. Department of Justice, Canada11

754 l AUGUST JOGC AOÛT 2015

Adolescent Pregnancy Guidelines

APPENDIX B Risks

Interventions/solutions

Socioeconomic Financial/housing

Consult social work

Smoking

Smoking cessation program: Kick Butt for 2; harm reduction strategies

Substance use/alcohol

Addiction counselling

Violence

Screen for violence (see validated questionnaire)

Mood

Screen for depression, ± referral to psychiatry

Compliance with appointment

Adolescent-focused multidisciplinary care Provide assistance with transportation School curriculum, prenatal class

Maternal Anemia

Dietician, food donation, vitamins

Inadequate nutrition

Prenatal nutrition program, Buns in the Oven

STI

Screen/treat STI initial visit; each trimester, if symptomatic

Neonatal Prematurity

Accurate dating scan Screen/treat STI initial visit; each trimester, if symptomatic Frequent visits in 2nd and 3rd trimester Screen for substance use and violence in pregnancy

LBW, very LBW, IUGR, stillbirth

Frequent visits in 2nd and 3rd trimester 32 week ultrasound for growth Assessment of fetal well-being Nutritional assessment/

Postnatal Repeat pregnancy

Assess desire Contraception counselling during pregnancy Follow-up at 1 to 2 weeks and 6 weeks postpartum and beyond Provide free contraception (CCAP)

Breastfeeding

Lactation consultant (pre- and post pregnancy) Breastfeeding class

Postpartum depression

Assess risk in pregnancy, refer to psychiatry if necessary Follow-up at 2 and 6 weeks postpartum

CCAP: Comionate Contraceptive Assistance Program (available through Society of Obstetricians and Gynaecologists of Canada)

AUGUST JOGC AOÛT 2015 l 755

SOGC clinical practice guideline

APPENDIX C Screening questions relating to domestic violence 1.

Do you feel safe in your relationship with your partner or family? Code: Yes No Unsure/declined to answer

2.

Are there situations in the past 6 months when you have felt afraid of your partner or a family member? Code: Yes

by partner

by family member

No Unsure/declined to answer 3.

In the past 6 months, have you ever been a victim of domestic violence from your partner or a family member? Code: Yes

If yes, by

Family member

Yes/No

Partner, current

Yes/No

Partner, previous

Yes/No

Other

Yes/No

No Unsure/declined to answer 4.

In the past 6 months, have you ever been hit, kicked, punched, or physically hurt by a partner or family member? Code: Yes

If yes, by

Family member

Yes/No

Partner, current

Yes/No

Partner, previous

Yes/No

Other

Yes/No

No Unsure/declined to answer 5.

In the past 6 months, have you ever been forced to have sex or do sexual things that you did not want to do by a partner or family member? Code: Yes

If yes, by

Family member

Yes/No

Partner, current

Yes/No

Partner, previous

Yes/No

Other

Yes/No

No Unsecure/declined to answer Note: “Fig. 1. Screening questions on domestic violence and the coding of answers.” Journal of Pediatric and Adolescent Gynecology.60 Reproduced with permission of Elsevier Inc.

756 l AUGUST JOGC AOÛT 2015

SOGC CLINICAL PRACTICE GUIDELINE No. 322, April 2015

Endometrial Ablation in the Management of Abnormal Uterine Bleeding This clinical practice guideline has been reviewed by the Clinical Practice–Gynaecology Committee and approved by the Executive and Board of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Philippe Laberge, MD, Quebec QC Nicholas Leyland, MD, Ancaster ON Ally Murji, MD, Toronto ON Claude Fortin, MD, Montreal QC Paul Martyn, MD, Sydney, Australia George Vilos, MD, London ON CLINICAL PRACTICE–GYNAECOLOGY COMMITTEE Nicholas Leyland, MD (Co-chair), Hamilton ON Wendy Wolfman, MD (Co-chair), Toronto ON

Abstract Background: Abnormal uterine bleeding (AUB) is the direct cause of a significant health care burden for women, their families, and society as a whole. Up to 30% of women will seek medical assistance for the problem during their reproductive years. Objective: To provide current evidence-based guidelines on the techniques and technologies used in endometrial ablation (EA), a minimally invasive technique for the management of AUB of benign origin. Methods: of the guideline committee were selected on the basis of individual expertise to represent a range of practical and academic experience in of both location in Canada and type of practice, as well as subspecialty expertise and general background in gynaecology. The committee reviewed all available evidence in the English medical literature, including published guidelines, and evaluated surgical and patient outcomes for the various EA techniques. Recommendations were established by consensus.

Violaine Marcoux, MD, Montreal QC

Evidence: Published literature was retrieved through searches of MEDLINE and The Cochrane Library in 2013 and 2014 using appropriate controlled vocabulary and key words (endometrial ablation, hysteroscopy, menorrhagia, heavy menstrual bleeding, AUB, hysterectomy). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies written in English from January 2000 to November 2014. Searches were updated on a regular basis and incorporated in the guideline to December 2014.

Frank Potestio, MD, Thunder Bay ON



Catherine Allaire, MD, Vancouver BC Alaa Awadalla, MD, Winnipeg MB Sheila Dunn, MD, Toronto ON Mark Heywood, MD, Vancouver BC Madeleine Lemyre, MD, Quebec QC

David Rittenberg, MD, Halifax NS Sukhbir Singh, MD, Ottawa ON Grace Yeung, MD, London ON Disclosure statements have been received from all contributors. The literature searches and bibliographic for this guideline were undertaken by Becky Skidmore, Medical Research Analyst, Society of Obstetricians and Gynaecologists of Canada.

Keywords: Endometrial ablation, hysteroscopy, menorrhagia, heavy menstrual bleeding, abnormal uterine bleeding, hysterectomy.

Grey (unpublished) literature was identifies through searching the websites of health technology assessment and health technologyrelated agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies.

Values: The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). Results: This document reviews the evidence regarding the available techniques and technologies for EA, preoperative and postoperative care, operative set-up, anaesthesia, and practical considerations for practice.

J Obstet Gynaecol Can 2015;37(4):362–376

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

362 l APRIL JOGC AVRIL 2015

Endometrial Ablation in the Management of Abnormal Uterine Bleeding

Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

*The quality of evidence reported in here has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.51 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care.51

Benefits, harms, and costs: Implementation of the guideline recommendations will improve the provision of EA as an effective treatment of AUB. Following these recommendations would allow the surgical procedure to be performed safely and maximize success for patients. Conclusions: EA is a safe and effective minimally invasive option for the treatment of AUB of benign etiology. Summary Statements 1. Endometrial ablation is a safe and effective minimally invasive surgical procedure that has become a well-established alternative to medical treatment or hysterectomy to treat abnormal uterine bleeding in select cases. (I) 2. Endometrial preparation can be used to facilitate resectoscopic endometrial ablation (EA) and can be considered for some nonresectoscopic techniques. For resectoscopic EA, preoperative endometrial thinning results in higher short-term amenorrhea rates, decreased irrigant fluid absorption, and shorter operative time than no treatment. (I)

allow the use of local rather than general anaesthesia. However, both techniques have comparable patient satisfaction and reduction of heavy menstrual bleeding. (I) 4. Both resectoscopic and non-resectoscopic endometrial ablation (EA) have low complication rates. Uterine perforation, fluid overload, hematometra, and cervical lacerations are more common with resectoscopic EA; perioperative nausea/vomiting, uterine cramping, and pain are more common with nonresectoscopic EA. (I) 5. All non-resectoscopic endometrial ablation devices available in Canada have demonstrated effectiveness in decreasing menstrual flow and result in high patient satisfaction. The choice of which device to use depends primarily on surgical judgement and the availability of resources. (I) 6. The use of local anaesthetic and blocks, oral analgesia, and conscious sedation allows for the provision of non-resectoscopic EA in lower resource-intense environments including regulated non-hospital settings. (II-2)

3. Non-resectoscopic techniques are technically easier to perform than resectoscopic techniques, have shorter operative times, and

7. Low-risk patients with satisfactory pain tolerance are good candidates to undergo endometrial ablation in settings outside the operating room or in free-standing surgical centres. (II-2)

ABBREVIATIONS

8. Both resectoscopic and non-resectoscopic endometrial ablation are relatively safe procedures with low complication rates. The complications perforation with potential injury to contiguous structures, hemorrhage, and infection. (II-2)

AUB

abnormal uterine bleeding

CS

Caesarean section

D&C

dilatation and curettage

EA

endometrial ablation

FDA

United States Food and Drug istration

Recommendations

GnRH

gonadotropin releasing hormone

HSG

hysterosalpingogram

1. Preoperative assessment should be comprehensive to rule out any contraindication to endometrial ablation. (II-2A)

LNG-IUS levonorgestrel intrauterine system NSAIDS non-steroidal anti-inflammatories RCT

randomized control trial

9. Combined hysteroscopic sterilization and endometrial ablation can be safe and efficacious while favouring a minimally invasive approach. (II-2)

2. Patients should be counselled about the need for permanent contraception following endometrial ablation. (II-2B) 3. Recommended evaluations for abnormal uterine bleeding, including but not limited to endometrial sampling and an

APRIL JOGC AVRIL 2015 l 363

SOGC clinical practice guideline

assessment of the uterine cavity, are necessary components of the preoperative assessment. (II-2B) 4. Clinicians should be vigilant for complications unique to resectoscopic endometrial ablation such as those related to fluid distention media and electrosurgical injuries. (III-A) 5. For resectoscopic endometrial ablation, a strict protocol should be followed for fluid monitoring and management to minimize the risk of complications of distension medium overload. (III-A) 6. If uterine perforation is suspected to have occurred during cervical dilatation or with the resectoscope (without electrosurgery), the procedure should be abandoned and the patient should be closely monitored for signs of intraperitoneal hemorrhage or visceral injury. If the perforation occurs with electrosurgery or if the mechanism of perforation is uncertain, abdominal exploration is warranted to obtain hemostasis and rule out visceral injury. (III-B) 7. With resectoscopic endometrial ablation, if uterine perforation has been ruled out acute hemorrhage may be managed by using intrauterine Foley balloon tamponade, injecting intracervical vasopressors, or istering rectal misoprostol. (III-B) 8. If repeat endometrial ablation (EA) is considered following nonresectoscopic or resectoscopic EA, it should be performed by a hysteroscopic surgeon with direct visualization of the cavity. Patients should be counselled about the increased risk of complications with repeat EA. (II-2A) 9. If significant intracavitary pathology is present, resectoscopic endometrial ablation combined with hysteroscopic myomectomy or polypectomy should be considered in a non-fertility sparing setting. (II-3A)

INTRODUCTION

E

ndometrial ablation refers to a number of minimally invasive surgical procedures designed to treat AUB, which is defined as changes in frequency of menses, duration of flow, or amount of blood loss. EA consists of targeted destruction or removal of the endothelial surface of the uterine cavity in selected women who have no desire for future fertility. The procedure was designed to treat heavy menstrual bleeding refractory to medical therapy and not caused by structural uterine pathology. It is a less invasive alternative to hysterectomy. Although endometrial destruction through the endocervical canal dates back to 1937, this technique became more widely adopted in 1981 with laser EA, followed by rollerball and loop resection in the late 1980s. In the last 20 years, non-resectoscopic ablation techniques have become available. They use different energy sources to achieve endometrial destruction of the endometrium, including heated liquid (either free circulating or confined within a balloon), radiofrequency electricity, and tissue freezing. Currently, 6 of these systems are available in Canada. The use of microwave energy has been discontinued in Canada. According to the Association of Obstetricians and Gynecologists of Quebec, 3646 cases of EA were performed in Quebec in 2012, more than twice those

364 l APRIL JOGC AVRIL 2015

performed in 2000. EA is now more prevalent than vaginal hysterectomy in Quebec. However, the impact of EA on hysterectomy rates remains uncertain. American statistics from 6 states show EA being used as an “additive medical technology rather than a substitute” for hysterectomy.1 In the United Kingdom, there has been a significant reduction in hysterectomy rates over the past 20 years, explained in part by both improved medical treatment and increased use of EA techniques.2,3 EA improves treatment access for those women who have AUB and provides an alternative to major procedures such as hysterectomy. In the past 10 years alone there have been more than 600 publications on the subject of EA. This guideline reviews the indications and contraindications for performing EA (Table 2) and compares resectoscopic and nonresectoscopic techniques. The document also includes discussions of operative set-up, anaesthesia, preoperative and postoperative care, and some special considerations in clinical practice. A patient information sheet has been included to help patients better understand the benefits and limitations of this procedure (Appendix). COMPARISON OF EA TO OTHER THERAPIES EA Versus LNG-IUS

The LNG-IUS is a simple treatment option for women with AUB and is more cost-effective than any surgical technique, including EA. In one meta-analysis of 6 randomized trials, LNG-IUS and EA had similar patient efficacy up to 2 years after treatment.4 A Cochrane review concluded that EA and LNG-IUS had similar patient satisfaction, although EA was associated with a greater reduction in menstrual bleeding.5 During the first 6 months of use, the LNGIUS may be associated with a number of progestogenic side effects including but not limited to irregular bleeding, breast tenderness, and headache. CLINICAL TIP This option (LNG-IUS) should be discussed prior to any surgical option for women with AUB and a normal cavity.

EA Versus Hysterectomy

In a review of 9 prospective randomized clinical trials, hysterectomy was associated with improved control of pain and bleeding.6 In another study at 4 years’ follow-up 98% of women in the hysterectomy group versus 85% in the EA group were satisfied.7 However, hysterectomy was associated with a higher risk of adverse events, severe complications, and longer hospital stay. In a large retrospective study with 11 years’ follow-up, risk of surgery for subsequent pelvic floor repair and stress urinary incontinence associated with EA was lower than with hysterectomy.8 Although the direct

Endometrial Ablation in the Management of Abnormal Uterine Bleeding

costs of EA are about half that of hysterectomy, it seems that the costs of the 2 procedures become equivalent at 4 years because some women with EA will need additional treatment. Age < 40 years, prior tubal ligation, and preoperative dysmenorrhea are independent predictors of EA failure and subsequent re-intervention.9,10 Summary Statement

1. Endometrial ablation is a safe and effective minimally invasive surgical procedure that has become a well-established alternative to medical treatment or hysterectomy to treat abnormal uterine bleeding in select cases. (I) Recommendation

1. Preoperative assessment should be comprehensive to rule out any contraindication to endometrial ablation. (II-2A) PREOPERATIVE AND POSTOPERATIVE CARE Preoperative Care

The work-up of patients with AUB and the algorithm for decision-making have been previously described.11 Patients must not desire future fertility as serious maternal– fetal complications have been reported in pregnancies following EA (uterine rupture causing maternal death, limb defects, premature labour).12 Therefore, women must be counselled that EA is not considered a sterilization method. Women must also be appropriately counselled about realistic expectations of ablation outcomes. The goal of EA is to reduce bleeding symptoms; amenorrhea, although possible, cannot be guaranteed. Endometrial preparation can be considered preoperatively as a thin endometrium can improve visualization for the resectoscopic techniques and improve patient outcomes. A thin endometrium can be achieved by scheduling the procedure in the immediate post-menstrual phase, performing curettage prior to the procedure or istering of preoperative hormonal therapy. A systematic review suggested that preoperative endometrial thinning with GnRH agonists and danazol resulted in higher rates of amenorrhea at 12 and 24 months than placebo/no treatment.13 Whether or not this difference is maintained beyond 24 months is uncertain. GnRH agonists and danazol also had a beneficial effect on the intrauterine operating environment with respect to shorter operating time and reduced absorption of distention media. The disadvantages of these agents include the costs and side effects. Randomized data assessing the value of progestins in preoperative endometrial thinning prior to EA are scarce. In a study of resectoscopic EA,

Table 2. Indications and contraindications to EA Indications

• AUB of benign origin • EA may be considered as a primary intervention in circumstances such as intolerance to or failure of medical therapy, or patient preference • EA may be considered for patients who refuse or are poor surgical candidates for hysterectomy Absolute contraindications

• Pregnancy • Desire to preserve fertility • Known or suspected endometrial hyperplasia or cancer • Cervical cancer • Active pelvic infection • Specific contraindications related to non-resectoscopic techniques* *See “Special Considerations”

amenorrhea rates at 12-month follow-up were 39% for endometrial preparation with GnRH agonists compared with 34% for danazol, 26% for medroxyprogesterone acetate, and 18% for D&C.14 The use of endometrial preparation prior to non-resectoscopic EA will depend on the product monograph for each individual device. Meta-analysis of a few randomized trials on secondgeneration devices (radiofrequency ablation and balloon devices) suggest that preoperative endometrial thinning does not improve postoperative rates of amenorrhea.13 No RCTs have yet ed or refuted the role of antibiotic prophylaxis before EA by any technique.15 Postoperative Care

Patients can usually be discharged within 1 to 3 hours of EA depending on the type of anaesthesia used. They can resume their normal activities progressively, but are advised to abstain from sexual intercourse for one week. Pain can be managed with NSAIDS or opiates, and will usually resolve within 24 hours. Light vaginal bleeding or pinkish discharge is usual and can last up to several weeks following the procedure. Patients are counselled to seek medical care if they have fever, intense pain, or profuse vaginal bleeding. Summary Statement

2. Endometrial preparation can be used to facilitate resectoscopic endometrial ablation (EA) and can be considered for some non-resectoscopic techniques. For resectoscopic EA, preoperative endometrial thinning results in higher short-term amenorrhea rates, decreased irrigant fluid absorption, and shorter operative time than no treatment. (I) APRIL JOGC AVRIL 2015 l 365

SOGC clinical practice guideline

Recommendations

2. Patients should be counselled about the need for permanent contraception following endometrial ablation. (II-2B) 3. Recommended evaluations for abnormal uterine bleeding, including but not limited to endometrial sampling and an assessment of the uterine cavity, are necessary components of the preoperative assessment. (II-2B) CLINICAL TIP Required investigations prior to EA include: • pregnancy test, • Papanicolaou test within 2 years, • cervical cultures if clinically appropriate, • endometrial sampling, and • assessment of uterine cavity for Müllerian anomalies or intracavitary pathology using transvaginal ultrasound, contrast infusion sonography, or diagnostic hysteroscopy. (See also SOGC Clinical Practice Guideline No. 292, Abnormal Uterine Bleeding in Pre-Menopausal Women.11) Because it is often difficult to interpret residual menstrual discharge post procedure, the efficacy of the EA should be assessed no earlier than 6 to 12 weeks postoperatively.

COMPARISON OF RESECTOSCOPIC AND NON-RESECTOSCOPIC EA TECHNIQUES

The first-generation techniques introduced in the 1980s consisted of targeted endometrial destruction under direct hysteroscopic visualization. These techniques included laser ablation and electrosurgical endometrial resection or ablation. Despite their efficacy, the first-generation methods had certain disadvantages. They required a skilled hysteroscopic surgeon and an operating room environment. Their uncommon but serious complications of fluid overload and uterine perforation led to the advent of simpler, less -dependant alternatives. These second-generation techniques, also known as nonresectoscopic ablation, use a variety of energy sources to non-selectively destroy the endometrial lining. The advantage of these newer technologies is that they require shorter surgical time and less specialized training, and they can be performed in the outpatient setting. They also help to avert complications associated with the use of fluid distention media while achieving similar clinical outcomes.16 For these reasons non-resectoscopic procedures have become increasing popular.17 Resectoscopic EA

Resectoscopic endometrial resection/ablation is an attempt to destroy the basal endometrial layer to prevent 366 l APRIL JOGC AVRIL 2015

further endometrial proliferation. Operative hysteroscopy, first described by Neuwirth in 1976, involved resection of submucosal myomas using a modified urological resectoscope.18 Laser ablation was described by Goldrath in 1981,19 but lost favour due to its expense and unreliability. Loop electrode and rollerball ablation using bipolar or monopolar radiofrequency electrosurgery were subsequently described by DeCherney and Polan in 1983 and Lin et al. in 1988, as reported in a previous summary of ablation techniques.20 Patients are placed in ed lithotomy position and the cervix dilated to at least 10 mm. Most operative hysteroscopic systems employ a 9 mm (27 French) scope. Hysteroscopes are usually rigid, with operative hysteroscopy using 12, 15, or 30 degrees of angulation. After uterine distension is achieved, the cavity is inspected and endometrial lesions or abnormalities are mapped. Importantly, intrauterine landmarks (tubal ostia, internal cervical os, and/or the characteristic appearance of the endometrium) are identified to confirm that the cavity has been entered and ensure that the operator has not created a false age. Focal lesions are biopsied, resected, and sent separately to the pathology laboratory. The rollerball is used at the fundus and ostial regions with a touch technique applying no pressure. The treatment endpoint is a visual change in the endometrium to a yellowbrown honeycomb appearance indicating myometrial tissue has been reached. Tissue destruction to a depth of 4 to 6 mm will usually destroy the basal endometrial layer. The uterine walls can be ablated with the ball electrode or resected using the loop electrode, which also provides a specimen for histology. The electrode should always be visible, in with tissue, and moving toward the surgeon when activated. Prolonged activation of the electrode should be avoided to prevent capacitive coupling and other causes of electrosurgical injuries. The surgeon should avoid ablating beyond the cervico-uterine junction to avoid cervical stenosis. Endometrial polyps and small submucosal fibroids can be resected using the resectoscope, but larger (> 3 cm) myoma resection requires advanced operative hysteroscopy skills. Endometrial resection may result in more fluid absorption, which is associated with longer operating times.16 Use of a fluid management system is recommended. Bipolar resectoscopic systems require the use of normal saline as a distention medium, thereby eliminating concerns about hyponatremia; however, large quantities of normal saline can still result in fluid overload complications.

Endometrial Ablation in the Management of Abnormal Uterine Bleeding

Efficacy of Resectoscopic EA

Early studies reported high rates of improvement in heavy menstrual bleeding and high rates of patient satisfaction. O’Connor and Magos reported a 20% repeat surgery rate including a 9% hysterectomy rate over 5 years follow-up in a group of 525 patients undergoing endometrial resection.21 Martyn and Allan reported similar results with a repeat surgery rate of 19.2% including an 11.6% hysterectomy rate at 5 years of follow-up.22 The presence of fibroids and dysmenorrhea did not increase the risk of failure. A meta-analysis of 21 randomized trials comparing different resectoscopic techniques of endometrial destruction showed no difference in rates of amenorrhea and subsequent hysterectomy.16 First-generation techniques showed improvement in bleeding in 72.5% to 79.5% at 1-year follow-up and high patient satisfaction rates. Advantages and Disadvantages of Resectoscopic EA

Compared with the non-resectoscopic techniques, the resectoscopic EA offers certain advantages. It allows for accurate assessment of uterine pathology with directed biopsies, documentation with photography, and concurrent treatment of intracavitary pathology. It can also be used in patients who have had previous EA or transmyometrial surgery. However, resectoscopic EA is a skill-dependent procedure that requires an operative room environment and has a higher complication rate than non-resectoscopic methods. Distending Media for Resectoscopic EA

Distending media provide uterine distension and irrigate blood and tissue fragments from the surgical field. A nonelectrolyte solution is required for monopolar resectoscopic surgery, but normal saline can be used with bipolar systems. The following are common distending media: Conductive solutions (electrolytic/crystalloids) •• Normal saline (290 mOsm/L): isotonic/isonatremic Non-conductive (non-ionic, non-electolytic) •• mannitol (275 mOsm/L): isotonic/hyponatremic, induces diuresis •• glycine 1.5% (200 mOsm/L): hypotonic/hyponatremic; acidic with a pH of 6.1 •• sorbitol 3.3% (165 mOsm/L): hypotonic/ hyponatremic •• cystosol (mannitol 0.54% and sorbitol 2.7%): isotonic/hyponatremic Osmotically active particles must be added to hypotonic solutions to prevent complications from fluid absorption. Although absorption of isotonic fluids may also lower

serum sodium, it is less likely to cause cerebral edema than the absorption of hypotonic media. Fluid absorption increases significantly when intrauterine pressure exceeds mean arterial pressure. For every 100 mL of non-electrolyte solution absorbed, serum sodium falls by 1 meq. Electronic fluid management systems provide an accurate measurement of fluid deficits and can safeguard against complications of excess absorption. Excess absorption of isotonic solutions may be less dangerous than absorption of hypotonic solutions because there is a smaller chance of cerebral edema. Excessive fluid absorption may be prevented by pre-treatment of the endometrium,14 intracervical injection of pressor agents (vasopressin, epinephrine) and the use of distension pressure less than that of the patient’s mean arterial pressure. Electronic fluid monitoring systems, which allow regulation of the flow rate, infusion pressure, outflow suction, and fluid deficit may be more accurate in calculating fluid deficits than traditional gravity infusion systems and manual estimation of fluid deficit. Non-resectoscopic EA

Currently various energy sources are used in 6 nonresectoscopic EA devices approved by Health Canada: bipolar radiofrequency ablation(NovaSure), cryotherapy (Her Option),23 heated fluid freely circulated in the uterine cavity (Hydro ThermAblator), and fluid contained in a balloon (Thermachoice, Thermablate EAS, and Cavaterm). Specifications of each of these devices are compared in Table 3. Future technologies such as the Aurora ablation system (radiofrequency energy and heated Argon gas forming plasma energy) have promising preliminary results.24 In the absence of large differences in effectiveness and with low complication rates for each of the devices, the choice of which to use depends primarily on the following practical issues and patient factors: •• availability of scientific evidence •• cost effectiveness •• surgeon preference •• ease of use in outpatient/clinic setting •• requirement of endometrial preparation •• uterine cavity characteristics (size, cavitary pathology) CLINICAL TIP • For safety and appropriate intracavitary device placement, pre- and post -procedural diagnostic hysteroscopy or intraprocedural ultrasound guidance may be considered. • The balloon technologies involve coagulation of the endometrium that eventually leads to fibrosis. The maximum effect of this process is seen at 6 months post procedure rather than the 2 to 4 weeks seen with other technologies.

APRIL JOGC AVRIL 2015 l 367

Novasure

Her Option

HydroThermAblator

Mechanism of action

Device size (mm)

Treatment time (min)

Advantages

Disadvantages

Procedural points

Bipolar radiofrequency

7.2

1 to 2

Rapid treatment time

Cavity limitations (mostly suitable for normal cavities)

After cervical dilatation to Hegar 8 (25 fr), the device is inserted against the fundus then slightly retracted. It is deployed after proper seating. Pending a CO2 perforation detection check, negative pressure is applied and power is delivered until 50 Ohms of tissue impedance is reached. Blood/steam from the cavity is removed during the procedure.

Cryo-ablation at −90°C

Saline at 90°C circulated freely

No endometrial preparation required

5.5

7.8

10 to 18

3 to heat fluid, 10 to treat

High amenorrhea and satisfactioes

Cost of disposable equipment

Minimal anaesthesia

Long treatment time

Minimal or no cervical dilatation

Variability of outcome data23

Able to treat larger cavities

Requires ultrasound guidance and hormonal endometrial preparation

Direct visualization of treatment effect

Requires hormonal endometrial preparation

Able to treat irregular cavities (fibroids)

Safety: fluid leaks may cause burns

Short learning curve

Long treatment time

Short learning curve

Cramping from balloon distention

Seating the device requires practice

After cervical dilatation to Hegar 5–5½ (15 fr), a disposable 4.5mm cryoprobe is used to form an elliptical freezing zone starting at both cornua. Concurrent trans-abdominal ultrasound allows visualization of the freezing process. Frequently additional applications are necessary to treat the lower uterine body. After cervical dilatation, a disposable sheath that adapts to a 2.7–3.0 mm hysteroscope is inserted. The fluid is heated to target temperature for 3 min followed by a 10 min treatment time under direct visualization. Loss of more than 10 mL of fluid (through the cervix or the Fallopian tubes) will shut the system off automatically.

Hot liquid-filled silicone balloon devices Thermachoice III

5% dextrose at 87°C

5.5

8

Long-term safety and effectiveness data

Thermablate EAS

Glycerine at 173°C

6

Cavaterm

1.5% Glycine at 75°C to 80°C

8

2.2

10

Short learning curve

Long treatment time

The cervix is dilated, the cavity is measured, and the pear-shaped balloon catheter is inserted. Automated treatment maintains a pressure of 180 to 185 mmHg. Safety features monitor and prevent excess temperature and pressure. Endometrial preparation (hormonal/mechanical) is optional.

Rapid treatment time

RCT results not yet available

Fluid takes 8 min to heat prior to catheter insertion. During the treatment, the balloon undergoes serial of pressurizations (200 mmHg) and depressurizations. Fluid pressure is monitored by transducers that react to contractions or relaxations of the uterus. Endometrial preparation (hormonal/mechanical) is optional.

Simple to use

Cramping

Adjustable balloon length

Long treatment time

During the treatment, the fluid is maintained at approximately 200 mmHg. A safety mechanism will stop the procedure if it exceeds 250 mmHg. Endometrial preparation (hormonal/mechanical) is optional.

SOGC clinical practice guideline

368 l APRIL JOGC AVRIL 2015

Table 3. Comparison of non-resectoscopic endometrial ablation devices

Endometrial Ablation in the Management of Abnormal Uterine Bleeding

Comparing the Efficacy of Non-resectoscopic Devices

Patient satisfaction and re-intervention rates may be more clinically meaningful than absolute amenorrhea rates in comparing outcomes of procedures using nonresectoscopic devices. All of these devices work well and lead to high levels of patient satisfaction, as demonstrated by the FDA’s pivotal trials that showed satisfaction rates of 86% to 99% at 1 year.25 Direct comparisons of non-resectoscopic devices are scarce, and differences between trials with respect to outcome measures, preoperative endometrial preparation, practice settings, and follow-up times make it challenging to compare outcomes accurately. NovaSure radiofrequency ablation has been the most studied in randomized trials comparing it with Hydro ThermAblator and the hot liquid balloons Thermachoice and Cavaterm. NovaSure versus Hydro ThermAblator At 12 months’ follow-up, NovaSure had significantly higher rates of patient satisfaction (87% vs. 68%) and amenorrhea (47% vs 24%) than Hydro ThermAblator.26 This benefit persisted at 5 years, with NovaSure having significantly higher satisfaction rates (81% vs. 48%), higher amenorrhea rates (55% vs. 37%), and fewer surgical re-interventions (15% vs. 35%).27 NovaSure versus Thermachoice At the 5-year follow-up, both groups had similar improvements in health-related quality of life measures and no significant differences in amenorrhea rates (48% vs. 32%) and surgical re-interventions (10% vs. 13%).28 NovaSure versus Cavaterm In a small randomized trial of 57 patients at 1-year follow-up, there was no difference in patient satisfaction (92% vs. 83%) or re-intervention rates between groups. Amenorrhea rates, however, were significantly higher with NovaSure (42% vs. 12%).29 A network meta-analysis reported that bipolar radio frequency EA resulted in higher rates of amenorrhea than thermal balloon at 12 months.30 This has also been confirmed by other systematic reviews.31 However, there was no difference between techniques in patient satisfaction or number of women still experiencing heavy bleeding. EFFECTIVENESS OF RESECTOSCOPIC VERSUS NON-RESECTOSCOPIC TECHNIQUES

Primary outcome measures when evaluating EA procedures include rates of amenorrhea, patient satisfaction, and surgical re-intervention. A Cochrane Database review

compared resectoscopic and non-resectoscopic techniques and reported similar amenorrhea rates at 1 year (37% vs. 28%) and at 2 to 5 years (53% vs. 48%).16 Because women who suffer from menorraghia are likely to be satisfied with either hypomenorrhea or normal menses, satisfaction rates for both types of ablations are high.32 In the Cochrane meta-analysis, satisfaction rates were also comparable at 1 year (91% vs. 88%) and at 2 to 5 years (93% vs. 87%).16 In an updated analysis of 25 RCTs with over 4000 patients, the rates of amenorrhea and patient satisfaction were not significantly different, even up to 10 years after surgery.33 The surgical re-intervention rate (repeat ablation and/or hysterectomy) for AUB has been reported to be similar between techniques (21% vs. 25% at 2 to 5 years).16 However, analysis of studies with longer follow-up shows that non-resectoscopic EA has a lower re-intervention rate (RR 0.6, 95% CI 0.38 to 0.96) than resectoscopic EA.33 Although clinical outcomes between techniques were comparable, non-resectoscopic procedures required shorter surgical time, were more likely to be performed under local anaesthesia, and resulted in patients’ quicker return to normal activity.32,33 The overall perioperative complication rate was low with both techniques (< 2.5% each), but the non-resectoscopic procedures had a lower incidence of uterine perforation, fluid overload, hematometra and cervical laceration.32,33 These advantages were offset by increased nausea/vomiting and uterine cramping in the perioperative period.33 A higher incidence of equipment failure of second-generation devices was reported in earlier trials, but this is becoming less of a concern with updated models. Summary Statements

3. Non-resectoscopic techniques are technically easier to perform than resectoscopic techniques, have shorter operative times, and allow the use of local rather than general anaesthesia. However, both techniques have comparable patient satisfaction and reduction of heavy menstrual bleeding. (I) 4. Both resectoscopic and non-resectoscopic endometrial ablation (EA) have low complication rates. Uterine perforation, fluid overload, hematometra, and cervical lacerations are more common with resectoscopic EA; perioperative nausea/vomiting, uterine cramping, and pain are more common with non-resectoscopic EA. (I) 5. All non-resectoscopic endometrial ablation devices available in Canada have demonstrated effectiveness in decreasing menstrual flow and result in high patient satisfaction. The choice of which device to use depends primarily on surgical judgement and the availability of resources. (I) APRIL JOGC AVRIL 2015 l 369

SOGC clinical practice guideline

ANAESTHESIA AND OPERATIVE SET-UP

COMPLICATIONS OF ENDOMETRIAL ABLATION

Resectoscopic ablation is frequently performed under general or regional anaesthesia in the operating room. However, in the appropriate setting, it can also be safely and effectively performed using a local paracervical block with intravenous sedation.

The most common adverse events following EA are pelvic pain, cramping, and nausea/vomiting. These will generally resolve within 12 to 24 hours of the procedure. Other problems that can develop post-procedure are hematometrium, pyometrium, or endometritis. More severe complications are rare with both techniques of EA, but can include injury to contiguous pelvic structures such as pelvic blood vessels, the bowel, and urinary tract anatomic components. Procedural complications such as severe pain, bleeding, uterine perforation, and infection may require emergent surgical management.16

Local, regional, or general anaesthesia can be used for nonresectoscopic EA. A main advantage of non-resectoscopic proce­ dures is that they may be conducted under local anaesthesia in a lower resource-intense environment than the operating room. Performing such procedures in the operating room rather than through a hysteroscopic procedure in another setting adds significant instrumentation costs but no value to the patient. In addition to local anaesthesia by paracervical block, oral or intravenous conscious sedation may be used depending on patient pain tolerance and surgeon preference. NSAIDS can be istered preoperatively and are moderately effective in diminishing uterine contractions during and after the procedure.34 Procedure Room Versus Operating Room Setting

In the United States non-resectoscopic EA is frequently an office-based procedure, and provider payment processes promote these less resource-intense environments.35 Currently no mechanisms in the Canadian health care system compensate providers for non-resectoscopic EA in such a setting. EA performed in a hospital-based procedure room or a free-standing surgical centre rather than an operating room offers the advantages of a patient-centred environment, easier scheduling, and reduced costs per case. Appropriate low-risk patient selection and a satisfactory pain management strategy are critical in this environment. Procedure rooms must have appropriate emergency equipment available and all personnel must be trained in appropriate adverse event protocols. A systematic review comparing non-resectoscopic EA performed in the outpatient setting to resectoscopic EA in the operating room, showed varying amounts of costsavings.31 In the Canadian setting, an estimated savings of $562 per patient receiving EA has been attributed to the introduction of balloon devices in the outpatient setting.31 Summary Statements

6. The use of local anaesthetic and blocks, oral analgesia, and conscious sedation allows for the provision of non-resectoscopic EA in lower resource-intense environments including regulated non-hospital settings. (II-2) 7. Low-risk patients with satisfactory pain tolerance are good candidates to undergo endometrial ablation in settings outside the operating room or free-standing surgical centres. (II-2) 370 l APRIL JOGC AVRIL 2015

The FDA has a reporting system for non-resectoscopic ablation complications, and bowel injury is the most common complication reported to its Manufacturer and Facility Device (MAUDE) database.36 Other major complications reported more infrequently are urinary tract injuries, immediate hysterectomy, gas embolism, necrotizing fasciitis, and death. The incidence of such complications is unavailable from such databases as the denominator (total number of cases) is not known. However, the majority of these adverse events were associated with non-compliance with the manufacturers’ instructions for use. To mitigate the risk of injury with non-resectoscopic procedures, surgeons may consider post-dilatation hysteroscopy or concurrent ultrasound surveillance during the procedure. Serious Complications of EA

Uterine perforation has been reported in 0.3% of nonresectoscopic EA procedures and 1.3% of resectoscopic ablations or resections.16 If uterine perforation is suspected to have occurred during cervical dilatation or with the resectoscope (without electrosurgery), the procedure should be abandoned and the patient should be closely monitored for signs of intraperitoneal hemorrhage or visceral injury. If the perforation occurs while using electrosurgery or if the mechanism of perforation is uncertain, abdominal exploration is warranted to obtain hemostasis and rule out visceral injury. Perioperative hemorrhage has been reported in 1.2% of women undergoing non-resectoscopic ablation and 3.0% of those undergoing resectoscopic ablation.16 Hematometra have been reported in 0.9% of women undergoing non-resectoscopic ablation and in 2.4 of those undergoing in resectoscopic ablation.16 Although intrauterine scarring is an expected result of EA, hematometra will occur when areas of the endometrium are adherent and there is endometrial bleeding behind the occlusion. Hematometra and cervical stenosis may be

Endometrial Ablation in the Management of Abnormal Uterine Bleeding

managed by cervical dilation, hysteroscopic adhesiolysis and drainage, or hormonal endometrial suppression. For persistent pain despite minimally invasive treatment, hysterectomy may be indicated. Postablation tubal sterilization syndrome has been reported to occur at a rate as high as 10%.37 Some women who have undergone tubal ligation prior to EA experience cyclic or intermittent pelvic pain. The proposed etiology is bleeding from active endometrium trapped in the uterine cornua. This can be managed laparoscopically by excision of the tubal stumps or hysterectomy. Pelvic infections and fever occur in the immediate postoperative period in approximately 1% of women who have undergone EA.16 In a meta-analysis, the incidence of infectious complications included endometritis (1.4 to 2.0%), myometritis (0 to 0.9%), pelvic inflammatory disease (1.1%), and pelvic abscess (0 to 1.1%).16 Long-term recurrent AUB after EA may be caused by endometrial proliferation, adenomyosis, or (rarely) pre-malignant or malignant condition of the uterus. Investigation should include an endometrial biopsy if more than 1 year has ed since the procedure. Because dense intrauterine synechiae sometimes follow EA, endometrial biopsy, even D&C, may often be impossible.38 Transvaginal ultrasound can also be used to exclude abnormal proliferation of the endometrium. When adequate sampling of the endometrium cannot be obtained and AUB persists, with ultrasonic evidence of a thickened endometrium, hysterectomy is generally indicated for both curative and diagnostic purposes.38 CLINICAL TIP • For resectoscopic EA, if uterine perforation has been ruled out, acute hemorrhage may be managed with intrauterine Foley balloon tamponade, intracervical vasopressors injection, or rectal misoprostol istration. • Hematometra should be suspected in a patient with a history of an EA who presents with amenorrhea and cyclic pain, even remote from the procedure.39 This can be diagnosed by transvaginal ultrasound and prevented by ensuring complete ablation of the uterine fundus, cornua, and tubal ostia while avoiding ablation of the cervix or cervico-uterine junction. • Tips for istering paracervical block : 40

–– Infiltration of the cervix carries the risks of intravascular injection and toxicity of the local anaesthetic. These risks can be minimized by infiltrating slowly, using lower concentrations of local anaesthetic, frequently aspirating, and monitoring for symptoms of intravasation (tinnitus, blurring of vision, peri-oral/facial numbness). If the local anaesthetic contains epinephrine, patients may experience palpitations, tachycardia, or feelings of anxiety. Basic resuscitative equipment should be available. –– Allow the block to take effect by waiting 10 to 15 minutes prior to proceeding with cervical dilatation.

Complications Specific to Resectoscopic EA

Resectoscopic EA has potential complications specific to this surgical modality. Careful fluid management is critical to the safe use of hysteroscopic EA. In addition, surgeons must possess a comprehensive understanding of potential electrosurgical injuries during hysteroscopic EA. Safe hysteroscopic surgery requires careful fluid management to avoid excessive intravasation of hysteroscopic distension media. Adherence to a strict protocol of fluid monitoring and management criteria will minimize the risk of complications of distension medium overload such as cardiovascular compromise and pulmonary edema, electrolyte abnormalities, and encephalopathy. Table 4 provides an approach to prudent management of hysteroscopic distention fluid issues. Electrosurgical injuries with monopolar operative hysteroscopy can occur due to capacitive coupling and defective insulation and result in cervical, vaginal, or perineal burns. There is an increased risk of this occurring when the tip of the resectoscope is in the cervical canal, when the cervix is over-dilated, or when there are electrode insulation defects. There is a greater degree of capacitive coupling injury with higher voltage outputs, which may occur with use of coagulation mode, long uninterrupted periods of electrode activation, and non with tissue.41 Risks of capacitive coupling can be reduced by preventing cervical over-dilatation, using the lower voltage “cut” current, avoiding prolonged and uninterrupted activation, checking for insulation defects, ensuring with tissue during activation, and using a weighted speculum during the procedure to disperse any stray currents. Summary Statement

8. Both resectoscopic and non-resectoscopic endometrial ablation are relatively safe procedures with low complication rates. The complications perforation with potential injury to contiguous structures, hemorrhage, and infection. (II-2) Recommendations

4. Clinicians should be vigilant for complications unique to resectoscopic endometrial ablation such as those related to fluid distention media and electrosurgical injuries. (III-A) 5. For resectoscopic endometrial ablation, a strict protocol should be followed for fluid monitoring and management to minimize the risk of complications of distension medium overload. (III-A) 6. If uterine perforation is suspected to have occurred during cervical dilatation or with the resectoscope APRIL JOGC AVRIL 2015 l 371

SOGC clinical practice guideline

Table 4. Management of hysteroscopic distention fluid losses Measurement of Intake and Output (I&O) During Hysteroscopy a. I&O should be measured accurately, ideally by an electronic fluid management system, for all operative hysteroscopy procedures. b. I&O values for all distention media should be monitored and fluid deficits reported to the surgeon and anaesthesiologist. c. The circulating nurse should seek assistance, and additional staff if required, to monitor fluid I&O. d. Final I&O values or fluid deficit should be recorded on the operative record. e. Final I&O values should be reported to the surgeon and anaesthesiologist at the end of the procedure. Excess Fluid Deficit for Non-conductive Solutions At a fluid deficit of 500 cc:

• Ensure anaesthesiologist and surgeon are aware of the deficit in return of uterine distension fluid. At a fluid deficit of 1000 cc:

• The procedure should be completed as expeditiously as possible. • Consider placing Foley catheter in bladder for accurate monitoring of urine output. • Consider fluid restriction and IV to keep vein open. • Consider IV diuretic ( e.g. furosemide) istration. At a fluid deficit of 1500 cc:

• The procedure should be discontinued immediately. • Serum electrolyte values should be obtained and abnormalities managed appropriately. • Observe patient for signs of fluid overload and encephalopathym, changes in level of consciousness, seizure activity, pulmonary edema, and tachypnea. • it patient for observation and management of complications. • If normal saline is used as the distending medium, consider completing and terminating the procedure at volumes of 2000 cc and 2500 cc, respectively.

(without electrosurgery), the procedure should be abandoned and the patient should be closely monitored for signs of intraperitoneal hemorrhage or visceral injury. If the perforation occurs with electrosurgery or if the mechanism of perforation is uncertain, abdominal exploration is warranted to obtain hemostasis and rule out visceral injury. (III-B) 7. With resectoscopic endometrial ablation, if uterine perforation has been ruled out acute hemorrhage may be managed by using intrauterine Foley balloon tamponade, injecting intracervical vasopressors, or istering rectal misoprostol. (III-B) SPECIAL CONSIDERATIONS Repeat Ablation

Irrespective of technique, EA has a success rate of 73% to 85%. Therefore, EA failures raise the issue of repeat ablation or hysterectomy. The decision for repeat ablation versus another approach will depend on the surgeon’s skill and the patient’s consent, appropriately informed about possible complications. If the initial EA was deemed a failure because it did not reduce menstrual flow and if the symptoms are highly suggestive of adenomyosis, definitive management should be considered. 372 l APRIL JOGC AVRIL 2015

If repeat EA is considered, a hysteroscopic approach using the resectoscope is recommended. With the possible exception of the HydroThermAblator,40 a nonresectoscopic blind procedure is generally contraindicated in this clinical scenario, as is a global EA technique under hysteroscopic visualization. Complication rates of repeat EA are statistically higher than primary procedures. The risks of perforation, higher fluid absorption, and bleeding have been reported to be in the order of 9.3% to 11% compared with 2.05% for primary ablation.42 Repeat ablation should therefore be performed by skilled surgeons with experience in hysteroscopic surgery. When repeat procedures are performed in patients with the appropriate indications, success rates of avoiding hysterectomy have been reported to be about 55% to 60%.43 Concomitant Hysteroscopic (Essure) Tubal Sterilization

Hysteroscopic sterilization has rapidly replaced laparoscopic sterilization in the United States but has not yet been widely accepted in Canada. Essure is highly successful, with a reported 5-year effectiveness of 99.8% and most failures related to deviations from protocol.44 Over the last few years there have been multiple reports on the concomitant use of Essure and different ablation techniques, most

Endometrial Ablation in the Management of Abnormal Uterine Bleeding

often non-resectoscopic procedures such as NovaSure, Thermachoice, Thermablate, HydroThermAblator.45 In most cases, both procedures were reported to be successful for the ablation and placement of the implants at rate of 83% to 89%. The NovaSure requires placement of implants after the procedure, while balloon thermal transfer and circulating saline could be performed before or after hysteroscopic tubal sterilization. Problems with combined Essure placement arise from the FDA’s mandatory requirement of confirming postoperative tubal occlusion by HSG at 3 months. Obliteration of the uterine cavity following EA may make confirmation of tubal occlusions by HSG difficult. However, in other countries including Canada, HSG is not mandatory following hysteroscopic sterilization and many articles advocate using three-dimensional US and X-ray to confirm bilateral placement and the non-migration of the tubal inserts.46 Previous Caesarean Section

The literature regarding EA in patients with previous CS consists primarily of small retrospective cohorts studies. For resectoscopic EA, there are generally no restrictions following previous CS. However, caution should be exercised over the CS scar as myometrial thinning may predispose it to perforation or thermal injury. For a patient with previous transmural myomectomy, obtaining adequate visualization of the cavity using a pressure pump should allow for safe treatment. For the available non-resectoscopic technologies, no restriction on the minimum myometrial thickness has been mentioned. However, caution is recommended with patients who have had more than 2 CS. Non-resectoscopic EA is contraindicated in patients with previous classical Caesarean section or transmural myomectomies. Fiveyear data on satisfaction, treatment failure, and operative complications of non-resectoscopic EA in patients with previous CS are similar to those in patients without previous CS.47 Intracavitary Pathology and Non-Resectoscopic EA

Intracavitary fibroids and polyps were excluded from the original randomized controlled trials evaluating non-resectoscopic EA techniques. These procedures were originally designed to treat normal uterine cavities. Subsequently, various attempts have been made to examine the utility of these technologies in distorted cavities with submucosal fibroids. The HydroThermAblator, which relies on freely circulating heated fluid under direct visualization, may be suited to treat distorted cavities as it does not rely on the fixed shape of a mesh or balloon. A prospective study of patients with type 0 or type 1 submucosal fibroids

< 4 cm reported an amenorrhea rate of 39% with the HydroThermAblator treatment. However, amenorrhea rates were significantly higher for patients with normal cavities (62% at 30 months’ follow-up).48 Rates of re-intervention were also significantly higher in patients with distorted cavities.48 Women with types 1 and 2 submucosal fibroids < 3 cm who were followed prospectively following treatment with NovaSure had amenorrhea rates of 69% at 1 year.49 Thermachoice also demonstrated a decrease in menstrual flow in 4 women with submucosal myomas < 3 cm.50 Despite encouraging results showing that nonresectoscopic EA may be beneficial in treating AUB in women with small (< 3 cm) submucosal fibroids, further research is still required. Where possible, hysteroscopic myomectomy/polypectomy combined with resectoscopic EA should be used to treat women with symptomatic intracavitary pathology. Summary Statement

9. Combined hysteroscopic sterilization and endometrial ablation can be safe and efficacious while favouring a minimally invasive approach. (II-2) Recommendations

8. If repeat endometrial ablation (EA) is considered following non-resectoscopic or resectoscopic EA, it should be performed by a hysteroscopic surgeon with direct visualization of the cavity. Patients should be counselled about the increased risk of complications with repeat EA. (II-2A) 9. If significant intracavitary pathology is present, resectoscopic endometrial ablation combined with hysteroscopic myomectomy or polypectomy should be considered in a non-fertility sparing setting. (II-3A) REFERENCES 1. Farquhar CM, Naoom S, Steiner CA. The impact of endometrial ablation on hysterectomy rates in women with benign uterine conditions in the United States. Int J Technol Assess Health Care 2002;18:625–34. 2. Reid PC. Endometrial ablation in England—coming of age? An examination of hospital episode statistics 1989/1990 to 2004/2005. Eur J Obstet Gynecol Reprod Biol 2007;135:191–4. 3. Cooper K, Lee A, Chien P, Raja E, Timmaraju V, Bhattacharya S. Outcomes following hysterectomy or endometrial ablation for heavy menstrual bleeding: retrospective analysis of hospital episode statistics in Scotland. BJOG. 2011;118(10):1171–9. 4. Kaunitz AM, Meredith S, Inki P, Kubba A, Sanchez-Ramos L. Levonorgestrel-releasing intrauterine system and endometrial ablation in heavy menstrual bleeding: a systematic review and meta-analysis. Obstet Gynecol 2009;113:1104–16. 5. Lethaby AE, Cooke I, Rees M. Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding. Cochrane Database Syst Rev 2005;(4):CD002126.

APRIL JOGC AVRIL 2015 l 373

SOGC clinical practice guideline

6. Matteson KA, Abed H, Wheeler TL, Sung VW, Rahn DD, Schaffer JI, et al. A systematic review comparing hysterectomy with less-invasive treatments for abnormal uterine bleeding. J Minim Invasive Gynecol 2012;19:13–28.

25. Sharp HT. Assessment of new technology in the treatment of idiopathic menorrhagia and uterine leiomyomata. Obstet Gynecol 2006;108:990–1003.

7. Munro MG, Dickersin K, Clark MA, Langenberg P, Scherer RW, Frick KD, et al. The Surgical Treatments Outcomes Project for Dysfunctional Uterine Bleeding: summary of an Agency for Health Research and Qualitysponsored randomized trial of endometrial ablation versus hysterectomy for women with heavy menstrual bleeding. Menopause 2011;18:445–52.

26. Penninx JPM, Mol BW, Engels R, van Rumste MME, Kleijn C, Koks CAM, et al. Bipolar radiofrequency endometrial ablation compared with hydrothermablation for dysfunctional uterine bleeding: a randomized controlled trial. Obstet Gynecol 2010;116:819–26.

8. Bhattacharya S, Middleton LJ, Tsourapas A, Lee AJ, Champaneria R, Daniels JP, et al. Hysterectomy, endometrial ablation and Mirena® for heavy menstrual bleeding: a systematic review of clinical effectiveness and costeffectiveness analysis. Health Technol Assess. 2011;15(19):iii–xvi–1–252. 9. Longinotti MK, Jacobson GF, Hung Y-Y, Learman LA. Probability of hysterectomy after endometrial ablation. Obstet Gynecol 2008;112:1214–20. 10. El-Nashar SA, Hopkins MR, Creedon DJ, St Sauver JL, Weaver AL, McGree ME, et al. Prediction of treatment outcomes after global endometrial ablation. Obstet Gynecol 2009;113:97–106. 11. Singh S, Best C, Dunn S, Leyland N, Wolfman WL; SOGC Clinical Practice–Gynaecology Committee. Abnormal uterine bleeding in pre-menopausal women. SOGC Clinical Practice Guideline, No. 292, May 2013. J Obstet Gynaecol Can 2013;35:473–9. 12. Laberge PY. Serious and deadly complications from pregnancy after endometrial ablation: two case reports and review of the literature. J Gynecol Obstet Biol Reprod (Paris) 2008;37:609–13. 13. Tan YH, Lethaby A. Pre-operative endometrial thinning agents before endometrial destruction for heavy menstrual bleeding. Cochrane Database Syst Rev 2013;11:CD010241. 14. Shawki O, Peters A, Abraham-Hebert S. Hysteroscopic endometrial destruction, optimum method for preoperative endometrial preparation: a prospective, randomized, multicenter evaluation. JSLS 2002;6:23–7. 15. Thinkhamrop J, Laopaiboon M, Lumbiganon P. Prophylactic antibiotics for transcervical intrauterine procedures. Cochrane Database Syst Rev 2007;(3):CD005637. 16. Lethaby A, Hickey M, Garry R, Penninx J. Endometrial resection/ ablation techniques for heavy menstrual bleeding. Cochrane Database Syst Rev 2009;(4):CD001501. 17. Deb S, Flora K, Atiomo W. A survey of preferences and practices of endometrial ablation/resection for menorrhagia in the United Kingdom. Fertil Steril 2008;90:1812–7. 18. Neuwirth RS, Amin HK. Excision of submucus fibroids with hysteroscopic control. Am J Obstetr Gynecol 1976;126:95–9. 19. Goldrath MH, Fuller TA, Segal S. Laser photovaporization of endometrium for the treatment of menorrhagia. Am J Obstet Gynecol 1981;140:14–9. 20. Vilos GA. Hysteroscopic and nonhysteroscopic endometrial ablation. Obstet Gynecol Clin North Am 2004;31:687–704, xi. 21. O’Connor H, Magos A. Endometrial resection for the treatment of menorrhagia. N Engl J Med 1996;335:151–6. 22. Martyn P, Allan B. Long-term follow-up of endometrial ablation. J Am Assoc Gynecol Laparosc 1998;5:115–8. 23. Townsend DE, Duleba AJ, Wilkes MM. Durability of treatment effects after endometrial cryoablation versus rollerball electroablation for abnormal uterine bleeding: two-year results of a multicenter randomized trial. Am J Obstet Gynecol 2003;188:699–701. 24. Sabbah R, Laberge P, Fortin C, Thiel J, Garza-Leal J, Fullop T, et al. A multi-center, single-arm, international clinical study of the safety and efficacy of the AURORA endometrial ablation system. Preliminary clinical results. J Minim Invasive Gynecol 2011;18:S82.

374 l APRIL JOGC AVRIL 2015

27. Penninx JPM, Herman MC, Mol BW, Bongers MY. Five-year follow-up after comparing bipolar endometrial ablation with hydrothermablation for menorrhagia. Obstet Gynecol 2011;118:1287–92. 28. Kleijn JH, Engels R, Bourdrez P, Mol BWJ, Bongers MY. Five-year follow up of a randomised controlled trial comparing NovaSure and ThermaChoice endometrial ablation. BJOG. 2008;115:193–8. 29. Abbott J, Hawe J, Hunter D, Garry R. A double-blind randomized trial comparing the Cavaterm and the NovaSure endometrial ablation systems for the treatment of dysfunctional uterine bleeding. Fertil Steril 2003;80:203–8. 30. Daniels JP, Middleton LJ, Champaneria R, Khan KS, Cooper K, Mol BWJ, et al. Second generation endometrial ablation techniques for heavy menstrual bleeding: network meta-analysis. BMJ 2012;344:e2564. 31. Kroft J, Liu G. First- versus second-generation endometrial ablation devices for treatment of menorrhagia: a systematic review, metaanalysis and appraisal of economic evaluations. J Obstet Gynaecol Can. 2013;35:1010–9. 32. Middleton LJ, Champaneria R, Daniels JP, Bhattacharya S, Cooper KG, Hilken NH, et al. Hysterectomy, endometrial destruction, and levonorgestrel releasing intrauterine system (Mirena) for heavy menstrual bleeding: systematic review and meta-analysis of data from individual patients. BMJ 2010;341:c3929. 33. Lethaby A, Penninx J, Hickey M, Garry R, Marjoribanks J. Endometrial resection and ablation techniques for heavy menstrual bleeding. Cochrane Database Syst Rev. 2013;8:CD001501. 34. Ahmad G, O’Flynn H, Attarbashi S, Duffy JM, Watson A. Pain relief for outpatient hysteroscopy. Cochrane Database Syst Rev. 2010;(11):CD007710. 35. Glasser MH. Practical tips for office hysteroscopy and second-generation “global” endometrial ablation. J Minim Invasive Gynecol 2009;16:384–99. 36. Gardner S, Schultz DG. Complications associated with global endometrial ablation: the utility of the MAUDE database. Obstet Gynecol 2004;103(5 Pt 1):995–6. 37. McCausland A, McCausland V. Frequency of symptomatic cornual hematometra and postablation tubal sterilization syndrome after total rollerball endometrial ablation: a 10-year follow-up. Am J Obstet Gynecol 2002;186:1274–80; discussion 1280–3. 38. Gadzinski JA, Sheran J, Garbe G, Fitzgerald G, Mueller E, Wagner S. Obstet Gynecol 2014;123(Suppl 1):124S. doi: 10.1097/01. AOG.0000447083.64986.03. 39. McCausland A, McCausland V. Long-term complications of endometrial ablation: cause, diagnosis, treatment, and prevention. J Minim Invasive Gynecol 2007;14:399–406. 40. Glasser MH, Heinlein PK, Hung Y-Y. Office endometrial ablation with local anaesthesia using the HydroThermAblator system: comparison of outcomes in patients with submucous myomas with those with normal cavities in 246 cases performed over 5(1/2) years. J Minim Invasive Gynecol 2009;16:700–7. 41. Munro MG. Mechanisms of thermal injury to the lower genital tract with radiofrequency resectoscopic surgery. J Minim Invasive Gynecol 2006;13:36–42. 42. MacLean-Fraser E, Penava D, Vilos GA. Perioperative complication rates of primary and repeat hysteroscopic endometrial ablations. J Am Assoc Gynecol Laparosc 2002;9:175–7.

Endometrial Ablation in the Management of Abnormal Uterine Bleeding

43. Hansen BB, Dreisler E, Stampe Sørensen S. Outcome of repeated hysteroscopic resection of the endometrium. J Minim Invasive Gynecol 2008;15:704–6. 44. Connor VF. Essure: a review six years later. J Minim Invasive Gynecol 2009;16:282–90.

48. Glasser MH, Heinlein PK, Hung Y-Y. Office endometrial ablation with local anaesthesia using the HydroThermAblator system: comparison of outcomes in patients with submucous myomas with those with normal cavities in 246 cases performed over 5(1/2) years. J Minim Invasive Gynecol 2009;16:700–7.

45. Donnadieu AC, Deffieux X, Gervaise A, Faivre E, Frydman R, Fernandez H. Essure sterilization associated with endometrial ablation. Int J Gynaecol Obstet 2007;97:139–42.

49. Sabbah R, Desaulniers G. Use of the NovaSure impedance controlled endometrial ablation system in patients with intracavitary disease: 12-month follow-up results of a prospective, single-arm clinical study. J Minim Invasive Gynecol 2006;13:467–71.

46. Mircea CN, Goojha C, Thiel JA. Concomitant NovaSure endometrial ablation and Essure tubal sterilization: a review of 100 cases. J Obstet Gynaecol Can 2011;33:361–6.

50. Soysal ME, Soysal SK, Vicdan K. Thermal balloon ablation in myoma-induced menorrhagia under local anaesthesia. Gynecol Obstet Invest 2001;51:128–33.

47. Khan Z, El-Nashar SA, Hopkins MR, Famuyide AO. Efficacy and safety of global endometrial ablation after cesarean delivery: a cohort study. Am J Obstet Gynecol2011;205:450.e1–4.

51. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

Appendix begins on next page

APRIL JOGC AVRIL 2015 l 375

SOGC clinical practice guideline

APPENDIX ENDOMETRIAL ABLATION PATIENT INFORMATION SHEET Endometrial ablation is an alternative surgical procedure for heavy menstrual bleeding. It attempts to destroy or remove the endometrium—the lining of your uterus. This can replace hysterectomy in many cases. This is a day surgery procedure. The technique varies depending on the method used to destroy the endometrium. Most EA procedures can be done in an outpatient surgical centre while others must be performed in an operating room. Factors such as the size of your uterus, presence of fibroid tumours, and experience of the surgeon will help determine which endometrial ablation method is best for you. While medications are typically recommended as first line treatment for heavy menstrual bleeding, endometrial ablation may be an option if medications don’t help or you decline to try them. Endometrial ablation is not recommended for women who:

Endometrial ablation risks may include:

• wish to become pregnant in the future,

• perforation of the uterine wall,

• have cancer of the uterus,

• damage to nearby organs, and/or

• have large fibroid tumours in the uterus, and/or

• pain, bleeding, or infection.

• have had recent pelvic infection. Future pregnancy Many women stop having periods after endometrial ablation, but pregnancy is still possible in some women. Most of these pregnancies will have an abnormal outcome. Women who wish to become pregnant in the future should not consider endometrial ablation. Some women may choose to undergo a sterilization procedure at the time of endometrial ablation or consider other forms of reliable contraception to prevent pregnancy. Concomitant laparoscopic tubal ligation would usually require general anaesthetic. Preparation for surgery

• Check for abnormal endometrial cells. Your doctor may take a small sample of the lining of your uterus using a small endometrial biopsy instrument. This is done in the office before surgery. • Thin your endometrium. Endometrial ablation is often performed more successfully when the uterine lining is thin. This can be accomplished with preoperative medications or by undergoing a D and C (dilation and curettage) on the day of surgery. • Discuss method of anaesthesia. Most procedures can be performed with conscious sedation and local anaesthetic block. In some instances general anaesthesia is required. The procedure Endometrial ablation can be performed in your doctor’s office, but some types of endometrial ablation are performed in a hospital operating room, especially if you will need general anaesthesia. The cervix is dilated to allow for the age of the instruments used in endometrial ablation. Endometrial ablation procedures vary by the method used to destroy your endometrium.

• Electrosurgery. This method uses a small hysteroscope to view the uterine cavity during the procedure. An electrode is used to resect or destroy the lining of the uterus. • Free-flowing hot fluid. Saline fluid heated to 80°C to 90°C is circulated within the uterus for about 10 minutes. • Heated balloon. A balloon device is inserted through your cervix and then inflated with fluid heated to 87°C for about 2 to 10 minutes. • Bipolar radiofrequency. This uses a bipolar wire mesh electrode that s the uterine cavity. The instrument transmits high frequency electrical energy that vaporizes the endometrial tissue in about 90 seconds. After the procedure After endometrial ablation, you may experience:

• Cramps. You may have menstrual-like cramps for a few days. • Vaginal discharge. A watery discharge, mixed with blood, may occur for a few weeks. The discharge is typically heaviest for the first few days after the procedure. • Frequent urination. You may need to urine more often during the first 24 hours after endometrial ablation. Avoid intercourse for one week after surgery. All endometrial ablation techniques show similar improvement in bleeding pattern. It may take a few months to see the final results of surgery, but endometrial ablation causes marked reduction in menstrual blood loss in over 80% of patients. Most women will have lighter periods or spotting, and some will stop having periods entirely. You should continue to use contraception.

376 l APRIL JOGC AVRIL 2015

SOGC CLINICAL PRACTICE GUIDELINE No. 296, September 2013 (Reviewed March 2015)

Induction of Labour: Review This clinical practice guideline review has been prepared by Clinical Practice Obstetrics Committee and approved by the Executive and Board of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Dean Leduc, MD, Ottawa ON Anne Biringer, MD, Toronto ON Lily Lee, RN, MSN, Vancouver BC Jessica Dy, MD, Ottawa ON CLINICAL PRACTICE OBSTETRICS COMMITTEE Hussam Azzam (Chair), MD, Thompson MB Jon Barrett, MD, Toronto ON Anne Biringer, MD, Toronto ON Kim Campbell, RM, Vancouver BC Louise Duperron, MD, Montreal QC Jessica Dy, MD, Ottawa ON Ellen Giesbrecht, MD, Vancouver BC Lisa Graves, MD, Hamilton ON Michael Helewa, MD, Winnipeg MB Ian Lange, MD, Calgary AB Lily Lee, RN, MSN, Vancouver BC Suzanne Muise, MD, Camana Bay, Grand Cayman Barbara Parish, MD, Halifax NS Disclosure statements have been received from all contributors.

J Obstet Gynaecol Can 2015;37(4):380–381

T

he issue of induction of labour and risk of Caesarean section has been a topic of recent discussion, catalyzed by the publication of a new review paper in the Canadian Medical Association Journal.1 In response to an influx of queries regarding the CMAJ paper and its potential effect on SOG guidelines, the Clinical Practice Obstetrics Committee has reviewed the SOGC Induction of Labour guidelines published in 20132 and concluded that no update or revision to the SOGC is required at this time. The committee emphasized that the CMAJ meta-analysis included no new information or studies that were not used in the 2013 SOGC guideline. It is also important to note that results from the CMAJ review paper report on an induction group encoming all indications for induction of labour, with term labour defined as 37 to 42 weeks’ gestation and measured outcomes limited to Caesarean section. The SOGC guideline recommends requiring an obstetrical or medical indication (e.g. premature rupture of membranes, hypertension, intrauterine growth restriction) for induction of labour before 41 weeks. This is consistent with guidelines published by the Royal College of Obstetricians and Gynaecologists and the American Congress of Obstetricians and Gynecologists. The data does confirm that induction of labour for specific indications is not associated with higher risk of Caesarean section and in some indications, such as post-term induction, it lowers the risk of Caesarean section. It is important to note that these study findings should not be generalized to any and all inductions of labour, especially when no indications exist; SOGC stands by its recommendation that induction of labour should be carried out only after careful discussion with women who have specific indications. The SOGC is aware of two clinical trials underway that are examining induction of labour versus expectant management.3,4 The outcomes of these studies will be

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

380 l APRIL JOGC AVRIL 2015

Induction of Labour: Review

monitored by the Clinical Practice Obstetrics Committee for potential change of practice implications. It is to be noted that, to ensure the best quality of care, the SOGC is currently developing a standard of practice under which evidence will be reviewed on a regular basis to decide whether all or part of a guideline should be updated based on new robust (Canadian Task Force on Preventive Health Care5 level I) evidence.

2. Leduc D, Biringer A, Lee L, Dy J; Clinical Practice Obstetrics Committee, Society of Obsetricians and Gynaecologists of Canada. Induction of labour. SOGC Clinical Practice Guideline No. 296, September 2013. J Obstet Gynaecol Can 2013;36:248–52. 3. Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). A Randomized Trial of Induction Versus Expectant Management (ARRIVE). Bethesda, MD: US National Institute of Health; 2014. Available at: http://clinicaltrials.gov/ct2/show/ NCT01990612?term=ARRIVE&rank=2. Accessed on December 10, 2014.

REFERENCES

4. Nottingham Clinical Trials Unit. Induction of labour versus expectant management for women over 35 years of age. Nothingham, GB: NCTU; 2013. Available at: http://www.35-39trial.org. Accessed on December 10, 2014.

1. Mishanina E, Rogozinska E, Thatthi T, Uddin-Khan R, Khan KS, et al. Use of labour induction and risk of cesarean delivery: a systematic review and meta-analysis. CMAJ 2014;186:665–73.

5. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W; Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

APRIL JOGC AVRIL 2015 l 381

SOGC CLINICAL PRACTICE GUIDELINE No. 321, March 2015

The Management of Uterine Fibroids in Women With Otherwise Unexplained Infertility This clinical practice guideline was prepared by the Reproductive Endocrinology and Infertility Committee, reviewed by Family Physician Advisory and Clinical Practice Gynaecology Committees, and approved by the Executive and Board of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Belina Carranza-Mamane, MD, Sherbrooke QC Jon Havelock, MD, Vancouver BC Robert Hemmings, MD, Montreal QC REPRODUCTIVE ENDOCRINOLOGY AND INFERTILITY COMMITTEE Anthony Cheung (Co-chair), MD, Vancouver BC Sony Sierra (Co-chair), MD, Toronto ON Belina Carranza-Mamane, MD, Sherbrooke QC Allison Case, MD, Saskatoon SK Cathie Dwyer, RN, Toronto ON James Graham, MD, Calgary AB Jon Havelock, MD, Vancouver BC Robert Hemmings, MD, Montreal QC Kimberly Liu, MD, Toronto ON Ward Murdock, MD, Fredericton NB Tannys Vause, MD, Ottawa ON Benjamin Wong, MD, Calgary AB SPECIAL CONTRIBUTOR Margaret Burnett, MD, Winnipeg MB Disclosure statements have been received from all contributors.

Keywords: Female infertility, unexplained infertility, fibroid, leiomyoma, myomectomy, uterine artery embolization, in vitro fertilization, ovarian reserve, ulipristal acetate, magnetic resonance-guided focused ultrasound surgery.

Abstract Objective: To provide recommendations regarding the best management of fibroids in couples who present with infertility. Usual and novel treatment options for fibroids will be reviewed with emphasis on their applicability in women who wish to conceive. Options: Management of fibroids in women wishing to conceive first involves documentation of the presence of the fibroid and determination of likelihood of the fibroid impacting on the ability to conceive. Treatment of fibroids in this instance is primarily surgical, but must be weighed against the evidence of surgical management improving clinical outcomes, and risks specific to surgical management and approach. Outcomes: The outcomes of primary concern are the improvement in pregnancy rates and outcomes with management of fibroids in women with infertility. Evidence: Published literature was retrieved through searches of PubMed, MEDLINE, the Cochrane Library in November 2013 using appropriate controlled vocabulary (e.g., leiomyoma, infertility, uterine artery embolization, fertilization in vitro) and key words (e.g., fibroid, myomectomy). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies published in English and French. There were no date restrictions. Searches were updated on a regular basis and incorporated in the guideline to November 2013. Grey (unpublished literature) was identified through searching the websites of health technology assessment and health technologyrelated agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Values: The quality of evidence in this document was rated using the criteria described by the Canadian Task Force on Preventive Health Care (Table). Benefits, harms, and costs: These recommendations are expected to allow adequate management of women with fibroids and infertility, maximizing their chances of pregnancy by minimizing risks introduced by unnecessary myomectomies. Reducing complications and eliminating unnecessary interventions are also expected to decrease costs to the health care system.

J Obstet Gynaecol Can 2015;37(3):277–285

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

MARCH JOGC MARS 2015 l 277

SOGC clinical practice guideline

Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action

*The quality of evidence reported in here has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.52 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care.52

Summary Statements   1. Subserosal fibroids do not appear to have an impact on fertility; the effect of intramural fibroids remains unclear. If intramural fibroids do have an impact on fertility, it appears to be small and to be even less significant when the endometrium is not involved. (II-3)   2. Because current medical therapy for fibroids is associated with suppression of ovulation, reduction of estrogen production, or disruption of the target action of estrogen or progesterone at the receptor level, and it has the potential to interfere in endometrial development and implantation, there is no role for medical therapy as a stand-alone treatment for fibroids in the infertile population. (III)   3. Preoperative assessment of submucosal fibroids is essential to the decision on the best approach for treatment. (III)   4. There is little evidence on the use of Foley catheters, estrogen, or intrauterine devices for the prevention of intrauterine adhesions following hysteroscopic myomectomy. (II-3)

ABBREVIATIONS R

clinical pregnancy rates

FSH

follicle-stimulating hormone

IR

implantation rates

IVF

in vitro fertilization

LBR

live birth rates

MR

miscarriage rates

MRGfUS magnetic resonance-guided focused ultrasound surgery MRI

magnetic resonance imaging

OBR

ongoing pregnancy rates

RCT

randomized control trial

UAE

uterine artery emolization

278 l MARCH JOGC MARS 2015

  5. In the infertile population, cumulative pregnancy rates by the laparoscopic and the minilaparotomy approaches are similar, but the laparoscopic approach is associated with a quicker recovery, less postoperative pain, and less febrile morbidity. (II-2)   6. There are lower pregnancy rates, higher miscarriage rates, and more adverse pregnancy outcomes following uterine artery embolization than after myomectomy. (II-3) Studies also suggest that uterine artery embolization is associated with loss of ovarian reserve, especially in older patients. (III) Recommendations   1. In women with infertility, an effort should be made to adequately evaluate and classify fibroids, particularly those impinging on the endometrial cavity, using transvaginal ultrasound, hysteroscopy, hysterosonography, or magnetic resonance imaging. (III-A)   2. Preoperative assessment of submucosal fibroids should include, in addition to an assessment of fibroid size and location within the uterine cavity, evaluation of the degree of invasion of the cavity and thickness of residual myometrium to the serosa. A combination of hysteroscopy and transvaginal ultrasound or hysterosonography are the modalities of choice. (III-B)   3. Submucosal fibroids are managed hysteroscopically. The fibroid size should be < 5 cm, although larger fibroids have been managed hysteroscopically, but repeat procedures are often necessary. (III-B)   4. A hysterosalpingogram is not an appropriate exam to evaluate and classify fibroids. (III-D)   5. In women with otherwise unexplained infertility, submucosal fibroids should be removed in order to improve conception and pregnancy rates. (II-2A)   6. Removal of subserosal fibroids is not recommended. (III-D)   7. There is fair evidence to recommend against myomectomy in women with intramural fibroids (hysteroscopically confirmed intact endometrium) and otherwise unexplained infertility, regardless of their size. (II-2D) If the patient has no other options, the benefits of myomectomy should be weighed against the risks, and management of intramural fibroids should be individualized. (III-C)

The Management of Uterine Fibroids in Women With Otherwise Unexplained Infertility

  8. If fibroids are removed abdominally, efforts should be made to use an anterior uterine incision to minimize the formation of postoperative adhesions. (II-2A)

pathological examination).9 The main drawbacks of MRI evaluation are lack of accessibility and high cost.8

  9. Widespread use of the laparoscopic approach to myomectomy may be limited by the technical difficulty of this procedure. Patient selection should be individualized based on the number, size, and location of uterine fibroids and the skill of the surgeon. (III-A)

Hysterosalpingography is often performed to assess tubal patency in women with infertility and to exclude intrauterine pathology. However, the sensitivity and positive predictive value of this test for the identification of intrauterine lesions can be as low as 50% and 28.6% respectively.12 Hysterosalpingography cannot therefore be considered reliable to exclude endometrial distortion secondary to submucosal myomas.

10. Women, fertile or infertile, seeking future pregnancy should not generally be offered uterine artery embolization as a treatment option for uterine fibroids. (II-3E)

INTRODUCTION

U

terine fibroids, myomas, or leiomyomata are smooth muscle cell tumours and are the most common benign gynaecologic tumour in women of reproductive age.1 They are often found as part of the investigation of a couple presenting with infertility, and their origin is monoclonal.2 They are rarely found before menarche and usually regress after menopause.3 They are hormonally responsive, and estrogens appear to promote their growth.4,5 Local estrogen concentrations have been shown to be higher in myomas than in the surrounding myometrium, possibly because of a higher concentration of aromatase.6 Hormonal responsiveness appears to be greater in submucosal than subserosal myomas.7 EVALUATION AND CLASSIFICATION OF FIBROIDS

Submucosal fibroids have a negative impact on rates of implantation, clinical pregnancy, ongoing pregnancy, miscarriage, and live birth. An important feature of fibroid classification systems is the evaluation of the uterine cavity in order to define a fibroid as submucosal. Many studies have not included proper evaluation of the cavity, and therefore potential biases can be expected in their results. Imaging is now recognized as a necessary tool in the preoperative evaluation of myomas, especially for uterussparing procedures.8 Ultrasound has been shown to be an adequate, rapid, safe, and cost-effective means of evaluating the size, number, and location of fibroids.9 Transvaginal ultrasound may identify fibroids of up to 4 to 5 mm in diameter.10 Ultrasound may, however, be suboptimal for multiple fibroids, because of acoustic shadowing, and for the proper evaluation of endometrial impingement. Interobserver variation has also been found to be greater with this technique than with MRI.11 MRI has been well studied in the evaluation of fibroid uteruses, especially for fibroid mapping and submucosal penetration. It was shown to be the most reliable method of evaluation when compared with vaginal ultrasound, hysterosonography, and hysteroscopy, with 100% sensitivity and 91% specificity (gold standard was

Hysterosonography, which has the advantages of pelvic ultrasound, has been advocated as superior to transvaginal ultrasound alone13 and equal to hysteroscopy in the evaluation of endometrial impingement.14 It has been shown to be highly sensitive and specific in the identification of submucosal myomas. Its main drawbacks are the risk of infection (approximately 1%) and the discomfort associated with the injection of sterile saline.13 No studies to date have evaluated the optimal mode of evaluating uterine myoma in women presenting with infertility. It is also unclear whether all women with infertility should have the integrity of their endometrial cavity evaluated. However, it seems clear that part of the heterogeneity in the results of studies attempting to clarify the relationships between fibroids and infertility and the impact of treatment on conception is due to inadequate classification of fibroids, and in particular their impact on the endometrial cavity. Recommendations

1. In women with infertility, an effort should be made to adequately evaluate and classify fibroids, particularly those impinging on the endometrial cavity, using transvaginal ultrasound, hysteroscopy, hysterosonography, or magnetic resonance imaging. (III-A) 2. Preoperative assessment of submucosal fibroids should include, in addition to an assessment of fibroid size and location within the uterine cavity, evaluation of the degree of invasion of the cavity and thickness of residual myometrium to the serosa. A combination of hysteroscopy and transvaginal ultrasound or hysterosonography are the modalities of choice. (III-B) 3. Submucosal fibroids are managed hysteroscopically. The fibroid size should be < 5 cm, although larger fibroids have been managed hysteroscopically, but repeat procedures are often necessary. (III-B) 4. A hysterosalpingogram is not an appropriate exam to evaluate and classify fibroids. (III-D)

MARCH JOGC MARS 2015 l 279

SOGC clinical practice guideline

IMPACT OF FIBROIDS ON REPRODUCTIVE FUNCTION

The prevalence of fibroids in the infertile population of women is controversial. According to Donnez,15 approximately 5% to 10% of women presenting with infertility are found to have one or multiple fibroids. However, when all other causes of infertility are excluded, fibroids are found in only 1% to 2% of the remaining women.16 Both infertility and age have been associated with the presence of myomas and may therefore confound results of studies attempting to clarify the relationship between fibroids and infertility.17 There have been no appropriately designed studies to demonstrate a direct causal relationship between the presence of fibroids and infertility. Many hypotheses have been generated to explain how fibroids might cause infertility. Perfusion studies have shown that blood flow to uterine fibroids is less than that to the adjacent myometrium.18–20 Blood flow to the uterine arteries is also different in fibroid uteruses than non-fibroid uteruses.21 This and the fact that there may be endometrial inflammation and an altered local hormonal environment may impede embryo implantation. Myomas also seem to alter uterine contractility possibly interfering with sperm and ovum interaction or embryo migration.4,15 This may especially be true in uteruses with multiple large fibroids with important cavity distortion. Six systematic reviews or meta-analyses published between 2001 and 201015,22–26 assessed whether fibroids have an impact on fertility. On the whole, it appears that women with fibroids have decreased fertility. The presence of fibroids, regardless of location, significantly decreases both implantation and clinical pregnancy rates (RR 0.821; 95% CI 0.722 to 0.932, P = 0.002 and RR 0.849; 95% CI 0.734 to 0.982, P < 0.03 respectively).25 The impact of fibroid number and size on fertility has not been clearly elucidated.17 Reproductive success does, however, seem to be related to fibroid location. Subserosal fibroids do not appear to have an impact on fertility; all systematic reviews and meta-analyses agreed on this point. Submucosal fibroids (fibroids with endometrial impingement), however, have been shown uniformly to have a negative impact on rates of implantation, clinical pregnancy, miscarriage, and live birth/ongoing pregnancy, although available studies are few and small (IR: RR 0.283; 95% CI 0.123 to 0.649, P = 0.003; R: RR 0.363; 95% CI 0.179 to 0.737, P = 0.005; MR: RR 1.678; 95% CI 1.373 to 2.051, P = 0.022; LBR/OPR: RR 0.318; 95% CI 0.119 to 0.850, P < 0.001).25 280 l MARCH JOGC MARS 2015

The greatest debate remains on the impact and treatment of intramural fibroids. Part of the disagreement between studies may result from inappropriate evaluation of the endometrial cavity causing the erroneous inclusion of submucosal fibroids in the group of intramural fibroids. Considering only the most recent good quality meta-analysis, intramural fibroids do seem to have an impact on both IR and R (RR 0.684; 95% CI 0.587 to 0.796, P < 0.001 and RR 0.810; 0.696 to 0.941, P = 0.006, respectively) but less than that of submucosal fibroids. Although the number of studies reporting this outcome was small, there was no impact found on LBR/ OPR.25 This finding remained significant regardless of study design and when looking exclusively at studies on IVF, except that Sunkara et al.27 found a reduction in LBR in women undergoing IVF in the presence of intramural fibroids (RR 0.79; 95% CI 0.70 to 0.88, P < 0.001). This discrepancy in IVF studies could be explained by the authors’ not controlling for age and number of IVF cycles. Considering only studies that included an adequate hysteroscopic evaluation of the uterine cavity, implantation remains the only rate significantly affected by the presence of intramural fibroids.25 Fibroid size did not seem to have an impact on these results, although large intramural fibroids would presumably have been treated surgically and hence not included in such studies. Most studies included intramural fibroids < 5 cm. No studies have examined the distance between fibroid edge and endometrium. Only one retrospective study evaluated the impact of a single intramural fibroid on IVF outcomes for severe male factor. Endometrial cavity was assessed using hysteroscopy in all patients. Fibroid sizes ranged from 5 to 43 mm. IR and R were similar between cases (n = 61) and controls (n = 444).28 Miscarriage rates were found to be increased in women with intramural fibroids (RR 1.747; 95% CI 1.22 to 2.489, P = 0.002), but this effect was lost when only studies with adequate cavity involvement evaluation were included.25 Another way of assessing whether a uterine pathology has an impact on conception rates is to evaluate whether pregnancy rates increase more after removal than after expectant management. It is equally important to ensure that treatment does not have an intrinsically negative impact on fertility, particularly in surgical treatments that can result in the formation of scar tissue and adhesions known to have deleterious effects on conception rates. Studies on treatment for leiomyomas in women with infertility have been few and small. Two types of control groups have been used: women with fibroids left in situ and women with unexplained infertility without fibroids. No large trials have evaluated the impact of myomectomy in women with submucosal fibroids. A meta-analysis of

The Management of Uterine Fibroids in Women With Otherwise Unexplained Infertility

the small studies available found an apparent benefit of hysteroscopic myomectomy over fibroids left in situ on R (RR 2.034, 95% CI 1.081 to 3.826, P = 0.028). Pregnancy rates after myomectomy become statistically similar to those in women with infertility without fibroids.25 In the matter of the surgical removal of intramural fibroids to improve fertility, data fail to show a clear benefit of myomectomy over myomas left in situ. Summary Statement

1. Subserosal fibroids do not appear to have an impact on fertility; the effect of intramural fibroids remains unclear. If intramural fibroids do have an impact on fertility, it appears to be small and to be even less significant when the endometrium is not involved. (II-3) MEDICAL MANAGEMENT

Contemporary medical management of uterine fibroids exploits the estrogen- and progesterone-responsiveness of uterine fibroids; however, no pharmacological agent is curative of fibroids. As a result, medical therapy is essentially a treatment option for the control of symptoms. Several agents exist for the management of uterine fibroids through symptom control, reduction in fibroid volume, and reduction in menstrual blood loss. Most commonly used agents have been GnRH analogues. Newer, novel therapies including aromatase inhibitors, mifepristone, selective estrogen receptor modulators, and selective progesterone receptor modulators have shown promise in symptom improvement and fibroid regression without the hypoestrogenic symptoms associated with GnRH analogues. Summary Statement

2. Because current medical therapy for fibroids is associated with suppression of ovulation, reduction of estrogen production, or disruption of target action of estrogen or progesterone at the receptor level, and it has the potential to interfere in endometrial development and implantation, there is no role for medical therapy as stand-alone treatment for fibroids in the infertile population. (III) SURGICAL MANAGEMENT

Well-designed surgical intervention trials for myomectomy and infertility are sparse, with a single RCT published to date.28 This study demonstrated an improvement in spontaneous conception rates after the surgical removal of submucosal fibroids, but pregnancy rates following the removal of intramural or subserosal fibroids were no more improved than in the expectant management group of women with intramural-subserosal fibroids in situ.

A recent meta-analysis demonstrated similar findings, with an improvement in pregnancy rates in infertile patients undergoing surgical removal of submucosal fibroids, but not in those undergoing surgical removal of intramural fibroids.25 Surgical treatment of fibroids can be associated with morbidity. It has been associated with both pelvic and intrauterine adhesions, so any potential benefit from the removal of the fibroids may be negated by the detrimental effect of the surgery on uterine integrity. In addition, the consequences of myomectomy on pregnancy outcomes are not negligible. It is therefore imperative that surgical management of fibroids for infertility be undertaken only when there is evidence to improvement in pregnancy outcomes through surgical intervention. There may, however, be instances when surgical removal of fibroids in an infertile patient may be undertaken for reasons other than fertility enhancement, such as relief of pressure symptoms or surgical management of menstrual disturbances secondary to fibroids. Recommendations

5. In women with otherwise unexplained infertility, submucosal fibroids should be removed in order to improve conception and pregnancy rates. (II-2) 6. Removal of subserosal fibroids is not recommended. (III-D) 7. There is fair evidence to recommend against myomectomy in women with intramural fibroids (hysteroscopically confirmed intact endometrium) and otherwise unexplained infertility, regardless of the size of the fibroids. (II-2D) If the patient has no other options, the benefits of myomectomy should be weighed against the risks, and management of intramural fibroids should be individualized. (III-C) Surgical approach to fibroids can be either vaginal or abdominal. The abdominal approach may be either by laparotomy or laparoscopy. The specific approach will depend on fibroid size and location and on skill of the practitioner. The decision to proceed with myomectomy for improvement in fertility outcomes, especially when laparotomy is recommended, should be weighed against the patient’s clinical fertility history, subsequent plans for fertility treatment, and estimated fecundability with or without myomectomy. Hysteroscopic Myomectomy

Hysteroscopic myomectomy is the least invasive surgical approach to fibroid removal. It is most effective for patients with submucosal fibroids completely within the uterine cavity (Type 0) or with at least 50% of the fibroid MARCH JOGC MARS 2015 l 281

SOGC clinical practice guideline

volume within the uterine cavity (Type I). Fibroids with less than 50% of the fibroid volume in the cavity (Type II) are much more difficult to resect completely and are more often associated with the need for repeated procedures.29,30 Additionally, it has generally been recommended that hysteroscopic myomectomy be undertaken with fibroids under 5 cm; however fibroids greater than 5 cm and Type II fibroids have been resected hysteroscopically.31 Summary Statement

3. Preoperative assessment of submucosal fibroids is essential to the decision on the best approach for treatment. (III) Of late, complications that may further impair fertility after hysteroscopic myomectomy, intrauterine adhesions are the most concerning. The incidence of intrauterine adhesions after hysteroscopic myomectomy was shown in one study to be 7.5%.32 Postoperative adjuvant therapy, including estrogen therapy for 4 to 8 weeks or insertion of an intrauterine device, pediatric Foley catheter, or other balloon for 1 week postoperatively, have all been used to prevent further adhesion development. However, there is scant evidence to the use of these postoperative therapies.33,34 Summary Statement

4. There is little evidence on the use of Foley catheters, estrogen, or intrauterine devices for the prevention of intrauterine adhesions following hysteroscopic myomectomy. (II-3) Abdominal Myomectomy

Abdominal myomectomy is an effective surgical procedure for women wishing to preserve their fertility and who have pressure symptoms due to the mass effect of large fibroids. It may also be performed in women wishing to preserve their fertility with symptomatic menorrhagia that is neither controlled by medical management nor effectively managed by hysteroscopic myomectomy. With improvements in hysteroscopic myomectomy techniques, the use of abdominal myomectomy to improve fecundity has narrowed to a small subgroup of infertile patients with fibroids. The current indication for abdominal myomectomy is for infertile patients with large (> 5 cm) Type II submucosal fibroids or Type II fibroids with < 1 cm between the external surface of the fibroid and the uterine serosa. The goal, similar to that of hysteroscopic myomectomy for infertility, is to remove the fibroid in its entirety and to restore normal uterine cavity size and architecture. Abdominal myomectomy may be conducted through a subumbilical vertical incision for large fibroids, as a mini-laparotomy through a Pfannenstiel incision for smaller fibroids (typically < 10 cm), or laparoscopically. 282 l MARCH JOGC MARS 2015

Postoperative formation of adhesions after myomectomy is extremely high: in one study it was 94% with uterine incisions on the posterior wall and 55% when the incision occurred on the anterior uterine wall. Obviously these adhesions may have a negative impact on fertility in women where this is already a concern. These adhesions were lysed at secondlook laparoscopy 6 weeks post myomectomy, with a 67% cumulative pregnancy rate 12 months post myomectomy.35 Recommendation

8. If fibroids are removed abdominally, efforts should be made to use an anterior uterine incision to minimize the formation of postoperative adhesions. (II-2A) Best practice for adhesion prevention in gynaecologic surgery has been thoroughly described elsewhere.36 Two RCTs with a combined 267 patients compared reproductive outcomes of laparoscopic myomectomy and myomectomy by laparotomy. In the first study of patients undergoing myomectomy for infertility and at least 1 fibroid > 5 cm, pregnancy rates were similar following in the laparoscopy and laparotomy groups (53.6% vs. 55.9%).37 There was lower febrile morbidity in the laparoscopy group (26.2% vs. 12.1%), shorter hospital stay, and a lower postoperative drop in hemoglobin. In the second study, 12 months postoperatively, cumulative pregnancy rates were similar in the laparoscopy and laparotomy groups (52.9% vs. 38.2%).38 Miscarriage rates and preterm delivery rates were also similar between groups and similar to expected rates in the general population. Interestingly, in the subgroup of patients undergoing myomectomy for non-fertility indications the cumulative pregnancy rate was greater in the laparoscopy subgroup (73.7% vs. 50%). In this study, it appears myomectomy was not considered a contraindication to vaginal delivery, and 31% of all patients who delivered underwent a successful vaginal delivery. Summary Statement

5. In the infertile population, cumulative pregnancy rates by the laparoscopic and minilaparotomy approaches are similar, but the laparoscopic approach is associated with a quicker recovery, less postoperative pain, and less febrile morbidity. (II-2) Recommendation

9. Widespread use of the laparoscopic approach to myomectomy may be limited by the technical difficulty of this procedure. Patient selection should be individualized based on the number, size, and location of uterine fibroids and the skill of the surgeon. (III-A)

The Management of Uterine Fibroids in Women With Otherwise Unexplained Infertility

NEW METHODS OF TREATMENT OF FIBROIDS AND INFERTILITY

The last decade has seen increasing demand for safe and effective uterus- and “reproductive potential”-sparing treatment options for symptomatic uterine fibroids. The goal of this section is to review the important new techniques for uterus-sparing treatment of uterine fibroids and particularly their use in women with fibroids and infertility. Newer uterus-sparing treatments include laser ablation, laparoscopic and vaginal occlusion of uterine arteries, MRGfUS, and UAE. However, many of these techniques have not been used on a large scale, and data on their reproductive outcomes in patients trying to conceive are insufficient to make recommendations. Here we review 2 techniques other than myomectomy, namely UAE and MRgFUS, that are currently being evaluated for patients who desire to keep their fertility. Uterine Artery Embolization: Technique and Indications

UAE was first introduced in 1995 for treatment of uterine fibroids.39 Uterine embolization has been well studied as an alternative to myomectomy and hysterectomy, mainly in women who no longer desire children, and it has progressively become one of the most widely used noninvasive conservative methods of treatment of uterine fibroids after myomectomy. Current contraindications to UAE include pregnancy, infertility (or desire for future pregnancy), clinical findings and imaging suggestive of gynaecological malignancy, anaphylactic reaction to contrast material, renal failure, and coagulopathy.40 MRI studies during the hours following embolization have shown a transient ischemia of the uterine corpus and fundus affecting the endometrium and inner and middle myometrial layers, which subsides 48 to 72 hours later, but the fibroids undergo irreversible infarction.41 Although intra-abdominal adhesions have been described to develop following this process, they are much less common than adhesions following myomectomy.42,43 These findings imply, however, possible irreversible damage to the endometrium and formation of adhesion, which may be deleterious to women who already suffer from infertility. Fertility in patients following UAE

Spontaneous pregnancy may be possible following UAE, but this conservative method of treatment is currently contraindicated in women seeking future pregnancy. In general, data on UAE in women with fibroids and infertility remains difficult to interpret because of patient

heterogeneity (studies include women undergoing UAE for symptomatic fibroids, but also women with postpartum hemorrhage) and the almost exclusive inclusion of women who no longer desired pregnancy. The best comparative evidence available is in an RCT by Mara et al.44 121 patients wishing to become pregnant and having intramural fibroids > 4 cm were randomized to either UAE (n = 58) or abdominal (open or laparoscopic according to surgeon preference) myomectomy (n = 63). Of patients who attempted to conceive, 50% of the UAE group versus 78% of the myomectomy group were able to do so. The RR for UAE patients of not getting pregnant was 2.22 (95% CI 1.11 to 4.44), and of miscarriage was 2.79 (95% CI 1.25 to 6.22). Therefore, myomectomy was associated with more pregnancies and deliveries than UAE and a lower rate of miscarriage up to 2 years post therapy. Another finding that raises concerns about the use of UAE in women with infertility is the fact that significantly more women in the UAE group presented with an FSH > 10 IU/L 6 months after the procedure (13.8% vs. 3.2%; P < 0.05), although the numbers were small. Other studies have found loss of ovarian reserve and an increase in ovarian failure in women undergoing UAE, particularly in women in later reproductive years. Transient or permanent amenorrhea associated with a decrease in ovarian reserve has been reported, with an incidence of 1% to 2% in women under 45.45 A prospective study by Hovsepian et al. found that in patients between the ages of 35 and 40 there was a transient increase in FSH 3 months after UAE, but that after 6 months, FSH levels were similar to those of patients having undergone myomectomy or hysterectomy.46 Another study found a loss of ovarian reserve in patients around 45 years of age expressed by increased FSH and decreased anti-Müllerian hormone lasting for at least 24 months following UAE and hysterectomy.47 It is important to mention that FSH is a poor marker of ovarian reserve and a poor predictor of ovarian response to IVF. It is also a later marker than antral follicle count or anti-Müllerian hormone, which have been shown to have much higher sensitivities and specificities for response to IVF. As IVF is usually required in women with unexplained infertility, ovarian reserve should be an important concern in treatment of fibroids. Unfortunately, no data using adequate markers were found regarding the impact of UAE on ovarian reserve in women of reproductive age. The incidences of Caesarean section and postpartum hemorrhage were also both found to be higher following UAE (66% vs. 48.5% and 13.9% vs. 2.5%, respectively) than in control pregnancies matched for age and fibroid location.48 MARCH JOGC MARS 2015 l 283

SOGC clinical practice guideline

Concerns also remain about the formation of synechia from smaller particles lodging in the endometrial vasculature and about the obstetrical outcomes of women who undergo UAE and then conceive. UAE has been associated with increased risks of spontaneous miscarriage, preterm delivery, abnormal placentation, and postpartum hemorrhage.49 Summary Statement

6. There are lower pregnancy rates, higher miscarriage rates, and more adverse pregnancy outcomes following uterine artery embolization than after myomectomy. (II-3) Studies also suggest that uterine artery embolization is associated with loss of ovarian reserve, especially in older patients. (III) Recommendation

10. Women, fertile or infertile, seeking future pregnancy should not generally be offered uterine artery embolization as a treatment option for uterine fibroids. (II-3E) Magnetic Resonance-guided Focused Ultrasound Surgery

In 2004, the United States Federal Drug istration approved the use of MRgFUS for treatment of uterine fibroids. This technique involves the destruction of uterine fibroid tissue by coagulative necrosis through heating tissue to over 70°C by focusing many high frequency ultrasound beams on the target tissue. For maximum accuracy, the ultrasound beams are guided with MRI, which has the best resolution and sensitivity to detect uterine fibroids.50 International experience of 54 pregnancies in 51 women following MRgFUS was recently reported from 13 sites.51 These women had previously declared that they were not interested in future pregnancy and their mean age was 37.2 years. The miscarriage rate was 26%; 42% of the women had delivered at the time of publication, while 20% of the pregnancies were ongoing. 64% of women had a vaginal delivery and the mean weight at birth was 3.3 kg. There were 2 placenta praevia in this group of patients. Only 1 patient had a serious complication after a myomectomy done at the time of a Caesarean section. Her second pregnancy was uneventful. There are currently no data comparing MRgFUS with myomectomy and no studies of its use in women with fibroids and infertility as their main complaints. Further studies are needed before offering this treatment to women with fibroids and otherwise unexplained infertility. 284 l MARCH JOGC MARS 2015

SUMMARY

Women presenting with both fibroids and a history of otherwise unexplained infertility represent a challenge. These women may or may not be symptomatic from these fibroids. They may have one or more fibroids that are only detectable through ultrasound examination or the fibroids may be easily palpable on abdominal examination. With such a heterogeneous disorder, studies are difficult to perform and adequate conclusions difficult to draw. The effect of fibroids on reproduction remains in question. Submucosal fibroids seem to have an impact, whereas subserosal do not. Intramural fibroids might have an impact, but randomized studies with adequate evaluation of intracavitary involvement are necessary to adequately evaluate whether the benefits of treatment will outweigh the serious surgical and obstetrical risks that follow myomectomy. Treatment of fibroids should be individualized, and symptomatology may be a decisive factor in whether or not a fibroid is removed. Myomectomy remains the gold standard for treatment. REFERENCES 1. Salman T, Davis C. Uterine fibroids, management and effect on fertility. Curr Opin Obstet Gynecol 2010;22:295–303. 2. Okolo S. Incidence, aetiology and epidemiology of uterine fibroids. Baillieres Best Pract Res Clin Obstet Gynaecol 2008;22:571–88. 3. Englund K, Blanck A, Gustavsson I, Lundkvist U, Sjoblom P, Norgren A, Lindblom B. Sex steroid receptors in human myometrium and fibroids: Changes during the menstrual cycle and gonadotropin-releasing hormone treatment. J Clin Endocrinal Metab 1998;83:4092–6. 4. Buttram VC Jr, Reiter RC. Uterine leiomyomata: etiology, symptomatology, and management. Fertil Steril 1981;36:433–45. 5. Marsh EE, Bulun SE. Steroid hormones and leiomyomas. Obstet Gynecol Clin North Am 2006;33:59–67. 6. Parker WH. Etiology, symptomatology, and diagnosis of uterine myomas. Fertil Steril 2007;87:725–36. 7. Marugo M, Centonze M, Bernasconi D, Fazzuoli L, Berta S, Giordano G. Estrogen and progesterone receptors in uterine leiomyomas. Acta Obstet Gynecol Scand 1989;68:731–5. 8. McLucas B. Diagnosis, imaging and anatomical classification of uterine fibroids. Best Pract Res Clin Obstet Gynaecol 2008;22:627–42. 9. Dueholm M, Lundorf E, Hansen ES, Ledertoug S, Olesen F. Accuracy of magnetic resonance imaging and transvaginal ultrasonography in the diagnosis, mapping, and measurement of uterine myomas. Am J Obstet Gynecol 2002;186:409–15. 10. Hurley V. Imaging techniques for fibroid detection. Baillieres Best Pract Res Clin Obstet Gynaecol 1998;12:213–24. 11. Dueholm M, Lundorf E, Sorensen JS, Ledertoug S, Olesen F, Laursen H. Reproducibility of evaluation of the uterus by transvaginal sonography, hysterosonographic examination, hysteroscopy and magnetic resonance imaging. Hum Reprod 2002;17:195–200. 12. Soares SR, Barbosa dos Reis MM, Camargos AF. Diagnostic accuracy of sonohysterography, transvaginal sonography, and hysterosalpingography in patients with uterine cavity diseases. Fertil Steril 2000;73:406–11.

The Management of Uterine Fibroids in Women With Otherwise Unexplained Infertility

13. Dueholm M, Forman A, Jensen ML, Laursen H, Kracht P. Transvaginal sonography combined with saline contrast sonohysterography in evaluating the uterine cavity in premenopausal patients with abnormal uterine bleeding. Ultrasound Obstet Gynecol 2001;18:54–61. 14. Dueholm M, Lundorf E, Hansen ES, Ledertoug S, Olesen F. Evaluation of the uterine cavity with magnetic resonance imaging, transvaginal sonography, hysterosonographic examination, and diagnostic hysteroscopy. Fertil Steril 2001;76:350–7. 15. Donnez J, Jadoul P. What are the implications of myomas on fertility? A need for a debate? Hum Reprod 2002;17:1424–30. 16. Cook H, Ezzati M, Segars JH, McCarthy K. The impact of uterine leiomyomas on reproductive outcomes. Minerva Ginecol 2010;62:225–36. 17. Olive DL, Pritts EA. Fibroids and reproduction. Semin Reprod Med 2010;28:218–27. 18. de Souza NM, Brosens JJ, Schwieso JE, Paraschos T, Winston RM. The potential value of magnetic resonance imaging in infertility. Clin Radiol 1995;50:75–9. 19. Forssman L. Blood flow in myomatous uteri as measured by intra-arterial 133Xenon. Acta Obstet Gynecol Scand 1976;55:21–4. 20. Forssman, L. Distribution of blood flow in myomatous uteri as measured by locally injected 133Xenon. Acta Obstet Gynecol Scand 1976;55:101–4. 21. Kurjak A, Kupesic-Urek S, Miric D. The assessment of benign uterine tumor vascularization by transvaginal color Doppler. Ultrasound Med Biol 1992;18:645–9. 22. Griffiths AN, D’Angelo A, Amso NN. Surgical treatment of fibroids for subfertility. Cochrane Database Syst Rev 2006;(3):CD003857 11. 23. Klatsky PC, Tran ND, Caughey AB, Fujimoto VY. Fibroids and reproductive outcomes: a systematic literature review from conception to delivery. Am J Obstet Gynecol 2008;198:357–66. 24. Pritts EA. Fibroids and infertility: a systematic review of the evidence. Obstet Gynecol Surv 2001;56:483–91. 25. Pritts EA, Parker WH, Olive DL. Fibroids and infertility: an updated systematic review of the evidence. Fertil Steril 2009;91:1215–23. 26. Somigliana E, Vercellini P, Daguati R, Pasin R, De Giorgi O, Crosignani PG. Fibroids and female reproduction: a critical analysis of the evidence. Hum Reprod Update 2007;13:465–76. 27. Sunkara SK, Khairy M, El-Toukhy T, Khalaf Y, Coomarasamy A. The effect of intramural fibroids without uterine cavity involvement on the outcome of IVF treatment: a systematic review and meta-analysis. Human Reprod 2010;25:418–29. 28. Bozdag G, Esinler I, Boynukalin K, Aksu T, Gunalp S, Gurgan T. Single intramural leiomyoma with normal hysteroscopic findings does not affect ICSI-embryo transfer outcome. Reproductive Biomedicine Online 2009;19:276–80. 28. Casini ML, Rossi F, Agostini R, Unfer V. Effects of position of fibroids on fertility. Gynecol Endocrinol 2006;22:106–9. 29. Wamsteker K, Emanuel MH, de Kruif JH. Transcervical hysteroscopic resection of submucous fibroids for abnormal uterine bleeding: results regarding the degree of intramural extension. Obstet Gynecol 1993;82:736–40. 30. Vercellini P, Zàina B, Yaylayan L, Pisacreta A, De Georgi O, Crosignani PG. Hysteroscopic myomectomy: long-term effects on menstrual pattern and fertility. Obstet Gynecol 1999;94:341–7. 31. Camanni M, Bonino L, Delpiano EM, Ferrero B, Migliaretti G, Deltetto F. Hysteroscopic management of large symptomatic submucous uterine myomas. J Minim Invasive Gynecol 2010;17:59–65. 32. Touboul C, Fernandez H, Deffieux X, Berry R, Frydman R, Gervaise A. Uternine syndechiae after bipolar hysteroscopic resection of submucosal myomas in patients with infertility. Fertil Steril 2009;92:1690–3. 33. Kodaman PH, Arici A. Intrauterine adhesions and fertility outcome: how to optimize success? Curr Opin Obstet Gynecol 2007;19:207–14.

34. Tonguc EA, Var T, Yilmaz N, Batioglu S. Intrauterine device or estrogen treatment after hysteroscopic septum resection. Int J Gynaecol Obstet 2010;109:226–9. 35. Tulandi T, Murray C, Guralnick M. Adhesion formation and reproductive outcome after myomectomy and second-look laparoscopy. Obstet Gynecol 1983;82:213–5. 36. Robertson D, Lefebvre G; Society of Obstetricians and Gynaecologists of Canada Clinical Practice Gynaecology Committee. Adhesion prevention in gynaecological surgery. SOGC Clinical Practice Guideline, No. 243, June 2010. J Obstet Gynaecol Can 2010;32:598–608. 37. Seracchioli R, Rossi S, Govoni F, Rossi E, Venturoli S, Bulletti C, et al. Fertility and obstetric outcome after laparoscopic myomectomy of large myomata: a randomized comparison with abdominal myomectomy. Hum Reprod 2000;15:2663–8. 38. Palomba S, Zupi E, Falbo A, Russo T, Marconi D, Tolino A, et al. A multicenter randomized, controlled study comparing laparoscopic versus minilaparotomic myomectomy: reproductive outcomes. Fertil Steril 2007;88:933–41. 39. Ravina JH, Herbreteau D, Ciraru-Vigneron N, Bouret JM, Houdart E, Aymard A, et al. Arterial embolisation to treat uterine myomata. Lancet 1995;346:671–2. 40. Radeleff B, Eiers M, Bellemann N, Ramsauer S, Rimbach S, Kauczor HU, et al. Expulsion of dominant submucosal fibroids after uterine artery embolization. Eur J Radiol 2010;75(1):e57–e63. 41. Scheurig-Muenkler C, Wagner M, Franiel T, Hamm B, Kroencke TJ. Effect of uterine artery embolization on uterine and leiomyoma perfusion: evidence of transient myometrial ischemia on magnetic resonance imaging. J Vasc Interv Radiol 2010;21:1347–53. 42. Agdi M, Tulandi T. Endoscopic management of uterine fibroids. Best Pract Res Clin Obstet Gynaecol 2008;22:707–16. 43. Agdi M, Valenti D, Tulandi T. Intraabdominal adhesions after uterine artery embolization. Am J Obstet Gynecol 2008;199:482.e1–482.e3. 44. Mara M, Maskova J, Fucikova Z, Kuzel D, Belsan T, Sosna O. Midterm clinical and first reproductive results of a randomized controlled trial comparing uterine fibroid embolization and myomectomy. Cardiovasc Intervent Radiol 2008;31:73–85. 45. Goodwin SC, McLucas B, Lee M, Chen G, Perrella R, Vedantham S, et al. Uterine artery embolization for the treatment of uterine leiomyomata midterm results. J Vasc Intervent Radiol 1999;10:1159–65. 46. Hovsepian DM, Ratts VS, Rodriguez M, Huang JS, Aubuchon MG, Pilgram TK. A prospective comparison of the impact of uterine artery embolization, myomectomy, and hysterectomy on ovarian function. J Vasc Intervent Radiol 2006;17:1111–5. 47. Hehenkamp WJ, Volkers NA, Broekmans FJ, de Jong FH, Themmen AP, Birnie E, et al. Loss of ovarian reserve after uterine artery embolization: a randomized comparison with hysterectomy. Hum Reprod 2007;22:1996–2005. 48. Homer H, Saridogan E. Uterine artery embolization for fibroids is associated with an increased risk of miscarriage. Fertil Steril 2010;94:324–30. 49. Berkane N, Moutafoff-Borie C. Impact of previous uterine artery embolization on fertility. Curr Opin Obstet Gynecol 2010;22:242–7. 50. Jolesz FA, Hynynen K. Magnetic resonance image-guided focused ultrasound surgery. Cancer J 2002;8(Suppl 1):S100–S112. 51. Rabinovici J, David M, Fukunishi H, Morita Y, Gostout BS, Stewart EA; MRgFUS Study Group. Pregnancy outcome after magnetic resonanceguided focused ultrasound surgery (MRgFUS) for conservative treatment of uterine fibroids. Fertil Steril 2010;93,199–209. 52. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

MARCH JOGC MARS 2015 l 285

SOGC CLINICAL PRACTICE GUIDELINE No. 318, February 2015 (Replaces, No. 128, May 2003)

The Management of Uterine Leiomyomas This clinical practice guideline has been prepared by the Uterine Leiomyomas Working Group, reviewed by the Clinical Practice Gynaecology, Reproductive Endocrinology & Infertility, and Family Physician Advisory Committees, and approved by the Executive and Board of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS George A. Vilos, MD, London ON Catherine Allaire, MD, Vancouver BC Philippe-Yves Laberge, MD, Quebec QC Nicholas Leyland, MD, MHCM, Hamilton ON SPECIAL CONTRIBUTORS Angelos G. Vilos, MD, London, ON Ally Murji, MD, MPH, Toronto, ON Innie Chen, MD, Ottawa, ON Disclosure statements have been received from all contributors. The literature searches and bibliographic for this guideline were undertaken by Becky Skidmore, Medical Reserch Analyst, Society of Obstetricians and Gynaecologists of Canada.

Abstract Objectives: The aim of this guideline is to provide clinicians with an understanding of the pathophysiology, prevalence, and clinical significance of myomata and the best evidence available on treatment modalities. Options: The areas of clinical practice considered in formulating this guideline were assessment, medical treatments, conservative treatments of myolysis, selective uterine artery occlusion, and surgical alternatives including myomectomy and hysterectomy. The risk-to-benefit ratio must be examined individually by the woman and her health care provider.

Key Words: Myoma, leiomyoma, fibroid, myomectomy, uterine artery embolization, hysterectomy, heavy menstrual bleeding, menorrhagia

Outcomes: Implementation of this guideline should optimize the decision-making process of women and their health care providers in proceeding with further investigation or therapy for uterine leiomyomas, having considered the disease process and available treatment options, and reviewed the risks and anticipated benefits. Evidence: Published literature was retrieved through searches of PubMed, CINAHL, and Cochrane Systematic Reviews in February 2013, using appropriate controlled vocabulary (uterine fibroids, myoma, leiomyoma, myomectomy, myolysis, heavy menstrual bleeding, and menorrhagia) and key words (myoma, leiomyoma, fibroid, myomectomy, uterine artery embolization, hysterectomy, heavy menstrual bleeding, menorrhagia). The reference lists of articles identified were also searched for other relevant publications. Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date limits but results were limited to English or French language materials. Searches were updated on a regular basis and incorporated in the guideline to January 2014. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology–related agencies, clinical practice guideline collections, and national and international medical specialty societies. Benefits, Harms, and Costs: The majority of fibroids are asymptomatic and require no intervention or further investigations. For symptomatic fibroids such as those causing menstrual abnormalities (e.g. heavy, irregular, and prolonged uterine bleeding), iron defficiency anemia, or bulk symptoms (e.g., pelvic pressure/pain, obstructive symptoms), hysterectomy is a definitive solution. However, it is not the preferred solution for women who wish to preserve fertility and/or their uterus. The selected treatment should be directed towards an improvement in symptomatology and quality of life. The cost of the therapy to the health care system and to women with fibroids must be interpreted in the context of the cost of untreated disease conditions and the cost of ongoing or repeat investigative or treatment modalities. Values: The quality of evidence in this document was rated using the criteria described in the Report of the Caadian Task Force on Preventive Health Care (Table 1).

J Obstet Gynaecol Can 2015;37(2):157–178

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

FEBRUARY JOGC FÉVRIER 2015 l 157

SOGC Clinical Practice Guideline

Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action

*The quality of evidence reported in here has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.204 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care.204

Summary Statements   1. Uterine fibroids are common, appearing in 70% of women by age 50; the 20% to 50% that are symptomatic have considerable social and economic impact in Canada. (II-3)   2. The presence of uterine fibroids can lead to a variety of clinical challenges. (III)   3. Concern about possible complications related to fibroids in pregnancy is not an indication for myomectomy except in women who have had a previous pregnancy with complications related to these fibroids. (III)   4. Women who have fibroids detected in pregnancy may require additional maternal and fetal surveillance. (II-2)   5. Effective medical treatments for women with abnormal uterine bleeding associated with uterine fibroids include the levonorgestrel intrauterine system, (I) gonadotropin-releasing hormone analogues, (I) selective progesterone receptor modulators, (I) oral contraceptives, (II-2) progestins, (II-2) and danazol. (II-2)   6. Effective medical treatments for women with bulk symptoms associated with fibroids include selective progesterone receptor modulators and gonadotropin-releasing hormone analogues. (I)   7. Hysterectomy is the most effective treatment for symptomatic uterine fibroids. (III)   8. Myomectomy is an option for women who wish to preserve their uterus or enhance fertility, but carries the potential for further intervention. (II-2)   9. Of the conservative interventional treatments currently available, uterine artery embolization has the longest track record and has been shown to be effective in properly selected patients. (II-3) 10. Newer focused energy delivery methods are promising but lack long-term data. (III) Recommendations   1. Women with asymptomatic fibroids should be reassured that there is no evidence to substantiate major concern about malignancy and that hysterectomy is not indicated. (III-D)

158 l FEBRUARY JOGC FÉVRIER 2015

  2. Treatment of women with uterine leiomyomas must be individualized based on symptomatology, size and location of fibroids, age, need and desire of the patient to preserve fertility or the uterus, the availability of therapy, and the experience of the therapist. (III-B)   3. In women who do not wish to preserve fertility and/or their uterus and who have been counselled regarding the alternatives and risks, hysterectomy by the least invasive approach possible may be offered as the definitive treatment for symptomatic uterine fibroids and is associated with a high level of satisfaction. (II-2A)   4. Hysteroscopic myomectomy should be considered firstline conservative surgical therapy for the management of symptomatic intracavitary fibroids. (II-3A)   5. Surgical planning for myomectomy should be based on mapping the location, size, and number of fibroids with the help of appropriate imaging. (III-A)   6. When morcellation is necessary to remove the specimen, the patient should be informed about possible risks and complications, including the fact that in rare cases fibroid(s) may contain unexpected malignancy and that laparoscopic power morcellation may spread the cancer, potentially worsening their prognosis. (III-B)   7. Anemia should be corrected prior to proceeding with elective surgery. (II-2A) Selective progesterone receptor modulators and gonadotropin-releasing hormone analogues are effective at correcting anemia and should be considered preoperatively in anemic patients. (I-A)   8. Use of vasopressin, bupivacaine and epinephrine, misoprostol, peri-cervical tourniquet, or gelatin-thrombin matrix reduce blood loss at myomectomy and should be considered. (I-A)   9. Uterine artery occlusion by embolization or surgical methods may be offered to selected women with symptomatic uterine fibroids who wish to preserve their uterus. Women choosing uterine artery occlusion for the treatment of fibroids should be counselled regarding possible risks, including the likelihood that fecundity and pregnancy may be impacted. (II-3A)

The Management of Uterine Leiomyomas

10. In women who present with acute uterine bleeding associated with uterine fibroids, conservative management with estrogens, selective progesterone receptor modulators, antifibrinolytics, Foley catheter tamponade, and/or operative hysteroscopic intervention may be considered, but hysterectomy may become necessary in some cases. In centres where available, intervention by uterine artery embolization may be considered. (III-B)

INTRODUCTION Clinical Importance of Uterine Fibroids

T

he fibroid, myoma, and leiomyoma are synonymous and are the commonest gynaecological tumours, with a prevalence of 70% to 80% in women who have reached the age of 50.1 In 95 061 US nurses, aged 25 to 44 years, the incidence was 8.9/1000 for white women and 30.9/1000 for black women.2 The prevalence increases with age, peaking in women in their 40s. A hysterectomy study has found leiomyomas in 77% of uterine specimens.3 In many women, myomas may be asymptomatic and are diagnosed incidentally on clinical examination or imaging. However, myomas can cause significant morbidity including menstrual abnormalities (e.g. heavy, irregular, and prolonged uterine bleeding), iron defficiency anemia, bulk symptoms (e.g. pelvic pressure/pain, obstructive symptoms), and fertility issues. Symptomatic fibroids have a considerable ABBREVIATIONS AAGL

American Association of Gynecologic Laparoscopists

AUB

abnormal uterine bleeding

EA

endometrial ablation

ER α

estrogen receptor alpha

FDA

United States Food and Drug istration

FIGO

International Federation of Gynecology and Obstetrics

GnRH

gonadotropin-releasing hormone

HRT

hormone replacement therapy

LNG-IUS

levonorgestrel intrauterine system

MRg-FUS magnetic resonance-guided focused ultrasound MRI

magnetic resonance imaging

NETA

norethindrone acetate

PR

progesterone receptor

QoL

quality of life

RF

radio frequency

RFVTA

radio frequency volumetric thermal ablation

SERM

selective estrogen receptor modulator

SPRM

selective progesterone receptor modulator

UAE

uterine artery embolization

UAO

uterine artery occlusion

UPA

ulipristal acetate

impact on women’s quality of life as well as their productivity: in one survey of more than 21 000 women from 8 different countries, including 2500 from Canada, these symptoms had a negative impact on sexual life (43%), performance at work (28%), and relationship, and family (27%).4–6 Of 11 880 screened Canadian women, aged 20 to 49 years, 12.0% indicated they had been diagnosed with uterine fibroids, including 3.2% reporting current fibroids. Those with moderate to severe fibroid symptoms experienced a significantly heavier burden of illness, with lost productivity and reduced QoL.7 Uterine fibroids are currently the most common indication for hysterectomy worldwide, and in Canada they for 30% of all hysterectomies, the second most common surgery for women after Caesarean section.8 Hysterectomy is associated with significant morbidity, mortality, and economic burden on the health care system,9–10 and 1 in 4 Canadian women over age 45 have had a hysterectomy.8 The social and economic impact of uterine fibroids is therefore considerable. Summary Statement

1. Uterine fibroids are common, appearing in 70% of women by age 50; the 20% to 50% that are symptomatic have considerable social and economic impact in Canada. (II-3) Pathophysiology of Myomas

Uterine fibroids are monoclonal tumours that arise from the uterine smooth muscle tissue (i.e. the myometrium). They are benign neoplasms composed of disordered “myofibroblasts” buried in abundant quantities of extracellular matrix that s for a substantial portion of tumour volume. The initiating events for fibroid genesis remain speculative. The cells proliferate at a modest rate and their growth is dependant on the ovarian steroids estrogen and progesterone and therefore most fibroids shrink after menopause. The biologically potent estrogen estradiol induces the production of PR by means of ER-α. PR is essential for the response of fibroid tissue to progesterone secreted by the ovaries. Progesterone and PR are indispensable to tumour growth, increasing cell proliferation and survival and enhancing extracellular matrix formation. In the absence of progesterone and PR, estrogen and ER-α are not sufficient for fibroid growth.11 Myomas can be single or multiple and can vary in size, location, and perfusion. Myomas are commonly classified into 3 subgroups based on their location: subserosal (projecting outside the uterus), intramural (within the FEBRUARY JOGC FÉVRIER 2015 l 159

SOGC Clinical Practice Guideline

Figure 1. The FIGO leiomyoma subclassification system12 S – Submusosal

Leiomyoma Subclassification System

O – Other

Hybrid leiomyomas (impact both endometrium and serosa)

myometrium), and or submucosal (projecting into the cavity of the uterus). A newer, more detailed classification system has been devised and advocated by FIGO (Figure 1).12 Recognized risk factors for development of uterine fibroids include nulliparity, early menarche, increased frequency of menses, history of dysmenorrhea, family history of uterine fibroids, African descent, obesity, and age (peak incidence at 40 to 50). Clinical conditions that seem to increase risk of fibroids include hypertension and diabetes.13 Clinical Presentation

The presence of uterine fibroids can lead to various clinical challenges. The need for and choice of intervention must be individualized to the clinical situation. The most common symptom of uterine leiomyoma is AUB. In a published series of myomectomies, 30% of women suffered from heavy menstrual bleeding.14–15 The mechanism of leiomyoma-associated AUB is unknown. Increased endometrial surface area, vascular dysregulation, and interference with endometrial hemostasis have been offered as possible explanations.16 Clinicians with patients presenting with AUB should refer to the SOGC clinical practice guideline on the management of AUB.17 Pelvic pain is rare with fibroids and usually signifies degeneration, torsion, or possibly associated adenomyosis and/or endometriosis. Pelvic pressure, bowel dysfunction, and bladder symptoms such as urinary frequency and urgency may be present with larger fibroids. Urinary symptoms should be investigated prior to surgical 160 l FEBRUARY JOGC FÉVRIER 2015

0

Pedunculated intracavitary

1

< 50% intramural

2

≥ 50% intramural

3

s endometrium; 100% intramural

4

Intramural

5

Subserosal ≥ 50% intramural

6

Subserosal < 50% intramural

7

Subserosal pedunculated

8

Other (specify e.g. cervical, parasitic)

Two numbers are listed separated by a hyphen. By convention, the first refers to the relationship with the endometrium while the second refers to the relationship to the serosa. One example is below

2-5

Submusocal and subserosal, each with less than half the diameter in the endometrial and peritoneal cavities, respectively.

management of fibroids to exclude other possible causes.15 In the postmenopausal woman presenting with new onset of pain and/or bleeding in new or existing fibroids, leiomyosarcoma should be considered.18 Fibroids and Fertility

A new SOGC guideline on the management of uterine fibroids in women with otherwise unexplained infertility will be published in the spring of 2015.19 Fibroids in Pregnancy

Estimates of the prevalence of fibroids in pregnancy vary depending on the quality of the ultrasound study and the race and age of the women being studied. A recent ultrasound study found the prevalence to be 18% in African-American women, 8% in white women, and 10% in Hispanic women.20 Most ultrasound studies found that fibroids remain the same size or become smaller during pregnancy.21–23 In a 2011 report, 171 pregnant women with fibroids were followed by serial ultrasound. Postpartum, 36% of women had no identifiable fibroid and 79% of remaining fibroids had decreased in size.24 One study reported an increase in myoma size during pregnancy.25 Several large retrospective studies of ultrasounds and medical records of pregnant women have reported on the impact of fibroids on pregnancy outcomes.26–30 A 2008 meta-analysis found an overall increased risk of malpresentation (OR 2.9; 95% CI 2.6 to 3.2), Caesarean delivery (OR 3.7; 95% CI 3.5 to 3.9), and preterm delivery

The Management of Uterine Leiomyomas

(OR 1.5; 95% CI 1.3 to 1.7).31
 In 2010, a study including 72 000 pregnancies reported significant differences in odds ratios for placenta previa, abruption, premature rupture of membranes, preterm birth < 34 weeks, and intrauterine fetal death, but the differences were all < 2%, which would not be considered clinically relevant.32 It would seem that women with fibroids, especially large ones, merit close obstetrical follow-up but are likely to have a good outcome. Traditional teaching has been that myomectomy, other than for symptomatic pedunculated fibroids, should not be performed in pregnant women because of the increased risk of uncontrolled bleeding. However, a number of case series report good outcomes after myomectomy performed during pregnancy or at the time of Caesarian section, therefore it can be considered as an option if clinically necessary.33–36 Concerns about Malignancy

Leiomyosarcomas In clinical practice, the mere finding of pelvic tumours in symptomatic or asymptomatic women may raise the concern of malignancy in both patients and health care providers. In a review of 6815 patients who underwent myomectomy between 1950 and 1993, only 18 patients (0.26%) had leiomyosarcomas. In the subpopulation of women whose masses had grown rapidly, the prevalence was the same at 0.27%.37 Based on this evidence, rapid growth of a fibroid does not seem to be a predictor of leiomyosarcoma. However postmenopausal growth or onset of symptoms should carry a higher index of suspicion for malignancy. Other case series have estimated the incidence of leiomyosarcoma at 0.22% to 0.49%, although in women in their 6th decade it may rise to 1% of hysterectomy specimens.37,38 Most recent reviews are consistent with older studies and estimate that in women undergoing surgery for fibroids approximately 1 in 400 (0.25%) is at risk of having a leiomyosarcoma.39 Although incidental uterine leiomyosarcomas have been encountered during routine resectoscopic myomectomy,40 their incidence appears to be lower than that reported following hysterectomy (0.13%).41 Whether leiomyosarcomas develop from leiomyomas or arise independently is not known. The challenge lies in the fact that leiomyomas and leiomyosarcomas cannot reliably be distinguished clinically or by any imaging technique. Smooth muscle tumours of uncertain malignant potential Morphologically, there exists a spectrum of uterine smooth muscle tumours with conventionally well-defined histologic criteria and predictable clinical outcomes at

the 2 extremes, leiomyomas and leiomyosarcomas. The spectrum includes several variants with unusual features showing various combinations and permutations of 3 histologic criteria including nuclear atypia, mitotic index, and zonal necrosis that may indicate malignancy. Frequently, these variants pose diagnostic challenges because they exhibit some features of malignancy but do not meet full criteria and therefore cannot be clearly interpreted and classified as either benign or malignant. Furthermore, the behavioural and clinical outcomes associated with some of these variants have not yet been elucidated. This uncertainty frequently leads to therapeutic dilemmas, especially when the diagnosis is made in myomectomy specimens from women who wish to maintain or enhance their fertility. In 2003, the World Health Organization labelled these tumours “smooth muscle tumours of uncertain malignant potential” (STUMP).42,43 Other malignancies Other uterine malignancies such as cervical cancer and endometrial cancer may be present and contribute to AUB; these should be ruled out by appropriate evaluation and screening. Summary Statements

2. The presence of uterine fibroids can lead to a variety of clinical challenges. (III) 3. Concern about possible complications related to fibroids in pregnancy is not an indication for myomectomy except in women who have had a previous pregnancy with complications related to these fibroids. (III) 4. Women who have fibroids detected in pregnancy may require additional maternal and fetal surveillance. (II-2) Recommendation

1. Women with asymptomatic fibroids should be reassured that there is no evidence to substantiate major concern about malignancy and that hysterectomy is not indicated. (III-D) Evaluation

On physical examination, an enlarged, mobile uterus (correlating to a weight of approximately 300 g or 12 weeks of pregnancy) with irregular contour is consistent with fibroids. Ultrasonography (transabdominal, transvaginal, contrast sonohysterorography) is the most widely used modality because of its availability, ease of use, and cost-effectiveness. It is particularly helpful to assess myoma growth and the FEBRUARY JOGC FÉVRIER 2015 l 161

SOGC Clinical Practice Guideline

adnexae if these cannot be palpated separately with confidence.44 Contrast infusion saline or gel sonography and 2D and 3D sonohysterography are very accurate diagnostic procedures to detect submucosal lesions, all with sensitivity and specificity of 98% to 100%.45,46 In women with large fibroids, diagnostic imaging occasionally demonstrates hydronephrosis, the clinical significance of which is unknown. Complete ureteric obstruction is extremely rare.47 CT is of limited value in delineating the location of myomas relative to the endometrium or myometrium.48 MRI is the most accurate modality in assessing the adnexae49 and the uterus because it provides information on the size, location, number, and perfusion of leiomyomas as well as the presence of other uterine pathology including adenomyosis and/or adenomyoma.50–52 Treatment

The majority of uterine leiomyomas are asymptomatic and will not require therapy. However, 20% to 50% are clinically symptomatic, causing AUB, iron deficiency anemia, bulk effects, and/or reproductive issues,53 and may require treatment. Treatment of women with uterine leiomyomas must be individualized, based on symptomatology, the size and location of fibroids, age, the needs and desires of the patient for preservation of fertility or the uterus, the availability of therapy, and the experience of the therapist. Symptomatic uterine fibroids may be treated medically, surgically, or with a combination of both (Figure 2). Expectant Management

Prospective imaging studies indicate that 3% to 7% of untreated fibroids in premenopausal women regress over 6 months to 3 years.54,55 Most women experience shrinkage of fibroids and relief of symptoms at menopause; therefore, depending on the severity of their symptoms, women who are approaching menopause may choose to wait for the onset of menopause before deciding on treatment. Postmenopausal hormone replacement therapy is not contraindicated in the presence of fibroids and does not lead to the development of new fibroids, although it may be associated with some myoma growth, which may in turn lead to clinical symptoms.56,57 MEDICAL MANAGEMENT

Until recently, medical management options for uterine leiomyomas have been of limited value because of their moderate efficacy and/or associated adverse effects. Novel therapies at the receptor and gene levels have emerged or are undergoing investigation and may eventually offer better long-term management options.58 162 l FEBRUARY JOGC FÉVRIER 2015

Because estrogen upregulation of both ERs and PRs during the follicular phase is followed by progesteroneinduced mitogenesis during the luteal phase, all hormonal therapies to control uterine bleeding aim to regulate the effect of these 2 gonadal steroids. Oral Contraceptives

There is no evidence that low-dose oral contraceptives cause benign fibroids to grow, thus uterine fibroids are not a contraindication to their use. Oral contraceptives are effective in reducing menstrual bleeding in the short-term and may prevent the development of uterine fibroids.59 Progestins/Levonorgestrel Intrauterine System Progestogens are natural or synthetic progestational hormones which may potentially have dual actions on fibroid growth. While the natural hormone progesterone augments epidermal growth factor, which stimulates fibroid growth, it also inhibits insulin-like growth factor-1, which may inhibit growth.60 Progestogens also down-regulate both estrogen and progesterone receptors in fibroids, which may act as another mechanism in modulating fibroid biology and growth.61 Both natural progesterone and synthetic progestins cause endometrial atrophy, which has the potential to decrease menstrual blood loss in women with fibroids. One study concluded that the LNG-IUS significantly reduces menstrual blood loss and uterine volume in women with menorrhagia, with and without fibroids, while it does not significantly reduce fibroid volume.62 Another RCT found that although the rate of treatment failure was similar in both groups, the LNG-IUS was more effective in reducing menstrual blood loss than combined oral contraceptives in women with fibroid-related menorrhagia.59 A systematic review reported on both oral progestogens and the LNG-IUS for the treatment of leiomyomas. The authors found that the oral progestogen lynestrenol was not as effective as leuprolin in reducing uterine fibroid size at 16 weeks,63 and they concluded that evidence was lacking to the use of progestogens for treating premenopausal women with uterine fibroids.64 Gonadotropin-Releasing Hormone Agonists GnRH agonists are available in nasal spray, subcutaneous injections, and slow-release injections. In general, fibroids may be expected to shrink by up to 50% of their initial volume within 3 months of therapy. However, GnRH agonist treatment is restricted to a 3- to 6-month interval, following which regrowth of fibroids usually occurs within 12 weeks. Prolonged use of GnRH agonists with estrogen add-back therapy requires investigation. However, there is

The Management of Uterine Leiomyomas

Figure 2. Algorithm for the management of uterine myomas Uterine myomas Asymptomatic

Symptomatic

Clinical surveillance

Enhance fertility

Retain fertility

See SOGC Guideline19

AUB

f

Medical therapy: - SPRM (Ulipristal) - OC - Danazol - LNG-IUS - Tranexamic acid - GnRH agonist ± add-back Surgical therapy: Myomectomy - Hysteroscopic - Laparoscopic - Laparotomic

Post-menopause

Pre-menopause

Retain uterus

Bulk effects ± AUB

Investigations: - Endometrial biopsy - Imaging - Hysteroscopy

Other

Bulk effects ± AUB

Medical therapy: - SPRM (Ulipristal) - GnRH-agonist ± add-back

Interventional therapy: - UAE - MRg-FUS - Myolysis

Surgical therapy Myomectomy - Hysteroscopic - Laparoscopic - Laparotomic

Surgical therapy: Myomectomy ± EA - Hysteroscopic - Laparoscopic - Laparotomic

Hysterectomy ± BSO

Hysteroscopic myomectomy

BSO: bilateral salpingo-oophorectomy; MRg-FUS: Magnetic resonance-guided focused ultrasound; OC: oral contraceptives

evidence that progestin add-back negatively impacts the effectiveness of GnRH agonists on fibroid size.65,66 GnRH agonists are useful preoperatively to shrink fibroids and to reduce anemia related to uterine bleeding.47,67 Gonadotropin-Releasing Hormone Antagonists While GnRH agonists work by down-regulation and desensitization of the GnRH receptors, GnRH antagonists work via the classical competitive blockage mechanism. The main advantage of using GnRH antagonists is their lack of the initial “flare” effect seen with GnRH agonist stimulation and supraphysiological amounts of follicle stimulating hormone, luteinizing hormone, and estradiol, and hence have a much shorter onset of action and treatment period.68,69 The use of GnRH antagonists as a treatment for fibroids requires further evaluation. Androgens (Danazol) Danazol is chemically related to 17-α ethinyl testosterone. It competes with natural androgens, progesterone, and

glucocorticoids in receptor binding and acts at different levels of the hypothalamic-pituitary-ovarian-uterine axis. Aside from its androgenic effects, it also lowers estrogen levels by suppressing gonadotropin secretion at the levels of the hypothalamus and inhibits ovarian steroidogenesis.70 Danazol has been associated with a reduction in volume of fibroids in the order of 20% to 25%.71 Although the use of danazol for the shrinkage of uterine fibroids has been described in cohort studies, a systematic review did not find any randomized trials comparing its efficacy with placebo or other treatments.72 Although the long-term response to danazol is modest, it may offer an advantage in reducing myoma associated heavy menstrual bleeding.71 Aromatase Inhibitors (Letrozole) Myometrial cultured cells overexpress aromatase P450 and synthesize sufficient estradiol to accelerate their own cell growth. Aromatase inhibitors may serve to block the aromatase activity and growth of leiomyomata.73 FEBRUARY JOGC FÉVRIER 2015 l 163

SOGC Clinical Practice Guideline

Letrozole, an aromatase inhibitor, inhibits the conversion of androgen into estrogen. In a systematic review, only one trial involving 70 participants was included. Significantly fewer women reported hot flushes in the letrozole group than in the GnRH agonist group (0/33 vs. 26/27, P < 0.05). Use of letrozole reduced fibroid volume by 46% and use of a GnRH agonist by 32% after 12 weeks of treatment, although these results were not statistically significant. The authors concluded that the evidence is currently insufficient to the use of aromatase inhibitor drugs in the treatment of women with uterine fibroids.74 Estrogen Receptor Antagonists (Fulvestrant) The estrogen receptor antagonist fulvestrant promotes degradation and down-regulation of estrogen receptors.75 However, fulvestrant was not as effective as the GnRH agonist goserelin in reducing fibroid and uterine volume and in inducing amenorrhea.76 Selective Estrogen Receptor Modulators SERMs are nonsteroidal drugs that bind to estrogen receptors and may act as agonists or antagonists to produce tissue-specific effects. They are generally used for treating and preventing recurrence of estrogen receptor positive breast cancers. Tamoxifen has agonist properties on the uterus, but raloxifene is the most studied SERM for treatment of leiomyomata.77,78 Given the conflicted and limited data regarding the use of raloxifene alone, it is difficult to ascertain its true effect on uterine fibroids, though it may be a useful adjunct to a GnRH agonist in inducing fibroid shrinkage. Selective Progesterone Receptor Modulators Compared with the myometrium, fibroids overexpress estrogen and progesterone receptors,79 and there is “crosstalk” between ER and PR.80 It has been shown that fibroids grow primarily during the secretory phase of the menstrual cycle,81,82 and exogenous progesterone increases mitotic activity and cellularity in fibroids.83 In a randomized trial of a GnRH analogue plus addback therapy with progestin alone versus progestin plus estrogen, the authors reported that, in most instances, the add-back progestin alone (but not the progestin plus estrogen) negated the effects of the GnRH analogue on fibroid volume reduction.84 Progesterone is therefore essential for fibroid growth, and these observations have stimulated research for the development of progesterone antagonist and/or SPRM drugs. SPRMs are progesterone receptor ligands that have agonist, antagonist, partial, or mixed effects on progesterone target tissues.85 164 l FEBRUARY JOGC FÉVRIER 2015

While mifepristone is thought to have almost pure antagonistic properties, other SPRMs such as ulipristal acetate exhibit mixed agonist and antagonist properties. Though the exact mechanisms of this new class of medications are still being studied, several studies have evaluated their effectiveness in the shrinkage of fibroids and control of menstrual bleeding symptoms. While several other SPRMs are currently under investigation, here we present the evidence for SPRMs that have been studied in randomized controlled trials. Mifepristone Mifepristone (RU-486) is a progesterone receptor modulator that has almost pure antagonistic properties and may directly decrease the PR in the myometrium and leiomyoma. Though the exact mechanism for myoma size reduction is unclear, a 2013 meta-analysis of 11 RCTs involving 780 premenopausal women with symptomatic leiomyomas concluded that mifepristone significantly reduced uterine and leiomyoma volume and alleviated leioma-related symptoms. The authors recommended 2.5 mg daily for 3 to 6 months as the optimum treatment. There is insufficient evidence that mifepristone treatment led to atypical endometrial hyperplasia.86 Ulipristal acetate UPA is an SPRM that also exhibits antiproliferative effects on leiomyoma cells and the endometrium.87 One RCT that investigated the effects of UPA versus placebo before surgical treatment of symptomatic fibroids showed a reduction in myoma volume with 13 weeks of 5 mg and 10 mg of UPA of 21.2% and 12.3%, respectively, while the placebo group had a median 3% growth of myoma volume (P < 0.01).88 Patients also experienced significant decreased uterine bleeding symptoms with treatment. In a parallel RCT, UPA appeared to be no less effective than leuprolide acetate in controlling heavy menstrual bleeding: 90% of the 5 mg group and 98% of the 10 mg group experienced controlled bleeding symptoms versus 89% of the leuprolide acetate group. Median time to amenorrhea was 7 days, 5 days, and 21 days for the 5 mg, 10 mg, and leuprolide acetate groups, respectively (P < 0.001 for 10 mg vs. leuprolide acetate). However, in of uterine volumes, the 47% reduction in the leuprolide acetate group was significantly greater than the reductions of 20% in the 5 mg group and 22% in the 10 mg group. No differences were seen in hemoglobin at the end of the treatment period. Vasomotor symptoms were experienced in 11% of the 5 mg and 10% of the 10 mg groups versus 40% of the leuprolide acetate group (P < 0.001).89 Novel PRM-associated endometrial changes have been noticed with the SPRM class of drugs and appear to be benign and fully reversible.89 These changes may be

The Management of Uterine Leiomyomas

confused with endometrial hyperplasia by a pathologist who is not informed that the patient received UPA treatment or who has not been updated on the potential effect of UPA on the endometrium. It is important that the pathologist be aware of the use and effects of UPA. A recent study investigated the efficacy and safety of UPA for long-term treatment of symptomatic uterine fibroids by repeated intermittent 3-month open-label UPA courses (10 mg daily), each followed by randomized doubleblind 10-day courses of NETA 10 mg daily or placebo. The study concluded that NETA did not affect fibroid volume or endometrial histology, and repeated 3-month UPA courses effectively and safely controlled bleeding and shrunk fibroids in patients with symptomatic fibroids.90 Fibroid volume reduction in patients receiving UPA also appears to be maintained in the majority of patients for 6 months after the end of treatment.88 Summary Statements

5. Effective medical treatments for women with abnormal uterine bleeding associated with uterine fibroids include the levonorgestrel intrauterine system, (I) gonadotropin-releasing hormone analogues, (I) selective progesterone receptor modulators, (I) oral contraceptives, (II-2) progestins, (II-2) and danazol. (II-2) 6. Effective medical treatments for women with bulk symptoms associated with fibroids include selective progesterone receptor modulators and gonadotropin-releasing hormone analogues. (I) Recommendation

2. Treatment of women with uterine leiomyomas must be individualized based on symptomatology, size and location of fibroids, age, need and desire of the patient to preserve fertility or the uterus, the availability of therapy, and the experience of the therapist. (III-B) SURGICAL THERAPIES Hysterectomy

In women who have completed childbearing, hysterectomy is indicated as a permanent solution for symptomatic leiomyomas. The only indications for hysterectomy in a woman with completely asymptomatic fibroids are enlarging fibroids after menopause without HRT, which raises concerns of leiomyosarcoma, even though it remains very rare. 91,92 Women with asymptomatic fibroids should be reassured that there is no evidence to substantiate concern about malignancy, and that hysterectomy is not indicated. Hysterectomy need not be recommended as a prophylaxis

against increased operative morbidity associated with future growth.93 Type of hysterectomy

The choice and type of hysterectomy, whether it is performed by abdominal, laparoscopic, or vaginal route, should be based on surgeon’s training, experience, and comfort and on clinical practice guidelines.93 The least invasive approach feasible should be used. The advantages of abdominal supracervical or total hysterectomy are questionable, as randomized trials have demonstrated no differences in sexual and urinary function outcomes in women treated with the 2 procedures. However, there may be less blood loss and complications associated with supracervical hysterectomy.94–96 Summary Statement

7. Hysterectomy is the most effective treatment for symptomatic uterine fibroids. (III) Myomectomy

Myomectomy is an alternative to hysterectomy for women who wish to retain their uterus, regardless of their fertility desire. Removal of fibroids should be considered if they are thought to be associated with heavy mentrual bleeding, pelvic pain and/or pressure symptoms, and in some cases reproductive issues.19 Although myomectomy allows preservation of the uterus, there is a higher risk of blood loss and greater operative time with myomectomy than with hysterectomy, athough the risk of ureteric injury may be decreased with myomectomy. Fibroids have a 15% recurrence rate and 10% of women undergoing a myomectomy will eventually require hysterectomy within 5 to 10 years.97 Risk of recurrence is associated with age, preoperative number of fibroids, uterine size, associated disease, and childbirth after myomectomy.98 Five years following laparoscopic myomectomy, the cumulative probability of recurrence (new or unremoved fibroids) in women who subsequently gave birth was 42%. In those who did not give birth, it was 55%.99 Women should be counselled about the risks of requiring a hysterectomy at the time of a planned myomectomy. This would depend on the intraoperative findings and the course of the surgery. Hysterectomy remains the treatment of choice for the vast majority of women who require a surgical solution.93 Surgical planning

Myomectomy can be performed according to the number, size, and location of fibroids by laparotomy, minilaparotomy, laparoscopy, hysteroscopy, or a combination of FEBRUARY JOGC FÉVRIER 2015 l 165

SOGC Clinical Practice Guideline

these.100 Surgical planning should be based on an accurate mapping of the location, size, and number of fibroids with preoperative imaging. It is particularly important to identify the presence and size of the submucosal component to myomas as this may affect the approach taken. Summary Statement

8. Myomectomy is an option for women who wish to preserve their uterus or enhance fertility, but carries the risk of requiring further intervention. (II-2) Hysteroscopic myomectomy

An AAGL practice guideline for the diagnosis and manage­ ment of submucous leiomyomas was published in 2012.101 Hysteroscopic myomectomy has been shown to be effective for treatment of AUB in 5 series involving 1422 women. Failure rates ranged from 14.5% to 30% at 3 to 4 years’ follow-up.102 It should be considered as first-line conservative surgical therapy for the management of symptomatic intracavitary fibroids. In general, submucous myomas (types 0, I, and II) up to 4 to 5 cm in diameter can be removed hysteroscopically by experienced surgeons. Type II myomas are more likely to require a 2-staged procedure than types 0 and I because of the risk of excessive fluid absorption and uterine perforation, and caution should be used particularly with those with less than 5 mm thickness between the fibroid and the uterine serosa.103,104 Myomectomy plus endometrial ablation

When the main symptom is heavy menstrual bleeding, consideration should be given to concomittant EA at the time of transcervical resection of myoma when preservation of fertility is not desired. A cohort study showed a higher success rate in controlling bleeding when ablation was added to myomectomy.105 In selecting patients for transcervical resection of myoma, it is important to consider other factors that increase the risk of needing subsequent surgery. Women in whom myomectomy results in a normal uterus without residual myomas are at a low risk of requiring further treatment. Predictors of an increased risk for additional treatment include the presence of multiple myomas, large intramural or subserous myomas, adenomyosis, and young age at the time of treatment.106–108 Perforation of the uterus can occur with uterine sounding, dilation, or use of the resectoscope. The preoperative use of laminaria or misoprostol decreases the force needed for cervical dilation and reduces the risk of perforation. If perforation occurs with mechanical instruments and no visceral injury is suspected the patient can be observed expectantly. Laparoscopy should be considered if there is 166 l FEBRUARY JOGC FÉVRIER 2015

a large defect or heavy bleeding. If perforation occurs with an activated electrode, until proven otherwise a visceral or vascular injury should be assumed, and laparoscopy or laparotomy is recommended.109,110 Excessive fluid absorption is another potential risk. An AAGL practice guideline for the management of hysteroscopic distending media was published in 2013.111 The use of the lowest distention pressure necessary for good visualization and the careful selection of the safest distending medium will lower the risks and sequelae of excessive fluid absorption.110 Burns to the vulva, vagina, and cervix from stray electrical current during resectoscopic procedures have been documented.112–114 Laparoscopic myomectomy

The benefits of the laparoscopic approach are well known and have been found superior to laparotomic myomectomy in of less blood loss, diminished postoperative pain, fewer overall complications, faster recovery, and significant cosmetic advantage.115–118 However, laparoscopic myomectomy usually takes longer to accomplish and requires extra training, surgical expertise, and specialized equipment. The size or the number of fibroids that can be removed by laparoscopy seem to be limited only by the surgeon’s experience and technique.119 Multilayer suturing may be challenging, as may the identification and excision of smaller fibroids. Laparoscopic removal of larger fibroids in more difficult locations such as in the lower segment or at the cervical junction may present more risk of complications such as profuse bleeding; in those cases an open approach may be preferable. Consideration should also be given to the prolonged operative time required with the laparoscopic approach when faced with cases of very large (> 10 cm) or multiple leiomyomas; in these cases a myomectomy by laparotomy may be more appropriate. Injuries can occur with laparoscopic entry, and their occurrence should be minimized by following good surgical principles and the recommendations in the SOGC clinical practice guideline on laparoscopic entry.120 A prospective study reported that the short-term morbidity of laparoscopic myomectomy was similar to that of laparoscopic hysterectomy.121 Uterine scar integrity and rupture following laparoscopic myomectomy have not been fully evaluated. Uterine rupture during subsequent pregnancy seems to be a rare event and its possibility should not systematically preclude a trial of vaginal delivery.122–124 However,

The Management of Uterine Leiomyomas

because of the relatively poor quality of available evidence, close follow-up should be exercised in all cases. Uterine rupture during pregnancy after myomectomy has been reported to possibly be linked to the absence of multilayer closure in cases of deep intramural leiomyoma or to the excessive use of electrosurgical energy.125,126 Some indirect evidence based on MRI assessment of myometrial repair after Caesarian section suggests that a waiting period of 6 months between myomectomy and subsequent pregnancy would allow for optimal tissue repair of the myometrium.127

in benign gynaecological surgery and is more costly than conventional laparoscopic surgery.134

A meta-analysis of 6 randomized controlled trials from 1996 to 2007 concluded that rates of major complications, pregnancy rates and outcomes, and myoma recurrence in laparoscopic and laparotomic myomectomy were comparable.115 Two RCTs on laparoscopic versus laparotomic myomectomy reported pregnancy rates of 54% and 57%, respectively.128,129

The currently available evidence indicates that one in 400 women undergoing surgery for fibroids is at risk of having a leimomyosarcoma.39 According to the American Cancer Society’s surveillance, epidemiology, and end results data, 5-year survival for leiomyosarcoma is 60% for stage I, 35% for stage II, 22% for stage III, and 15% for stage IV.145

Mini-laparotomy

Mini-laparotomy, used as an alternative to laparoscopy, has the proposed advantage of easier suturing of the myometrium while providing a less invasive approach than conventional laparotomy. A randomized study of laparoscopic versus mini-laparotomic myomectomy reported lower decline in hemoglobin, reduced postoperative ileus and pain, and shorter hospitalization in the laparoscopy group.117 Mini-laparotomy can also be used in laparoscopically assisted mini-laparotomy. In one study, 51 women were randomized to open myomectomy, mini-laparotomy, or laparoscopically-assisted mini-laparotomy. The latter 2 approaches were associated with decreased postoperative pain and less blood loss than myomectomy by laparotomy.100 In another prospective study of 116 patients, a shorter uterine incision was found in the laparoscopically assisted myomectomy, but the estimated blood loss was greater. Complications and postoperative return to normal activities were comparable between the groups.130 Robotic assisted laparoscopy

Robotic assisted gynaecological surgery has increased exponentially in popularity in the last decade. Up to 9.5% of hysterectomies were done with the assistance of the robot in a retrospective U.S. cohort of 264 758 cases.131 However, robotic assisted myomectomy was associated in one study with greater blood loss than standard laparoscopic myomectomy.132 This, along with other well-designed studies that consistently show a longer operative time,133 prompted the AAGL to state that at this time robotic surgery offers no significant advantage

Specimen morcellation

Because laparoscopic hysterectomy and myomectomy often requires morcellation of the specimen, complications related to this step may occur, including vascular or visceral trauma with the use of a mechanical rotating blade.135 Furthermore, morcellation can lead to dissemination of leiomyoma chips leading to parasitic leiomyomas (leiomyomatosis) or dissemination of incidental leiomyosarcoma.136–144

An increased rate of recurrence and lower rate of survival following morcellation of a uterine sarcoma has been reported in several studies, implying that morcellation results in the upstaging of the disease. In cases of myomectomy, the initial steps of the procedure, including uterine incision and myoma manipulation and enucleation, are likely to spread and upstage the disease prior to myoma extraction by any method of morcellation. These findings reinforce the need for careful preoperative assessment of patients and consideration of using enclosed morcellation techniques if feasible. For laparoscopic morcellation, spillage may be minimized by placing the specimen in a bag and using the mechanical morcellator inside the bag. However use of a bag may limit visualization and has not been well studied. For larger specimens, a minilaparotomy with or without use of self-retaining retractor can be performed and the specimen be morcellated mechanically or with a scalpel blade within a bag. If the specimen is delivered vaginally and requires morcellation, again a bag can be used to enclose it to mimimize spillage. In light of concerns over morcellation of unsuspected leiomyosarcomas, the FDA issued a warning about laparoscopic power morcellation in April 2014. This prompted Health Canada (May 2014) to make the following recommendations to health-care professionals treating women with uterine fibroids146: •• Recognize the prevalence of unsuspected uterine sarcoma in patients under consideration for hysterectomy or myomectomy for the treatment of uterine fibroids. •• Consider the treatment alternatives for women with symptomatic uterine fibroids and review these options FEBRUARY JOGC FÉVRIER 2015 l 167

SOGC Clinical Practice Guideline

Table 2. Summary of recommendations regarding uterine morcellation Society of Gynecologic Oncology (December 2013)147 The use of power morcellator is generally contraindicated in the presence of documented or highly suspected malignancy, and it may be inadvisable in premalignant conditions or risk-reducing surgery. No reliable method is currently available to differentiate benign from malignant leiomyomas (leiomyosarcomas or endometrial stromal sarcomas) before they are removed. Furthermore, these diseases offer an extremely poor prognosis even when specimens are removed intact. Patients and doctors should communicate about the risks, benefits, and alternatives of all procedures so that a patient is able to make an informed and voluntary decision about accepting or declining medical care. American Association of Gynecologic Laparoscopists (April 2014)148 Most women with uterine cancer can be diagnosed prior to surgical intervention. Between 1 in 400 and 1 in 1000 women who undergo hysterectomy for presumed benign uterine myomas will be diagnosed with uterine leiomyosarcoma. The prognosis of patients with uterine leiomyosarcoma is universally poor and may be worsened in the setting of power morcellation. American College of Obstetricians and Gynecologists (May 2014)149 Recommend comprehensive patient counselling and including the following points in consent: There is a risk of inadvertent uterine leiomyosarcoma diagnosis when a myomectomy/hysterectomy is being performed for a benign leiomyoma (2:1000) Morcellation will increase peritoneal dissemination if uterine leiomyosarcoma is diagnosed and may worsen patients’ prognosis. Minimally invasive surgical approach does decrease perioperative risks to the patient. U.S. Food and Drug istration (April 2014)150 1 in 350 women undergoing hysterectomy or myomectomy for the treatment of fibroids is found to have an unsuspected uterine cancer. Laparoscopic power morcellation poses a risk of spreading unsuspected cancerous tissue, notably uterine sarcomas, beyond the uterus. The FDA discourages the use of laparoscopic power morcellation during hysterectomy or myomectomy for uterine fibroids

with each prospective surgical patient. Apart from a laparoscopic approach, alternative surgical procedures exist that do not require electric morcellation and potential tissue spread to the peritoneal cavity. Also, some surgeons and centres may recommend closed morcellation in a bag as a way to reduce the risk of inadvertent spread of uterine tissue. •• Be aware and inform patients that laparoscopic electric morcellation of unsuspected uterine sarcoma during hysterectomy or myomectomy may disseminate the disease and negatively impact prognosis. Numerous societies have responded to the FDA warning with very thorough reviews and discussion of the issue (Table 2).147–150 Recommendations

3. In women who do not wish to preserve fertility and/ or their uterus and who have been counselled

168 l FEBRUARY JOGC FÉVRIER 2015

regarding the alternatives and risks, hysterectomy by the least invasive approach possible may be offered as the definitive treatment for symptomatic uterine fibroids and is associated with a high level of satisfaction. (II-2A) 4. Hysteroscopic myomectomy should be considered firstline conservative surgical therapy for the management of symptomatic intracavitary fibroids. (II-3A) 5. Surgical planning for myomectomy should be based on mapping the location, size, and number of fibroids with the help of appropriate imaging. (III-A) 6. When morcellation is necessary to remove the specimen, the patient should be informed about possible risks and complications, including the fact that in rare cases fibroid(s) may contain unexpected malignancy and that laparoscopic power morcellation may spread the cancer, potentially worsening their prognosis. (III-B)

The Management of Uterine Leiomyomas

Pre-operative Evaluation and Adjuncts

Prior to proceeding with surgery for fibroids, appropriate evaluation and patient preparation, including correction of anemia and shrinkage of fibroid and uterine volume, are of paramount importance since preoperative anemia and uterine size can have a significant bearing on surgical outcomes. A recent large study reported that preoperative anemia, even to a mild degree, is independently associated with an increased risk of 30-day morbidity and mortality in patients undergoing major non-cardiac surgery.151 For preoperative treatment, a variety of pharmacological agents have been shown to be safe and effective. Iron should be provided in the presence of anemia together with preoperatve adjuncts to correct the anemia. GnRH agonists

A Cochrane review showed significant improvement with GnRH agonist over placebo or no treatment in preoperative hemoglobin and hematocrit and in reduction of uterine and myoma volumes.152 Compared with no treatment prior to hysterectomy, GnRH agonists reduce intraoperative bleeding and operative time, increase postoperative hemoglobin and haematocrit values, and decrease postoperative complications and length of hospital stay. They also increase the proportion of hysterectomies performed vaginally rather than abdominally and decrease the proportion of vertical incisions compared with no treatment.152 In a 2001 systematic review and meta-analysis, when GnRH agonists were used prior to myomectomy, intraoperative bleeding and rates of vertical incisions were also reduced, while postoperative hemoglobin was slightly increased. However, patients treated with GnRH agonists were more likely to have recurrence of fibroids at 6 months after myomectomy compared to no treatment. No differences were seen in rates of postoperative complications. No differences were seen in rates of blood transfusion for either type of surgery.153 A 2011 systematic review of GnRH-a showed no reduction in operative time but did show decreased introperative blood loss.154 However there is controversy over the ability to dissect myomas from myometrium after exposure to GnRH agonist.155 A double-blind, placebo-controlled trial of GnRH agonist prior to hysteroscopic myomectomy found no differences in the number of complete fibroid resections, operative times, or amounts of fluid absorbed.156 Ulipristal acetate

The 2 RCTs mentioned previously have shown the effectiveness of 3 months’ treatment to correct anemia and reduce uterine fibroid size.89,90 There were no surgical

parameters reported in these studies and surgical experience is variable. Intraoperative Adjuncts

A number of intraoperative adjuncts have been used in an effort to reduce blood loss and improve surgical outcomes in leiomyoma surgery. Misoprostol

Misoprostol is a prostaglandin E1 analogue which reduces uterine blood flow, increases myometrial contractions, and has potential to reduce blood loss during uterine surgery.156 The evidence for misoprostol as an adjunct for hysterectomy is limited and conflicting. In one randomized trial, no benefit was observed in the use of misoprostol alone for abdominal hysterectomy, but misoprostol 400 μg by rectum combined with intravenous oxytocin (10 U/hour) in women undergoing laparoscopically assisted vaginal hysterectomy was found to significantly improve operative outcomes compared with placebo.156 Placebo-controlled randomized studies have shown that a single dose of misoprostol 400 μg given vaginally 1 hour prior 157 or rectally 30 minutes prior158 to abdominal myomectomy resulted in a statistically significant reduction in operative time,157 operative blood loss, postoperative hemoglobin drop, and need for postoperative blood transfusion.157,158 No differences were observed in length of hospital stay.157 The role of misoprostol for cervical priming before operative hysteroscopy has also been reported, though not all patients in this study had fibroids as the indication for surgery. The authors found that the misoprostol group had significantly smaller initial dilation estimated by Hegar dilator, less need for surgical dilation, shorter time for cervical dilation to Hegar 9, shorter operative time, and fewer occurrences of cervical lacerations than the placebo group. Though not statistically significant, there were also fewer instances of false ages (1.4% vs 6.3%) and perforations (0% vs. 2.5%) observed.159 Oxytocin

While recent evidence suggests the presence of oxytocin receptors in uterine myomas,160 the evidence for its use as an intraoperative adjunct is somewhat conflicting. One study of women undergoing laparoscopically assisted vaginal hysterectomy indicated reduced blood loss and transfusion rates with intraoperative 20 U of oxytocin in 1000 mL of saline solution running at 40 mu/min compared to saline placebo. No differences were seen in postoperative complications and length of stay.161 FEBRUARY JOGC FÉVRIER 2015 l 169

SOGC Clinical Practice Guideline

For myomectomy, a systematic review of 2 randomized trials that compared intraoperative oxytocin against placebo for operative outcomes at myomectomy did not suggest a benefit for operative bleeding, although the pooled numbers may be difficult to interpret due to the significant heterogeneity between the 2 trials.162 Vasopressin

Vasopressin is a naturally occurring hormone that can cause vascular spasm and uterine muscle contraction, and hence has the potential to prevent bleeding during uterine surgery. As there have been several reports of cardiovascular collapse following intra-myometrial injection of vasopressin, caution should be taken to ensure proper dilution and clean communication with the anaesthesiologist.163 One randomized trial of women undergoing abdominal hysterectomy for uterine fibroids found that injection of 5 mL of 10 U in 10 mL of normal saline 1 cm medial to the uterine vessels bilaterally decreased total blood loss by approximately 40%. No differences were seen in postoperative hemoglobin, need for transfusion, or operative time.164 In a systematic review of interventions to reduce hemorrhage during myomectomy,162 2 trials comparing vasopressin to placebo showed a pooled mean difference of 298.7 mL in blood loss.165,166 No statistical differences were seen in need for blood transfusion, duration of surgery, duration of hospital stay, postoperative adhesions, or pregnancy rates at 1 year after myomectomy. Two trials compared vasopressin to tourniquets in myomectomy. In one trial, dilute vasopressin (20 units in 20 mL saline injected prior to uterine incision) had effects comparable to mechanical vascular occlusion (Penrose drain tourniquet and vascular clamps at the infundibulopelvic ligament) with respect to blood loss, postoperative morbidity, and transfusion requirements.166 In contrast, another study reported less blood loss in the vasopressin (20 U in 20 mL) group than in the tourniquet group (512.7 ± 400 mL) (P = 0.036). However, no statistically significant differences were seen in the hemoglobin drop, number of transfusions, intraoperative blood pressure, or highest postoperative pulse and temperature.166 A recent study compared intraoperative bleeding during laparoscopic myomectomy using dilute vasopressin (6 U in 20 mL) with Roeder knot loop ligation at the base of the fibroid with use of vasopressin alone and with placebo. Blood loss in the placebo (mean ± SD, 363.7 ± 147.8 mL) and vasopressin only (224.4 ± 131.2 mL) groups was significantly reduced by the addition of loop ligation at the base of the myoma (58.7 ± 27.5 mL).167 170 l FEBRUARY JOGC FÉVRIER 2015

Bupivacaine and epinephrine

In one study on laparoscopic myomectomy, the use of bupivacaine (50 mL of 0.25%) and epinephrine (0.5 mL of 1 mg/mL) was significantly more effective than placebo in reducing intraoperative bleeding, total operative time, myoma enucleation time, and subjective surgical difficulty as measured on a 1 to 10 visual analogue scale. Analgesic requirement was also reduced in the bupivacaine group (P < 0.05 for all comparisons). No differences in blood pressure or heart rate were observed.168 Antifibrinolytics

Tranexamic acid is a synthetic derivative of lysine with antifibrinolytic activity that has been used to reduce blood loss and need for blood transfusion in surgical procedures.169 However, only 1 trial has studied its effect during abdominal myomectomy using intravenous tranexamic acid (10 mg/kg patient body weight to a maximum of 1 g) given 15 minutes before skin incision versus placebo. The trial did show average reduced blood loss of 243 mL, but did not reach the authors’ level of clinical significance (250 mL).170 Gelatin-thrombin matrix

Gelatin-thrombin matrix is a hemostatic sealant with bovine derived gelatin and thrombin components. In contrast to fibrin glue, gelatin-thrombin matrix is hydrophilic and adheres well to wet tissue. When applied to tissue, the large concentration of thrombin and gelatin can result in rapid hemostasis, which may be useful in gynaecologic surgery.162 In one randomized study, application of the gelatinthrombin matrix to the site of uterine bleeding resulted in less intraoperative and postoperative blood loss than no application during abdominal myomectomy.162 Five of 25 (20%) patients in the control group required a blood transfusion, while none in the treatment group were transfused (P < 0.001). Intraoperative Uterine Artery Occlusion

Another option is to perform UAO by laparoscopy at the time of myomectomy, although the benefit seems controversial. In one study comparing laparoscopic myomectomy with or without UAO, blood loss did not differ significantly and operating time was slightly longer when UAO was performed.171 In another study, the mean operative time was significantly longer (107 minutes vs. 93 minutes; P = 0.03), but there was less intraoperative blood loss (84 mL vs. 137 mL; P < 0.001) in the UAO group, with no blood transfusions.172 Peri-cervical tourniquet

In 2 trials, occlusion of the uterine artery with or without occlusion of the ovarian arteries significantly reduced

The Management of Uterine Leiomyomas

blood loss during myomectomy and the need for blood transfusion.173,174 Anti-adhesion barriers

After the completion of myomectomy, application of antiadhesion barriers has been proposed and there is evidence of significant reduction in adhesion formation with some of them.175–177 However, none of these adjuncts has demonstrated an improvement in fertility and pregnancy outcomes. Recommendations

7. Anemia should be corrected prior to proceeding with elective surgery. (II-2A). Selective progesterone receptor modulators and gonadotropin-releasing hormone analogues are effective at correcting anemia and should be considered preoperatively in anemic patients. (I-A) 8. Use of vasopressin, bupivacaine and epinephrine, misoprostol, peri-cervical tourniquet, or gelatinthrombin matrix reduce blood loss at myomectomy and should be considered. (I-A) OTHER CONSERVATIVE TREATMENTS Uterine Artery Embolization

An SOGC clinical practice guideline on UAE has been published,178 and an up-to-date-review of UAE to treat uterine fibroids is included in the SOGC guideline.19 UAE is a procedure carried out by interventional radiologists and consists of injecting an occluding agent into one or both uterine arteries. First described in 1995, it has become one of the most common alternative conservative therapies offered to women with sympotomatic uterine fibroids. The procedure is minimally invasive and performed with the patient awake, but it is associated with significant immediate post-procedure discomfort, although recovery and return to function are rapid. Very large uteri (over 20 weeks) may not have a clinically significant response. Single submucosal fibroids or subserosal fibroids may respond better to surgery than UAE. Though successful pregnancies have been reported following UAE,179 an RCT comparing UAE to myomectomy showed that pregnancy rates were lower and miscarriage rates higher following UAE.180 This option is still best reserved for women who do not desire future pregnancy. A 2013 review and meta-analysis reported on complications and re-intervention of UAE for symptomatic uterine fibroids. Common complications were vaginal discharge and fever (4.0%), bilateral UAE

failure (4.0%), and postembolization syndrome (2.9%). The study concluded that overall, UAE has a significantly lower rate of major complications relative to surgery, but it comes at the cost of increased risk of re-intervention in the future.181 Educating patients about the rate and types of complications of UAE versus surgery, as well as the potential for reintervention, should help the patient and clinician come to a reasoned decision. Recommendation

9. Uterine artery occlusion by embolization or surgical methods may be offered to selected women with symptomatic uterine fibroids who wish to preserve their uterus. Women choosing uterine artery occlusion for the treatment of fibroids should be counselled regarding possible risks, including the likelihood that fecundity and pregnancy outcomes. (II-3A) Focused Energy Delivery Systems

A number of focused energy delivery systems have been tested in the past decade including those based upon radiofrequency electricity, supercooled cryoprobes, and most recently, MRg-FUS or high frequency ultrasound guided transcutaneous focused ultrasound ablation.182–185 A major disadvantage of all systems and techniques used to desiccate or ablate fibroids may be that they treat one fibroid at a time and they target the centre of fibroids, while fibroids have been shown to grow mostly from their periphery.186 These technologies are relatively new and although many are promising, they often lack long-term data, which interferes with our ability to present all risks and benefits with assurance. Ongoing research and data collection are required to assess the relative merit of newer options as the technology continues to expand. MR-guided focused ultrasound

The ExAblate 2000 (InSightec Inc., Haifa, Israel) was the first clinical MRg-FUS system approved by the FDA for treating uterine fibroids. Case series for MRg-FUS ranging from 51 to 359 patients have been published and shortterm efficacy is adequate, but complications such as skin burns have occurred in up to 7% of patients and at least one bowel perforation was reported.182,187,188 Disadvantages of the MRg-FUS system include high exclusion rate, requirement of an MR machine, prolonged time (minutes to several hours), treatment of 1 fibroid at a time, and ablation of fibroids centrally, while fibroids seem to grow peripherally. FEBRUARY JOGC FÉVRIER 2015 l 171

SOGC Clinical Practice Guideline

Radiofrequency myolysis

A new development in laparoscopic myolysis involves delivering of RF energy to myomas under ultrasonic guidance in an attempt to dessicate them directly. The a RFVTA system by Halt Medical has been approved for fibroid treatment in Canada. Mapping of myomas is performed by laparoscopic and ultrasound visualization. When a myoma is targeted for ablation, the RF probe is inserted percutaneously under laparoscopic guidance through a 2-mm skin incision. A recent multicentre trial concluded that RFVTA of myomas is well tolerated and results in rapid recovery, high patient satisfaction, improved quality of life, and effective symptom relief.189 Total mean fibroid volume was reduced by 45.1% and mean blood loss by 38.3% at 12 months post-procedure. Disadvantages of the Halt System include the requirement of laparoscopy and concomitant use of ultrasound, additional percutaneous skin incision(s), its treatment of 1 fibroid at a time (< 8 cm diameter), and its ablation of fibroids centrally while fibroids grow peripherally. Summary Statements

  9. Of the conservative interventional treatments currently available, uterine artery embolization has the longest track record and has been shown to be effective in properly selected patients. (II-3) 10. Newer focused energy delivery methods are promising but lack long-term data. (III) SPECIAL CONSIDERATIONS Acute Uterine Bleeding

Acute uterine bleeding unrelated to pregnancy has been defined as that which is sufficient in volume, in the opinion of the treating clinician, to require urgent or emergent intervention.190 Women with fibroids may present with acute intraperitoneal or vaginal hemorrhage, which can become life-threatening on rare occasions. Since acute uterine bleeding may or may not be associated with leiomyomas, the approach to investigation and treatment should be the same.45 Endometrial biopsy and sonographic and hysteroscopic evaluation of the uterine cavity may be limited because of patient instability, excessive bleeding, and/or blood clots. Although the evidence is very limited, after resuscitation is initiated and other causes of bleeding are ruled out by history, physical examination, and preliminary imaging, the usual approach used for acute uterine bleeding should be for uterine hemorrhage associated with fibroids.17,191,192 Only a few treatments used for acute bleeding have been studied in the context of uterine fibroids. 172 l FEBRUARY JOGC FÉVRIER 2015

Tranexamic acid, 1 g intravenously over 10 minutes or orally, 3 times daily for 5 to 7 days, has also been shown to be relatively effective when used to treat heavy menstrual bleeding in patients with fibroids.193–195 There is no evidence that tranexamic acid increases the incidence of thromboembolic disease, even when used in women at high risk. The risk of thromboembolism is less than 1%.196,197 Of all the hormonal options available for women with fibroids, ulipristal acetate has the most rapid documented onset of action and control of bleeding, with 80% of women achieving a pictorial blood assessment chart score < 75 within 7 days. However in the published studies, the treatment was initiated at onset of regular menses, and the results may not be applicable to intermenstrual bleeding or acute hemorrhage.198 Placement of an intrauterine Foley catheter has been described as a method to temporize bleeding until hormonal/medical therapies can take effect. The Foley balloon is left inflated for 1 to 48 hours depending on a number of factors, including the suspected cause of the bleeding.199,200 Occasionally, fibroids are found prolapsing through the cervix and their removal (myoma extraction) will usually stop the bleeding. Submucous fibroids may bleed heavily and some may prolapse through the cervix after initiation of GnRH agonist therapy or treatment by uterine fibroid embolization.201 There are case reports of emergency EA to control acute uterine bleeding. 202,203 EA and hysteroscopic myomectomy of submucous fibroids associated with bleeding is an option, but may be technically difficult due to poor visualization. If the woman does not respond to conservative measures, UAE can be performed if it is readily available. In cases where the bleeding is severe and not responsive to any of these measures, an emergency hysterectomy may need to be performed. Recommendation

10. In women who present with acute uterine bleeding associated with uterine fibroids, conservative management with estrogens, selective progesterone receptor modulators, antifibrinolytics, Foley catheter tamponade, and/or operative hysteroscopic intervention may be considered, but hysterectomy may become necessary in some cases. In centres where available, intervention by uterine artery embolization may be considered. (III-B)

The Management of Uterine Leiomyomas

REFERENCES 1. Day Baird D, Dunson DB, Hill MC, Cousins D, Schectman JM. High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence. Am J Obstet Gynecol 2003;188:100–7. 2. Marshall LM, Spiegelman D, Barbieri RL, Goldman MB, Manson JE, Colditz GA, et al. Variation in the incidence of uterine leiomyoma among premenopausal women by age and race. Obstet Gynecol 1997;90:967–73. 3. Cramer SF, Patel A. The frequency of uterine leiomyomas. Am J Clin Pathol 1990;94:435–8.

20. Laughlin SK, Baird DD, Savitz DA, Herring AH, Hartmann KE. Prevalence of uterine leiomyomas in the first trimester of pregnancy: an ultrasound-screening study. Obstet Gynecol 2009;113:630–5. 21. Muram D, Gillieson M, Walters JH. Myomas of the uterus in pregnancy: ultrasonographic follow-up. Am J Obstet Gynecol 1980;138:16–9. 22. Neiger R, Sonek JD, Croom CS, Ventolini G. Pregnancy-related changes in the size of uterine leiomyomas. J Reprod Med 2006;51:671–4. 23. Hammoud AO, Asaad R, Berman J, Treadwell MC, Blackwell S, Diamond MP. Volume change of uterine myomas during pregnancy: do myomas really grow? J Minim Invasive Gynecol 2006;13:386-90.

4. Zimmermann A, Bernuit D, Gerlinger C, Schaefers M, Geppert K. Prevalence, symptoms and management of uterine fibroids: an international internet-based survey of 21,746 women. BMC Womens Health 2012;12:6 (26 March 2012). Available at: http://www.biomedcentral.com/1472-6874/12/6. Accessed on November 10, 2014.

24. Laughlin SK, Herrings AH, Savitz DA, Olsham AF, Fielding JR, Hartman KE, et al. Pregnancy-related fibroid reduction. Fertil Steril 2010;94:2421–3.

5. Downes E, Sikirica V, Gilabert-Estelles J, Bolge SC, Dodd SL, Maroulis C, et al. The burden of uterine fibroids in five European countries. Eur J Obstet Gynecol Reprod Biol 2010;152:96–102.

26. Exacoustos C, Rosati P. Ultrasound diagnosis of uterine myomas and complications in pregnancy. Obstet Gynecol 1993;82:97–101.

25. De Vivo A, Mancuso A, Giacobbe A, Savasta LM, De Dominici R, Dugo N, et al. Uterine myomas during pregnancy: a longitudinal sonographic study. Ultrasound Obstet Gynecol 2011;37:361–5.

6. Pritts EA, Parker WH, Olive DL. Fibroids and infertility: an updated systematic review of the evidence. Fertil Steril 2009;91:1215–23.

27. Sheiner E, Bashiri A, Levy A, Hershkovitz R, Katz M, Mazor M. Obstetric characteristics and perinatal outcome of pregnancies with uterine leiomyomas. J Reprod Med 2004;49:182–6.

7. Vilos GA, Vilos A, Ferrazzi S. Symptomatic uterine fibroids (UFs) are common in premenopausal Canadian women and lead to reduced quality of life (QoL) across multiple domains. J Obstet Gynecol Can 2014;36(6 Suppl 1):S26. [abstract]

28. Qidwai GI, Caughey AB, Jacoby AF. Obstetric outcomes in women with sonographically identified uterine leiomyomata. Obstet Gynecol 2006;107(2 Pt 1):376–82.

8. Canadian Institute for Health Information, Statistics Canada. Health indicators. Ottawa: CIHI; 2010. Available at: https://secure.cihi.ca/free_ products/Healthindicators2010_en.pdf. Accessed on November 10, 2014. 9. Boyd LR, Novesky AP, Curtin JP. Effect of surgical volume on route of hysterectomy and short-term morbidity. Obstet Gynecol 2010;116:909–15. 10. Clark-Pearson DL, Geller EL. Complications of hysterectomy. Obstet Gynecol 2013;121:654–73. 11. Bulun SE. Uterine fibroids. N Engl J Med 2013;369:1344–55. 12. Munro MG, Critchley HO, Broder MS, Fraser IS. The FIGO Classification System (“PALM-COEIN”) for causes of abnormal uterine bleeding in non-gravid women in the reproductive years, including guidelines for clinical investigation. Int J Gynaecol Obstet 2011;113:3–13. 13. Flake GP, Andersen J, Dixon D. Etiology and pathophysiology of uterine leiomyomas; a review. Environ Health Perspect 2003;111:1037–54. 14. Buttram VC, Reiter RC. Uterine leiomyomata: etiology, symptomatology and management. Fertil Steril 1981;36:433–45. 15. Lumsden MA, Wallace EM. Clinical presentation of uterine fibroids. Baillieres Clin Obstet Gynaecol 1998;12:177–95. 16. Miura S, Khan KN, Kitajima M, Hiraki K, Moriyama S, Masuzaki H, et al. Differential infiltration of macrophages and prostaglandin by different uterine leiomyomas. Hum Reprod 2006;21:2545–54. 17. Singh S, Best C, Dunn S, Leyland N, Wolfman W; Society of Obstetrics and Gynaecology Canada Clinical Practice – Gynaecology Committee. Abnormal uterine bleeding in pre-menopausal women. SOGC Clinical Practice Guidelines, No. 292, May 2013. J Obstet Gynaecol Can 2013;35(5 Suppl 1):473–9. 18. Schwartz LB, Diamond MP, Schwartz PE. Leiomyosarcomas: clinical presentation. Am J Obstet Gynecol 1993;168(1 Pt 1):180–3. 19. Carranza-Mamane B, Havelock J, Hemmings R; Society of Obstetrics and Gynaecology Canada Reproductive Endocrinology and Infertility Committee. The management of uterine fibroids in women with otherwise unexplained infertility. SOGC Clinical Practice Guidelines. J Obstet Gynaecol Can 2015 (in press).

29. Vergani P, Locatelli A, Ghidini A, Andreani M, Sala F, Pezzullo JC. Large uterine leiomyomata and risk of cesarean delivery. Obstet Gynecol 2007;109(2 Pt 1):410–4. 30. Chen YH, Lin HC, Chen SF, Lin HC. Increased risk of preterm births among women with uterine leiomyoma: a nationwide population-based study. Hum Reprod 2009;24:3049–56. 31. Klatsky PC, Tran ND, Caughey AB, Fujimoto VY. Fibroids and reproductive outcomes: a systematic literature review from conception to delivery. Am J Obstet Gynecol 2008;198:357–66. 32. Stout MJ, Odibo AO, Graseck AS, Macones GA, Crane JP, Cahill AG. Leiomyomas at routine second-trimester ultrasound examination and adverse obstetric outcomes. Obstet Gynecol 2010;116:1056–63. 33. Lolis DE, Kalantaridou SN, Makrydimas G, Sotiriadis A, Navrozoglou I, Zikopoulos K, et al. Successful myomectomy during pregnancy. Hum Reprod 2003;18:1699–702. 34. Mu YL, Wang S, Hao J, Shi M, Yelian FD, Wang XT. Successful pregnancies with uterine leiomyomas and myomectomy at the time of caesarean section. Postgrad Med J 2011;87:601–4.
 35. Gbadebo AA, Charles AA, Austin O. Myomectomy at caesarean section: descriptive study of clinical outcome in a tropical setting. J Ayub Med Coll Abbottabad 2009;21:7–9.
 36. Park BJ, Kim YW. Safety of cesarean myomectomy. J Obstet Gynaecol Res 2009;35:906–11. 37. Parker WH, Fu YS, Berek JS. Uterine sarcoma in patients operated on for presumed leiomyoma and rapidly growing leiomyoma. Obstet Gynecol 1994;83:414–8. 38. Leibsohn S, d’Ablaing G, Mishell DR Jr., Schlaerth JB. Leiomyosarcoma in a series of hysterectomies performed for presumed uterine leiomyomas. Am J Obstet Gynecol 1990;162:968–74; discussion 974–6. 39. Knight J, Falcone T. Tissue extraction by morcellation: a clinical dilemma. J Min Invas Gynecol 2014;21:319–20. 40. Vilos GA, Harding PG, Sugimoto AK, Ettler HC, Bernier MJ. Hysteroscopic endomyometrial resection of three uterine sarcomas. J Am Assoc Gynecol Laparosc 2001;8:545–51.

FEBRUARY JOGC FÉVRIER 2015 l 173

SOGC Clinical Practice Guideline

41. Vilos GA, Edris F, Abu-Rafea B, Hollett-Caines J, Ettler HC, Al-Mubarak A. Miscellaneous uterine malignant neoplasms detected during hysteroscopic surgery. J Min Invas Gynecol 2009;16:318–25. 42. Ip PP, Tse KY, Tam KF. Uterine smooth muscle tumors other than the ordinary leiomyomas and leiomyosarcomas: a review of selected variants with emphasis on recent advances and unusual morphology that may cause concern for malignancy. Adv Anat Pathol 2010;17:91–112. 43. Vilos GA, Marks J, Ettler HC, Vilos AG, Prefontaine M, Abu-Rafea B. Uterine smooth muscle tumors of uncertain malignant potential; diagnostic challenges and therapeutic dilemmas. Report of 2 cases and review of literature. J Min Invas Gynecol 2012;19:288–95. 44. Cantuaria GH, Anglioli R, Frost L, Duncan R, Penalver MA. Comparison of bimanual examination with ultrasound before hysterectomy for uterine leiomyoma. Obstet Gynecol 1998;92:109–12. 45. Farquhar C, Ekeroma A, Furness S, Arroll B. A systematic review of transvaginal ultrasonography, sonohysterography and hysteroscopy for the investigation of abnormal uterine bleeding in premenopausal women. Acta Obstet Gynecol Scand 2003;82:493–504. 46. Makris N, Kalmantis K, Startados N, Papadimitriou A, Mantzaris G, Antsaklis A. Three dimensional hysterosonography versus hysteroscopy for the detection of intracavitary uterine abnormalities. Int J Gynecol Obstet 2007;95:6–9. 47. Vercellini P, Crosignani PG, Mangioni C, Imparato E, Ferrari A, De Giorgi O. Treatment with a gonadotrophin releasing hormone agonist before hysterectomy for leiomyomas: results of a multicentre, randomized controlled trial. Br J Obstet Gynaecol 1998;105:1148–54. 48. Bradley LD, Falcone T, Magen AB. Radiographic imaging techniques for the diagnosis of abnormal uterine bleeding. Obstet Gynecol Clin North Am 2000;27:245–76. 49. Adusumilli S, Hussain HK, Caoili EM, Weadock WJ, Murray JP, Johnson TD, et al. MRI of sonographically indeterminate adnexal masses. AJR Am J Roentgenol 2006;187:732–40. 50. Dueholm M, Lundorf E, Hansen ES, Ledertoug S, Olesen F. Accuracy of magnetic resonance imaging and transvaginal ultrasonography in the diagnosis, mapping, and measurement of uterine myomas. Am J Obstet Gynecol 2002;186:409–15. 51. Omary RA, Vasireddy S, Chrisman HB, Ryu RK, Pereles FS, Carr JC, et al. The effect of pelvic MR imaging on the diagnosis and treatment of women with presumed symptomatic uterine fibroids. J Vasc Interv Radiol 2002;13:1149–53. 52. Stamatopoulos , Mikos T, Grimbizis GF, Dimitriadis AS, Efstratiou I, Stamatopoulos P, et al. Value of magnetic resonance imaging in diagnosis of adenomyosis and myomas of the uterus. J Min Invas Gynecol 2012:19:620–6. 53. Myers ER, Barber MD, Gustilo-Ashby T, Couchman G, Matchar DB, McCrory DC. Management of uterine leiomyomata: what do we really know? Obstet Gynecol 2002;100:8–17. 54. Peddada SD, Laughlin SK, Miner K, Guyon JP, Haneke K, Vahdat HL, et al. Growth of uterine leiomyomata among premenopausal black and white women. Proc Natl Acad Sci USA. 2008;105:19887–92. 55. DeWaay DJ, Syrop CH, Nygaard IE, Davis WA, Van Voorhis BJ. Natural history of uterine polyps and leiomyomata. Obstet Gynecol 2002;100:3–7. 56. Ang WC, Farrell E, Vollenhoven B. Effect of hormone replacement therapies and selective estrogen receptor modulators in postmenopausal women with uterine leiomyomas: a systematic review. Climacteric 2001;4:284–92. 57. Yang CH, Lee JN, Hsu SC, Kuo CH, Tsai EM. Effect of hormone replacement therapy on uterine fibroids in postmenopausal women— a 3-year study. Maturitas 2002;43:35–9. 58. Al-Hendy A, Salama S. Gene therapy and uterine leiomyoma: a review. Hum Reprod Update 2006;12:385–400.

174 l FEBRUARY JOGC FÉVRIER 2015

59. Sayed GH, Zakherah MS, El-Nashar SA, Shaaban MM. A randomized clinical trial of a levonorgestrel-releasing intrauterine system and a low-dose combined oral contraceptive for fibroid-related menorrhagia. Int J Gynaecol Obstet 2011;112:126–30. 60. Maruo T, Ohara N, Yoshida S, Nakabayashi K, Sasaki H, Xu Q, et al. Translational research with progesterone receptor modulator motivated by the use of levonorgestrel-releasing intrauterine system. Contraception 2010;82:435–41. 61. Englund K, Blanck A, Gustavsson I, Lundkvist U, Sjöblom P, Norgren A, et al. Sex steroid receptors in human myometrium and fibroids: changes during the menstrual cycle and gonadotropin-releasing hormone treatment. J Clin Endocrinol Metab 1998 11;83:4092–6. 62. Magalhães J, Aldrighi JM, de Lima GR. Uterine volume and menstrual patterns in s of the levonorgestrel-releasing intrauterine system with idiopathic menorrhagia or menorrhagia due to leiomyomas. Contraception 2007;75:193–8. 63. Verspyck E, Marpeau L, Lucas C. Leuprorelin depot 3.75 mg versus lynestrenol in the preoperative treatment of symptomatic uterine myomas: a multicentre randomised trial. Eur J Obstet Gynecol Reprod Biol 2000;89:7–13. 64. Sangkomkamhang US, Lumbiganon P, Laopaiboon M, Mol BW. Progestogens or progestogen-releasing intrauterine systems for uterine fibroids. Cochrane Database Syst Rev 2013;2:CD008994. 65. Carr BR, Marshburn PB, Weatherall PT, Bradshaw KD, Breslau NA, Byrd W, et al. An evaluation of the effect of gonadotropin-releasing hormone analogs and medroxyprogesterone acetate on uterine leiomyomata volume by magnetic resonance imaging: a prospective, randomized, double blind, placebo-controlled, crossover trial. J Clin Endocrinol Metab 1993;76:1217–23. 66. Friedman AJ, Daly M, Juneau-Norcross M, Rein MS, Fine C, Gleason R, et al. A prospective, randomized trial of gonadotropin-releasing hormone agonist plus estrogen-progestin or progestin “add-back” regimens for women with leiomyomata uteri. J Clin Endocrinol Metab 1993;76:1439–45. 67. Friedman AJ, Hoffman DI, Comite F, Browneller RW, Miller JD. Treatment of leiomyomata uteri with leuprolide acetate depot: a double-blind, placebo-controlled, multicenter study. The Leuprolide Study Group. Obstet Gynecol 1991;77:720–5. 68. Reissmann T, Diedrich K, Comaru-Schally AM, Schally AV. Introduction of LHRH-antagonists into the treatment of gynaecological disorders. Human Reprod 1994;9:767–9. 69. Britten JL, Malik M, Levy G, Mendoza M, Catherino WH. Gonadotropin-releasing hormone (GnRH) agonist leuprolide acetate and GnRH antagonist cetrorelix acetate directly inhibit leiomyoma extracellular matrix production. Fertil Steril 2012;98:1299–307. 70. Panidis D, Vavilis D, Rousso D, Stergiopoulos K, Kalogeropoulos A. Danazol influences gonadotropin secretion acting at the hypothalamic level. Int J Gynaecol Obstet 1994;45:241–6. 71. ACOG Committee on Practice Bulletins-Gynecology. ACOG practice bulletin: surgical alternatives to hysterectomy in the management of leiomyomas. Int J Gynaecol Obstet 2001;73:285–94. 72. Ke LQ, Yang K, Li J, Li CM. Danazol for uterine fibroids. Cochrane Database Syst Rev 2009;3:CD007692. 73. Sumitani H, Shozu M, Segawa T, Murakami K, Yang HJ, Shimada K, et al. In situ estrogen synthesized by aromatase P450 in uterine leiomyoma cells promotes cell growth probably via an autocrine/intracrine mechanism. Endocrinology 2000;141:3852–61. 74. Song H, Lu D, Navaratnam K, Shi G. Aromatase inhibitors for uterine fibroids. Cochrane Database Syst Rev 2013;10:CD009505. 75. Wakeling AE, Dukes M, Bowler J. A potent specific pure antiestrogen with clinical potential. Cancer Res 1991;51:3867–73.

The Management of Uterine Leiomyomas

76. Donnez J, Hervais Vivancos B, Kudela M, Audebert A, Jadoul P. A randomized, placebo-controlled, dose-ranging trial comparing fulvestrant with goserelin in premenopausal patients with uterine fibroids awaiting hysterectomy. Fertil Steril 2003;79:1380–9. 77. Dutertre M, Smith CL. Molecular mechanisms of selective estrogen receptor modulator (SERM) action. J Pharmacol Exp Ther 2000;295:431–7. 78. Deng L, Wu T, Chen XY, Xie L, Yang J. Selective estrogen receptor modulators (SERMs) for uterine leiomyomas. Cochrane Database Syst Rev 2012;10:CD005287. 79. Chegini N, Ma C, Tang XM, Williams RS. Effects of GnRH analogues, ‘add-back’ steroid therapy, antiestrogen and antiprogestins on leiomyoma and myometrial smooth muscle cell growth and transforming growth factor-beta expression. Mol Hum Reprod 2002;8:1071–8. 80. Maruo T, Ohara N, Wang J, Matsuo H. Sex steroidal regulation of uterine leiomyoma growth and apoptosis. Hum Reprod Update 2004;10:207–20. 81. Kawaguschi K, Fujii S, Konishi I, Nanbu Y, Nonogaki H, Mori T. Mitotic activity in uterine leiomyomas during the menstrual cycle. Am J Obstet Gynecol 1989;160:637–41. 82. Kawaguschi K, Fujii S, Konishi I, Iwai T, Nanbu Y, Nonogaki H, et al. Immunohistochemical analysis of oestrogen receptors, progesterone receptors and Ki-67 in leiomyoma and myometrium during the menstrual cycle and pregnancy. Virchows Arch A Pathol Anat Histopathol 1991;419:309–15.

93. Lefebvre G, Allaire A, Jeffrey J, Vilos G. Hysterectomy; Socoiety of Obstetricians Clinical Practice Committee. SOGC Clinical Practice Guidelines, No. 109, January 2002. J Obstet Gynaecol Can 2002;24:37–48. 94. Thakar R, Ayers S, Clarkson P, Stanton S, Manyonda I. Outcomes after total versus subtotal abdominal hysterectomy. N Engl J Med 2002;347:1318–25. 95. Learman LA, Summitt RL Jr, Varner RE, McNeeley SG, Goodman-Gruen D, Richter HE, et al.; Total or Supracervical Hysterectomy (TOSH) Research Group. A randomized comparison of total or supracervical hysterectomy: surgical complications and clinical outcomes. Obstet Gynecol 2003;102:453–62. 96. American Association of Gynecologic Laparoscopists (AAGL). Practice report: practice guidelines for laparoscopic/subtotal supracervical hysterectomy. J Min Invas Gynecol 2014;21:9–16. 97. Garcia CR. Management of the symptomatic fibroid in women older than 40 years of age: hysterectomy or myomectomy? Obstet Gynecol Clin North Am 1993;20:337–48. 98. Yoo EH, Lee PI, Huh CY, Kim DH, Lee BS, Lee JK, et al. Predictors of leiomyoma recurrence after laparoscopic myomectomy. J Minim Invasive Gynecol 2007;14:690–7. 99. Al-Mahrizi S, Tulandi T. Treatment of uterine fibroids for abnormal uterine bleeding: myomectomy and uterine artery embolization. Best Pract Res Clin Obstet Gynaecol 2007;21:995–1005.

83. Seagaloff A, Weed JC, Sternberg WH, Parson W. The progesterone therapy of human uterine leiomyomas. J Clin Endocrinol Metrab 1949;9:1273–91.

100. Cagnacci A, Pirillo D, Malmusi S, Arangino S, Alessandrini C, Volpe A. Early outcome of myomectomy by laparotomy, minilaparotomy and laparoscopically assisted minilaparotomy. A randomized prospective study. Hum Reprod 2003;18:2590–4.

84. Friedman AJ, Daly M, Juneau-Norcross M, Gleason R, Rein MS, LeBoff M. Long-term medical therapy for leiomyomata uteri: a prospective, randomized study of leuprolide acetate depot plus either oestrogen-progestin or progestin ‘add-back’ for 2 years. Hum Reprod 1994;9:1618–25.

101. American Association of Gynecologic Laparoscopists (AAGL): Advancing Minimally Invasive Gynecology Worldwide. AAGL practice report: practice guidelines for the diagnosis and management of submucous leiomyomas. J Minim Invasive Gynecol 2012;19:152–71.

85. Chwalisz K, Perez MC, Demanno D, Winkel C, Schubert G, Elger W. Selective progesterone receptor modulator development and use in the treatment of leiomyomata and endometriosis. Endocr Rev 2005;26:423–38. 86. Shen Q, Hua Y, Jiang W, Zhang W, Chen M, Zhu X. Effects of mifepristone on uterine leiomyoma in premenopausal women: a meta-analysis. Fertil Steril 2013;100:1722–6. 87. Chabbert-Buffet N, Pintiaux-Kairis A, Bouchard P; VA2914 Study Group. Effects of the progesterone receptor modulator VA2914 in a continuous low dose on the hypothalamic-pituitary-ovarian axis and endometrium in normal women: a prospective, randomized, placebo-controlled trial. J Clin Endocrinol Metab 2007;92:3582–9. 88. Donnez J, Tatarchuk TF, Bouchard P, Puscasiu L, Zakharenko NF, Ivanova T, et al. Ulipristal acetate versus placebo for fibroid treatment before surgery. N Engl J Med 2012;366:409–20. 89. Donnez J, Tomaszewski J, Vazquez F, Bouchard P, Lemieszczuk B, Baro F, et al. Ulipristal acetate versus leuprolide acetate for uterine fibroids. N Engl J Med 2012;366:421–32. 90. Donnez J, Vazquez F, Tomaszewski J, Nouri K, Bouchard P, Fa B, et al. PEARL III and PEARL III Extension Study Group. Longterm treatment of uterine fibroids with ulipristal acetate*. Fertil Steril 2014;101(6):1565–73. 91. Weber AM, Mitchinson AR, Gidwani GP, Mascha E, Walters MD. Uterine myomas and factors associated with hysterectomy in premenopausal women. Am J Obstet Gynecol 1997;176:1213–7. 92. Friedman AJ, Haas ST. Should uterine size be an indication for surgical intervention in women with myomas? Am J Obstet Gynecol 1993;168 (3 Pt 10):751–5.

102. Munro MG. Abnormal uterine bleeding: surgical management – part 3. J Am Assoc Gynecol Laparosc 2001;8:18–47. 103. College National des Gynécologues et Obstétriciens Français (CNGOF). Actualisation de la prise en charge des myomes [Myoma management recommandations]. J Gynecol Obstet Biol Reprod 2011;40:693–708. 104. Wamsteker K, Emanuel MH, de Kruif JH. Transcervical hysteroscopic resection of submucous fibroids for abnormal uterine bleeding: results regarding the degree of intramural extension. Obstet Gynecol 1993;82:736–40. 105. Loffer FD. Improving results of hysteroscopic submucusal myomectomy for menorrhagia by concomitant endometrial ablation. J Min Invas Gynecol 2005;12:254–60. 106. Emanuel MH, Wamsteker K, Hart AA, Metz G, Lammes FB. Long-term results of hysteroscopic myomectomy for abnormal uterine bleeding. Obstet Gynecol 1999;93(5 Pt 1):743–8. 107. Hart R, Molnar BG, Magos A. Long-term follow-up of hysteroscopic myomectmoy assessed by survical analysis. Br J Obstet Gynaecol 1999;106:700–5. 108. Margiani R, Mossa B, Ebano V, Perniola G, Melluso J, Napolitano C. Transcervical myomectomy: long-term effects on abnormal uterine bleeding. Clin Exp Obstet Gynecol 2005;32:23–6. 109. Bradley LD. Complications in hysteroscopy: prevention, treatment and legal risk. Curr Opin Obstet Gynecol 2002;14:409–15. 110. Vilos GA. Chapter on hysteroscopic surgery: indications, contraindications and complications. In: Pasic R, Levine RA. Practical manual of hysteroscopy and endometrial ablation: a clinical cookbook. Boca Raton, FL: CRC Press 2004:237–58.

FEBRUARY JOGC FÉVRIER 2015 l 175

SOGC Clinical Practice Guideline

111. AAGL Advancing Minimally Invasive Gynecology Worldwide, Munro MG, Storz K, Abbott JA, Falcone T, Jacobs VR, et al. AAGL practice report. practice guidelines for the management of hysteroscopic distendng media. J Minim Invasive Gynecol 2013;20:137–48.

128. Seracchioli R, Rossi S, Govoni F, Rossi E, Venturoli S, Bulletti C, et al. Fertility and obstetric outcome after laparoscopic myomectomy of large myomata: a randomized comparison with abdominal myomectomy. Hum Reprod 2000;15:2663–8.

112. Vilos GA, Brown S, Graham G, McCulloch S, Borg P. Genital tract electrical burns during hysteroscopic endometrial ablation: report of 13 cases in the United States and Canada. J Am Assoc Gynecol Laparosc 2000;7:141–7.

129. Hurst BS, Matthew, ML, Marshburn PB. Laparoscopic myomectomy for symptomatic uterine myomas. Fertil Steril 2005;83:1–23.

113. Vilos GA, McCulloch S, Borg P, Zheng W, Denstedt J. Intended and stray radiofrequency electrical currents during resectoscopic surgery. J Am Assoc Gynecol Laparsc 2000;7:55–63. 114. Vilos GA, Newton DW, Odell RC, Abu-Rafea B, Vilos AG. Characterization and mitigation of stray radiofrequency currents during monopolar resectoscopic electrosurgery. J Minim Invasive Gynecol 2006;13:134–40. 115. Jin C, Hu Y, Chen XC, Zheng FY, Lin F, Zhou K, et al. Laparoscopic versus open myomectomy – a meta-analysis of randomized controlled trials. Eur J Obstet Gynecol Reprod Biol 2009;145:14–21.
 116. Holzer A, Jirecek ST, Illievich UM, Huber J, Wenzl RJ. Laparoscopic versus open myomectomy: a double-blind study to evaluate postoperative pain. Anesth Analg 2006;102:1480–4. 117. Alessandri F, Lijoi D, Mistrangelo E, Ferrero S, Ragni N. Randomized study of laparoscopic versus minilaparotomic myomectomy for uterine myomas. J Minim Invasive Gynecol 2006;13:92–7.
 118. Malzoni M, Tinelli R, Cosentino F, Iuzzolino D, Surico D, Reich H. Laparoscopy versus minilaparotomy in women with symptomatic uterine myomas: short-term and fertility results. Fertil Steril 2010;93:2368–73. 119. Sinha R, Hegde A, Warty N, Patil N. Laparoscopic excision of very large myomas. J Am Assoc Gynecol Laparosc 2003;10:461–8. 120. Vilos GA, Ternamian A, Dempster J, Laberge PY; Society of Obstetricians and Gynaecologists of Canada Clinical Practice Gynaecology Committee. Laparoscopic entry: a review of techniques, technologies, and complications. SOGC Clinical Practice Guidelines, No. 193, May 2007. J Obstet Gynaecol Can 2007;29:433–65.

130. Prapas Y, Kalogiannidis I, Prapas N. Laparoscopy vs laparoscopically assisted myomectomy in the management of uterine myomas: a prospective study. Am J Obstet Gynecol 2009;200:144–6. 131. Wright JD, Ananth CV, Lewin SN, Burke WM, Lu YS, Neugut AI, et al. Robotically assisted vs laparoscopic hysterectomy among women with benign gynecologic disease. JAMA 2013;309:689–98. 132. Gargiulo AR, Srouji SS, Missmer SA, Correia KF, Vellinga T, Einarsson JI. Robot-assisted laparoscopic myomectomy compared with standard laparoscopic myomectomy. Obstet Gynecol 2012;120(2 Pt 1):284–91. 133. Liu H, Lu D, Wang L, Shi G, Song H, Clarke J. Robotic surgery for benign gynaecological disease. Cochrane Database Syst Rev 2012;2:CD008978. 134. AAGL Advancing Minimally Invasive Gynecology Worldwide. AAGL position statement: robotic-assisted laparoscopic surgery in benign gynecology. J Min Invasiv Gynecol 2013;20:2–9. 135. Milad M, Milad E. Laparoscopic morcellator-related complications. J Min Invas Gynecol 2014;21:486–91. 136. Sizzi O, Rossetti A, Malzoni M, Minelli L, La Grotta F, Soranna L, et al. Italian multicenter study on complications of laparoscopic myomectomy. J Minim Invasive Gynecol 2007;14:453–62.
 137. Cucinella G, Granese R, Calagna G, Somigliana E, Perino A. Parasitic myomas after laparoscopic surgery: an emerging complication in the use of morcellator? Description of four cases. Fertil Steril 2011;96:e90-e96. 138. Hilger WS, Magrina JF. Removal of pelvic leiomyomata and endometriosis five years after supracervical hysterectomy. Obstet Gynecol 2006;108(3 Pt 2):772–4. 139. Hutchins FL Jr, Reinoehl EM. Retained myoma after laparoscopic supracervical hysterectomy with morcellation. J Am Assoc Gynecol Laparosc 1998;5:293–5.

121. Lemyre M, Bujold E, Lathi R, Bhagan L, Huang JQ, Nezhat C. Comparison of morbidity associated with laparoscopic myomectomy and hysterectomy for the treatment of uterine leiomyomas. J Obstet Gynaecol Can 2012;34:57–62.

140. Ordulu Z, Dal Cin P, Chong WWS, Choy KW, Lee C, Muto MG, et al. Disseminated peritoneal leiomyomatosis after laparoscopic supracervical hysterectomy with characteristic molecular cytogenetic findings of uterine leiomyoma. Genes Chromosomes Cancer 2010;49:1152–60.

122. Gyamfi-Bannerman C, Gilbert S, Landon MB, Spong CY, Rouse DJ, Varner MW, et al.; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network. Risk of uterine rupture and placenta accreta with prior uterine surgery outside of the lower segment. Obstet Gynecol. 2012;120:1332–7.

141. Sinha R, Sundaram M, Mahajan C, Sambhus A. Multiple leiomyomas after laparoscopic hysterectomy: report of two cases. J Minim Invasive Gynecol 2007;14:123–7.

123. Kumakiri J, Takeuchi H, Itoh S, Kitade M, Kikuchi I, Shimanuki H, et al. Prospective evaluation for the feasibility and safety of vaginal birth after laparoscopic myomectomy. J Minim Invasive Gynecol 2008;15:420–4.
 124. Seracchioli R, Manuzzi L, Vianello F, Gualerzi B, Savelli L, Paradisi R, et al. Obstetric and delivery outcome of pregnancies achieved after laparoscopic myomectomy. Fertil Steril 2006;86:159–65.
 125. Seinera P, Arisio R, Decko A, Farina C, Crana F. Laparoscopic myomectomy: indications, surgical technique and complications. Hum Reprod 1997;12:1927–30.

142. Worthington-Kirsch R, Hutchins FJ Jr. Retained myoma fragment after LASH procedure. Clin Radiol 2001;56:777–8. 143. Sihna R, Sundaran M, Lakhotia S. Recurrent leiomyomatosis. J Min Invas Gynecol 2009;16:668–8. 144. Ribič-Pucelj M, Cvjetićanin B, Šalamun V. Leiomyomatosis peritonealis disseminata as a possible result of laparoscopic myomectomy— report of four cases. Gynecol Surg 2013;10:253–6. 145. Amercian Cancer Society. Survival rates for uterine sarcoma, by stage. Atlanta, GA: American Cancer Society; 2014. Available at: http://www.cancer.org/cancer/uterinesarcoma/detailedguide/ uterine-sarcoma-survival-rates. Accessed on November 11, 2014.

126. Parker WH, Einarsson J, Istre O, Dubuisson JB. Risk factors for uterine rupture after laparoscopic myomectomy. J Minim Invasive Gynecol 2010;17:551–4.

146. Health Canada. Laparoscopic electric morcellators - risk of spread of unsuspected uterine sarcoma - notice to hospitals. Ottawa: Health Canada; 2014. Available at http://healthycanadians.gc.ca/recall-alert-rappel-avis/ hc-sc/2014/39409a-eng.php. Accessed on November 11, 2014.

127. Dicle O, Kücükler C, Pirnar T, Erata Y, Posaci C. Magnetic resonance imaging evaluation of incision healing after cesarean sections. Eur Radiol 1997;7:31–4.

147. Society of Gynecologic Oncology. SGO position statement: morcellation. Chicago: SGO; 2013. Available at https://www.sgo.org/newsroom/ position-statements-2/morcellation. Accessed on November 11, 2014.

176 l FEBRUARY JOGC FÉVRIER 2015

The Management of Uterine Leiomyomas

148. AAGL Advancing Minimally Invasive Gynecology Worldwide. Morcellation during uterine tissue extraction. J Minim Invasive Gynecol 2014;21:517–30.

164. Okin CR, Guido RS, Meyn LA, Ramanathan S. Vasopressin during abdominal hysterectomy: a randomized controlled trial. Obstet Gynecol 2001;97:867–72.

149. American College of Obstetricians and Gynecologists. Power morcellation and occult malignancy in gynecologic surgery. Washington, DC: ACOG; 2014. Available at http://www.acog.org/ Resources-And-Publications/Task-Force-and-Work-Group-Reports/ Power-Morcellation-and-Occult-Malignancy-in-Gynecologic-Surgery. Accessed on November 22, 2014.

165. Ginsburg ES, Benson CB, Garfield JM, Gleason RE, Friedman AJ. The effect of operative technique and uterine size on blood loss during myomectomy: a prospective randomized study. Fertil Steril 1993;60:956–62.

150. Food and Drug istration. Quantitative assessment of the prevalence of unsuspected uterine sarcoma in women undergoing treatment of uterine fibroids: summary and key findings. Silver Spring, MD: FDA; 2014. Available at http://www.fda.gov/s/ MedicalDevices/Safety/AlertsandNotices/UCM393589.pdf. Accesssed on November 11, 2014. 151. Mussalam KM, Tamim HM, Richards T, Spahn DR, Rosendaal FR, Habbal A, et al. Preoperative anaemia and postoperative outcomes in non-cardiac surgery: a retrospective cohort study. Lancet 2011;378(9800:1396–407. 152. Lethaby A, Vollenhoven B, Sowter M. Pre-operative GnRH analogue therapy before hysterectomy or myomectomy for uterine fibroids. Cochrane Database Syst Rev 2001;(2):CD000547. 153. Chen I, Motan T, Kiddoo D. Gonadotropin-releasing hormone agonist in laparoscopic myomectomy: systematic review and meta-analysis of randomized controlled trials. J Minim Invasive Gynecol 2011;18:303–9.
 154. De Falco M, Staibano S, Mascolo M, Mignogna C, Improda L, Ciociola F, et al. Leiomyoma pseudocapsule after pre-surgical tratment with gonadotropin-releasing hormone agonists: relationship between clinical features and immunohistochemical changes. Eur J Obstet Gynecol Reprod Biol 2009;144:44–7. 155. Mavrelos D, Ben-Nagi J, Davies A, Lee C, Salim R, Jurkovic D. The value of pre-operative treatment with GnRH analogues in women with submucous fibroids: a double-blind, placebo-controlled randomized trial. Hum Reprod 2010;25:2264–9. 156. Chang FW, Yu MH, Ku CH, Chen CH, Wu GJ, Liu JY. Effect of uterotonics on intra-operative blood loss during laparoscopyassisted vaginal hysterectomy: a randomised controlled trial. BJOG 2006;113:47–52. 157. Celik H, Sapmaz E. Use of a single preoperative dose of misoprostol is efficacious for patients who undergo abdominal myomectomy. Fertil Steril 2003;79:1207–10. 158. Frederick S, Frederick J, Fletcher H, Reid M, Hardie M, Gardner W. A trial comparing the use of rectal misoprostol plus perivascular vasopressin with perivascular vasopressin alone to decrease myometrial bleeding at the time of abdominal myomectomy. Fertil Steril 2013;100:1044–9. 159. Preutthipan S, Herabutya Y. Vaginal misoprostol for cervical priming before operative hysteroscopy: a randomized controlled trial. Obstet Gynecol 2000;96:890–4. 160. Cesen-Cummings K, Houston KD, Copland JA, Moorman VJ, Walker CL, Davis BJ. Uterine leiomyomas express myometrial contractile-associated proteins involved in pregnancy-related hormone signaling. J Soc Gynecol Investig 2003;10:11–20. 161. Wang CJ, Yuen LT, Yen CF, Lee CL, Soong YK. A simplified method to decrease operative blood loss in laparoscopic-assisted vaginal hysterectomy for the large uterus. J Am Assoc Gynecol Laparosc 2004;11:370–3.


166. Fletcher H, Frederick J, Hardie M, Simeon D. A randomized comparison of vasopressin and tourniquet as hemostatic agents during myomectomy. Obstet Gynecol 1996;87:1014–8. 167. Zhao F, Jiao Y, Guo Z, Hou R, Wang M. Evaluation of loop ligation of larger myoma pseudocapsule combined with vasopressin on laparoscopic myomectomy. Fertil Steril 2011;95:762–6. 168. Zullo F, Palomba S, Corea D, Pellicano M, Russo T, Falbo A, et al. Bupivacaine plus epinephrine for laparoscopic myomectomy: a randomized placebo-controlled trial. Obstet Gynecol 2004;104:243–9. 169. Wellington K, Wagstaff AJ. Tranexamic acid: a review of its use in the management of menorrhagia. Drugs 2003;63:1417–33. 170. Caglar GS, Tasci Y, Kayikcioglu F, Haberal A. Intravenous tranexamic acid use in myomectomy: a prospective randomized double-blind placebo controlled study. Eur J Obstet Gynecol Reprod Biol 2008;137:227–31. 171. Bae JH, Chong GO, Seong WJ, Hong DG, Lee YS. Benefit of uterine artery ligation in laparoscopic myomectomy. Fertil Steril 2011;95:775–8.
 172. Chang WC, Huang PS, Wang PH, Chang DY, Huang SC, Chen SY, et al. Comparison of laparoscopic myomectomy using in situ morcellation with and without uterine artery ligation for treatment of symptomatic myomas. J Minim Invasive Gynecol 2012;19:715–21. 173. Ikechebelu JI, Ezeama CO, Obiechina NJ. The use of tourniquet to reduce blood loss at myomectomy. Niger J Clin Pract 2010;13:154–8. 174. Taylor A, Sharma M, Tsirkas P, Di Spiezio Sardo A, Setchell M, Magos A. Reducing blood loss at open myomectomy using triple tourniquets: a randomised controlled trial. BJOG 2005;112:340–5. 175. Tinelli A, Malvasi A, Guido M, Tsin DA, Hudelist G, Hurst B, et al. Adhesion formation after intracapsular myomectomy with or without adhesion barrier. Fertil Steril 2011;95:1780–5.
 176. Mettler L, Hucke J, Bojahr B, Tinneberg HR, Leyland N, Avelar R. A safety and efficacy study of a resorbable hydrogel for reduction of post-operative adhesions following myomectomy. Hum Reprod 2008;23:1093–100. 177. Takeuchi H, Kitade M, Kikuchi I, Shimanuki H, Kumakiri J, Kinoshita K. Adhesion-prevention effects of fibrin sealants after laparoscopic myomectomy as determined by second-look laparoscopy: a prospective, randomized, controlled study. J Reprod Med 2005;50:571–7.
 178. Lefebvre GG, Vilos G, Asch M; Society of Obstetricians and Gynaecologists of Canada; Canadian Association of Radiologists; Canadian Interventional Radiology Association. Uterine fibroid embolization (UFE). SOGC Clinical Practice Guidelines, No. 150, October 2004. J Obstet Gynaecol Can 2004;26:913–28. 179. Pron G, Mocarski E, Bennett J, Vilos G, Common A, Vanderburgh L; Ontario UFE Collaborative Group. Pregnancy after uterine artery embolization for leiomyomata: the Ontario multicenter trial. Obstet Gynecol 2005;105:67–76.

162. Kongnyuy EJ, Wiysonge CS. Interventions to reduce haemorrhage during myomectomy for fibroids. Cochrane Database Syst Rev 2011;(11):CD005355.

180. Mara M, Kubinova K. Embolization of uterine fibroids from the point of view of the gynecologist: pros and cons. Int J Womens Health 2014;6:623–9.

163. Riess ML, Ulrichs JG, Pagel PS, Woehlck HJ. Case report: severe vasospasm mimics hypotension after high-dose intrauterine vasopressin. Anesth Analg 2011;113:1103–5.

181. Martin J, Bhanot K, Athreya S. Complications and reinterventions in uterine artery embolization for symptomatic uterine fibroids: a literature review and meta-analysis. Cardiovasc Intervent Radiol 2013;36:395–402.

FEBRUARY JOGC FÉVRIER 2015 l 177

SOGC Clinical Practice Guideline

182. Zupi E, Sbracia M, Marconi D, Munro MG. Myolysis of uterine fibroids: is there a role? Clin Obstet Gynecol 2006;49:821–33. 183. National Institute for Health and Clinical Excellence (NICE). IPG 413: magnetic resonance image-guided transcutaneous focused ultrasound for uterine fibroids. London: NICE; 2014. Available at https://www.nice.org.uk/guidance/ipg413/resources/guidancemagnetic-resonance-imageguided-transcutaneous-focused-ultrasound-foruterine-fibroids-pdf. Accessed on November 11, 2014. 184. Ghezzi F, Cromi A, Bergamini V, Scarperi S, Bolis P, Franchi M. Midterm outcome of radiofrequency thermal ablation for symptomatic uterine myomas. Surg Endosc 2007;21:2081–5. 185. Pansky M, Cowan BD, Frank M, Hampton HL, Zimberg S. Laparoscopically assisted uterine fibroid cryoablation. Am J Obstet Gynecol 2009;201:571–7. 186. Bourlev V, Pavlovitch S, Stygar D, Volkov N, Lindblom B, Olovsson M. Different proliferative and apoptotic activity in peripheral versus central parts of human uterine leiomyomas. Gynecol Obstet Invest 2003;55:199–204. 187. Bouwsma EV, Hesley GK, Woodrum DA, Weaver AL, Leppert PC, Peterson LG, et al. Comparing focused ultrasound and uterine artery embolization for uterine fibroids-rationale and design of the Fibroid Interventions: Reducing Symptoms Today and Tomorrow (FIRSTT) trial. Fertil Steril 2011;96:704–10. 188. Bouwsma EV, Gorny KR, Hesley GK, Jensen JR, Peterson LG, Stewart EA. Magnetic resonance-guided focused ultrasound surgery for leiomyoma-associated infertility. Fertil Steril 2011;96:e9–e12.

193. Lakhani KP, Marsh MS, Purcell W, Hardiman P. Uterine artery blood flow parameters in women with dysfunctional uterine bleeding and uterine fibroids: the effects of tranexamic acid. Ultrasound Obstet Gynecol 1998;11:23–8. 194. Lukes AS, Moore KA, Muse KN, Gersten JK, Hecht BR, Edlund M, et al. Tranexamic acid treatment for heavy menstrual bleeding: a randomized controlled trial. Obstet Gynecol 2010;116:865–75. 195. Naoulou B, Tsai MC. Efficacy of tranexamic acid in the treatment of idiopathic and non-functional heavy menstrual bleeding: a systematic review. Acta Obstet Gynecol Scand 2012;91:529–37. 196. Lindoff C, Rybo G, Astedt B. Treatment with tranexamic acid during pregnancy, and the risk of thrombo-embolic complications. Thromb Haemost 1993;70:238–40. 197. Sundstrom A, Seaman H, Kieler H, Alfredsson L. The risk of venous thromboembolism associated with the use of tranexamic acid and other drugs used to treat menorrhagia: a case-control study using the General Practice Research Database. BJOG 2009;116:91–7. 198. Donnez J, Tomaszewski J, Vazquez F, Bouchard P, Lemieszczuk B, Baro F, et al. Ulipristal acetate versus leuprolide acetate for uterine fibroids. N Engl J Med 2012;366:421–32. 199. Hamani Y, Ben-Shachar I, Kalish Y, Porat S. Intrauterine balloon tamponade as a treatment for immune thrombocytopenic purpurainduced severe uterine bleeding. Fertil Steril 2010;94:2769.e13-e5. 200. Goldrath MH. Uterine tamponade for the control of acute uterine bleeding. Am J Obstet Gynecol 1983;147:869–72.

189. Chudnoff SG, Berman JM, Levine DJ, Harris M, Guido RS, Banks E. Outpatient procedure for the treatment and relief of symptomatic uterine myomas. Obstet Gynecol 2013;121:1075–82.

201. Thorp JM, Katz VL. Submucous myomas treated with gonadotropin releasing hormone agonist and resulting in vaginal hemorrhage. A case report. J Reprod Med 1991;36:625–6.

190. Munro MG; Southern California Permanente Medical Group’s Abnormal Uterine Bleeding Working Group. Acute uterine bleeding unrelated to pregnancy: a Southern California Permanente Medical Group practice guideline. Perm J 2013;17:43–56.

202. Richards SR. Endometrial ablation for life-threatening abnormal uterine bleeding. A report of two cases. J Reprod Med 1994 Sep;39:741–2.

191. Friedman AJ. Combined oestrogen-progestin treatment of vaginal hemorrhage following gonadotropin-releasing hormone agonist therapy of uterine myomas. Hum Reprod 1993;8:540–2. 192. Thomas MA, Gass ML, Scott MC, Liu JH. Multiple therapies for vaginal bleeding secondary to large uterine myomas. Int J Gynaecol Obstet 1991;36:239–41.

178 l FEBRUARY JOGC FÉVRIER 2015

203. Osuga Y, Okagaki R, Ozaki S, Matsumi H, Fujii T, Iwase H, et al. Successful emergency endometrial ablation for intractable uterine bleeding in a postmenopausal woman complicated with liver cirrhosis and morbid obesity. Surg Endosc 2001;15:898. 204. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

SOGC CLINICAL PRACTICE GUIDELINE No. 330, December 2015

Obstetrical Anal Sphincter Injuries (OASIS): Prevention, Recognition, and Repair This clinical practice guideline has been prepared by the Urogynaecology Committee, reviewed by the Clinical Practice–Obstetrics and the Family Physician Advisory committees, and approved by the Executive and Board of the Society of Obstetricians and Gynaecologists of Canada PRINCIPAL AUTHORS Marie-Andrée Harvey, MD, MSc, Kingston ON Marianne Pierce, MD, Halifax NS UROGYNAECOLOGY COMMITTEE Jens-Erik Walter, MD (Chair), Montreal QC Queena Chou, MD, London ON Phaedra Diamond, MD, Toronto ON Annette Epp, MD, Saskatoon SK Roxana Geoffrion, MD, Vancouver BC Marie-Andrée Harvey, MD, Kingston ON Annick Larochelle, MD, Montreal QC Kenny Maslow, MD, Winnipeg MB Grace Neustaedter, RN, Calgary AB Dante Pascali, MD, Ottawa ON Marianne Pierce, MD, Halifax NS Jane Schulz, MD, Edmonton AB David Wilkie, MD, Vancouver BC SPECIAL CONTRIBUTORS Abdul Sultan, MB ChB, MD, FRCOG Ranee Thakar, MBBS, MD, MRCOG Disclosure statements have been received from all contributors.

Key words: Anal sphincter injury, anal incontinence, obstetrical complications, sphincteroplasty, perineal laceration, overlap repair, end-to-end repair, pregnancy.

Abstract Objective: To review the evidence relating to obstetrical anal sphincter injuries (OASIS) with respect to diagnosis, repair techniques and outcomes. To formulate recommendations as to patient counselling regarding route of delivery for subsequent pregnancy after OASIS. Options: Obstetrical care providers caring for women with OASIS have the option of repairing the anal sphincter using end-toend or overlapping techniques. They may also be involved in counselling women with prior OASIS regarding the route of delivery for future pregnancies. Outcomes: The outcome measured is anal continence following primary OASIS repair and after subsequent childbirth. Evidence: Published literature was retrieved through searches of Medline, EMBASE, and The Cochrane Library in May 2011 using appropriate controlled vocabulary (e.g., anal canal, obstetrics, obstetric labour complication, pregnancy complication, treatment outcome, surgery, quality of life) and key words (obstetrical anal sphincter injur*, anus sphincter, anus injury, delivery, obstetrical care, surgery, suturing method, overlap, end-to-end, feces incontinence). Results were restricted to systematic reviews, randomized control trials/ controlled clinical trials, and observational. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to September 2014. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Values: The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). Benefits, harms, and costs: Benefits from implementation of these guidelines include: improved diagnosis of OASIS, optimal functional outcomes following repair, and evidence-based counselling of women for future childbirth.

J Obstet Gynaecol Can 2015;37(12):1131–1148

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

DECEMBER JOGC DÉCEMBRE 2015 l 1131

SOGC clinical practice guideline

Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.125 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care.125

Summary Statements

Recommendations

  1. Obstetrical anal sphincter injuries may lead to significant comorbidities, including anal incontinence, rectovaginal fistula, and pain. (II-2)

  1. All women should be carefully examined for perineal or vaginal tears; those with a tear that is more than superficial in depth should have a systematic rectal examination for obstetrical anal sphincter injury prior to repair. (II-2B)

  2. Obstetrical anal sphincter injuries are more commonly associated with forceps deliveries than with vacuum-assisted vaginal deliveries. (II-2)   3. Obstetrical anal sphincter injuries (OASIS) repair:

a. Suture-related morbidity is similar at 6 weeks following the use of either polyglactin 2-0 or polydioxanone 3-0 for OASIS repairs. (I)



b. Repair of the internal anal sphincter is recommended as women who demonstrate an internal anal sphincter defect on postpartum ultrasound have more anal incontinence. (III)



c. Repair of the external anal sphincter should include the fascial sheath. An overlapping technique often requires more dissection and mobilization of the sphincter ends and is only possible with full thickness 3b sphincter tears or greater. (III)



d. A persistent defect of the external anal sphincter remote from delivery may increase the risk of worsening symptoms following subsequent vaginal deliveries. (II-2)

  4. Obstetrical anal sphincter injuries are associated with an increased risk of postpartum urinary retention. (II-2)   5. After a successful repair of obstetrical anal sphincter injuries, most women can safely deliver vaginally in a future pregnancy. (III)   6. Counselling women about future delivery plans:

a. The risk of recurrence of an obstetrical anal sphincter injury at a subsequent delivery is 4% to 8%. (II-2)



b. It was calculated that 2.3 Caesarean sections at the cost of increased maternal risk would be required to prevent one case of anal incontinence in a woman with prior obstetrical anal sphincter injury. (II-2)

1132 l DECEMBER JOGC DÉCEMBRE 2015

  2. The World Health Organization classification should be used to classify obstetrical anal sphincter injury. This distinguishes the degree of external sphincter tear (3a: < 50% or 3b: ≥ 50%) and the presence of internal sphincter defects (3c). A button -hole injury is distinct and should be classified separately as such. (III-B)   3. In women having a spontaneous vaginal delivery, the rate of obstetrical anal sphincter injury is decreased when the obstetrical care provider slows the fetal head at crowning. (II-2A)   4. Episiotomy:

a. At the time of either a spontaneous vaginal or instrumental delivery, the obstetrical care provider should follow a policy of “restricted” episiotomy (i.e., only if indicated), rather than “liberal” use (i.e. routine), for the prevention of obstetrical anal sphincter injuries. (I-A)



b. If an episiotomy is deemed indicated, preference for a mediolateral over a midline should be considered. (II-2B) The optimal cutting angle appears to be no less than 45 degrees, ideally around 60 degrees. (II-2B)

  5. Repair can be delayed for 8 to 12 hours with no detrimental effect. Delay may be required so a more experienced care provider is available for the repair. (I-A)   6. Prophylactic single dose intravenous antibiotics (2nd generation cephalosporin, e.g. cefotetan or cefoxitin) should be istered for the reduction of perineal wound complications following the repair of obstetrical anal sphincter injury. (I-A)   7. Laxatives (e.g., lactulose) should be prescribed following the primary repair of obstetrical anal sphincter injury as they are associated with earlier and less painful first bowel motions and earlier discharge from hospital. Constipating agents and bulking agents are not recommended. (I-A)

Obstetrical Anal Sphincter Injuries (OASIS): Prevention, Recognition, and Repair

  8. Non-steroidal anti-inflammatories and acetaminophen are the first-line analgesics. Opioids should only be used with caution. Constipation should be avoided by using a laxative or stool softener. (I-A)   9. Following obstetrical anal sphincter injury, providers should disclose to women the degree of injury and arrange follow-up. Detailed documentation of the injury and its repair is required. (III-L) 10. Women with anal incontinence following obstetrical anal sphincter injury should be referred for pelvic floor physiotherapy. (I-A)

INTRODUCTION

W

hile maternal mortality related to childbirth is now rare in the developed world, there continues to be significant maternal morbidity—including that related to the pelvic floor function. A group of women who are at risk of pelvic floor dysfunction following delivery include those in whom the anal sphincter is disrupted during childbirth.

Definitions

Perineal trauma occurs either spontaneously with vaginal delivery or secondarily as an extension to an episiotomy. Severe perineal trauma can involve damage to the anal sphincters and anal mucosa. Obstetric anal sphincter injuries include third and fourth degree perineal tears. Third degree tears involve a partial or complete disruption of the anal sphincter complex which includes the external anal sphincter and the internal anal sphincter. Fourth degree tears involve disruption of the anal mucosa in addition to division of the anal sphincter complex. Clinical Impact

OASIS can have a significant impact on women by impairing their quality of life in both the short and long term. One of the most distressing immediate complications of perineal injury is perineal pain. Short-term perineal pain is associated with edema and bruising, which can be the result of tight sutures, infection, or wound breakdown. Perineal pain can lead to urinary retention and defecation problems in the immediate postpartum period. In the long term, women with perineal pain may have dyspareunia and altered sexual function. Additionally, complications ABBREVIATIONS AI

anal incontinence

EAS

external anal sphincter

IAS

internal anal sphincter

NSAID non-steroidal anti-inflammatory OASIS obstetric anal sphincter injuries RTC

randomized control trial

SVD

spontaneous vaginal delivery

WHO

World Health Organization

of severe perineal tears include abscess formation, wound breakdown, and rectovaginal fistulae. Injury to the anal sphincter is recognized as the most common cause of anal incontinence and anorectal symptoms in otherwise healthy women. Obstetrical sphincter injuries have a variety of long-term complications of which anal incontinence is the most distressing and disabling. Anal incontinence incorporates a range of symptoms including: flatal incontinence, ive soiling, or incontinence of liquid or solid stool.1 Fecal urgency can also be a symptom experienced by many women. Any of these symptoms can potentially be a hygienic, social, and psychological problem for women. Women are not always forthcoming with symptoms of anal incontinence either due to embarrassment or they feel that the symptoms are a normal result of vaginal delivery. The true prevalence of AI related to OASIS may be underestimated. The reported rates of AI following the primary repair of OASIS range between 15% and 61%, with a mean of 39%.2 This high prevalence highlights the need to ensure our surgical techniques and postoperative management are optimal. Sustaining an OASIS can have a significant impact on a women’s physical and emotional health. There are personal costs to the patient with pad use and missed time from work, and costs to women and the health care system including appointments and treatments. It may also make women apprehensive about future childbirth and adversely affect the remainder of their reproductive lives. Missed tears or inadequate repair may also present a potential source for litigation. Obstetrical trauma that can lead to AI includes structural damage to the anal sphincter complex, pudendal neuropathy (by direct compression or stretching), or both. Despite sphincter repairs, some women may have residual defects and AI symptoms. The onset of symptoms of AI may occur immediately or several years after delivery; anal incontinence may only appear in old age, when the aging process adds to the delivery insult. Summary Statement

1. Obstetrical anal sphincter injuries lead to significant comorbidities, including anal incontinence, rectovaginal fistula, and pain. (II-2) DIAGNOSIS OF OASIS

Careful examination of the perineum, including a rectal examination for those with a tear that is more than superficial in depth, should be performed in all women prior to suturing.3 Formal training in the recognition of OASIS improves the detection of such injuries,4 as DECEMBER JOGC DÉCEMBRE 2015 l 1133

SOGC clinical practice guideline

Figure 1. Urogenital musculature

Table 2. Classification of OASIS First degree

Injury to perineal skin only

Second degree

Injury to perineum involving perineal muscles but not involving the anal sphincter

Third degree

Injury to perineum involving the anal sphincter complex:

3a

Less than 50% of EAS thickness torn

3b

More than 50% of EAS thickness torn

3c

Both EAS and IAS torn

Fourth degree

incident rises from 11% to 24.5% when the obstetrical care provider’s examination was repeated by a trained fellow.5 The inspection should be done with adequate lighting and analgesia and include: •• inspection of perineum with labial parting, •• inspection of the distal (caudal) posterior vagina, and •• inspection for a third degree tear behind an “intact perineum.” Palpation is best done3 with the examiner’s dominant index inserted in the anus, and the ipsilateral thumb in the vagina. The 2 fingers then palpate with a “pill-rolling” motion to assess thickness. When the external sphincter tears, the ends retract and a cavity is often palpated along the course of the sphincter muscle. This may be less evident in the presence of an epidural. Special attention should then be given to the IAS. The IAS is a continuation of the circular smooth muscle of the rectum. This muscle appears pale (like raw white fish), is not very thick, and can be found 6 to 8 mm above (cephalad to) the anal margin (Figure 1; for a more detailed illustration, see online eFigure 1). Examination of the IAS will also permit detection of a button-hole injury. Recommendation

1. All women should be carefully examined for perineal or vaginal tears; those with a tear that is more than superficial in depth should have a systematic rectal examination for obstetrical anal sphincter injury prior to repair. (II-2B) 1134 l DECEMBER JOGC DÉCEMBRE 2015

Injury to perineum involving the anal sphincter complex (EAS and IAS) and anal epithelium

GRADING OF SEVERITY

Traditionally, the severity of perineal tear was limited to 4 grades: grade 1 (superficial vaginal and/or perineal skin), grade 2 (vaginal muscles), grade 3 (in or through external anal sphincter muscle), and grade 4 (external and internal anal sphincters and anorectal lumen).6 As there was a lack of consistency in the classification of a partial anal sphincter, with up to 33% of consultant obstetricians classifying a complete or partial tear of the EAS as a second degree tear,7 Sultan8 devised a more specific classification, later adopted by the WHO9 and the International Consultation on Incontinence.10 In this classification, grade 3 is further refined as involving the anal sphincter complex and is divided into 3a, 3b, 3c (Table 2). The type of third degree tear seems to have an impact on symptoms, with OASIS grade 3a and 3b having a better prognosis than 3c. In fact, those with a 3c OASIS had symptoms similar in severity to those with a fourth degree laceration.11 A button-hole injury, where only the vaginal and rectal mucosa are involved, should not be reported as a third or fourth degree tear if found in isolation. Documentation of the presence or absence of a tear, as evidenced on rectal examination, should be disclosed to the patient and incorporated into the delivery note, and repair should be done to avoid fistulization. Such a grading system takes into the degree of tearing experienced by the external sphincter separately from that of the internal sphincter. Such distinction is meant to improve reporting, guide repair, and facilitate outcome research.

Obstetrical Anal Sphincter Injuries (OASIS): Prevention, Recognition, and Repair

Recommendation

Table 3. Risks factors for OASIS

2. The World Health Organization classification should be used to classify obstetrical anal sphincter injury. This distinguishes the degree of external sphincter tear (3a: < 50% or 3b: ≥ 50%) and the presence of internal sphincter defects (3c). A button-hole injury is distinct and should be classified separately as such. (III-B)

Maternal risks factors Primiparity

OR* 3.5 to 9.8

19–24

Age (> 35)24 Age (> 27)

1.1 1.9

23

Race19,23

1.4 to 2.5

Maternal diabetes19,23

1.2 to 1.4

Infibulation

1.8 to 2.7

25

Delivery risks factors

EPIDEMIOLOGY OF OASIS

The incidence of OASIS may vary according to many variables including use of any type of episiotomy (lateral, mediolateral, or midline), type of delivery (spontaneous or assisted vaginal), and type of instrument used (vacuum or forceps); parity, type of obstetrical care provider, and race. Overall, studies looking at the incidence of OASIS based on the WHO’s International Classification of Diseases12 report an incidence of 4% to 6.6% of all vaginal birth,13–16 with higher rates in assisted deliveries (6%) than in SVD (5.7%).17 An OASIS is often misdiagnosed at the time of delivery by obstetrical care providers. One study reported that the overall rate of missed OASIS ranged from 26% to 87%.5 In that study of primiparous women, all women were examined by a trained fellow after the examination and grading of tear by the obstetrical care provider and confirmed by endoanal ultrasound prior to repair (considered the gold standard). When examined systematically as described above, all but 1.6% (3/182) of women were correctly diagnosed on exam; the other 3 had occult OASIS representing the falsenegative rate of examination, 2 of which only affected the internal sphincter, and would have thus been undetectable on physical examination. When the diagnosis of OASIS is obtained from endoanal ultrasound evaluation within 2 months of delivery, the incidence of any degree of anal sphincter defect in primiparous women is reported to be as high as 27% to 35%, and between 4% and 8.5% of multiparous women have a new sphincter defect.15,18 Risk Factors for OASIS

Risk factors commonly associated with obstetric anal sphincter tears include maternal, delivery, and infant characteristics. Table 3 shows a summary of OR for various risks factors from studies reporting this information.19–35

OR

Operative vaginal delivery† Vacuum19,21,24,26

1.5 to 3.5

Forceps

2.3 to 5.6

19,21,24,26,27

Vacuum + forceps24,28

8.1

Episiotomy Midline26 Mediolateral

2.3 to 5.5 0.21

26,29

Mediolat episiotomy + instrumental29 Vacuum

0.11

Forceps

0.08

Midline episiotomy + instrumental (nulliparous)30 Vacuum

4.5

Forceps

8.6

Unspecified episiotomy + instrumental

31

Vacuum

2.9

Forceps

3.9

Epidural23

1.1 to 2.2

Second stage >1 h‡

1.5

Shoulder dystocia

2.7 to 3.3

VBAC21,32

1.4 to 5.5

Water birth27

1.46

Oxytocin augmentation‡33

1.2

Infant risks factors

OR

Birth weight > 4000 gm20

2.2 to 3.0

Malpresentation23

2.0

Postmaturity20,24

1.1 to 2.5

Fetal distress

1.3

OP§ SVD23

2.0

Instrumental34,35

4.7

*All OR 95% confidence intervals are significant, i.e. do not cross 1 †Presence of episiotomy not dissociated from instrumental ‡In primiparous §Occiput posterior VBAC: Vaginal birth after Caesarean

Maternal Risk Factors Maternal risk factors are presented in the first section of Table 3. Obesity is protective, in a dose–response manner (BMI 25 to < 30: 0.89 [95% CI 0.85 to 0.95]; 30 to < 35: DECEMBER JOGC DÉCEMBRE 2015 l 1135

SOGC clinical practice guideline

— —

43.2

30.8

239.5 4.8

5.8

3.0

75.6 6.2

124.4

191.8

13.5

8.6

86.5 6.9

6.2

62.6

1.6

10.2

8.6

10.1

12.6

7.6 3.8

3.6

4.0

3.8

7.9

Infant Risk Factors Specific infant characteristics appearing to independently increase the risk of OASIS are presented in the third section of Table 3.

—

33.8

9.7

15.9

21.6

40.6

41.0

24.4

Slowing down the delivery of the head and instructing women to not push at the delivery of the head, using thus only the uterine expulsive efforts, decreases the incidence of OASIS by 50% to 70%, as shown by multicentre studies in Norway.39,40

0

1

5

4

3

2

4

3

3.2

25.3

Head Control 6

336

5.3 103

5.6 66

7.0

6.3 38

21

1.0

13.6 25

235

Risk factors for OASIS often become apparent late in labour, and the degree to which these factors can potentially be modified during labour is yet to be determined. However, some methods of performing the delivery may show evidence of protection.38

17 OP + episiotomy + epidural + forceps

The protective role of perineal (whereby the delivery care provider holds the perineum with a sponge, applying medial pressure) in isolation is unclear. A Cochrane review including RCTs on the topic41 failed to show a benefit; however, the results were heavily influenced by a large RCT of handspoised versus hands-on techniques, which included both slowing the head and ing the perineum. In the study, midwives assigned to poised hands were also allowed to slow the head (by applying pressure on the head itself to control its speed of expulsion) if delivering too fast, which effectively biased the results. OR: odds ratio; OP: occiput posterior

18 OP + episiotomy + forceps

15

33 OP + episiotomy

OP + vacuum

26

32

OP + forceps

61

Prolonged second stage + epidural + forceps + episiotomy

32 Prolonged second stage + forceps + episiotomy

1136 l DECEMBER JOGC DÉCEMBRE 2015

Epidural + forceps + episiotomy

63

366

Forceps + episiotomy

Epidural

220 Episiotomy

138 Prolonged second stage

52

101 Vacuum

Fetal position OP

91

122

Perineal

Forceps

Characteristic

Delivery Risk Factors Risks factors occurring at the time of delivery that may be independently associated with OASIS are included in the second section of Table 3. The impact of midline episiotomy and forceps, together or in isolation, are presented in Table 4.37

INTERVENTIONS TO PREVENT OASIS

No vacuum, forceps, episiotomy or OP (reference group)

Number with factor in vaginal control group Number with factor in sphincter tear group

Table 4. Risk of OASIS after instrumental delivery, with or without episiotomy (90% midline)

Estimated OR for factor being related to tear

95% lower confidence limit for OR

23.2

95% upper confidence limit for OR

0.84 [95% CI 0.76 to 0.92]; and BMI > 35: 0.70 [95% CI 0.59 to 0.82]).36

A 2011 Cochrane review showed that the application of warm compresses to the perineum (OR 0.5) as well as intra-partum perineal massage (OR 0.5) both decrease the risk of OASIS.41,42 Perineal massage is done with lubricant, using a gentle, slow massage, with 2 fingers of the [obstetrical care provider’s] gloved hand moving from side to side just inside the patient’s vagina. Mild, downward pressure

Obstetrical Anal Sphincter Injuries (OASIS): Prevention, Recognition, and Repair

(towards the rectum) is applied with steady, lateral strokes, which last 1 second in each direction.43

Figure 2. Episiotomy sites

Delivery Position

While kneeling versus sitting has no impact on rate of OASIS, a standing position (upright position without buttocks : upright standing, squatting, kneeling) versus a sitting position (upright position but with of the ischial tuberosities, with or without sacral ) might increase the risk of OASIS, as shown in a retrospective analysis of 814 women (650 standing, 264 sitting, any parity) in which women standing for their delivery had a nearly 7-fold increase in OASIS (2.5% vs. 0.38%).44 A 2012 RCT comparing traditional method of delivery (no ive second stage, and active second stage in the dorsal lithotomy) versus “alternate” method of delivery (ive second stage lasting up to strong urge or 120 min, and active second stage in the lateral “Gasquet” position – with upper hip flexed, foot on stirrup higher than knee) showed no difference in rate of OASIS.45 Episiotomy

There is no doubt that restricted use of episiotomy, of any type, is preferable in women having a spontaneous vaginal delivery.46 The results of a pilot RCT of routine versus restrictive mediolateral episiotomy in nulliparous women, undergoing instrumental delivery did not reach statistical significance due to a small sample size.47 Most studies identify midline episiotomy as a risk factor,48 but some do not.19 This might be related to poor coding in those studies that assess the outcome based on database information.49 However, while the published rate of OASIS following mediolateral episiotomy varies between 0.5% to 7%, it may reach as high as 17% to 19% following a midline episiotomy.26–50 In those having an operative vaginal delivery, a retrospective large Dutch database study suggested that a mediolateral or lateral episiotomy lead to less anal sphincter injuries than no episiotomy or a midline episiotomy.29 The impact of mediolateral episiotomy is somewhat controversial in instrumental deliveries in primiparous women. Some authors report an independent increased risk of OASIS if a mediolateral episiotomy is performed during instrumented birth (OR 4.04);51 however, once adjusted for instrumental delivery, the type of episiotomy no longer remained a risk factor. Others report a lower rates of OASIS 52–54 and severe perineal trauma (high vaginal sulcus and OASIS combined)46 with mediolateral episiotomy than with no episiotomy (OR 0.2 to 0.8). The balance of the evidence suggests that a mediolateral episiotomy likely does not increase the risk of OASIS at the time of instrumental delivery of a primiparous

woman, and in fact, may decrease the incidence of OASIS compared with no episiotomy. There is only one published RCT (published in 1980) comparing rates of OASIS between midline and mediolateral episiotomy in nulliparas.55 In that study, 12% of women who had a midline episiotomy sustained an OASIS, versus 2% of those who had a mediolateral. This study had significant limitations including a number of protocol violations. For example, if an obstetrical care provider was opposed to midline incisions, a mediolateral episiotomy was performed instead and the patient excluded from the analysis. In a prospective cohort study of 1302 women who delivered vaginally, and who all received an episiotomy, 426 received midline and 876 mediolateral episiotomy, according to the practitioner’s preferences.56 Deep perineal tears (which included but were not limited to OASIS) were present in 14.8% of those who had a midline episiotomy versus 7% of those who had a mediolateral episiotomy. The terminology used in the literature is at times unclear between midline, mediolateral, and lateral episiotomies. A standardization has been proposed57 (as shown in Figure 2; for a more detailed illustration, see online eFigure 2). A midline episiotomy (line #1) should indicate those starting in the midline and continuing at a 0° angle from the vertical; mediolateral (line #4) episiotomies should represent those done starting in the midline but at an angle greater than 0° from the vertical line; while a lateral (#5) episiotomy starts off the midline and is carried at an angle greater than 0° from the vertical. Other incisions shown include: modified median (inverted “T” incision, #2), “J”-shaped episiotomy (#3), and the seldom used radical lateral (Schuchardt incision, #6).58 DECEMBER JOGC DÉCEMBRE 2015 l 1137

SOGC clinical practice guideline

The angle of the episiotomy affects the occurrence of OASIS. A more acute (vertical) angle appears to increase the risk of OASIS; in an RCT comparing mediolateral episiotomies made at 60° and 40° angles from the vertical, the risk of OASIS was 2.4% versus 5.5%, respectively (did not reach statistical significance); however, 60º episiotomies carried higher short-term pain.59 This likely reflects how far away from the anal sphincter complex the incision is. The impact of the starting point of the episiotomy (mediolateral vs. lateral) appears less important. In a large RCT, published only in abstract form in 2014, comparing mediolateral to lateral episiotomies.60 In this trial of 790 women, the incidence of OASIS did not differ between a mediolateral (60° off the midline) and a lateral incision (1 to 2 cm laterally from the midline, angled towards the ischial tuberosity): 1.5% versus 1.3%, respectively. There also seem to have no impact on postpartum pain or sexually between mediolateral and lateral.61 Looking at healed episiotomy scars, the risk of sustaining an OASIS is decreased when58: •• the tip of the episiotomy is further away from a vertical line drawn from the vagina to anus: OR 0.30 for each 5.5 mm increase in the distance between the midline vertical line and the tip of the episiotomy, •• a lateral incision is done: OR 0.44 for each 4.5 mm distance increase off the midline for the incision start (i.e. less OASIS when the incision started off the 6 o’clock location on the introitus, e.g. 4 o’clock), •• a longer episiotomy was done: OR 0.25 for each increase of 5.5 mm in episiotomy length, and/or •• the healed angle is between 15° and 60°. In another study, primigravidas who had mediolateral episiotomies and OASIS had, when examined 3 months postpartum, a mean healed angle of 30°, compared with 38° in those without OASIS.62 However, it was shown that there is a 20° difference between the incision angle of an episiotomy (typically performed when the head is crowning) and the sutured angle once healed: whereas the incision angle was 40° from midline, the angle measured once healed and scarred was 20°.63 In other words, to obtain a healed angle of 30°, one must incise at a 50° angle. Instrumental Delivery

If instrumental delivery is indicated, vacuum extraction carries less risk to the anal sphincter than forceps.64,65 Most data the use of mediolateral episiotomy to protect against OASIS in primiparous women having instrumental delivery over no episiotomy.29,53,66,67 When 1138 l DECEMBER JOGC DÉCEMBRE 2015

a midline episiotomy is performed concurrently with an operative vaginal delivery, it acts synergistically in increasing OASIS.30,68 It is possible that early removal of forceps (after delivery is assured, but before the largest diameter of the head is expelled) may also assist in limiting OASIS in forceps and vacuum deliveries, when combined with other practices such as rotating an occiput posterior baby to an occiput anterior position, selecting a vacuum instead of a forceps, performing a mediolateral episiotomy rather than a midline (only if an episiotomy is deemed necessary), and using minimal necessary maternal expulsive efforts at time of expulsion.64 Some have raised the point of informed consent at the time of instrumental delivery, arguing that disclosure of the OASIS risk should be included, as well as the risks and benefits of any alternative such as Caesarean section.69 Clearly, performing a Caesarean would prevent OASIS, but performing it late in labour may not fully protect the anal canal, as nerve injury can still occur.70,71 Other

Studies evaluating antepartum perineal massage,72 pushing position (kneeling vs. sitting),73 open versus closed glottis pushing,74 Ritgen’s manoeuvre,75 water birth,76 and delayed pushing (in women with epidural)77 failed to show evidence of a protective effect on the anal canal. Summary Statement

2. Obstetrical anal sphincter injuries are more commonly associated with forceps deliveries than with vacuum-assisted vaginal deliveries. (II-2) Recommendations

3. In women having a spontaneous vaginal delivery, the rate of obstetrical anal sphincter injury is decreased when the obstetrical care provider slows the fetal head at crowning. (II-2A) 4. Episiotomy: a. At the time of either a spontaneous vaginal or instrumental delivery, the obstetrical care provider should follow a policy of “restricted” episiotomy (i.e. only if indicated), rather than “liberal” use (i.e. routine), for the prevention of obstetrical anal sphincter injury. (I-A) b. If an episiotomy is deemed indicated, preference for a mediolateral over a midline should be considered. (II-2B) The optimal cutting angle appears to be no less than 45 degrees, ideally around 60 degrees. (II-2B)

Obstetrical Anal Sphincter Injuries (OASIS): Prevention, Recognition, and Repair

PRINCIPLES AND TYPES OF REPAIRS

Obstetric anal sphincter injuries should be repaired by appropriately trained clinicians comfortable with such repairs. Repairs are typically carried out in the delivery room or the operating room. The operating room offers the benefits of access to optimal lighting, appropriate equipment, and aseptic conditions.3 Additional equipment may be required for anal sphincter repairs including selfretaining retractors and Allis clamps. There have been no studies that have evaluated anaesthetics used in the repair of obstetric anal sphincter injuries. Although commonly repaired under local anaesthetic, general or regional anaesthesia maybe optimal as they provide both analgesia and muscle relaxation.3 The EAS has inherent tone and when torn does retract within its capsular sheath. With muscle relaxation, the extent of the tear can be thoroughly evaluated and the sphincter ends can be identified, grasped, and repaired by either the end-to-end or the overlap technique. Local anaesthetic may be sufficient when only the superficial fibres of the EAS are disrupted,78 although without good analgesia, it may be difficult to make a proper diagnosis. In the United Kingdom, experts recommend completing the repair under general or epidural anaesthesia.79 The SOGC Urogynaecology Committee does not feel this is always necessary, as long as adequate analgesia is provided, either using local infiltration or pudendal nerve block. Suture Material

Although the type of suture material used in the repair of obstetric anal sphincter tears may be important, there has been very little research carried out comparing different suture types used for sphincter repairs. Both absorbable and delayed absorbable sutures are commonly used. Although some colorectal surgeons use non-absorbable sutures for secondary repairs of anal sphincters, there is concern that such sutures may result in stitch abscesses or suture ends may cause discomfort requiring their removal.80 The suture ends should be cut short and the knots covered by the overlying superficial perineal muscles in order to minimize any discomfort from suture ends and knots. Monofilament sutures maybe beneficial as they are less likely to harbour organisms and predispose to infection.78 A randomized trial by Williams et al.81 (n = 112), compared OASIS repairs with polyglactin (Vicryl) and polydioxanone (PDS). At 6 weeks, there was no significant difference in suture-related morbidity. There may be benefit to delayed absorbable suture with respect to longer term functional outcomes but this has yet to be evaluated in clinical trials. Many of the more recently published studies have used delayed absorbable sutures but have not been undertaken

to compare suture material. Randomized trials with longer term outcomes including anal incontinence are required to compare suture materials. Repair of the Anal Mucosa

Following a fourth degree perineal tear, the anal mucosa can be approximated by a number of techniques.78 The mucosal repair can be carried out with an interrupted 3-0 Vicryl suture with the knots tied in the anal lumen or external to the anal canal. Alternatively the anal mucosa can be approximated with a 3-0 PDS suture with a submucosal continuous suture. There are currently no studies that suggest a benefit from any of these repair techniques for the anal mucosa with respect to outcomes including anovaginal and rectovaginal fistulas. However figure-ofeight sutures should not be used as they can cause ischemia and poor healing of the anorectal mucosa. Separate Repair of the IAS

The literature related to the techniques of repairing the anal sphincter following obstetric trauma has primarily focused on the repair of the external anal sphincter. However, the muscles involved in maintaining anal continence include not only the EAS but also the internal anal sphincter. The internal sphincter is a 3 to 5 mm thick continuation of the rectal smooth muscle and is under autonomic control. The IAS is responsible for maintaining continence at rest, by contributing to 70% to 85% of the resting anal pressure, and, to a lesser degree, of the anal pressure in response to sudden and constant rectal distension (40% and 65%, respectively).10 In response to rectal distension by feces, liquids, or gases, the pressures in the IAS drop to allow “sampling” (whereby the rectal content transiently enters in with sensory nerve ending of the anal canal to determine the bowel content (liquid, gas, or solid) and allow processing and decision about appropriateness of evacuation), associated with a reflex recto-anal contractile reflex if time is inconvenient.82 Damage to the IAS muscle may lead to a poor seal and an impaired sampling reflex,10 leading to ive incontinence. Sultan and Thakar78 described identifying and approximating the IAS with interrupted sutures in addition to the overlap repair of the EAS. It can be difficult to identify the IAS which lies between the EAS and the anal mucosa. In comparison to the striated muscle of the EAS, the IAS is thin with a pale pink appearance in close proximity to the anal mucosa. It may appear similar to a “fascial” layer. A small prospective study, with historical controls, published by Lindqvist and Jernetz in 2010,83 DECEMBER JOGC DÉCEMBRE 2015 l 1139

SOGC clinical practice guideline

suggested that identifying and separately suturing the IAS may improve anal continence at 1 year. Both previously mentioned studies approximated the IAS in an “endto-end” fashion using delayed absorbable sutures. In a randomized trial of obstetric sphincter repairs,84 9 women had sphincter tears that included the IAS and were independently approximated. In all 9 women the IAS was intact on follow-up endoanal ultrasound. Studies looking at functional results following OASIS repair report that more women with an IAS defect on endoanal ultrasound 6 months postpartum have anal incontinence, and those with incontinence report worse degree of symptoms than those without IAS.22,65,85,86 EAS Repair Techniques

When repairing a torn anal sphincter following vaginal delivery the external anal sphincter can be approximated by 1 of 2 repair techniques; end-to-end repair or overlap repair. The torn ends of the EAS, normally under tonic contraction, tend to retract within their sheaths and can be found latero-posteriorly to the tear, often by palpation of a depression downward rather than lateral. The muscle ends must be identified and grasped with Allis clamps. With an end-to-end repair (for a detailed illustration, see online eFigure 3), the EAS ends may need to be mobilized using Metzenbaum scissors for the dissection. The muscle ends are then approximated end-to-end with 2 or 3 mattress sutures. In theory, mattress sutures may cause less tissue necrosis although there is no evidence to one technique over the other. Sutures should include the fascial sheath.3 With an overlap repair (for a detailed illustration, see online eFigure 3), the torn EAS muscle ends often needs much more dissection and mobilization.3 The dissection is carried out using the ischioanal fat laterally as a landmark. The full lengths of the torn ends of the EAS (including fascial sheath) are overlapped in a double-breasted fashion.80 This type of repair is only possible with 3b or greater OASIS.50 Following the anal sphincter repair, which approximates the disrupted anal sphincter complex, the perineal body is reconstructed by suturing the perineal muscles. This takes tension off and provides for the underlying muscle repair. The vaginal mucosa and perineal skin are repaired in the usual fashion. A rectovaginal exam at the completion of the repair is carried out to confirm the adequacy of the repair. If an obstetrical care provider is insufficiently experienced in the repair of third and fourth degree tear and an experienced obstetrical care provider is not available immediately or locally, repair can be delayed for 8 to 12 1140 l DECEMBER JOGC DÉCEMBRE 2015

hours with no impact on anal incontinence and pelvic floor symptoms.87 Summary Statement

3. Obstetrical anal sphincter injuries (OASIS) repair: a. Suture-related morbidity is similar at 6 weeks following the use of either polyglactin 2-0 or polydioxanone 3-0 following repair. (I) b. Repair of the internal anal sphincter is recommended as women who demonstrate an internal anal sphincter defect on postpartum ultrasound have more anal incontinence. (III) c. Repair of the external anal sphincter should include the fascial sheath. An overlapping technique often requires more dissection and mobilization of the sphincter ends and is only possible with full thickness 3b sphincter tears or greater. (III) d. A persistent defect of the external anal sphincter remote from delivery may increase the risk of worsening symptoms following subsequent vaginal deliveries. (II-2) Recommendation

5. Repair can be delayed for 8 to 12 hours with no detrimental effect. Delay may be required so a more experienced care provider is available for the repair. (I-A) Comparison of Repair Techniques

Historically, the most popular technique for the primary repair of obstetrical anal sphincter injuries has been the end-to-end approximation of the external anal sphincter with interrupted or figure-of-eight sutures. In contrast, the technique commonly used by colorectal surgeons to repair anal sphincter tears remote from delivery or unrelated to delivery is the overlap technique. The overlap technique, described by Parks and Martlin88 for the secondary repair of anal sphincters, was first evaluated for the primary repair of obstetric anal sphincter tears by Sultan et al. in his 1999 seminal study.89 The small study (n = 27) showed that in comparison to matched historical controls with end-to-end repairs, overlap repairs resulted in less anal incontinence (8% vs. 41%).90 Following this study several randomized trials have been published comparing end-toend approximation and overlap repair of the EAS. A 2013 Cochrane review compared the effectiveness of these 2 immediate primary repair techniques in reducing subsequent anal incontinence, perineal pain, dyspareunia and improving quality of life.50 The authors included 6 trials involving 588 women.81,84,91 Three trials followed women for 12 months.91 The only outcomes showing a difference

Obstetrical Anal Sphincter Injuries (OASIS): Prevention, Recognition, and Repair

was for fecal urgency and fecal incontinence score, in favour of the overlapping repair from one trial with 52 women followed up at 12 months.91 An overlap repair resulted in fewer with deterioration of incontinence from 6 weeks to 12 months later (n = 41).91 Another trial showed that at 36 months, these differences were no longer present.92 However, the data are limited given the heterogeneity in the outcome measures, time points, and reported results. These studies included primiparous and parous women and partial and complete third degree tears. Furthermore, their surgical experience is not evaluated in the included studies. Consequently, the current literature does not recommending one obstetric anal sphincter repair technique over the other POSTOPERATIVE MANAGEMENT Prophylactic Antibiotics

Only one randomized trial compared the effect of a single IV dose of a second generation cephalosporin (cefotetan or cefoxitin) on postpartum perineal wound complications (purulent discharge, or abscess and breakdown of repair) 2 weeks following third and fourth degree tears.80 Prophylactic antibiotics given at the time of obstetrical anal sphincter repair decreases maternal morbidity related to perineal wound complications: 8.2% of women who received antibiotics and 24.1% of women who received placebo suffered a wound complication (P < 0.05), with a relative risk of 0.34 (95% CI 0.12 to 0.96).93,94 This Cochrane review reported that the study was limited by a high (27.2%) proportion of lack of follow-up. There are currently no studies that have evaluated the value of additional doses of antibiotics following repair of third and fourth degree perineal tears. Recommendation

6. Prophylactic single dose intravenous antibiotics (2nd generation cephalosporin, e.g., cefotetan or cefoxitin) should be istered for the reduction of perineal wound complications following the repair of obstetrical anal sphincter injury. (I-A) Postoperative Bowel Regimen

Postoperative bowel regimens following the primary repair of OASIS vary. Some regimens consist of laxatives and bulking agents to avoid constipation and any potential disruption of the repair from the age of hard stool. Other regimens consist of bowel confinement techniques with the concern that bowel motions in the immediate postoperative period may threaten the integrity of the repair. Mahony et al.95 performed a randomized trial to compare a laxative regiment (lactulose) with a constipating regiment

(codeine phosphate) in the 3 days following repair of primary OASIS in 105 women. Laxative use was associated with a significantly earlier and less painful first bowel motion and an earlier hospital discharge postpartum. Troublesome constipation was noted in 19% of women receiving the constipating regimen compared to 5% receiving the laxative regimen. Two patients that received the constipating regimen required hospital ission for fecal impaction. Overall there were no significant differences in continence scores or anal manometry and endoanal scan findings between the groups at 3 months postpartum. In 2007 Eogan et al.96 randomized (n = 147) women to receive laxatives alone (lactulose) or laxatives and a bulking agent (lactulose and ispaghula husk, Fybogel) for 10 days after the repair of OASIS. Incontinence in the immediate postnatal period was more frequent in women taking the 2 preparations than in those taking lactulose alone (33% vs. 18%). There were no significant differences between the groups with respect to time to first bowel motion, length of hospital stay, or overall satisfaction related to bowel habits, and no significant difference in functional outcomes at 3 months. Recommendation

7. Laxatives (e.g., lactulose) should be prescribed following the primary repair of obstetrical anal sphincter injury as they are associated with earlier and less painful first bowel motions and earlier discharge from hospital. Constipating agents and bulking agents are not recommended (I-A). Postoperative Analgesia

While there are no data regarding the use of analgesics following repair of OASIS, a Cochrane review published in 200397 found that rectal analgesia including diclofenac reduces perineal trauma related pain during the first 24 hours following birth and results in women using less additional analgesia during the first 48 hours. Because of the constipating effect of opioids, an NSAID in conjunction with acetaminophen is likely preferable as first-line management of perineal pain. Although rectal istration of NSAID may be better, it should be avoided in cases of fourth degree laceration, because it theoretically could impair.98 However, opioids should not be withheld, but rather used along with a stool softener. Recommendation

8. Non-steroidal anti-inflammatories and acetaminophen are the first-line analgesics. Opioids should only be used with caution. Constipation should be avoided by using a laxative or stool softener. (1-A)

DECEMBER JOGC DÉCEMBRE 2015 l 1141

SOGC clinical practice guideline

Bladder Catheterization

Studies have demonstrated a relationship between significant perineal trauma and postpartum urinary retention.99–102 Glavind and Bjork looked specifically at sphincter injuries and found sphincter rupture was observed in 33% of women with postpartum urinary retention compared with 1% of the total population of women giving birth during the study period.101 The pathophysiology of postpartum urinary retention related to perineal injury is unclear but maybe related to perineal discomfort, urethral and perineal edema, and neurologic damage. Summary Statement

4. Obstetrical anal sphincter injuries are associated with an increased risk of postpartum urinary retention. (II-2) RISK MANAGEMENT/DOCUMENTATION

Operative delivery, while often indicated, is a risk factor for sphincter tear, and obstetrical care providers should consider discussing the possibility of operative delivery and any potential sequelae prior to labour. The decision for instrumental delivery should take into consideration the potential for anal sphincter injury. In addition, prolonged labour may be associated with sphincter tears and practitioners may consider discussing this with patients in situations when labour progression is slow. When faced with an OASIS, the obstetrical care giver should document (ideally as a formal operative note) the delivery course, including indication for operative vaginal delivery, consent obtained, description of procedure, type and extent of perineal injury, repair method and suture used, and antibiotics istered. Furthermore, the patient should be informed of the injury sustained, and upon discharge a follow-up plan should be made. Recommendation

9. Following obstetrical anal sphincter injury, providers should disclose to women the degree of injury and arrange follow-up. Detailed documentation of the injury and its repair is required. (III-L) OUTCOMES FOLLOWING REPAIR

The outcomes following the primary repair of obstetric anal sphincter injuries are difficult to establish as there is significant heterogeneity between studies. Studies vary greatly with respect to repair techniques, outcome measures, and follow-up intervals. A summary of outcomes following primary OASIS repair is presented in Table 5.3,103–105 1142 l DECEMBER JOGC DÉCEMBRE 2015

The outcomes following OASIS repair appear to be related to the extent of the initial sphincter tear, with 3c or fourthth degree OASIS showing worse results than other types (see Table 6).11,25,94 Remote from delivery (median follow-up 14 years), the extent of sphincter damage was found to be independent of the development of fecal incontinence.106 Following OASIS, the incidence of anal incontinence may increase with time: from 3–6 months to 3–8 years following delivery, the rate went from 31% to 54%.107 Women’s continence over time may be affected by aging, subsequent deliveries, and lifestyle factors. Overall, the outcomes following the primary repair of OASIS are not encouraging, with studies reporting that many women suffer from various degrees of anal incontinence. Fortunately, the management of anal incontinence, including that following repaired OASIS, can be successful with pelvic floor physiotherapy. 108,109 Recommendation

10. Women with anal incontinence following obstetrical anal sphincter injury should be referred for pelvic floor physiotherapy. (I-A) SUBSEQUENT PREGNANCY

Many factors may be taken into in counselling women following an OASIS: the functional status (i.e. symptoms experienced shortly and remotely from the index delivery), the extent of residual anatomical and/or functional defects as shown on anal ultrasound and/or anal manometry, and the patient’s wishes. A woman who had an OASIS after her first delivery has 3.8to 5.9-fold greater odds of a repeat OASIS at her next delivery than a woman without prior OASIS (Table 7).103–105,110–114 Although higher than in women without a prior OASIS, the risk of having a recurrent OASIS is the same for a woman with previous OASIS as the baseline risk at first delivery; both around 5.3% in Ontario.33 The vast majority of women with a previous OASIS will not have a recurrent OASIS during a subsequent vaginal delivery. In fact, 64% to 90% of all OASIS occurring at a second delivery are in women without a previous OASIS.112,113 Overall, the rate of anal incontinence in women with OASIS and a subsequent vaginal delivery worsens in 19% to 56% of women,115–118 particularly if a women had transient anal incontinence after the index OASIS.116 On the basis of these studies, the Royal College of Obstetrics and

Obstetrical Anal Sphincter Injuries (OASIS): Prevention, Recognition, and Repair

Table 5. Summary of outcomes from primary OASIS repair Reference Sultan and Thakar 20093 (35 studies)

Repair technique/injury

Follow-up Interval(s)

Outcome measure(s)

Prevalence mean (range)

End-to-end repair

1–30 months

Anal incontinence (flatal and/or fecal incontinence)

39% (15 to 61%) (35 studies)

Liquid or solid fecal incontinence

14% (2 to 29%) (25 studies)

Fecal urgency

6% to 28%

Sonographic anal sphincter defects

34% to 91%

Anal incontinence with coitus (flatal and/or fecal incontinence)

17%

Anal incontinence

11%

Bagade and Mackenzie 2010

End-to-end or overlap, n = 79

6 months

Fecal incontinence

7.5%

Tjandra et al. 2008

End-to-end, n = 114

18.8 months

Fecal incontinence (Wexner ≥ 1)

20.7%

Samarasekera et al. 2008

Unspecified, n = 53

≥ 10 years

Overall anal incontinence (Wexner ≥ 1)

53%

Flatal incontinence

51%

Incontinence to liquid

32%

Incontinence to solid

26%

Table 6. Outcomes following OASIS repairs according to the extent of the initial sphincter tear. Reference

Degree of injury

Type of repair

Follow-up Interval(s)

Outcome measure(s)

Prevalence

Nichols et al. 2005

4th, n = 17

unspecified

6 to 8 weeks

Anal incontinence and/or fecal urgency

3rd: 28%

Roos et al. 201011

3a or 3b: n = 439

8 to 12 weeks

3b or 4: n = 92

End-to-end or overlap

Bothersome fecal incontinence or fecal urgency

3c and 4th had worse scores on symptoms questionnaires than 3a and 3b

3rd and 4th,

unspecified

6 months

Worsening bowel control after pregnancy

3rd, n = 39

Fenner et al 200326

Any incontinence to liquid stool

n = 165

4th: 59%

4th: 30.8% 3rd: 3.6%

Table 7. Risks of OASIS at next delivery, based on presence of OASIS at 1st delivery OASIS at 1st delivery OASIS at subsequent delivery

3.7% to 7.5%

Gynaecologistsis recommend that “All women who have sustained an obstetric anal sphincter injury in a previous pregnancy and who are symptomatic or have abnormal endoanal ultrasonography and/or manometry should have the option of elective Caesarean birth.”79 A 2003 study using a decision analysis modeling explored universal Caesarean section in continent women with previous OASIS.119 Based on the literature, they used the following assumptions: 5.1% risk of repeat OASIS, anal incontinence rate of 44% after 2nd OASIS. To prevent one case of anal incontinence (flatus, liquid, or stool) in women with prior OASIS who were presumed continent 2.3 elective Caesarean sections would need to be done, at

104,105,110–114

No OASIS at 1st delivery 0.6% to 3.2%104,105,112,113

the cost of increased maternal risks, including an increased morbidity rate from 4.2% following vaginal delivery to 11.3% after Caesarean section. Furthermore, there would be one maternal death for 1880 cases of anal incontinence averted. The balance of risks and benefits should be discussed when counselling women on the route of future deliveries after OASIS in a previous pregnancy. Outcome of Subsequent Vaginal Delivery Depending on Symptoms Following OASIS at Index Delivery

Only one published study assessed anal symptoms in women with a subsequent delivery based on their symptoms after the index OASIS.116 Women who DECEMBER JOGC DÉCEMBRE 2015 l 1143

SOGC clinical practice guideline

sustained a fourth degree tear in a previous delivery associated with transient anal incontinence had a greater rate of developing subsequent anal incontinence after a subsequent vaginal delivery (39%, 9/23; 4 of these women became permanently incontinent compared with 7% [2/29] of asymptomatic women after their OASIS). In a recent preliminary report, low baseline symptom scores may predict good outcomes after a vaginal delivery in women with prior OASIS.120 Outcome of Subsequent Vaginal Delivery Depending on Finding on Endoanal Ultrasound Following OASIS at Index Delivery

The literature is limited in number and size of studies, but the presence of a persistent defect appears to increase the risk of worsening symptoms. In women who had ultrasound evidence of anal sphincter injury 3 months following a first vaginal delivery (any degree of tear), a subsequent vaginal delivery may increase the rate of abnormal anorectal symptoms (38%), compared with women who did not have another child (16%; not statistically significant). Women without ultrasound evidence of OASIS 3 months postpartum had a rate of anal incontinence of 3% in the absence of a subsequent pregnancy versus 10% if they delivered again (not statistically significant).118 In women who have a second vaginal delivery, the presence of anal injury on antenatal ultrasound between deliveries increases the rate of worsening anorectal symptoms: from 7% of women following a subsequent vaginal delivery without evidence of persistent defect, to 37% if ultrasound showed a pre-existing injury (no significant difference).121 Outcome of Subsequent Vaginal Delivery Depending on Combined Finding on Endoanal Ultrasound and Anal Manometry Following OASIS at Index Delivery

Sultan reported his results following antenatal counselling for the route of delivery in subsequent pregnancy for women with previous OASIS,114 with updated results presented in 2013.122 In his study, substantial anal compromised was defined as either: •• external sphincter defect on ultrasound > 30° and a maximum squeeze pressure increment of < 20 mmHg on anal manometry; OR •• defect <30° and a maximum squeeze pressure increment of < 20 mmHg; OR •• no defect and a maximum squeeze pressure increment of < 20 mmHg. 1144 l DECEMBER JOGC DÉCEMBRE 2015

Women who had substantial anal compromise were counselled on having a Caesarean section. All others were counselled on vaginal delivery. In those women who delivered as counselled (75% of the study group), results on anal manometry did not significantly change and anorectal symptoms did not worsen following delivery. Similar results have been presented as abstracts.123 Summary Statements

5. After a successful repair of obstetrical anal sphincter injuries, most women can safely deliver vaginally in a future pregnancy. (III) 6. Counselling women about future delivery plans: a. The risk of recurrence of an obstetrical anal sphincter injuries at a subsequent delivery is 4% to 8%. (II-2) b. It was calculated that 2.3 Caesarean sections at the cost of increased maternal risk would be required to prevent one case of anal incontinence in a woman with prior obstetrical anal sphincter injuries. (II-2) LEARNING MODEL

For the past decade, Sultan and his group has devised a hands-on workshop on OASIS repair. The hands-on part uses both an artificial model and a repair of fresh anuses originating from male pig.4 It has been shown that a surgical skill laboratory improves learners’ acquisition of the skills necessary to repair OASIS as evidenced on the Objective Structured Assessment of Technical Skills and written examination istered before and after an OASIS repair workshop.124 SUMMARY

Obstetrical anal sphincter injuries represent a significant morbidity encountered after vaginal delivery. Some intrapartum measures can be taken to diminish the risk of occurrence. Careful examination after every delivery is of paramount importance to avoid missing an OASIS. Systematic repair of the entire anal sphincter complex should be done by a trained caregiver; full disclosure and close follow-up should be offered. Most women following OASIS are good candidates to have a subsequent vaginal delivery; antenatal evaluation of symptoms and anal function testing can help guide the choice of future mode of delivery. REFERENCES 1. Haylen BT, de Ridder D, Freeman RM, Swift SE, Berghmans B, Lee J, et al. An International Urogynecological Association (IUGA)/ International Continence Society (ICS) t report on the terminology for female pelvic floor dysfunction. Neurourol Urodyn 2010;29:4–20.

Obstetrical Anal Sphincter Injuries (OASIS): Prevention, Recognition, and Repair

2. Sultan AH, Kettle C. Diagnosis of perineal trauma. In: Sultan AH, Thakar R, Fenner DE, eds. Perineal and anal sphincter trauma. 1st ed. London (GB): Springer-Lerlag; 2009. p. 13–9. 3. Sultan AH, Thakar R. Third and fourth degree tears. In: Sultan AH, Thakar R, Fenner DE, eds. Perineal and anal sphincter trauma. 1st ed. London (GB): Springer-Verlag; 2009. p. 33–51. 4. Andrews V, Thakar R, Sultan AH. Structured hands-on training in repair of obstetric anal sphincter injuries (OASIS): an audit of clinical practice. Int Urogynecol J Pelvic Floor Dysfunct 2009;20:193–9.

21. Richter HE, Brumfield CG, Cliver SP, Burgio KL, Neely CL, Varner RE. Risk factors associated with anal sphincter tear: a comparison of primiparous patients, vaginal births after cesarean deliveries, and patients with previous vaginal delivery. Am J Obstet Gynecol 2002;187:1194–8. 22. Richter HE, Fielding JR, Bradley CS, Handa VL, Fine P, Fitzgerald MP, et al. Endoanal ultrasound findings and fecal incontinence symptoms in women with and without recognized anal sphincter tears. Obstet Gynecol. 2006;108:1394–401.

5. Andrews V, Sultan AH, Thakar R, Jones PW. Occult anal sphincter injuries—myth or reality? BJOG 2006;113:195–200.

23. Gerdin E, Sverrisdottir G, Badi A, Carlsson B, Graf W. The role of maternal age and episiotomy in the risk of anal sphincter tears during childbirth. Aust N Z J Obstet Gynaecol 2007;47:286–90.

6. Cunningham F, Leveno KJ, Bloor S, Hauth J, Rouse DJ, Spong C. Normal labor and delivery. In: Cunningham F, Leveno KJ, Bloor S, Hauth J, Rouse DJ, Spong C, eds. William’s Obstetrics, 23rd ed. New York (NY): McGraw-Hill; 2011.

24. Baghestan E, Irgens LM, Bordahl PE, Rasmussen S. Trends in risk factors for obstetric anal sphincter injuries in Norway. Obstet Gynecol 2010;116:25–34.

7. Fernando RJ, Sultan AH, Radley S, Jones PW, Johanson RB. Management of obstetric anal sphincter injury: a systematic review & national practice survey. BMC Health Serv Res 2002;2:9. 8. Sultan AH. Obstetrical perineal injury and anal incontinence. Clin Risk 1999;5:193–6. 9. Thach T. Methods of repair for obstetric anal sphincter injury: RHL commentary. Geneva (CH): World Health Organization, The WHO Reproductive Health Library; 2006. 10. Koelbl H, Nitti V, Baessler K, Salvatore S, Sultan A, Yamaguchi O. Pathophysiology of urinary incontinence, faecal incontinence and pelvic organ prolapse. In: Abrams P, Cardozo L, Khoury S, Wein A, eds. Incontinence, 4th ed. St Hillier, (GB): Health Publication; 2009: p. 255–330. 11. Roos AM, Thakar R, Sultan AH. Outcome of primary repair of obstetric anal sphincter injuries (OASIS): does the grade of tear matter? Ultrasound Obstet Gynecol 2010;36:368–74. 12. World Health Organization. International Classification of Diseases (ICD). Geneva (CG): WHO; 2015. Available at: http://www.who.int/ classifications/icd/en. Accessed on September 15, 2015. 13. Baghestan E, Bordahl PE, Rasmussen SA, Sande AK, Lyslo I, Solvang I. A validation of the diagnosis of obstetric sphincter tears in two Norwegian databases, the Medical Birth Registry and the Patient istration System. Acta Obstet Gynecol Scand 2007;86:205–9. 14. Laine K, Gissler M, Pirhonen J. Changing incidence of anal sphincter tears in four Nordic countries through the last decades. Eur J Obstet Gynecol Reprod Biol 2009;146:71–5. 15. Sultan AH, Kamm MA, Hudson CN, Thomas JM, Bartram CI. Anal-sphincter disruption during vaginal delivery. N Engl J Med 1993;329:1905–11. 16. Fretheim A, Odgaard-Jensen J, Rottingen JA, Reinar LM, Vangen S, Tanbo T. The impact of an intervention programme employing a hands-on technique to reduce the incidence of anal sphincter tears: interrupted time-series reanalysis. BMJ Open 2013;3:e003355. 17. Ekeus C, Nilsson E, Gottvall K. Increasing incidence of anal sphincter tears among primiparas in Sweden: a population-based study. Acta Obstet Gynecol Scand 2008;87:564–73. 18. Oberwalder M, Connor J, Wexner SD. Meta-analysis to determine the incidence of obstetric anal sphincter damage. Br J Surg 2003;90:1333–7.

25. Berggren V, Gottvall K, Isman E, Bergstrom S, Ekeus C. Infibulated women have an increased risk of anal sphincter tears at delivery: a population-based Swedish study of 250 000 births. Acta Obstet Gynecol Scand. 2013;92:101–8. 26. Fenner DE, Genberg B, Brahma P, Marek L, DeLancey JO. Fecal and urinary incontinence after vaginal delivery with anal sphincter disruption in an obstetrics unit in the United States. Am J Obstet Gynecol 2003;189:1543–9. 27. Mherson KC, Beggs AD, Sultan AH, Thakar R. Can the risk of obstetric anal sphincter injuries (OASIS) be predicted using a risk-scoring system? BMC Res Notes 2014;7:471. 28. Murphy DJ, Macleod M, Bahl R, Strachan B. A cohort study of maternal and neonatal morbidity in relation to use of sequential instruments at operative vaginal delivery. Eur J Obstet Gynecol Reprod Biol 2011;156:41–5. 29. de Leeuw JW, de Wit C, Kuijken JP, Bruinse HW. Mediolateral episiotomy reduces the risk for anal sphincter injury during operative vaginal delivery. BJOG 2008;115:104-8. 30. Kudish B, Blackwell S, McNeeley SG, Bujold E, Kruger M, Hendrix SL, et al. Operative vaginal delivery and midline episiotomy: a bad combination for the perineum. Am J Obstet Gynecol 2006;195:749–54. 31. Dandolu V, Chatwani A, Harmanli O, Floro C, Gaughan JP, Hernandez E. Risk factors for obstetrical anal sphincter lacerations. Int Urogynecol J 2005;16:304–7. 32. Risnen S, Vehvilinen-Julkunen K, Cartwright R, Gissler M, Heinonen S. A prior cesarean section and incidence of obstetric anal sphincter injury. Int Urogynecol J Pelvic Floor Dysfunct. 2013;24. 33. Boggs EW, Berger H, Urquia M, Mcdermott C. Mode of delivery following obstetric anal sphincter injury. Int Urogynecol J Pelvic Floor Dysfunct 2013;24(Suppl 1):S30. 34. Rognant S, Benoist G, Creveuil C, Dreyfus M. Obstetrical situations with a high risk of anal sphincter laceration in vacuum-assisted deliveries. Acta Obstet Gynecol Scand 2012;91:862–8. 35. Wu JM, Williams KS, Hundley AF, Connolly A, Visco AG, Stubbs T. Occiput posterior fetal head position increases the risk of anal sphincter injury in vacuum-assisted deliveries. Am J Obstet Gynecol 2005;193:525–9. 36. Lindholm ES, Altman D. Risk of obstetric anal sphincter lacerations among obese women. BJOG 2013;120:1110–5.

19. Handa VL, Danielsen BH, Gilbert WM. Obstetric anal sphincter lacerations. Obstet Gynecol 2001;98:225–30.

37. Fitzgerald MP, Weber AM, Howden N, Cundiff GW, Brown MB; Pelvic Floor Disorders Network. Risk factors for anal sphincter tear during vaginal delivery. Obstet Gynecol 2007;109:29–34.

20. Zetterstrom J, Lopez A, Anzen B, Norman M, Holmstrom B, Mellgren A. Anal sphincter tears at vaginal delivery: risk factors and clinical outcome of primary repair. Obstet Gynecol 1999;94:21–8.

38. Thakar R, Eason E. Prevention of perineal trauma. In: Sultan AH, Thakar R, Fenner DE, eds. Perineal and anal sphincter trauma. 1st ed. London (GB): Springer-Verlag; 2009: p. 52–64.

DECEMBER JOGC DÉCEMBRE 2015 l 1145

SOGC clinical practice guideline

39. Laine K, Pirhonen T, Rolland R, Pirhonen J. Decreasing the incidence of anal sphincter tears during delivery. Obstet Gynecol 2008;111:1053–7. 40. Hals E, Oian P, Pirhonen T, Gissler M, Hjelle S, Nilsen EB, et al. A multicenter interventional program to reduce the incidence of anal sphincter tears. Obstet Gynecol 2010;116:901–8. 41. Aasheim V, Nilsen AB, Lukasse M, Reinar LM. Perineal techniques during the second stage of labour for reducing perineal trauma. Cochrane Database Syst Rev 2011;12(CD006672). 42. Stamp G, Kruzins G, Crowther C. Perineal massage in labour and prevention of perineal trauma: randomised controlled trial. BMJ. 2001;322(7297):1277–80. 43. Albers LL, Sedler KD, Bedrick EJ, Teaf D, Peralta P. Midwifery care measures in the second stage of labor and reduction of genital tract trauma at birth: a randomized trial. J Midwifery Womens Health 2005;50:365–72. 44. Gareberg B, Magnusson B, Sultan B, Wennerholm U-B, Wennergren M, Hagberg H. Birth in standing position: a high frequency of third degree tears. Acta Obstet Gynecol Scand 1994;73:630–3. 45. Walker C, Rodriguez T, Herranz A, Espinosa JA, Sanchez E, Espuna-Pons M. Alternative model of birth to reduce the risk of assisted vaginal delivery and perineal trauma. Int Urogynecol J 2012;23:1249–56. 46. Carroli G, Mignini L. Episiotomy for vaginal birth. Cochrane Database Syst Rev 2009;1(CD000081). 47. Murphy DJ, Macleod M, Bahl R, Goyder K, Howarth L, Strachan B. A randomised controlled trial of routine versus restrictive use of episiotomy at operative vaginal delivery: a multicentre pilot study. BJOG 2008;115:1695–702. 48. Aytan H, Tapisiz OL, Tuncay G, Avsar FA. Severe perineal lacerations in nulliparous women and episiotomy type. Eur J Obstet Gynecol Reprod Biol 2005;121:46–50. 49. Brubaker L, Bradley CS, Handa VL, Richter HE, Visco A, Brown MB, et al. Anal sphincter laceration at vaginal delivery: is this event coded accurately? Obstet Gynecol 2007;109:1141–5. 50. Fernando RJ, Sultan AH, Kettle C, Thakar R. Methods of repair for obstetric anal sphincter injury. Cochrane Database Syst Rev 2013;12:CD002866. 51. Andrews V, Sultan AH, Thakar R, Jones PW. Risk factors for obstetric anal sphincter injury: a prospective study. Birth 2006;33:117–22. 52. de Leeuw JW, Struijk PC, Vierhout ME, Wallenburg HCS. Risk factors for third degree perineal ruptures during delivery. Br J Obstet Gynaecol. 2001;108:383–7. 53. Raisanen SH, Vehvilainen-Julkunen K, Gissler M, Heinonen S. Lateral episiotomy protects primiparous but not multiparous women from obstetric anal sphincter rupture. Acta Obstet Gynecol Scand 2009;88:1365–72. 54. Revicky V, Nirmal D, Mukhopadhyay S, Morris EP, Nieto JJ. Could a mediolateral episiotomy prevent obstetric anal sphincter injury? Eur J Obstet Gynecol Reprod Biol 2010;150:142–6. 55. Coats PM, Chan KK, Wilkins M, Beard RJ. A comparison between midline and mediolateral episiotomies. Br J Obstet Gynaecol 1980;87:408–12. 56. Sooklim R, Thinkhamrop J, Lumbiganon P, Prasertcharoensuk W, Pattamadilok J, Seekorn K, et al. The outcomes of midline versus medio-lateral episiotomy. Reprod Health 2007;4:10. 57. Kalis V, Laine K, de Leeuw JW, Ismail KM, Tincello DG. Classification of episiotomy: towards a standardisation of terminology. BJOG 2012;119:522–6. 58. Stedenfeldt M, Pirhonen J, Blix E, Wilsgaard T, Vonen B, Oian P. Episiotomy characteristics and risks for obstetric anal sphincter injuries: a case-control study. BJOG 2012;119:724–30.

1146 l DECEMBER JOGC DÉCEMBRE 2015

59. El Din ASS, Kamal MM, Amin MA. Comparison between two incision angles of mediolateral episiotomy in primiparous women: a randomized controlled trial. J Obstet Gynaecol Res 2014;40:1877–82. 60. Karbanova J, Rusavy Z, Betincova L, Jansova M, Parizek A, Kalis V. Clinical evaluation of peripartum outcomes of mediolateral versus lateral episiotomy. Int J Gynaecol Obstet 2014;124:72–6. 61. Fodstad K, Staff AC, Laine K. Effect of different episiotomy techniques on perineal pain and sexual activity 3 months after delivery. Int Urogynecol J Pelvic Floor Dysfunct 2014;25:1629–37. 62. Eogan M, Daly L, O’Connell PR, O’Herlihy C. Does the angle of episiotomy affect the incidence of anal sphincter injury? BJOG 2006;113:190–4. 63. Kalis V, Karbanova J, Horak M, Lobovsky L, Kralickova M, Rokyta Z. The incision angle of mediolateral episiotomy before delivery and after repair. Int J Gynaecol Obstet 2008;103:5–8. 64. Hirsch E, Haney EI, Gordon TE, Silver RK. Reducing high-order perineal laceration during operative vaginal delivery. Am J Obstet Gynecol 2008;2008:668–5. 65. O’Mahony F, Hofmeyr GJ, Menon V. Choice of instruments for assisted vaginal delivery. Cochrane Database Syst Rev 2010;11(CD005455). 66. Macleod M, Strachan B, Bahl R, Howarth L, Goyder K, Van de Venne M, et al. A prospective cohort study of maternal and neonatal morbidity in relation to use of episiotomy at operative vaginal delivery. BJOG 2008;115:1688–94. 67. Jango H, Langhoff-Roos J, Rosthoj S, Sakse A. Modifiable risk factors of obstetric anal sphincter injury in primiparous women: a population-based cohort study. Am J Obstet Gynecol 2014;210:59.e1–e6. 68. Steed HH, Corbett TC, Mayes DC. The value of routine episiotomy in forceps deliveries. J SOGC 2000;22:583–6. 69. Farrell SA. Cesarean section versus forceps-assisted vaginal birth: it’s time to include pelvic injury in the risk-benefit equation. CMAJ 2002;166:337–8. 70. Donnelly V, Fynes M, Campbell D, Johnson H, O’Connell PR, O’Herlihy C. Obstetric events leading to anal sphincter damage. Obstet Gynecol 1998;92:955–61. 71. Fynes M, Donnelly VS, O’Connell PR, O’Herlihy C. Cesarean delivery and anal sphincter injury. Obstet Gynecol 1998;92(4 Pt 1):496–500. 72. Beckmann MM, Garrett AJ. Antenatal perineal massage for reducing perineal trauma. Cochrane Database Syst Rev 2006;1(CD005123). 73. Altman D, Ragnar I, Ekstrom A, Tyden T, Olsson SE. Anal sphincter lacerations and upright delivery postures—a risk analysis from a randomized controlled trial. Int Urogynecol J 2007;18:141–6. 74. Yildirim G, Beji NK. Effects of pushing techniques in birth on mother and fetus: a randomized study. Birth 2008;35:25–30. 75. Jonsson ER, Elfaghi I, Rydhstrom H, Herbst A. Modified Ritgen’s maneuver for anal sphincter injury at delivery: a randomized controlled trial. Obstet Gynecol 2008;112(2 Pt 1):212–7. 76. Cluett ER, Burns E. Immersion in water in labour and birth. Cochrane Database Syst Rev 2009;2(CD000111). 77. Fitzpatrick M. A randomised clinical trial comparing the effects of delayed versus immediate pushing with epidural analgesia on mode of delivery and faecal continence. BJOG. 2002;109:1359–65. 78. Sultan AH, Thakar R. Lower genital tract and anal sphincter trauma. Best Pract Res Clin Obstet Gynaecol 2002;16:99–115. 79. Royal College of Obstetricians and Gynaecologists. The management of third- and fourth-degree perineal tears. 2007 Green Top Guideline No. 29. London (GB): RCOG; 2015. Available at: https://www.rcog.org. uk/en/guidelines-research-services/guidelines/gtg29. Accessed on September 15, 2015.

Obstetrical Anal Sphincter Injuries (OASIS): Prevention, Recognition, and Repair

80. Duggal N, Mercado C, Daniels K, Bujor A, Caughey AB, El Sayed YY. Antibiotic prophylaxis for prevention of postpartum perineal wound complications: a randomized controlled trial. Obstet Gynecol 2008;111:1268–73. 81. Williams A, Adams EJ, Tincello DG, Alfirevic Z, Walkinshaw SA, Richmond DH. How to repair an anal sphincter injury after vaginal delivery: results of a randomised controlled trial. BJOG 2006;113:201–7. 82. Lunniss J, Scott S. Pathophysiology of anal incontinence. In: Sultan AH, Thakar R, Fenner DE, eds. Perineal and anal sphincter trauma, 1st ed. London (GB): Springer-Verlag; 2009: p. 89–101. 83. Lindqvist PG, Jernetz M. A modified surgical approach to women with obstetric anal sphincter tears by separate suturing of external and internal anal sphincter. A modified approach to obstetric anal sphincter injury. BMC Pregnancy Childbirth. 2010;10:51. 84. Fitzpatrick M, Behan M, O’Connell PR, O’Herlihy C. A randomized clinical trial comparing primary overlap with approximation repair of third-degree obstetric tears. Am J Obstet Gynecol 2000;183:1220–4. 85. Nichols CM, Nam M, Ramakrishnan V, Lamb EH, Currie N. Anal sphincter defects and bowel symptoms in women with and without recognized anal sphincter trauma. Am J Obstet Gynecol. 2006;194:1450–4. 86. Nichols CM, Lamb EH, Ramakrishnan V. Differences in outcomes after third- versus fourth-degree perineal laceration repair: a prospective study. Am J Obstet Gynecol 2005;193:530–4. 87. Nordenstam J, Mellgren A, Altman D, Lopez A, Johansson C, Anzen B, et al. Immediate or delayed repair of obstetric anal sphincter tears— a randomised controlled trial. BJOG 2008;115:857–65. 88. Parks AG, Martlin JF. Late repair of injuries of the anal sphincter. Proc R Soc Med 1971;64:1187–9. 89. Sultan AH, Monga AK, Kumar D, Stanton SL. Primary repair of obstetric anal sphincter rupture using the overlap technique. Br J Obstet Gynaecol 1999;106:318–23. 90. Sultan AH, Kamm MA, Hudson CN, Bartram CI. Third degree obstetric anal sphincter tears: risk factors and outcome of primary repair. BMJ 1994;308:887–91. 91. Fernando RJ, Sultan AH, Kettle C, Radley S, Jones P, O’Brien PMS. Repair techniques for obstetric anal sphincter injuries: a randomized controlled trial. Obstet Gynecol 2006;107:1261–8. 92. Farrell SA, Flowerdew G, Gilmour D, Turnbull GK, Schmidt MH, Baskett TF, et al. Overlapping compared with end-to-end repair of complete third-degree or fourth-degree obstetric tears: three-year followup of a randomized controlled trial. Obstet Gynecol 2012;120:803–8. 93. Buppasiri P, Lumbiganon P, Thinkhamrop J, Thinkhamrop B. Antibiotic prophylaxis for third- and fourth-degree perineal tear during vaginal birth. Cochrane Database Syst Rev 2014;10(CD005125). 94. Fernando R, Sultan AH, Kettle C, Thakar R, Radley S. Methods of repair for obstetric anal sphincter injury. Cochrane Database Syst Rev2006;3(CD002866).

99. Yip S-K, Brieger G, Hin L-Y, Chung T. Urinary retention in the postpartum period. The relationship between obstetric factors and the postpartum post-void residual bladder volume. Acta Obstet Gynecol Scand 1997;76:667–72. 100. Ching-Chung L, Shuenn-Dhy C, Ling-Hong T, Ching-Chang H, Chao-Lun C, Po-Jen C. Postpartum urinary retention: assessment of contributing factors and long-term clinical impact. Aust N Z J Obstet Gynaecol 2002;42:365–8. 101. Glavind K, Bjork J. Incidence and treatment of urinary retention postpartum. Int Urogynecol J 2003;14:119–21. 102. Musselwhite KL, Faris P, Moore K, Berci D, King KM. Use of epidural anesthesia and the risk of acute postpartum urinary retention. Am J Obstet Gynecol. 2007;196:472.e1-.e5. 103. Payne TN, Carey JC, Rayburn WF. Prior third- or fourth-degree perineal tears and recurrence risks. Int J Gynaecol Obstet 1999;64:55–7. 104. Dandolu V, Gaughan JP, Chatwani AJ, Harmanli O, Mabine B, Hernandez E. Risk of recurrence of anal sphincter lacerations. Obstet Gynecol 2005;105:831–5. 105. Lowder JL, Burrows LJ, Krohn MA, Weber AM. Risk factors for primary and subsequent anal sphincter lacerations: a comparison of cohorts by parity and prior mode of delivery. Am J Obstet Gynecol 2007;196:344–5. 106. de Leeuw JW, Vierhout ME, Struijk PC, Hop WC, Wallenburg HC. Anal sphincter damage after vaginal delivery: functional outcome and risk factors for fecal incontinence. Acta Obstet Gynecol Scand 2001;80:830–4. 107. Wegnelius G, Hammarstrom M. Complete rupture of anal sphincter in primiparas: long-term effects and subsequent delivery. Acta Obstet Gynecol Scand 2011;90:258–63. 108. Fynes MM, Marshall K, Cassidy M, Behan M, Walsh D, O’Connell PR, et al. A prospective, randomized study comparing the effect of augmented bio with sensory bio alone on fecal incontinence after obstetric trauma. Dis Colon Rectum 1999;42:753–61. 109. Mahony RT, Malone PA, Nalty J, Behan M, O’Connell PR, O’Herlihy C. Randomized clinical trial of intra-anal electromyographic bio physiotherapy with intra-anal electromyographic bio augmented with electrical stimulation of the anal sphincter in the early treatment of postpartum fecal incontinence. Am J Obstet Gynecol 2004;191:885–90. 110. Parmar S, Towner D, Xing G, Wallach S. Recurrent anal sphincter injury: a population based study. Am J Obstet Gynecol 2012;206(1Suppl 1):S150. 111. Jango H, Langhoff-Roos J, Rosthoj S, Sakse A. Risk factors of recurrent anal sphincter ruptures: a population-based cohort study. Acta Obstet Gynecol Scand. 2012;91(s159):93–4. 112. Spydslaug A, Trogstad LI, Skrondal A, Eskild A. Recurrent risk of anal sphincter laceration among women with vaginal deliveries. Obstet Gynecol 2005;105:307–13. 113. Peleg D, Kennedy CM, Merrill D, Zlatnik FJ. Risk of repetition of a severe perineal laceration. Obstet Gynecol. 1999;93:1021–4.

95. Mahony R, Behan M, O’Herlihy C, O’Connell PR. Randomized, clinical trial of bowel confinement vs. laxative use after primary repair of a thirddegree obstetric anal sphincter tear. Dis Colon Rectum 2004;47:12–7.

114. Scheer I, Thakar R, Sultan AH. Mode of delivery after previous obstetric anal sphincter injuries (OASIS)--a reappraisal? Int Urogynecol J 2009;20:1095–101.

96. Eogan M, Daly L, Behan M, O’Connell PR, O’Herlihy C. Randomised clinical trial of a laxative alone versus a laxative and a bulking agent after primary repair of obstetric anal sphincter injury. BJOG 2007;114:736–40.

115. Poen AC, Felt-Bersma RJ, Strijers RL, Dekker GA, Cuesta MA, Meuwissen SG. Third-degree obstetric perineal tear: long-term clinical and functional results after primary repair. Br J Surg 1998;85:1433–8.

97. Hedayati H, Parsons J, Crowther CA. Rectal analgesia for pain from perineal trauma following childbirth. Cochrane Database Syst Rev 2003;3(CD003931).

116. Bek KM, Laurberg S. Risks of anal incontinence from subsequent vaginal delivery after a complete obstetric anal sphincter tear. Br J Obstet Gynaecol 1992;99:724–6.

98. McCarthy DM. Mechanisms of mucosal injury and healing: the role of non-steroidal anti-inflammatory drugs. Scand J Gastroenterol 1995;30:208(Suppl):24–9.

117. Tetzschner T, Sorensen M, Lose G, Christiansen J. Anal and urinary incontinence in women with obstetric anal sphincter rupture. Br J Obstet Gynaecol 1996;103:1034–40.

DECEMBER JOGC DÉCEMBRE 2015 l 1147

SOGC clinical practice guideline

118. Faltin DL, Sangalli MR, Roche B, Floris L, Boulvain M, Weil A. Does a second delivery increase the risk of anal incontinence? Br J Obstet Gynaecol 2001;108:684–8. 119. McKenna DS, Ester JB, Fischer JR. Elective cesarean delivery for women with a previous anal sphincter rupture. Am J Obstet Gynecol 2003;189:1251–6. 120. Jango H, Langhoff-Roos J, Sakse A. Does mode of second delivery after obstetric anal sphincter rupture influence the risk of anal incontinence? Acta Obstet Gynecol Scand 2012;91(Supp):41–2. 121. Mahony R, Behan M, O’Connell PR, O’Herlihy C. Effect of second vaginal delivery on anal function in patients at risk of occult anal sphincter injury after first forceps delivery. Dis Colon Rectum 2008;51:1361–6. 122. Daly JO, Sultan AH, Van delft KW, Thakar R. Outcome of childbirth after previous obstetric anal sphincter injury. 38th Annual Meeting of

1148 l DECEMBER JOGC DÉCEMBRE 2015

the International Urogynecological Association, IUGA. Int Urogynecol J Pelvic Floor Dysfunct 2013;24(Suppl 1):S69–S70. 123. Karmarkar R, Bhide AA, Digesu A, Khullar V, Fernando R. Mode of delivery after previous obstetric anal sphincter injuries (OASIS)a prospective observational study. Int Urogynecol J Pelvic Floor Dysfunct 2014;25(1 Suppl 1): S190–S1. 124. Siddighi S, Kleeman SD, Baggish MS, Rooney CM, Pauls RN, Karram MM. Effects of an educational workshop on performance of fourth-degree perineal laceration repair. Obstet Gynecol 2007;109(2 Pt 1):289–94. 125. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canad ian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

SOGC CLINICAL PRACTICE GUIDELINE No. 324, May 2015 (Replaces #201, December 2007)

Pre-conception Folic Acid and Multivitamin Supplementation for the Primary and Secondary Prevention of Neural Tube Defects and Other Folic Acid-Sensitive Congenital Anomalies This Clinical Practice Guideline was prepared by the Genetics Committee, reviewed by the Family Physician Advisory Committee, and approved by the Executive and Board of the Society of Obstetricians and Gynaecologists of Canada.

Aideen Moore, MD, Toronto ON

PRINCIPAL AUTHOR

Michiel Van den Hof, MD, Halifax NS

R. Douglas Wilson, MD, Calgary AB

Disclosure statements have been received from all contributors.

GENETICS COMMITTEE R. Douglas Wilson (Chair), MD, Calgary AB François Audibert, MD, Montreal QC Jo-Ann Brock, MD, Halifax NS June Carroll, MD, Toronto ON Lola Cartier, MSc, Montreal QC Alain Gagnon, MD, Vancouver BC Jo-Ann Johnson, MD, Calgary AB Sylvie Langlois, MD, Vancouver BC Lynn Murphy-Kaulbeck, MD, Moncton NB Nanette Okun, MD, Toronto ON Melanie Pastuck, RN, Calgary AB SPECIAL CONTRIBUTORS Paromita Deb-Rinker, PhD, Ottawa ON

William Mundle, MD, Windsor ON Deborah O’Connor, PhD RD, Toronto ON Joel Ray, MD, Toronto ON

Abstract Objective: To provide updated information on the pre- and postconception use of oral folic acid with or without a multivitamin/ micronutrient supplement for the prevention of neural tube defects and other congenital anomalies. This will help physicians, midwives, nurses, and other health care workers to assist in the education of women about the proper use and dosage of folic acid/multivitamin supplementation before and during pregnancy. Evidence: Published literature was retrieved through searches of PubMed, Medline, CINAHL, and the Cochrane Library in January 2011 using appropriate controlled vocabulary and key words (e.g., folic acid, prenatal multivitamins, folate sensitive birth defects, congenital anomaly risk reduction, pre-conception counselling). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies published in English from 1985 and June 2014. Searches were updated on a regular basis and incorporated in the guideline to June 2014 Grey (unpublished) literature was identified through searching the

Linda Dodds, MD, Halifax NS Juan Andres Leon, MD, Ottawa ON Hélène Lowell, RD DtP, Ottawa ON Wei Luo, MB MSc, Ottawa ON Amanda MacFarlane, PhD, Ottawa ON Rachel McMillan, BSc, Ottawa ON

J Obstet Gynaecol Can 2015;37(6):534–549 Key Words: Folic acid, folate, prenatal multivitamins, micronutrients, neural tube defect, spina bifida, myelomeningocele, congenital anomalies, fetal anomalies, folate sensitive birth defects, congenital anomaly risk reduction, preconception counseling, birth defects, pregnancy, prevention

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

534 l JUNE JOGC JUIN 2015

Pre-conception Folic Acid/Multivitamin Supplementation for the Prevention of Neural Tube Defects and Other Congenital Anomalies

Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

*The quality of evidence reported in here has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.193 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care.193

websites of health technology assessment and health technologyrelated agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Costs, risks, and benefits: The financial costs are those of daily vitamin supplementation and eating a healthy folate-enriched diet. The risks are of a reported association of dietary folic acid supplementation with fetal epigenetic modifications and with an increased likelihood of a twin pregnancy. These associations may require consideration before initiating folic acid supplementation. The benefit of folic acid oral supplementation or dietary folate intake combined with a multivitamin/micronutrient supplement is an associated decrease in neural tube defects and perhaps in other specific birth defects and obstetrical complications. Values: The quality of evidence in the document was rated using the criteria described in the Report of the Canadian Task Force on Preventative Health Care (Table 1). Summary Statement In Canada multivitamin tablets with folic acid are usually available in 3 formats: regular over-the-counter multivitamins with 0.4 to 0.6 mg folic acid, prenatal over-the-counter multivitamins with 1.0 mg folic acid, and prescription multivitamins with 5.0 mg folic acid. (III) Recommendations 1. Women should be advised to maintain a healthy folate-rich diet; however, folic acid/multivitamin supplementation is needed to achieve the red blood cell folate levels associated with maximal protection against neural tube defect. (III-A) 2. All women in the reproductive age group (12–45 years of age) who have preserved fertility (a pregnancy is possible) should be advised about the benefits of folic acid in a multivitamin supplementation during medical wellness visits (birth control renewal, Pap testing, yearly gynaecological examination) whether or not a pregnancy is contemplated. Because so many pregnancies are unplanned, this applies to all women who may become pregnant. (III-A) 3. Folic acid supplementation is unlikely to mask vitamin B12 deficiency (pernicious anemia). Investigations (examination or laboratory) are not required prior to initiating folic acid

supplementation for women with a risk for primary or recurrent neural tube or other folic acid-sensitive congenital anomalies who are considering a pregnancy. It is recommended that folic acid be taken in a multivitamin including 2.6 ug/day of vitamin B12 to mitigate even theoretical concerns. (II-2A) 4. Women at HIGH RISK, for whom a folic acid dose greater than 1 mg is indicated, taking a multivitamin tablet containing folic acid, should be advised to follow the product label and not to take more than 1 daily dose of the multivitamin supplement. Additional tablets containing only folic acid should be taken to achieve the desired dose. (II-2A) 5. Women with a LOW RISK for a neural tube defect or other folic acid-sensitive congenital anomaly and a male partner with low risk require a diet of folate-rich foods and a daily oral multivitamin supplement containing 0.4 mg folic acid for at least 2 to 3 months before conception, throughout the pregnancy, and for 4 to 6 weeks postpartum or as long as breast-feeding continues. (II-2A) 6. Women with a MODERATE RISK for a neural tube defect or other folic acid-sensitive congenital anomaly or a male partner with moderate risk require a diet of folate-rich foods and daily oral supplementation with a multivitamin containing 1.0 mg folic acid, beginning at least 3 months before conception. Women should continue this regime until 12 weeks’ gestational age. (1-A) From 12 weeks’ gestational age, continuing through the pregnancy, and for 4 to 6 weeks postpartum or as long as breast-feeding continues, continued daily supplementation should consist of a multivitamin with 0.4 to 1.0 mg folic acid. (II-2A) 7. Women with an increased or HIGH RISK for a neural tube defect, a male partner with a personal history of neural tube defect, or history of a previous neural tube defect pregnancy in either partner require a diet of folate-rich foods and a daily oral supplement with 4.0 mg folic acid for at least 3 months before conception and until 12 weeks’ gestational age. From 12 weeks’ gestational age, continuing throughout the pregnancy, and for 4 to 6 weeks postpartum or as long as breast-feeding continues, continued daily supplementation should consist of a multivitamin with 0.4 to 1.0 mg folic acid. (I-A). The same dietary and supplementation regime should be followed if either partner has had a previous pregnancy with a neural tube defect. (II-2A)

JUNE JOGC JUIN 2015 l 535

SOGC clinical practice guideline

INTRODUCTION

I

t has been estimated that 4% to 5% of babies are born with a serious congenital anomaly1; 2% to 3% will have congenital anomalies (malformations, deformations or disruptions) that can be recognized prenatally by noninvasive ultrasound screening or anticipated through invasive diagnostic testing and 2% will have developmental or functional anomalies and minor congenital anomalies recognized at birth or during the first year of life.1 Folic acid, taken orally prior to conception and during the early stages of pregnancy, plays a role in preventing neural tube defects2–25 and has been associated with preventing other folic acid-sensitive congenital anomalies such as heart defects,15,26–30 urinary tract anomalies,15,28,31 oral facial clefts,15,32–40 and limb defects.15 FOLIC ACID SUPPLEMENTATION AND THE PREVENTION OF BIRTH DEFECTS

The initial NTD translational research study investigated folic acid supplementation for recurrence prevention of NTDs in a randomized double-blind clinical trial involving 1195 completed high risk pregnancies in women from 33 centres.2 The NTD recurrence rate decreased from 3.5% in a non-supplemented group to 1% for women randomized to the group receiving an oral 4 mg folic acid supplementation daily prior to pregnancy and throughout the first 6 weeks of pregnancy. The second NTD translational research study was a randomized controlled trial for the primary prevention of NTD occurrence.3 The frequency of NTDs was zero in 2471 women receiving 0.8 mg per day of folic acid compared with 6 cases in 2391 women not receiving folic acid. This RCT study ed previous case–control studies that had provided evidence that pregnant women using multivitamins containing folic acid or dietary folic acid had a lower risk of occurrence NTDs than women not taking supplements.10–14 ABBREVIATIONS aOR

adjusted odds ratio

BMI

body mass index

CI

confidence interval

GI

gastrointestinal

MTHFR 5,10-methylenetetrahydrofolate reductase NTD

neural tube defect

OR

odds ratio

RBC

red blood cell

RCT

randomized controlled trial

536 l JUNE JOGC JUIN 2015

These 2 landmark RCT studies have provided the folic acid supplementation dosing evidence (from initial experimental expert opinion) for NTD primary prevention and recurrence, but they were completed in female populations without the additional exposure or benefit of folic acid food fortification that is at present in the North American food environment. These RCT folic acid dose results may need to be adjusted due to the present food environment “with folic acid fortified white flour products but more research is required for optimization of oral supplementation dose (maximum benefit; minimum or no risk) with non-pregnant pre-conception exposure to fortified food products.16 ORAL FOLIC ACID SUPPLEMENTATION PREGNANCY CARE

Oral pre-conception folic acid dietary intake or supplementation is required as it is the primary source for the trans-placental transfer of folate/folic acid to the embryo/fetus. No specific studies have been published looking at the embryonic cell folate availability in humans during this embryonic target period of 0 to 8 weeks (conception to 10 gestational weeks). Canadian researchers have made strong contributions in this area of prevention.41–76 Women should be advised to maintain a nutritionally healthy diet, as recommended in Eating Well with Canada’s Food Guide.42 Good or excellent sources of natural folate include broccoli, spinach, peas, Brussels sprouts, corn, lentils, and oranges. Counselling should emphasize that the recurrence risk for a fetus with an NTD is shared by both mother’s and father’s personal reproductive history, but only the mother is treated with the supplemental dose of pre-conception/ first trimester folic acid. Folic Acid Food Fortification and Oral Supplementation

In Canada, since 1998, in an effort to reduce the rate of NTDs, there has been mandatory folic acid fortification of white flour, enriched pasta, and cornmeal. Food fortification coincided with an observed decrease in NTDs in live-born infants,1,6,16 but a proportion of the documented NTD decrease may also be related to an increased use of prenatal tests and subsequent pregnancy termination (secondary prevention) rather than to fortification alone.45,46 It is possible that certain prevalence data populations may not have included termination of pregnancy prior to the 20 weeks’ gestation information in their reported rate.

Pre-conception Folic Acid/Multivitamin Supplementation for the Prevention of Neural Tube Defects and Other Congenital Anomalies

Sherwood et al. assessed the dietary folate intake of pregnant and lactating women at the presently mandated and predicted folic acid fortification levels to determine the prevalence of inadequate and excessive intakes. The conclusion was, at the present mandated levels of food fortification, many pregnant and lactating women are still unlikely to meet their appropriate folate requirements from dietary sources alone, however the actual level of inadequacy cannot be determined until the level of folic acid in the food supply is known with greater precision.50 RBC folate testing/screening for the prevention of birth defects in certain co-existing maternal health conditions requires more investigation to determine the actual effectiveness and use of this testing. Factors that may affect the ability to achieve adequate maternal folic acid tissue levels

Optimization of oral maternal folic acid supplementation is difficult because it relies on folic acid dose, type of folate supplement, bio-availability of the folate from foods, timing of supplementation initiation, maternal metabolism/genetic factors, and many other factors.71–76 Recommendations

1. Women should be advised to maintain a healthy folate-rich diet; however, folic acid/multivitamin supplementation is needed to achieve the red blood cell folate levels associated with maximal protection against neural tube defect. (III-A) 2. All women in the reproductive age group (12–45 years of age) who have preserved fertility (a pregnancy is possible) should be advised about the benefits of folic acid in a multivitamin supplementation during medical wellness visits (birth control renewal, Pap testing, yearly gynaecological examination) whether or not a pregnancy is contemplated. Because so many pregnancies are unplanned this applies to all women who may become pregnant. (III-A)

vitamin supplementation,78–80 as well as to an increase of prenatal diagnosis/termination.45,46 Recurrence risks may reflect the genetic contribution in different regional or population incidence and folic acid NTD sensitivity (Table 2), as there is still an estimated 1% recurrence rate even with the 4 to 5 mg folic acid prophylaxis supplementation approach.1,6,7,81–91 Table 2 summarizes the increasing NTD clinical risk groups, based on the family relationship of the affected individual to the “at-risk” fetus and the specific NTD population background risk (based on ethnic/genetic population demographics). The Canadian population risk varies across the country, with the highest NTD risk in Newfoundland and the lowest NTD risk in British Columbia.77 Table 3 summarizes the evidence-based risk factors for low maternal RBC or serum folate status that are associated specifically with neural tube defects.15,19-22,41,77–79,81,82,92–106 Table 4 summarizes the commonly used medications/ drugs prescribed for certain medical therapies that have been shown to have interactions with folate metabolism and may alter RBC folate levels with a resulting increased risk for congenital anomaly outcomes.100–103 Table 5 summarizes the studies with case–control, cohort, or RCT comparisons (odds ratio) and decreased, increased, or no effects on specific congenital anomalies.15,30,37,38,40,53 Folic acid in combination with multivitamin supplements has been shown to reduce certain other congenital anomalies such as heart defects,15,26–30 urinary tract anomalies,15,28,31 oral facial clefts,15,32–40 and limb defects.15At present, multifactorial inheritance (genetic and environmental factors)79,107,108 is the most commonly reported etiology for NTDs, but monogenic, chromosomal, and teratogenic etiologies have specific effects and have not been well studied in their association with folic acid deprivation or supplementation.109 The risk categories for fetal NTD outcome should consider the 2 major effect pathways:

Background for NTD Prevention

1. Genetic factors including gene polymorphisms that affect the efficiency of folate metabolism, gene mutations, affects related to DNA methylation/ epigenetics, and associated chromosomal anomalies, and

In Canada, the prevalence of NTDs in newborns has declined since 1998 due to food fortification and increased

2. Environmental factors such as dietary folate intake (food fortification and/or dietary supplementation), gastrointestinal absorption efficiency, teratogenic medication exposure (epilepsy or folate antagonist medications), glucose metabolism (obesity, diabetes type I and II), drugs, smoking, alcohol, and “proposed” folate receptor auto-antibodies.

FOLIC ACID FOR CONGENITAL ANOMALIES PREVENTION AND EVALUATION

Neural tube defects are severe congenital anomalies that occur due to a lack of neural tube closure at either the upper, middle, or lower portion of the spine in the third to fourth week after conception (day 26 to day 28 postconception).77

JUNE JOGC JUIN 2015 l 537

SOGC clinical practice guideline

Table 2. Anencephaly and spina bifida approximate recurrence risk with no food folic acid fortification or folate supplementation Recurrence risk, % based on population NTD incidence Population incidence 5 per 1000

Relationship of NTD affected individual to the at-risk fetus

Population incidence 2 per 1000

Population incidence 1 per 1000

One sibling

5

2

2

Two siblings

12

10

10

One parent

4

4

4

One second-degree relative

2

1

1

One third degree relative

1

0.75

0.5

Adapted from Firth HV, Hurst JA, Hall JG. Oxford desk reference. Clinical genetics. Oxford: Oxford University Press; 2006.77 NTD: neural tube defect

Table 3. Identified increased risk factors for fetal NTD or low maternal RBC folate status Personal/family history or ethnic risk1–5,19–22

NTD: maternal or paternal affected, previous affected fetus for either parent, child, sibling, or second /third degree relative MTHFR genotype 677TT carrier homozygous 677CST carrier heterozygous

Medical/surgical condition41,77–79,100–103

GI: malabsorption/inflammatory bowel, Crohn’s, active Celiac disease, gastric by surgery, advanced liver disease Renal: kidney dialysis Pre-gestational diabetes (type I or II) Anti-epilepsy or folate-inhibiting medications (see Table 4)

Maternal co-morbidities81,92–97

Maternal obesity: BMI > 30 kg/m2 or 80 kg (pre-pregnancy weight)

Maternal lifestyle factors82,98,99,190–192

Smoking Alcohol overuse Non-prescription drug use/abuse Low socio-economic status Poor/restricted diet

NTD: neural tube defect; RBC: red blood cell; MTHFR: methylenete trahydrofolate reductase; GI: gastrointestinal

Table 4. Interactions between drugs or medications and folic acid 1. Biology reduced folic acid activity 2. Reduced folic acid levels

Interference with erythrocyte maturation

Chloramphenicol

Other

Metformin

Impaired absorption

Sulfasalazine

Increased metabolism

Phenobarbital

Methotrexate

Phenytoin

3. Other interactions

Not reported

Primidone Triamterene Barbiturates

538 l JUNE JOGC JUIN 2015

Pre-conception Folic Acid/Multivitamin Supplementation for the Prevention of Neural Tube Defects and Other Congenital Anomalies

Table 5. Summary of congenital anomalies (decreased or increased or no effect) following folic acid food fortification Study reference

Case–Control (95% CI)

Cohort/RCT (95% CI)

Neural tube defect

0.67 (0.58–0.77)

0.52 (0.39–0.69)

Oral facial cleft

0.63 (0.54–0.73)

0.58 (0.28–1.19)

Cardiovascular defects

0.78 (0.67–0.92)

0.61 (0.40–0.92)

Limb reduction defects

0.48 (0.30–0.76)

0.57 (0.38–0.85)

Cleft palate

0.76 (0.62–0.93)

0.42 (0.06–2.84)

Urinary tract defects

0.48 (0.30–0.76)

0.68 (0.35–1.31)

Congenital hydrocephalus

0.37 (0.24–0.56)

1.54 (0.53–4.50)

Cleft lip and palate

0.75 (0.65–0.88)

Cleft palate only

0.88 (0.76–1.01)

Anomaly Meta-analysis

Goh et al. (2006)15

Johnson and Little (2008)38

Single Population Li et al. (2013)30

Heart defects isolated and complex

0.52 (0.34–0.78) 0.27 (0.14–0.55)

Godwin et al. (2008)40

Spina bifida

0.51 (0.36–0.73)

OS atrial septal defects

0.80 (0.69–0.93)

Ureteric obstruction

1.45 (1.24–1.70)

Abdominal wall defect

1.40 (1.04–1.88)

Pyloric stenosis

1.49 (1.18–1.89)

Anencephaly

0.84 (0.76–0.94)

Spina bifida

0.66 (0.61–0.71)

TGA

0.88 (0.81–0.96)

Cleft palate only

0.88 (0.82–0.95)

Pyloric stenosis

0.95 (0.90–0.99)

Omphalocele

0.79 (0.66–0.95)

Upper limb reduction

0.89 (0.80–0.99)

Cleft lip ± palate

0.61 (0.39–0.96)

Canfield et al. (2005)53

O’Neill (2007)37

Cleft palate only Goh et al (2006)

15

No effect identified for

Folic acid 0.4 mg daily

0.75 (0.50–1.11)

Folate diet only

0.36 (0.17–0.77)

Supplement + diet

1.07 (0.56–2.03) Trisomy 21 Pyloric stenosis Undescended testis Hypospadias

RCT: randomized control trial; OS: ostium secunda; TGA: transposition of the great arteries

Details for the genetic and environmental factors/ considerations with fetal and pediatric outcomes are available in the references.19–22,110–149 POTENTIAL CAUTION FOR MATERNAL, FETAL, CHILDHOOD, OR GENERAL POPULATION WITH FOLIC ACID SUPPLEMENTATION Benefit

Folic acid, in a 0.4 to 1.0 mg daily dose60,150–152 is not known to cause demonstrable harm to the developing fetus or to the pregnant woman. The risk of maternal or fetal toxicity

from oral folic acid intake due to vitamin supplements and/or fortified foods is low. Folic acid is a water soluble vitamin, so any excess intake is anticipated to be excreted in the urine. Folic acid has not been shown to promote or to prevent breast cancer.153–155 Ovarian cancer studies suggest (but not with statistical significance) that relatively high dietary folate intake may be associated with a reduction in ovarian cancer risk among woman with high alcohol and methionine intake.156 JUNE JOGC JUIN 2015 l 539

SOGC clinical practice guideline

Evidence has been reported for a decreased prevalence of preeclampsia with maternal folic acid supplementation.143,157–160 An Australian study found that high serum folate did not mask the macrocytosis of cobalamin (vitamin B12) deficiency of pernicious anemia.161 A Cochrane Review found no conclusive evidence of benefit of folic acid supplementation on pregnancy outcomes (preterm birth, stillbirths, neonatal deaths, low birth weight babies, pre-delivery anemia, or low pre-delivery red cell folate).162 Risks and Cautions

Folic acid dosing above the recommended supplementation amounts (supra-physiologic doses) has not been shown to have any added fetal/maternal health or developmental benefits, although recent epigenetic/ methylation studies in animals and humans have indicated that some caution and research is required. The folic acid doses of 5 mg have not been reported to have maternal or fetal risks, but long-term high-dose 5 mg folic acid use has not been well studied in a prenatal population.3,10–14,35,36, 54,55,163 Recent summary conclusions from colorectal cancer reviews of the topic are still cautionary.164–177 Two studies show no association of folic acid with colorectal adenoma or recurrence.178,179 FETAL AND PEDIATRIC ISSUES Benefit

Pediatric ongoing health benefits have been identified following prenatal multivitamin supplementation before and in early pregnancy.40,128 Maternal use of prenatal multivitamins is associated with a decreased risk for pediatric brain tumours (OR 0.73, 95% CI 0.60 to 0.88),40,146,180 neuroblastoma (OR 0.53, 95% CI 0.42 to 0.68),40 leukemia (OR 0.61, 95% CI 0.50 to 0.74),40,147 Wilms’ tumour,142 primitive neuroectodermal tumours,145 and ependymomas.145 It was stated that it is not known which constituent(s) among the multivitamins confers this protective effect. A study looking at maternal use of folic acid supplementation and the diagnosis of childhood autism found that folic acid supplementation around the time of conception was associated with lower risk of autistic disorder in a Norwegian cohort. The adjusted OR for autistic disorder in children of folic acid s was 0.61 (95% CI 0.41 to 0.90). These findings cannot establish causality but they do the use of prenatal folic acid supplementation.148,149 540 l JUNE JOGC JUIN 2015

Risks and Cautions

Folic acid and multivitamin supplementation is possibly associated with an increased incidence of twins, although positive and negative twinning findings have been reported with the possible confounders of in vitro fertilization and ovarian stimulation or other environmental hormones. A clear relationship between folic acid supplementation and twinning has not been confirmed.60,181–183 A slightly increased risk of wheeze and respiratory infection was found in the offspring whose mothers took folic acid supplements during pregnancy.184 It was suggested that methyl donors in the maternal diet during pregnancy may influence respiratory health in children consistent with epigenetic mechanisms. Zetstra-van der Woude et al. reported maternal high-dose folic acid (5 mg) was associated with an increased rate of asthma medication among children (recurrent asthma medication IRR [incidence rate ratio] = 1.14, 1.04 to 1.30 and recurrent inhaled corticosteroids IRR = 1.26, 1.07 to 1.47). In the cohort of 39 602 pregnancies, 2.9% were exposed to high-dose folic acid.185 Associations were clustered on the mother and adjusted for maternal age, maternal asthma medication, and dispensing of benzodiazepines during pregnancy.186 Veeranki et al. used a retrospective cohort of 167 333 mother–infant pairs to compare no prenatal folic acid exposure with first trimester only folic acid exposure and reported higher relative odds of bronchiolitis diagnosis (aOR 1.17, 1.11 to 1.22) and greater severity (aOR 1.16, 1.11 to 1.22). The effect was not significant in the other 2 exposed groups of “after the first trimester” or “both first trimester and after the first trimester”.186 Magdelijns et al.187 and Crider188 et al. did not confirm any meaningful association between folic acid supplementation during pregnancy with atopic diseases in the offspring. More population studies are required to understand whether there is an exposure and an effect risk for pediatric outcomes, but for now some caution in favour of using the lowest effective folic acid supplementation dose is required. Recommendations

3. Folic acid supplementation is unlikely to mask vitamin B12 deficiency (pernicious anemia). Investigations (examination or laboratory) are not required prior to initiating folic acid supplementation for women with a risk for primary or recurrent neural tube or other folic acid-sensitive congenital anomalies who are considering a pregnancy. It is recommended that folic acid be taken in a multivitamin including 2.6 ug/day of vitamin B12 to mitigate even theoretical concerns. (II-2A)

Pre-conception Folic Acid/Multivitamin Supplementation for the Prevention of Neural Tube Defects and Other Congenital Anomalies

4. Women at HIGH RISK, for whom a folic acid dose greater than 1 mg is indicated, taking a multivitamin tablet containing folic acid, should be advised to follow the product label and not to take more than 1 daily dose of the multivitamin supplement. Additional tablets containing only folic acid should be taken to achieve the desired dose. (II-2A) COUNSELLING AND FOLIC ACID SUPPLEMENTATION

Canadian data indicates clear socio-demographic differences among women with respect to their knowledge and use of folic acid. Although most women understood the benefits of folic acid supplementation, greater than 33% did not take folic acid supplements prior to becoming pregnant and less than 50% supplemented according to national guidelines. Targeted education and other interventions to improve folic acid use in younger women and women with lower socio-economic status is recommended.189 Han et al. reported that certain groups of women (from the Caribbean, Latin America, North Africa, Middle East, China, and South Pacific) who are immigrants to Canada take fewer folic acid supplements than Canadianborn women. This immigrant group may benefit from enhanced or directed pre-conception education and counselling.66 Folic acid supplementation and the NTD risk stratified for maternal BMI requires more consideration. A recent Chinese cohort study reported the association between folic acid supplementation and the reduced NTDs risk was weaker in overweight/obese mothers (overweight/obese was defined as BMI ≥ 24.0 kg/m2) than in underweight/ normal mothers (BMI < 24.0 kg/m2).190 Oral supplementation success may be variable because of compliance issues with daily oral tablet use (nausea, “forgot,” “don’t like to take pills”) but as a result of food fortification with folic acid, Canada has almost eliminated folate deficiency.191 The best predictor of prenatal multivitamin adherence in pregnant women is related to the women’s previous experiences with multivitamin use. The most important factors inhibiting prenatal vitamin use are fear or the experience of nausea, vomiting, and gagging. For women who took the supplemental vitamins, the most important factors were the dosing regimen, health care provider advice, and the mode of product distribution (prescription, over-the-counter, covered by insurance).191 The limited RCT data for folic acid supplementation in certain clinical scenarios requires the use of cohort and

case–control evaluation and expert opinion extrapolation. Alternate opinions regarding oral supplemental dosing have been published by Motherisk.192 Other long-term uses for folic acid in the other clinical use context (alcoholics, anemia, liver disease, kidney disease, malabsorption, cardiac disease, cancer treatment, regular multivitamin wellness use) are not considered or discussed in this guideline. Summary Statement

In Canada multivitamin tablets with folic acid are usually available in 3 formats: regular over-thecounter multivitamins with 0.4 to 0.6 mg folic acid, prenatal over-the-counter multivitamins with 1.0 mg folic acid, and prescription multivitamins with 5.0 mg folic acid. (III) The 3 clinically at-risk groups that will benefit from folic acid supplementation are derived from evidence-based review and expert opinion, and are based on the folic acidsensitive risk of teratogenic or genetic congenital anomaly, or the estimated risk of maternal folic acid deficiency. The supplemental folic acid requirements for the best benefitto-risk outcome have used the published Canadian female population (post fortification) RBC folate values. It is important to emphasize that all 3 risk recommendations for the clinically “at-risk” groups have pregnant women returning to or continuing the oral low dose 1.0 mg folic acid multivitamin supplementation at 12 weeks’ gestational age and continuing to minimize any unknown or potential risk for folic acid supplementation and the exposed mother or fetus/newborn. LOW risk group: Women or their male partners with no personal or family history of health risks for folic acidsensitive birth defects. MODERATE risk group: Women with the following personal or co-morbidity scenarios (1 to 5) or their male partner with a personal scenario (1 and 2): 1. Personal positive or family history of other folate sensitive congenital anomalies (limited to specific anomalies for cardiac, limb, cleft palate, urinary tract, congenital hydrocephaly) 2. Family history of NTD in a first or second-degree relative 3. Maternal diabetes (type I or II) with secondary fetal teratogenic risk. Measurement of red blood cell folate levels could be part of the pre-conception evaluation to determine the multivitamin and folic acid supplementation dose strategy (1.0 mg with RBC folate JUNE JOGC JUIN 2015 l 541

SOGC clinical practice guideline

< 906 and 0.4 to 0.6 mg with RBC folate > 906) with a multivitamin) 4. Teratogenic medications with secondary fetal teratogenic effects by folate inhibition via anticonvulsant medications (carbamazepine, valproic acid, phenytoin, primidone, phenobarbital), metformin, methotrexate, sulfasalazine, triamterene, trimethoprim (as in cotrimoxazole), and cholestyramine 5. Maternal GI malabsorption conditions secondary to co-existing medical or surgical conditions that have been shown to result in decreased RBC folate levels (Crohn’s or active Celiac disease, gastric by surgery, advanced liver disease, kidney dialysis, alcohol overuse) INCREASED/HIGH risk group: Women or their male partners with a personal NTD history or a previous neural tube defect pregnancy Recommendations

5. Women with a LOW RISK for a neural tube defect or other folic acid-sensitive congenital anomaly and a male partner with low risk require a diet of folate-rich foods and a daily oral multivitamin supplement containing 0.4 mg folic acid for at least 2 to 3 months before conception, throughout the pregnancy, and for 4 to 6 weeks postpartum or as long as breast-feeding continues. (II-2A) 6. Women with a MODERATE RISK for a neural tube defect or other folic acid-sensitive congenital anomaly or a male partner with moderate risk require a diet of folate-rich foods and daily oral supplementation with a multivitamin containing 1.0 mg folic acid, beginning at least 3 months before conception. Women should continue this regime until 12 weeks’ gestational age. (1-A) From 12 weeks’ gestational age, continuing through the pregnancy, and for 4 to 6 weeks postpartum or as long as breast-feeding continues, continued daily supplementation should consist of a multivitamin with 0.4 to 1.0 mg folic acid. (II-2A) 7. Women with an increased or HIGH RISK for a neural tube defect, a male partner with a personal history of neural tube defect, or history of a previous neural tube defect pregnancy in either partner require a diet of folate-rich foods and a daily oral supplement with 4.0 mg folic acid for at least 3 months before conception and until 12 weeks’ gestational age. From 12 weeks’ gestational age, continuing throughout the pregnancy, and for 4 to 6 weeks postpartum or as long as breast-feeding continues, continued daily supplementation should 542 l JUNE JOGC JUIN 2015

consist of a multivitamin with 0.4 to 1.0 mg folic acid. (I-A). The same dietary and supplementation regime should be followed if either partner has had a previous pregnancy with a neural tube defect. (II-2A) To achieve a dose of 4.0 mg/day folic acid, women should consume a multivitamin containing 1.0 mg folic acid and add 3 single 1.0 mg folic acid tablets. (See the appendix for a summary of the risk statuses, risk groups, and appropriate folic acid dosing.) Recognizing the challenge some clinical offices might face implementing the above recommendations based on the mode of product distribution (prescription, over-thecounter, covered by insurance) and compliance issues with taking daily multiple oral tablets,188 the following simplified regimen could be considered. However, it is important to keep in mind that the folic acid intake should be at the lowest effective and safest dose. Low or moderate risk group: a diet of folate-rich foods in addition to pre-conception and first trimester folic acid supplementation with an over-the-counter daily prenatal multivitamin containing 1.0 mg of folic acid. Increased/high risk group: a diet of folate-rich foods in addition to preconception and first trimester folic acid supplementation with a prescription daily multivitamin containing 5.0 mg of folic acid. See the Figure for a detailed decision tree. SUMMARY

Folic acid (in the diet and/or as a prenatal oral supplement) with a multivitamin/micronutrient has been shown to decrease or minimize specific congenital anomalies including neural tube defects with associated hydrocephalus, oral facial clefts with or without cleft palate, congenital heart disease, urinary tract anomalies, and limb defects, as well as some pediatric cancers. The 1998 public health initiative for fortification of flour has been very beneficial with respect to primary prevention of certain folic acid-sensitive birth defects. The comprehensive Canadian analysis of neural tube reduction after folic acid flour fortification has reported a 46% reduction. The observed reduction was greater for spina bifida (53%) than for anencephaly (38%) and encephalocele (31%). Further reductions in the incidence of other congenital anomalies sensitive to folic acid and multivitamins should be possible with the participation of key stakeholders. Public health surveillance strategies should be implemented to look for any adverse health outcomes (maternal; pediatric) that

Pre-conception Folic Acid/Multivitamin Supplementation for the Prevention of Neural Tube Defects and Other Congenital Anomalies

Decision tree for folic acid supplementation

Woman who may or plans to become pregnant

No known NTD risk factor and no prior pregnancy affected with folate sensitive congenital anomaly  daily multivitamin containing 0 .4 mg/day folic acid* 3 months prior to pregnancy and continuing throughout pregnancy

NTD risk factor† or prior pregnancy affected with other folate sensitive congenital anomaly (Box 1)‡

If pregnancy does not occur after 1 year, consider referral to fertility services

Previous pregnancy affected with NTD or personal history of NTD daily multivitamin and a total intake of 4 mg/day folic acid§ 3 months prior to pregnancy and through the first trimester, then a multivitamin containing 0 .4 mg/day folic acid* for the remainder of pregnancy . OR 5 mg¶

Other risk factors for NTD Pre-existing diabetes‖ Antiepileptic or folate inhibiting medication (Box 2) •1st or 2nd degree relative of woman or her partner with a history of NTD •GI malabsorptive conditions, such as Celiac disease, inflammatory bowel disease, or gastric by surgery •Advanced liver disease •Kidney dialysis •Alcohol over-use OR Prior pregnancy affected with a folate sensitive congenital anomaly (Box 1)‡  daily multivitamin containing 1 mg/day folic acid* 3 months prior to pregnancy and through the first trimester, then a multivitamin containing 0 .4 mg/day folic acid* for the remainder of pregnancy

If pregnancy does not occur after 6 to 8 months, change to 0 .4 mg/day* for 6 months; if pregnancy is not achieved in the following 6 months, consider referral to fertility services and RBC folate testing to ensure level >900 nmol/L .

BOX 1 Congenital anomalies which may be sensitive to folate (see text for anomaly detail): – – – –

Oral facial cleft (and palate) Certain cardiac defects Certain urinary tract anomalies Limb reduction defects

BOX 2 Practical list of folate-inhibiting medications: – Anticonvulsant medications: phenytoin, primidone, phenobarbital, carbamazepine, valproic acid – Metformin – Methotrexate (a medication that is highly teratogenic to the fetus). – Sulfasalazine – Triamterene  – Trimethoprim (as found in cotrimoxazole)

*Folic acid should be taken in the form of a multivitamin containing vitamin B12. Women should not take more than one multivitamin supplement each day. In large doses, some substances in multivitamins could be harmful. †Does NOT include spina bifida occulta as this is not a risk for NTD. ‡There are additional folate sensitive congenital anomalies that would benefit from the folic acid levels described. §To provide a dose of 4 mg/day folic acid, a multivitamin containing 1 mg folic acid should be consumed, with single folic acid tablets added to achieve the desired folic acid dose. ‖Peri-conceptional glycemic control is strongly recommended to reduce the risk of a congenital anomaly in the offspring of a woman with pre-pregnancy diabetes. ¶Folic acid intake should be at the safest and lowest effective dose; however, clinical offices that face challenges implementing recommendations for 4 mg folic acid daily because of the mode of product distribution or compliance issues with taking daily multiple oral tablets may consider the simplified regimen of one 5 mg folic acid multivitamin tablet daily. NTD: neural tube defect; GI: gastrointestinal

JUNE JOGC JUIN 2015 l 543

SOGC clinical practice guideline

could possibly be related to folic acid food fortification and additional folic acid supplementation recommendations.

17. Lopez-Camelo JS, Orioli IM, Dutra MDG, Nazer-Herrera J, Rivera N, Ojeda ME, et al. Reduction of birth prevalence rates of neural tube defects after folic acid fortification in Chile. Am J Med Genet 2005;135A:120–5.

ACKNOWLEDGEMENTS

18. Boulet SL, Yang Q, Mai C, Kirby RS, Collins JS, Robbins JM, et al. Trends in the postfortification prevalence of spina bifida and anencephaly in the United States. Birth Defects Res A Clin Mol Teratol 2008;82:517–32.

Expert opinion and guideline review were obtained from the Public Health Agency of Canada and Motherisk. REFERENCES 1. Andres J, Evans J, Royle C. Prevalence of congenital anomalies. Canadian Perinatal Health Report, 2008 ed. Ottawa: Public Health Agency of Canada; 2008:158–63. 2. MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 1991;338:131–7. 3. Czeizel AE, Dudas L. Prevention of the first occurrence of neural tube defects by periconceptional vitamin supplementation. N Engl J Med 1992;327:1832–5. 4. Czeizel AE. Prevention of congenital abnormalities by periconceptional multivitamin supplementation. BMJ 1993;306:1645–8. 5. Czeizel AE. Periconceptional folic acid and multivitamin supplementation for the prevention of neural tube defects and other congenital abnormalities. Birth Defects Res A Clin Mol Teratol 2009;85:260–8.

19. Greene NDE, Stanier P, Copp AJ. Genetics of human neural tube defects. Hum Mol Genet 2009;17:R113-R129. 20. Shaw GM, Lu W, Zhu H, Yang W, Briggs FSB, Carmichael SL, et al. 118 SNPs of folate-related genes and risks of spina bifida and conotruncal heart defects. BMC Medical Genet 2009;10:49. 21. Blom HK, Shaw GM, den Heijer M, Finnell RH. Neural tube defects and folate: case far from closed. Nat Rev Neurosci 2006;7:724–32. 22. Blom HJ. Folic acid, methylation and neural tube closure in humans. Birth Defects Res A Clin Mol Teratol 2009;85:295–302. 23. Castillo-Lancellotti C, Tur JA, Uauy R. Impact of folic acid fortification of flour on neural tube defects: a systematic review. Pub Health Nutr 2013;16:901–11. doi:10.1017/S1368980012003576. 24. Rosenthal J, Casas J, Taren D, Alverson CJ, Flores A, Frias J. Neural tube defects in Latin America and the impact of fortification: a literature review. Latin America. Pub Health Nutr 2014;17:537–50. doi:10.1017/S1368980013000256. 25. Branum AM, Bailey R, Singer BJ. Dietary supplement use and folate status during pregnancy in the United States. J Nutr 2013;143:486–92.

6. De Wals P, Tairou F, Van Allen MI, Uh SH, Lowry RB, Sibbald B, et al. Reduction of neural-tube defects after folic acid fortification in Canada. N Engl J Med 2007;357:135–42.

26. Shaw GM, O’Malley CD, Wasserman CR, Tolarova MM, Lammer EJ. Maternal periconceptional use of multivitamins and reduced risk for conotruncal heart defects and limb deficiencies among offspring. Am J Med Genet 1995;59:536–45.

7. Persad VL, Van den Hof MC, Dube JM, Zimmer P. Incidence of open neural tube defects in Nova Scotia after folic acid fortification. CMAJ 2002;167:241–5.

27. Botto LD, Khoury MJ, Mulinara J, Erickson JD. Periconceptional multivitamin use and the occurrence of conotruncal heart defects: results from a population-based, case-control study. Pediatr 1996;98:911–7.

8. Berry RJ, Li Z, Erickson JD, Li S, Moore CA, Wang H, et al. Prevention of neural-tube defects with folic acid in China. N Engl J Med. 1999;341:1485–90.

28. Czeizel AE. Reduction of urinary tract and cardiovascular defects by periconceptional multivitamin supplementation. Am J Med Genet 1996;62:179–83.

9. Martin RH, Nimrod C. Crohn’s disease, folic acid, and neural tube defects (NTD). BMJ 1984;289:228.

29. Goldmuntz E, Woyciechowski S, Renstrom D, Lupo PJ, Mitchell LE. Variants of folate metabolism genes and the risk of conotruncal cardiac defects. Cir Cardiovasc Genet 2008;1:126–32.

10. Mulinare J, Cordero JF, Erickson JD, Berry RJ. Periconceptional use of multivitamins and the occurrence of neural tube defects. JAMA 1988;260:3141–5. 11. Mills JL, Rhoads GG, Simpson JL, Cunningham GC, Conley MR, Lassman MR, et al. The absence of a relation between the periconceptional use of vitamins and neural tube defects. N Engl J Med 1989;321:430–5.

30. Li X, Li S, Mu D, Liu Z, Li Y, Lin Y, et al. The association between periconceptional folic acid supplementation and congenital heart defects: a case-control study in China. Prev Med 2013;66:385–9. 31. Li DK, Daling JR, Mueller BA, Hickok DE, Fantel AG, Weiss NS. Periconceptional multivitamin use in relation to the risk of congenital urinary tract anomalies. Epidemiology 1995;6:212–8.

12. Milunsky A, Jick H, Jick SS, Bruell CL, MacLaughlin DS, Rothman KJ, et al. Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects. JAMA 1989;262:2847–52.

32. Hayes C, Werler MM, Willett WC, Mitchell AA. Case-control study of periconceptional folic acid supplementation and oral clefts. Am J Epidemiol 1996;143:1229–34.

13. Centers for Disease Control (CDC). Use of folic acid for prevention of spina bifida and other neural tube defects 1983–1991. MMWR Morb Mortal Wkly Rep1991;40:513–6.

33. Shaw GM, Lammer EJ, Wasserman CR, O’Malley CD, Tolarova MM. Risks of orofacial clefts in children born to women using multivitamins containing folic acid periconceptionally. Lancet 1995;345:393–6.

14. Bower C, Stanley FJ. Dietary folate as a risk factor for neural tube defects: evidence from a case-control study in Western Australia. Med J Aust 1989;150:613–8.

34. Tolarova M, Harris J. Reduced recurrence of orofacial clefts after periconceptional supplementation with high-dose folic acid and multivitamins. Teratology 1995;51:71–8.

15. Goh YI, Bollano E, Einarson TR, Koren G. Prenatal multivitamin supplementation and rates of congenital anomalies: a meta-analysis. J Obstet Gynaecol Can 2006;28:680–9.

35. Badovinac RL, Werler MM, Williams PL, Kelsey KT, Hayes C. Folic acidcontaining supplement consumption during pregnancy and risk for oral clefts: a meta-analysis. Birth Defects Res A Clin Mol Teratol 2007;79:8–15.

16. Ray JG, Meier C, Vermeulen MJ, Boss S, Wyatt PR, Cole DE. Association of neural tube defects and folic acid food fortification in Canada. Lancet 2002;360:2047–8.

36. Yazdy MM, Honein MA, Xing J. Reduction in orofacial clefts following folic acid fortification of the U.S. grain supply. Birth Defects Res A Clin Mol Teratol 2007;79:16–23.

544 l JUNE JOGC JUIN 2015

Pre-conception Folic Acid/Multivitamin Supplementation for the Prevention of Neural Tube Defects and Other Congenital Anomalies

37. O’Neill J. Do folic acid supplements reduce facial clefts? Evid Based Dentistry 2008;9:82–3. 38. Johnson CY, Little J. Folate intake, markers of folate status and oral clefts: is the evidence converging? International J Epidemiol 2008;37:5:1041–58. 39. Wehby GL, Félix TM, Goco N, Richieri-Costa A, Chakraborty H, Souza J, et al. High dose folic acid supplementation, oral cleft recurrence and fetal growth. Int J Environ Res Public Health 2013;10:590–605. 40. Godwin KA, Sibbald B, Bedard T, Kuzeljevic B, Lowry RB, Arbour L. Changes in frequencies of select congenital anomalies since the onset of folic acid fortification in a Canadian birth defect registry. Can J Public Health 2008;99:271–5. 41. Van Allen MI, McCourt C, Lee NS; Public Health Agency of Canada. Preconception health: folic acid for the primary prevention of neural tube defects. A resource document for health professionals, Ottawa ON: PHAC; 2002. Available at: http://www.phac-aspc.gc.ca/fa-af/pdf/ backgrounder_full.pdf Accessed on May 1, 2013. 42. Health Canada. Prenatal nutrition guidelines for health professionals– background on Canada’s food guide. Eating well with Canada’s Food Guide. Ottawa ON: Health Canada; 2009. Available at: http://www.hc-sc.gc.ca/fn-an/pubs/nutrition/guide-prenatal-eng.php. Accessed on May 1, 2013. 43. Botto LD, Olney RS, Erickson JD. Vitamin supplements and the risk for congenital anomalies other than neural tube defects. Am J Med Genet 2004;125C:12–21. 44. Botto LD, Lisi A, Bower C, Canfield MA, Dattani N, DeVigan C, et al. Trends of selected malformations in relation to folic acid recommendations and fortifications: an international assessment. Birth Defects Res A Clin Mol Teratol 2006;76:693–705. 45. Peller AJ, Westgate MN, Holmes L. Trends in congenital malformations, 174–1999: effect of prenatal diagnosis and elective termination. Obstet Gynecol 2004;104:957–64. 46. Van Allen MI, Boyle E, Thiessen P, McFadden D, Cochrane D, Chambers GK, et al. The impact of prenatal diagnosis on neural tube defect (NTD) pregnancy versus birth incidence in British Columbia. J Appl Genet 2006;47:151–8. 47. Ray JG, Wyatt PR, Thompson MD, Vermeulen MJ, Meier C, Wong P-Y, et al. Vitamin B12 and the risk of neural tube defects in a folic-acidfortified population. Epidemiology 2007;18:3. 48. Ahn E, Kapur B, Koren G. Motherisk Update 2007. Study on circadian variation in folate pharmacokinetics. Can J Clin Pharmacol 2005;12(1):e4–e9. 49. Koren G, Pairaideau N. Motherisk Update 2007. Compliance with prenatal vitamins. Patients with morning sickness sometimes find it difficult. Can Fam Physician 2006;52:1392–3. 50. Sherwood LK, Houghton LA, Tarasuk V, O’Connor DL. One third of pregnant and lactating women may not be meeting their folate requirements from diet alone based on mandated levels of folic acid fortification. J Nutr 2006;136;2820–6. 51. Shakur YA, Garriguet D, Corey P, O’Connor DL. Folic acid fortification above mandated levels results in a low prevalence of folate inadequacy among Canadians. Am J Clin Nutr 2010;92:818–25. 52. Oakley GP, Bell KN, Weber MB. Recommendations for accelerating global action to prevent folic acid-preventable birth defects and other folate deficiency diseases: meeting of experts on preventing folic acidpreventable neural tube defects. Birth Defects Res A Clin Mol Teratol 2004;70:835–7. 53. Canfield MA, Collins JS, Boto LD, Williams LJ, Mai CT, Kirby RS, et al. Changes in the birth prevalence of selected birth defects after grain fortification with folic acid in the United States: findings from a multistate population-based study. Birth Defects Res A Clin Mol Teratol 2005;73:679–89.

54. Robbins JM, Tilford JM, Bird TM, Cleves MA, Reading A, Hobbs CA. Hospitalizations of newborns with folate-sensitive birth defects before and after fortification of foods with folic acid. Pediatr 2006;118:906–15. 55. Bell KN, Oakley GP. Tracking the prevention of folic acid-preventable spina bifida and anencephaly. Birth Defects Res A Clin Mol Teratol 2006:76;654–7. 56. Wald NJ. Folic acid and the prevention of neural tube defects. N Engl J Med 2004;350:101–3. 57. Hubner RA, Houlston RD, Muir KR. Should folic acid fortification be mandatory? BMJ 2007;334:1253. 58. Czeizel AE, Medveczky E. Periconceptional multivitamin supplementation and multimalformed offspring. Obstet Gynecol 2003;102:1255–61. 59. Bar-Oz B, Koren G, Nguyen P, Kapur BM. Folate fortification and supplementation—are we there yet? Reprod Toxicol 2008;25:408–12. 60. Brown JE, Jacobs D, Hartman T, Barosso G, Stang J, Gross M, et al. Predictors of red cell folate level in women attempting pregnancy. JAMA 1997;277:548–52. 61. Tam L, McDonald SD, Wen SW, Smith GN, Windrim RC, Walker MC. A survey of preconceptional folic acid use in a group of Canadian women. J Obstet Gynaecol Can 2005;27:232–6. 62. Cleves MA, Hobbs CA, Collins HB, Andrews N, Smith LN, Robbins JM. Folic acid use by women receiving routine gynecologic care. Obstet Gynecol 2004;103:746–53. 63. de Jong-van den Berg LTW, Hernandez-Diaz S, Werler MM, Louik C, Mitchell AA. Trends and predictors of folic acid awareness and periconceptional use in pregnant women. Am J Obstet Gynecol 2005;192:121–8. 64. Robbins JM, Cleves MA, Collins B, Andrews NA, Smith LN, Hobbs CA. Randomized trial of a physician-based intervention to increase the use of folic acid supplements among woman. Am J Obstet Gynecol 2005;192:1126–32. 65. Nguyen P, Tam C, O’Connor DL, Kapur B, Koren G. Steady state folate concentrations achieved with 5 compared with 1.1 mg folic acid supplementation among women of childbearing age. Am J Clin Nutr 2009;89:844–52. 66. Han A, Rotermann M, Fuller-Thomson E, Ray JG. Pre-conceptional folic acid supplement use according to maternal country of birth. J Obstet Gynecol Can. 2009;31:222–6. 67. Colapinto CK, O’Connor DL, Tremblay MS. Folate status of the population in the Canadian Health Measures Survey. CMAJ 2011;183:e100–e106 68. Tam C, McKenna K, Goh YI, Klieger-Grossman C, O’Connor DL, Einarson A, et al. Periconceptional folic acid supplementation: a new indication for therapeutic drug monitoring. Ther Drug Monit 2009;31:319–26. 69. Farrell, CJ, Kirsch SH, Herrmann M. Red cell or serum folate: what to do in clinical practice? Clin Chem Lab Med 2013;51:555–69. 70. Niesser M, Demmelmair H, Weith T, Moretti D, Rauh-Pfeiffer A, van Lipzig M, et al. Folate catabolites in spot urine as non-invasive biomarkers of folate status during habitual intake and folic acid supplementation. PLoS One 2013;8:e56194. 71. Colapinto CK, O’Connor DL, Dubois L, Tremblay MS. Folic acid supplement use is the most significant predictor of folate concentrations in Canadian women of childbearing age. Appl Physiol Nutr Metab 2012;37:284–92. 72. Miller EC, Liu N, Wen SW, Walker M. Why do Canadian women fail to achieve optimal pre-conceptional folic acid supplementation? An observational study. J Obstet Gynaecol Can 2011;33:1116–23.

JUNE JOGC JUIN 2015 l 545

SOGC clinical practice guideline

73. Richard-Tremblay A-A, Sheehy O, Audibert F, Ferreira E, Bérard A. Concordance between periconceptional folic acid supplementation and Canadian clinical guidelines. J Popul Ther Clin Pharmacol 2012;19:e150–e159. 74. Anderson CA, Beresford SA, McLerran D, Lampe JW, Deeb S, Feng Z, et al. Response of serum and red blood cell folate concentrations to folic acid supplementation depends on methylenetetrahydrofolate reductase C677T genotype: results from a crossover trial. Mol Nutr Food Res 2013;57:637–44. 75. Tam C, O’Connor D, Koren G. Circulating unmetabolized folic acid: relationship to folate status and effect of supplementation. Obstet Gynecol Int 2012;2012:485479. doi: 10.1155/2012/485179. 76. Obeid R, Holzgreve W, Pietrzik K. Is 5-methyltetrahydrofolate an alternative to folic acid for the prevention of neural tube defects? J Perinat Med 2013;41:469–83. 77. Firth HV, Hurst JA, Hall JG. Oxford desk reference. Clinical genetics. Oxford: Oxford University Press; 2006. 78. Health Canada. Canadian perinatal health report 2003. Canadian Perinatal Surveillance System. Ottawa: Minister of Public Works and Government Services Canada; 2003. 79. Hall JG, Friedman JM, Kenna BA, Popkin J, Jawanda M, Arnold W. Clinical, genetic, and epidemiological factors in neural tube defects. Am J Hum Genet 1988;43:827–37. 80. Chambers K, Popkin J, Arnold W, Irwin B, Hall JG. Neural tube defects in British Columbia. Lancet 1994;343:489–90. 81. Hall JG. Folic acid: the opportunity that still exists. CMAJ 2000;162:1571–2. 82. Neural tube defects. American College of Obstetrics and Gynecology Educational Bulletin 2003;44:754–64. (Re-affirmed 2011.) 83. Little J, Elwood JM, eds. Epidemiology and control of neural tube defects. Vol 20. In: Monograph in epidemiology and biostatistics. Oxford: Oxford University Press; 1992. 84. Baird PA. Neural tube defects in the Sikhs. Am J Med Genet 1983;16:49–56. 85. Hunter AGW. Neural tube defects in eastern Ontario and western Quebec: demography and family data. Am J Med Genet 1984;19:45–63. 86. Frecker M, Fraser FC. Epidemiological studies of neural tube defects in Newfoundland. Teratology 1987;36:355–61. 87. Dallaire L, Melancon SB, Potier M, Matthiew M-P, Ducharme G. Date of conception and prevention of neural tube defects. Clin Genet 1984;26:304–7. 88. McBride ML. Sib risks of anencephaly and spina bifida in British Columbia. Am J Med Genet 1979;3:377–87. 89. Dallaire L, Michaud J, Melancon SB, Potier M, Lambert M, Mitchell G, et al. Prenatal diagnosis of fetal anomalies during the second trimester of pregnancy: their characterization and delineation of defects in pregnancies at risk. Prenat Diagn 1991;11:629–35.

94. Oakley GP. The scientific basis for eliminating folic acid-preventable spina bifida: a modern miracle from epidemiology. Ann Epidemiol 2009;19:226–30. 95. Oakley GP. Folic acid-preventable spina bifida. A good start but much to be done. Am J Prev Med 2010;38:569–70. 96. Wilson RD, Désilets V, Wyatt P, Langlois S, Gagnon A, Allen V, et al.; Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada; The Motherrisk Program. Pre-conceptional vitamin/folic acid supplementation 2007: the use of folic acid in combination with a multivitamin supplement for the prevention of neural tube defects and other congenital anomalies. SOGC Clinical Practice Guidelines, No. 201, December 2007. J Obstet Gynaecol Can 2007;29:1003–13. 97. Evans JA. Pre-conceptional vitamin/folic acid supplementation 2007. J Obstet Gynaecol Can 2008;30:656–8. 98. Health Canada. Prenatal nutrition guidelines for health professionals. Folate contributes to a healthy pregnancy. Ottawa: Health Canada; 2009. Available at: http://www.hc-sc.gc.ca/fn-an/pubs/nutrition/ folate-eng.php. Accessed on May 1, 2013. 99. Health Canada. High dose folic acid supplementation – questions and answers for health professionals. Ottawa: Health Canada; 2010. Available at: http://www.hc-sc.gc.ca/fn-an/nutrition/prenatal/fol-qa-qr-eng.php. Accessed on May 1, 2013. 100. Lammer EJ, Sever LE, Oakley GP Jr. Teratogen updates: valproic acid. Teratology 1987;35:465–73. 101. Rosa FW. Spina bifida in infants of women treated with carbamazepine during pregnancy. N Engl J Med 1991;324:674–7. 102. Warkany J. Amniopterin and methotrexate: folic acid deficiency. Teratology 1978;17:353–8. 103. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation, 9th ed. A reference guide to fetal and neonatal risk. London: Royal College of Obstetricians and Gynaecologists; 2011. 104. American College of Obstetricians and Gynecologists (ACOG). ACOG education pamphlet AP 056. Good health before pregnancy: preconception care. Washington, DC: ACOG; 2015. Available at: http://www.acog.org/Patients/FAQs/Good-Health-Before-PregnancyPreconception-Care. Accessed on May 1, 2013. 105. American College of Obstetricians and Gynecologists (ACOG). ACOG education pamphlet AP 146. Reducing your risk of birth defects. Washington, DC: ACOG; 2014. Available at: http://www.acog.org/Patients/FAQs/Reducing-Risks-of-Birth-Defects. Accessed on May 1, 2013. 106. US Preventative Services Task Force. Folic acid for the prevention of neural tube defects. US Preventive Services Task Force recommendation statement. Ann Intern Med 2009;150:626–31. 107. Holmes LB, Driscoll SG, Atkins LA. Etiologic heterogeneity of neural tube defects. N Engl J Med 1976;294:365–9. 108. Khoury MJ, Erickson JD, James LM. Etiologic heterogeneity of neural tube defects: clues from epidemiology. Am J Epidem 1982;115:538–48.

90. Gucciardi E, Pietrusiak MA, Reynolds DL, Rouleau J. Incidence of neural tube defects in Ontario, 1986–1999. CMAJ 2002;167:237–40.

109. Jones KL. Smith’s recognizable patterns of human malformation, 6th ed. Philadelphia: WB Saunders; 2006:704–5.

91. Trimble BK, Baird PA. Congenital anomalies of the central nervous system. Incidence in British Columbia 1952–1972. Teratology 1978;17:1743–9.

110. Pietrzik K, Bailey L, Shane B. Folic acid and L-5 methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacodynamics. Clin Pharmacokinet 2010;48:535–48.

92. Oakley GP. Folate deficiency is an “imminent health hazard” causing a worldwide birth defects epidemic. Birth Defects Res A Clin Mol Teratol 2003;67:903–4.

111. Bodnar LM, Himes KP, Venkataramanan R, Chen JY, Evans RW, Meyer JL, et al. Maternal serum folate species in early pregnancy and risk of preterm birth. Am J Clin Nutr 2010;92:864–71.

93. Eichholzer M, Tonz O, Zimmerman R. Folic acid: a public-health challenge. Lancet 2006;367:1852–61.

112. Suh JR, Herbig AK, Stover PJ. New perspectives on folate catabolism. Annu Rev Nutr 2001;21:255–82.

546 l JUNE JOGC JUIN 2015

Pre-conception Folic Acid/Multivitamin Supplementation for the Prevention of Neural Tube Defects and Other Congenital Anomalies

113. van der Linden IJ, Den Heijer M, Alman LA, Gellekink H, Vermeulen SH, Kluijtmans LA, et al. The methionine synthase reductase 66A to G polymorphism is a maternal risk factor for spina bifida. J Mol Med (Berl) 2006;84:1047–54.

131. Bánhidy F, Dakhlaoui A, Puhó EH, Czeizel AAE. Is there a reduction of congenital abnormalities in the offspring of diabetic pregnant women after folic acid supplementation? A population-based case-control study. Congenit Anom (Kyoto) 2011;51:34–42.

114. Wallingford JB, Niswander LA, Shaw GM, Finnell RH. The continuing challenge of understanding, preventing, and treating neural tube defects. Science 2013;339:1222002. doi:10.1126/Science1222002

132. Matok I, Gorodischer R, Koren G, Landau D, Wiznitzer A, Levy A. Exposure to folic acid antagonists during the first trimester of pregnancy and the risk of major malformations. Br J Clin Pharmacol 2009;68:956–62.

115. Burdge GC, Lillycrop KA. Folic acid supplementation in pregnancy: are there devils in the detail? Br J Nutr 2012;180:1924–30. 116. Salbaum JM, Kappen C. Genetic and epigenomic footprints of folate. Prog Mol Biol Transl Sci 2012;108:129–58. 117. Greenburg JA, Bell SJ, Guan Y, Yu Y-H. Folic acid supplementation and pregnancy: more than just neural tube defect prevention. Rev Obstet Gynecol 2011;4:52–9. 118. Vasquez K, Kuizon S, Junaid M, El Idrissi A. Chapter 8. The effect of folic acid on GABA(A)-B 1 receptor subunit. In: El Idrissi A, L’Amoreaux WJ, editors. Taurine 8. Advances in experimental medicine and biology 775. New York: Springer Science+Business Media; 2013:101–8. doi: 10.1007/978-1-4614-6130-2_8 119. Hoyo C, Murtha AP, Schildkraut JM, Forman MR, Calingaert B, Demark-Wahnefried W, et al. Folic acid supplementation before and during pregnancy in the Newborn Epigenetics Study (NEST). BMC Public Health 2011;11:46. 120. Sie KK, Li J, Ly A, Sohn KJ, Croxford R, Kim YI. Effect of maternal and postweaning folic acid supplementation on global and gene-specific DNA methylation in the liver of the rat offspring. Mol Nutr Food Res 2013;67:677–85. 121. Babcook CJ, Ball RH, Feldkamp ML. Prevalence of aneuploidy and additional anatomic abnormalities in fetuses with open spina bifida: population based study in Utah. J Ultrasound Med 2000;9:619–23. 122. Kumar V, Singh A, Sharma SP, Srivastava A, Saxena A, Gangopadhyay AN. Clinical spectrum of neural tube defects with special reference to karyotyping study. J Pediatr Neurosci 2012;7:82–4. 123. Donnelly JC, Platt LD, Rebarber A, Zachary J, Grobman WA, Wapner RJ. Association of copy number variants with specific ultrasonographically detected fetal anomalies. Obstet Gynaecol 2014;124:83–90. 124. Desilets V, Oligny LL; Genetics Committee of the Society of Obstetricians and Gynaecology Canada; Family Physicians Advisory Committee; Medico–Legal Committee of the SOGC. Fetal and perinatal autopsy in prenatally diagnosed fetal abnormalities with normal karyotype. SOGC Technical Update, No. 267, October 2011. J Obstet Gynaecol Can 2011;33:1047–57. 125. Mills JL, Carter TC, Kay DM, Browne M, Brody LC, Liu A, et al. Folate and vitamin B12 related genes and risk for omphalocele. Hum Genet 2012;131:739–46. 126. Hollis ND, Allen EG, Oliver TR, Tinker SW, Druschel C, Hobbs CA, et al. Preconception folic acid supplementation and risk for chromosome 21 nondisjunction: a report from the National Down Syndrome Project. Amer J Med Genet A 2012;161A:438–44.

133. Ray JG, Langman LJ, Mamdani MM, Cole DEC. Absence of effect of folic acid flour fortification on anticolvulsant drug levels. Am J Med 2005;118:444–5. 134. Morrow JI, Hunt SJ, Russell AJ, Smithson WH, Parsons L, Robertson I, et al. Folic acid use and major congenital malformations in offspring of women with epilepsy: a prospective study from the UK Epilepsy and Pregnancy . J Neurol Neurosurg Psychiatry 2009;80:506–11. 135. Ha WA. Folic acid supplementation: too much of a good thing? J Neurol Neurosurg Psychiatry 2009;80:468. 136. Kjaer D, Horvath-Puhó E, Christensen J, Vestergaard M, Czeizel AE, Sørensen HT, et al. Antiepileptic drug use, folic acid supplementation, and congenital abnormalities: a population-based case-control study. BJOG 2008;115:98–103. 137. Werler MM, Ahrens KA, Bosco JLF, Mitchell AA, Anderka MT, Gilboa SM, et al. Use of antiepileptic medications in pregnancy in relation to risks of birth defects. Ann Epidemiol 2011;21:842–50. 138. Meijer WM, de Walle HE, Kerstjens-Frederikse WS, de Jong-van den Berg LT. Folic acid sensitive birth defects in association with intrauterine exposure to folic acid antagonists. Reprod Toxicol 2005;20:203–7. 139. Harden CL, Pennell PB, Koppel BS, Hovinga CA, Gidal B, Meador KJ, et al. Management issues for women with epilepsy—focus on pregnancy (an evidence-based review): III. Vitamin K, folic acid, blood levels, and breast-feeding: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Epilepsia 2009;50:1247–55. 140. Emes RD, Clifford H, Haworth KE, Farrell WE, Fryer AA, Carroll WD, et al. Antiepileptic drugs and the fetal epigenome. Epilepsia 2013;54:e16–e19. 141. Czeizel AE, Puhó EH, Langmar Z, Ács N, Bánhidy F. Possible association of folic acid supplementation during pregnancy with reduction of preterm birth: a population-based study. Eur J Obstet Gynecol Reprod Biol 2010;148:135–40. 142. van Uitert EM, Steegers-Theunissen RPM. Influence of maternal folate status on human fetal growth parameters. Mol Nutr Food Res 2012;00:1–14. 143. Kim MW, Hong SC, Choi JS, Han J-Y, Oh MJ, Kim HJ, et al. Homocysteine, folate, and pregnancy outcomes. J Obstet Gynaecol Can 2012;32:520–4.

127. Goh YI, Bollano E, Einarson TR, Koren G. Motherisk Update 2007. Prenatal multivitamin supplementation and rates of pediatric cancers: a meta-analysis. Clin Pharm Ther 2007;81:685–91.

144. Li Z, Ye R, Zhang L, Li H, Liu J, Ren A. Folic acid supplementation during early pregnancy and the risk of gestational hypertension and preeclampsia. Hypertension 2013;61:873–9.

128. Olshan AF, Smith JC, Bondy ML, Neglia JP, Pollock BH. Maternal vitamin use and the reduced risk of neuroblastoma. Epidemiol 2002;13:575–80.

145. Linabery AM, Johnson KJ, Ross JA. Childhood cancer incidence trends in association with US folic acid fortification (1986–2008). Pediatrics 2012;129:1125–33.

129. Allen VM, Armson BA; Genetics Committee and Maternal Fetal Medicine Committee of the Society of Obstetricians and Gynaecologists of Canada. Teratogenicity associated with pre-existing and gestational diabetes. SOGC Clinical Practice Guideline, No. 200, November 2007. J Obstet Gynaecol Can 2007;29:927–34. 130. Wentzel P. Can we prevent diabetic birth defects with micronutrients? Diabetes Obes Metab 2009;11:770–8.

146. Milne E, Greenop KR, Bower C, Miller M, van Bockxmeer FM, Scott RJ, et al. Maternal use of folic acid and other supplements and risk of childhood brain tumors. Cancer Epidemiol Biomarkers Prev 2012;21:1933–41. 147. Amigou A, Rudant J, Orsi L, Goujon-Bellec S, Leverger G, Baruchel A, et al. Folic acid supplementation, MTHFR and MTRR polymorphisms,

JUNE JOGC JUIN 2015 l 547

SOGC clinical practice guideline

and the risk of childhood leukemia: the ESCALE study (SFCE). Cancer Causes Control 2012;23:1265–77.

166. Lucock M, Yates Z. Folic acid fortification: a double-edged sword. Curr Opin Clin Nutr Metab Care 2009;12:555–64.

148. Surén P, Roth C, Bresnahan M, Haugen M, Hornig M, Hirtz D, et al. Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children. JAMA 2013;309:570–77.

167. Sauer J, Mason JB, Choi S-W. Too much folate—a risk factor for cancer and cardiovascular disease? Curr Opin Clin Nutr Metab Care 2009;12:30–6.

149. Berry RJ, Crider KS, Yeargin-Allsopp M. Periconceptional folic acid and risk of autism spectrum disorders. JAMA 2013;309:611–3.

168. Fife J, Raniga S, Hider PN, Frizelle FA. Folic acid supplementation and colorectal risk: a meta-analysis. Colorectal Dis 2009;13:132–7.

150. Simpson JL, Bailey LB, Pietrzik K, Shane B, Holzgreve W. Micronutrients and women of reproductive potential: required dietary intake and consequences of dietary deficiency or excess. Part I—folate, vitamin B12, vitamin B6. J Matern Fetal Neonatal Med 2010;23:1323–43.

169. Figueiredo JC, Mott LA, Giovannucci E, Wu K, Cole B, Grainge MJ, et al. Folic acid and prevention of colorectal adenomas: a combined analysis of randomized clinical trials. Int J Cancer 2011;129:192–203.

151. Ahn E, Nava-Ocampo AA, Koren G. Motherisk update 2007. Multivitamin supplement for pregnant women. New insights. Can Fam Physician 2004;50:705–6. 152. Simpson JL, Shulman LP, Brown H, Holzgreve W. Closing the folate gap in reproductive-age women. Contemp Ob Gyn 2010;55:34–40. 153. Ravdin PM, Cronin KA, Howlader N, Ber CD, Chlebowski RT, Feuer EJ, et al. The decrease in breast-cancer incidence in 2003 in the United States. New Engl J Med 2007;356:1670–4. 154. Kim YI. Does a high folate intake increase the risk of breast cancer? Nutr Rev 2006;64:468–75. 155. Lubecka-Pietruszewska K, Kaufman-Szymczyk A, Stefanska B, Fabianowska-Majewska K. Folic acid enforces DNA methylationmediated transcriptional silencing of PTEN, APC and RARbeta2 tumour suppressor genes in breast cancer. Biochem Biophy Res Comm 2013;430:623–8. 156. Navarro-Silvera SA, Jain M, Howe GR, Miller AB, Rohan TE. Dietary folate consumption and risk of ovarian cancer: a prospective cohort study. Eur J Cancer Prev 2006;15:511–5. 157. Kim MW, Ahn KH, Ryu JH, Hong SC, Lee JS, Nava-Ocampo AA, et al. Preventive effects of folic acid supplementation on adverse maternal and fetal outcomes. PLoS One 2014;9(5):e97273. 158. Dekker GA, de Vries JI, Doelitzsch PM, Huijgens PC, von Blomberg BM, Jakobs C, et al. Underlying disorders associated with severe early-onset preeclampsia. Am J Obstet Gynecol 1995;173:1042–8. 159. Rajkovic A, Mahomed K, Malinow MR, Sorenson TK, Woelk GB, Williams MA. Plasma homocyst(e)ine concentration in eclamptic and preeclamptic African women postpartum. Obstet Gynecol 1999;94:355–60. 160. Wen SW, Chen XK, Rodger M, White RR, Yanag Q, Smith GN, et al. Folic acid supplementation in early second trimester and the risk of preeclampsia. Am J Obstet Gynecol 2008;198:45 e1–e7. doi: 10.1016/jajog.2007.06.067 161. Metz J, McNel AR, Levin M. The relationship between serum cobalamin concentration and mean red cell volume at varying concentrations of serum folate. Clin Lab Haem 2004;26:323–5. 162. Lassi ZS, Salam RA, Haider BA, Bhutta ZA. Folic acid supplementation during pregnancy for maternal health and pregnancy outcomes. Cochrane Database Syst Rev 2013 Mar 28;3:CD006896. doi: 10.1002/14651858.CD006896.pub2.

170. Burh G, Bales CW. Nutritional supplements for older adults: review and recommendations—Part II. J Nutr Elder 2010;29:42–71. 171. Dunlap B, Shelke K, Salem SA, Keith LG. Folic acid and human reproduction—ten important issues for clinicians. J Exp Clin Assist Reprod 2011;8:2–16. 172. Toriello HV. Policy statement on folic acid and neural tube defects. Genet Med 2011;13:593–6. 173. Tulauliker VS, Arulkumaran S. Folic Acid in obstetric practice: a review. Obstet Gynecol Surv 2011;66:240–7. 174. Curtin K, Samowitz WS, Ulrich CM, Wolff RK, Herrick JS, Caan BJ, et al. Nutrients in folate-mediated, one-carbon metabolism and the risk of rectal tumors in men and women. Nutr Cancer 2011;63:357–66. 175. Miller JW, Ulrich CM. Folic acid and cancer—where are we today? Lancet 2013;381:974–6. 176. Vollset SE, Clarke R, Lewington S, Ebbing M, Halsey J, Lonn E, et al. Effects of folic acid supplementation on overall and site-specific cancer incidence during the randomised trials: meta-analyses of data on 50 000 individuals. Lancet 2013;381:1029–36. 177. No evidence of cancer risk from folate supplements. BMJ 2013;346:f546. 178. Song Y, Manson JE, Lee IM, Cook NR, Paul L, Selhub J, et al. Effect of combined folic acid, vitamin B(6), and vitamin B(12) on colorectal adenoma. J Natl Cancer Inst 2012;104:1562–75. 179. Castillo-Lancellotti C, Tur Mari JA, Uauy Dagach R. Folic acid supplementation and colorectal adenoma recurrence: systematic review. Nutr Hosp 2012;27:13–21. 180 Greenop KR, Miller M, de Klerk NH, Scott RJ, Attia J, Ashton LJ, et al. Maternal dietary intake of folate and vitamins B6 and B12 during pregnancy and risk of childhood brain tumors. Nutr Cancer 2014;66:800–9. doi: 10.1080/01635581.2014.916326. 181. Czeizel AE, Vargha P. Periconceptional folic acid/multivitamin supplementation and twin pregnancy. Am J Obstet Gynecol 2004;191:790–4. 182. Steinman G. Can the chance of having twins be modified by diet? Lancet 2006;367:1461–2.

163. Duffy TP. Hematologic aspects of pregnancy. In: Barrow GN, Duffy TP, eds. Medical complications during pregnancy, 5th ed. Philadelphia: WB Saunders; 1999:82–3.

183. Haggarty P, McCallum H, McBain H, Andrews K, Duthie S, McNeill G, et al. Effect of B vitamins and genetics on success of in-vitro fertilisation: prospective cohort study. Lancet 2006;367:1513–9.

164. Kennedy DA, Stern SJ, Moretti M, Matok I, Sarkar M, Nickel C, et al. Folate intake and the risk of colorectal cancer: a systemic review and meta-analysis. Cancer Epidemiol 2011;35:2–10.

184. Hågberg SE, London SJ, Stigum H, Nafstad P, Nystad W. Folic acid supplements in pregnancy and early childhood respiratory health. Arch Dis Child 2009;94:180–4.

165. Mason JB, Dickstein A, Jacques P, Haggarty P, Selhub J, Dallal G, et al. A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: a hypothesis. Cancer Epidemiol Biomarkers Prev 2007;16:1325–9.

185. Zetstra-van der Woude PA, De Walle HE, Hoek A, Bos HJ, Boezen HM, Koppelman GH, et al. Maternal high-dose folic acid during pregnancy and asthma medication in the offspring. Pharmacoepidemiol Drug Saf 2014;23:1059–65. doi: 10.1002/pds.3652

548 l JUNE JOGC JUIN 2015

Pre-conception Folic Acid/Multivitamin Supplementation for the Prevention of Neural Tube Defects and Other Congenital Anomalies

186. Veeranki SP, Gebretsadik T, Dorris SL, Mitchel EF, Hartert TV, Cooper WO, et al. Association of folic acid supplementation during pregnancy and infant bronchiolitis. Am J Epidemiol 2014;179:938–46.

190. Wang M, Wang ZP, Gao LJ, Gong R, Sun XH, Zhao ZT. Maternal body mass index and the association between folic acid supplements and neural tube defects. Acta Paediatr 2013;102:908–13.

187. Magdelijns FJH, Mommers M, Penders J, Smits L, Thijs C. Folic acid use in pregnancy and the development of atopy, asthma, and lung function in childhood. Pediatrics 2011;128:e135-e144.

191. Nguyen P, Thomas M, Koren G. Predictors of prenatal multivitamin adherence in pregnant women. J Clin Pharmacol 2009;49:735–42.

188. Crider KS, Cordero AM, Qi YP, Mulinare J, Fowling NF, Berry RJ. Prenatal folic acid and risk of asthma in children: a systematic review and meta-analysis. Am J Clin Nutr 2013;98:1272–81. 189. Nelson CRM, Loen JA, Evans J. The relationship between awareness and supplementation: which Canadian women know about folic acid and how does that translate into use? Can J Public Health 2014;105:e40–e46.

192. Kennedy D, Koren G. Motherisk update 2012. Identifying women who might benefit from higher doses of folic acid in pregnancy. Can Fam Physician 2012;58:394–7. 193. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

APPENDIX FOLIC ACID SUPPLEMENTATION Risk status

Folic acid dosing: A healthy folate-rich diet AND:

Female partner

Male partner

Low

No personal or family risk for NTD or folic acid-sensitive birth defects

No personal or family risk for NTD or folic acid-sensitive birth defects

Multivitamin with 0.4 to 1.0 mg folic acid for 2 to 3 months before conception, throughout pregnancy and for 6 weeks postpartum or to completion of lactation

Moderate

Personal history positive for folate sensitive anomalies.

Personal history positive for folate sensitive anomalies

Family history for NTD in first- or second-degree relative.

Family history for NTD in first- or second-degree relative

Multivitamin including 1. 0 mg folic acid for at least 3 months before conception to 12 weeks and then for remainder of pregnancy and 6 weeks postpartum or to completion of lactation

Diabetes type I or II Teratogenic medications by folate inhibition GI malabsorption that decreases RBC folate High

Personal NTD history.

Personal NTD history.

Previous NTD pregnancy

Previous NTD pregnancy

Multivitamin including 1.0 mg folic acid plus 3 × 1.0 mg folic acid (for total of 4.0 mg) OR prescription multivitamin including 5.0 mg folic acid* at least 3 months before conception until 12 weeks’ gestation, then a multivitamin including 0.4 to 1.0 mg folic acid for remainder of pregnancy and 6 weeks postpartum or to completion of lactation

*It is important to keep in mind that folic acid intake should be at the safest and lowest effective dose (4 mg/daily). However, clinical offices that face a challenge in implementing the recommended dose because of the mode of product distribution (prescription vs. over-the-counter, covered by insurance or not) and compliance issues with taking multiple oral tablets daily could consider the simplified regimen of the 5.0 mg folic acid prescription multivitamin. NTD: neural tube defect; GI: gastrointestinal; RBC: red blood cell

JUNE JOGC JUIN 2015 l 549

SOGC CLINICAL PRACTICE GUIDELINE No. 328, September 2015 (Replaces #156, March 2005)

Umbilical Cord Blood: Counselling, Collection, and Banking This clinical practice guideline has been prepared by the Cord Blood Banking Working Group, reviewed by the Clinical Practice – Obstetrics, Maternal Fetal Medicine, Family Physician Advisory, and Aboriginal Health Initiative Committees, and approved by the Executive and Board of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS B. Anthony Armson, MD, Halifax NS David S. Allan, MD, Toronto ON Robert F. Casper, MD, Toronto ON Disclosure statements have been received from all contributors.

Abstract Objective: To review current evidence regarding umbilical cord blood counselling, collection, and banking and to provide guidelines for Canadian health care professionals regarding patient education, informed consent, procedural aspects, and options for cord blood banking in Canada. Options: Selective or routine collection and banking of umbilical cord blood for future stem cell transplantation for autologous (self) or allogeneic (related or unrelated) treatment of malignant and nonmalignant disorders in children and adults. Cord blood can be collected using in utero or ex utero techniques. Outcomes: Umbilical cord blood counselling, collection, and banking, education of health care professionals, indications for cord blood collection, short- and long-term risk and benefits, maternal and perinatal morbidity, parental satisfaction, and health care costs.

Key Words: pregnancy, umbilical cord blood, informed consent, counselling, collection, storage, banking, stem cell transplantation, ethics, public, private, Canada.

J Obstet Gynaecol Can 2015;37(9):832–844

Evidence: Published literature was retrieved through searches of Medline and PubMed beginning in September 2013 using appropriate controlled MeSH vocabulary (fetal blood, pregnancy, transplantation, ethics) and key words (umbilical cord blood, banking, collection, pregnancy, transplantation, ethics, public, private). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date limits, but results were limited to English or French language materials. Searches were updated on a regular basis and incorporated in the guideline to September 2014. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technologyrelated agencies, clinical practice guideline collections, and national and international medical specialty societies. Values: The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). Benefits, Harms, and Costs: Umbilical cord blood is a readily available source of hematopoetic stem cells used with increasing frequency as an alternative to bone marrow or peripheral stem cell transplantation to treat malignant and non-malignant conditions in children and adults. There is minimal harm to the mother or newborn provided that priority is given to maternal/newborn safety during childbirth management. Recipients of umbilical cord stem cells may experience graft-versus-host disease, transfer of infection or genetic abnormalities, or therapeutic failure. The financial burden on the health system for public cord blood banking and on families for private cord blood banking is considerable. Recommendations 11. Health care professionals should be well-informed about cord blood collection and storage and about factors that influence the volume, quality, and ability to collect a cord blood unit. (III-A) 12. Health care professionals caring for women and families who choose private umbilical cord blood banking must disclose any financial interests or potential conflicts of interest. (III-A) 13. Pregnant women should be provided with unbiased information about umbilical cord blood banking options, including the benefits and limitations of public and private banks. (III-A) 14. Health care professionals should obtain consent from mothers for the collection of umbilical cord blood prior to the onset of active labour, ideally during the third trimester, with ample time to address any questions. (III-A)

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

832 l SEPTEMBER JOGC SEPTEMBRE 2015

Umbilical Cord Blood: Counselling, Collection, and Banking

Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.78 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care.78

15. Health care professionals must be trained in standardized proce­ dures (ex utero and in utero techniques) for cord blood collection to ensure the sterility and quality of the collected unit. (II-2A) 16. Umbilical cord blood should be collected with the goal of maximizing the content of hematopoietic progenitors through the volume collected. The decision to bank the unit will depend upon specific measures of graft potency. (II-2A) 17. Umbilical cord blood collection must not adversely affect the health of the mother or newborn. Cord blood collection should not interfere with delayed cord clamping. (III-E) 18. Health care professionals should inform pregnant women and their partners of the benefits of delayed cord clamping and of its impact on cord blood collection and banking. (II-2A) 19. Cord blood units collected for public or private banking can be used for biomedical research, provided consent is obtained, when units cannot be banked or when consent for banking is withdrawn. (II-3B) 10. Mothers may be approached to donate cells for biomedical research. Informed consent for research using cord blood should ideally be obtained prior to the onset of active labour or elective Caesarean section following established research ethics guidelines. (II-2A)

INTRODUCTION

S

ince the first umbilical cord blood transplant in 1988, cord blood has been established as an alternative source of HSC for bone marrow reconstitution.1 Cord blood has several advantages over bone marrow and mobilized peripheral blood HSC for transplantation, including its availability, negligible risk to the donor, less stringent HLA matching requirements, and less chance of GVHD. Limitations of UCB include insufficient quantity and quality of a single CBU to engraft adults, slow engraftment rates, and the potential for transfer of genetically abnormal

or premalignant cells. The establishment of cord blood banks has allowed rapid access to well-characterized CBU by transplant centres around the world, and to date, cord blood has been used in over 30 000 transplants.2 Hematopoietic Stem Cell Transplantation

Transplantation of blood-forming stem cells to regenerate the blood and immune system following dose-intensive radiation treatment remains a potentially life-saving procedure for patients with malignant and non-malignant blood and immune disorders such as leukemia, lymphoma, aplastic anemia, and inherited metabolic diseases.3 Blood-forming progenitors can be harvested from patients (autologous) or from healthy HLA-compatible (allogeneic) donors who are related or unrelated. Blood stem cells can be procured from bone marrow harvests, via apheresis of peripheral blood following cytokine stimulation or from umbilical cord blood.4–6 Health care professionals should understand that UCB contains blood-forming stem cells that can be used in HSC transplantation and also contains other progenitor cells that are involved in tissue repair and in the modulation of immune responses. Immune compatibility is determined by the HLA genes and is a dominant factor in the selection of an allogeneic donor or CBU. HLA-matched sibling donors are typically preferred but are available for only a minority of patients. With declining fertility rates in Canada over the past 50 years, patients will have diminishing odds of having an HLA-matched sibling donor7 and transplant recipients will rely more heavily on unrelated donors and umbilical cord SEPTEMBER JOGC SEPTEMBRE 2015 l 833

SOGC clinical practice guideline

blood donors. More than 23 million volunteer donors on 73 worldwide registries from 53 countries may be searched on a website facilitated by BMDW2 in accordance with standards established by the WMDA,8 which permits the identification of potential unrelated donors who are willing to donate bone marrow or peripheral blood stem cells, including donors listed in the Canadian Blood Services One Match Marrow and Stem Cell Network9 and the Stem Cell Donor Registry at Héma-Québec.10 The BMDW-d registries include banked umbilical cord blood from more than 611 000 donors from 48 public cord blood banks in 33 countries, which expands the options even further, especially for patients with more unusual HLA haplotypes.2 Role of Umbilical Cord Blood

Umbilical cord blood is highly enriched for blood-forming stem cells and offers some advantages in the setting of allogeneic transplantation. Cord blood inventories can be searched rapidly using sophisticated and coordinated global computerized search algorithms in accordance with guidelines established by the WMDA and units are readily available from a network of accredited banks worldwide.8 Another advantage of using cord blood is its greater flexibility in HLA matching. Although fully matched CBUs are associated with optimal outcomes in cord blood transplantation,11,12 disparities in HLA between donor and recipient are better tolerated than with unrelated donor transplantation because HLA matching requirements are less stringent and the risks of GVHD and graft failure are lower.13 Unrelated donor workups require confirmatory HLA typing and other testing for transmissible diseases and the general health status of the donor, and there may be logistical challenges that delay the collection of cells from unrelated donors; however, unrelated donors offer the prospect of future donor leukocyte infusions or additional cells for boosting the graft function, which is not possible with CBUs.

ABBREVIATIONS AABB

American Association of Blood Banks

BMDW

Bone Marrow Donors Worldwide

CBU

cord blood unit

CIBMTR Center for International Blood and Marrow Transplant Research FACT

Foundation for the Accreditation of Cellular Therapy

GVHD

graft-versus-host disease

HLA

human leukocyte antigen

HSC

hematopoietic stem cell

UCB

umbilical cord blood

WMDA

World Marrow Donor Association

834 l SEPTEMBER JOGC SEPTEMBRE 2015

The major disadvantage of cord blood transplantation is the limited dose of stem cells available in CBUs. UCB volume limits the utility of cord blood transplantation for larger recipients, including most adults, but it remains an issue even in pediatric transplantation. Despite being highly enriched for HSCs, the limited volume that can be collected (100 to 200 mL) means the total dose of stem cells may contribute to delayed engraftment following transplantation and increased risk of bleeding or infection in recipients.14,15 Several strategies to augment the speed of engraftment following UCB transplantation have been investigated, including methods to expand to HSCs ex vivo before transplantation, co-transplantation of mesenchymal stromal cells to accelerate homing and engraftment, and double cord blood transplantation16,17 These strategies, however, will likely introduce significant additional costs, and their role in transplantation remains under development. The cost of CBUs poses another significant barrier to more widespread use of cord blood as an alternative source of stem cells, especially with the high cost of obtaining CBUs from international public banks. It may be possible to acquire domestic CBUs at lower prices than typical international fees of US$25 000 to $40 000 per cord.18 During an era of cost containment, banks and transplant centres will need to address economic factors for banking establishments to remain viable and to allow transplant centres to embrace greater utilization of cord blood.19,20 Indications for Use of Cord Blood from a Family Member

A recent analysis of data from the CIBMTR reviewed the use of related allogeneic transplantation using umbilical cord blood stored in private family banks or through a directed donation program with a public bank. This approach may be useful when bone marrow or peripheral blood stem cells cannot be collected readily from a sibling, such as when siblings are infants. A total of 244 patients from 73 centres were reported to the CIBMTR between 2000 and 2012. Transplants were performed most commonly for acute leukemia (37%), thalassemia or sickle cell disease (29%), Fanconi anemia (7%), and inherited red cell, immune, or metabolic disorders (18%). The Eurocord registry has identified more than 500 patients transplanted with related cord blood from 1988 to 2010.21 Most recipients were children, and all but 29 were HLA-matched. Patients and their families who travel abroad to undergo related cord blood transplantation may be exposed to increased risks of complications that may jeopardize their safety and also be associated with significant personal expense.22 The regulatory oversight concerning transplantation is

Umbilical Cord Blood: Counselling, Collection, and Banking

dramatically different from Canada in some jurisdictions and for the safety of patients this form of medical tourism is highly discouraged. Recommendation

1. Health care professionals should be well-informed about cord blood collection and storage and about factors that influence volume, quality, and ability to collect a cord blood unit. (III-A) PUBLIC CORD BLOOD BANKING

Public cord blood banks are sponsored and funded nationally or locally to process and store donated umbilical CBUs. The donated CBUs are HLA-typed and entered into a national or international registry that allows them to be searched, in a manner similar to bone marrow registries, by transplant centres around the world in need of a donor. A CBU stored in a public bank is made available to any patient in need of a transplant for which it is a suitable match and is not reserved for the donating family. With public banks, there is no guarantee that donors or their family will necessarily have access to their specific donor unit in the future. Public banks do not directly charge the family for the processing and storage of the donated CBU, but a CBU obtained from a public bank outside of Canada can be extremely costly.18 The high cost of obtaining international CBUs has been the subject of much discussion, and prices for these units are beginning to decline. The cost of establishing and running a national public bank, however, is formidable and is borne by the general public. It may be possible to recover some costs of the public banking efforts through fees to international transplant centres, but reciprocity in reducing costs would allow transplant centres greater access to CBUs. Considerations Regarding Public Banking

Both public and family cord blood banking establishments in Canada must meet Health Canada regulatory requirements for cells, tissues, and organs.23 These regulations include all aspects of recruitment, collection, transportation, storage, testing, and documentation, and ultimately, the release of the units to transplant centres. Moreover, public banks should seek accreditation from international bodies such as AABB24 and FACT25 to remain relevant on the international stage. This is essential to their economic viability and the assurance of optimal quality and safety of the products. Public cord blood banking is ideally suited to addressing the needs of patients from ethnic minorities and patients with uncommon HLA haplotypes who remain underrepresented on worldwide registries of unrelated donors. The selection of partner hospitals,

therefore, should include a careful assessment of how well the bank can address issues such as ethnic diversity within the population of expectant mothers and issues that may impact access to mothers and the collection of large volume CBUs. The goal of public cord blood banks is to create an inventory of assessable CBUs suitable for hematopoietic stem cell transplantation. Public banks set very strict criteria for collection volume and total nucleated cell doses to create an inventory of high quality units that will be associated with more rapid engraftment and with acceptable rates of transplant-related complications. As a consequence, a significant number of CBUs donated to public banks are discarded or donated to research. Public cord blood banks are designed to serve the needs of patients and cannot reasonably accommodate every mother’s desire to donate cells. The practices of banking establishments and partner hospitals must adhere to the regulations outlined by Health Canada,23 and this imposes a level of standardization and reliance on protocols for health care professionals that often exceeds normal health care practices. Managing the impact of public cord blood banking on the perinatal routines and practices of the health care team and mothers is an important consideration. Mothers need to learn about public cord blood banking options well before delivery and should ideally provide permission to collect before the onset of active labour or early in labour while consent can reasonably be given. Working closely with health care professionals in the community, many public banking establishments obtain consent to collect first and then determine whether the unit is bankable based on the volume and total nucleated cell count at the time of collection. These parameters are meant to identify units with the greatest utility in the setting of transplantation. More than 80% of units selected for transplantation from the inventory of cord blood banks contain more than 1.2 × 109 nucleated cells,18 and more established banks replenish their inventories exclusively with units of more than 1.5 × 109 cells. If a collected unit meets initial screening criteria for eligibility, a more complete acquisition of maternal history, clinical findings, and lab testing for transmissible infectious diseases is performed. This 2-stage approach focuses time and resources on the units with the greatest likelihood of being requested by transplant centres. The extensive time and resources required to ister the maternal health questionnaire and arrange for the testing of infectious disease markers necessitates the involvement of personnel dedicated to the banking effort. These personnel need to work cooperatively with health care professionals to ensure that banking efforts are fruitful and that the needs of the SEPTEMBER JOGC SEPTEMBRE 2015 l 835

SOGC clinical practice guideline

mothers and babies are not compromised. When units are collected but do not meet the threshold for volume or total nucleated cell count needed for the unit to be banked, the cord blood can be made available for biomedical research through programs such as the Cord Blood for Research Program at Canadian Blood Services. Public cord blood banking is resource-intensive and banking facilities need to partner with birth units to meet the demands and expectations of transplant centres and their patients. Public banks and collecting hospitals should work collaboratively to identify compatible donors from underrepresented ethic groups, particularly First Nations, Inuit, and Metis. PRIVATE CORD BLOOD BANKING

Private (also known as family) cord blood banks store processed umbilical CBUs for the private use of the family. The family of the newborn child pays a fee to process and store the CBU and the mother is typically named the legal custodian of the banked CBU. Thus the banked CBU is accessible only to the family who banked it and will be available to them if and when required. Some Canadian private UCB banks also fund “medical needs” programs whereby the cost to process and store the UCB is waived for families whose expected child has a sibling in need of a bone marrow transplant. Private banks charge the family for processing and storing the CBU for their exclusive use by the family The average cost in Canada is about $1200 for processing and first year of cryopreservation. Subsequent yearly storage fees generally run between $100 and $130. Alternative payment plans are often offered, including an 18-year single-cost plan in some cases. Eighteen years is a logical term for such a plan, since the child from which the cord blood was collected will have reached the age of majority at the end of the term and can then decide whether or not to continue to bank the CBU.

Indeed, early Eurocord studies in patients with leukemia suggest that rates of GVHD following related cord blood transplants26 may be less than rates following unrelated cord blood transplantation.27 Similarly, in non-malignant diseases treated by related or unrelated cord blood transplants, Bizzetto found that the risk of acute GVHD was lower with related cord blood transplants compared to unrelated cord blood and the 3-year survival rate was better.28 Since CBUs are already paid for and stored in private banks, there is no cost to the medical system when the units are used except for specific hospital costs. The cost of obtaining public units, however, can be prohibitive, although they may be discounted or waived for domestic use and continue to decrease as worldwide inventories increase. The goal of private cord blood banks is to cryopreserve quality CBUs that may be used for hematopoietic stem cell transplantation or future regenerative medicine therapies. Thus private banks typically do not use the same banking criteria as public banks in of collection volume and total nucleated cell doses. Private banks appeal to families whose intended recipient for a hematopoietic stem cell transplant may be much smaller than the 60 kg recipient targeted by public banks. Several new technologies in development are intended to either expand the number of HSCs in a given CBU or improve the homing of the HSCs to the bone marrow with the aim of improving the speed of engraftment. These developing technologies are not routinely available at this time. Success in these technologies, however, would allow “small” units banked today to be useful for larger recipients in the future.

Because of the inheritance of HLA, the chance of any sibling being a full HLA match to another sibling is essentially 25%, and this chance increases with the number of siblings. The use of HLA-matched related CBUs may reduce the risk of GVHD and improve transplant outcomes over the use of unrelated cord blood transplantation if the number of cells in the stored unit is sufficient and if tests for transmissible disease are satisfactory.

Regenerative medicine refers to the process of replacing or repairing human cells, tissues or organs to return or establish normal functioning. Cord blood stem cells are presently being examined for use in regenerative medicine or for treating non-blood diseases including type 1 diabetes, cardiovascular repair, traumatic brain injury, cerebral palsy, autism, and hearing loss. Some of these trials are restricted to patients having access to their own (autologous) cord blood, whereas many of these research protocols have reported the use of allogeneic CBUs.29 Therapeutic cell doses have yet to be established. Private cord blood banks set their own acceptance criteria for banking CBUs, which results in a much higher percentage of their collected units being banked than those of public banks.

Although GVHD occurs less commonly following HLAmatched marrow and peripheral blood stem cell transplant in an era of high resolution HLA typing, studies of cord blood transplants show a significant reduction in GVHD.

A banked CBU from a person with no family history of disease treatable by bone marrow transplantation arguably has a very low chance of being used. The chance that a person will contract a disease treatable by their

Considerations Regarding Private Banking

836 l SEPTEMBER JOGC SEPTEMBRE 2015

Umbilical Cord Blood: Counselling, Collection, and Banking

stored cord blood by age 21 has been estimated to be approximately 0.005% to 0.04%.17 A more recent analysis of the likelihood of requiring a bone marrow transplant has taken into treatable diseases up to the age of 70 years, the upper limit for bone marrow or peripheral blood stem cell transplants at some centres. This is a model more representative of the concept of family banking, although it remains unclear how long autologous units can be stored with current cryopreservation methods. In that calculation, the probability of the need for hematopoietic transplantation for a family member is about 1/400 and may be as high as 1/200.30

accreditation standards applicable for publicly banked units, and the requirement for separate storage away from units that do not meet public banking criteria.8 In addition, the safety of infusing autologous banked units has been demonstrated in numerous settings although significant differences in indicators of CBU quality were reported in a recent study compared with publicly banked units.31 Increased collaboration between private and public banks may help to improve the quality of all CBUs collected.

With future advances in medical technology such as gene therapy, tissue therapeutics for treatment of non-blood diseases, and ex vivo cell expansion, the probability of a banked CBU, especially an autologous CBU, may increase, and this provides a compelling rationale for some families to privately bank their children’s cord blood. On the other hand, improvement in medical treatment of serious disease may make the need for stem cell transplantation less necessary in the future and result in a reduced probability of using a banked CBU. As a result, it is now impossible to predict the future value of family UCB banking. Private cord blood banks must provide accurate and transparent information regarding fees, likelihood of using the CBU, methods of opting out and other costs to patients and families.

Despite growing evidence of the therapeutic benefits of umbilical cord derived stem cells and promotion of umbilical cord blood collection for allogeneic, familydirected, or autologous use in the media, surveys reveal that the majority of pregnant women (70 to 80%) lack knowledge about stem cells and cord blood banking and want more information.32–36 While most women (80% to 90%) would prefer to receive information about cord blood banking from their health care professionals, prenatal education and counselling is only provided to a minority (15 to 30%).33,36,37 Consequently, many pregnant women receive information through printed material, the internet, or the media.36,37 Surveys from Canada, Europe, and the United States suggest that once informed, the majority of women would consider donating cord blood for therapeutic use.32,36,37 Overall, women appear to be more inclined to donate to public banks than to private or mixed banks.32,36,37 Approximately 80% of practicing obstetricians in the United States feel confident in discussing cord blood options with their patients, but less than 50% indicate that they have sufficient knowledge of cord blood donation to effectively answer patients’ questions about donation.38

Recommendation

2. Health care professionals caring for women and families who choose private umbilical cord blood banking must disclose any financial interests or potential conflicts of interest. (III-B) COORDINATION OF PRIVATE AND PUBLIC BANKS

CBUs that are stored in private banks cannot be searched by transplant centres for unrelated patients but may be used for autologous hematopoietic transplantation or allogeneic transplantation for another family member. Although uncommon at present, the use of autologous or related UCB transplantation may change in the future in response to ongoing studies of novel applications in areas such as regenerative therapy. Guidelines and transparency with respect to fees, chances of using the unit, methods of opting out and other costs should be available to patients and families. Transferring banked units from private banks to public banks is challenging and guiding principles have been established by the WMDA that highlight issues such as the requirement for donor consent for public banking at the time of collection, the need to meet regulatory and

EDUCATION OF PARENTS AND HEALTH CARE PROFESSIONALS

Not surprisingly, women are often misinformed and confused about the risks and benefits of umbilical cord blood donation and the advantages and limitations of cord blood banking options. In evaluating their choices, women may be motivated to donate their baby’s umbilical cord blood to a public cord blood bank as an altruistic act of civic responsibility or to a private bank for the potential future benefit of their child or immediate family.39 Physicians and other health care professionals are recognized as the primary source of information and guidance for pregnant women and should be wellinformed about the practical implications of umbilical cord blood collection and storage and the benefits and limitations of public and private cord banks. Health care professionals in perinatal facilities should become actively involved in the provision of education about cord blood SEPTEMBER JOGC SEPTEMBRE 2015 l 837

SOGC clinical practice guideline

banking and policies regarding cord blood collection and in the development of collection protocols to improve cord blood volume and quality.33,40,41 Though storage of cord blood for autologous use remains controversial, therapeutic indications for umbilical cord blood stem cells and the use of autologous and family-directed CBUs for transplantation is growing.42–46 Information about cord blood collection and banking provided by health care professionals must be balanced and accurate about its advantages and disadvantages.47 Prospective parents should understand that infants with an underlying genetic disease are very unlikely to be transplanted with autologous cord blood that generally harbours the same gene abnormality and that many diseases may not be amenable to therapy until new treatments are developed.42 Parents also should be informed about maternal infectious disease and genetic testing and the process for disclosure of abnormal findings. Physicians and health care professionals should provide unbiased information about both public and private cord blood banking and should encourage directed donation for immediate family with specific treatable diseases.48 Health care professionals are discouraged from endorsing specific cord blood banks and are obliged to disclose any financial or other conflicts of interest.42 Obstetricians should be knowledgeable enough about the present uses of umbilical cord blood to be able to have a discussion with patients and answer most questions. It is important to be able to discuss the differences between public and family banking and to know which options are available. Recommendation

3. Pregnant women should be provided with unbiased information about umbilical cord blood banking options, including the benefits and limitations of public and private banks. (III-A) INFORMED CONSENT

Because newborn infants are unable to consent to the collection, testing, donation, and storage of their cord blood, informed consent must be obtained and documented from the mother or father. Cord blood collected for therapeutic use or research is not considered waste material and it is generally agreed that informed consent for collection is required.49 Prenatal, pre-labour, and post-collection consent policies have been developed by cord blood banks and professional organizations to address the procedural and financial priorities of public and private blood banks,43,44 and so could be obtained at presentation in early labour. It is generally agreed that consent should be obtained prior 838 l SEPTEMBER JOGC SEPTEMBRE 2015

to the onset of active labour and ideally during the third trimester of the prenatal period.50 A phased consent policy for cord blood donation has been proposed and endorsed by the American Academy of Pediatrics.51 In phase one, information about cord blood banking including risks, benefits, advantages, and limitations is provided to parents as part of prenatal care. Donor registration with the cord blood bank and perinatal institution is also recommended. The second phase of the consent policy occurs when a woman is itted to the birth unit for labour and delivery. Eligibility criteria for cord blood collection include the absence of active labour, intact membranes, term singleton pregnancy, no history of viral, congenital, or genetic diseases and the ability of the mother to understand the implications of cord blood collection. The procedure for obtaining consent is limited to an explanation of the need to collect blood immediately following delivery, a description of the collection technique, and information about the possible risks of the procedure. The post-collection consent procedure addresses maternal infectious and genetic disease testing, access to health record information and newborn screening tests, maternal medical history, cord blood processing and storage, and the potential use of cord blood for therapeutic and research purposes. The mother’s right to refuse collection, processing, or storage of the cord blood at any time without prejudice must be inherent in the consent process. It is also important for parents to be assured that information related to the infant donor and the donor’s family will remain confidential and maintained by the cord blood bank so that parents or physicians can be notified of infectious or genetic diseases.49 Consent policies and procedures vary widely across regional and national jurisdictions, public and private cord blood banks, and perinatal care facilities. Standardization of informed consent for umbilical cord blood donation following AABB24 and FACT25 guidelines is recommended. Institutional review and approval of cord blood donation consent policies are also encouraged.49 If cord blood does not meet criteria for clinical use or when donors decide to terminate storage of a CBU, cord blood banks are encouraged to offer donors the opportunity to donate the cord blood to research, subject to donor consent.52 Recommendation

4. Health care professionals should obtain consent from mothers for the collection of umbilical cord blood prior to the onset of active labour, ideally during the third trimester, with ample time to address any questions. (III-A)

Umbilical Cord Blood: Counselling, Collection, and Banking

UMBILICAL CORD BLOOD COLLECTION

Umbilical cord blood is collected from the umbilical vein either before the placenta is delivered (in utero) or following placental delivery (ex utero). Both methods have advantages and disadvantages.53 Both techniques are in use at Canadian public cord blood banks, although the in utero technique is preferred by most public banks in the United States and many European countries because it can be performed in the delivery room by birth unit staff, is easy to learn, and does not usually require additional personnel or resources.53,54 All private banks use in utero collection methods. Evidence from comparative studies suggest that the in utero technique yields slightly higher volumes of cord blood and higher yields of total nucleated cells compared to the ex utero technique.55–57 The standard in utero method for cord blood collection uses a closed collection system to reduce the risk of infection and maternal fetal fluid contamination. The umbilical cord is double-clamped approximately 3 to 5 cm from the umbilicus and transected between the clamps. After the infant has been removed from the field, the cord is prepared for venipuncture using a povidone iodine applicator. The needle of the cord collection kit is then inserted into the umbilical vein and the CBU is collected by gravity. The time required to perform the cord collection procedure is approximately 5 to 10 minutes and additional personnel are not required.54,58,59 Factors known to reduce cord blood volume include maternal hypertension, smoking, multiple gestation, preterm delivery, intrauterine growth restriction, abnormal placentation, emergency CS, precipitous delivery, and maternal transfer.17,59 Factors associated with higher cord blood volumes and greater yield of nucleated cells include birth weight, placental weight, gestational age, induction of labour, prolonged labour, CS, early cord clamping, first born infants, Caucasian ethnicity, and female infant gender.60 Umbilical cord blood obtained after CS for acute fetal distress also appears to significantly increase total nucleated cells, CD34+ cells, and white blood cells without compromising cord volumes and should not preclude cord blood collection unless maternal and newborn safety may be compromised.61,62 A number of manoeuvres have been proposed to optimize cord blood volume. Using large syringes (50 to 60 cc) and a syringe withdrawal-saline flush-syringe withdrawal technique as part of the closed collection system have yielded significantly higher mean volume collected (150 to 175 mL), compared with standard in utero collection by gravity (75 to 100 mL). Clamping the umbilical cord within 30 seconds of delivery and placing the newborn

infant on the maternal abdomen after delivery have also been reported to improve recovery volume and CD34+ cell content;63,64 however, this early clamping defeats the benefits of delayed clamping. Ex utero cord blood collection is performed by dedicated, trained personnel in a separate room and standard collection bag as soon as possible after delivery of the placenta. The cord blood is collected by gravity with the placenta suspended on a specifically designed stand.54,65 Although this method allows birth unit staff to focus on maternal and infant health, the procedure requires additional trained personnel, resources, and cost but reduces the frequency of non-conformances associated with collection of units from staff that are not d with the bank. Disadvantages of this method are the possibility of lower cord blood volume and total nucleated cell counts. As with in utero collection, factors associated with increased collected volume using the ex utero technique include: singleton pregnancy, post-term pregnancy, induced labour, prolonged labour, CS, cord length greater than 30 cm, birth weight ≥ 3500 g, and placental weight > 700 g.48,54,66 Umbilical cord collection poses a number of logistical issues that may increase the burden for busy birth units. The consent procedure and associated paperwork adds time and inconvenience to the work of health care professionals. Collection procedures performed during the third stage of labour at a time when both mother and baby require attentive care and risk of postpartum hemorrhage must not jeopardize maternal newborn health. Birth unit personnel feel under pressure to obtain adequate volume of cord blood and to avoid bacterial contamination. Attention to the cord blood collection may also impact on the care of other mothers and infants. Consequently, umbilical cord blood collection should not interfere with the normal management of the third stage or compromise the safety of mother and baby.59,67 Contraindications to cord blood collection include preterm birth, serious maternal medical or obstetric complications, such as cardiac arrest, stroke, eclampsia or massive hemorrhage, and perinatal asphyxia. Regulatory Issues and Practice Standards for Collecting and Processing Umbilical Cord Blood

Cord blood banks must adhere to strict regulatory requirements and focus on additional factors to ensure that UCB units stored in the bank are of the highest quality and thus remain beneficial to transplant centres and their patients. Accreditation and compliance with nationally and internationally recognized regulatory bodies ensure that all aspects of recruitment, donor screening, collection SEPTEMBER JOGC SEPTEMBRE 2015 l 839

SOGC clinical practice guideline

and transport, processing, testing, freezing, storage, and distribution are standardized and meet international thresholds of quality. The use of current measures of graft potency is also critical so transplant centres and patients have confidence regarding the assurance of timely engraftment following transplantation. The collection and storage of UCB must adhere to Health Canada regulations under the cells, tissues, and organs guidelines23 to ensure the quality of CBUs in of HSC content, absence of infectious agents, and risk of transmitting genetic disease. In addition, international guidelines are provided by FACT and AABB. These shape operational issues related to cord blood banking in Canada and around the world through the International NetCord Foundation). Recommendations

5. Health care professionals must be trained in standardized proce­dures (ex utero and in utero techniques) for cord blood collection to ensure the sterility and quality of the collected unit. (II-2A) 6. Umbilical cord blood should be collected with the goal of maximizing the content of hematopoietic progenitors through the volume collected. The decision to bank the unit will depend upon specific measures of graft potency. (II-2A) 7. Umbilical cord blood collection must not adversely affect the health of the mother or newborn. Cord blood collection should not interfere with delayed cord clamping. (III-A) 8. Health care professionals should inform pregnant women and their partners of the benefits of delayed cord clamping and of its impact on cord blood collection and banking. (II-2A) Timing of Umbilical Cord Clamping

There is growing evidence of the benefit of delayed cord clamping for 1 to 3 minutes in preterm infants (< 37 weeks).68–71 Systematic reviews have demonstrated that delayed cord clamping in preterm infants results in reduced need for transfusions, better circulatory stability, improved blood pressure and decreased risk of intraventricular hemorrhage and necrotizing colitis.68,71 Recent evidence suggests that delayed cord clamping in very preterm and very low birth infants protects against motor disability at 7 months of age.70 In light of the this evidence, several professional organizations have recommended implementation of delayed cord clamping for preterm infants despite health care professionals’ concerns about the need for immediate resuscitation and risk of hypothermia.72 Since umbilical cord banking is generally contraindicated in preterm infants, delayed cord clamping in this population should have no impact on cord blood banking. 840 l SEPTEMBER JOGC SEPTEMBRE 2015

Delayed cord clamping in term infants has been consistently shown to enhance placental transfusion at birth and increase hemoglobin, hematocrit, ferritin levels, and iron stored up to 6 months of age.70,73,74 Though prevailing evidence also suggests that delayed cord clamping promotes higher iron stores in the longer term,70 delayed cord clamping did not affect iron status or neurodevelopment at age 12 months in a recent randomized controlled trial of healthy term-born infants in Sweden.75 Concerns have been raised regarding the increased risk of phototherapy for postnatal jaundice and polycythemia associated with delayed cord clamping.74 WHO recommends a 1 to 3 minute delayed cord clamping in term infants, particularly in populations where iron deficiency anemia is endemic and provided there is provision for screening and treatment of neonatal jaundice.76 SOGC recommends weighing the risk of neonatal jaundice against the physiological benefit of increased hemoglobin and iron levels,71 whereas ACOG concludes that there is insufficient evidence to or refute delayed cord clamping in term infants.72 Based on the available evidence, delayed cord clamping in health term infants appears to be beneficial provided that treatment for jaundice requiring phototherapy is available.70 Umbilical cord collection in preterm infants (< 37 weeks gestation) is generally contraindicated. Early cord clamping within 30 seconds of delivery is associated with optimal volume and progenitor cells for cord blood collection while delayed cord clamping for 1 to 3 minutes decreases the volume of cord blood available for collection. While cord blood collection following delayed cord clamping is not contraindicated, parents should be aware that the practice may preclude collection of sufficient cord blood for banking. RESEARCH AND POTENTIAL FUTURE USE OF UMBILICAL CORD BLOOD

There is increasing interest in the use of cord blood for novel indications in regenerative therapy or as a means of immune modulation. A recent systematic review identified a small number of published studies involving approximately 300 patients.29 The most common emerging area described in these studies addressed the repair of neurological conditions, including cerebral palsy. A large study using umbilical cord blood in the treatment of cerebral palsy is ongoing.77 Other diseases that may be amenable to cord blood transplantation include type I diabetes and liver disease. Some studies have investigated the use of mesenchymal stromal cells expanded from umbilical cord blood. It is not yet clear how effective cord blood-derived cells are in these novel

Umbilical Cord Blood: Counselling, Collection, and Banking

indications as most studies are uncontrolled and involve few subjects and are proof-of-principle in nature only. Moreover, strategies to culture cells from cord blood may complicate banking efforts and introduce new regulatory challenges. It remains to be seen whether public banks will develop methods to screen for umbilical CBUs that are better suited to applications in regenerative therapy or immune modulation or whether increasing numbers of public banks will develop methods to store HSCs or other cell types expanded from cord blood. UCB represents a rich source of progenitor cells with a broad range of biological functions and tremendous potential for the development of novel cell-based therapies. Recommendations

  9. Cord blood units collected for public or private banking can be used for biomedical research, provided consent is obtained, when units cannot be banked or when consent for banking is withdrawn. (II-3B) 10. Mothers may be approached to donate cells for biomedical research. Informed consent for research using cord blood should ideally be obtained prior to the onset of active labour or elective Caesarean section following established research ethics guidelines. (II-2A)

Public Cord Blood Collection in Canada as of 2015

The National Public Cord Blood Bank at Canadian Blood Services has been collecting and storing units since September 30, 2013, building on the recognized need for a national effort in public cord blood banking in Canada. The initial collection and manufacturing site is in Ottawa. A second manufacturing site and collection site in Edmonton became operational in July 2014, and additional collection sites in Vancouver and Brampton began contributing to the bank in January 2015. The bank intends to store more than 10 000 high quality units by 2018 and the units will have high cell content and engraftment potency, be searchable internationally through the BMDW, and reflect the ethnic diversity of Canada, including First Nations, Inuit, and Metis who have low UCB representation. Héma-Québec has a public cord blood bank that is FACT-accredited and has more than 9000 units stored since they first started collecting in 2004. The units are searchable through the BMDW and they have supplied cord blood for more than 100 Canadian and international patients. The collection hospitals are in Montreal and Laval. The Victoria Angel of Hope Registry is a third Canadian public cord blood bank d with the Cells for Life family bank in Toronto that continues to recruit expectant mothers. It has recently ed with BMDW and offers international searching of its inventory of several hundred CBUs.

CORD BLOOD BANKING IN CANADA

Current banking efforts reflect state of the art practices which will make the Canadian contribution important. Public banking activity has occurred in some regions of the country for several years (Alberta Cord Blood Bank, Héma-Québec Cord Blood Bank, and the Victoria Angel Registry of Hope), and the launch of the National Public Cord Blood Bank at Canadian Blood Services began in 2013. The establishment of a public bank with the capacity to store many high quality HLA-typed CBUs from a diverse cross-section of ethnicities should benefit both Canadian and international patients. Such a bank would increase the odds of finding a suitably matched CBU for patients in need of a hematopoietic cell transplant who do not have a matched sibling or unrelated donor. Recently, some public banks such as Héma-Québec have instituted a medical needs program to store, for up to 2 years, a CBU from a sibling of a child requiring a bone marrow transplant for the express use of that family member in need of the transplant. Private banks existed in Canada prior to public banking efforts and offer the possibility of a related cord blood transplant for patients and the option of possible autologous transplantation. Indications for autologous use, however, remain under debate and are not performed routinely.

SUMMARY

The National Public Cord Blood Bank was established by the Canadian Blood Services in 2013 and public cord blood banking will be available in selected Canadian sites focussed on the storage of a diverse ethnic cross-section of HLA-typed CBUs. Public cord blood banking at HémaQuebec and the Victoria Angel of Hope Registry continues to grow. Private cord blood banking facilities are located in major urban centres in Canada and provide the opportunity for family cord blood collection and storage from coast to coast. Health care professionals should be aware of current recommendations for education, counselling, obtaining informed consent, collection, and storage of umbilical cord blood. Information regarding cord blood banking options in Canada should be presented in a comprehensive and unbiased manner. REFERENCES 1. Gluckman E, Broxmeyer HA, Auerbach AD, Friedman HS, Douglas GW, Devergie A, et al. Hematopoietic reconstitution in a patient with Fanconi’s anemia by means of umbilical-cord blood from an HLA-identical sibling. N Engl J Med 1989;321:1174–8.

SEPTEMBER JOGC SEPTEMBRE 2015 l 841

SOGC clinical practice guideline

2. Bone Marrow Donors Worldwide. Leiden (NL): Bone Marrow Donors Worldwide, 2015. Available at: http://www.bmdw.org. Accessed on January 20, 2015.

19. Broxmeyer HE, Farag S. Background and future considerations for human cord blood hematopoietic cell transplantation, including economic concerns. Stem Cells Dev 2013;22(Suppl 1):103–10.

3. Gratwohl A, Baldomero H, weg J. Hematopoietic stem cell transplantation activity in Europe. Curr Opin Hematol 2013;20:485–93.

20. Brown N, Machin L, McLeod D. Immunitary bioeconomy: the economisation of life in the international cord blood market. Soc Sci Med 2011;72:1115–22.

4. Cohen Y, Nagler A. Umbilical cord blood transplantation—how, when and for whom? Blood Rev. 2004;18:167–79. 5. Martin PL, Carter SL, Kernan NA. Results of the Cord Blood Transplantation Study (COBLT): outcomes of unrelated donor umbilical cord blood transplantation in pediatric patients with lysosomal and peroxisomal storage diseases. Biol Blood Marrow Transplant 2006;12:184–94. 6. Rocha V, Labopin M, Sanz G, Arcese W, Schwerdtfeger R, Bosi A, et al.; Acute Leukemia Working Party of European Blood and Marrow Transplant Group; Eurocord-Netcord Registry. Transplants of umbilical cord blood or bone marrow from unrelated donors in adults with acute leukemia. N Engl J Med. 2004;351:2276–85. 7. Allan DS, Takach S, Smith S, Goldman M. Impact of declining fertility rates on donor options in blood and marrow transplantation. Biol Blood Marrow Transplant: 2009;15:1634–7. 8. World Marrow Donor Association. Leiden (NL): Bone Marrow Donors Worldwide, 2015. Available at: http://www.wmda.info. Accessed on May 27, 2015. 9. Canadian Blood Services. One Match Stem Cell and Marrow Network. Ottawa (ON): Canadian Blood Services; 2015. Available at: https://www.blood.ca/en/stem-cells?utm_source=onematch&utm_ medium=redirect&utm_campaign=onematch. Accessed on September 14, 2014. 10. Héma-Québec. Saint-Laurent (QC): Héma-Quebec; 2015. Available at: http://www.hema-quebec.qc.ca. Accessed on May 27, 2015. 11. Barker JN, Scaradavou A, Stevens CE. Combined effect of total nucleated cell dose and HLA match on transplantation outcome in 1061 cord blood recipients with hematologic malignancies. Blood 2010;115:1843–9. 12. Wagner JE, Barker JN, DeFor TE, Baker KS, Blazar BR, Eide C, et al. Transplantation of unrelated donor umbilical cord blood in 102 patients with malignant and nonmalignant diseases: influence of CD34 cell dose and HLA disparity on treatment-related mortality and survival. Blood 2002;100:1611–8. 13. Caillat-Zucman S, Le Deist F, Haddad E, Gannagé M, Dal Cortivo L, Jabado N, et al. Impact of HLA matching on outcome of hematopoietic stem cell transplantation in children with inherited diseases: a single-center comparative analysis of genoidentical, haploidentical or unrelated donors. Bone Marrow Transplant 2004;33:1089–95. 14. Jaime-Perez JC, Monreal-Robles, Rodrıguez-Romo LN, Herrera-Garza JL. Evaluation of volume and total nucleated cell count as cord blood selection parameters. Am J Clin Path 2011;136:721–6. 15. Gluckman E, Rocha V, Arcese W, Michel G, Sanz G, Chan KW, , et al. Factors associated with outcomes of unrelated cord blood transplant: guidelines for donor choice. Exp Hematol 2004;32:397–407. 16. Brunstein CG, Fuchs EJ, Carter SL, Karanes C, Costa LJ, Wu J, et al. Alternative donor transplantation after reduced intensity conditioning: results of parallel phase 2 trials using partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts. Blood 2011;118:282–8. 17. Ballen KK, Spitzer TR, Yeap BY, McAfee S, Dey BR, Attar E, et al. Double unrelated reduced-intensity umbilical cord blood transplantation in adults. Biol Blood Marrow Transplant 2007;13:82–9. 18. Bart T, Boo M, Balabanova S, Fischer Y, Nicoloso G, Foeken L, et al. Impact of selection of cord blood units from the United States and Swiss registries on the cost of banking operations. Transf Med Hemother 2013;40:14–20.

842 l SEPTEMBER JOGC SEPTEMBRE 2015

21. Gluckman E, Ruggeri A, Rocha V, Baudoux E, Boo M, Kurtzberg J, et al. Family-directed umbilical cord blood banking. Haematologica 2011;96:1700–7. 22. Hyun I. Therapeutic hope, spiritual distress, and the problem of stem cell tourism. Cell Stem Cell 2013;12:505–7. 23. Health Canada. Guidance document for cell, tissue, and organ establishments – safety of human cells, tissues and organs for transplantation. Adopted with minor revisions 08/26/2013. Ottawa (ON): Health Canada; 2013. Available at: http://www.hc-sc.gc.ca/ dhp-mps/brgtherap/reg-init/cell/cto_gd_ld-eng.php. Accessed on September 14, 2014. 24. American Association of Blood Banks. Standards for hematopoietic progenitor cell services. Bethesda (MD): AABB; 2015. Available at: http://www.aabb.org/Search/Pages/results.aspx?k=Standards%20 for%20hematopoietic%20progenitor%20cell%20services. Accessed on September 14, 2015. 25. Foundation for the Accreditation of Cellular Therapy (FACT). Omaha (NE): FACT; 2015. Available at: http://www.factwebsite.org. Accessed on May 27, 2015. 26. Eapen M. Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukemia: a comparison study. Lancet. 2007;369:1947–54. 27. Gluckman E, Rocha V, Boyer-Chammard A, Locatelli F, Arcese W, Pasquini R, et al. Outcome of cord-blood transplantation from related and unrelated donors. Eurocord Transplant Group and the European Blood and Marrow Transplantation Group. N Engl J Med. 1997;337:373–81. 28. Bizzetto R, Bonfim C, Rocha V. Outcomes after related and unrelated umbilical cord blood transplantation for heredity bone marrow failure syndromes other than Fanconi anemia. Haematologica. 2011;96:134–41. 29. Iafolla MAJ, Tay J, Allan DS. Transplantation of umbilical cord blood-derived cells for novel indications in regenerative or immunomodulatory therapy: a scoping review of clinical studies. Biol Blood Marrow Transplant 2014;20:20–5. 30. Nietfeld JJ, Harris DT. Cost-effectiveness of private umbilical cord blood banking. Obstet Gynecol 2010;115:1090. 31. Sun J, Allison J, McLaughlin C, Sledge L, Waters-Pick B, Wease S, et al. Differences in quality between privately and publicly banked umbilical cord blood units: a pilot study of autologous cord blood infusion in children with acquired neurologic disorders. Transfusion 2010;50:1980–7. 32. Fernandez CV, Gordon K, Van den Hof M, Taweel S, Baylis F. Knowledge and attitudes of pregnant women with regard to collection, testing and banking of cord blood stem cells. CMAJ 2003;168:695–8. 33. Perlow JH. Patients’ knowledge of umbilical cord blood banking. J Reprod Med 2006;51:642–8. 34. Kharaboyan L, Knoppers BM, Avard D, Nisker J. Understanding umbilical cord blood banking: what women need to know before deciding. Womens Health Issues 2007;17:277–80. 35. Fox NS, Stevens C, Ciubotariu R, Rubinstein P, McCullough LB, Chervenak FA. Umbilical cord blood collection: do patients really understand? J Perinat Med. 2007;35:314–21.

Umbilical Cord Blood: Counselling, Collection, and Banking

36. Katz G, Mills A, Garcia J, Hooper K, McGuckin C, Platz A, et al. Banking cord blood stem cells: attitude and knowledge of pregnant women in five European countries. Transfusion 2011;51:578–86.

54. Skoric D, Balint B, Petakov M, Sindjic M, Rodic P. Collection strategies and cryopreservation of umbilical cord blood. Transfus Med 2007;17:107–13.

37. Dinç H, Sahin NH. Pregnant women’s knowledge and attitudes about stem cells and cord blood banking. Int Nurs Rev 2009;56:250–6.

55. Omori A, Manabe M, Kudo K, Tanaka K, Takahashi K, Kashiwakura I. Influence of obstetric factors on the yield of mononuclear cells, CD34+ cell count and volume of placental/umbilical cord blood. J Obstet Gynaecol Res 2010;36:52–7.

38. Walker T, Steckler D, Spellman S, Haven D, Welte K, Boo M. Awareness and acceptance of public cord blood banking among practicing obstetricians in the United States. Transfusion 2012;52:787–93. 39. Porter M, Kerridge IH, Jordens CF. “Good mothering” or “good citizenship”? J Bioeth Inq 2012;9:41–7. 40. Herlihy MM, Delpapa EH. Obstetricians and their role in cord blood banking: promoting a public model. Obstet Gynecol 2013;121:851–5. 41. Smith FO, Thomson BG. Umbilical cord blood collection, banking, and transplantation: current status and issues relevant to perinatal caregivers. Birth 2000;27:127–35. 42. American College of Obstetricians and Gynecologists, Committee on Obstetric Practice; Committee on Genetics. ACOG Committee Opinion No. 399. Umbilical cord blood banking. Obstet Gynecol 2008;111:475–7. 43. Lubin BH, Shearer WT. American Academy of Pediatrics Section on Hematology/Oncology; American Academy of Pediatrics Section on Allergy/Immunology. Cord blood banking for potential future transplantation. Pediatrics 2007;119:165–70. 44. Royal College of Obstetricians & Gynaecologists. Umbilical Cord Blood Banking Scientific Impact Paper No. 2. Revised June 2006. London (GB): RCOG; 2006. Available at: https://www.rcog.org.uk/ globalassets/documents/guidelines/scientific-impact-papers/sip_2.pdf. Accessed on May 27, 2015. 45. New Zealand College of Midwives. Consensus statement: umbilical cord blood banking. Ratified at the NZCOM Annual General Meeting on August 14, 2013. Christchurch (NZ): New Zealand College of Midwives; 2013. Available at: http://www.midwife.org.nz/quality-practice/nzcomconsensus-statements. Accessed on May 27, 2015. 46. The Royal Australian and New Zealand College of Obstetricians and Gynaecologists. College Statement C-Obs 18. Umbilical cord blood banking. Endorsed: February 2003; Current: May 2013; Review March 2016. Victoria (AU): The Royal Australian and New Zealand College of Obstetricians and Gynaecologists; 2015. Available at: https://www.ranzcog.edu.au/college-statements-guidelines. html#obstetrics. Accessed on May 27, 2015. 47. Perlow JH. Umbilical cord blood banking options and the prenatal patient: an obstetrician’s perspective. Stem Cell Rev 2006;2:127–32.

56. Mancinelli F, Tamburini A, Spagnoli A, Malerba C, Suppo G, Lasorella R, et al. Optimizing umbilical cord blood collection: impact of obstetric factors versus quality of cord blood units. Transplant Proc 2006;38:1174–6. 57. Surbek DV, Schönfeld B, Tichelli A, Gratwohl A, Holzgreve W. Optimizing cord blood mononuclear cell yield: a randomized comparison of collection before vs after placenta delivery. Bone Marrow Transplant 1998;22:311–2. 58. Wong A, Yuen PM, Li K, Yu AL, Tsoi WC. Cord blood collection before and after placental delivery: levels of nucleated cells, haematopoietic progenitor cells, leukocyte subpopulations and macroscopic clots. Bone Marrow Transplant 2001;27:133–8. 59. Armson BA; Society of Obstetricians and Gynaecologists of Canada Maternal/Fetal Medicine Committee. Umbilical cord blood banking: implications for perinatal care providers. SOGCV Clinical Practice Guidelines, No 156, March 2005. J Obstet Gynaecol Can 2005;27:263–90. 60. Jones J, Stevens CE, Rubinstein P, Robertazzi RR, Kerr A, Cabbad MF. Obstetric predictors of placental/umbilical cord blood volume for transplantation. Am J Obstet Gynecol 2003;188:503–9. 61. Surbek DV, Visca E, Steinmann C, Tichelli A, Schatt S, Hahn S, et al. Umbilical cord blood collection before placental delivery during cesarean delivery increases cord blood volume and nucleated cell number available for transplantation. Am J Obstet Gynecol 2000;183:218–21. 62. Sparrow RL, Cauchi JA, Ramadi LT, Waugh CM, Kirkland MA. Influence of mode of birth and collection on WBC yields of umbilical cord blood units. Transfusion 2002;42:210–5. 63. Manegold G, Meyer-Monard S, Tichelli A, Pauli D, Holzgreve W, Troeger C. Cesarean section due to fetal distress increases the number of stem cells in umbilical cord blood. Transfusion 2008;48:871–6. 64. Picardi A, Tamburini A, Caravita T, De Angelis C, Ballatore G, Spagnoli A, et al. Diagnosis of acute foetal distress does not preclude banking of umbilical cord blood units. Transfus Med 2006;16:349–54. 65. Harris DT. Collection, processing, and banking of umbilical cord blood stem cells for clinical use in transplantation and regenerative medicine. Lab Med 2008;39:173–8.

48. Moise KJ Jr. Umbilical cord stem cells. Obstet Gynecol 2005;106:1393–407.

66. Lasky LC, Lane TA, Miller JP, Lindgren B, Patterson HA, Haley NR, et al. In utero or ex utero cord blood collection: which is better? Transfusion 2002;42:1261–7.

49. Sugarman J, Kurtzberg J, Box TL, Horner RD. Optimization of informed consent for umbilical cord blood banking. Am J Obstet Gynecol 2002;187:1642–6.

67. Ballen KK, Gluckman E, Broxmeyer HE. Umbilical cord blood transplantation: the first 25 years and beyond. Blood. 2013;122:491–8.

50. Broder SM, Ponsaran RS, Goldenberg AJ. US public cord blood banking practices: recruitment, donation, and the timing of consent. Transfusion 2013;53:679–87. 51. Vawter DE, Rogers-Chrysler G, Clay M, Pittelko L, Therkelsen D, Kim D, et al. A phased consent policy for cord blood donation. Transfusion 2002;42:1268–74. 52. Petrini C, Farisco M. Informed consent for cord blood donation. A theoretical and empirical study. Blood Transfus 2011;9:292–300. 53. Solves P, Moraga R, Saucedo E, Perales A, Soler MA, Larrea L, et al. Comparison between two strategies for umbilical cord blood collection. Bone Marrow Transplant 2003;31:269–73.

68. Rabe H, Diaz-Rossello JL, Duley L, Dowswell T. Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes. Cochrane Database Syst Rev 2012;8:CD003248. 69. Mercer JS, Vohr BR, Erickson-Owens DA, Padbury JF, Oh W. Seven-month developmental outcomes of very low birth weight infants enrolled in a randomized controlled trial of delayed versus immediate cord clamping. J Perinatol 2010;30:11–6, 22. 70. McDonald SJ, Middleton P, Dowswell T, Morris PS. Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes. Cochrane Database Syst Rev 2013;7:CD004074. 71. Garofalo M, Abenhaim HA. Early versus delayed cord clamping in term and preterm births: a review. J Obstet Gynaecol Can 2012;34:525–31.

SEPTEMBER JOGC SEPTEMBRE 2015 l 843

SOGC clinical practice guideline

72. American College of Obstetricians and Gynecologists, Committee on Obstetric Practice, Committee Opinion No. 543. Timing of umbilical cord clamping after birth. Obstet Gynecol 2012;12:1522–6. 73. Grisaru D, Deutsch V, Pick M, Fait G, Lessing JB, Dollberg S, et al. Placing the newborn on the maternal abdomen after delivery increases the volume and CD34 cell content in the umbilical cord blood collected: an old maneuver with new applications. Am J Obstet Gynecol 1999;180:1240–3. 74. Hutton EK, Hassan ES. Late vs early clamping of the umbilical cord in full-term neonates: systematic review and meta-analysis of controlled trials. JAMA 2007;297:1241–52. 75. Andersson O, Domellöf M, Andersson D, Hellström-Westas L. Effects of delayed cord clamping on iron status and neurodevelopment at age 12 months: a randomised trial. JAMA Pediatr. 2014;168:547–54.

844 l SEPTEMBER JOGC SEPTEMBRE 2015

76. World Health Organization. Optimal timing of cord clamping for the prevention of iron deficiency anaemia in infants. Geneva (CH): WHO; 2015. Available at: http://www.who.int/elena/titles/cord_ clamping/en. Accessed on May 27, 2015. 77. U.S. National Institutes of Health. ClinicalTrials.gov. NCT00593242, NCT01072370, NCT01147653, NCT01193660, NCT01506258, NCT01528436, NCT01601158, NCT01649648. Bethesda (MD): U.S. National Library of Medicine; 2015. Available at: http://www.clinicaltrials.gov. Accessed on May 27, 2015. 78. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canad ian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

SOGC CLINICAL PRACTICE GUIDELINE No. 320, March 2015 (Replaces No. 211, August 2008)

Vulvovaginitis: Screening for and Management of Trichomoniasis, Vulvovaginal Candidiasis, and Bacterial Vaginosis This clinical practice guideline has been prepared by the Infectious Diseases Committee, reviewed by the CANPAGO and Family Physician Advisory Committees, and approved by the Executive and Board of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Julie van Schalkwyk, MD, Vancouver BC Mark H. Yudin, MD, Toronto ON INFECTIOUS DISEASE COMMITTEE Mark H. Yudin, MD (Chair), Toronto ON Victoria Allen, MD, Halifax NS Celine Bouchard, MD, Quebec QC Marc Boucher, MD, Montreal QC Isabelle Boucoiran, MD, Vancouver BC Sheila Caddy, MD, Calgary AB Eliana Castillo, MD, Calgary AB V. Logan Kennedy, RN, Toronto ON Deborah M. Money, MD, Vancouver BC Kellie Murphy, MD, Toronto ON Gina Ogilvie, MD, Vancouver BC Caroline Paquet, RM, Trois-Rivieres QC Julie van Schalkwyk, MD, Vancouver BC Disclosure statements have been received from all contributors.

Key words: bacterial vaginosis, yeast, candidiasis, trichomonas vaginalis, trichomoniasis, vaginitis, treatment

J Obstet Gynaecol Can 2015;37(3):266–274

Abstract Objective: To review the evidence and provide recommendations on screening for and management of vulvovaginal candidiasis, trichomoniasis, and bacterial vaginosis. Outcomes: Outcomes evaluated include the efficacy of antibiotic treatment, cure rates for simple and complicated infections, and the implications of these conditions in pregnancy. Evidence: Published literature was retrieved through searches of MEDLINE, EMBASE, CINAHL, and The Cochrane Library in June 2013 using appropriate controlled vocabulary (e.g., vaginitis, trichomoniasis, vaginal candidiasis) and key words (bacterial vaginosis, yeast, candidiasis, trichomonas vaginalis, trichomoniasis, vaginitis, treatment). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date limits, but results were limited to English or French language materials. Searches were updated on a regular basis and incorporated in the guideline to May 2014. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, and national and international medical specialty societies. Values: The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). Summary Statements 1. Vulvovaginal candidiasis affects 75% of women at least once. Topical and oral antifungal azole medications are equally effective. (I) 2. Recurrent vulvovaginal candidiasis is defined as 4 or more episodes per year. (II-2) 3. Trichomonas vaginalis is a common non-viral sexually transmitted infection that is best detected by antigen testing using vaginal swabs collected and evaluated by immunoassay or nucleic acid amplification test. (II-2) 4. Cure rates are equal at up to 88% for trichomoniasis treated with oral metronidazole 2 g once or 500 mg twice daily for 7 days. Partner treatment, even without screening, enhances cure rates. (I-A)

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

266 l MARCH JOGC MARS 2015

Vulvovaginitis: Screening for and Management of Trichomoniasis, Vulvovaginal Candidiasis, and Bacterial Vaginosis

Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action

*The quality of evidence reported in here has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.76 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care.76

5. Current evidence of the efficacy of alternative therapies for bacterial vaginosis (probiotics, vitamin C) is limited. (I) Recommendations 1. Following initial therapy, treatment success of recurrent vulvovaginal candidiasis is enhanced by maintenance of weekly oral fluconazole for up to 6 months. (II-2A) 2. Symptomatic vulvovaginal candidiasis treated with topical azoles may require longer courses of therapy to be resolved. (1-A) 3. Test of cure following treatment of trichomoniasis with oral metronidazole is not recommended. (I-D) 4. Higher-dose therapy may be needed for treatment-resistant cases of trichomoniasis. (I-A) 5. In pregnancy, treatment of symptomatic Trichomonas vaginalis with oral metronidazole is warranted for the prevention of preterm birth. (I-A) 6. Bacterial vaginosis should be diagnosed using either clinical (Amsel’s) or laboratory (Gram stain with objective scoring system) criteria. (II-2A) 7. Symptomatic bacterial vaginosis should be treated with oral metronidazole 500 mg twice daily for 7 days. Alternatives include vaginal metronidazole gel and oral or vaginal clindamycin cream. (I-A) 8. Longer courses of therapy for bacterial vaginosis are recommended for women with documented multiple recurrences. (I-A)

ABBREVIATIONS HIV

human immunodeficiency virus

NAAT

nucleic acid amplification test

PHAC

Public Health Agency of Canada

STI

sexually transmitted infection

VVC

vulvovaginal candidiasis

VULVOVAGINAL CANDIDIASIS

V

ulvovaginal candidiasis is a very common condition that affects up to 75% of women at least once in their lifetime.1 Risk factors for VVC include sexual activity, recent antibiotic use, pregnancy, and immunosuppression from such conditions as poorly controlled HIV infection or diabetes.2,3 The Organisms

VVC is most often caused by Candida albicans4; however, other species of Candida such as glabrata, parapsilosis, and tropicalis are emerging.5 The main reservoir for Candida is thought to be the rectum, but vaginal colonization is also common. The factors associated with evolution from colonization to symptomatic infection are multiple and involve a combination of host susceptibility, host inflammatory responses, and Candidal virulence factors. Symptoms are thought to be caused by an overabundance of yeast and its penetration of vulvovaginal epithelial cells.6 The Disease

The signs and symptoms of uncomplicated VVC include a thick cottage-cheese–like discharge associated with vaginal and vulvar pruritus, pain, burning, erythema, and/or edema. External dysuria and dyspareunia may also occur. Complicated VVC may be defined as that which is recurrent (4 or more episodes in a 12 month period), associated with severe symptoms, the result of a non-albicans species, or present in a compromised host.7 This condition is more MARCH JOGC MARS 2015 l 267

SOGC clinical practice guideline

common in those with immunosuppression, diabetes, or both.8 Additional testing for HIV9 and diabetes may be warranted in these situations. Diagnosis

The diagnosis of VVC requires pelvic examination. The combination of thick white discharge and vulvar pruritis is neither sensitive nor specific on its own for diagnosis. Erythema and edema of vulvar and vaginal tissues, in conjunction with thick, white clumped vaginal discharge, are ive of the diagnosis. The vaginal secretions of VVC have a pH <  4.5, and budding yeast and pseudohyphae may be seen on wet mount. Whiff test is negative and gram stain may reveal polymorphonuclear cells, budding yeast, and pseudohyphae. When there is evidence of complicated VVC, collection of vaginal fluid for culture and yeast speciation may help direct therapy because there is an increased likelihood of non-albicans strains in such cases.10 Treatment

Treatment for VVC is necessary only in conjunction with symptoms. Identification of yeast on wet mount, gram stain/culture, or Pap screening in the absence of associated symptoms does not warrant therapy. Over 20% of women may have yeast as part of their natural vaginal microbiome and the majority will be asymptomatic.11 Treatment and dosage options for uncomplicated, recurrent, and nonalbicans VVC are summarized in Table 2.12–17 Pregnancy

In pregnancy, VVC can be prolonged and associated with more severe symptoms, and resolution of symptoms typically requires longer courses of therapy. Only topical azoles are recommended in pregnancy. Treatment using external imidazole creams and intravaginal ovules for up to 14 days may be required. Repeat treatments may also be needed. Oral fluconazole should be avoided in pregnancy as it may increase the risk of tetralogy of Fallot.18 The safety of oral fluconazole in the second and third trimesters has not been investigated. Intravaginal boric acid has been associated with a greater than 2-fold increased risk of birth defects when used during the first 4 months of pregnancy,19 and should thus be avoided during this time. Summary Statements

1. Vulvovaginal candidiasis affects 75% of women at least once. Topical and oral antifungal azole medications are equally effective. (I) 2. Recurrent vulvovaginal candidiasis is defined as 4 or more episodes per year. (II-2)

268 l MARCH JOGC MARS 2015

Recommendations

1. Following initial therapy, treatment success of recurrent vulvovaginal candidiasis is enhanced by maintenance of weekly oral fluconazole for up to 6 months. (II-2A) 2. Symptomatic vulvovaginal candidiasis treated with topical azoles may require longer courses of therapy to be resolved. (1-A) TRICHOMONAS VAGINALIS The Organism

T. vaginalis is an anaerobic parasitic protozoan flagellated organism that adheres to epithelial cells of the urogenital tract. For the most part, infection is limited to the genitourinary tract. With infection, the condition is referred to as Trichomoniasis. The Disease

The prevalence of T. vaginalis in the United States is reported as 3.1% among women of reproductive age (14–49).20 Globally, it is considered the most common non-viral STI, with an estimated 170 million cases reported annually.21 It is not a reportable disease in Canada, so precise data on Canadian prevalence is unavailable. The symptoms associated with infection can be variable: 64% to 90% of infected people may have no symptoms,22,23 and infection, especially in those who are asymptomatic, may persist for months or years. Men tend to have fewer symptoms than women and can therefore serve as asymptomatic vectors for infection.24 Men who are symptomatic may experience symptoms of urethritis: dysuria and a clear or mucopurulent discharge.25 In women, the organism can be found in the vagina, cervix, bladder, or Bartholin, Skene, or periurethral glands.26 Symptomatic women typically have a greatly increased volume of vaginal discharge; it may be malodorous, green or yellow in color, and frothy in appearance.27 In addition, significant pruritus with vulvitis and vaginitis, dysuria, and dyspareunia may occur. Some may exhibit hemorrhagic spots (petechiae) on the genital mucosa, referred to as Colpitis macularis (strawberry cervix).24 Diagnosis

Wet mount for microscopic visualization of the motile parasite has a sensitivity of up to 65%, and samples should be visualized within 10 minutes of collection to improve the likelihood of observing motility.28 Culture of T. vaginalis has high specificity (almost 100%) but a lower sensitivity (as low as 75%) for diagnosis. Rapid transport to the laboratory is ideal to insure the viability of

Vulvovaginitis: Screening for and Management of Trichomoniasis, Vulvovaginal Candidiasis, and Bacterial Vaginosis

Table 2. Treatment options for vulvovaginal candidiasis Uncomplicated VVC*

Therapy

Medication

Dose

Imidazole antifungals (over the counter)

Clotrimazole cream/ointment

1%: once daily × 7 days, or 2%: once daily × 3 days, or 10%: once only

Insert/ovule/suppository

200 mg: once daily × 3 days or 500 mg: once only

Miconazole cream/ointment

2%: once daily × 7 days, or 4%: once daily × 3 days

Insert/ovule/suppository

100 mg: once daily × 7 days, or 400 mg: once daily × 3 days, or 1200 mg: once only

Fluconazole (oral) (over the counter)

150 mg: once only

Terconazole cream (prescription only)

0.4%: once daily × 7 days

Imidazole cream

10 to 14 days, as for uncomplicated VVC above12

Fluconazole (oral)

150 mg: 3 doses, 72 hours apart11

Boric acid insert

300 to 600 mg daily × 14 days13

Clotrimazole insert

500 mg: once monthly × 6 months15

Fluconazole (oral)

150 mg: once weekly11

Boric acid insert

300 mg daily × 5 days at the beginning of each menstrual cycle13

Ketoconazole (oral)§

100 mg once daily14

Boric acid insert‖

300 to 600 mg nightly × 14

Flucytosine cream‖

5 g once daily × 14 days

Amphotericin B suppository‖

50 mg once daily × 14 days

Nystatin suppository

100 000 units once daily for 3 to 6 months1

Triazole antifungals Recurrent VVC† Induction

Maintenance‡

Non-albicans VVC

*These types of antifungal regimens are equally effective, with resolution of symptoms occurring in up to 90%.10 †Treatment for recurrent VVC requires induction therapy followed immediately by maintenance treatment. ‡Maintenance therapy should continue for 6 months. In cases of recurrence after completed therapy, induction and maintenance treatment should be repeated. Recurrence rates on maintenance treatment are low but can be as high as 50% in women off all therapy. §Monitoring is recommended for rare hepatotoxicity with long-term use and drug interactions. ‖Boric acid insert, flucytosine cream, and amphotericin B may be used in combination

the organism.29 Although the organism may be detected on Papanicolaou screening tests, this is not considered diagnostic because of the test’s low sensitivity for T. vaginalis.30 Antigen testing

Immunoassay dipstick testing is available as a rapid antigen test with results available in 10 minutes. Sensitivity (82–95%) and specificity (97–100%) are both high.29 NAATs are the most sensitive tests currently available for use with vaginal swabs. Urine and cervical swabs can also be used. Sensitivity and specificity for NAATs are both 95% to 100%.31 Because T. vaginalis is an STI, its diagnosis affords the opportunity to screen for other STIs. Treatment

Treatment for T. vaginalis consists of oral metronidazole either 2 g once or 500 mg twice daily for 7 days. Cure rates

with either of these regimens are as high as 88%, and are even higher when sexual partners are simultaneously treated.32 Approximately 5% of T. vaginalis strains will be resistant to metronidazole. High dose and/or longer metronidazole therapy tends to be effective in these situations.33 An alternate therapy for metronidazoletreatment–resistant cases is Tinidazole 2 g orally once.34,35 This is only available through Health Canada’s Special Access to Drugs and Health Products Program.36 Partner Treatment

The PHAC 2010 guidelines on STI do not recommend partner screening but do recommend treatment for all partners.7 Many men will be asymptomatic. Both patients and partners should be given the same type of treatment regimen. The 2010 Centres for Disease Control STI Guidelines suggest abstaining from intercourse until both MARCH JOGC MARS 2015 l 269

SOGC clinical practice guideline

patients are treated and asymptomatic.37 Test of cure is not recommended, but re-evaluation is suggested with symptom recurrence. There is an increased risk of HIV acquisition for both men and women with concomitant T. vaginalis infection, so it would be particularly important to screen and treat for this disease in HIV discordant couples.38 Pregnancy

T. vaginalis infection in pregnancy has been associated with preterm delivery. If the patient is symptomatic and testing reveals infection, treatment is warranted. Screening and treatment for asymptomatic infection in women with a history of preterm birth or preterm premature rupture of membranes is controversial. Some studies have shown benefit and others have shown higher rates of preterm birth in the treated group.39 The use of metronidazole in pregnancy is considered safe; numerous meta-analyses show no increased risk of teratogenic effects with metronidazole.40 The recommended dose of metronidazole in pregnancy is the same as for non-pregnant women. Side effects

Side effects of metronidazole may include nausea, vomiting, headache, insomnia, dizziness, drowsiness, rash, dry mouth, and metallic taste. A disulfiram reaction can occur if combined with alcohol. Avoidance of alcohol for at least one day after completing the treatment is recommended in the drug manufacturer’s product monograph. Summary Statements

3. Trichomonas vaginalis is a common non-viral sexually transmitted infection that is best detected by antigen testing using vaginal swabs collected and evaluated by immunoassay or nucleic acid amplification test. (II-2) 4. Cure rates are equal at up to 88% for trichomoniasis treated with oral metronidazole 2 g once or 500 mg twice daily for 7 days. Partner treatment, even without screening, enhances cure rates. (I-A) Recommendations

3. Test of cure following treatment of trichomoniasis with oral metronidazole is not recommended. (I-D) 4. Higher-dose therapy may be needed for treatmentresistant cases of trichomoniasis. (I-A) 5. In pregnancy, treatment of symptomatic Trichomonas vaginalis with oral metronidazole is warranted for the prevention of preterm birth. (I-A) BACTERIAL VAGINOSIS The Organism

Normal vaginal flora consists of both aerobic and anaerobic bacteria, with Lactobacillus species being the predominant 270 l MARCH JOGC MARS 2015

microorganisms and ing for greater than 95% of all bacteria present.41,42 Lactobacilli are believed to provide defense against infection in part by maintaining an acidic pH in the vagina and ensuring hydrogen peroxide is present in the environment. In contrast, bacterial vaginosis is a polymicrobial syndrome resulting in a decreased concentration of lactobacilli and an increase in pathogenic bacteria. There is no single organism whose presence confirms the diagnosis of bacterial vaginosis, but rather many different bacteria may be present, including Gardnerella vaginalis, Mobiluncus species, Bacteroides and Prevotella species, and Mycoplasma species.43,44 The Disease

Bacterial vaginosis is the most common lower genital tract disorder among women of reproductive age, the most common cause of vaginitis in both pregnant and non-pregnant women, and the most prevalent cause of vaginal discharge and odour.45,46 Prevalence rates are similar in pregnant and non-pregnant women. It has been linked to many different obstetric and gynaecologic complications such as preterm labour and delivery, preterm premature rupture of membranes, spontaneous abortion, chorioamnionitis, postpartum endometritis, post-Caesarean delivery wound infections, postsurgical infections, and subclinical pelvic inflammatory disease.47–55 Several risk factors have been identified that increase the risk of acquisition of bacterial vaginosis. It is more common in black women,56 women who smoke,57 and women who use vaginal douches or intravaginal products. 58,59 Although not currently considered an STI, bacterial vaginosis has been consistently associated with sexual activity. It is more common among women who are sexually active, and the risk seems to increase with both number of sexual partners and frequency of intercourse.60,61 Diagnosis

Bacterial vaginosis can be diagnosed clinically and/or microbiologically. The clinical diagnostic criteria published in 1983 by Amsel et al., still in use today, recommend diagnosis of bacterial vaginosis if 3 of the 4 following signs are present62: adherent and homogenous vaginal discharge; vaginal pH greater than 4.5; detection on saline wet mount of clue cells (vaginal epithelial cells with such a heavy coating of bacteria that the peripheral borders are obscured); and/or amine odour after the addition of potassium hydroxide (positive whiff test). Gram stain of vaginal fluid is the most widely used and evaluated microbiologic method for the diagnosis of bacterial vaginosis. Most laboratories use an objective diagnostic scheme that quantifies the number of Lactobacillus morphotypes and pathogenic bacteria, resulting in a score

Vulvovaginitis: Screening for and Management of Trichomoniasis, Vulvovaginal Candidiasis, and Bacterial Vaginosis

Table 3. Scoring system (0–10) for gram-stained vaginal smears Lactobacillus morphotypes

Gardnerella and Bacteroides spp. morphotypes

Curved gram-variable rods

0

4+

0

0

1

3+

1+

1+ or 2+

2

2+

2+

3+ or 4+

3

1+

3+

4

0

4+

Score

Table 4. Recommended treatment regimens for bacterial vaginosis Recommended Metronidazole 500 mg orally twice daily for 7 days Metronidazole gel 0.75%, one applicator (5 g) intravaginally once daily for 5 days Clindamycin cream 2%, one applicator (5 g) intravaginally once daily for 7 days Alternatives Metronidazole 2 g orally in a single dose Clindamycin 300 mg orally twice daily for 7 days

that is used to determine whether the infection is present. The most commonly used system was developed by Nugent and colleagues and is known as the Nugent score (Table 3).63 Bacterial vaginosis is diagnosed by a score of 7 or higher. A score of 4 to 6 is considered intermediate and a score of 0 to 3 is considered normal. Treatment

Although bacterial vaginosis has been associated with adverse gynaecologic outcomes, there is no compelling evidence that treatment decreases the likelihood of these complications. Therefore, treatment is usually reserved for women with bothersome symptoms. The treatments for bacterial vaginosis recommended in Canada in the PHAC’s guidelines on STI are presented in Table 4.7 The first line therapy is oral metronidazole 500 mg twice daily for 1 week. Reported cure rates following therapy have ranged from 75% to 85% and do not differ between oral and vaginal metrondiazole.64–66 Oral tinidazole has been studied as an alternative to metronidazole in trials in Europe and the United States. The evidence to date reveals similar cure rates with the possibility of a reduction in the number of doses required and in gastrointestinal side effects with tinidazole.67,68 This drug is not currently readily available in Canada. Recurrent Bacterial Vaginosis

Unfortunately, recurrence rates following treatment for bacterial vaginosis have been high in many studies, with up to one third of treated women recurring within

3 months,69 and with more women recurring the longer the length of follow-up.70,71 Before embarking on multiple courses of therapy, it is recommended to reconfirm the diagnosis. In women with documented recurrences, extending the course of therapy to continually suppress the growth of abnormal bacteria has been shown to be an effective strategy to decrease the likelihood of further recurrences. The first option is to use oral metronidazole 500 mg twice daily for 10 to 14 days. If this is not effective, the recommended therapy is metronidazole vaginal gel 0.75% one applicator (5 g) daily for 10 days, then 2 times per week for 3 to 6 months.7,72 This regimen results in a significant decrease in the likelihood of recurrences while on treatment and thereafter compared to placebo.72 There is also some evidence that condom use may decrease the likelihood of recurrence among sexually active women.49 Recently there has been increasing interest in exploring the use of probiotics and other agents for the treatment of incident and recurrent bacterial vaginosis. Unfortunately very little literature exists to guide clinicians in the use of these products. There is one published study from China in which women with recurrent bacterial vaginosis were randomized to either daily vaginal probiotic use or placebo. Women in the probiotic group had lower recurrence rates than those in the placebo group.73 Another study investigated the use of vaginal vitamin C tablets compared to placebo for the treatment of bacterial vaginosis. More women in the placebo group still had bacterial vaginosis at the end of the study period.74 Unfortunately, in both MARCH JOGC MARS 2015 l 271

SOGC clinical practice guideline

studies diagnosis was based on clinical (Amsel’s) criteria rather than Nugent score or Gram stain, and the total length of follow-up in the vitamin C study was only 20 days. Until there is more published data from welldesigned trials in this area, it is premature to make a judgement on the efficacy of these alternative therapies. Pregnancy

Vaginal discharge is common in pregnancy and may be physiologic. In women with persistent discharge, screening for lower genital tract infections (vaginal and cervical) is recommended. If bacterial vaginosis is diagnosed in a symptomatic pregnant woman, treatment is indicated. The PHAC guidelines on STI recommend using metronidazole 500 mg orally twice daily for 7 days or clindamycin 300 mg orally twice daily for 7 days.7 Topical agents are not recommended. Treatment has relatively moderate rates of success with high rates of recurrence in some women. For a detailed discussion of the implications of bacterial vaginosis in pregnancy and links to adverse pregnancy outcomes, including screening and treatment strategies in pregnant women, please see the SOGC Clinical Practice Guideline on the screening and management of bacterial vaginosis in pregnancy.75 Summary Statements

5. Current evidence of the efficacy of alternative therapies for bacterial vaginosis (probiotics, vitamin C) is limited. (I) Recommendations

6. Bacterial vaginosis should be diagnosed using either clinical (Amsel’s) or laboratory (Gram stain with objective scoring system) criteria. (II-2A) 7. Symptomatic bacterial vaginosis should be treated with oral metronidazole 500 mg twice daily for 7 days. Alternatives include vaginal metronidazole gel and oral or vaginal clindamycin cream. (I-A) 8. Longer courses of therapy for bacterial vaginosis are recommended for women with documented multiple recurrences. (I-A) REFERENCES 1. Sobel JD. Management of patients with recurrent vulvovaginal candidiasis. Drugs 2003;63:1059–66. 2. Ohmit S, Sobel J, Schuman P, Duerr A, Mayer K, Rompalo A, et al.; HIV Epidemiology Research Study (HERS) Group. Longitudinal study of mucosal Candida species colonization and candidiasis among human immunodeficiency virus (HIV)-seropositive and at-risk HIV-seronegative women. J Infect Dis 2003;188:118–27. 3. De Leon E, Jacober SJ, Sobel JD, Foxman B. Prevalence and risk factors for vaginal Candida colonization in women with type 1 and type 2 diabetes. BMC Infect Dis 2002;2:1.

272 l MARCH JOGC MARS 2015

4. Odds FC. Candidosis of the fenitalia. In: Odds FC. Candida and candidosis: a review and bibliography, 2nd ed. London: Bailliere Tindal; 1988, p.124. 5. Vermitsky JP, Self MJ, Chadwick SG, Trama JP, Adelson ME, Mordechai E, et al. Survey of vaginal-flora Candida species isolates from women of different age groups by use of species-specific PCR detection. J Clin Microbiol 2008;46:1501–3. 6. Sobel JD. Vulvovaginal candidosis. Lancet 2007;369:1961–71. 7. Public Health Agency of Canada. Canadian guidelines on sexually transmitted infections—updated January 2010. Ottawa: PHAC; 2010. Available at: http://www.phac-aspc.gc.ca/std-mts/sti-its/cgsti-ldcits/ index-eng.php. Accessed on November 6, 2013. 8. Nyirjesy P, Sobel JD. Genital mycotic infections in patients with diabetes. Postgrad Med 2013;125:33–46. 9. Watts DH, Springer G, Minkoff H, Hillier SL, Jacobsen L, Moxley M, et al. The occurrence of vaginal infections among HIV-infected and highrisk uninfected women: longitudinal findings of the Women’s Interagency HIV Study. J Aquir Immune Defic Syndr 2006;43:161–8. 10. Sobel JD, Kapernick PS, Zervos M, Reed BD, Hooton T, Soper D, et al. Treatment of complicated Candida vaginitis: comparison of single and sequential doses of fluconazole. Am J Obstet Gynecol 2001;185:363–9. 11. Pirotta MV, Garland SM. Genital Candida species detected in samples from women in Melbourne, Australia, before and after treatment with antibiotics. J Clin Microbiol 2006;44:3213–7. 12. Nurbai M, Grimshaw JM, Watson M, Bond CM, Mollison J, Ludbrook A. Oral versus intra-vaginal imidazole and triazole anti-fungal treatment of uncomplicated vulvovaginal candidiasis (thrush). Cochrane Database Syst Rev. 2007;(4):CD002845. 13. Sobel JD, Wiesenfeld HC, Martens M, Danna P, Hooton TM, Rompalo A, et al. Maintenance fluconazole therapy for recurrent vulvovaginal candidiasis. N Engl J Med 2004;351:876–83. 14. Pappas PG, Rex JH, Sobel JD, Filler SG, Dismukes WE, Walsh TJ, et al.; Infectious Diseases Society of America. Guidelines for treatment of candidiasis. Clin Infect Dis 2004;38:161–89. 15. Guaschino S, De Seta F, Sartore A, Ricci G, De Santo D, Piccoli M, et al. Efficacy of maintenance therapy with topical boric acid in comparison with oral itraconazole in the treatment of recurrent vulvovaginal candidiasis. Am J Obstet Gynecol 2001;184:598–602. 16. Sobel JD. Recurrent vulvovaginal candidiasis. A prospective study of the efficacy of maintenance ketoconazole therapy. N Engl J Med 1986;315:1455–8. 17. Roth AC, Milsom I, Forssman L, Wahlen P. Intermittent prophylactic treatment of recurrent vaginal candidiasis by postmenopausal application of a 500 mg clotrimazole vaginal tablet. Genitourin Med 1990;66:357–60. 18. Molgaard-Nielsen D, Pasternak B, Hviid A. Use of oral fluconazole during pregnancy and the risk of birth defects. N Eng J Med 2013;369:830–9. 19. Acs N, Banhidy F, Puho E, Czeizel AE. Teratogenic effects of vaginal boric acid treatment during pregnancy. Int J Gynaecol Obstet 2006;93:55–6. 20. Sutton M, Sternberg M, Koumans EH, McQuillan G, Berman S, Markowitz LE. The prevalence of Trichomonas vaginalis infection among reproductive age women in the United States, 2001-2004. Clin Infect Dis 2007;45:1319–26. 21. Gerbase AC, Rowley JT, Heymann DH, Berkeley SBF, Piot P. Global prevalence and incidence estimates of selected curable STDs. Sex Transm Dis 1998;74(Suppl 1):S12–S16. 22. Peterson P. Trichomonas vaginalis vaginitis. A comparative study of treatment and incidence. Am J Obstet Gyn 1938;35:1004–9.

Vulvovaginitis: Screening for and Management of Trichomoniasis, Vulvovaginal Candidiasis, and Bacterial Vaginosis

23. Paterson BA, Tabrizi SN, Garland SM, Fairley CK, Bowden FJ. The tampon test for trichomoniasis: a comparison between conventional methods and a polymerase chain reaction for Trichomonas vaginalis in women. Sex Transm Infect 1998;74:136–9. 24. Cudmore SL, Delgaty KL, Hayward-McClelland SF, Petrin DP, Garber GE. Treatment of infections caused by metronidazole-resistant Trichomonas vaginalis. Clin Microbiol Rev 2004;17;783–93. 25. Kuberski T. Trichomonas vaginalis associated with nongonococcal urethritis and prostatitis. Sex Transm Dis 1980;7:134–6. 26. Gupta PK, Frost JK. Cytopathology and histopathology of the female genital tract in Trichomonas vaginalis infection. In Honigberg BM (ed). Trichomonas parasitic in humans. New York: Springer-Verlag; 1990, pp. 274–90. 27. Heine P, MacGregor JA. Trichomonas vaginalis: a re-emerging pathogen. Clin Obstet Gynecol 1993;36:137–14. 28. Nye MB, Schwebke JR, Body BA. Comparison of APTIMA Trichomonas vaginalis transcription-mediated amplification to wet mount microscopy, culture, and polymerase chain reaction for diagnosis of trichomoniasis in men and women. Am J Obstet Gynecol 2009;200:188 e1–e7. 29. Huppert JS, Mortensen JE, Reed JL, Kahn JA, Rich KD, Miller WC, et al. Rapid antigen testing compares favorably with transcription mediated amplification assay for the detection of Trichomonas vaginalis in young women. Clin Infect Dis 2007;45:194–8. 30. Lobo TT, Feiho G, Carvalho SE, Costa PL, Chagas C, Xavier J, et al. A comparative evaluation of the Papanicolaou test for the diagnosis of trichomoniasis. Sex Transm Dis 2003;30:694–9. 31. Andrea SB, Chapin KC. Comparison of Aptima Trichomonas vaginalis transcription-mediated amplification assay and BD affirm VPIII for detection of T. vaginalis in symptomatic women: performance paramenters and epidemiological implications. J Clin Microbiol 2011;49:866–9.

42. Eschenbach DA. Bacterial vaginosis: emphasis on upper genital tract complications. Obstet Gynecol Clin North Am 1989;16:593–610. 43. Hill GB, Eschenbach DA, Holmes KK. Bacteriology of the vagina. Scand J Urol Nephrol Suppl 1985;86:23–39. 44. Hillier SL. Diagnostic microbiology of bacterial vaginosis. Am J Obstet Gynecol 1993;169:455–9. 45. Rein MF, Holmes KK. Non-specific vaginitis, vulvovaginal candidiasis, and trichomoniasis: clinical features, diagnosis and management. Curr Clin Top Infect Dis 1983;4:281–315. 46. Fleury FJ. Adult vaginitis. Clin Obstet Gynecol 1987;24:407–38. 47. Hillier SL, Nugent RP, Eschenbach DA, Krohn MA, Gibbs RS, Martin DH, et al.; Vaginal Infections and Prematurity Study Group. Association between bacterial vaginosis and preterm delivery of a low-birth-weight infant. N Engl J Med 1995;333:1737–42. 48. Gravett MG, Hammel D, Eschenbach DA, Holmes KK. Preterm labor associated with subclinical amniotic fluid infection and with bacterial vaginosis. Obstet Gynecol 1986;67:229–37. 49. Minkoff H, Brunebaum AN, Schwartz RH, Feldman J, Cummings M, Crombleholme W, et al. Risk factors for prematurity and premature rupture of membranes: a prospective study of the vaginal flora in pregnancy. Am J Obstet Gynecol 1984;150:965–72. 50. Leitich H, Bodner-Adler B, Brunbauer M, Kaider A, Egarter C, Husslein P. Bacterial vaginosis as a risk factor for preterm delivery: a meta-analysis. Am J Obstet Gynecol 2003;189:139–47. 51. Hillier SL, Martius J, Krohn MA, Kiviat N, Holmes KK, Eschenbach DA. A case-control study of chorioamnionic infection and histologic chorioamnionitis in prematurity. N Engl J Med 1988;319:972–8. 52. Watts DH, Krohn MA, Hillier SL, Eschenbach DA. Bacterial vaginosis as a risk factor for post-cesarean endometritis. Obstet Gynecol 1990;75:52–8.

32. Thin RN, Symonds MAE, Booker R, Cook S, Langlet F. Double-blind comparison of a single dose and a five-day course of metronidazole in the treatment of trichomoniasis. Br J Ven Dis,1979;55:354–6.

53. Soper DE, Bump RC, Hunt WG. Bacterial vaginosis and trichomonas vaginitis are risk factors for cuff cellulites after abdominal hysterectomy. Am J Obstet Gynecol 1990;163:1016–23.

33. Schmid G, Narcisi E, Mosure D, Secor WE, Higgins J, Moreno H. Prevalence of metronidazole-resistant Trichomonas vaginalis in a gynecology clinic. J Reprod Med 2001;46:545–9.

54. Korn AP, Bolan G, Padian N, Ohm-Smith M, Schacter J, Landers DV. Plasma cell endometritis in women with symptomatic bacterial vaginosis. Obstet Gynecol 1995;85:387–90.

34. Forna F, Gulmezoglu AM. Interventions for treating trichomoniasis in women. Cochrane Database Syst Rev 2003;(2):CD000218.

55. Wiesenfeld HC, Hillier SL, Krohn MA, Amortegui AA, Heine RP, Landers DV, et al. Lower genital tract infection and endometritis: insight into subclinical pelvic inflammatory disease. Obstet Gynecol 2002;100:456–63.

35. Sorvillo F, Kerndt P. Trichomonas vaginalis and amplification of HIV-1 transmission. Lancet 1998;351:213–4. 36. Health Canada. Guidance Document for Industry and Practitioners Special Access Programme for Drugs. Ottawa: Health Canada; 2013. Updated on December 20, 2013. Available at: http://www.hc-sc.gc.ca/ dhp-mps/access/drugs-drogues/index-eng.php. Accessed on May 17, 2014.

56. Goldenberg R, Klebanoff M, Nugent R, Krohn M, Hillier S, Andrews W; Vaginal Infections and Prematurity Study Group. Bacterial colonization of the vagina during pregnancy in four ethnic groups. Am J Obstet Gynecol 1996;174:1618–21.

37. Centers for Disease Control. Trichomoniasis. Atlanta (GA): CDC; 2013. Available at: http://www.cdc.gov/std/trichomonas/default.htm. Accessed on January 10, 2015.

57. Jonsson M, Karlsson R, Rylander E, Gustavsson A, Wadell G. The associations between risk behaviour and reported history of sexually transmitted diseases, among young women: a population based study. Int J STD AIDS 1997;8:501–5.

38. Ling J, Christensen J. A double-blind study of the value of treatment with a single dose tinidazole of partners to females with trichomoniasis. Acta Obstet Gynecol Scand 1981;60:199–201.

58. Hawes SE, Hillier SL, Benedetti J, Stevens CE, Koutsky LA, Wolner-Hanssen P, et al. Hydrogen peroxide-producing lactobacilli and acquisition of vaginal infections. J Infect Dis 1996;174:1058–63.

39. Klebanoff MA, Carey JC, Hauth JC, Hillier SL, Nugent RP, Thom EA, et al.; National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. Failure of metronidazole to prevent preterm delivery among pregnant women with asymptomatic Trichomonas vaginalis infection. N Engl J Med 2001;345:487–93.

59. Brown JM, Hess KL, Brown S, Murphy C, Waldman AL, Hezareh M. Intravaginal practices and risk of bacterial vaginosis and candidiasis infection among a cohort of women in the United States. Obstet Gynecol 2013;121:773–80.

40. Burtin P, Taddio A, Ariburnu O, Einarson TR, Koren G. Safety of metronidazole in pregnancy: a meta-analysis. Am J Obstet Gynecol 1995;172(2 Pt 1):525–9. 41. Spiegel CA, Amsel R, Eschenbach D, Schoenknecht F, Holmes KK. Anaerobic bacteria in nonspecific vaginitis. N Engl J Med 1980;303:601–7.

60. Verstraelen H, Verhelst R, Vaneechoutte M, Temmerman M. The epidemiology of bacterial vaginosis in relation to sexual behaviour. BMC Infect Dis 2010;10:81. 61. Fethers KA, Fairley CK, Hocking JS, Gurrin LC, Bradshaw CS. Sexual risk factors and bacterial vaginosis: a systematic review and meta-analysis. Clin Infect Dis 2008;47:1426–35.

MARCH JOGC MARS 2015 l 273

SOGC clinical practice guideline

62. Amsel R, Totten PA, Spiegel CA, Chen KCS, Eschenbach D, Holmes KK. Nonspecific vaginitis: diagnostic criteria and microbial and epidemiologic associations. Am J Med 1983;74:14–22. 63. Nugent RP, Krohn MA, Hillier SL. Reliability of diagnosing bacterial vaginosis is improved by a standardized method of Gram stain interpretation. J Clin Microbiol 1991;29:297–301. 64. Lugo-Miro VI, Green M, Mazur L. Comparison of different metronidazole therapeutic regimens for bacterial vaginosis. A meta-analysis. JAMA 1992;268:92–5. 65. Hanson JM, McGregor JA, Hillier SL, Eschenbach DA, Kreutner AK, Galask AP, et al. Metronidazole for bacterial vaginosis. A comparison of vaginal gel vs. oral therapy. J Reprod Med 2000;45:889–96. 66. Hillier S, Lipinski C, Briselden AM, Eschenbach DA. Efficacy of intravaginal 0.75% metronidazole gel for treatment of bacterial vaginosis. Obstet Gynecol 1993;81:963–7. 67. Livengood CH, Ferris DG, Wiesenfeld HC, Hillier SL, Soper DE, Nyirjesy P, et al. Effectiveness of two tinidazole regimens in treatment of bacterial vaginosis. A randomized controlled trial. Obstet Gynecol 2007;110:302–9. 68. Schwebke JR, Desmond RA. Tinidazole vs metronidazole for the treatment of bacterial vaginosis. Am J Obstet Gynecol 2011;204:211.e1–e6. 69. Hay P. Recurrent bacterial vaginosis. Curr Infect Dis Rep 2000;2:506–12. 70. Koumans EH, Markowitz LE, Hogan V; CDC BV Working Group. Indications for therapy and treatment recommendations for bacterial

274 l MARCH JOGC MARS 2015

vaginosis in nonpregnant and pregnant women: a synthesis of data. Clin Infect Dis 2002;35(Suppl 2):S152–S72. 71. Bradshaw CS, Morton AN, Hocking J, Garland SM, Morris MB, Moss LM, et al. High recurrence rates of bacterial vaginosis over the course of 12 months after oral metronidazole therapy and factors associated with recurrence. J Infect Dis 2006;193:1478–86. 72. Sobel JD, Ferris D, Schwebke J, Nyirjesy P, Wiesenfeld HC, Peipert J, et al. Suppressive antibacterial therapy with 0.75% metronidazole vaginal gel to prevent recurrent bacterial vaginosis. Am J Obstet Gynecol 2006;194:1283–9. 73. Ya W, Reifer C, Miller LE. Efficacy of vaginal probiotic capsules for recurrent bacterial vaginosis: a double-blind, randomized, placebocontrolled study. Am J Obstet Gynecol 2010:203:120.e1–e6. 74. Petersen EE, Magnani P. Efficacy and safety of vitamin C vaginal tablets in the treatment of non-specific vaginitis. A randomised, double blind, placebo-controlled trial. Eur J Ob Gyn Reprod Biol 2004;117:70–5. 75. Yudin MH, Money DM; Society of Obstetricians and Gynaecologists of Canada Infectious Diseases Committee. Screening and management of bacterial vaginosis in pregnancy. SOGC Clinical Practice Guideline, No. 211, August 2008. J Obstet Gynaecol Can 2008;30:702–8. 76. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

SOGC CLINICAL PRACTICE GUIDELINE No. 310, August 2014

Guidelines for the Care of Pregnant Women Living With HIV and Interventions to Reduce Perinatal Transmission This clinical practice guideline has been prepared by the Infectious Diseases Committee, reviewed by Family Physician Advisory Committee and the Aboriginal Health Initiative Committee, and approved by Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Deborah Money, MD, Vancouver BC Karen Tulloch, BSharm, Vancouver BC Isabelle Boucoiran, MD, Montreal QC Sheila Caddy, MD, Edmonton AB INFECTIOUS DISEASES COMMITTEE Mark H. Yudin, MD (Chair), Toronto ON Victoria Allen, MD, Halifax NS Celine Bouchard, MD, Quebec QC Marc Boucher, MD, Montreal QC Isabelle Boucoiran, MD, Montreal QC Sheila Caddy, MD, Calgary AB Eliana Castillo, MD, Calgary AB Heather Gottlieb, MD, Calgary AB V. Logan Kennedy, RN, Toronto ON Deborah Money, MD, Vancouver BC

Abstract Objective: This guideline reviews the evidence relating to the care of pregnant women living with HIV and the prevention of perinatal HIV transmission. Prenatal care of pregnancies complicated by HIV infection should include monitoring by a multidisciplinary team with experts in this area. Outcomes: Outcomes evaluated include the impact of HIV on pregnancy outcome and the efficacy and safety of antiretroviral therapy and other measures to decrease the risk of vertical transmission. Evidence: Published literature was retrieved through searches of PubMed and The Cochrane Library in 2012 and 2013 using appropriate controlled vocabulary (HIV, anti-retroviral agents, pregnancy, delivery) and key words (HIV, pregnancy, antiretroviral agents, vertical transmission, perinatal transmission). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies published in English or French. There were no date restrictions. Searches were updated on a regular basis and incorporated in the guideline to June 2013. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Values: The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1).

Kellie Murphy, MD, Toronto ON Gina Ogilvie, MD, Vancouver BC Caroline Paquet, RM, Trois-Rivieres QC Julie van Schalkwyk, MD, Vancouver BC SPECIAL CONTRIBUTORS Ariane Alimenti, MD, Vancouver BC

Key Words: HIV, pregnancy, antiretroviral agents, vertical transmission, perinatal transmission

Neora Pick, MD, Vancouver BC Disclosure statements have been received from all contributors.

J Obstet Gynaecol Can 2014;36(8 eSuppl A):S1–S46

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

AUGUST JOGC AOÛT 2014 l S1

SOGC CLINICAL PRACTICE GUIDELINE

Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.154 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care.154

Recommendations 01. All women living with HIV who are planning a pregnancy or who become pregnant should have their individual situations discussed with experts in the area, with referral to both HIV treatment programs and obstetrical care providers, and an overall plan should be made for their pregnancy care. (II-2A) 02. All pregnant women should be offered HIV testing, with appropriate pre- and post-test counselling, as part of their routine prenatal care in each pregnancy. This testing should be repeated in each trimester in women who are recognized to be at high and ongoing risk for HIV infection. (II-2A) 03. Pregnant women living with HIV should be made aware that with the consistent use of combination antiretroviral therapy and abstinence from breastfeeding, the risk of perinatal transmission is < 1%. (I-A) 04. All pregnant women living with HIV should be treated with combination antiretroviral therapy regardless of baseline CD4 and viral load. (II-2A) 05. Antiretroviral therapy should not be discontinued during the first trimester for obstetrical reasons, but if the woman is not on therapy and there is no urgent medical indication for combination antiretroviral therapy, it can be delayed until after 14 weeks’ gestation. (III-B) 06. All women living with HIV (both those who still have a detectable viral load after exposure to antiretroviral therapy and those who are antiretroviral-naive) should have their virus genotyped and, if possible, tested for phenotypic resistance to assist in optimizing antiretroviral therapy. It is advisable to discuss the interpretation of the genotype testing and any changes to the antiretroviral therapy with experienced clinicians. Testing for HLA-B*5701, if not done previously, is recommended in case abacavir might be required. (II-2B) 07. A combination antiretroviral therapy regimen including a dual nucleoside reverse transcriptase inhibitor (NRTI) backbone that includes one or more NRTIs and a boosted protease inhibitor should be favoured because there is higher confidence

S2 l AUGUST JOGC AOÛT 2014

in its safety and efficacy in pregnancy. Whenever possible, antiretrovirals known to cross the placenta to the fetal compartment should be used. (II-2B) 08. Whenever possible, drugs with no safety data should be avoided during the period of organogenesis. Efavirenz should not be prescribed in the first trimester of pregnancy because of its possible teratogenicity; however, if exposure has occurred and the neural tube has closed, efavirenz can be continued. Nevirapine should not be started in pregnancy, unless indicated by the woman’s resistance patterns, because it is associated with a high rate of serious adverse outcomes in this situation; however ongoing, pre-pregnancy treatment with nevirapine can be continued through pregnancy if tolerance and efficacy are established. (II-3D) 09. If antiretroviral therapy is discontinued for any reason during pregnancy, all drugs should be discontinued at once (unless the woman is on non-nucleoside reverse transcriptase inhibitors; in that case a tail of 2 nucleoside reverse transcriptase inhibitors is recommended for 1 week), and all drugs should be resumed simultaneously to minimize the risk of viral resistance developing during therapy. Antiretroviral therapy should be resumed as quickly as possible after discontinuance to minimize the risk of rebound viremia and the potentially increased risk of vertical transmission. (II-1A) 10. If a pregnant woman has significant nausea of pregnancy, do not begin antiretroviral therapy until her nausea is adequately controlled. Most antinauseants used in pregnancy can be coistered with antiretrovirals. If the woman is already on antiretrovirals and has hyperemesis of pregnancy, discontinue all antiretrovirals at once, and then reinstate all at once, when nausea and vomiting are controlled (unless the woman is on non-nucleoside reverse transcriptase inhibitors [NNRTIs], in which case a tail of 2 nucleoside reverse transcriptase inhibitors is recommended for 1 week to prevent future NNRTI resistance). (II-2D) 11. Therapy should be individualized to maximize adherence to the prescribed antiretroviral regimen. (III-A)

Guidelines for the Care of Pregnant Women Living With HIV and Interventions to Reduce Perinatal Transmission

12. Routine dose adjustment of the combination antiretroviral therapy is not recommended in pregnancy. (III-D) 13. The woman’s clinical, virological, and immunological statuses should be assessed every 4 to 8 weeks during pregnancy, and again 6 weeks postpartum. Routine criteria should be used to assess the woman’s response to, and the possible failure of, antiretroviral therapy. The toxicity of the antiretrovirals should also be monitored at these times. Specific testing should be individualized for the known toxicities of the woman’s antiretroviral therapy regimen. (III-B) 14. As for all pregnant women, all those living with HIV, regardless of age, should be offered, through an informed consent process, dating ultrasound and non-invasive prenatal genetic screening for the most common clinically significant fetal aneuploidies. (III-A) 15. A detailed obstetrical ultrasound at 19 to 20 weeks’ gestation is recommended. Additional ultrasounds, for fetal growth and amniotic fluid volume, are recommended at least each trimester, or as guided by obstetrical indications. (II-3B)

ABBREVIATIONS ALT

alanine aminotransferase

AST

aspartate aminotransferase

cART

combination antiretroviral therapy

CBC

complete blood count

CD4-cell CD4+ T-lymphocyte cell CDC

Centre for Disease Control

CMV

cytomegalovirus

HSP Canadian Perinatal HIV Surveillance Program DDI

didanosine

DMPA

medroxyprogesterone acetate

EIA

enzyme immunoassay

FDA

(United States) Food and Drug istration

FPV

fosamprenavir

HBV

hepatitis B virus

HCV

hepatitis C virus

HIV

human immunodeficiency virus

IDV

indinavir

IV

intravenous

LDH

lactate dehydrogenase

MAC

mycobacterium avium complex

NIH

(United States) National Institutes of Health

16. As for all pregnant women, those living with HIV should be screened periodically for substance use, and drug addiction should be addressed as needed in conjunction with HIV management. (III-A) 17. Mode of delivery should be discussed in detail with all women: a. Women on optimal antiretroviral therapy with acceptable plasma viral load suppression (less than 1000 c/mL) over the last 4 weeks prior to delivery are recommended to have a vaginal delivery in the absence of other obstetrical indications for Caesarean section. If Caesarean section is recommended for obstetrical indications, it can be conducted at 39 weeks, as usual for those indications. (I-A) b. Women not on optimal antiretroviral therapy (i.e., no antiretroviral therapy, monotherapy only, or with an incompletely suppressed viral load) should be offered a scheduled pre-labour Caesarean section at approximately 38 weeks’ gestation. (II-2A) 18. Intravenous zidovudine should be initiated as soon as labour onset until delivery, in combination with an oral combination antiretroviral regimen, regardless of mode of delivery, current antiretroviral regimen, or viral load. (III-B) 19. Intrapartum, a single dose of oral nevirapine (200 mg) remains an option in the unusual circumstance of a woman living with HIV who has not received antenatal antiretroviral therapy in pregnancy. (II-2B) 20. Plans for ongoing HIV care should be established prenatally, and unless otherwise indicated, maternal antiretroviral therapy should be continued after delivery and reassessed for ongoing therapy by providers of adult HIV care. (II-1A) 21. HIV-exposed newborns should receive antiretroviral therapy for 6 weeks to prevent vertical transmission of HIV. (I-A) 22. Health care practitioners who care for HIV-exposed newborns should provide timely diagnostic HIV testing: HIV polymerase chain reaction at birth, 1 month, and 3 to 4 months and HIV serology at 18 months (II-A), and they should monitor both short- and long-term outcomes, including screening for adverse effects of antiretroviral therapy and for developmental delay. (III-A) 23. Breast-feeding is not recommended regardless of plasma HIV viral load and use of antiretroviral therapy. (I-E) 24. The pregnancy should be ed with surveillance programs to allow the collection of provincial and national data to guide future pregnancy policies. Women undergoing antiretroviral therapy in pregnancy should also be offered inclusion in appropriate studies. (III-B)

NNRTI non-nucleoside/nucleotide analogue reverse transcriptase inhibitor NRTI

nucleoside/nucleotide analogue reverse transcriptase inhibitor

NVF

nelfinavir

P

pneumocystis jiroveci pneumonia

PCR

polymerase chain reaction

PI

protease inhibitor

PO

per os

RNA

ribonucleic acid

RR

relative risk

ZDV zidovudine

This document’s Executive Summary was previously published in: J Obstet Gynaecol Can 2014;36(8):721–734

AUGUST JOGC AOÛT 2014 l S3

SOGC CLINICAL PRACTICE GUIDELINE

INTRODUCTION

S

upportive non-directive counselling regarding reproductive choices, high-risk prenatal care, modified management of labour and delivery, and postpartum and infant care are all important components in the comprehensive care of the woman living with HIV and her infant. The provision of pregnancy and reproductive health care to women living with HIV should involve collaboration with individuals experienced in the management of high-risk pregnancy and HIV care of women and infants. In Canada, several clinics provide multidisciplinary care and guidance for this population of adults and children living with or exposed to HIV, in coordination with provincial authorities. Longitudinal surveillance on pregnancy outcomes in women living with HIV is tracked by the HSP through information provided by clinicians who care for pregnant women living with HIV and their infants. This is vital for the continuous quality improvement of antiretroviral prescribing in pregnancy. BACKGROUND Scope

This guideline primarily addresses the management of HIV during pregnancy and does not comprehensively address pre-pregnancy planning issues. Canadian HIV pregnancy planning guidelines are available.1 Similarly, HIV care of non-pregnant women is addressed in guidelines available elsewhere2 and is not discussed in this document. Management of HIV in pregnant women with comorbidities is addressed in brief; readers are referred to available guidelines for detailed discussion of this3 and other aspects of caring for people living with HIV (Table 2). Epidemiology of Perinatal HIV

In 2011, the t United Nations Programme on HIV/AIDS and the World Health Organization (WHO) estimated that a total of 34 million people worldwide were living with HIV, approximately half of whom were women.4 The number of people living with HIV in Canada continues to rise, from an estimated 64 000 in 2008 to 71 300 in 2011.5 The estimated prevalence rate in Canada in 2011 was 208.0 per 100 000 population (range: 171.0 to 245.1 per 100 000 population), 23% to 28% of whom were women.5 According to 2009 statistics, women for approximately 26% of the new HIV diagnoses in Canada.6 Cumulative surveillance data report that two thirds of positive test results for HIV occurred in women of reproductive age, with 37.6% in women aged 30 to 39 years and 32.5% in women aged 20 to 29 years.6 S4 l AUGUST JOGC AOÛT 2014

Combination antiretroviral therapy has been demonstrated to prolong the lives of people living with HIV,7 and has also significantly reduced the rate of vertical transmission of HIV from a baseline risk of 25% without intervention to < 2% in the context of comprehensive pregnancy care and cART istered antenatally, intrapartum, and to the infant in the early neonatal period.8,9 As a result of these factors more women living with HIV are considering their reproductive options and choosing to become pregnant.1 However, the vertical transmission of HIV remains a great concern globally, as an estimated 26% of women living with HIV remain unaware of their HIV status,6 and the majority of childhood HIV infections are acquired in this manner.3 The HSP identified a total of 2692 women known by care providers to be living with HIV who delivered infants between 1990 and 2010.10 Based on rates of spontaneous and therapeutic abortions in Canada, it is estimated that an equal number of women have been pregnant but have not delivered a living infant.10 The incidence of pregnancies in women living with HIV in Canada has been gradually increasing at different rates from province to province.10 With the implementation of cART for pregnant women in the late 1990s, the HSP documented a substantial reduction in HIV transmission rates from 20.2% (1990–1996) to 2.9% (1997–2010). Overall, the HIV perinatal transmission rate in women who have accessed care is 0.4% in Canada.10 However, despite the availability of routine HIV testing in pregnancy and effective interventions to reduce vertical transmission, there were a total of 93 infants perinatally infected with HIV in Canada between 2000 and 2010.11 PRE-CONCEPTION PLANNING

Detailed information and recommendations regarding preconception planning for people with HIV is beyond the scope of this document. These issues are addressed in detail in the Canadian HIV Pregnancy Planning Guidelines1 and in the National Institutes of Health Perinatal Guidelines.3 In brief, the following important clinical issues need to be considered with respect to pregnancy planning and counselling in individuals living with HIV: 1. use of effective methods of birth control if not desiring pregnancy; 2. pre-conceptional health including the intake of folic acid; 3. transmission between partners during conception; and 4. antiretroviral and other drugs in pregnancy planning.

https://www.iasusa.org/guidelines

http://www.cfenet.ubc.ca/therapeutic-guidelines/adult http://www.cfenet.ubc.ca/therapeutic-guidelines/opportunistic-infection http://cfenet.ubc.ca/therapeutic-guidelines/primary-care http://www.aidsinfo.nih.gov/guidelines

Antiretroviral treatment of adult HIV infection: 2012 recommendations

Adult HIV infection therapeutic guidelines

Opportunistic infections therapeutic guidelines

Primary care guidelines

Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents.

http://www.sogc.org/guidelines/documents/gui256G1104E.pdf http://sogc.org/wp-content/s/2013/01/185E-G-December2006.pdf http://sogc.org/wp-content/s/2013/01/120E-G-October2002.pdf

Substance use in pregnancy clinical practice guidelines

HIV screening in pregnancy clinical practice guidelines

Management of nausea and vomiting of pregnancy clinical practice guidelines

http://sogc.org/wp-content/s/2013/01/143E-G3-April2004.pdf

http://sogc.org/wp-content/s/2013/01/143E-G2-March2004.pdf

http://sogc.org/wp-content/s/2013/01/143E-G1-February2004.pdf

http://www.sogc.org/guidelines/documents/gui245G1008E.pdf

Alcohol use and pregnancy consensus clinical guidelines

Canadian contraception consensus

http://www.sogc.org/guidelines/documents/gui278G1206E.pdf

Canadian HIV pregnancy planning guidelines

Recommendations for the use of antiretroviral drugs in pregnant HIV-1 infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States

Guidelines for prevention and treatment of opportunistic infections in adults and adolescents

Website

Topic

Table 2. Guidelines related to the care of people living with HIV Issuing agency

Society of Obstetricians and Gynaecologists of Canada

Centers for Disease Control and Prevention, National Institutes of Health, HIV Medicine Association of the Infectious Diseases Society of America

BC Centre for Excellence in HIV/AIDS

International AIDS Society, US

Guidelines for the Care of Pregnant Women Living With HIV and Interventions to Reduce Perinatal Transmission

AUGUST JOGC AOÛT 2014 l S5

SOGC CLINICAL PRACTICE GUIDELINE

Recommendation

Recommendation

1. All women living with HIV who are planning a pregnancy or who become pregnant should have their individual situations discussed with experts in the area, with referral to both HIV treatment programs and obstetrical care providers, and an overall plan should be made for their pregnancy care. (II-2A)

2. All pregnant women should be offered HIV testing, with appropriate pre- and post-test counselling, as part of their routine prenatal care in each pregnancy. This testing should be repeated in each trimester in women who are recognized to be at high and ongoing risk for HIV infection. (II-2A)

NEW DIAGNOSIS OF HIV IN A PREGNANT WOMAN

All pregnant women should be offered HIV testing, with appropriate pre- and post-test counselling as part of their routine prenatal care in each pregnancy.12 Some provinces have managed this through opt-in testing and others through opt-out testing. Women involved in ongoing high-risk HIV transmission activities (see Appendix 1) who are HIV negative on initial testing should be retested each trimester, and if possible again near term. Testing women for the first time during labour and delivery is not optimal, and HIV issues should be addressed whenever possible early in the pregnancy in order to optimize the health outcomes of both the woman and her infant. Rapid HIV antibody testing (also known as point-of-care HIV testing) in the labour and delivery setting is now available in some facilities and should be used as an important last opportunity to identify women living with HIV before delivery and to provide emergency pro­phylaxis to decrease the risk of perinatal transmission.12–14 (see Appendix 1) A clinician who is familiar with HIV management in pregnancy should evaluate every pregnant woman who is newly diagnosed with HIV. Women should be informed about their HIV diagnosis in person, and and counselling should be provided for the woman and her family. Women should be made aware of the improved natural history of HIV, specifically that with adherence to care and therapy, individuals living with HIV now experience an improved quality of life and prolonged life expectancy.15 Women should also be made aware that with the use of cART and abstinence from breastfeeding the risk of vertical transmission is < 1%.10 Immediate assessment of risk transmission to others is important, and the woman should be counselled regarding the need for safe sexual practices. All previous children that may have been exposed in the past and all sexual or drug use partners should be offered testing. Public health consultation should be sought to adhere to provincial regulations on reportable diseases. Disclosure to family and friends not at risk of HIV is not required and should be considered carefully in light of the unfortunate persistence of stigmatization. Non-judgemental counselling regarding continuation of the pregnancy based on a complete understanding of the woman’s medical and social circumstances is important. S6 l AUGUST JOGC AOÛT 2014

NEW DIAGNOSIS OF PREGNANCY IN A WOMAN LIVING WITH HIV

A clinician familiar with HIV management should evaluate each woman living with HIV who becomes pregnant. Medical care recommendations for the pregnant woman living with HIV will depend on the woman’s wish to continue or discontinue the pregnancy, her HIV disease status, and her cART medication history. Pregnancy dating should be done through taking a careful history and conducting a dating ultrasound. Women should be made aware that with the use of cART and abstinence from breastfeeding the risk of vertical transmission is < 1% in Canada.10 In the event that the woman does not wish to continue the pregnancy, access to termination of pregnancy services should be facilitated. Health care providers should use this opportunity to continue to engage in and optimize HIV care and to provide reproductive health counselling, including contraception, to reduce the future occurrence of an unintended pregnancy. The HIV status of the exposed sexual or drug use partner should also be queried, and if the partner is not known to be living with HIV, testing is recommended. If the woman desires to continue the pregnancy, immediate review of HIV status including recent CD4-cell count, HIV viral load, and antiretroviral medication use is warranted. Specific recommendations regarding antiretroviral drug therapy management and trimester-specific information are discussed in more depth below. Overall, it is important to consider that all pregnant women living with HIV present high-risk pregnancies. Their medical therapy requires coordination and communication between HIV specialists and obstetrical providers. If, for geographic reasons, a woman is unable to attend for specialist consultations, these can be provided virtually through effective communications between care providers in remote settings and urban sub-specialists. Recommendation

3. Pregnant women living with HIV should be made aware that with the consistent use of combination antiretroviral therapy and abstinence from breastfeeding, the risk of perinatal transmission is < 1%. (I-A)

Guidelines for the Care of Pregnant Women Living With HIV and Interventions to Reduce Perinatal Transmission

ANTIRETROVIRAL DRUG THERAPY DURING PREGNANCY Background

Antiretroviral drug therapy is indicated for all pregnant women living with HIV, regardless of their HIV viral load or CD4-cell count, for the woman’s own health, for the prevention of HIV transmission to a partner, and for the prevention of HIV vertical transmission.3,10,11,16 In general, the recommendations for the use of antiretroviral therapy for the benefit of maternal health during pregnancy are similar for all women regardless of pregnancy status.2 However there are a number of important considerations based on limited experience and/or specific concerns with some antiretroviral drugs in pregnancy.3 While optimizing maternal care and health is of prime importance, it is important whenever possible to limit exposure of the developing fetus to potentially toxic medications. There are still minimal data available on the pharmacokinetics and safety of many antiretroviral drugs, particularly the newer agents, in pregnancy (see Table 3 and Appendix 2); therefore all treatment decisions during pregnancy require full discussion between the patient and her physician with regard to known and unknown benefits and risks. Antiretroviral agents istered in pregnancy have demonstrated a reduction in the risk of vertical transmission of HIV.3 Both published literature and analysis of Canadian data inform treatment in pregnancy. Literature from resource-rich countries provides information on optimizing antiretroviral therapy for both maternal health and the prevention of vertical transmission, while literature from resource-poor countries provides insight on recommendations for the care of pregnant women living with HIV with absent or delayed prenatal care. A detailed table describing results of major studies on antiretroviral prophylaxis to prevent perinatal transmission of HIV is available in the NIH perinatal guidelines.3 The Pediatric AIDS Clinical Trials Group 076 (PACTG 076) was the first major randomized, placebo-controlled study to demonstrate that zidovudine istered PO antepartum (between 14 and 34 weeks’ gestation), intravenously intrapartum, and PO to the infant for 6 weeks could significantly reduce the risk of perinatal transmission of HIV (25.5% in the placebo group vs. 8.3% in the zidovudine treated group, P < 0.01).17 Follow-up results confirmed these findings with no evidence of any long-term toxicity, other than transient anemia, in infants up to 5 years of age.18–20 Subsequent clinical trials and observational studies have demonstrated that further reductions in vertical transmission, to rates as low as < 1% can be achieved with

the antenatal istration of cART (with at least 2 or 3 agents) to the pregnant woman.3 In the entire Canadian cohort, the rate of vertical transmission was as low as 0.4% (6 out of 1585) when the mother received at least 4 weeks of cART before delivery.10,11 Antiretroviral agents reduce the risk of vertical transmission through a number of mechanisms, including: 1. lowering maternal viral load using antenatal cART, 2. providing infant pre-exposure prophylaxis using intrapartum antiretroviral therapy that rapidly crosses the placenta in order to achieve adequate systemic drug levels in the infant, and 3. providing infant post-exposure prophylaxis.3 It is important to note, however, that while lowering maternal viral load is important, antiretroviral prophylaxis is effective even in women with low viral loads. Among women with baseline viral loads less than 1000 copies/mL, those who received antenatal antiretroviral therapy demonstrated a lower HIV vertical transmission rate than those who did not (1.0% vs. 9.8%, P < 0.001).16 Two primary treatment strategies have been evaluated in resource-poor countries and are relevant in the developed world for managing women living with HIV with absent or delayed prenatal care who are not receiving recommended antenatal cART. The first strategy involves use of shorter course regimens of either mono or dual antiretroviral therapy (e.g., zidovudine or zidovudine-lamivudine)21,22 or intrapartum single-dose nevirapine.23,24 The second strategy involves istration of cART to infants who are born in high transmission risk settings.25 Overall, both strategies have demonstrated benefit in reducing transmission; however, transmission rates are still significantly higher than those reported with antenatal cART, intrapartum and infant prophylaxis. In a large African randomized trial (HIVNET 012), pregnant women living with HIV received either: 1. 1 single-dose nevirapine 200 mg in labour and 1 dose of nevirapine to their infant within 72 hours of birth, or 2. oral zidovudine while in labour and the same to their infant for one week after birth. Nevirapine significantly reduced the risk of vertical HIV transmission at 14 to 16 weeks of age by approximately 50% (13% vs. 25%, P < 0.001) compared with zidovudine.23 It is important to note that none of the women received antenatal antiretroviral therapy and almost all women in this study breastfed their infants. Because single-dose nevirapine AUGUST JOGC AOÛT 2014 l S7

SOGC CLINICAL PRACTICE GUIDELINE

Table 3. Summary of antiretroviral drugs in pregnancy with dosing recommendations Nucleoside reverse transcriptase inhibitors (NRTIs)

NRTI class concerns

Recommended for use as part of combination regimens, usually including 2 NRTIs with either an NNRTI or one or more PIs. Use of single or dual NRTIs alone is not recommended.

Causal relationship between mitochondrial toxicity and NRTI exposure in utero has not been established (see text for details).

Zidovudine (ZDV)

Recommendations for use in pregnancy

FDA pregnancy category C

ZDV plus 3TC is a recommended dual NRTI backbone for pregnant women.

High placental transfer (cord-to-maternal blood ratio 0.80) Animal data3 Vaginal carcinoma reported in mice and rats at 3 times and 24 times the usual human dose Embryotoxic in rats and rabbits at high doses No evidence of teratogenicity in rats or rabbits unless given at extremely high doses to rats (e.g., 300 times usual human dose) Human data PACTG 076 randomized, placebo-controlled trial in pregnant women showed no increase in congenital abnormalities19,155; the WITS cohort study reported 10-fold increase in risk of hypospadias in women receiving ZDV in the first trimester.156 No evidence of human teratogenicity; APR birth defects with first trimester exposure 3.3% (124 of 3789 births, 95% CI 2.7%–3.9%)42

Do not combine with stavudine (antagonistic mechanism of action); discontinue stavudine at time of istration of intrapartum intravenous ZDV. Dosing Retrovir 300 mg twice daily or 200 mg 3 times daily Combivir (ZDV 300 mg/3TC 150 mg) 1 tablet twice daily Trizivir (ZDV 300 mg/3TC 150 mg/ABC 300 mg) 1 tablet twice daily Pharmacokinetics similar in third trimester of pregnancy and non-pregnant patients; no dose alteration required in pregnancy157 Adverse events/concerns in pregnancy Overall, well tolerated in pregnancy and infants; higher incidence of anemia reported in neonates; however, reversible within 6 weeks of discontinuing ZDV19,155

Infants exposed in utero have shown no differences in immunology, neurology, or growth to infants receiving placebo, based on approximately 6 years of follow-up. Lamivudine (3TC)

Recommendations for use in pregnancy

FDA pregnancy category C

3TC plus ZDV is a recommended dual NRTI backbone for pregnant women.

High placental transfer (cord-to-maternal blood ratio 0.86)158 Animal data3

A preferred NRTI for dual NRTI backbone (in combination with TDF) for pregnant women with chronic HBV infection

No evidence of toxicity or teratogenicity in rabbits or rats at 35 to 130 times usual human dose

Dosing

Embryotoxic in rabbits at doses similar to human doses, however no indication of this effect in rats at 35 times usual human dose Human data No adequate or well-controlled studies in pregnant women. No evidence of human teratogenicity: APR birth defects with first trimester exposure 3.1% (127 of 4088 births, 95% CI 2.6%–3.7%)42

3TC 150 mg twice daily or 300 mg once daily Combivir (ZDV 300 mg/3TC 150 mg) 1 tablet twice daily Trizivir (ZDV 300 mg/3TC 150 mg/ABC 300 mg) 1 tablet twice daily Kivexa (3TC 300 mg/ABC 600 mg) 1 tablet once daily A phase I study, evaluating both daily and twice-daily dosing, showed pharmacokinetics were similar in the third trimester of pregnancy and postpartum159; larger study reports 22% higher drug clearance in pregnant women; however, level of exposure was therapeutic.158 No dose alteration is required in pregnancy. Adverse events/concerns in pregnancy Overall, well tolerated in pregnancy; also active against HBV

Abacavir (ABC)

Recommendations for use in pregnancy

FDA pregnancy category C

Alternative NRTI for dual NRTI backbone of combination regimens

High placental transfer (cord-to-maternal blood ratio 1.0)160

Dosing

Animal data3

Ziagen 300 mg twice daily or 600 mg once daily

Developmental toxicity (decreased fetal weight and reduced crownrump length) and increased incidence of fetal anasarca and skeletal malformations in rats, at 35 times usual human dose; toxic effects to embryo and fetus in rats at 8 times usual human dose

Kivexa (3TC 300 mg/ABC 600 mg) 1 tablet once daily

No evidence of developmental toxicity or increase in fetal malformation observed in rabbits at 8.5 times usual human dose Carcinogenic in rats at 6 to 32 times usual human dose Human data No adequate or well-controlled studies in pregnant women

Phase I study showed drug area under the curve concentrations were similar in pregnant, postpartum, and non-pregnant individuals. No dose alteration is required in pregnancy.161 Adverse events/concerns in pregnancy Severe hypersensitivity reaction that may be fatal has been reported; testing for the HLA-B*5701 allele identifies patients at risk of reaction; patients with the HLA*B-5701 allele should not be given ABC.

No evidence of human teratogenicity: APR birth defects with first trimester exposure 3.0% (25 of 823 births; 95% CI 2.0%–4.5%)42 continued S8 l AUGUST JOGC AOÛT 2014

Guidelines for the Care of Pregnant Women Living With HIV and Interventions to Reduce Perinatal Transmission

Table 3. Continued Emtricitabine (FTC)

Recommendations for use in pregnancy

FDA pregnancy category B

Alternative NRTI for dual NRTI backbone of combination regimens

High placental transfer (cord-to-maternal blood ratio 1.2)162,163

One of preferred NRTI for dual NRTI backbone (in combination with TDF) for women with chronic hepatitis B infection

Animal data

3

No evidence of carcinogenicity in mice or rats at doses up to 26 times and 31 times usual human dose, respectively

Dosing

No evidence of developmental toxicity or teratogenicity in mice or rabbits at doses 60 times and 120 times usual human dose, respectively

Truvada (TDF 300 mg/FTC 200 mg) 1 tablet once daily

Human data No adequate or well-controlled studies in pregnant women No evidence of human teratogenicity: APR birth defects with first trimester exposure 2.3% (21 of 899 births; 95% CI 1.4%–3.5%)42

Emtriva (not available in Canada) 200 mg once daily A phase II pharmacokinetic study showed that FTC concentrations were lower in the third trimester than postpartum164; however, current data is insufficient to recommend a dosage adjustment in pregnancy. Adverse events/concerns in pregnancy Overall, well tolerated in pregnancy; also active against HBV

Tenofovir (TDF) (nucleotide analogue reverse transcriptase inhibitor)

Recommendations for use in pregnancy

FDA pregnancy category B

Alternative NRTI for dual NRTI backbone of combination regimens

High placental transfer (cord-to-maternal blood ratio 0.6-1.03)165,166

Preferred NRTI in combination with 3TC or FTC in women with chronic hepatitis B infection

Animal data3 Carcinogenic in female mice at 16 times usual human dose; however, there is no indication of this effect in rats at 5 times usual human dose.

Dosing

No evidence of gross structural abnormalities observed in fetal monkeys at 25 times usual human dose; however, low birth weights and reduction in fetal bone porosity were observed.

Truvada (TDF 300 mg/FTC 200 mg) 1 tablet once daily

Chronic istration of TDF at high doses to immature animals of multiple species has resulted in reversible bone abnormalities (ranging from decreased bone mineral density and content to severe, pathologic osteomalacia) and evidence of nephrotoxicity in monkeys at doses 12 to 50 times usual human dose.

A pharmacokinetic study showed that TDF AUC is lower in third trimester than postpartum; however, trough concentrations were similar in both groups.165 No dose alteration is required in pregnancy.

Human data No evidence of human teratogenicity: APR birth defects with first trimester exposure 2.3% (31 of 1370 births; 95% CI 1.5%–3.2%)42 Currently no evidence of nephrotoxicity or decreased growth and development in infants exposed in utero

Viread 300 mg once daily Atripla (TDF 300 mg/FTC 200 mg/EFV 600 mg) 1 tablet once daily at nighttime; not recommended in pregnancy (see Efavirenz below)

Adverse events/concerns in pregnancy Overall, well tolerated in pregnancy; clinical studies in humans (particularly children) show bone demineralization with chronic use; clinical significance is unknown.

Cross-sectional study in HIV-exposed uninfected infants reported comparable outcomes (low birth weight and length measurements, quantitative bone ultrasound, and parameters of bone metabolism) between infants with and without in utero exposure to TDF.57 A cohort study in HIV-exposed uninfected infants compared outcomes of low birth weight and small for gestational age, newborn length for age, and head circumference for age in infants with or without in utero exposure to TDF. No between-group differences were found at birth; at age 1 year, infants exposed to TDF had lower length for age and head circumference for age. The clinical significance of these findings has not been determined.167 Didanosine (DDI)

Recommendations for use in pregnancy

FDA pregnancy category B

Alternative NRTI for dual NRTI backbone of combination regimens

Moderate placental transfer (cord-to-maternal blood ratio 0.38)160

Do not prescribe with stavudine (possible fatal lactic acidosis).

Animal data3

Dosing

No evidence of toxicity or teratogenicity in rats or rabbits Human data

Videx EC or Videx oral solution: ≥ 60 kg: 400 mg once daily (with tenofovir give 250 mg PO daily); < 60 kg: 250 mg once daily (with tenofovir give 200 mg once daily)

No adequate or well-controlled studies in pregnant women

Take 30 minutes before or 2 hours after a meal.

APR birth defects with first trimester exposure 4.6% (19 of 409 births; 95% CI 2.8%–7.2%). No pattern of defects was discovered.42

Phase I study showed pharmacokinetics were similar in third trimester of pregnancy and postpartum.168 No dose alteration is required in pregnancy. Adverse events/concerns in pregnancy Fatal lactic acidosis has been reported in pregnant women who received the combination of DDI and d4T; physicians should avoid prescribing this combination. continued AUGUST JOGC AOÛT 2014 l S9

SOGC CLINICAL PRACTICE GUIDELINE

Table 3. Continued Stavudine (d4T)

Recommendations for use in pregnancy

FDA pregnancy category C

Alternate NRTI for dual NRTI backbone of combination regimens

High placental transfer (cord-to-maternal blood ratio 0.5–0.8 in macaques)169

Do not combine with ZDV (antagonistic mechanism of action); discontinue d4T at time of istration of intrapartum IV ZDV.

Animal data3

Do not combine with DDI (risk of fatal lactic acidosis).

No evidence of developmental toxicity or teratogenicity in rats at 399 times usual human dose or rabbits at 183 times usual human dose

Dosing

Human data

Take without regard to meals.

No adequate or well-controlled studies in pregnant women No evidence of human teratogenicity: APR birth defects with first trimester exposure 2.5% (20 of 801 births; 95% CI 1.5%–3.8%)42

Zerit ≥ 60 kg: 40 mg twice daily, < 60 kg: 30 mg twice daily A phase I/II study showed pharmacokinetics in pregnancy were similar to those in non-pregnant adults.170 No dose alteration is required in pregnancy. Adverse events/concerns in pregnancy Fatal lactic acidosis has been reported in pregnant women who received the combination of DDI and d4T. Physicians should avoid prescribing this combination.

Non-nucleoside reverse transcriptase inhibitors

NRTI class concerns

NNRTIs are recommended for use in combination regimens with 2 NRTI drugs (alternative to using a PI).

Hypersensitivity reactions, including hepatic toxicity and (more common in women) rash; it is unclear whether these reactions are increased in pregnancy.

Nevirapine (NVP)

Recommendations for use in pregnancy

FDA pregnancy category B

Preferred NNRTI for use in combination with dual NRTI backbone

High placenta transfer (cord-to-maternal blood ratio 0.90)26

Do not newly initiate in pregnancy because of risk of fatal rash and hepatotoxicity.

Animal data3 Hepatocellular adenoma and carcinoma reported in mice and rats; relevance to humans not known

Women who are tolerating NVP and become pregnant may continue taking NVP.

No evidence of teratogenicity in rats and rabbits at twice the usual human dose; however, low birth weights observed

Dosing

Human data Limited well-controlled studies of NVP in pregnant women; no evidence of human teratogenicity; antiretroviral pregnancy registry 2.7% (28 of 1020 births, 95% CI 1.8%–4.0%)42

Viramune 200 mg once daily for 14 days, then 200 mg twice daily; repeat lead-in period if therapy is discontinued for greater than 7 days. A pharmacokinetic study has shown that pharmacokinetic parameters in the second and third trimester are similar to those postpartum171; however, a second study has shown that NVP concentrations are lower in women in the third trimester than in non-pregnant women172; current data is insufficient to recommend a dose adjustment in pregnancy. Adverse events/concerns in pregnancy Severe potentially fatal hepatotoxicity and hypersensitive skin reactions have been reported; some data have suggested that women with CD4 counts > 250 cells/mm3 are at greater risk of reaction3; Canadian data has been reported for toxicity across a wide range of CD4 counts in women exposed to NVP for the first time during pregnancy58; these toxicities have not been reported in women or infants receiving single-dose NVP for the prevention of vertical transmission. Emergence of NVP resistance following single-dose NVP has been shown; istration of postpartum antiretrovirals to the mother (and infant) may reduce the detection of drug-resistant strains. continued

S10 l AUGUST JOGC AOÛT 2014

Guidelines for the Care of Pregnant Women Living With HIV and Interventions to Reduce Perinatal Transmission

Table 3. Continued Efavirenz (EFV)

Recommendations for use in pregnancy

FDA pregnancy category D

Contraindicated in first trimester of pregnancy

Moderate placenta transfer (cord blood concentrations similar to maternal plasma concentration in rats, rabbits, primates)3

Women receiving EFV should be instructed to avoid pregnancy; recommend barrier contraception in combination with other hormonal contraceptives.

Animal data3 Hepatocellular carcinoma and adenoma and pulmonary alveolar/ bronchiolar adenomas reported in female mice; however, no indication of this effect in male mice or in rats Significant central nervous system malformations (anencephaly, anopthmalmia, cleft palate) reported in monkeys receiving EFV in first trimester at doses comparable to human therapeutic exposure Human data Limited well-controlled studies in pregnant women; a meta-analysis of birth defects observed in cohorts of infants with first trimester exposure (1437 live births) found no increased risk of overall birth defects than in infants exposed to non-EFV-based regimens (RR 0.85; 95% CI 0.61–1.20), with one neural tube defect observed43; a large prospective study of a cohort of antiretroviral-exposed infants (13 124 live births) found significant association between EFV exposure in the first trimester and neurological defects (adjusted OR 3.15; 95% CI 1.09–9.09).44

Dosing Sustiva 600 mg once daily at bedtime Atripla (TDF 300 mg/FTC 200 mg/EFV 600 mg) 1 tablet once daily at bedtime May take on an empty stomach to reduce side effects Limited pharmacokinetic data available; one pharmacokinetic study has shown that EFV AUC is lower in the third trimester than postpartum; however, a majority of third trimester levels were above target exposure.173 No dose alteration is required in pregnancy. Adverse events/concerns in pregnancy Avoid in first trimester of pregnancy as described above.

APR 2.7% (18 of 679 births, 95% CI 1.6%–4.2%); 6 retrospective case reports of central nervous system defects (including 3 cases of meningomyelocele), 1 prospective case report of neural tube defect, and 1 prospective case report of bilateral facial clefts and anopthalmia in humans receiving EFV in first trimester42 Etravirine (ETR)

Recommendations for use in pregnancy

FDA pregnancy category B

Insufficient safety and pharmacokinetic data to recommend use during pregnancy

Placental transfer unknown (cord-to-maternal blood ratio from case report data 0.33)174

Dosing

Animal data3

Intelence 200 mg twice daily

Hepatocellular carcinoma and adenoma reported in mice; however, no indication of this effect in rats

Take with food to increase total AUC drug concentration.

No evidence of embryotoxicity or teratogenicity in rabbits or rats at doses comparable to human therapeutic exposure

Single pharmacokinetic study in 4 pregnant women reported that drug levels and AUC were similar to those in non-pregnant adults.174 Dose adjustment is not currently required in pregnancy.

Human data No adequate or well-controlled studies and few case report data in pregnant women Rilpivirine (RPV)

Recommendations for use in pregnancy

FDA pregnancy category B Placental transfer unknown

Insufficient safety and pharmacokinetic data to recommend use during pregnancy

Animal data3

Dosing

Hepatocellular carcinoma reported in mice; however, no indication of this effect in rats No evidence of embryotoxicity or teratogenicity in rats or rabbits at doses 15 times and 70 times usual human dose, respectively Human data No published data for human pregnancy

Edurant 25 mg once daily Complera (TDF 300 mg/FTC 200 mg/RPV 25 mg) 1 tablet once daily Take with food (avoid protein-rich nutritional drinks) to increase total AUC and peak drug concentration. No pharmacokinetic studies in pregnancy; unknown whether dose adjustment is required continued

AUGUST JOGC AOÛT 2014 l S11

SOGC CLINICAL PRACTICE GUIDELINE

Table 3. Continued Protease inhibitors

PI class concerns

PIs are recommended for use in combination regimens with 2 NRTI drugs (alternative to using an NNRT).

Hyperglycemia and new onset or exacerbation of existing diabetes have been reported with PIs; unclear whether pregnancy increases risk. Data regarding preterm delivery in women receiving PIs are conflicting (see text for details).

Lopinavir-ritonavir (LPV/r)

Recommendations for use in pregnancy

FDA pregnancy category C

Preferred PI for use in combination with dual NRTI backbone

Low placental transfer (cord-to-maternal blood ratio LPV 0.20, RTV minimal)

Dosing

Animal data3 Hepatocellular carcinoma and adenoma reported in mice at doses 2 times (LPV) and 5 times (RTV) usual human dose

Kaletra (LPV/r 200 mg/50 mg; LPV/r 100 mg/50 mg; oral solution LPV/r 400 mg/100 mg in each 5 mL) 400 mg LPV twice daily; take with food to reduce stomach upset.

There are no adequate or well-controlled studies in pregnant women.

Pharmacokinetic studies show AUC is decreased in third trimester.175,176 Increasing the dose of LPV/r from 400 mg/100 mg twice a day to 600 mg/150 mg twice a day resulted in AUC similar to non-pregnant adults taking the standard dose177,178; may consider increased dose to LPV/r 600 mg/150 mg twice daily in third trimester, particularly in women who have previously had PI.

No evidence of human teratogenicity; APR 2.4% (21 of 883 births, 95% CI 1.5%–3.6%)42

No data exist evaluating LPV/r drug levels using once-daily dosing in pregnancy; once-daily dosing is not recommended.

Embryotoxic in rats; no evidence of teratogenicity in rats or rabbits Human data

Adverse events/concerns in pregnancy Well tolerated; short-term safety data in Phase I/II clinical studies Atazanavir (ATV)

Recommendations for use in pregnancy

Approved by FDA for use in pregnancy

Alternative PI for use in combination with dual NRTI backbone

FDA pregnancy category B Low placental transfer (cord-to-maternal blood ratio 0.10–0.20)

Dosing Must be combined with low-dose RTV (ATV/r) in pregnancy

Animal data3

Reyataz ATV/r 300/100mg once daily

Benign hepatocellular adenomas reported in female mice at 3 times usual human dose; no evidence of teratogenicity in rats or rabbits at similar or 2 times usual dose respectively; weight loss or weight gain suppression observed at 1.3 times usual human dose

Take with food to increase absorption and minimize stomach upset.

Human data No adequate or well-controlled studies have been reported in pregnant women. No evidence of human teratogenicity; APR 1.9% (13 of 669 births; 95% CI 1.0%–3.3%)42

Three pharmacokinetic studies evaluating ATV/r 300 mg /100 mg (without any interacting medications) have shown lower plasma concentrations in the third trimester than in non-pregnant adults; however, most women achieved an HIV viral load < 50 copies/mL and did not require dose adjustment.50,52,53 Two pharmacokinetic studies evaluating ATV/r 400 mg/100 mg (without any interacting medications) in the third trimester have shown drug ATV AUC similar to non-pregnant controls.52,53 TDF reduces ATV exposure 25% in pregnant women; increasing the dose to ATV/r 400 mg/100 mg in women receiving TDF has shown ATV AUC similar to that in non-pregnant control subjects.53 Standard dose ATV/r 300 mg/100 mg can be used in pregnancy; consider increasing the dose in third trimester to ATV/r 400 mg/100 mg if combined with either an H2-receptor antagonist or tenofovir. Data are insufficient to combined use of ATV + TDF + H2-receptor antagonist. Adverse events/concerns in pregnancy ATV increases indirect (unconjugated) bilirubin; the theoretical concern that increased bilirubin may exacerbate physiologic hyperbilirubinemia in infants has not yet been indicated in clinical trials.179 continued

S12 l AUGUST JOGC AOÛT 2014

Guidelines for the Care of Pregnant Women Living With HIV and Interventions to Reduce Perinatal Transmission

Table 3. Continued Ritonavir (RTV)

Recommendations for use in pregnancy

FDA pregnancy category B Minimal placental transfer

Use only at low-dose in combination with a second PI to increase the serum drug levels of the second PI.

Animal data3

Dosing

Hepatocellular carcinoma and adenomas observed in male mice at high doses; developmental toxicity (decreased body weight, ossification delays) observed at high doses

Take with food to minimize stomach upset.

Human data Limited experience at full dose in human pregnancy; when used for low-dose RTV boosting there is no evidence of human teratogenicity; APR 2.2% (39 of 1741 births, 95% CI 1.6%–3.0%).42

Norvir 100–400 mg PO per day in 1–2 divided doses (depending on combination with specific PI) Phase I and II pharmacokinetic studies using therapeutic RTV dosing and studies of other PIs using RTV as a low-dose booster have shown lower RTV levels in pregnancy than postpartum53,180; no dose adjustments are recommended in pregnancy.

Darunavir (DRV)

Recommendations for use in pregnancy

FDA pregnancy category C

Insufficient safety and pharmacokinetic data to recommend use during pregnancy

Placental transfer unknown (cord-to-maternal blood ratio based on case reports 0.24)181

Dosing

Animal data3

Must be combined with low-dose RTV (DRV/r).

Hepatocellular carcinoma and adenomas observed in mice and rats; no evidence of embryotoxicity or teratogenicity in mice, rats, or rabbits at doses 50% and 5% that of usual human doses

Prezista antiretroviral-naive patients or antiretroviral-experienced patients without DRV resistance mutations: DRV/r 800 mg/100 mg once daily; antiretroviral experience patients with resistance mutations: DRV/r 600 mg/100 mg twice daily

Human data No adequate or well-controlled studies in pregnancy Few pregnancy exposures have been reported to the APR; no conclusion can be made about risk of birth defects.

Take with food to minimize stomach upset. Pharmacokinetic studies evaluating DRV/r as 600 mg/100 mg twice daily or 800 mg/100 mg once daily have shown 17%–35% reductions in DRV levels in third trimester of pregnancy compared to postpartum.180–182 DRV/r 600 mg/100 mg twice daily provides adequate drug exposure during pregnancy. Until more data are available, twice-daily DRV is suggested. If once-daily dosing is used, virological response and DRV concentration if available should be monitored.

Saquinavir (SQV)

Recommendations for use in pregnancy

FDA pregnancy category B

Alternative PI for use in combination with dual NRTI backbone

Minimal placental transfer Animal data

3

Dosing Must be combined with low-dose RTV (SQV/r).

No evidence or carcinogenicity, embryotoxicity, or teratogenicity in mice, rats, or rabbits at doses 21%–26% of usual human doses

Invirase SQV/r 1000 mg/100 mg twice daily

Human data

Pharmacokinetic study data is conflicting; one study evaluating SQV/r 1000 mg/100 mg twice daily has shown comparable drug levels in second and third trimesters and postpartum183; a second study using the same dosing has shown a 50% decrease in third trimester levels without loss of virologic control184; data is insufficient to recommend a dosage adjustment in pregnancy and too limited to recommend once-daily dosing.

No adequate or well-conducted clinical studies have been conducted in pregnant women. Few pregnancy exposures have been reported to the APR; no conclusion can be made about the risk of birth defects.

Take with meals or within 2 hours after a meal.

Adverse events/concerns in pregnancy Well tolerated, short-term safety demonstrated for mothers and infants; baseline ECG is recommended before starting because PR and/or QT interval prolongation have been observed; no evidence that pregnancy increases risk continued

AUGUST JOGC AOÛT 2014 l S13

SOGC CLINICAL PRACTICE GUIDELINE

Table 3. Continued Nelfinavir (NVF)

Recommendations for use in pregnancy

FDA pregnancy category B Minimal placental transfer

Use in special circumstances when alternative agents are not tolerated in combination with dual NRTI backbone.

Animal data3

Dosing

Thyroid follicular cell adenoma and carcinoma has been observed in rats receiving similar to 3 times usual human dose; no evidence of embryonic or teratogenicity has been observed in rats or rabbits. Human data No evidence of human teratogenicity; APR 3.9% (47 of 1204 births, 95% CI 2.9%–5.2%)42 Well tolerated; short-term safety has been demonstrated for mothers and infants.

Viracept 1250 mg twice daily (750 mg three times daily not recommended in pregnancy) Pharmacokinetic study data is conflicting; one Phase I/II pharmacokinetic study has shown that adequate drug levels are achieved throughout pregnancy using 1250 mg twice daily185; two other studies have shown lower NVF concentrations in the third trimester compared to the second trimester and postpartum; however, viral load was adequately suppressed186,187; data is insufficient to recommend a dosage adjustment in pregnancy. Adverse events/concerns in pregnancy Extensive experience in pregnancy; however, clinical trials in nonpregnant NVF based regimens had lower rate of viral response compared to LPV/r or EFV based regimens, with similar viral response rates compared to ATV/r and NVP. The concern regarding the presence of the impurity EMS, a potential carcinogen and teratogen in animals, in NVF manufactured before 2008 has been mitigated by establishment of maximum allowed EMS limits established by the FDA.

Indinavir (IDV)

Recommendations for use in pregnancy

FDA pregnancy category C Minimal placental transfer

For use in special circumstances when alternative agents cannot be used in combination with dual NRTI backbone

Animal data3

Dosing

Thyroid adenomas observed in rats at 1.3 times usual human dose; however, no indication of any tumour types in mice

Must be combined with low-dose RTV (IDV/r) in pregnancy. Crixivan IDV/r 800 mg/100–200 mg twice daily

No evidence of embryotoxicity or teratogenicity in rabbits or dogs at 3% and 50% of maternal levels; increased incidence of supernumerary and cervical ribs observed in rats at doses comparable to human doses

Two pharmaco­kinetic studies evaluating IDV without RTV have shown IDV concentrations are lower in the third trimester than in postpartum and non-pregnant patients, and 2 pharmacokinetic studies evaluating IDV 400 mg twice daily combined with low-dose RTV have shown decreases in IDV levels during pregnancy without loss of virologic control.3

Exacerbation of physiologic neonate hyperbilirubinemia did not occur in Rhesus monkeys with third trimester in utero exposure. Human data No adequate or well-controlled studies in pregnant women have been reported. No evidence of human teratogenicity; APR 2.1% (6 of 286 births, 95% CI 0.8%–4.5%)42

Optimal dose in pregnancy is not established; HIV levels and trough IDV concentration should be monitored; must be combined with low-dose RTV. Adverse events/concerns in pregnancy IDV increases indirect (unconjugated) bilirubin; evidence for a theoretical concern regarding increased bilirubin exacerbating physiologic hyperbilirubinemia in infants has not been reported; there is a potential for renal stones; it is unclear if pregnancy increases risk.

Fosamprenavir (FPV)

Recommendations for use in pregnancy

FDA pregnancy category C Placental transfer unknown

Safety and pharmacokinetic data are insufficient to recommend use during pregnancy.

Animal data3

Dosing

Hepatocellular carcinoma and adenoma have been observed in rats and mice at doses ranging from 0.3 to 1.4 times usual human dose. Embryotoxic in rabbits; no evidence of gross structural abnormalities in rats or rabbits; however, minor skeletal variations (decreased ossification of femur, humerus, trochlea) and decreased body weights have been observed. Human data No adequate or well-conducted studies have been conducted in pregnant women. Few pregnancy exposures have been reported to the APR; no conclusion can be made about risk of birth defects.

Recommended to be combined with low-dose RTV (FPV/r) in pregnancy Lexiva antiretroviral naïve patients: FPV 1400 mg twice daily or FPV/r 1400 mg/100–200 mg once daily; Telzir antiretroviral naïve patients: FPV/r 700 mg/100 mg twice daily; PI experienced patients: FPV 700 mg/100 mg twice daily Limited pharmacokinetic data are available; one study evaluating FPV/r 700 mg/100 mg twice daily has shown lower amprenavir (active moiety) concentrations during pregnancy than in postpartum and non-pregnant patients; however, levels were considered adequate for patients without PI resistance mutations188; no data are available for using FPV in pregnancy without low-dose RTV; preliminary evidence suggests no dose adjustment is required in pregnancy and data is too limited to recommend once-daily or unboosted FPV. continued

S14 l AUGUST JOGC AOÛT 2014

Guidelines for the Care of Pregnant Women Living With HIV and Interventions to Reduce Perinatal Transmission

Table 3. Continued Tipranavir (TPV)

Recommendations for use in pregnancy

FDA pregnancy category C

Safety and pharmacokinetic data are insufficient to recommend use during pregnancy.

Placental transfer unknown; moderate transfer reported in one case report (cord-to-maternal blood ratio 0.41)189

Dosing

Animal data3

Must be combined with low-dose ritonavir (TPV/r).

Hepatocellular carcinoma and adenoma was observed in mice; this effect was not observed in rats.

Aptivus TPV/r 500 mg/200 mg twice daily

No evidence of embryotoxicity or gross structural abnormalities in rats or rabbits at doses 0.2 to 1.1 times usual human dose have been reported; however, growth in inhibition was observed in rats at 0.8 times human doses. Human data No adequate or well-controlled studies in pregnant women have been reported.

No pharmacokinetic studies in pregnancy have been reported; it is not known whether dose adjustment is required. Adverse events/concern in pregnancy Severe potentially fatal clinical hepatitis and intracranial hemorrhage have been reported in non-pregnant population; no evidence pregnancy increases risk.

Few pregnancy exposures have been reported to the APR; no conclusion can be made about risk of birth defects. Entry Inhibitors Enfuviritide (T20)

Recommendations for use in pregnancy

FDA pregnancy category B

Safety and pharmacokinetic data are insufficient to recommend use in pregnancy.

No placental transfer based on single case report189 No evidence of teratogenicity in rats or rabbits at 27 or 3 times the usual human dose, respectively3 No adequate or well-documented studies in pregnant women have been reported.

Dosing Fuzeon 90 mg (1 mL) subcutaneously twice daily No pharmacokinetics studies in pregnancy have been reported; it is not known whether dose adjustment is required.

Maraviroc (MVC)

Recommendations for use in pregnancy

FDA pregnancy category B Placental transfer unknown

Safety and pharmacokinetic data are insufficient to recommend use during pregnancy.

Animal Data3

Dosing

No evidence of embryotoxicity, carcinogenicity, or teratogenicity has been found in rats or rabbits at 20 times and 5 times usual human dose, respectively.

Celsentri 150 mg twice daily when given with strong CYP3A inhibitors; 300 mg twice daily when given with drugs that are not strong CYP3A inducers or inhibitors; 600 mg twice daily when given with CYP3A inducers

Human Data

No pharmacokinetic studies in pregnancy have been reported; it is not known whether dose adjustment is required.

No adequate or well-documented studies in pregnant women have been reported. Few pregnancy exposures have been reported to the APR; no conclusion can be made about the risk of birth defects. Integrase Inhibitors Raltegravir (RAL)

Recommendations for use in pregnancy

FDA pregnancy category C

Safety and pharmacokinetic data are insufficient to recommend use during pregnancy.

Placental transfer unknown (cord-to-maternal blood ratio from case reports 1.0)190

Dosing

Animal Data3

Isentress 400 mg twice daily

There has been no evidence shown of embryotoxicity, carcinogenicity, or teratogenicity in rats or rabbits at 3 to 4 times the usual human dose; however, an increase in incidence of supernumerary ribs was reported in rats at 3 times usual human dose.

A pharmacokinetic study published in abstract form reports no differences between women in the third trimester and postpartum and non-pregnant patients191; preliminary evidence suggests no dose alteration is required in pregnancy.

Human Data No adequate or well-documented studies in pregnant women have been reported. Few pregnancy exposures have been reported to the APR; no conclusion can be made about the risk of birth defects. continued

AUGUST JOGC AOÛT 2014 l S15

SOGC CLINICAL PRACTICE GUIDELINE

Table 3. Continued Elvitegravir (EVG)-Cobicistat (COBI)

Recommendations for use in pregnancy

FDA pregnancy category B Placental transfer unknown

Safety and pharmacokinetic data are insufficient to recommend use during pregnancy.

Animal Data3,192

Dosing

EVG: No evidence of teratogenicity or an effect on reproductive function has been reported in rats or rabbits at doses 23 and 0.2 times higher, respectively, than the usual human dose. COBI: No evidence of teratogenicity or effect on reproductive function has been reported in rats or rabbits at doses 1.8 and 4.3 times higher, respectively, than the usual human dose.

Stribild (TDF 300 mg/FTC 200 mg/EVG 150 mg/COBI 150 mg) 1 tablet once daily with food No pharmacokinetics studies in pregnancy have been reported; it is not known whether dose adjustment is required.

Human Data No adequate or well-documented studies have been reported in pregnant women. APR: Antiretroviral Pregnancy Registry; IV: intravenous, FTC: emtricitabine; EVF: efavirenz; RR: relative risk; OR: odds ratio; AUC: area under the curve; RPV: rilpinavir; LPV/r: lopinavir/ritonavir; SQV: saquinavir; ECG: electrocardiogram; CYP: cytochrome P450; EMS: ethyl methane­sulfonate

rapidly crosses the placenta and achieves adequate infant blood levels,26,27 is easily istered, and is well tolerated in both women and infants, it has been recommended as a treatment strategy for women living with HIV who present in labour and are not receiving antenatal antiretroviral therapy. Nevirapine possesses a long half-life, however, and therefore use of even a single dose exposes women to an extended period of nevirapine monotherapy, potentially increasing the risk of nevirapine drug-resistant mutations.28 One strategy to limit the emergence of nevirapine resistance after single-dose nevirapine is to provide the woman with an antiretroviral tail (e.g., postpartum addition of 2 NRTIs for a period of 3 to 14 days).29–33 The HPTN 040/PACTG 040 study evaluated the alternative treatment strategy of istering prophylactic cART to infants born to women living with HIV who were not receiving antenatal antiretroviral therapy.25 Forty-one percent of women in this study received intrapartum intravenous zidovudine and the majority of infants were formula-fed. This study demonstrated that the cART (the addition of either 3 doses of infant nevirapine or 2 weeks of lamivudine/ nelfinavir to 6 weeks of zidovudine) was superior in reducing the risk of vertical HIV transmission (2.2% and 2.4%, respectively) to 6 weeks of infant zidovudine therapy alone (4.8%, P = 0.046). The rate of neutropenia was higher in the 3-drug regimen (27.5% with zidovudine/nelfinavir/ lamivudine) than in the 2-drug (14.9% with zidovudine/ nevirapine) and 1-drug (16.4% with zidovudine) regimens. Principles behind using combination antiretroviral therapy in pregnancy

Antiretroviral treatment recommendations for the pregnant woman living with HIV are based on the principle that therapies of known benefit to the woman should be offered S16 l AUGUST JOGC AOÛT 2014

and not withheld during pregnancy. The benefits of cART for the overall health of the woman and for prevention of vertical transmission are known; however, there is need for improved understanding of the short- and longterm effects of antiretroviral drug therapy in pregnancy; therefore parameters of maternal and fetal well-being need to be closely monitored. Overall, the benefit of prevention of vertical transmission of HIV is considered to outweigh the potential risks associated with antiretroviral medications, provided these agents are istered per treatment recommendations and with close monitoring and follow-up by experts in the area of HIV and obstetrics. Selection of a specific antiretroviral drug therapy regimen in a pregnant woman living with HIV must take into the inter-related issues of: 1. the stage of pregnancy, 2. the current and co-morbid health status of the woman, 3. her HIV-resistance profile, 4. what is currently known about the use of specific drugs in pregnancy and the risk of teratogenicity, 5. unique pharmacokinetic considerations, including altered kinetics in pregnancy and issues of placental age of medications, 6. the woman’s social status and intravenous drug use, and 7. the ability of the woman to cope with the antiretroviral drug therapy pill burden. Timing of initiation of combination antiretroviral therapy in pregnancy

The timing of initiation will depend on the woman’s HIV disease status (e.g., CD4-cell count and HIV viral load), her

Guidelines for the Care of Pregnant Women Living With HIV and Interventions to Reduce Perinatal Transmission

preparedness to start cART, and her degree of nausea and vomiting of pregnancy. Adult HIV treatment guidelines are available elsewhere2 and are not discussed in detail here. In brief, they recommend initiation of cART for all individuals regardless of CD4-cell counts. In the obstetrical setting there are controversies about the timing of cART initiation in pregnant women who have not already been treated. While cART may reduce the risk of HIV vertical transmission,34 there may also be risks in exposing the fetus to cART. Women with CD4-cell counts < 200 cells/mm3 are at high risk of opportunistic infections35,36; therefore, cART should be started immediately, regardless of gestational age, in conjunction with prophylaxis for opportunistic infections as described below. Women with CD4-cell counts between 200 to 350 cells/mm3 may be at risk of experiencing more common infections (e.g., herpes zoster, bacterial pneumonia), therefore cART should be initiated as soon as possible—usually after the first trimester is completed (week 14). In other cases, although 14 weeks is the general recommendation for cART initiation, delayed initiation of cART until the detailed anatomy ultrasound (i.e., week 18) may be considered in women with CD4-cell counts > 350 cells/mm3 on a case-by-case basis. Antiretroviral drug resistance testing should be performed before starting an antiretroviral regimen; however, if it is determined that cART needs to be started urgently, decisions to start can be made based on the woman’s antiretroviral history and adjusted later if necessary. All women should be counselled about the importance of adherence to the regimen, and should be recommended to continue therapy after delivery. Detailed guidelines regarding management and prophylaxis of opportunistic infections, including specific recommendations for pregnant women, are available35 and are not discussed in detail here. In brief, consideration for antibiotic prophylaxis against the following opportunistic infections must be made based on CD4-cell count: < 200 cells/mm3 requires prophylaxis against P; < 100 cells/mm3 requires additional prophylaxis against Toxoplasmosis gondii (if Toxoplasmosis immunoglobulin G serology is positive and an agent other than cotrimoxazole is used as prophylaxis for P); < 50 cells/mm3 requires additional prophylaxis against MAC after obtaining MAC blood cultures and an ophthalmology referral to rule out CMV retinitis. Treatment and prophylaxis of all opportunistic infections must be provided as required with consideration of potential toxicities in pregnancy. While this is well discussed in available guidelines,35 agents of note to avoid, particularly in the first trimester of pregnancy, include continuous oral fluconazole and clarithromycin.37,38 Cotrimoxazole (a folate antagonist which readily crosses the

placenta) may be safely used throughout pregnancy; however, consideration should be given to increasing the folic acid dose to 5 mg per day in the first trimester and monitoring infants postpartum due to increased risk of neonatal hyperbilirubinemia.39 Continuation of therapy in women already receiving combination antiretroviral therapy prior to pregnancy

In most cases, the current antiretroviral regimen should be continued if the regimen is effective in suppressing HIV viral load and is tolerated by the woman. Significant nausea and vomiting of pregnancy may complicate a woman’s ability to adhere to medication and needs to be addressed and aggressively managed.40 There are two main populations of women in whom switching of antiretroviral medications may be considered. The first is pregnant women living with HIV who are receiving efavirenz and present pre-conception or very early for care in the first trimester. As discussed below and more thoroughly in Appendix 2, efavirenz is not a desirable choice in the first trimester due to its association with neural tube defects in primates and in case reports in humans.41–44 Because most women will present after the 5- to 6-week gestational age time window for neural tube closure, the NIH guidelines endorse continuation of efavirenz in all pregnant woman including those who present for care in the first trimester.3 However because women may not always present after neural tube closure, and because there is a risk of women remaining on a potentially teratogenic medication postpartum, particularly those who do not receive adequate contraception, these guidelines still recommend considering switching the woman from efavirenz to an alternative antiretroviral agent that has greater safety and efficacy data in pregnancy. If efavirenz is received during the first trimester, however, ultrasound evaluation of neural tube closure is very important. Changing antiretroviral medications may also be considered in women who are receiving an antiretroviral agent for which there is little known safety and efficacy data for use in pregnancy (see Appendix 2). It is important to consider the safety and risk of continuing each antiretroviral medication, and prior to any changes to medication there should be discussion between the woman, her HIV care provider, and her obstetrical care provider. Selection of cART regimen in pregnancy

Antiretroviral drug resistance testing should be performed as described above before starting cART and test results used to help determine the optimal regimen. A cART regimen should usually include a dual NRTI backbone AUGUST JOGC AOÛT 2014 l S17

SOGC CLINICAL PRACTICE GUIDELINE

that includes one or more NRTIs with high levels of transplacental age (e.g., zidovudine, lamivudine, emtricitabine, tenofovir, abacavir) and an additional boosted protease inhibitor (see Appendix 2). Consistent adherence to antiretroviral therapy is critical to its efficacy and to preventing the development of resistance. In particular, with complications in pregnancy such as nausea and vomiting of pregnancy, there may be circumstances when cART needs to be discontinued. In this case, regardless of reason, the woman should be advised to discontinue all drugs at once, and to resume all drugs simultaneously to minimize the risk of viral resistance developing during therapy (unless on an NNRTI, then a tail of 2 NRTIs is recommended for 1 week). Resume antiretroviral therapy as quickly as possible after discontinuing, to minimize the risk of rebound viremia and the potentially increased risk of vertical transmission. In the antiretroviral naive and in a presumed or proven pan-sensitive virus the recommended NRTI backbone is zidovudine-lamivudine 300 mg/150 mg 1 tablet PO twice daily with lopinavir-ritonavir 200 mg/50 mg 2 tablets PO twice daily. This regimen requires twice-daily dosing and monthly hemoglobin monitoring as zidovudine can cause pure red cell aplasia.45 If women are unable to tolerate or adhere to a twice-daily dosing regimen an alternative regimen is abacavir-lamivudine 600 mg/300 mg 1 tablet PO once daily and boosted atazanavir (atazanavir 300 mg plus ritonavir 100 mg PO once daily). Testing for, and confirmation of the absence of the inherited HLA*B5701 gene must be done prior to initiation of any abacavir-containing medication to reduce the risk of a severe allergic reaction.46 Atazanavir is associated with increased maternal indirect bilirubin. Although the clinical significance has not been determined, bilirubin should be monitored monthly in the mother and the infant after delivery.47,48 It is important to note that both of the above listed boosted protease inhibitor regimens may require increased dosing (e.g., abacavir-lamivudine 3 tablets PO twice daily, atazanavir 400 mg PO once daily with ritonavir 100 mg PO once daily) in the third trimester as a result of increased volume of distribution of pregnancy.47,49–53 These empiric dose increases should be considered, particularly if the woman’s HIV viral load becomes detectable, cART adherence has been verified and HIV resistance has been ruled out. If available, therapeutic drug level monitoring may also be considered in the third trimester to guide the need for protease inhibitor dose adjustment.54 In pregnant women with HIV and HBV co-infection, the dual NRTI backbone should include 2 NRTI agents that are also active against HBV (e.g., lamivudine, emtricitabine, tenofovir)2,3,55,56; therefore, the recommended first-line S18 l AUGUST JOGC AOÛT 2014

regimen in these women is tenofovir-emtricitabine and boosted atazanavir/ritonavir as described above. HBV DNA levels should be monitored and should become undetectable on this regimen. Because chronic istration of tenofovir to pregnant monkeys has resulted in a slight reduction in fetal bone porosity (a finding which has conflicting results in human studies) and is associated with nephrotoxic effects, tenofovir is not recommended as a first-line agent in pregnancy except with an HBV co-infection, drug resistance, and/or medication adherence issues.3,56,57 If women are unable to tolerate or are resistant to the PIs lopinavir and/or atazanavir, alternative cART regimens may need to be considered including (a) boosted darunavir/ ritonavir (darunavir 800 mg PO daily with ritonavir 100 mg PO daily or darunavir 600 mg PO twice daily with ritonavir 100 mg PO twice daily), or (b) efavirenz 600 mg PO at nighttime, if the virus is sensitive and after the early first trimester of pregnancy, ideally after a detailed ultrasound and screening have confirmed the absence of a neural tube defect. Nevirapine initiation in pregnancy has been associated with 10% life-threatening toxicity (fatal rash and hepatotoxicity) and its initiation in pregnancy is not recommended if there is a suitable alternative.2,3 Although some data have suggested that nevirapine may be safe if a woman’s CD4 cell count is > 250 cells/mm3, Canadian data have suggested that toxicity has occurred at a wide range of CD4-cell counts in women exposed to nevirapine for the first time during pregnancy.58 Women who have been receiving and tolerating nevirapine prior to becoming pregnant (regardless of CD4-cell count) can continue to receive this agent.2,3 All other antiretroviral agents used in adult HIV care must be individually assessed on a case-bycase basis, depending on the woman’s clinical and personal circumstances, co-infections, HLA*B5701 results, genotype of virus, and available options. Detailed information on each antiretroviral agent is provided in Appendix 2; however, it is recommended that consultation be made with experts in the areas of HIV and obstetric care. Because antiretroviral medications are used as a part of combination regimens it is difficult to ascertain the contribution that an individual agent has on potential maternal and/or fetal toxicity. Studies that have evaluated the results of cART have shown variable results. Some early studies have reported serious maternal toxicities including hepatotoxicity,59–61 higher rates of neonatal malformations,62,63 increased risk of prematurity and low birth weight,64–70 or serious neonatal complications including mitochondrial toxicity.69–75 Other studies, however, suggest that there are generally few serious effects for the mother or infant associated with cART.17,76–82

Guidelines for the Care of Pregnant Women Living With HIV and Interventions to Reduce Perinatal Transmission

The concerns surrounding the use of efavirenz (teratogen), nevirapine (rash and hepatotoxicity), tenofovir (bone abnormalities, nephrotoxicity), and atazanavir (hyperbilirubinemia) in pregnancy have been discussed. Women living with HIV who are on antiretroviral therapy are also at a higher risk of preterm delivery than those who are not (18% vs. 9% in Canada).83,84 There is conflicting evidence about whether cART further increases this risk.67,85–92 Data to suggest an association between antiretroviral drug therapy (including protease inhibitor use) and premature delivery or low birth weight infants are mixed; however, a causal relationship has not been established88,93–95 and PIs should not be withheld during pregnancy. There is also conflicting evidence as to whether women taking regimens that include PIs are at increased risk for impaired glucose tolerance or gestational diabetes in pregnancy.64,96–98 Standard glucose screening at 24 to 28 weeks is recommended in pregnant women living with HIV; if a woman is receiving a PIbased regimen, the clinician may choose to perform this screening test earlier.3,99 Recommendations

  4. All pregnant women living with HIV should be treated with combination antiretroviral therapy regardless of baseline CD4 and viral load. (II-2A)   5. Antiretroviral therapy should not be discontinued during the first trimester for obstetrical reasons, but if the woman is not on therapy and there is no urgent medical indication for combination antiretroviral therapy, it can be delayed until after 14 weeks’ gestation. (III-B)   6. All women living with HIV (both those who still have a detectable viral load after exposure to antiretroviral therapy and those who are antiretroviral-naive) should have their virus genotyped and, if possible, tested for phenotypic resistance to assist in optimizing antiretroviral therapy. It is advisable to discuss the interpretation of the genotype testing and any changes to the antiretroviral therapy with experienced clinicians. Testing for HLA-B*5701, if not done previously, is recommended in case abacavir might be required. (II-2B)   7. A combination antiretroviral therapy regimen including a dual nucleoside reverse transcriptase inhibitor (NRTI) backbone that includes one or more NRTIs and a boosted protease inhibitor should be favoured because there is higher confidence in its safety and efficacy in pregnancy. Whenever possible, antiretrovirals known to cross the placenta to the fetal compartment should be used. (II-2B)

  8. Whenever possible, drugs with no safety data should be avoided during the period of organogenesis. Efavirenz should not be prescribed in the first trimester of pregnancy because of its possible teratogenicity; however, if exposure has occurred and the neural tube has closed, efavirenz can be continued. Nevirapine should not be started in pregnancy, unless indicated by the woman’s resistance patterns, because it is associated with a high rate of serious adverse outcomes in this situation; however ongoing, pre-pregnancy treatment with nevirapine can be continued through pregnancy if tolerance and efficacy are established. (II-3D)   9. If antiretroviral therapy is discontinued for any reason during pregnancy, all drugs should be discontinued at once (unless the woman is on nonnucleoside reverse transcriptase inhibitors; in that case a tail of 2 nucleoside reverse transcriptase inhibitors is recommended for 1 week), and all drugs should be resumed simultaneously to minimize the risk of viral resistance developing during therapy. Antiretroviral therapy should be resumed as quickly as possible after discontinuance to minimize the risk of rebound viremia and the potentially increased risk of vertical transmission. (II-1A) 10. If a pregnant woman has significant nausea of pregnancy, do not begin antiretroviral therapy until her nausea is adequately controlled. Most antinauseants used in pregnancy can be coistered with antiretrovirals. If the woman is already on antiretrovirals and has hyperemesis of pregnancy, discontinue all antiretrovirals at once, and then reinstate all at once, when nausea and vomiting are controlled (unless the woman is on non-nucleoside reverse transcriptase inhibitors [NNRTIs], in which case a tail of 2 nucleoside reverse transcriptase inhibitors is recommended for 1 week to prevent future NNRTI resistance). (II-2D) 11. Therapy should be individualized to maximize adherence to the prescribed antiretroviral regimen. (III-A) 12. Routine dose adjustment of the combination antiretroviral therapy is not recommended in pregnancy. (III-D) ANTEPARTUM MANAGEMENT General Considerations

It is important to consider the broad context of a woman’s life when managing her HIV and prenatal care. Considerations include: AUGUST JOGC AOÛT 2014 l S19

SOGC CLINICAL PRACTICE GUIDELINE

•• Providing empathetic, non-judgemental care to women living with HIV and their children, in the spirit of professionalism.100 •• Addressing early and systematically the woman’s need for social , with at least one interview with a social worker. Pregnant women living with HIV in Canada commonly experience challenging social and economic environments, with 25% of infections linked to drug use.10,11 The aim of the comprehensive assessment by a social worker is to determine the woman’s needs and to propose culturally relevant and follow-up if required. •• Maintaining confidentiality, including with relatives.100 •• Encouraging the testing of partners and previous children if their HIV status is unknown.101 The medical and psychological needs of the fathers should be addressed, and the men referred to other health care providers if necessary.102 •• Advising on the use of, and facilitating access to, condoms for the purpose of preventing transmission of HIV and other sexually transmitted infections.103 If both of the couple are living with HIV, they should be informed of the possible risk of superinfection associated with unprotected sex.104 •• Respecting the wishes of a mother who refuses antenatal cART after being fully informed and counselled. A plan for the care of the newborn should be prepared prior to delivery.100 Inclusion of de-identified data of the mother and infant pairs in provincial and national surveillance programs is highly recommended. The HSP, an initiative of the Canadian Pediatric AIDS Research Group (ARG) collects important public health data, which inform allocation of resources and management of future pregnancies.10,11 First Trimester (Weeks 0 to 13)

Early pregnancy offers the opportunity for complete HIV and obstetrical assessments and permits planning for prenatal genetic screening. In addition to the standard antenatal assessments for all pregnant women, assessment should include the following: documentation of history of prior HIV-related illnesses and past CD4-cell counts and plasma HIV viral loads; assessment for symptoms of opportunistic infections; complete physical examination including a pelvic examination and cervical Pap smear; screening for sexually transmitted infections (including chlamydia, gonorrhea, syphilis); screening for HBV (using HBsAg, anti-HBs, and anti-HBc), HCV (HCV antibody and HCV PCR status if antibody positive) and tuberculosis (induration of > 5 mm S20 l AUGUST JOGC AOÛT 2014

using purified protein derivative); and evaluation of immunization status. In addition to standard prenatal blood work, the following blood work should also be obtained: CD4-cell count (absolute count and fraction), HIV viral load, baseline CBC and differential, and liver (AST, ALT, LDH) and renal (urea, serum creatinine) function testing (see Table 4 and Table 5). All pregnant women who are living with HIV, regardless of age, should be offered, through an informed consent process, dating ultrasound and prenatal genetic screening for the most common clinically significant fetal aneuploidies. Timely referral is critical to ensure women are able to undergo the type of screening test they have chosen. Ideally, first trimester biochemical screening and nuchal translucency measurements (at 11 to 14 weeks) should be obtained to integrate with second trimester biochemical screening, and these results should be used to inform the need for invasive testing.105 If integrated prenatal screening is not accessible, then pregnant women living with HIV should be offered the non-invasive screening for aneuploidy based on gestational age that is available in the area. As maternal serum testing of fetal aneuploidy becomes more available, this method of testing will be preferred over amniocentesis, particularly in this population. Nausea and vomiting can be a significant issue for all pregnant women, and in women living with HIV, it may affect their ability to adhere to the prescribed antiretroviral regimen. Evaluation of nausea and vomiting of pregnancy should be conducted and aggressive management of this condition, starting with a prescription for doxylaminepyridoxine as needed,40 is necessary to facilitate the initiation and/or continuation of antiretroviral medications. Important considerations when evaluating nausea and vomiting of pregnancy in a woman living with HIV should include antiretroviral-related lactic acidosis or pancreatitis, as well as opportunistic infections including intestinal protozoa if the woman is at risk (e.g., CD4-cell count < 200 cells/mm3) and symptoms are accompanied by diarrhea. In particular, in women with very advanced HIV disease, alternative causes for nausea should be considered (e.g., gastric lymphoma, central nervous system lesions, or infections causing increased intracranial pressure).35 As outlined above, the timing of initiation of antiretroviral therapy will depend on current CD4-cell count and maternal conditions including nausea and vomiting. Antiretroviral therapy and prophylaxis or treatment of opportunistic infections should be started immediately if CD4-cell count is < 200 cells/mm3 and/or there are AIDS-defining illnesses requiring therapy. In other cases, it is advisable to ensure

√ opt

√ √

Phosphatemia§

Urinalysis & urine culture

√ √ √ √ √

Toxoplasma IgG

Syphilis (RPR)

Varicella IgG

HAV IgG

HBsAg, anti-HBs, anti-HBc

HCV IgG¶

√ √

Pap smear

HSV history#

GBS screen anorectal swab**

√

Cervix chlamydia & gonorrhea NAAT

uE3, hCG, AFP, inhibin A

√

√ 11–13+6 NT √ 15–20+6

√ opt

√ opt

√ opt

√ opt

√ opt

√ opt

15–17 weeks

√ detailed

√ opt

√

√

√

√

√

√

19–20 weeks

√ opt growth

√

√ opt

√ opt

√ opt

√ opt

√ opt

√ opt

24–26 weeks

√ growth

√ 154

√

√

√

√

√

√

28–30 weeks

√

√ opt growth

√ opt

√

√

√

√

√

√

32–36 weeks

√

√

√

√

√

√

Delivery

√

√

√

√

√

√

√

4–6 weeks

**Group B streptococcus anorectal swab is recommended at 35 to 37 weeks, or sooner if delivery is anticipated within 5 weeks.

#If there is a positive genital herpes history, recommend starting prophylactic treatment (e.g., valacyclovir 500 mg orally twice daily) at 34 to 36 weeks to prevent recurrent herpes simplex virus at delivery.

¶Confirm positive result of HCV antibodies with HCV PCR.

‖Screen for gestational diabetes using 50 g glucose challenge test (1 h plasma glucose [PG]) or 75 g oral glucose tolerance test (fasting PG, 1 h PG, 2 h PG).99 If a woman is receiving a PI-based regimen, particularly if initiated before pregnancy, consideration can be given to performing this screening test earlier.

§Phosphatemia should be monitored in women receiving tenofovir-based regimens because it is a potential cause of tubular toxicity.3,56,57

‡HLA-B*5701 testing is recommended at baseline or if not previously done before initiating therapy with abacavir.

†HIV genotypic drug testing is recommended at time of first HIV plasma viral load, at time of initiation of antiretrovirals, and if and when treatment fails or viral load suppression is incomplete (> 250 HIV copies/mL).

*Integrate initial visit laboratory tests and/investigations (as indicated) with all others if the visit occurs after 10 weeks’ gestation.

opt: optional; BUN: blood urea nitrogen; HAV: hepatitis A virus; NT: nuchal translucency; PAPP-A: pregnancy associated plasma protein A; uE3: unconjugated estriol; hCG: human chorionic gonadotropin; AFP: alphafetoprotein; NAAT: nucleic acid amplification test; HSV: Herpes simplex virus; GBS: group B streptococcus.

Sexually transmitted & other infections

PAPP-A

√ dating

√

Rubella IgG

Ultrasound

√

CMV IgG

Ultrasound & prenatal screening

√

Blood type

Serology

Gestational diabetes screen‖

Fasting glucose

Blood type

Blood glucose √

√ opt

√

Creatinine, BUN

√

√ opt

Renal function

√ opt

AST, ALT, LDH, bilirubin

Liver function tests

√

CBC with differential

Hematologic assessment

√

√

HLA-B*5701‡

√ opt

√

HIV genotypic drug resistance†

Drug resistance & abacavir hypersensitivity testing

√

HIV viral load

HIV plasma viral load

√ opt

√

CD4

Immunologic assessment

10–13+6 weeks

Initial visit*

Table 4. Recommended laboratory tests and investigations for pregnant women living with HIV by visit and gestational age

Guidelines for the Care of Pregnant Women Living With HIV and Interventions to Reduce Perinatal Transmission

AUGUST JOGC AOÛT 2014 l S21

SOGC CLINICAL PRACTICE GUIDELINE

Table 5. United States Food and Drug istration pharmaceutical pregnancy categories213 A

Adequate and well-controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk during later trimesters).

B

Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women OR Animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester.

C

Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant woman despite potential risks.

D

There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experiences or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

X

Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits.

nausea and vomiting is controlled prior to initiating antiretroviral therapy. Women who are receiving antiretroviral therapy prior to pregnancy should not discontinue their medication regimen during the first trimester. All drug therapy should be reviewed for safety in pregnancy, particularly in the first trimester period of embryogenesis. Women should be counselled on all relevant aspects of ensuring a healthy pregnancy including maintaining a healthy diet and lifestyle. Women should start or ideally continue taking folic acid 1 mg daily for at least the first 3 months of their pregnancy. If necessary, in cases of food insecurity, resources should be offered to improve nutrition. Notably, malnutrition and micronutrient deficiencies have been linked to vertical transmission risk.106 Live vaccines (varicella zoster and measles, mumps and rubella) are contraindicated in pregnancy.107 Women with negative serologies for these infections should be considered for immunization postpartum, depending on their CD4 count, and the schedule of recommended immunization for adults living with HIV should be followed.33 In particular, HBV, pneumococcus, and influenza vaccines can be safely istered in pregnancy. Within a harm reduction model, women should be encouraged to stop smoking, drinking alcohol, and using recreational drugs and should be referred for appropriate counselling and/or treatment.1,108,109 Other harm reduction strategies that can be offered if appropriate include nicotine replacement treatment and opiate harm reduction measures such as methadone and/or buprenorphine programs. Second Trimester (Weeks 14 to 27)

Assessment of the status of the woman’s HIV, review of laboratory investigations from the first trimester, and re-evaluation of antiretroviral drug therapy should be completed during the second trimester. The women’s S22 l AUGUST JOGC AOÛT 2014

clinical, virological, and immunologic status including CD4-cell count, HIV viral load, CBC, AST, ALT, LDH, bilirubin, blood urea nitrogen, creatinine, as well as any other blood work as indicated by clinical history and specific cART regimen, should be assessed every 4 to 8 weeks throughout pregnancy (see Table 4). Because comorbidities affect many women living with HIV, more frequent evaluations may be appropriate. Consideration for repeat urine cultures in second and third trimester should be made given the higher rates of hospitalization for urinary tract infections in women living with HIV.110 All women should be screened for gestational diabetes between 24 and 28 weeks as recommended in most recent guidelines.99 As discussed above, there is conflicting evidence on whether cART regimens containing PIs increase the risk of hyperglycemia or new-onset or exacerbated diabetes in pregnancy (see also Appendix 2). If a woman is receiving a PI-based regimen, particularly one initiated before pregnancy, consideration can be given to earlier screening for gestational diabetes. The second part of the integrated prenatal screening tests (i.e., second trimester biochemical screening) should be performed at 15 to 19 weeks.105 A detailed ultrasound at 18 to 20 weeks is recommended to assess growth and fetal anatomy.105 If aneuploidy or any other fetal infection or syndrome that has prenatal diagnostics is a concern, invasive testing should be considered. Invasive testing should only occur if statistical risk of the condition is higher than the risk of the procedure, taking into consideration the biochemical, serologic, and ultrasound results.105 When amniocentesis is performed, the woman should ideally be on cART, but the timing may not permit full suppression of her HIV viral load prior to the procedure. In the pre-cART era, the risk of vertical transmission in women who underwent

Guidelines for the Care of Pregnant Women Living With HIV and Interventions to Reduce Perinatal Transmission

amniocentesis was twice as high as those who did not (30% vs. 16%, RR = 1.85; 95% CI 0.69–4.98.111 Since the initiation of cART and the recommendation to treat all pregnant women, there have been no documented transmissions.112–115 However, it is impossible to rule out a residual small increase in risk of transmission with amniocentesis in women on cART with a fully suppressed plasma viral load. Noninvasive molecular prenatal testing should be considered as an option to avoid invasive testing.116 General obstetrical management with referral of the woman to services as needed is appropriate at this time. A review of the care providers involved and the delivery plan, including location of delivery, can be initiated at this time (at the 19- to 20-week and 23- to 24-week visits). Third Trimester (Weeks 28 to 40)

The efficacy and toxicity of the particular cART regimen for each woman should be determined by CD4-cell count, HIV viral load, and hematologic, liver, and renal parameters in the third trimester, approximately every 4 to 8 weeks (see Table 4). Given the risk of placental dysfunction associated with increased rates of intrauterine growth restriction and oligohydramnios in the pregnancies of women living with HIV,117 follow-up growth ultrasound should preferably be done monthly, but if this is not possible, a third trimester scan can assist in determining whether there has been placental or fetal compromise. Considering the higher rate of preterm birth in this population,67,83,86,92 close clinical follow-up is recommended and the schedule of some obstetrical assessments (e.g., group B streptococcus screening) and prophylaxis (e.g., genital herpes prophylaxis) may need to be adjusted. Adherence to cART regimens should be emphasized at each visit throughout pregnancy; however, this is critical in the third trimester because virologic suppression (HIV viral load < 50 copies/mL) should be achieved at this time. If the woman’s viral load has not been suppressed or has appeared to rebound, a number of factors must be considered. Health care providers should reassess overall adherence, clarify any reasons for non-adherence, and attempt to implement strategies or provide tools to assist the woman in taking her medication. Inpatient directly observed therapy may be considered.118 Clinicians should also reassess dosing adequacy and consider the need for increased dosing of antiretroviral medications in the third trimester. Therapeutic drug level monitoring may also be considered to guide the need for dose adjustment.54 In all cases viral genotype history should be reassessed and current HIV viral load sample sent for repeat genotyping if applicable.

Between 30 to 35 weeks it is important that a plan for location and mode of delivery is established and a formula-feeding plan has been arranged for the infant. Women living with HIV are recommended to formula feed their infants; to avoid the 9.3% (3.8 to 14.8%) increased risk of post-natal transmission of HIV through breast milk, breastfeeding is not recommended.119–121 The risk of disclosure that may arise when a women does not breastfeed may compromise her confidentiality. Health care providers should assist with a plan before delivery that can help women feel more comfortable when discussing feeding with family and friends. Plans for ongoing HIV care should also be established at this time (see Postpartum Management). Delivery Plans and Mode of Delivery

Planning the hospital location for delivery should take into consideration the woman’s gestational history, home location and transportability, facilities at her regional hospital, and the comfort and experience of the local care providers. If delivery is being considered outside a regional tertiary care facility, information on pregnancy history and management plans should be provided to the facility prior to the woman’s estimated date of delivery, communication with local care providers should be established, and arrangements should be made to ensure that required intrapartum and postpartum antiretroviral drugs are available at the designated facility. Mode of delivery has been reviewed extensively with both cohort studies and a randomized controlled trial of intended mode of delivery. The burden of evidence s a vaginal delivery if obstetrically appropriate and if virologic suppression has been achieved.8,16,122–124 The initial studies that identified elective Caesarean section as a method to reduce vertical transmission were conducted in women who were not receiving any antiretroviral drug therapy or who received monotherapy with zidovudine only. Evidence to elective Caesarean section in the current cART era, when all women (even with viral loads < 1000 copies/mL) are recommended to initiate cART in pregnancy,16 is absent. European surveillance data124,125 did not show a significant benefit of elective Caesarean delivery in the cohort of women with undetectable viral loads while on cART. Therefore, the evidence s elective Caesarean section at 38 weeks to minimize the risk of presentation in spontaneous labour only in women who have an unknown viral load, who have a viral load > 1000 copies/mL, or who are not on cART regardless of viral load. The booking time of 38 weeks for Caesarean section, rather than the usual 39 weeks, is proposed because avoidance of labour in this setting is paramount. Considering the potential complications of operative AUGUST JOGC AOÛT 2014 l S23

SOGC CLINICAL PRACTICE GUIDELINE

delivery, however, women who receive antepartum cART, are adherent to therapy, and have an HIV viral load < 1000 copies/mL near term (i.e., obtained within 4 weeks of delivery) can be delivered vaginally, reserving Caesarean sections for obstetrical indications only. It is also important to note that the benefit of Caesarean section shown in early studies appears to have been found exclusively in prelabour elective Caesarean sections; no benefit was shown for emergency Caesarean sections.8,123 Recommendations

13. The woman’s clinical, virological, and immunological statuses should be assessed every 4 to 8 weeks during pregnancy, and again 6 weeks postpartum. Routine criteria should be used to assess the woman’s response to, and the possible failure of, antiretroviral therapy. The toxicity of the antiretrovirals should also be monitored at these times. Specific testing should be individualized for the known toxicities of the woman’s antiretroviral therapy regimen. (III-B) 14. As for all pregnant women, all those living with HIV, regardless of age, should be offered, through an informed consent process, dating ultrasound and non-invasive prenatal genetic screening for the most common clinically significant fetal aneuploidies. (III-A) 15. A detailed obstetrical ultrasound at 19 to 20 weeks’ gestation is recommended. Additional ultrasounds, for fetal growth and amniotic fluid volume, are recommended at least each trimester, or as guided by obstetrical indications. (II-3B) 16. As for all pregnant women, those living with HIV should be screened periodically for substance use, and drug addiction should be addressed as needed in conjunction with HIV management. (III-A) 17. Mode of delivery should be discussed in detail with all women: a. Women on optimal antiretroviral therapy with acceptable plasma viral load suppression (less than 1000 c/mL) over the last 4 weeks prior to delivery are recommended to have a vaginal delivery in the absence of other obstetrical indications for Caesarean section. If Caesarean section is recommended for obstetrical indications, it can be conducted at 39 weeks, as usual for those indications. (I-A) b. Women not on optimal antiretroviral therapy (i.e., no antiretroviral therapy, monotherapy only, or with an incompletely suppressed viral load) should be offered a scheduled pre-labour Caesarean section at approximately 38 weeks’ gestation. (II-2A)

S24 l AUGUST JOGC AOÛT 2014

INTRAPARTUM MANAGEMENT Intrapartum management for women known to be living with HIV

All women known to be living with HIV should be instructed to attend the labour and delivery department immediately upon rupture of membranes or regular contractions so that measures can be taken to decrease the risk of vertical HIV transmission. All oral antenatal antiretroviral medications, with the exception of stavudine, should be continued for as long as possible during labour. Stavudine should not be istered concomitantly with IV zidovudine because of an antagonistic drug interaction.46 There are no randomized controlled trial data on the additional benefit of intrapartum IV zidovudine in women who have been receiving antenatal cART. A large cohort study of > 5000 pregnant women living with HIV, who received intrapartum IV zidovudine in addition to various (mono, dual, triple) antenatal antiretroviral therapy regimens, reported a significant benefit of IV zidovudine in reducing vertical transmission among those women with HIV viral loads > 10 000 copies/mL (5.3% vs. 22.7%, P = 0.009) at delivery.126,127 However, there was no additional benefit of IV zidovudine reported among women with HIV viral loads < 400 copies/mL at delivery (0.6% vs. 0%, P > 0.99), and data were not provided for women with viral loads from 400 to 9999 copies/mL. Based on this cohort data, the most recent perinatal guidelines published by the NIH in the United States endorse intrapartum IV zidovudine for women living with HIV who are receiving antenatal cART and have an HIV viral load > 400 copies/mL (or unknown viral load) near delivery; however, they do not recommend its istration for those women on cART with an HIV viral load ≤ 400 copies/mL.3 Canadian data, however, show that 8.7% of women with previously suppressed viral load have unpredictably elevated viral loads at time of delivery.128 On the basis of this evidence, intrapartum IV zidovudine (2 mg/kg IV load over 1 hour followed by 1 mg/kg/hour until delivery) continues to remain the standard of care in Canada and is recommended for all women, regardless of mode of delivery, current antiretroviral regimen, or viral load. Intravenous zidovudine should be istered as soon as it is determined the woman is in active labour and/ or has ruptured membranes, or at least 2 to 3 hours prior to Caesarean section. If in the future rapid HIV viral load measurements become available on day of delivery, decisions regarding the need for IV zidovudine could be modified. Women who did not receive any antiretroviral therapy during pregnancy should also receive a single dose of oral nevirapine (200 mg) as soon as possible at the onset of labour or at least 2 to 3 hours prior to Caesarean section. This recommendation also differs somewhat from that

Guidelines for the Care of Pregnant Women Living With HIV and Interventions to Reduce Perinatal Transmission

in the NIH perinatal guidelines,3 where intrapartum IV zidovudine (but not single-dose oral nevirapine) and combination infant antiretroviral with zidovudine plus 3 doses of nevirapine is recommended for women who were not receiving antepartum antiretroviral therapy (or those with incomplete viral load suppression). However, in our experience a number of practicalities must be considered when women present in labour, including the frequent difficulty of obtaining IV access, which makes the istration of IV zidovudine difficult or impossible. Because single-dose oral nevirapine has been demonstrated to reduce vertical transmission of HIV,23 it continues to be recommended for intrapartum istration to women living with HIV who have not received antenatal therapy, in addition to istration of cART to their infants. The addition of 7 days of lamivudine-zidovudine postpartum for the mother is recommended in order to mitigate the risk of nevirapine resistance.31 Mode of delivery has been described in detail above. Elective Caesarean section at 38 weeks of gestation to reduce the risk of vertical transmission of HIV is recommended for women with a viral load > 1000 copies/mL at delivery or those with an unknown viral load (e.g., have not accessed care and/or are not taking antiretroviral drug therapy) near the time of delivery. Importantly, there are limited data to the benefit of emergency Caesarean section for the purpose of reducing the risk of vertical HIV transmission. Women on optimal antiretroviral therapy with acceptable plasma viral load suppression (less than 1000 c/mL) over the last 4 weeks prior to delivery are recommended to have a vaginal delivery (in the absence of other obstetrical indications for Caesarean section). If Caesarean section is recommended for obstetrical indications, this can be conducted at 39 weeks usual for those indications. Data from the pre-cART era indicate that obstetrical interventions that increase the exposure of the infant to maternal blood, such as invasive monitoring or episiotomies, may increase the risk of transmission.129–132 Extrapolating these data into the present era of cART, it is recommended that interventions that potentially increase fetal exposure, including scalp electrodes, intrauterine catheters,133 prolonged rupture of membranes, operative vaginal deliveries, and episiotomies, should be avoided if possible. However, some Canadian data have been reassuring about the risk of HIV transmission in HIV-suppressed women with prolonged membrane rupture.133 Additional important considerations during the intrapartum period include, among others: epidural anaesthesia is not contraindicated; if a woman is group B streptococcus positive, continue to initiate antibiotic

prophylaxis according to protocol; and, if a woman has ruptured membranes and is not in labour, initiate oxytocin induction of labour in addition to intravenous zidovudine (the medications are compatible). Intrapartum management for woman of unknown HIV status and/or ongoing HIV risk

Many women who are at risk for HIV infection do not receive antenatal care and present late in their pregnancy or in early labour with unknown HIV status. Women at particular risk of HIV infection include those who use injection drugs and have shared needles; have had a recent illness suggestive of seroconversion; have had regular unprotected sex with a partner known to be living with HIV or at significant risk for HIV infection; or have had a diagnosis of a sexually transmitted infection during the pregnancy. Women who have been recently incarcerated or who have emigrated from areas with endemic HIV are also at increased risk if they have not been recently screened. Women with unknown HIV status or at continued risk of HIV infection since their last negative HIV serology result should be offered (if available in the institution) rapid HIV antibody testing in the labour and delivery setting with appropriate pre- and post-test counselling. If the test result is positive, the woman should be informed of the result, and confirmatory HIV PCR and antibody tests should be performed.12,13 Maternal intrapartum antiretroviral drug therapy (intravenous zidovudine and single-dose oral nevirapine) plus postpartum zidovudine-lamivudine (Combivir, 1 tablet orally twice daily for 7 days; see Postpartum Management) and infant prophylactic cART (see Infant Management) should be initiated pending results of the confirmatory test. If the confirmatory test is negative, maternal and infant antiretroviral drugs may be discontinued. It is recommended that all women who have not been tested in pregnancy, particularly those who are recognized to be at high and ongoing risk for HIV infection, be offered HIV testing as soon as possible, with appropriate pre- and post-test counselling. Women involved in ongoing high-risk HIV transmission activities who are HIV negative on initial testing should be retested each trimester,12 and if possible again near term. HIV testing should also occur with the woman’s knowledge and verbal consent, and appropriate pre- and post-test counselling should accompany each test. If rapid HIV antibody testing is not available within the institution and/or delivery is imminent and HIV seropositivity is a possibility, HIV PCR and HIV antibody tests should be performed. Intrapartum and postpartum (IV zidovudine, single-dose oral nevirapine, Combivir) AUGUST JOGC AOÛT 2014 l S25

SOGC CLINICAL PRACTICE GUIDELINE

antiretroviral drugs therapy should be offered to the woman, and all infants should receive prophylactic antiretroviral therapy pending results (see Infant Management). If the HIV antibody test is negative and the woman is out of the seroconversion period (e.i., has not engaged in high-risk activities within the previous 4 weeks) and/or HIV PCR is negative, infant antiretroviral prophylactic therapy and maternal zidovudine-lamivudine may be discontinued. If the woman at risk is found to be living with HIV, a full 6-week course of infant antiretroviral prophylactic therapy should be completed and the woman should receive a complete 7-day course of oral zidovudine-lamivudine to prevent the emergence of nevirapine-resistant virus. A referral should be made for ongoing HIV assessment and care for both the mother and the infant for all women who are determined to be living with HIV during labour or delivery. Appendix 3 summarizes intrapartum and postpartum recommendations and includes a management algorithm for women known to be living with HIV or in whom HIV infection has not been ruled out. Recommendations

18. Intravenous zidovudine should be initiated as soon as labour onset until delivery, in combination with an oral combination antiretroviral regimen, regardless of mode of delivery, current antiretroviral regimen, or viral load. (III-B) 19. Intrapartum, a single dose of oral nevirapine (200 mg) remains an option in the unusual circumstance of a woman living with HIV who has not received antenatal antiretroviral therapy in pregnancy. (II-2B) POSTPARTUM MANAGEMENT

Postpartum care involves collaborative efforts between obstetric care providers, HIV specialists, and other multidisciplinary health care providers to ensure coordinated HIV care for both the mother and her infant. A number of comprehensive issues that must be addressed include contraception, continuation of and adherence to antiretroviral drug therapy regimens, infant feeding and pediatric care, and the woman’s needs for mental health services, social services, and/or treatment of substance use. The use of ergotamine should be avoided because of the risk of exaggerated vasoconstriction in women receiving protease inhibitor therapy.134 Oxytocin, misoprostol, and prostaglandin F2 alpha are recommended agents for managing postpartum hemorrhage. A number of studies have evaluated the risk of infectious morbidity following delivery in women living with HIV.135–139 Some studies S26 l AUGUST JOGC AOÛT 2014

report higher rates of endometritis and pneumonia following Caesarean section in women living with HIV than in women without,136 but others do not.135 Endometritis does, however, occur in a higher percentage of all women following Caesarean section, and routine preoperative prophylactic antibiotics have been demonstrated to decrease postoperative infection.140 Preoperative antibiotics are therefore recommended for all women who undergo elective or emergent Caesarean section, including women living with HIV, to decrease infectious postoperative complications.141 Women who were receiving antenatal antiretroviral therapy should have their complete regimen resumed after delivery as soon as oral intake is tolerated. Women who were not receiving antenatal antiretroviral therapy but who received single-dose nevirapine during labour should receive 7 days of zidovudine-lamivudine, 1 tablet orally twice daily, to reduce the risk of developing nevirapine resistance. Zidovudine-lamivudine therapy can be discontinued before completion of the 7-day treatment period if confirmatory HIV testing results show that the woman is not living with HIV. Plans for ongoing HIV care should be established prenatally, and unless otherwise indicated, maternal antiretroviral therapy should be continued after delivery and reassessed for ongoing therapy by providers of adult HIV care. Based on future pregnancy planning and adult HIV status, antiretroviral treatment modifications may be appropriate. Adherence in the postpartum period can be challenging142,143 and is important. There is a risk of HIV transmission through breast milk119,121; therefore breastfeeding is contraindicated regardless of maternal antiretroviral therapy or viral load. Management of the effects of not breastfeeding should include measures such as acetaminophen, ibuprofen, and cold compresses to minimize pain from engorgement. Bromocriptine and cabergoline, the classical therapies used for lactation suppression, are ergot derivates, whose co-istration with PIs is contraindicated. Women who test positive on rapid HIV antibody testing or who are believed to be at high risk of HIV (when rapid HIV antibody testing is not available) are advised to pump their breast milk, but they should not feed it to the infant unless a confirmatory HIV test is negative. An early return to fertility can be expected as a result of not breastfeeding. It is critical to discuss safer sex practices and effective contraception methods with the women. Condom use is recommended to reduce the risk of transmission between partners; however, the contraception failure rate with condoms is reported to be as high as 14% as commonly used.144 Oral contraceptives may also be used by women living with HIV, particularly

Guidelines for the Care of Pregnant Women Living With HIV and Interventions to Reduce Perinatal Transmission

with the use of condoms as part of a dual-protection strategy. Drug interactions between antiretroviral drugs and oral contraceptives have been documented; therefore it is important to assess for potential interactions between specific antiretroviral agents and oral contraceptives. This information is available in the NIH Perinatal HIV Guidelines3 and on the Motherisk website.145 Nonoral contraceptive methods including DMPA (DepoProvera), contraceptive patch or vaginal ring, and levonorgestrel IUD are also options; however, data for them in combination with antiretroviral medications is not available. The side effect profile of DMPA has been shown to be the same in women living with and without HIV146; however, consideration should be given to the bone loss seen in women using DMPA, since bone loss in women living with HIV is already faster than in their uninfected counterparts. Data on copper or levonorgestrel IUD use in women living with HIV are limited, but given the value of this method for successful contraception and low general rates of infection, use in women with CD4-cell counts > 200 cells/mm3 is appropriate.144 Linkage to care is important for all women living with HIV, particularly those who are newly diagnosed with HIV during labour and delivery. All women should have arrangements for follow-up care with providers experienced in the management of HIV. Recommendation

20. Plans for ongoing HIV care should be established prenatally, and unless otherwise indicated, maternal antiretroviral therapy should be continued after delivery and reassessed for ongoing therapy by providers of adult HIV care. (II-1A) INFANT MANAGEMENT

Mothers should be offered antiretroviral prophylaxis for their infants regardless of maternal antenatal or intrapartum antiretroviral therapy, viral load, or mode of delivery. The recommended regimen will depend on the presumed level of risk. Infants born to a mother known to be living with HIV and a viral load < 1000 copies/mL should be offered prophylactic therapy with oral zidovudine for 6 weeks. Intravenous zidovudine may be used if the infant is unable to tolerate oral intake. The dose of zidovudine is determined based on gestational age, with a twice-daily dosing regimen now recommended for all infants (see Appendix 4). The infant zidovudine prophylaxis should be started as soon as possible, no later than 6 to 12 hours after birth. Infants born to a mother known to be living with HIV and who has a known or projected viral load > 1000 copies/mL

or to a mother known to be living with HIV and who did not receive any antepartum antiretroviral therapy (this includes a mother who is presumed to be living with HIV based on a positive rapid HIV antibody test result) should receive prophylactic cART with a 3-drug regimen including zidovudine for 6 weeks combined with 3 doses of nevirapine in the first week of life (at birth, day 2, and day 6 of life) and twice-daily oral lamivudine for 2 weeks. This recommendation is made on the basis of the HPTN040/PACTG 1043 trial which enrolled women living with HIV who were not receiving antenatal antiretrovirals and demonstrated that combination regimens had better efficacy (2.2%) in reducing vertical transmission to infants intrapartum than zidovudine alone (4.8%).25 While this trial does not address whether prophylactic cART provides additional protection against transmission in infants born to mothers who have suboptimal viral suppression near delivery (i.e., > 1000 copies/mL), extrapolation of those results suggests that prophylactic cART should be recommended, particularly in situations involving vaginal delivery. Although the HTPN040/PACTG 1043 trial evaluated a 2-drug zidovudine and nevirapine combination regimen, the addition of a third agent, lamivudine, is recommended in order to prevent the emergence of nevirapine resistance should the infant be infected with HIV. The rationale for this recommendation is to provide a highly active antiretroviral regimen throughout the first 2 weeks of life when nevirapine is expected to be circulating at decreasing but significant levels, due to its very long half-life (median 30 hours, range 18 to 50 hours in newborns).27 In settings where rapid HIV antibody testing is not yet available, the optimal management strategy for infants born to women with unknown HIV status and considered at high risk of HIV infection has not been established in a randomized clinical trial. In this clinical scenario, the potential benefit of preventing vertical transmission of HIV is believed to outweigh the potential risks of the infant’s unnecessary exposure to antiretrovirals; therefore combination infant prophylaxis (with zidovudine, 3-dose nevirapine, and lamivudine) is recommended until confirmatory HIV test results are available. Surveillance and poll-result data reported out of the United Kingdom, Ireland, and United States indicate increasing use of prophylactic cART for infants in high-risk situations.147,148 Until HIV-negative status can be confirmed, pumping breast milk, but not feeding it to the infant is recommended. Dosing recommendations and commercial names for the prophylactic antiretroviral agents are specified in Appendix 1. Of note, hepatic clearance is slower in preterm infants, but pharmacokinetic data informing dosing are limited, particularly in infants with a birth weight below 1.5 kg.149,150 AUGUST JOGC AOÛT 2014 l S27

SOGC CLINICAL PRACTICE GUIDELINE

Breastfeeding remains contraindicated for mothers living with HIV regardless of maternal viral load, antepartum cART regimen, and continuation of postpartum antiretroviral therapy. In Malawi, peripartum HIV transmission through breastfeeding was found to be as high as 4% at 48 weeks when mothers were prescribed cART or infants received daily nevirapine prophylaxis versus 7% in the absence of maternal or infant antiretrovirals.118 Canadian surveillance data and a meta-analysis also show high rates of postpartum virologic rebound due to nonadherence among women who are prescribed ongoing cART.142,143 It is important to discuss feeding practices with the mother during antenatal visits, using a sensitive approach and acknowledging the mother’s cultural beliefs about infant feeding. Because premastication by caregivers living with HIV has been implicated as a potential route of HIV transmission to young infants, health care practitioners should also inquire specifically about premastication and advise caregivers living with HIV to avoid this practice. Infants exposed to HIV should be tested for HIV infection by a virological test at birth, 4 weeks, and 3 to 4 months of age to determine HIV status. Additional testing for infants at high risk of vertical transmission should be discussed with a pediatric HIV specialist. HIV RNA PCR (or nucleid acid amplification test) is the virological test currently used for diagnostic purposes. HIV infection can be excluded when two HIV virological tests are nonreactive, one collected after 4 weeks of age and the other at least 4 weeks after the end of prophylactic antiretrovirals. Serological EIA tests are not indicative of infant status due to the presence of detectable maternal HIV antibodies up to 18 to 24 months of age. A confirmatory HIV EIA test is recommended to document seroconversion after 18 months of age. If an HIV PCR is reactive, a confirmatory RNA PCR test should be requested immediately. When an infant is found to be infected with HIV, antiretroviral prophylaxis should be discontinued, and an urgent referral to an HIV specialist should be made for HIV therapy and comprehensive care. Early initiation of cART has been shown to improve longterm outcomes151 and may prevent the establishment of viral reservoirs in infected infants.152 Infants should also be monitored with a CBC and differential at baseline and at 4 weeks of age. Zidovudine prophylaxis is generally well tolerated, but low grade anemia or neutropenia with elevated platelet count are not uncommon after receipt of 4 weeks of zidovudine prophylaxis.18,19,93,153 If hemoglobin levels are below 100 g/L S28 l AUGUST JOGC AOÛT 2014

and expected to be further decreased with continued zidovudine exposure, early discontinuation of zidovudine prophylaxis at 4 weeks may be considered. Hematologic toxicity may be more common with exposure to cART; however, data are limited.3 In high-risk newborns receiving cART prophylaxis for the first 2 weeks of life, clinicians should consider obtaining an earlier CBC to monitor for toxicity. There is no evidence for nevirapine associated rash or hepatic toxicity in infants receiving either singledose or extended-dose nevirapine. Infants rarely present symptoms of mitochondrial toxicity; however, if an infant presents with unexplained neurologic or gastrointestinal symptoms, hepatic function (ALT, AST) and serum lactate should be measured.71,73 All infants born to women living with HIV should be referred for ongoing assessment and care to a pediatrician with expertise in this area. Developmental follow-up is crucial for HIV-exposed uninfected children. Factors such as poverty, food insecurity, low literacy, inexperience in parenting, and parental substance or alcohol use put infants at higher risk for failure-to-thrive, developmental delay, and behavioural disorders. Family physicians and pediatricians play an essential role in identifying and addressing such issues in uninfected HIV-exposed infants and children, and they should facilitate referrals to specialists and developmental resources. Long-term follow-up of children who were perinatally exposed to HIV and antiretrovirals is recommended into adulthood, due to unknown and theoretical concerns regarding the potential for carcinogenicity of nucleoside analogue antiretroviral drugs or other long-term effects of antiretroviral medications. 3 Including all HIV-exposed mother-infant pairs in the national surveillance program (HSP) is essential to keep generating important epidemiological data and to continued access to resources for these vulnerable families. Recommendations

21. HIV-exposed newborns should receive antiretroviral therapy for 6 weeks to prevent vertical transmission of HIV. (I-A) 22. Health care practitioners who care for HIV-exposed newborns should provide timely diagnostic HIV testing: HIV polymerase chain reaction at birth, 1 month, and 3 to 4 months and HIV serology at 18 months (II-A), and they should monitor both short- and long-term outcomes, including screening for adverse effects of antiretroviral therapy and for developmental delay. (III-A)

Guidelines for the Care of Pregnant Women Living With HIV and Interventions to Reduce Perinatal Transmission

23. Breast-feeding is not recommended regardless of plasma HIV viral load and use of antiretroviral therapy. (I-E) 24. The pregnancy should be ed with surveillance programs to allow the collection of provincial and national data to guide future pregnancy policies. Women undergoing antiretroviral therapy in pregnancy should also be offered inclusion in appropriate studies. (III-B) REFERENCES 1. Loutfy MR, Margolese S, Money DM, Gysler M, Hamilton S, Yudin MH. Canadian HIV pregnancy planning guidelines. J Obstet Gynaecol Can 2012;34:575–90. 2. on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents. Rockville (MD): Department of Health and Human Services; 2013. Available at: http://www.aidsinfo.nih.gov/guidelines/html/1/ adult-and-adolescent-arv-guidelines/0. Accessed on June 15, 2013. 3. on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States. Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf. Accessed on June 15, 2013. 4. UNAIDS, WHO, UNICEF. Global HIV/AIDS response: epidemic update and health sector progress towards Universal Access: progress report 2011. Geneva (CH): UNAIDS; 2011. Available at: http://www.unaids.org/en/media/unaids/contentassets/documents/ unaidspublication/2011/20111130_ua_report_en.pdf. Accessed on June 15, 2013. 5. Public Health Agency of Canada. Estimates of HIV prevalence and incidence in Canada. Ottawa: PHAC; 2011. Available at: http://www.phac-aspc.gc.ca/aids-sida/publication/survreport/ estimat2011-eng.php. Accessed on June 15, 2013. 6. Public Health Agency of Canada. Population-specific HIV/AIDS status report: women. Ottawa: PHAC; 2012. Available at: http://library.catie.ca/pdf/ATI-20000s/26407.pdf. Accessed on June 15, 2013. 7. Dybul M, Fauci AS, Bartlett JG, Kaplan JE, Pau AK; on Clinical Practices for Treatment of HIV. Guidelines for using antiretroviral agents among HIV-infected adults and adolescents. Ann Intern Med 2002;137:381–33. 8. The International Perinatal HIV Group. The mode of delivery and the risk of vertical transmission of human immunodeficiency virus type 1—a meta-analysis of 15 prospective cohort studies. N Engl J Med 1999;340:977–87. 9. Woman and Infants Transmission Study Investigators. Trends in motherto-infant transmission of HIV-1 in the WITS cohort: impact of 076 and HAART therapy. Paper presented at: Second Global Conference on Global Strategies for the Prevention of HIV Transmission from Mothers to Infants; September 1–5, 1999; Montreal. 10. Forbes JC, Alimenti AM, Singer J, Brophy JC, Bitnun A, Samson LM, et al. A national review of vertical HIV transmission. AIDS 2012;26:757–63. 11. Public Health Agency of Canada. HIV/AIDS Epi Updates: Chapter 7 Perinatal HIV Transmission in Canada. Ottawa: PHAC; 2010. Available at: http://www.phac-aspc.gc.ca/aids-sida/publication/epi/2010/pdf/ EN_Chapter7_Web.pdf. Accessed on June 15, 2013.

12. Keenan-Lindsay L, Yudin MH, Boucher M, Cohen HR, Gruslin A, MacKinnon CJ, et al.; Maternal Fetal Medicine Committee, Society of Obstetricians and Gynaecologists of Canada. HIV screening in pregnancy. SOGC Clinical Practice Guidelines, No. 185, December 2006. J Obstet Gynaecol Can 2006;28:1103–12. 13. Public Health Agency of Canada. Point-of-care HIV Testing using rapid HIV test kits: guidance for health-care professionals. Ottawa: PHAC; 2017. Available at: http://www.phac-aspc.gc.ca/publicat/ ccdr-rmtc/07vol33/33s2/. Accessed on June 15, 2013. 14. Centers for Disease Control and Prevention, US Department of Health and Human Services. Rapid HIV-1 antibody testing during labor and delivery for women of unknown HIV status: a practical guide and model protocol. Available at: http://www.cdc.gov/hiv/topics/testing/resources/ guidelines/rt-labor&delivery_appendixA.htm. Accessed on June 15, 2013. 15. Lohse N, Hansen AB, Pedersen G, Kronborg G, Gerstoft J, Sørensen HT, et al. Survival of persons with and without HIV infection in Denmark, 1995-2005. Ann Intern Med 2007;146:87–95. 16. Ioannidis JP, Abrams EJ, Ammann A, Bulterys M, Goedert JJ, Gray L, et al. Perinatal transmission of human immunodeficiency virus type 1 by pregnant women with RNA virus loads <1000 copies/ml. J Infect Dis 2001;183:539–45. 17. Connor EM, Sperling RS, Gelber R, Kiselev P, Scott G, O’Sullivan MJ, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med 1994;331:1173–80. 18. Sperling RS, Shapiro DE, Coombs RW, Todd JA, Herman SA, McSherry GD, et al. Maternal viral load, zidovudine treatment, and the risk of transmission of human immunodeficiency virus type 1 from mother to infant. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med 1996;335:1621–29. 19. Culnane M, Fowler M, Lee SS, McSherry G, Brady M, O’Donnell K, et al. Lack of long-term effects of in utero exposure to zidovudine among uninfected children born to HIV-infected women. Pediatric AIDS Clinical Trials Group Protocol 219/076 Teams. JAMA 1999;281:151–7. 20. Feiterna-Sperling C, Weizsaecker K, Buhrer C, Casteleyn S, Loui A, Schmitz T, et al. Hematologic effects of maternal antiretroviral therapy and transmission prophylaxis in HIV-1-exposed uninfected newborn infants. J Acquir Immune Defic Syndr 2007;45:43–51. 21. Petra Study Team. Efficacy of three short-course regimens of zidovudine and lamivudine in preventing early and late transmission of HIV-1 from mother to child in Tanzania, South Africa, and Uganda (Petra study): a randomised, double-blind, placebo-controlled trial. Lancet 2002;359:1178–86. 22. Wiktor SZ, Ekpini E, Karon JM, Nkengasong J, Maurice C, Severin ST, et al. Short-course oral zidovudine for prevention of mother-to-child transmission of HIV-1 in Abidjan, Cote d’Ivoire: a randomised trial. Lancet 1999;353:781–5. 23. Guay LA, Musoke P, Fleming T, Bagenda D, Allen M, Nakabiito C, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet 1999;354:795–802. 24. Jackson JB, Musoke P, Fleming T, Guay LA, Bagenda D, Allen M, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: 18-month follow-up of the HIVNET 012 randomised trial. Lancet 2003;362:859–68. 25. Nielsen-Saines K, Watts DH, Veloso VG, Bryson YJ, Joao EC, Pilotto JH, et al. Three postpartum antiretroviral regimens to prevent intrapartum HIV infection. N Engl J Med 2012;366:2368–79.

AUGUST JOGC AOÛT 2014 l S29

SOGC CLINICAL PRACTICE GUIDELINE

26. Mirochnick M, Fenton T, Gagnier P, Pav J, Gwynne M, Siminski S, et al. Pharmacokinetics of nevirapine in human immunodeficiency virus type 1-infected pregnant women and their neonates. Pediatric AIDS Clinical Trials Group Protocol 250 Team. J Infect Dis 1998;178:368–74.

42. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for 1 January 1989 through 31 July 2012. Available at: http://www.apregistry.com/forms/ interim_report.pdf. Accessed on June 15, 2013.

27. Mirochnick M, Nielsen-Saines K, Pilotto JH, Pinto J, Jiménez E, Veloso VG, et al.; NICHD/HPTN 040/PACTG 1043 Protocol Team. Nevirapine concentrations in newborns receiving an extended prophylactic regimen. J Acquir Immune Defic Syndr 2008;47:334–7.

43. Ford N, Calmy A, Mofenson L. Safety of efavirenz in the first trimester of pregnancy: an updated systematic review and meta-analysis. AIDS 2011;25:2301–4.

28. Eshleman SH, Jackson JB. Nevirapine resistance after single dose prophylaxis. AIDS Rev 2002;4:59–63. 29. Van Dyke RB, Ngo-Giang-Huong N, Shapiro DE, Frenkel L, Britto P, Roongpisuthipong A, et al. A comparison of 3 regimens to prevent nevirapine resistance mutations in HIV-infected pregnant women receiving a single intrapartum dose of nevirapine. Clin Infect Dis 2012;54:285–93. 30. Chaix ML, Ekouevi DK, Rouet F, Tonwe-Gold B, Viho I, Bequet L, et al. Low risk of nevirapine resistance mutations in the prevention of motherto-child transmission of HIV-1: Agence Nationale de Recherches sur le SIDA Ditrame Plus, Abidjan, Cote d’Ivoire. J Infect Dis 2006;193:482–7. 31. McIntyre JA, Hopley M, Moodley D, Eklund M, Gray GE, Hall DB, et al. Efficacy of short-course AZT plus 3TC to reduce nevirapine resistance in the prevention of mother-to-child HIV transmission: a randomized clinical trial. PLoS Med 2009;6:e1000172. 32. Chi BH, Ellis GM, Chintu N, Cantrell RA, Sinkala M, Aldrovandi GM, et al. Intrapartum tenofovir and emtricitabine reduces low-concentration drug resistance selected by single-dose nevirapine for perinatal HIV prevention. AIDS Res Hum Retroviruses 2009;25:1099–106. 33. TEmAA ANRS 12109 Study Group; Arrive E, Chaix ML, Nerrienet E, Blanche S, Rouzioux C, Avit D, et al. Maternal and neonatal tenofovir and emtricitabine to prevent vertical transmission of HIV-1: tolerance and resistance. AIDS 2010;24:2481–8. 34. Tubiana R, Le Chenadec J, Rouzioux C, Mandelbrot L, Hamrene K, Dollfus C, et al. Factors associated with mother-to-child transmission of HIV-1 despite a maternal viral load <500 copies/ml at delivery: a casecontrol study nested in the French perinatal cohort (EPF-ANRS CO1). Clin Infect Dis 2010;50:585–96. 35. on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. Accessed on June 18, 2013. 36. British Columbia Centre for Excellence in HIV/AIDS. Therapeutic guidelines for opportunistic infections. Available at: http://cfenet.ubc.ca/ sites/default/files/s/docs/Opportunistic_Infection_Therapeutic_ Guidelines.pdf. Accessed on June 15, 2013.

44. Sibiude J, Mandelbrot L, Blanche S, Le Chenadec J, Boullag-Bonnet N, Faye A, et al. Birth defects and ART in the French Perinatal Cohort, a prospective exhaustive study among 13,124 live births from 1994 to 2010. Paper presented at: 20th Conference on Retroviruses and Opportunistic Infections (CROI); March 3–6, 2013; Atlanta. Abstract 81. 45. ViiV Healthcare. Product monograph. Combivir (Lamivudine/ Zidovudine). Mississauga ON; 2012. 46. ViiV Healthcare. Product monograph. Ziagen (Abacavir Sulfate). Laval QC; 2012. 47. Bristol-Myers Squibb. Product monograph. Reyataz (Atazanavir). Montreal QC; 2012. 48. Mandelbrot L, Mazy F, Floch-Tudal C, Meier F, Azria E, Crenn-Hebert C, et al. Atazanavir in pregnancy: impact on neonatal hyperbilirubinemia. Eur J Obstet Gynecol Reprod Biol 2011;157:18–21. 49. AbbVie Corporation. Product monograph. Kaletra (Lopinavir/Ritonavir). St-Laurent QC; 2012. 50. Ripamonti D, Cattaneo D, Maggiolo F, Airoldi M, Frigerio L, Bertuletti P, et al. Atazanavir plus low-dose ritonavir in pregnancy: pharmacokinetics and placental transfer. AIDS 2007;21:2409–15. 51. Eley T, Child M, Wang Y, Vandeloise E, Sevinsky H, Liao S, et al. The steady state pharmacokinetics (PK) of atazanavir/ritonavir (ATV/RTV) during pregnancy in HIV+ women. Paper presented at: 47th Infectious Diseases Society of America; Oct 29–Nov 1, 2009; Philadelphia. 52. Conradie F, Zorrilla C, Josipovic D, Botes M, Osiyemi O, Vandeloise E, et al. Safety and exposure of once-daily ritonavir-boosted atazanavir in HIV-infected pregnant women. HIV Med 2011;12:570–9. 53. Mirochnick M, Best BM, Stek AM, Capparelli EV, Hu C, Burchett SK, et al. Atazanavir pharmacokinetics with and without tenofovir during pregnancy. J Acquir Immune Defic Syndr 2011;56:412–9. 54. Roustit M, Jlaiel M, Leclercq P, Stanke-Labesque F. Pharmacokinetics and therapeutic drug monitoring of antiretrovirals in pregnant women. Br J Clin Pharmacol 2008;66:179–95. 55. Gilead Sciences Canada. Product monograph. Truvada (Emtricitabine/ Tenofovir Disoproxil Fumarate). Mississauga, ON; 2012. 56. Gilead Sciences. Product monograph. Viread (Tenofovir Disoproxil Fumarate). Foster City, CA; 2012.

37. Briggs G, Freeman R, Yaffe S. Fluconazole. In: Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2011:574–5.

57. Viganò A1, Mora S, Giacomet V, Stucchi S, Manfredini V, Gabiano C, et al. In utero exposure to tenofovir disoproxil fumarate does not impair growth and bone health in HIV-uninfected children born to HIV-infected mothers. Antivir Ther 2011;16:1259–66.

38. Briggs G, Freeman R, Yaffe S. Clarithromycin. In: drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2011:298–9.

58. van Schalkwyk JE, Alimenti A, Khoo D, Maan E, Forbes JC, Burdge DR, et al. Serious toxicity associated with continuous nevirapine-based HAART in pregnancy. BJOG 2008;115:1297–1302.

39. Briggs G, Freeman R, Yaffe S. Sulfonamides. In: Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2011:1371–4.

59. Thompson CA. Antiretroviral combination may put pregnant women at risk of fatal lactic acidosis. Am J Health Syst Pharm 2001;58:291.

40. Arsenault MY, Lane CA, MacKinnon CJ, Bartellas E, Cargill YM, Klein MC, et al. The management of nausea and vomiting of pregnancy. J Obstet Gynaecol Can 2002;24:817-31; quiz 832–3. 41. Bristol-Myers Squibb Canada. Product monograph. Sustiva (Efavirenz). Montreal; 2012.

S30 l AUGUST JOGC AOÛT 2014

60. Hill JB, Sheffield JS, Zeeman GG, Wendel GD Jr. Hepatotoxicity with antiretroviral treatment of pregnant women. Obstet Gynecol 2001;98:909–11. 61. Sarner L, Fakoya A. Acute onset lactic acidosis and pancreatitis in the third trimester of pregnancy in HIV-1 positive women taking antiretroviral medication. Sex Transm Infect 2002;78:58–9.

Guidelines for the Care of Pregnant Women Living With HIV and Interventions to Reduce Perinatal Transmission

62. Jungmann EM, Mercey D, DeRuiter A, Edwards S, Donoghue S, Booth T, et al. Is first trimester exposure to the combination of antiretroviral therapy and folate antagonists a risk factor for congenital abnormalities? Sex Transm Infect 2001;77:441–3. 63. Buchholz B, Beichert M, Holzwarth N, Hien S, Schaible T, Niessen K. Congenital malformations in children of HIV-1 Positive mothers naive or treated with different regimes of antiretroviral drugs in pregnancy. Paper presented at: 14th International AIDS Conference; July 2002; Barcelona. Abstract WePeB5933. Available at: http://www.iasociety.org/Abstracts/ A5664.aspx. Accessed on June 13, 2013. 64. Chmait R, Franklin P, Spector SA, Hull AD. Protease inhibitors and decreased birth weight in HIV-infected pregnant women with impaired glucose tolerance. J Perinatol 2002;22:370–3. 65. Lorenzi P, Spicher VM, Laubereau B, Hirschel B, Kind C, Rudin C, et al. Antiretroviral therapies in pregnancy: maternal, fetal and neonatal effects. Swiss HIV Cohort Study, the Swiss Collaborative HIV and Pregnancy Study, and the Swiss Neonatal HIV Study. AIDS 1998;12:F241–7.

78. Bucceri AM, Somigliana E, Matrone R, Ferraris G, Rossi G, Grossi E, et al. Combination antiretroviral therapy in 100 HIV-1-infected pregnant women. Hum Reprod 2002;17:436–41. 79. Clarke SM, Mulcahy F, Healy CM, Condon S, Butler KM. The efficacy and tolerability of combination antiretroviral therapy in pregnancy: infant and maternal outcome. Int J STD AIDS 2000;11:220–3. 80. Grubert TA, Wintergerst U, Lutz-Friedrich R, Belohradsky BH, Rolinski B. Long-term antiretroviral combination therapy including lamivudine in HIV-1 infected women during pregnancy. AIDS 1999;13:1430–1. 81. Morris AB, Cu-Uvin S, Harwell JI, Garb J, Zorrilla C, Vajaranant M, et al. Multicenter review of protease inhibitors in 89 pregnancies. J Acquir Immune Defic Syndr 2000;25:306–11. 82. European Collaborative Study. Exposure to antiretroviral therapy in utero or early life: the health of uninfected children born to HIV-infected women. J Acquir Immune Defic Syndr 2003;32:380–7.

66. Cooper ER, Charurat M, Mofenson L, Hanson IC, Pitt J, Diaz C, et al.; Women and Infants’ Transmission Study Group. Combination antiretroviral strategies for the treatment of pregnant HIV-1-infected women and prevention of perinatal HIV-1 transmission. J Acquir Immune Defic Syndr 2002;29:484–94.

83. Wagner EC, Chaworth-Musters T, Berg KB, Albert AY, van Schalkwyk JE, Maan EJ, et al. Do protease inhibitor-containing HAART regimens increase risk of preterm birth in HIV-positive women? Paper presented at: 21st Annual Canadian Conference on HIV/AIDS Research; April 2012; Montreal. Can J Infect Dis Med Microbiol 2012;23(Suppl A):36A.

67. Tuomala RE, Shapiro DE, Mofenson LM, Bryson Y, Culnane M, Hughes MD, et al. Antiretroviral therapy during pregnancy and the risk of an adverse outcome. N Engl J Med 2002;346:1863–70.

84. Lopez M, Figueras F, Hernandez S, Lonca M, Garcia R, Palacio M, et al. Association of HIV infection with spontaneous and iatrogenic preterm delivery: effect of HAART. AIDS 2012;26:37–43.

68. Goldstein PJ, Smit R, Stevens M, Sever JL. Association between HIV in pregnancy and antiretroviral therapy, including protease inhibitors and low birth weight infants. Infect Dis Obstet Gynecol 2000;8:94–8.

85. Chen JY, Ribaudo HJ, Souda S, Parekh N, Ogwu A, Lockman S, et al. Highly active antiretroviral therapy and adverse birth outcomes among HIV-infected women in Botswana. J Infect Dis 2012;206:1695–705.

69. Blanche S, Tardieu M, Rustin P, Slama A, Barret B, Firtion G, et al. Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues. Lancet 1999;354:1084–9.

86. Kakkar F, Lamarre V, Soudeyns H, Dah C, Lapointe N, Boucher M. Use of boosted protease inhibitors in pregnancy and risk of prematurity among HIV-exposed uninfected infants in Montreal. Paper presented at: 21st Annual Canadian Conference on HIV/AIDS Research; April 2012; Montreal. Can J Infect Dis Med Microbiol 2012;23(Suppl A):36A.

70. Mandelbrot L, Landreau-Mascaro A, Rekacewicz C, Berrebi A, Bénifla JL, Burgard M, et al.; Agence Nationale de Recherches sur le SIDA (ANRS) 075 Study Group. Lamivudine-zidovudine combination for prevention of maternal-infant transmission of HIV-1. JAMA 2001;285:2083–93. 71. Alimenti A, Burdge DR, Ogilvie GS, Money DM, Forbes JC. Lactic acidemia in human immunodeficiency virus-uninfected infants exposed to perinatal antiretroviral therapy. Pediatr Infect Dis J 2003;22:782–9. 72. Forster C, Boix H, Acolet D, Tudor-Williams G, Lyall E. Lactic acidosis and hypoglycaemia in three neonates exposed to HAART in utero. Paper presented at: 7th Annual Conference of the British HIV Association; April 27–29, 2001; Brighton. Abstract O20. Available at: http://www.natap.org/ 2001/7thbhiva/BHIVA.pdf. Accessed on June 13, 2013.

87. European Collaborative Study; Swiss Mother and Child HIV Cohort Study. Combination antiretroviral therapy and duration of pregnancy. AIDS 2000;14:2913–20. 88. Thorne C, Patel D, Newell ML. Increased risk of adverse pregnancy outcomes in HIV-infected women treated with highly active antiretroviral therapy in Europe. AIDS 2004;18:2337–9. 89. Tuomala RE, Watts DH, Li D, Pitt J, Hammill H, Landesman S, et al. Improved obstetric outcomes and few maternal toxicities are associated with antiretroviral therapy, including highly active antiretroviral therapy during pregnancy. J Acquir Immune Defic Syndr 2005;38:449–73.

73. Giaquinto C, De Romeo A, Giacomet V, Rampon O, Ruga E, Burlina A, et al. Lactic acid levels in children perinatally treated with antiretroviral agents to prevent HIV transmission. Paper presented at: 14th International AIDS Conference; Barcelona, Spain. AIDS 2001;15:1074–5.

90. Szyld EG, Warley EM, Freimanis L, Gonin R, Cahn PE, Calvet GA, et al.; NISDI Perinatal Study Group. Maternal antiretroviral drugs during pregnancy and infant low birth weight and preterm birth. AIDS 2006;20:2345–53.

74. Shiramizu B, Shikuma KM, Kamemoto L, Gerschenson M, Erdem G, Pinti M, et al. Placenta and cord blood mitochondrial DNA toxicity in HIV-infected women receiving nucleoside reverse transcriptase inhibitors during pregnancy. J Acquir Immune Defic Syndr 2003;32:370–4.

91. Cotter AM, Garcia AG, Duthely ML, Luke B, O’Sullivan MJ. Is antiretroviral therapy during pregnancy associated with an increased risk of preterm delivery, low birth weight, or stillbirth? J Infect Dis 2006;193:1195–201.

75. Poirier MC, Divi RL, Al-Harthi L, Olivero OA, Nguyen V, Walker B, et al.; Women and Infants Transmission Study (WITS) Group. Long-term mitochondrial toxicity in HIV-uninfected infants born to HIV-infected mothers. J Acquir Immune Defic Syndr 2003;33:175–83.

92. Patel K, Shapiro DE, Brogly SB, Gonin R, Cahn PE, Calvet GA, et al.; NISDI Perinatal Study Group. Prenatal protease inhibitor use and risk of preterm birth among HIV-infected women initiating antiretroviral drugs during pregnancy. J Infect Dis. 2010;201:1035–44.

76. Silverman NS, Watts DH, Hitti J, Money DM, Livingston E, Axelrod J, et al. Initial multicenter experience with double nucleoside therapy for human immunodeficiency virus infection during pregnancy. Infect Dis Obstet Gynecol 1998;6:237–43.

93. Heidari S, Mofenson L, Cotton MF, Marlink R, Cahn P, Katabira E. Antiretroviral drugs for preventing mother-to-child transmission of HIV: a review of potential effects on HIV-exposed but uninfected children. J Acquir Immune Defic Syndr 2011;57:290–6.

77. McGowan JP, Crane M, Wiznia AA, Blum S. Combination antiretroviral therapy in human immunodeficiency virus-infected pregnant women. Obstet Gynecol 1999;94:641–6.

94. Kourtis AP, Schmid CH, Jamieson DJ, Lau J. Use of antiretroviral therapy in pregnant HIV-infected women and the risk of premature delivery: a meta-analysis. AIDS 2007;21:607–15.

AUGUST JOGC AOÛT 2014 l S31

SOGC CLINICAL PRACTICE GUIDELINE

95. Beckerman K, Albano J, Martine-Tristani M, Seekins D, Storfer S, David N, et al. Pre-term birth (PTB), low birth weight (LBW) and fetal antiretroviral (ARV) exposure; gestational age (EGA) and birth weight data from 10022 singleton live births (LB) reported to the Antiretroviral Pregnancy Registry (APR) 1989 through 31 January 2009. Paper presented at: 28th International AIDS Conference; July 18–23, 2010; Vienna. Abstract WEAX0105. Available at: http://www.iasociety.org/Abstracts/ A200735420.aspx. Accessed on June 13, 2013. 96. Dinsmoor MJ, Forrest ST. Lack of an effect of protease inhibitor use on glucose tolerance during pregnancy. Infect Dis Obstet Gynecol 2002;10:187–91. 97. Tang JH, Sheffield JS, Grimes J, McElwee B, Roberts SW, Laibl V, et al. Effect of protease inhibitor therapy on glucose intolerance in pregnancy. Obstet Gynecol 2006;107:1115–9. 98. Hitti J, Andersen J, McComsey G, Liu T, Melvin A, Smith L, et al.; AIDS Clinical Trials Group 5084 Study Team. Protease inhibitor-based antiretroviral therapy and glucose tolerance in pregnancy: AIDS Clinical Trials Group A5084. Am J Obstet Gynecol 2007;196:331.e1–331.e7. 99. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Clinical practice guidelines for the prevention and management of diabetes in Canada. Can J Diabetes 2013;37(Suppl 1):S1–S212. 100. Powderly WG, Carr A. AIDS 2001. Clinical treatment. Overview. AIDS 2001;15(Suppl 5):S159–S60. 101. Brubaker SG, Bukusi EA, Odoyo J, Achando J, Okumu A, Cohen CR. Pregnancy and HIV transmission among HIV-discordant couples in clinical trial in Kisumu, Kenya. HIV Medicine 2011;12:316–21. 102. Baggaley R, van Praag E. Antiretroviral interventions to reduce mother-to-child transmission of human immunodeficiency virus: challenges for health systems, communities and society. Bull World Health Organ 2000;78:1036–44. 103. Weller S, Davis K. Condom effectiveness in reducing heterosexual HIV transmission. Cochrane Database Syst Rev. 2002;(1):CD003255. 104. Waters L, Smit E. HIV-1 superinfection. Curr Opin Infect Dis 2012;25:42–50. 105. Chitayat D, Langlois S, Wilson RD; Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada; Prenatal Diagnosis Committee of the Canadian College of Medical Geneticists. Prenatal screening for fetal aneuploidy in singleton pregnancies. SOGC Clinical Practice Guidelines, No. 261, February 2007. J Obstet Gynaecol Can 2011;33:736–50. 106. Anema A, Vogenthaler N, Frongillo EA, Kadiyala S, Weiser SD. Food insecurity and HIV/AIDS: current knowledge, gaps, and research priorities. Curr HIV/AIDS Rep 2009;6:224–31. 107. Gruslin A, Steben M, Halperin S, Money DM, Yudin MH; Infectious Diseases Committee of the Society of Obstetricians and Gynaecologists of Canada. Immunization in pregnancy. SOGC Clinical Practice Guidelines, No. 236, November 2009. J Obstet Gynaecol Can 2009;31:1085–101. 108. Carson G, Cox LV, Crane J, Croteau P, Graves L, Kluka S, et al. Alcohol use and pregnancy consensus clinical guidelines. SOGC Clinical Practice Guidelines, No. 245, August 2010. J Obstet Gynaecol Can 2010;32(Suppl 3):S1–S31. 109. Wong S, Ordean A, Kahan M; Maternal Fetal Medicine Committee, Family Physicians Advisory Committee, Medico-Legal Committee, Society of Obstetrics and Gynaecology Canada. Substance use in pregnancy. SOGC Clinical Practice Guidelines, No. 256, April 2011. J Obstet Gynaecol Can 2011;33:367–84. 110. Bansil P, Jamieson DJ, Posner SF, Kourtis AP. Hospitalizations of pregnant HIV-infected women in the United States in the era of highly active antiretroviral therapy (HAART). J Womens Health (Larchmt) 2007;16:159–62.

S32 l AUGUST JOGC AOÛT 2014

111. Maiques V, Garcia-Tejedor A, Perales A, Cordoba J, Esteban RJ. HIV detection in amniotic fluid samples. Amniocentesis can be performed in HIV pregnant women? Eur J Obstet Gynecol Reprod Biol 2003;108:137–41. 112. Somigliana E, Bucceri AM, Tibaldi C, Alberico S, Ravizza M, Savasi V, et al.; Italian Collaborative Study on HIV Infection in Pregnancy. Early invasive diagnostic techniques in pregnant women who are infected with the HIV: a multicenter case series. Am J Obstet Gynecol 2005;193:437–42. 113. Coll O, Suy A, Hernandez S, Pisa S, Lonca M, Thorne C, et al. Prenatal diagnosis in human immunodeficiency virus-infected women: a new screening program for chromosomal anomalies. Am J Obstet Gynecol. 2006;194:192–8. 114. Ekoukou D, Khuong-Josses MA, Ghibaudo N, Mechali D, Rotten D. Amniocentesis in pregnant HIV-infected patients. Absence of motherto-child viral transmission in a series of selected patients. Eur J Obstet Gynecol Reprod Biol 2008;140:212–7. 115. Mandelbrot L, Jasseron C, Ekoukou D, Batallan A, Bongain A, Pannier E, et al. Amniocentesis and mother-to-child human immunodeficiency virus transmission in the Agence Nationale de Recherches sur le SIDA et les Hepatites Virales French Perinatal Cohort. Am J Obstet Gynecol 2009;200(2):160.e1–9. 116. Gagnon A, Davies G, Wilson RD; Genetics Committee, Society of Obstetricians and Gynaecologists of Canada. Prenatal invasive procedures in women with hepatitis B, hepatitis C, and/or human immunodeficiency virus infections. SOGC Clinical Practice Guidelines, No. 309, July 2014. J Obstet Gynaecol Can 2014;36:648–53. 117. Brocklehurst P, French R. The association between maternal HIV infection and perinatal outcome: a systematic review of the literature and meta-analysis. Br J Obstet Gynaecol 1998;105:836–48. 118. McCabe CJ, Goldie SJ, Fisman DN. The cost-effectiveness of directly observed highly-active antiretroviral therapy in the third trimester in HIV-infected pregnant women. PLoS One 2010;5:e10154. 119. Breastfeeding and HIV International Transmission Study Group; Coutsoudis A, Dabis F, Fawzi W, Gaillard P, Haverkamp G, Harris DR, et al. Late postnatal transmission of HIV-1 in breast-fed children: an individual patient data meta-analysis. J Infect Dis 2004;189:2154–66. 120. Nduati R, John G, Mbori-Ngacha D, Richardson B, Overbaugh J, Mwatha A, et al. Effect of breastfeeding and formula feeding on transmission of HIV-1: a randomized clinical trial. JAMA 2000;283:1167–74. 121. Dunn DT, Newell ML, Ades AE, Peckham CS. Risk of human immunodeficiency virus type 1 transmission through breastfeeding. Lancet 1992;340:585–8. 122. European Mode of Delivery Collaboration. Elective caesarean-section versus vaginal delivery in prevention of vertical HIV-1 transmission: a randomised clinical trial. Lancet 1999;353:1035–9. 123. Garcia PM, Kalish LA, Pitt J, Quinn TC, Burchett SK, Kornegay J, et al. Maternal levels of plasma human immunodeficiency virus type 1 RNA and the risk of perinatal transmission. N Engl J Med 1999;341:394–402. 124. Townsend CL, Cortina-Borja M, Peckham CS, de Ruiter A, Lyall H, Tookey PA. Low rates of mother-to-child transmission of HIV following effective pregnancy interventions in the United Kingdom and Ireland, 2000-2006. AIDS 2008;22:973–81. 125. European Collaborative Study. Mother-to-child transmission of HIV infection in the era of highly active antiretroviral therapy. Clin Infect Dis 2005;40:458–65. 126. ViiV Healthcare. Product monograph. Retrovir (Zidovudine). Laval, QC; 2012.

Guidelines for the Care of Pregnant Women Living With HIV and Interventions to Reduce Perinatal Transmission

127. Warszawski J, Tubiana R, Le Chenadec J, Blanche S, Teglas JP, Dollfus C, et al. Mother-to-child HIV transmission despite antiretroviral therapy in the ANRS French Perinatal Cohort. AIDS 2008;22:289–99. 128. Money D, van Schalkwyk J, Alimenti A, et al. HIV viral rebound near delivery in previously suppressed, combination antiretroviral therapy (cART) treated pregnant women. Paper presented at: 20th Conference on Retroviruses and Opportunistic infections; March 2013; Atlanta and at the 22nd Annual Canadian Conference on HIV/AIDS Research; April 2013; Vancouver. Can J Infect Dis Med Microbiol 2013;24(Suppl A):20.

142. Nachega JB, Uthman OA, Anderson J, Peltzer K, Wampold S, Cotton MF, et al. Adherence to antiretroviral therapy during and after pregnancy in low-income, middle-income, and high-income countries: a systematic review and meta-analysis. AIDS 2012;26:2039–52. 143. Kaida A, Forrest J, Money D, Burdge D, Forbes J, Fernandes K, et al. Antiretroviral adherence during pregnancy and postpartum among HIV-positive women enrolled in the Drug Treatment Program in British Columbia, Canada. Paper presented at: 18th Annual Canadian Conference on HIV/AIDS Research; April 23–26, 2009; Vancouver. Can J Infect Dis Med Microbiol 2009;20(B):25B.

129. Boyer PJ, Dillon M, Navaie M, Deveikis A, Keller M, O’Rourke S, et al. Factors predictive of maternal-fetal transmission of HIV-1. Preliminary analysis of zidovudine given during pregnancy and/or delivery. JAMA 1994;271:1925–30.

144. Black A, Francoeur D, Rowe T, Collins J, Miller D, Brown T, et al.; Contraception Guidelines Committee. Canadian contraception consensus. SOGC Clinical Practice Guidelines, No. 143: Part 1 of 3, February 2004. J Obstet Gynaecol Can 2004;26:143–56.

130. Mandelbrot L, Mayaux MJ, Bongain A, Berrebi A, Moudoub-Jeanpetit Y, Bénifla JL, et al. Obstetric factors and mother-to-child transmission of human immunodeficiency virus type 1: the French perinatal cohorts. SEROGEST French Pediatric HIV Infection Study Group. Am J Obstet Gynecol 1996;175:661–7.

145. Toronto General Hospital Immunodeficiency Clinic website. Drug interaction tables. Available at: http://www.hivclinic.ca/main/drugs_ interact.html. Accessed on June 15, 2013.

131. Mofenson LM, Lambert JS, Stiehm ER, Bethel J, Meyer WA 3rd, Whitehouse J, et al. Risk factors for perinatal transmission of human immunodeficiency virus type 1 in women treated with zidovudine. Pediatric AIDS Clinical Trials Group Study 185 Team. N Engl J Med 1999;341:385–93. 132. Shapiro DE, Sperling RS, Mandelbrot L, Britto P, Cunningham BE. Risk factors for perinatal human immunodeficiency virus transmission in patients receiving zidovudine prophylaxis. Pediatric AIDS Clinical Trials Group protocol 076 Study Group. Obstet Gynecol 1999;94:897–908. 133. Mark S, Murphy KE, Read S, Bitnun A, Yudin MH. HIV motherto-child transmission, mode of delivery, and duration of rupture of membranes: experience in the current era. Infect Dis Obstet Gynecol 2012;2012:267969. doi: 10.1155/2012/267969. Epub 2012 May 28. 134. Cvetkovic RS, Goa KL. Lopinavir/ritonavir: a review of its use in the management of HIV infection. Drugs 2003;63:769–802. 135. Cavasin H, Dola T, Uribe O, Biswas M, Do M, Bhuiyan A, et al. Postoperative infectious morbidities of cesarean delivery in human immunodeficiency virus-infected women. Infect Dis Obstet Gynecol 2009;2009:827405. doi: 10.1155/2009/827405. Epub 2009 May 25. 136. Louis J, Landon MB, Gersnoviez RJ, Leveno KJ, Spong CY, Rouse DJ, et al.; Maternal-Fetal Medicine Units Network, National Institute of Child Health and Human Development. Perioperative morbidity and mortality among human immunodeficiency virus infected women undergoing cesarean delivery. Obstet Gynecol 2007;110:385–90. 137. Urbani G, de Vries MM, Cronje HS, Niemand I, Bam RH, Beyer E. Complications associated with cesarean section in HIV-infected patients. Int J Gynaecol Obstet 2001;74:9–15. 138. Read JS, Tuomala R, Kpamegan E, Zorrilla C, Landesman S, Brown G, et al.; Women and Infants Transmission Study Group. Mode of delivery and postpartum morbidity among HIV-infected women: the women and infants transmission study. J Acquir Immune Defic Syndr 2001;26:236–45. 139. Watts DH, Lambert JS, Stiehm ER, Bethel J, Whitehouse J, Fowler MG, et al. Complications according to mode of delivery among human immunodeficiency virus-infected women with CD4 lymphocyte counts of < or = 500/microL. Am J Obstet Gynecol 2000;183:100–7. 140. Smaill F, Hofmeyr GJ. Antibiotic prophylaxis for cesarean section. Cochrane Database Syst Rev. 2002;(3):CD000933. 141. van Schalkwyk J, Van Eyk N; Society of Obstetricians and Gynaecologists of Canada Infectious Diseases Committee. Antibiotic prophylaxis in obstetric procedures. SOGC Clinical Practice Guidelines, No. 247, September 2010. J Obstet Gynaecol Can 2010;32:878–92.

146. Watts DH, Park JG, Cohn SE, Yu S, Hitti J, Stek A, et al. Safety and tolerability of depot medroxyprogesterone acetate among HIV-infected women on antiretroviral therapy: ACTG A5093. Contraception 2008;77:84–90. 147. Haile-Selassie H, Townsend C, Tookey P. Use of neonatal post-exposure prophylaxis for prevention of mother-to-child HIV transmission in the UK and Ireland, 2001-2008. HIV Med 2011;12:422–7. 148. McKeegan K, Rutstein R, Lowenthal E. Postnatal infant HIV prophylaxis: a survey of U.S. practice. AIDS Patient Care STDS 2011;25:1–4. 149. Mirochnick M, Capparelli E, Connor J. Pharmacokinetics of zidovudine in infants: a population analysis across studies. Clin Pharmacol Ther 1999;66:16–24. 150. Capparelli EV, Mirochnick M, Dankner WM, Blanchard S, Mofenson L, McSherry GD, et al.; Pediatric AIDS Clinical Trials Group 331 Investigators. Pharmacokinetics and tolerance of zidovudine in preterm infants. J Pediatr 2003;142:47–52. 151. Laughton B, Cornell M, Grove D, Kidd M, Springer PE, Dobbels E, et al. Early antiretroviral therapy improves neurodevelopmental outcomes in infants. AIDS 2012;26:1685–90. 152. Persaud D, Gay H, Ziemniak C, Chen YH, Piatak M, Chun T-W, et al. Functional HIV Cure after very early ART of an Infected infant. Paper presented at: 20th Conference on Retroviruses and Opportunistic Infections (CROI). March 3–6, 2013; Atlanta. Abstract 48LB. 153. Mirpuri J, Jain L. Issues of prematurity and HIV infection. Clin Perinatol 2010;37:887–905, xi. 154. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8. 155. Sperling RS, Shapiro DE, McSherry GD, Britto P, Cunningham BE, Culnane M, et al. Safety of the maternal-infant zidovudine regimen utilized in the Pediatric AIDS Clinical Trial Group 076 Study. AIDS 1998;12:1805–13. 156. Watts DH, Li D, Handelsman E, Tilson H, Paul M, Foca M, et al. Assessment of birth defects according to maternal therapy among infants in the Women and Infants Transmission Study. J Acquir Immune Defic Syndr 2007;44:299–305. 157. O’Sullivan MJ, Boyer PJ, Scott GB, Parks WP, Weller S, Blum MR, et al. The pharmacokinetics and safety of zidovudine in the third trimester of pregnancy for women infected with human immunodeficiency virus and their infants: phase I acquired immunodeficiency syndrome clinical trials group study (protocol 082). Zidovudine Collaborative Working Group. Am J Obstet Gynecol 1993;168:1510–6.

AUGUST JOGC AOÛT 2014 l S33

SOGC CLINICAL PRACTICE GUIDELINE

158. Benaboud S, Treluyer JM, Urien S, Blanche S, Bouazza N, Chappuy H, et al. Pregnancy-related effects on lamivudine pharmacokinetics in a population study with 228 women. Antimicrob Agents Chemother 2012;56:776–82.

173. Cressey TR, Stek A, Capparelli E, Bowonwatanuwong C, Prommas S, Sirivatanapa P, et al.; IMPAACT P1026s Team. Efavirenz pharmacokinetics during the third trimester of pregnancy and postpartum. J Acquir Immune Defic Syndr 2012;59:245–52.

159. Moodley J, Moodley D, Pillay K, Coovadia H, Saba J, van Leeuwen R, et al. Pharmacokinetics and antiretroviral activity of lamivudine alone or when coistered with zidovudine in human immunodeficiency virus type 1-infected pregnant women and their offspring. J Infect Dis 1998;178:1327–33.

174. Izurieta P, Kakuda TN, Feys C, Witek J. Safety and pharmacokinetics of etravirine in pregnant HIV-1-infected women. HIV Med 2011;12:257–8.

160. Chappuy H, Tréluyer JM, Jullien V, Dimet J, Rey E, Fouché M, et al. Maternal-fetal transfer and amniotic fluid accumulation of nucleoside analogue reverse transcriptase inhibitors in human immunodeficiency virus-infected pregnant women. Antimicrob Agents Chemother 2004;48:4332–6. 161. Best BM, Mirochnick M, Capparelli EV, Stek A, Burchett SK, Holland DT, et al. Impact of pregnancy on abacavir pharmacokinetics. AIDS 2006;20:553–60. 162. Stek AM, Best BM, Luo W, Capparelli E, Burchett S, Hu C, et al. Effect of pregnancy on emtricitabine pharmacokinetics. HIV Med 2012;13:226–35. 163. Hirt D, Urien S, Rey E, Arrivé E, Ekouévi DK, Coffié P, et al. Population pharmacokinetics of emtricitabine in human immunodeficiency virus type 1-infected pregnant women and their neonates. Antimicrob Agents Chemother 2009;53:1067–73. 164. Best B, Stek A, Hu C, Burchett S, Rossi S, Smith E, et al. High-dose lopinavir and standard-dose emtricitabine pharmacokinetics during pregnancy and postpartum. Paper presented at: 15th Conference on Retroviruses and Opportunistic Infections (CROI); February 2008; Boston. Abstract 629. 165. Burchett S, Best B, Mirochnick M, Hu C, Capparelli E, Fletcher C, et al. Tenofovir pharmacokinetics during pregnancy, at delivery, and postpartum. Paper presented at: 14th Conference on Retroviruses and Opportunistic Infections (CROI). February 2007; Los Angeles. Abstract 738b. 166. Bonora S, de Requena D, Chiesa E, Maccabruni A, Forleo M, Vichi F, et al., and TARGET Study Group. 2007. Transplacental age of tenofovir and other ARVs at delivery. Paper presented at: 14th Conference on Retroviruses and Opportunistic Infections (CROI). February 2007; Los Angeles. Abstract 738a. 167. Siberry GK, Williams PL, Mendez H, Seage GR 3rd, Jacobson DL, Hazra R, et al.; Pediatric HIV/AIDS Cohort Study (PHACS). Safety of tenofovir use during pregnancy: early growth outcomes in HIV-exposed uninfected infants. AIDS 2012;26:1151–9. 168. Wang Y, Livingston E, Patil S, McKinney RE, Bardeguez AD, Gandia J, et al. Pharmacokinetics of didanosine in antepartum and postpartum human immunodeficiency virus-infected pregnant women and their neonates: an AIDS clinical trials group study. J Infect Dis 1999;180:1536–41. 169. Odinecs A, Nosbisch C, Keller RD, Baughman WL, Unadkat JD. In vivo maternal-fetal pharmacokinetics of stavudine (2’,3’-didehydro3’-deoxythymidine) in pigtailed macaques (Macaca nemestrina). Antimicrob Agents Chemother 1996;40:196–202. 170. Wade NA, Unadkat JD, Huang S, Shapiro DE, Mathias A, Yasin S, et al. Pharmacokinetics and safety of stavudine in HIV-infected pregnant women and their infants: Pediatric AIDS Clinical Trials Group protocol 332. J Infect Dis 2004;190:2167–74. 171. Capparelli EV, Aweeka F, Hitti J, Stek A, Hu C, Burchett SK, et al.; PACTG 1026S Study Team; PACTG P1022 Study Team. Chronic istration of nevirapine during pregnancy: impact of pregnancy on pharmacokinetics. HIV Med 2008;9:214–20. 172. von Hentig N, Carlebach A, Gute P, Knecht G, Klauke S, Rohrbacher M, et al. A comparison of the steady-state pharmacokinetics of nevirapine in men, nonpregnant women and women in late pregnancy. Br J Clin Pharmacol 2006;62:552–9.

S34 l AUGUST JOGC AOÛT 2014

175. Stek AM, Mirochnick M, Capparelli E, Best BM, Hu C, Burchett SK, et al. Reduced lopinavir exposure during pregnancy. AIDS 2006;20:1931–9. 176. Bouillon-Pichault M, Jullien V, Azria E, Pannier E, Firtion G, Krivine A, et al. Population analysis of the pregnancy-related modifications in lopinavir pharmacokinetics and their possible consequences for dose adjustment. J Antimicrob Chemother 2009;63:1223–32. 177. Mirochnick M, Best BM, Stek AM, Pannier E, Firtion G, Krivine A, et al. Lopinavir exposure with an increased dose during pregnancy. J Acquir Immune Defic Syndr 2008;49:485–91. 178. Best BM, Stek AM, Mirochnick M, Hu C, Li H, Burchett SK, et al. Lopinavir tablet pharmacokinetics with an increased dose during pregnancy. J Acquir Immune Defic Syndr 2010;54:381–8. 179. Eley T, Bertz R, Hardy H, Burger D. Atazanavir pharmacokinetics, efficacy and safety in pregnancy: a systematic review. Antivir Ther 2013;18:361–75. 180. Colbers A, Molto J, Ivanovic J, Hidalgo Tenori C, Weizsäcker K, van der Ende I, et al, on behalf of the PANNA network. A comparison of the pharmacokinetics of darunavir, atazanavir and ritonavir during pregnancy and post-partum. Paper presented at: 19th Conference on Retroviruses and Opportunistic Infections (CROI); March 5-8, 2012; Seattle. Abstract 1013. Available at: http://www.pannastudy.com/web/s/files/Poster_PANNA_ CROI_2012.pdf. Accessed on June 15, 2013. 181. Capparelli E, Best B, Stek A, Rossil S, Burchett SK, Kreitchman R, et al. Pharmacokinetics of darunavir once or twice daily during pregnancy and postpartum. Paper presented at: 3rd International Workshop on HIV Pediatrics; July 15–16, 2011; Rome. Abstract P72. Available at: http://regist2.virology-education.com/abstractbook/2011_8.pdf. Accessed on July 15, 2013. 182. Zorrilla C, Wright R, Osiyemi O, Yasin S, Baugh B, Brown K, et al. Total and unbound darunavir pharmacokinetics in HIV-1+ pregnant women. Paper presented at: 19th Conference on Retroviruses and Opportunistic Infections (CROI); March 5-8, 2012; Seattle. Abstract 1012. 183. van der Lugt J, Colbers A, Molto J, Hawkins D, van der Ende M, Vogel M, et al.; SARA Study Team. The pharmacokinetics, safety and efficacy of boosted saquinavir tablets in HIV type-1-infected pregnant women. Antivir Ther 2009;14:443–50. 184. Martinez-Rebollar M, Lonca M, Perez I, Soy D, Brunet M, Martin R, et al. Pharmacokinetic study of saquinavir 500 mg plus ritonavir (1000/100 mg twice a day) in HIV-positive pregnant women. Ther Drug Monit 2011;33:772–7. 185. Bryson Y, Mirochnick M, Stek A, Mofenson LM, Connor J, Capparelli E, et al.; PACTG 353 Team. Pharmacokinetics and safety of nelfinavir when used in combination with zidovudine and lamivudine in HIV-infected pregnant women: Pediatric AIDS Clinical Trials Group (PACTG). Protocol 353. HIV Clin Trials 2008;9:115–25. 186. Villani P, Floridia M, Pirillo MF, Cusato M, Tamburrini E, Cavaliere AF, et al. Pharmacokinetics of nelfinavir in HIV-1-infected pregnant and nonpregnant women. Br J Clin Pharmacol 2006;62:309–15. 187. Fang A, Valluri SR, O’Sullivan MJ, Maupin R, Jones T, Delke I, et al. Safety and pharmacokinetics of nelfinavir during the second and third trimesters of pregnancy and postpartum. HIV Clin Trials 2012;13:46–59. 188. Capparelli E, Stek A, Best B, et al. Boosted fosamprenavir pharmacokinetics during pregnancy. Paper presented at: 17th Conference on Retroviruses and Opportunistic Infections (CROI); February 2010; San Francisco. Abstract 908.

Guidelines for the Care of Pregnant Women Living With HIV and Interventions to Reduce Perinatal Transmission

189. Weizsaecker K, Kurowski M, Hoffmeister B, Schurmann D, Feiterna-Sperling C. Pharmacokinetic profile in late pregnancy and cord blood concentration of tipranavir and enfuvirtide. Int J STD AIDS 2011;22:294–5. 190. Best B, Capparelli E, Stek A, Burchett SK, Huo Y, Aweeka F, et al. Raltegravir pharmacokinetics during pregnancy. Paper presented at: 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 12–15, 2010; Boston. Abstract H-1668a. Available at: http://www.abstractsonline.com/ plan/ViewAbstract.aspx?mID=2583&sKey=1496d8f3-434c42ff-960b-ff213a2769a6&cKey=8897bf34-bf8d-46af-801109f3093246cf&mKey=%7b93AEED6A-54D4-4EF6-99BDA9B3CE9FACD9%7d. Accessed on June 15, 2013. 191. Boucoiran I, Tulloch K, Pick N, Kakkar F, van Schalkwyk J, Money D, et al. Third trimester raltegravir initiation: the impact on maternal HIV viral load and obstetrical outcome. Paper presented at: 40th Annual Scientific Meeting of the Infectious Diseases Society for Obstetrics and Gynecology (IDSOG); August 2013; Santa Ana Pueblo, NM, USA.

of clear evidence for mitochondrial disease in children who died before 5 years of age in five United States cohorts. J Acquir Immune Defic Syndr 2000;25:261–8. 202. Brogly SB, Ylitalo N, Mofenson LM, Oleske J, Van Dyke R, Crain MJ, et al. In utero nucleoside reverse transcriptase inhibitor exposure and signs of possible mitochondrial dysfunction in HIV-uninfected children. AIDS 2007;21:929–38. 203. Brogly SB, Foca M, Deville JG, Mirochnick M, Scott GB, Mofenson LM, et al. Potential confounding of the association between exposure to nucleoside analogues and mitochondrial dysfunction in HIV-uninfected and indeterminate infants. J Acquir Immune Defic Syndr 2010;53:154–7. 204. Aldrovandi GM, Chu C, Shearer WT, Li D, Walter J, Thompson B, et al. Antiretroviral exposure and lymphocyte mtDNA content among uninfected infants of HIV-1-infected women. Pediatrics 2009;124:e1189–97. 205. Chaponda M, Pirmohamed M. Hypersensitivity reactions to HIV therapy. Br J Clin Pharmacol 2011;71:659–71.

192. Gilead Sciences Canada. Product monograph. Stribild (Elvitegravir/ Cobicistat/Emtricitabine/Tenofovir). Mississauga ON; 2012.

206. Boehringer Ingelheim (Canada). Product monograph. Viramune (Nevirapine). Burlington, ON; 2011.

193. U.S. Preventive Services Task Force. Screening for syphilis infection in pregnancy: U.S. Preventive Services Task Force reaffirmation recommendation statement. Ann Intern Med 2009;150:705–9.

207. McKoy JM, Bennett CL, Scheetz MH, Differding V, Chandler KL, Scarsi KK, et al. Hepatotoxicity associated with long- versus short-course HIV-prophylactic nevirapine use: a systematic review and meta-analysis from the Research on Adverse Drug events And Reports (RADAR) project. Drug Saf 2009;32:147–58.

194. Warnke D, Barreto J, Temesgen Z. Antiretroviral drugs. J Clin Pharmacol 2007;47:1570–9. 195. Weinberg A, Forster-Harwood J, McFarland EJ, Pappas J, Davies JK, Kinzie K, et al. Resistance to antiretrovirals in HIV-infected pregnant women. J Clin Virol 2009;45:39–42. 196. Bristol-Myers Squibb Canada. Product monograph. Videx-EC (Didanosine). Montreal; 2010. 197. Thorne C, Newell ML. Safety of agents used to prevent mother-tochild transmission of HIV: is there any cause for concern? Drug Saf 2007;30:203–13. 198. Bunders MJ, Bekker V, Scherpbier HJ, Boer K, Godfried M, Kuijpers TW. Haematological parameters of HIV-1-uninfected infants born to HIV-1-infected mothers. Acta Paediatr 2005;94:1571–7. 199. Faure N, Bristol-Myers Squibb Canada. Important drug warning Videx-Zerit. Ottawa: Government of Canada; 2013. Available at: http://www.healthycanadians.gc.ca/recall-alert-rappel-avis/ hc-sc/2002/14642a-eng.php. Accessed on June 15, 2013. 200. Barret B, Tardieu M, Rustin P, Lacroix C, Chabrol B, Desguerre I, et al.; French Perinatal Cohort Study Group, Persistent mitochondrial dysfunction in HIV-1-exposed but uninfected infants: clinical screening in a large prospective cohort. AIDS 2003;17:1769–85. 201. Perinatal Surveillance Review Working Group. Nucleoside exposure in the children of HIV-infected women receiving antiretroviral drugs: absence

208. Watts DH, Balasubramanian R, Maupin RT Jr, Delke I, Dorenbaum A, Fiore S, et al.; PACTG 316 Study Team. Maternal toxicity and pregnancy complications in human immunodeficiency virus-infected women receiving antiretroviral therapy: PACTG 316. Am J Obstet Gynecol 2004;190:506–16. 209. Merck Canada. Product monograph. Crixivan (Indinavir). Kirkland QC; 2012. 210. Schuurmans N, Mackinnon C, Lane C, Etches D. Prevention and management of postpartum hemorrhage. J Obstet Gynaecol Can 2000:88:1–10. 211. Pinnetti C, Baroncelli S, Villani P, Fantoni M, Tozzi V, De Luca A, et al. Rapid HIV-RNA decline following addition of raltegravir and tenofovir to ongoing highly active antiretroviral therapy in a woman presenting with high-level HIV viraemia at week 38 of pregnancy. J Antimicrob Chemother 2010;65:2050–2. 212. Taylor N, Touzeau V, Geit M, Gisinger M, Egle A, Greil R, et al. Raltegravir in pregnancy: a case series presentation. Int J STD AIDS 2011;22:358–60. 213. U.S. Food and Drug istration. Summary of proposed rule on pregnancy and lactation labeling. Available at: http://www.fda.gov/ Drugs/DevelopmentApprovalProcess/DevelopmentResources/ Labeling/ucm093310.htm. Accessed on June 15, 2013.

Appendix begins on next page

AUGUST JOGC AOÛT 2014 l S35

SOGC CLINICAL PRACTICE GUIDELINE

APPENDIX 1. RECOMMENDATIONS AND MANAGEMENT ALGORITHM FOR WOMEN WITH UNKNOWN HIV STATUS OR ONGOING RISK OF HIV INFECTION Indications of High-risk for HIV Infection –  Self-identifies as being at high risk of HIV –  Sex partner of an HIV-infected person –  Ongoing use of injection drugs or sex with a person using injection drugs –  Diagnosis of a sexually transmitted infection during pregnancy –  Belonging to a population with a high prevalence of HIV (e.g., recent incarceration, recent immigrant, or refugee from an –  HIV-endemic country) Recommendations for Testing In institutions where rapid HIV antibody testing is NOT available: 1. the provincial centre for disease control to access prenatal HIV serology results. If laboratory results are not available proceed to #2.

2. a. If the woman’s HIV status is not available or if she is at ongoing risk of HIV infection since her last serology test result: i. draw STAT HIV EIA (antibody) and send blood (4 mL) in a gold top tube to local CDC laboratory; ii. draw STAT diagnostic HIV PCR test and send blood (4 mL) in an EDTA tube to local CDC laboratory.

b. If the woman is unavailable for testing: i. draw HIV EIA (antibody) from the infant within 48 hours of age as a first priority and send blood (minimum 2 mL) in a gold top tube to local CDC laboratory; ii. draw diagnostic HIV PCR from the infant within 48 hours of age and send blood (minimum 2 mL) in an EDTA tube to local CDC laboratory.

3. Until HIV test results are known:



a. Initiate maternal and infant treatment for prevention of HIV vertical transmission.



b. If any test is positive in mother or infant, refer to local multidisciplinary HIV clinic.



c. If all HIV EIA and HIV PCR tests drawn are negative in the mother and infant, discontinue all antiretroviral drug therapy.

In institutions where rapid HIV antibody testing is available 1. provincial centre for disease control to access prenatal HIV serology results. If laboratory results are not available proceed to #2.

2. a. All women should be offered rapid HIV antibody testing. A protocol for rapid HIV testing should be established in each institution.

b. For women considered at high risk of HIV with undocumented prenatal HIV serology or who have ongoing risk of HIV since their most recent HIV serology result, also draw a confirmatory prenatal diagnostic HIV PCR test and send blood (4 mL in EDTA tube) and appropriate requisition to local CDC.

Pre-test discussion points Offer information about: –  HIV and the nature of the test; –  the reasons HIV testing is recommended (risk of transmission, long-term health of the woman); –  the expected benefits of testing (treatment of woman and infant, decreased transmission); –  the voluntary nature of testing. Answer any questions. Post-test discussion points Inform the woman of the test result. Non-reactive (negative test): no antibodies to HIV were detected Discuss any needs for harm reduction or further testing and the possibility of acute infection if there was high-risk behaviour in the last 4 weeks (i.e., the implications of the “window period” of infection when antibodies have not yet been produced). Inform the woman that confirmatory test results will be available in approximately one week. Inform the woman of treatment recommendations to prevent HIV vertical transmission. continued

S36 l AUGUST JOGC AOÛT 2014

Guidelines for the Care of Pregnant Women Living With HIV and Interventions to Reduce Perinatal Transmission

APPENDIX 1. Continued Invalid: test will not work with blood sample provided Inform the woman: –  that there may be a possibility of infection if high-risk behaviour at any time during pregnancy; –  that confirmatory testing results will be available in approximately one week; –  about treatment recommendations to prevent HIV vertical transmission. Preliminary reactive (preliminary positive): antibodies to HIV were detected OR indeterminate: unable to interpret result Discuss with woman: –  the possibility of HIV infection; –  the need for a confirmatory blood test (diagnostic HIV PCR results available in approximately one week); –  immediate treatment recommendations to prevent HIV vertical transmission; –  steps to prevent transmission; –  the follow-up care and available to her. Post-test documentation Notify the local health authority of any preliminary positive result. Document discussions in the woman’s Health Record. Ensure information for the woman is available in the Health Record. Recommended intervention based on rapid HIV test result HIGH risk of HIV and undocumented prenatal HIV serology (or ongoing risk of HIV risk since most recent HIV test) Preliminary reactive or

Initiate treatment for prevention of HIV vertical transmission

Indeterminate or Invalid: Non-reactive but involved in high-risk HIV transmission activity in previous 4-weeks (within possible ‘window’ period of infection):

Initiate treatment for prevention of HIV vertical transmission

Non-reactive and no identifiable risk within the past 4 weeks

No further intervention.

LOW risk of HIV and undocumented prenatal HIV serology Preliminary reactive or

Initiate treatment for prevention of HIV vertical transmission

Indeterminate Non-reactive or

No further intervention

Invalid continued

AUGUST JOGC AOÛT 2014 l S37

SOGC CLINICAL PRACTICE GUIDELINE

APPENDIX 1. Continued

MANAGEMENT ALGORITHM FOR WOMAN OF UNKNOWN HIV STATUS OR ONGOING HIV RISK in institutions where rapid HIV antiboby test is AVAILABLE (ZDV = Zidovudine, 3TC = Lamivudine, NVP = Nevirapine)

Unknown HIV status or ongoing HIV risk since last HIV serology was performed local health services authority to access serology results if available

High risk: self identifies, ongoing injection drug use, sex partner of person infected with HIV or using injection drugs, diagnosis of a sexually transmitted infection during pregnancy, from a population with a high prevalence of HIV (e.g., recent incarceration of refugee from an HIV endemic country)

HIGH HIV risk

LOW HIV risk

Rapid HIV test and diagnostic HIV PCR

Preliminary reactive OR indeterminate OR invalid

Mother: IV ZDV loading dose and infusion during labour

Rapid HIV test

Non-reactive

Recent high-risk activities in previous 4 weeks?

Yes

No

Mother: IV ZDV loading dose and infusion during labour

No Therapy

Single-dose NVP and

and ZDV-3TC (Combivir®) x 7 days postpartum

Non-reactive OR invalid

and

and Single-dose NVP

Preliminary reactive OR indeterminate

No Therapy

ZDV-3TC (Combivir®) x 7 days postpartum

Infant: ZDV x 6 weeks

Infant: ZDV x 6 weeks

and

and

3-doses NVP (day 0, 2, 6)

3-doses NVP (day 0, 2, 6)

and

and

3TC x 2 weeks

3TC x 2 weeks continued

S38 l AUGUST JOGC AOÛT 2014

Guidelines for the Care of Pregnant Women Living With HIV and Interventions to Reduce Perinatal Transmission

APPENDIX 1. Continued

MANAGEMENT ALGORITHM FOR WOMAN OF UNKNOWN HIV STATUS OR ONGOING HIV RISK in institutions where rapid HIV antiboby test is NOT AVAILABLE (ZDV = Zidovudine, 3TC = Lamivudine, NVP = Nevirapine)

Unknown HIV status or ongoing HIV risk since last HIV serology was performed local health services authority to access serology results if available

HIGH HIV risk

High risk: self identifies, ongoing injection drug use, sex partner of person infected with HIV or using injection drugs, diagnosis of a sexually transmitted infection during pregnancy, from a population with a high prevalence of HIV (e.g., recent incarceration of refugee from an HIV endemic country)

Mother: STAT HIV EIA (antibody) and diagnostic HIV PCR

Mother: IV ZDV loading dose and infusion during labour and Single-dose NVP and

LOW HIV risk

No Therapy

A) If any test is POSITIVE in mother or infant: Refer to local multidisciplinary HIV clinic B) If all HIV EIA and HIV PCR tests drawn are NEGATIVE in mother and infant: DISCONTINUE ALL antiretroviral drug therapy

ZDV-3TC (Combivir®) x 7 days postpartum

Infant: if mother is unavailable for testing: HIV EIA (antibody) and diagnostic HIV PCR within 48 hr of age Note: if difficult to obtain sample HIV EIA is priority test

Infant: consider istering combination prophylactic therapy *: ZDV x 6 weeks and 3-doses NVP (day 0, 2, 6) and 3TC x 2 weeks

*Alternative consideration is single agent prophylactic therapy: ZDV x 6 weeks

AUGUST JOGC AOÛT 2014 l S39

SOGC CLINICAL PRACTICE GUIDELINE

APPENDIX 2. SUMMARY INFORMATION ON ANTIRETROVIRAL MEDICATIONS IN PREGNANCY Nucleoside/Nucleotide Analogue Reverse Transcriptase Inhibitors (NRTIs) Drugs in this class function as a group of competitive substrate inhibitors that are intracellularly phosphorylated to form the active triphosphate nucleoside moiety and incorporated into HIV DNA, which terminates the action of the reverse transcriptase enzyme and prevents the conversion of viral RNA into DNA.153 NRTIs are recommended for use as part of combination regimens, which usually include a backbone of 2 NRTIs with the addition of either a non-NRTI (NNRTI) or one or more PIs. The use of single or dual NRTIs alone is not recommended for treatment of HIV infection because rapidly developing resistance outpaces their ability to suppress viral replication for prolonged periods.2,3 Among this class of drugs the first-line agents for use in the dual NRTI backbone in pregnancy are zidovudine (ZDV) and lamivudine (3TC); alternative agents include abacavir (ABC), emtricitabine (FTC; not available in Canada as a single agent), and tenofovir (TDF). TDF would be a preferred NRTI, in combination with 3TC or FTC, for pregnant women with chronic hepatitis B infection. DDI and stavudine (d4T) are reserved for use only in special circumstances because they are more toxic than other available agents. Various combinations of NRTIs can be employed. Clinical safety and efficacy data in pregnancy have been most reported for the first-line recommended combination of ZDV and 3TC. This combination is formulated as a fixed-dose combination tablet, Combivir, and is generally well tolerated in pregnancy. It does, however, require twice-daily dosing, and resistance to either ZDV or 3TC is common in antiretroviralexperienced women.193 Alternative agents or combinations of agents (ABC, FTC, TDF) may be considered in a number of situations including when there is resistance to first-line agents; a woman conceives on an effective treatment regimen containing alternative agents; tolerability is a concern; and regimen simplification is desirable. When selecting combination regimens it is important to consider HIV resistance profiles; the potential for adverse events related to the additive; any co-morbid medical conditions including HBV; concomitant medications and the potential for drug-drug interactions; and convenience of dosing. Two notable combinations that should be avoided are d4T in combination with ZDV, because they have competing intracellular mechanisms of activation,124 or d4T with DDI, because the combination has a higher reported risk of a potentially fatal lactic acidosis and hepatic steatosis reaction.194 NRTI pharmacokinetics are similar in pregnant and non-pregnant women and dosing adjustments are not required in pregnancy. All NRTIs, with the exception of DDI, readily cross the placenta and have high cord-to-maternal blood ratios greater than 0.60.3,41 All NRTI agents are categorized as either FDA pregnancy category B (TDF, DDI) or C, and none have been demonstrated to be associated with any known human teratogenic syndrome in pregnancy. Although not considered to be a teratogen, animal studies have demonstrated that chronic istration of high doses of TDF to pregnant monkeys has resulted in a slight reduction in fetal bone porosity. Continued istration of high dose TDF to infant monkeys (and other species) has resulted in reversible bone abnormalities ranging from reduction in bone mineral density to severe pathologic osteomalacia. Evidence of renal toxicity has also been observed in newborn monkeys given high doses of TDF.4,41,54 Because of the limited data on use in human pregnancy and concern regarding potential fetal effects and nephrotoxicity, TDF is recommended as an alternative (vs. first-line) drug for use in pregnancy, unless the woman is co-infected with HBV.3 Additional Considerations in Pregnancy Bone marrow toxicity is a concern with the NRTIs. In the ACTG 076 study there were no significant toxicities noted in the women who received ZDV monotherapy,16 and in short and longer term follow-up studies (up to 5 years of age post in utero exposure) transient anemia in the neonate is the only significant adverse effect reported.17–19 Overall, transient and mild hemoglobin reductions have been observed in most infants exposed to antiretroviral drugs and these resolve by age 3 to 6 months after discontinuation of antiretroviral prophylaxis3,92,151 In utero exposure to cART appears to be associated with increased severity of anemia. Neutropenia and/or lymphopenia have also been reported, with resolution at age 8 to 24 months.3,92,151 The clinical significance of this is not established and there is no evidence of an increase in antibiotic use or an increase in the frequency or severity of infections in these infants.195,196 Mitochondrial toxicity/dysfunction has been reported. NRTIs are able to bind to mitochondrial gamma DNA polymerase in different organ systems, resulting in mitochondrial toxicity.92,195 The clinical effects in adults can include myopathy, bone marrow suppression, pancreatitis, peripheral neuropathy and hepatic steatosis. Serum lactate, which accumulates when mitochondrial function is significantly altered, has been used as an indirect marker of mitochondrial toxicity. Mitochondrial toxicity has been most strongly associated with d4T, DDI, zalcitabine (no longer marketed in Canada), and ZDV.92 As described above, the combination of d4T and DDI should be avoided because of a higher incidence of fatal lactic acidosis in people receiving cART; it is unknown whether pregnancy increases the risk further.197 Data for an association between mitochondrial dysfunction and in utero exposure to NRTI therapy are conflicting. In the French Pediatric Cohort study, the total incidence of clinical symptoms of mitochondrial dysfunction at 18 months was 0.26% (95% confidence interval [CI] 0.10 to 0.54) in exposed children compared with 0.01% in the general population, and the mortality rate was 0.07%.198 These findings have not been duplicated in other studies,81,199,200 and severity of maternal illness has been identified as a potential confounding factor.201,202 Antiretroviral-exposed infants may have transiently elevated lactic acid levels for up to 6 months; however, the clinical significance of this has not been determined.70,72 Overall, it appears that severe clinically evident mitochondrial diseases secondary to in utero antiretroviral exposure are likely to be rare. Abacavir hypersensitivity—ABC has been associated with a severe, potentially fatal hypersensitivity reaction.45,203 Testing for carriage of the HLA-B*5701 allele identifies patients at risk of reaction, and patients with the allele should not be given ABC.45 Re-challenge with ABC in patients who have experienced ABC hypersensitivity is contraindicated. To date, there is no evidence that in utero exposure to ABC increases the risk of any hypersensitivity reaction in the infant. continued

S40 l AUGUST JOGC AOÛT 2014

Guidelines for the Care of Pregnant Women Living With HIV and Interventions to Reduce Perinatal Transmission

APPENDIX 2. Continued Non-Nucleoside Reverse Transcriptase Inhibitors Drugs in this class function as non-competitive inhibitors of reverse transcriptase by binding and inducing a conformational change in the enzyme, which alters its active site and prevents its ability to convert viral RNA to DNA.153 NNRTIs are recommended for use in pregnancy in combination with a dual NRTI backbone. Initiation of nevirapine (NVP) is not recommended in pregnancy because of the risk of potentially fatal rash and hepatotoxicity. Women who are tolerating NVP and who become pregnant may continue taking NVP. While a preferred agent in the non-pregnant adult, efavirenz (EFV) is contraindicated in the first trimester of pregnancy because of its association with neural tube defects in primates and in case reports in humans.40 However, if given inadvertently during this period, the overall risk posed by EFV is low; ultrasound evaluation of neural tube closure should be done to guide counselling on fetal status. The use of EFV in later trimesters should be reserved for when other agents cannot be used or are not tolerated. Currently available safety and pharmacokinetic data are insufficient to the use of etravirine (ETR) or rilpivirine (RPV) in pregnancy. NNRTI pharmacokinetics are similar in pregnant and non-pregnant women, and dose adjustments are not required in pregnancy. The extent of placental transfer varies within the class, ranging from high with NVP (which also rapidly crosses the placenta) to moderate with EFV. The extent of placental transfer with the newer NNRTIs, ETR, and RPV, is currently unknown. Teratogenicity data for NNRTIs is more limited and variable than for NRTIs. There is no evidence of animal or human teratogenicity with NVP (FDA pregnancy category B), and no evidence of teratogenicity in animals with ETR or RPV (FDA pregnancy category B); however, there is very limited information on these agents in human pregnancy.3,41 Efavirenz, however, is classified as FDA pregnancy category D, and should not be used in the first trimester of pregnancy. Non-pregnant women who are receiving EFV should be counselled to avoid pregnancy. Central nervous system malformations including anencephaly, cleft palate, and anophthalmia were reported in 3 of 20 (15%) of monkeys exposed to efavirenz plasma concentrations similar to human therapeutic concentrations in the first trimester.3 While the Antiretroviral Pregnancy Registry has reported a birth defect incidence of only 2.7% (comparable to the baseline population risk),41 there have been a total of 7 (1 prospective, 6 retrospective) reported cases of central nervous system defects, including 3 cases of meningomyelocele, in humans following first trimester EFV exposure.4,41 Meta-analysis of cohort studies reporting first trimester EFV exposure in 1437 women did not detect an increased risk of birth defects.42 However, a report from a large French perinatal cohort did find a significant association between exposure to EFV in the first trimester and neurological defects.43 Additional Considerations in Pregnancy Nevirapine (NVP) has been reported to cause severe, life threatening and in some cases fatal hepatotoxicity and hypersensitivity skin reactions.203,204 The risk of toxicity is higher in women than men; however, it does not appear that pregnancy increases the risk.3,195,204 There are data to suggest that the greatest risk of toxicity occurs during the first 6 to 18 weeks of therapy and increases approximately 10-fold when NVP is initiated at baseline CD4-cell counts greater than 250 cells/mm3.3,195,204 However, a Canadian study found that toxicity occurred at a wide range of CD4-cell counts in women exposed to NVP for the first time in pregnancy.57 Neither rash nor hepatoxicity have been reported in women or infants receiving intrapartum single-dose or extended-dose NVP therapy for prevention of vertical transmission.22,205 As described above, NVP should not be initiated in pregnancy regardless of CD4-cell count; however, women who become pregnant while receiving and tolerating NVP may continue without interruption. Protease Inhibitors Drugs in this class function as competitive inhibitors that bind to the HIV protease enzyme and prevent the conversion of HIV viral particles into mature infectious forms.153 PIs are recommended in pregnancy in combination with a dual NRTI backbone. Individual PIs are most commonly istered together with low-dose ritonavir (r), which functions as a pharmacokinetic booster to increase serum drug levels of the first PI. Short-term studies have demonstrated the safety and tolerance of the co-formulated combination of lopinavir/ritonavir (LPV/r), and as a result of this and clinical experience with its use, LPV/r is considered the first-line agent for use in pregnancy. Alternative agents for use include boosted atazanavir (ATV/r), which has growing short-term safety and efficacy data in pregnancy; boosted darunavir (DRV/r), and boosted saquinavir (SQV/r), which has also been shown to be well tolerated and safe in short-term studies, but requires a baseline electrocardiogram prior to the start of therapy. Because of associated adverse effect profiles and/or pharmacokinetic limitations in pregnancy, boosted indinavir (IDV/r) and nelfinavir (NVF) should be reserved for use in special circumstances when other agents cannot be used. Current data in pregnancy are insufficient to recommend use of the newer agents including boosted fosamprenavir (FPV/r) or tipranavir (TPV/r). The pharmacokinetics of PIs are variable in pregnancy, particularly in the second and third trimester. Current data suggest that exposure to LPV/r, ATV, and NVF is decreased during the second and third trimesters. However, the clinical significance of reduced exposure to antiretroviral drugs during pregnancy is not clear. The need for a dose increase in pregnancy will depend on the treatment experience of the specific woman, the use of concomitant interacting medications (e.g., TDF or histamine receptor antagonists with ATV), and virologic response to the prescribed dose throughout pregnancy. HIV viral load must be followed closely, particularly in the second and third trimesters, to ensure virology failures due to increased plasma volumes, and subsequent reduced PI concentrations, do not occur. Consideration should be given to a PI dose increase in this situation. There is currently no standard recommendation for monitoring drug levels in pregnancy; however, if available, therapeutic drug monitoring may also be considered to guide the need for PI dose adjustment.53 All PIs have minimal to low placental transfer to the fetus, with cord-to-maternal blood ratios < 0.3. All PIs are classified as FDA pregnancy category B or C. None of the PIs have been demonstrated to cause gross structural abnormalities in animals; however, minor skeletal variations (e.g., increase in supernumerary ribs, ossification delays) and growth inhibition has been reported with high dose ritonavir (RTV), IDV, TPV/r , and FPV. The majority of PIs have not been demonstrated to be teratogenic in human studies; however, data with the use of DRV, FPV or TPR/r in human pregnancy are limited.3,41 continued AUGUST JOGC AOÛT 2014 l S41

SOGC CLINICAL PRACTICE GUIDELINE

APPENDIX 2. Continued Additional Considerations in Pregnancy Preterm delivery could be a greater risk with combination antiretroviral therapy (vs. none, mono or dual NRTI therapy), but evidence to date is conflicting. Some studies have suggested an approximate 2-fold increase risk of preterm delivery (< 37 weeks) with combination antiretroviral therapy than with no treatment, particularly when therapy is initiated prior to pregnancy versus in the third trimester.87,92 A 2007 meta-analysis of 14 published clinical studies suggested that combination regimens that include a PI (vs. no PI) may be at highest risk of preterm delivery,85,93 and data from the Antiretroviral Pregnancy Registry has suggested an increase in low birth weight infants since the introduction of combination therapy, with PI-containing regimens identified as a significant risk factor.41 Other studies, however, have not detected an association between antepartum antiretroviral therapy or PI use and preterm delivery or low birth weight infants.82,93 Overall, data to suggest an association between in utero antiretroviral therapy (including PI use) and premature delivery or low birth weight infants are mixed. However, a causal relationship has not been established, and PIs should not be withheld because of the possibility of an increased risk of preterm delivery. Glucose intolerance/diabetes could be a greater risk with combination antiretroviral regimens containing PIs in pregnancy, but evidence is conflicting. The risk of glucose intolerance was reported to be increased by PIs in one retrospective study,63 but was not observed in others.95–97 Secondary analysis of data from 2 prospective cohorts found an increased risk of gestational diabetes only when PIs were initiated prior to pregnancy or during the first trimester.206 Overall, it is recommended that women living with HIV and taking antiretroviral drugs during pregnancy should receive standard glucose screening (i.e., 1 h 50 g glucose loading test at 24–28 weeks’ gestation); if a women is receiving a PI-based regimen, particularly if initiated before pregnancy, the clinician may choose to perform this screening test earlier. Hyperbilirubinemia commonly occurs in patients, including pregnant women, who receive the PIs ATV and IDV.46,207 These agents increase indirect (unconjugated) bilirubin from directly inhibiting uridine diphosphate-glucuronosyl transferase (UGT), the enzyme responsible for the conversion of indirect to direct (conjugated) bilirubin. There is a theoretical concern that in utero exposure to IDV or ATV may exacerbate physiologic hyperbilirubinemia in neonates as a result of the transfer of indirect bilirubin from the mother and/or a direct transplacental drug effect on bilirubin metabolism in the fetus. Hyperbilirubinemia has been observed in neonates following in utero exposure to atazanavir; however, there is no evidence of severe hyperbilirubinemia elevations or clinical signs of acute or chronic bilirubin encephalopathy.46,47 Exacerbation of physiologic neonatal hyperbilirubin has not been reported with in utero exposure to IDV. It is recommended that all infants exposed to ATV (and IDV) should be monitored for development of hyperbilirubinemia in the first few days of life.46 Postpartum hemorrhage should not be managed with ergot derivatives (e.g., ergonavine maleate), because the combined use of this drug class with PIs may result in serious and potentially life threatening vasoconstriction reactions characterized by peripheral vasospasm and ischemia of the extremities and other tissues.48 Other alternatives including oxytocin and/or prostaglandins may be used if required.3,208 Entry (fusion) Inhibitors This class of drugs includes 2 agents, enfuviride and maraviroc, that act extracellularly to prevent HIV from attaching to the target cell surface and entering the host target cell. Enfuviritide binds to glycoproteins (gp41) on the viral surface to inhibit virus–cell membrane fusion. Maraviroc prevents virus binding to the CCR5 co-receptor on host cells to prevent the entry of virus into the cell. Because HIV can use other co-receptors, such as CXCR4, an HIV tropism test must be performed to determine whether maraviroc will be effective. Current data is insufficient to recommend the use of fusion inhibitors in pregnancy. Data regarding their pharmacokinetics in pregnancy are minimal, and it is not known whether dose adjustments are required. Placental transfer to the fetus is also unknown. Both agents are classified as FDA pregnancy category D because animal studies have not demonstrated any evidence of teratogenicity; however, there is no (maraviroc) or very limited (enfuviritide) experience of their use in human pregnancy. Integrase Inhibitors This class of drugs includes 2 agents, raltegravir and elvitegravir (EVG), that function as competitive inhibitors of the HIV integrase enzyme, preventing the insertion or integration of HIV genetic DNA into the host cell DNA (i.e., strand transfer inhibition). Elvitegravir is currently only available as part of a fixed-dose combination tablet with the pharmacokinetic enhancer cobicistat (COBI) and the NRTIs tenofovir and emtricitabine (TDF 300 mg/FTC 300 mg/EVG 150 mg/COBI 150 mg). Current data are insufficient to recommend the use of integrase inhibitors in pregnancy. No pharmacokinetic data or placental transfer information is available for elvitegravir-cobicistat. Limited pharmacokinetic data suggest that although raltegravir shows extensive variability in the third trimester, postpartum and historical data show consistent exposure, and standard dosing appears appropriate in pregnancy. Case report data suggest a high placental transfer rate to the fetus, with a reported cord-to-maternal blood ratio of approximately 1.0.41,209 Raltegavir is classified as FDA pregnancy category C; animal studies have not found evidence of gross developmental abnormalities; however, increases in the incidence of supernumerary ribs have been observed in rats receiving raltegravir doses 3 times the recommended human dose. There is only limited experience with raltegravir in human pregnancy; case report data show the addition of raltegravir in the third trimester to rapidly decrease viral load at the time of delivery.190,210,211 Elvitegravir and colbicistat (as components of the combination antiretroviral Stribil) are classified as FDA pregnancy category B; animal studies have not shown evidence of teratogenicity or gross structural abnormalities. There are no reported data in human pregnancies.212

S42 l AUGUST JOGC AOÛT 2014

Guidelines for the Care of Pregnant Women Living With HIV and Interventions to Reduce Perinatal Transmission

APPENDIX 3. SUMMARY OF RECOMMENDATIONS AND MANAGEMENT ALGORITHM FOR WOMEN WITH KNOWN HIV INFECTION OR WOMEN IN WHOM HIV INFECTION HAS NOT BEEN RULED OUT This Appendix applies to women with known HIV infection, to women with potential HIV infection based on rapid HIV antibody test results, and (when rapid HIV antibody testing is not available) to women considered at high risk of HIV infection, but whose HIV status is unknown. 1. Maximal confidentiality of the woman’s HIV status should be maintained. 2. Standard universal precautions should be undertaken for protection from blood and bodily fluids (use gown, mask, eye protection, and gloves during delivery) according to details available in an infection control manual. No additional precautions are required. 3. Laboratory tests: a. On ission, tests should be performed for

• CBC, differential, creatinine, urea, AST, ALT, bilirubin, and glucose; • HIV viral load; and • CD4-cell count. b. Performance of prenatal blood tests, including HBV and HCV serology, RPR, rubella, and varicella IgG, should be verified. c. The placenta should be sent to pathology for examination after delivery. d. Appropriate blood test results should be obtained for any study in which the woman has previously consented to participate. 4. General management of labour and delivery: a. Epidurals are not contraindicated. b. Artificial rupture of membranes should be avoided unless necessary for obstetrical management. c. Prolonged rupture of membranes should be avoided if possible. d. Oxytocin should be istered as per protocol if there is rupture of membranes and the woman is not in labour. e. The use of scalp electrodes, fetal scalp sampling, or intrauterine pressure catheters should be avoided unless absolutely necessary. f. Intermittent auscultation or external fetal monitoring should be used based on usual obstetrical guidelines for fetal surveillance. g. Group B streptococcus prophylaxis should be offered as per standard guidelines. h. Because of the risk of exaggerated vasoconstriction in women receiving PIs, ergonovine maleate should be avoided in the management of postpartum hemorrhage. 5. Mode of delivery should be discussed in detail with women known to be living with HIV. a. Women on optimal antenatal antiretroviral therapy with a recent (within last 4 weeks) HIV viral load ≤ 1000 copies/mL are recommended to have a vaginal delivery if obstetrically appropriate and the woman was adherent to antenatal antiretroviral therapy. b. Women not on optimal antiretroviral therapy (e.g., no antenatal antiretroviral therapy or with a recent [within last 4 weeks] HIV viral load or projected viral load > 1000 copies/mL) should be offered a pre-labour Caesarean section at approximately 38 weeks of completed gestation. If the woman is in labour or there has been rupture of membranes, Caesarean section has not been shown to reduce transmission. 6. Antenatally prescribed antiretroviral therapy should usually be continued for as long as possible during labour; however, oral stavudine (d4T or Zerit) should be discontinued because of its antagonistic interaction with intravenous zidovudine. 7. Intrapartum antiretroviral therapy should be initiated

• with rupture of membranes at any time; • with onset of labour—spontaneous or induced, even if preterm; • at induction of labour if rapid progression is anticipated; • at least 2 hours prior to planned Caesarean section; and • in any situation when delivery is anticipated. a. All women throughout labour and delivery, regardless of their antepartum antiretroviral regimen and mode of delivery, should be given

• zidovudine 2 mg/kg IV loading dose over 1 hour, followed by • zidovudine 1 mg/kg/hr IV infusion until delivery.

If the labour stops and the infusion is discontinued for greater than 6 hours, the loading dose should be re-istered and continuous infusion resumed when labour recommences.

b. Women who did not receive any antenatal antiretroviral therapy during pregnancy should also be given one single-dose of nevirapine 200 mg orally as soon as possible at onset of labour or presentation to labour/delivery suite. continued AUGUST JOGC AOÛT 2014 l S43

SOGC CLINICAL PRACTICE GUIDELINE

APPENDIX 3. Continued   8. Postpartum antiretroviral therapy a. Women who have been receiving antenatal antiretroviral therapy should have their complete regimen resumed after delivery as soon as oral intake is tolerated, unless otherwise indicated. b. Women who have not been receiving antenatal antiretroviral therapy but have received single-dose nevirapine during labour should receive 7 days of Combivir (zidovudine-lamivudine), 1 tablet orally twice daily, to reduce the risk of the development of nevirapine resistance. An adult HIV care provider should be consulted to determine the need to continue the therapy or begin an alternate antiretroviral regimen.   9. Prophylaxis against opportunistic infections should be offered to women who are immunocompromised. 10. Assessment and discussion of contraception, mental health, need for social services, or treatment of substance use indicated should be undertaken prior to discharge. 11. Breastfeeding is contraindicated in women with known HIV infection regardless of maternal antiretroviral therapy and viral load. In women in whom HIV infection has not been ruled out, breast milk pumping and avoidance of breast milk infant feeding is recommended until HIV negative status is confirmed,

MANAGEMENT ALGORITHM FOR HIV INFECTED WOMAN AND HER INFANT

(VL = viral load, ART = antiretroviral therapy, ZDV = Zidovudine, 3TC = Lamivudine, NVP = Nevirapine)

Mother

Received antenatal ART and VL  1000 copies/mL

Continued combination antenatal ART

Infant

IV ZDV loading dose and infusion during labour

ZDV x 6 weeks*

Received antenatal ART but VL > 1000 copies/mL (known or projected)

Continue combination antenatal ART IV ZDV loading dose and infusion during labour Caesarean section if not in active labour

Did not receive ART in pregnancy

IV ZDV loading dose and infusion during labour and Single-dose NVP and ZDV-3TC (Combivir®) x 7 days postpartum Caesarean section if not in active labour

Combination ART: ZDV x 6 weeks and 3-doses NVP (day 0, 2, 6) and 2-weeks 3TC

* Use of combination ART for prophylaxis may be warranted in circumstances when infant is born to a mother with poor adherence to antenatal ART and/or with non-suppressed VL (i.e., VL 40-999 copies/mL) particularly when delivered vaginally. Consult with pediatrician with expertise in HIV.

S44 l AUGUST JOGC AOÛT 2014

Guidelines for the Care of Pregnant Women Living With HIV and Interventions to Reduce Perinatal Transmission

APPENDIX 4. SUMMARY OF RECOMMENDATIONS FOR INFANTS BORN TO MOTHERS WITH KNOWN HIV INFECTION OR IN WHOM HIV INFECTION HAS NOT BEEN RULED OUT This Appendix applies to infants born to mothers with known HIV infection, mothers with potential HIV infection based on rapid HIV antibody test result, and mothers considered at high risk of HIV infection but with unknown HIV status when rapid HIV antibody test is not available. 1. Maximal confidentiality of the woman’s HIV status should be maintained. 2. Standard universal precautions should be undertaken for protection from blood and bodily fluids (use gown, mask, eye protection, and gloves during delivery) according to details available in an infection control manual. No additional precautions are required. 3. Wash injection site prior to intramuscular injections or blood sampling. 4. Breastfeeding is contraindicated in women with known HIV infection regardless of maternal antiretroviral therapy and viral load. In women in whom HIV infection has not been ruled out, breast milk pumping and avoidance of breast milk infant feeding is recommended until HIV negative status is confirmed. 5. Prophylaxis should be offered to prevent HIV vertical transmission to the infant, whether or not the mother received antiretroviral therapy at delivery. a. All infants should be given oral or intravenous zidovudine beginning immediately after birth. Oral therapy is preferred, but if the infant is unable to tolerate oral feeds, intravenous therapy may be used. Zidovudine (ZDV, AZT, Retrovir) Dosage Gestational age

Recommended (twice daily dosing for all infants)

Term (≥ 35 weeks’ gestation)

ZDV 4 mg/kg/dose PO every 12 hours for 6 weeks

Alternate (three times daily dosing for preterm infants)

or ZDV 3 mg/kg/dose IV* every 12 hours

30–34 weeks’ gestation

ZDV 2 mg/kg/dose PO every 12 hours for 2 weeks, then 3 mg/kg/dose PO every 12 hours until 6 weeks or

ZDV 2 mg/kg/dose PO (or 1.5mg/kg/dose IV*) every 12 hours for 2 weeks, then every 8 hours until 6 weeks.

ZDV 1.5 mg/kg/dose IV* every 12 hours for 2 weeks, then 2.3 mg/kg/dose IV* every 12 hours until 6 weeks < 29 weeks’ gestation

ZDV 2 mg/kg/dose PO every 12 hours for 4 weeks, then 3 mg/kg/dose PO every 12 hours until 6 weeks or

ZDV 2 mg/kg/dose PO (1.5 mg/kg/dose IV*) every 12 hours for 4 weeks, then every 8 hours until 6 weeks.

ZDV 1.5 mg/kg/dose IV* every 12 hours for 4 weeks, then 2.3 mg/kg/dose IV every 12 hours until 6 weeks *Use IV formulation only when the infant is unable to tolerate oral feeds.

b. Combination antiretroviral therapy with nevirapine and lamivudine (in addition to zidovudine) is given to infants born to mothers who were not on optimal antiretroviral therapy (e.g., received no antenatal antiretroviral therapy) or with a recent HIV viral load (measured within last 4 weeks) or projected HIV viral load greater than 1000 copies/mL. Note: For infants born to mothers considered at high risk of HIV infection, but with unknown HIV status, when the rapid HIV antibody test is not available prophylaxis with only single agent zidovudine may still be considered. Nevirapine dosage (there is no IV formulation available):

• Infant > 2 kg: 12 mg PO for a total of 3 doses. First dose given immediately after birth (day 0), second dose given at 2 days of age, third dose given at 6 days of age.

• Infant 1.5–2 kg: 8 mg PO for a total of 3 doses. First dose given immediately after birth (day 0), second dose given at 2 days of age, third dose given at 6 days of age.

Lamivudine (3TC) dosage (there is no IV formulation available):

• Infant > 2 kg: 6 mg PO every 12 hours for 2 weeks. • Infant 1.5–2 kg: 4 mg PO every 12 hours for 2 weeks. 6. Laboratory tests to be ordered within 48 hours after birth:

• CBC, differential, creatinine, urea, AST, ALT, bilirubin • For infants born to mothers with known HIV infection or potential HIV infection based on rapid HIV antibody testing, infant

diagnostic HIV PCR should be performed with blood (minimum 2 mL in EDTA tube) and appropriate requisition sent to the local CDC. continued AUGUST JOGC AOÛT 2014 l S45

SOGC CLINICAL PRACTICE GUIDELINE

APPENDIX 4. Continued • For infants born to mothers with unknown HIV status (where rapid HIV antibody testing is not available), HIV EIA (antibody) is

the priority test over HIV PCR if a blood sample from the infant is difficult to obtain. Blood (minimum 2 mL in gold top tube) and appropriate requisition should be sent to the local CDC. Infant diagnostic HIV PCR should be conducted within 48 hours, with blood (minimum 2 mL in EDTA tube) and appropriate requisition sent to the local CDC.

7. Check maternal hepatitis B status. If the mother tests positive for hepatitis B surface antigen or has unknown status, ister first dose of hepatitis B vaccine and hepatitis B immune globulin to the infant within 12 hours after birth. 8. The remainder of the zidovudine bottle should be supplied to the parent/guardian on discharge to treat the infant for the entire 6-week course. If nevirapine and lamivudine (3TC) are required for the infant, adequate medication should be provided to the parent/guardian on discharge from hospital to complete the treatment course. 9. Infants born to mothers considered at high risk of HIV infection, but with unknown HIV status (when the rapid HIV antibody test is not available) should be referred to the local multidisciplinary HIV clinic if any HIV test (HIV EIA or HIV PCR) drawn is positive in mother or infant. If all HIV tests (HIV EIA and HIV PCR) drawn are negative in both mother and infant all antiretroviral drug therapy may be discontinued.

S46 l AUGUST JOGC AOÛT 2014

SOGC CLINICAL PRACTICE GUIDELINES No. 303, February 2014

Determination of Gestational Age by Ultrasound This clinical practice guideline has been prepared by the Diagnostic Imaging Committee, reviewed by the Family Physician Advisory Committee, and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Kimberly Butt, MD, Fredericton NB Ken Lim, MD, Vancouver BC DIAGNOSTIC IMAGING COMMITTEE Ken Lim, MD (Chair), Vancouver BC Stephen Bly, MD, Ottawa ON Kimberly Butt, MD, Fredericton NB Yvonne Cargill, MD, Ottawa ON Greg Davies, MD, Kingston ON Nanette Denis, RDMS, Saskatoon SK Gail Hazlitt, RN, RDMS, Winnipeg MB Lucie Morin, MD, Montreal QC Annie Ouellet, MD, Sherbrooke QC Shia Salem, MD, Toronto, ON Disclosure statements have been received from all contributors.

Abstract Objective: To assist clinicians in asg gestational age based on ultrasound biometry. Outcomes: To determine whether ultrasound dating provides more accurate gestational age assessment than menstrual dating with or without the use of ultrasound. To provide maternity health care providers and researchers with evidence-based guidelines for the assignment of gestational age. To determine which ultrasound biometric parameters are superior when gestational age is uncertain. To determine whether ultrasound gestational age assessment is cost effective. Keywords: ultrasound, gestational age, dating

Evidence: Published literature was retrieved through searches of PubMed or MEDLINE and The Cochrane Library in 2013 using appropriate controlled vocabulary and key words (gestational age, ultrasound biometry, ultrasound dating). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies written in English. There were no date restrictions. Searches were updated on a regular basis and incorporated in the guideline to July 31, 2013. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Values: The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). Benefits, harms, and costs: Accurate assignment of gestational age may reduce post-dates labour induction and may improve obstetric care through allowing the optimal timing of necessary interventions and the avoidance of unnecessary ones. More accurate dating allows for optimal performance of prenatal screening tests for aneuploidy. A national algorithm for the assignment of gestational age may reduce practice variations across Canada for clinicians and researchers. Potential harms include the possible reassignment of dates when significant fetal pathology (such as fetal growth restriction or macrosomia) result in a discrepancy between ultrasound biometric and clinical gestational age. Such reassignment may lead to the omission of appropriate—or the performance of inappropriate—fetal interventions. Summary Statements 1. When performed with quality and precision, ultrasound alone is more accurate than a “certain” menstrual date for determining gestational age in the first and second trimesters (≤ 23 weeks) in spontaneous conceptions, and it is the best method for estimating the delivery date. (II) 2. In the absence of better assessment of gestational age, routine ultrasound in the first or second trimester reduces inductions for post-term pregnancies. (I)

J Obstet Gynaecol Can 2014;36(2):171–181

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

FEBRUARY JOGC FÉVRIER 2014 l 171

SOGC Clinical Practice Guidelines

Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.118 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care.118

3. Ideally, every pregnant woman should be offered a first-trimester dating ultrasound; however, if the availability of obstetrical ultrasound is limited, it is reasonable to use a second-trimester scan to assess gestational age. (I) 4. Notwithstanding Summary Statements 1, 2, and 3, women vary greatly in their awareness of their internal functions, including ovulation, and this self-knowledge can sometimes be very accurate. (III) Recommendations 1. First-trimester crown-rump length is the best parameter for determining gestational age and should be used whenever appropriate. (I-A) 2. If there is more than one first-trimester scan with a mean sac diameter or crown-rump length measurement, the earliest ultrasound with a crown-rump length equivalent to at least 7 weeks (or 10 mm) should be used to determine the gestational age. (III-B) 3. Between the 12th and 14th weeks, crown-rump length and biparietal diameter are similar in accuracy. It is recommended that crown-rump length be used up to 84 mm, and the biparietal diameter be used for measurements > 84 mm. (II-1A) 4. Although transvaginal ultrasound may better visualize early embryonic structures than a transabdominal approach, it is not more accurate in determining gestational age. Crown-rump length measurement from either transabdominal or transvaginal ultrasound may be used to determine gestational age. (II-1C) 5. If a second- or third-trimester scan is used to determine gestational age, a combination of multiple biometric parameters (biparietal diameter, head circumference, abdominal circumference, and femur length) should be used to determine gestational age, rather than a single parameter. (II-1A) 6. When the assignment of gestational age is based on a thirdtrimester ultrasound, it is difficult to confirm an accurate due date. Follow-up of interval growth is suggested 2 to 3 weeks following the ultrasound. (III-C)

172 l FEBRUARY JOGC FÉVRIER 2014

INTRODUCTION

T

he accurate dating of pregnancy is critically important for pregnancy management from the first trimester to delivery, and is particularly necessary for determining viability in premature labour and in post-dates deliveries.1 Prior to the widespread use of ultrasound, caregivers relied on a combination of history and physical examination to clinically determine gestational age. Ultrasound gave clinicians a method to measure the fetus and therefore to estimate gestational age. Much of our current clinical practice is based on studies from the 1980s and 1990s. As new information emerges in fields, such as reproductive biology, perinatal epidemiology, and medical imaging, our current clinical practice is being challenged. “Certain” menstrual dating, for example, is less certain than previously thought. When ultrasound is performed with quality and precision, there is evidence to suggest that dating a pregnancy using ultrasound measurements is clinically superior to using menstrual dating with or without ultrasound, and this has been advocated and adopted in other jurisdictions.2–6 GESTATIONAL AGE ESTIMATES USING CLINICAL DATING

The clinical estimate of gestational age typically relies on clinical history (menstrual cycle length, regularity, and recall of the first day of the last menstrual period), followed by confirmation by physical examination or other signs and symptoms.7–9

Determination of Gestational Age by Ultrasound

Dating Based on Menstrual History

Dating by certain menstrual history is inexpensive and readily available. Typically, the EDD is based on a 280day gestation from the first day of the LMP. Certain menstrual dating criteria assume regular cycles, ovulation at the midpoint of the cycle, fertilization on the middle day of the cycle, correct recall of the onset of the LMP, and the woman having been free of oral contraceptives for several months prior. Women vary greatly in their awareness of their internal functions, including ovulation. Their self-knowledge of ovulation can sometimes be very accurate; however, the only truly certain clinical history is one in which the dates of ovulation, fertilization, and implantation are precisely known, as in ART, in which records include the date of oocyte retrieval, and other methods of timed ovulation and fertilization. Unfortunately, without timed ovulation and fertilization as in ART and other timed methods, clinical history is often not reliable.10 Campbell et al. demonstrated that 45% of pregnant women are uncertain of menstrual dates as a result of poor recall, irregular cycles, bleeding in early pregnancy, or oral contraceptive use within 2 months of conception.11 Even if menstrual history is correct, the exact time of ovulation, fertilization, and implantation cannot be known. Women may undergo several “waves” of follicular development during a normal menstrual cycle, which may mean ovulatory inconsistency during any given cycle.12,13 Sperm may survive for 5 to 7 days in the female reproductive tract, a “known” conception date is therefore not completely reliable.14 Recent studies suggest the ovulation-to-implantation duration can vary by as much as

ABBREVIATIONS AC

abdominal circumference

ART

assisted reproductive technology

BPD

biparietal diameter

CRL

crown-rump length

EDD

estimated due date

FL

femur length

HC

head circumference

ISUOG International Society of Ultrasound in Obstetrics and Gynecology LMP

last menstrual period

MSD

mean sac diameter

PPV

positive predictive value

TA

transabdominal

TV

transvaginal

US

ultrasound

11 days, and this may affect fetal size and growth.15 Even in women who are certain of menstrual dating, delayed ovulation is an important cause of perceived prolonged pregnancy and is more likely to occur than early ovulation.16 Some authors have suggested that 282 days should be used instead of 280 to improve dating accuracy, since it is more likely that women will ovulate later rather than earlier than predicted.9 All of these factors conspire to make it difficult to accurately predict gestational age based on menstrual history. Dating Based on Clinical Examination

The size of the uterus, estimated through pelvic or abdominal examination, can be roughly correlated with gestational age; however, factors that affect uterine size (such as fibroids) and maternal body characteristics (such as obesity) will affect such an estimate. The uterus is approximately the size of a grapefruit at 10 to 12 weeks. At 20 weeks the fundus reaches the umbilicus. After 20 weeks the symphysis fundal height, in centimetres, should correlate with the week of gestation.7,17 Fetal heart tones are audible at 11 to 12 weeks with electronic Doppler devices, and this audibility can also assist in the clinical assignment of gestational age.10 Gestational Age Estimation Based on Ultrasound Findings

Ultrasound biometric measurements determine gestational age based on the assumption that the size of the embryo or fetus is consistent with its age. Biological variation in size is less during the first trimester than in the third trimester. Ultrasound estimation of gestational age in the first trimester is therefore more accurate than later in pregnancy.18 Full descriptions of each parameter and published ranges of accuracy are outlined in Table 2. The determination of gestational age in the first trimester uses the mean gestational sac diameter and/or the crown– rump length. During the first 3 to 5 menstrual weeks an intrauterine pregnancy is first signaled by the presence of a gestational sac.19 The gestational sac represents the chorionic cavity, and its echogenic rim represents the implanting chorionic villi and associated decidual tissue.20 The smallest gestational sac size that can be clearly distinguished by high frequency transvaginal transducers is 2 to 3 mm, which corresponds to a gestational age of about 32 to 33 days.21 The MSD is a commonly used, standardized, way to estimate gestational age during early pregnancy. It is less reliable when the MSD exceeds 14 mm or when the embryo can be identified.22 The growth of the MSD is approximately 1 mm per day.23 CRL has lower interobservor variability than MSD, and may thus be better for dating a pregnancy.24 FEBRUARY JOGC FÉVRIER 2014 l 173

SOGC Clinical Practice Guidelines

Yolk Sac

When the yolk sac appears in the gestational sac it provides confirmation of an intrauterine pregnancy and may be initially visible as early as the start of the 5th week or as late as the 6th week. It grows to a maximal size of 6 mm by 10 weeks and gradually migrates to the periphery of the chorionic cavity. At the end of the first trimester it becomes undetectable. Although the presence of the yolk sac is helpful in determining the presence of an intrauterine pregnancy, direct measurement of this structure is not useful in determining gestational age.25 Crown-Rump Length

Direct measurement of the CRL provides the most accurate estimate of gestational age once the embryo is clearly seen. Ideally, either the best CRL or the average of several satisfactory measurements should be used.26 The CRL measurement is reported to be accurate for dating to within 3 to 8 days.22,27–39 The MSD should not be used to estimate gestational age once the CRL can be measured.22,39,40 The narrowest confidence interval appears to be between 7 and 60 mm for CRL.3,29,30,40 The slope of the embryonic growth curve is small before this time and it can be difficult to clearly identify a very early fetus; thus, it is this committee’s expert opinion that reliability and measurability is best when the CRL is at least 10 mm. If more than one scan is performed in the first trimester, the earliest scan with a CRL of at least 10 mm should be used. To avoid performing extra ultrasounds, it is acceptable to time the dating scan to coincide with nuchal translucency screening (if available). Several studies have evaluated CRL and BPD between 12 and 14 weeks, with conflicting results. The majority suggest there is no clinically important difference among confidence intervals, suggesting that either CRL or BPD should be used at this gestational age.41–44 The 84 mm threshold for CRL for estimating gestational age, as suggested by the ISUOG, seems reasonable.6 Recommendations

1. First-trimester crown-rump length is the best parameter for determining gestational age and should be used whenever appropriate. (I-A) 2. If there is more than one first-trimester scan with a mean sac diameter or crown-rump length measurement, the earliest ultrasound with a crownrump length equivalent to at least 7 weeks (or 10 mm) should be used to determine the gestational age. (III-B)

174 l FEBRUARY JOGC FÉVRIER 2014

3. Between the 12th and 14th weeks, crown-rump length and biparietal diameter are similar in accuracy. It is recommended that crown-rump length be used up to 84 mm, and the biparietal diameter be used for measurements > 84 mm. (II-1A) Transabdominal Versus Transvaginal Ultrasonography

Transvaginal ultrasound is typically used to evaluate early first trimester pregnancy structures, such as the gestational sac, yolk sac, and embryo. Original studies comparing transabdominal and transvaginal techniques in early pregnancy demonstrated that TV was the superior method.45–47 Perhaps because of better technology, more recent studies have not found the same result. Grisolia et al. concluded that the accuracy of TV ultrasound has not been shown to be superior to TA ultrasound in dating pregnancies.31 Other authors have found that TA is comparable to TV in determining gestational age if CRL is measurable after 6 weeks.31,48–50 Recommendation

4. Although transvaginal ultrasound may better visualize early embryonic structures than a transabdominal approach, it is not more accurate in determining gestational age. Crown-rump length measurement from either transabdominal or transvaginal ultrasound may be used to determine gestational age. (II-1C) Crown-Rump Length in Pregnancies Conceived by Assisted Reproductive Technology

When the conception date is known absolutely, as with timed ovulation/fertilization during ART, the EDD should be calculated based on the fertilization date. Studies have demonstrated that the CRL measurements in IVF pregnancies are those to be expected in naturally conceived pregnancies, suggesting that study results can be extrapolated between the 2 populations.30,51,52 Second and Third Trimester

In the second and third trimesters, estimation of gestational age is accomplished by measuring the biparietal diameter, head circumference, abdominal circumference, and femur length. These measurements are only as good as the quality of the images. Optimal imaging can be difficult in some clinical situations, such as in a late pregnancy abnormal lie when the head is deep in the maternal pelvis, maternal obesity, or multiple gestation. Normal biological variation appears to have more influence on measurements in the second and third trimester. Thus, in the second half of pregnancy these measurements are less reliable than first trimester CRL, and they become increasingly inaccurate as gestation progresses

The mean of 3 orthogonal sac “inner to inner” diameter measurements (mm). Cursers should be placed on the gestational sac and not the surrounding echogenic region.

The crown-rump length is the longest straight line length of the embryo from the outer margin of the cephalic end to the rump. The neck position should be neutral.

Axial plane through a symmetrical calvarium that includes the third ventricle, thalami, falx cerebrum, and cavum septi pellicidi anteriorly and the tentorial hiatus posteriorly.

Mean sac diameter

Crown-rump length

Biparietal diameter

True axial plane at the level of the bifurcation of the portal vein (into right and left branches) and the stomach. The measurement should be as tight to skin as possible.

Both the femoral head or greater trochanter and the femoral condyle are simultaneously visualized. The cursor should be placed at the junction of bone and cartilage and only the bone measured

Abdominal circumference

Femur length

T: trimester

The head circumference is obtained in the identical plane to the BPD. The trace/ellipse should follow the outer perimeter of the bony skull, not the overlying skin, as that will falsely increase the head circumference

Head circumference

The calipers should be placed at the maximal diameter from the outer edge of the proximal skull wall to the inner edge of the distal skull.

Description

Parameter

Varies with ethnicity.

Ideally, the ultrasound transducer should be aligned perpendicular to the long axis of the femur.

The cerebellum is not included in this image.

The best CRL or the average of several satisfactory measurements should be used.

GA = 30 days plus MSD measured in mm.

Should not be used once CRL can be measured.

Should not be averaged with the CRL.

Notes

Hadlock (1987)73

3rd T: 18 to 35 days

Hadlock (1987)73

3rd T: 21 days

Chervenak (1998)61

Hadlock (1991)54

Hadlock (1984)72

2nd T: 7 to 17 days

Chervenak (1998)61

Hadlock (1991)54

Hadlock (1984)72

Chervenak (1998)61

Hadlock (1991)54

Hadlock (1987)73

Hadlock (1984)72

Chervenak (1998)61

Hadlock (1991)54

Hadlock (1987)73

Hadlock (1984)72

Bovicelli (1981)28

2nd T: 7 to 15 days

2nd T: 7 to 12 days

Daya (1993)30 Sladevickus (2004)42

Grisolia (2003)31 2nd T: 7 to 12 days

Sladevickus (2004)42

Daya (1993)30

Grisolia (2003)31

Daya (1993)30

Grisolia (2003)31

References

1st T: 3 to 8 days

3 to 8 days

4 to 11 days

Approximate accuracy of dates

Table 2. Common definitions of ultrasound biometry parameters and estimates of accuracy for predicting gestational age

Determination of Gestational Age by Ultrasound

FEBRUARY JOGC FÉVRIER 2014 l 175

SOGC Clinical Practice Guidelines

(Table 2).18,53 Maternal and fetal pathology may affect them, so their inclusion or exclusion in the determination of gestational age requires clinical judgement. The BPD is less reliable in determining gestational age when there are variations in skull shape, such as dolichocephaly or brachycephaly; hence some authors feel that BPD is less reliable than HC.9,53–57 As a single parameter, HC correlates better to gestational age than the other 3 standard parameters in the second trimester, and as with all others, it becomes less accurate with increasing gestational age.58–61 It is more challenging to measure the fetal AC than the other parameters. The abdomen has no bright echoes of bone, it is not always symmetrical, and its size will vary with fetal respiration and central body flexion/extension. Of all the fetal biometric parameters, this measurement has the most variability as it is somewhat dependant on fetal growth factors and body position.54,61–63 Femur length varies somewhat with ethnicity. Short femurs are commonly a normal variant, however this finding may also indicate fetal growth restriction, aneuploidy, and— when severely shortened—skeletal dysplasias.53,64–69 Composite Versus Single Biometry Measurement

Using multiple parameters is superior to using a single second trimester parameter.63,70,71 As more parameters are used, accuracy improves; however, there is no significant benefit beyond 3 commonly used parameters.3,61,70–73 Multiple parameters are also useful if any one parameter is affected by a fetal condition/syndrome, such as achondroplasia on femur length. It is prudent to evaluate the etiology of an aberrant measurement to determine its clinical significance. Commonly, clinicians use the unweighted mean of all 4 biometric parameters (BPD, HC, AC, and FL). However, it is clear that all 4 are not equally correlative, thus many authors have created regression equations using various combinations of biometric parameters to improve accuracy.54,61,74,75 It is not clear which method is superior in determining gestational age.61,72 Until more research is available, it is reasonable to use either when estimating second or third trimester gestational age. Up to 23 weeks, second trimester US has a 95% CI of less than a week for predicting gestational age, comparable to first trimester US.61 In the late second trimester, clinical judgement should be exercised. Since the confidence intervals in the third trimester are quite large (2 to 2.4 weeks), it is not clear that US determined gestational age is superior to clinical history and the application of judicious clinical judgement may be 176 l FEBRUARY JOGC FÉVRIER 2014

warranted. There is also a concern that when gestational age assessment is based on a third trimester scan only, the fetus may in fact be growth restricted,61 and gestational age therefore underestimated. Hence, a follow-up scan for growth in such circumstances should be considered to evaluate interval growth. Recommendations

5. If a second- or third-trimester scan is used to determine gestational age, a combination of multiple biometric parameters (biparietal diameter, head circumference, abdominal circumference, and femur length) should be used to determine gestational age, rather than a single parameter. (II-1A) 6. When the assignment of gestational age is based on a third-trimester ultrasound, it is difficult to confirm an accurate due date. Follow-up of interval growth is suggested 2 to 3 weeks following the ultrasound. (III-C) Other Biometry

Measurement of the transcerebellar diameter, foot length, clavicle length, intra/interorbital diameters, kidney length, sacral length, scapula length, as well as the length of other long bones of the extremity have also been evaluated to determine gestational age. Studies have not shown that these parameters improve the assessment of gestational age beyond that achieved with standard biometry, however they may be useful in clinical situations in which traditional biometry is difficult to attain (such as uteroplacental insufficiency) or when fetal abnormalities are present.76–86 Signs of Fetal Maturity

Identification of certain US findings suggest that a fetus has reached the third trimester and may correlate with fetal lung maturity and gestational age. These parameters are the epiphyseal ossification centres of the distal femur, proximal tibia, and proximal humerus. The measurement of these ossification centres does not precisely correlate with gestational age; however, their presence may be helpful late in pregnancy when the gestational age is not known. The presence of distal femoral epiphysis has a PPV of 96% for indicating a pregnancy of at least 32 weeks, the proximal tibial epiphysis has a PPV of 83% for indicating a pregnancy of at least 37 weeks, and the proximal humeral epiphysis has a PPV of 100% for indicating a pregnancy of at least 38 weeks.87–91 WHAT IS THE BEST METHOD FOR ASG GESTATIONAL AGE?

Currently, most centres in Canada use a combined approach in which US is used to confirm reliable

Determination of Gestational Age by Ultrasound

menstrual dating. If there is an unreliable menstrual history, the US prediction of EDD is used. Clinical judgement is used to resolve conflicting data. However, centres vary in of confidence intervals and biometry charts used. Many studies evaluating menstrual dating, compared with US dating, in the first and second trimesters have found US dating superior for predicting the actual date of delivery.92–98 No study has shown that it is inferior to menstrual dating. Menstrual dating underestimates the US-based EDD by an average of 2 to 3 days.95 Ultrasound dating alone was significantly better in predicting the actual date of delivery than any of the dating policies using menstrual dates alone or in combination with US.9,99 Many studies document that the use of US dates reduces the rate of post-dates pregnancy by about 70% even in the face of certain menstrual history.92,96,97,99,100 The most recent Cochrane systematic review found reduced rates of induction for post-term pregnancy (OR 0.59; 95% CI 0.42 to 0.83) among women who underwent routine US in early pregnancy (< 24 weeks) and concluded that early pregnancy US enables better gestational age assessment, as well as conferring other benefits.101 Using US-based gestational age assignment would also result in improved performance of prenatal screening programs. Using US estimates exclusively would increase sensitivity for Down syndrome anywhere from 9% to 16%, and/or decrease false-positive rates (for a set sensitivity) by 2.6%.102,103 There might be a very slight increase in the screening positive rate for open neural tube defects, but this is more than offset by the decrease in false-positive rates for Down syndrome. The common practice of using certain menstrual dates confirmed by US is inferior to using US alone.104 In the context of serum screening, first and early second-trimester US parameters perform similarly.100,102,104–106 Some clinicians fear that the exclusive use of US-based estimates of gestational age would result in pregnancy complications because of the potential to miss early growth discordance. A large-for-gestational-age fetus might be mistakenly assigned a greater gestational age because of its larger size or an early growth-restricted fetus may be incorrectly assigned a later due date. This may potentially mask an underlying fetal or placental problem leading to pregnancy complications, such as preterm birth, preeclampsia, and fetuses small for gestational age, or it may cause a delay in the recognition of fetal abnormalities. There is disagreement in the literature as to whether a significant discordance

between menstrual and US estimates of gestational age is associated with an increased risk of obstetrical complications.107–114 Interestingly, an unreliable menstrual history itself confers an increased risk of adverse pregnancy outcomes.112 Although there may be a risk in using US dating exclusively, some of this risk would remain whenever there is discordance between menstrual and US estimates, regardless of which method of gestational age assignment is used. Furthermore, the clinical management of such situations is unclear. More research is needed in this area. Summary Statements

1. When performed with quality and precision, ultrasound alone is more accurate than a “certain” menstrual date for determining gestational age in the first and second trimesters (≤ 23 weeks) in spontaneous conceptions, and it is the best method for estimating the delivery date. (II) 2. In the absence of better assessment of gestational age, routine ultrasound in the first or second trimester reduces inductions for post-term pregnancies. (I) SHOULD ROUTINE FIRST TRIMESTER DATING ULTRASOUNDS BE OFFERED TO ALL PREGNANT WOMEN?

A routine first trimester US has many advantages: early identification of gross anomalies and multiple gestations, more precise dating, improved performance of prenatal screening, and an opportunity to perform nuchal translucency as part of prenatal genetic screening. In many jurisdictions, a dating US is performed routinely in all women, regardless of menstrual history. The availability, quality, and health care cost of obstetrical US is a significant factor in local patterns of practice.2 Crowther et al. found routine early US (< 17 weeks) provided more precise estimates of gestational age than later US (18 to 22 weeks), reduced the need to adjust the EDD in mid-gestation, and decreased maternal anxiety.115 The balance of the literature s using first trimester US to reduce the incidence of induction for post-dates pregnancy.18,99,100,116–118 Although no comprehensive cost benefit analysis has been done on routine early US for dating, the current literature suggests significant benefits are present. Ideally, where it is readily available, a first trimester US for dating should be performed. Where nuchal translucency is available, this scan can serve both functions. When a first trimester US cannot be obtained, the available evidence suggests the second trimester US can be used for similar benefits.101 FEBRUARY JOGC FÉVRIER 2014 l 177

SOGC Clinical Practice Guidelines

Summary Statements

3. Ideally, every pregnant woman should be offered a first trimester dating ultrasound; however, if the availability of obstetrical ultrasound is limited, it is reasonable to use a second trimester scan to assess gestational age. (I) 4. Notwithstanding Summary Statements 1, 2, and 3, women vary greatly in their awareness of their internal functions, including ovulation, and this selfknowledge can sometimes be very accurate. (III) SUMMARY

The accurate determination of gestational age is required for many aspects of antenatal care. In the past, it was probably felt that a few days of inaccuracy was acceptable; however, emerging data suggests that a few days inaccuracy can affect things, such as the performance of maternal serum screening, the assessment of post-dates pregnancy, and the subsequent induction of labour. Based on the available research, the use of US-derived dates is the best method to determine gestational age for clinical use. It is not, however, intended to be used to determine the exact date of conception because of biological variability in reproduction, fetal size, and development. Clinical history may have value in determining gestational age, and on rare occasions may supersede US dating; however, in order to achieve the most clinical benefit, the use of US dating should predominate. REFERENCES

10. Johnson TR, Niebyl JR. Preconception and prenatal care: part of the continuum. In: obstetrics: normal and problem pregnancies. 4th ed. Philadelphia: Churchill Livingstone; 2002. 11. Campbell S, Warsof SL, Little D, Cooper DJ. Routine ultrasound screening for the prediction of gestational age. Obstet Gynecol 1985;65:613–20. 12. Baerwald AR, Adams GP, Pierson RA. A new model for ovarian follicular development during the human menstrual cycle. Fertil Steril 2003;80:116–22. 13. Baerwald AR, Adams GP, Pierson RA. Characterization of ovarian follicular wave dynamics in women. Biol Reprod 2003;69:1023–31. 14. Leppaluoto P. Vaginal flora and sperm survival. J Reprod Med 1974;12:99–107. 15. Mahendru AA, Daemen A, Everett TR, Wilkinson IB, McEniery CM, Abdallah Y, et al. Impact of ovulation and implantation timing on first trimester crown-rump length and gestational age. Ultrasound Obstet Gynecol 2012;40:630–5. 16. Saito M, Keijiro Y, Akinori H, Takahiro K, Nozumu N, Kohei K. Time of ovulation and prolonged pregnancy. Am J Obstet Gynecol 1976;112:31–8. 17. Beazley JM, Underhill RA. Fallacy of the fundal height. BMJ 1970;4:404–6. 18. Caughey AB, Nicholson JM, Washington AE. First- vs second-trimester ultrasound: the effect on pregnancy dating and perinatal outcomes. Am J Obstet Gynecol 2008;198:703–5. 19. Laing FC, Frates MC. Ultrasound evaluation during the first trimester of pregnancy. In: Callen PW, ed. Ultrasonography in obstetrics and gynecology, 4th ed. Philadelphia: WB Saunders, 2000. 20. Timor-Tritsh IE, Farine D, Rosen MG. A close look at early embryonic development with the high-frequency transvaginal transducer. Am J Obstet Gynecol 1988;159:676–81. 21. Rowling SE, Langer JE, Coleman BG, Nisenbaum HL, Horii SC, Arger PH, et al. Sonography during early pregnancy: dependence of threshold and discriminatory values on transducer frequency. AJR Am J Roentgenol 1999;172:983–8.

1. Kalish RB, Chervenak FA. Sonographic determination of gestational age. Ultrasound Rev Obstet Gynecol 2005;5:254–8.

22. Nyberg DA, Mack LA, Laing FC, Patten R. Distinguishing normal from abnormal gestational sac growth in early pregnancy. J Ultrasound Med 1987;6(1):23–7.

2. Hughes R, Aitken E, Anderson J, Barry C, Benton M, Elliot J; National Institute for Health and Clinical Excellence. Antenatal care. Routine care for the healthy pregnant woman. NICE clinical guideline 62. London: RCOG Press; 2008.

23. MacKenzie AP, Stephenson CD, Funai EF. Prenatal assessment of gestational age. UpToDate. Version 16.3, October 1 2008. Available at: http://www.uptodate.com/contents/prenatal-assessment-ofgestational-age? Accessed on April 21, 2013.

3. Bottomley C, Bourne T. Dating and growth in the first trimester. Best Pract Res Clin Obstet Gynaecol 2009;23:439–52. 4. Gardosi J. Dating of pregnancy: time to forget the last menstrual period. Ultrasound Obstet Gynecol 1997;9:367–8.

24. Pexsters A. Clinical implications of intra- and interobserver reproducibility of transvaginal sonographic measurement of gestational sac and crown-rump length at 6-9 weeks’ gestation. Ultrasound Obstet Gynecol 2011;38:510–5.

5. Gardosi J, Geirsson RT. Routine ultrasound is the method of choice for dating pregnancy. Br J Obstet Gynaecol 1998;105:933–6.

25. Sauerbrei E, Cooperbeg PL, Poland JB. Ultrasound demonstration of the normal fetal yolk sac. J Clin Ultrasound 1980;8:217–20.

6. Salomon LJ, Alfirevic Z, Bilardo CM, Chalouhi GE, Ghi T, Kagan KO, et al. ISUOG practice guidelines: performance of first-trimester fetal ultrasound scan. Ultrasound Obstet Gynecol 2013;41(1):102–13.

26. Salomon LJ, Bernard JP, Duyme M, Dorion A, Ville Y. Revisiting firsttrimester biometry. Ultrasound Obstet Gynecol 2003;22:63–6.

7. Andersen HF, Johnson TR Jr, Flora JD Jr, Barclay ML. Gestational age assessment. II. Prediction from combined clinical observations. Am J Obstet Gynecol 1981;140(1):770–4.

27. Tezuka N, Saito H, Hiroi M. Comparison of the accuracy of gestational age estimation from fetal heart rate and crown-rump length. Prim Care Update Ob Gyns 1998;5:193.

8. Andersen HF, Johnson TR Jr., Barclay ML, Flora JD Jr. Gestational age assessment. I. analysis of individual clinical observations. Am J Obstet Gynecol 1981;139:173–7.

28. Bovicelli L, Orsini LF, Rizzo N, Calderoni P, Pazzaglia FL, Michelacci L. Estimation of gestational age during the first trimester by real-time measurement of fetal crown-rump length and biparietal diameter. J Clin Ultrasound 1981;9:71–5.

9. Nguyen TH, Larsen T, Engholm G, Moller H. Evaluation of ultrasoundestimated date of delivery in 17,450 spontaneous singleton births: do we need to modify Naegele’s rule? Ultrasound Obstet Gynecol. 1999;14:23–8.

29. Hadlock FP, Shah YP, Kanon DJ, Lindsey JV. Fetal crown-rump length: reevaluation of relation to menstrual age (5-18 weeks) with highresolution real-time US. Radiology 1992;182:501–5.

178 l FEBRUARY JOGC FÉVRIER 2014

Determination of Gestational Age by Ultrasound

30. Daya S. Accuracy of gestational age estimation by means of fetal crownrump length measurement. Am J Obstet Gynecol 1993;168:903–8. 31. Grisolia G, Milano K, Pilu G, Banzi C, David C, Gabrielli S, et al. Biometry of early pregnancy with transvaginal sonography. Ultrasound Obstet Gynecol. 1993;3:403–11. 32. Robinson HP, Fleming JE. A critical evaluation of sonar “crown-rump length” measurements. Br J Obstet Gynaecol 1975;82:702–10. 33. van de Velde EH, Broeders GH, Horbach JG, Esser-Rath VW. Estimation of pregnancy duration by means of ultrasonic measurements of the fetal crown-rump length. Eur J Obstet Gynecol Reprod Biol 1980;10:225–30. 34. Vollebergh JH, Jongsma HW, van Dongen PW. The accuracy of ultrasonic measurement of fetal crown-rump length. Eur J Obstet Gynecol.Reprod Biol 1989;30:253–6. 35. Silva PD, Mahairas G, Schaper AM, Schauberger CW. Early crown rump length. A good predictor of gestational age. J Reprod Med 1990;35:641–4. 36. Wisser J, Dirschedl P, Krone S. Estimation of gestational age by transvaginal sonographic measurement of greatest embryonic length in dated human embryos. Ultrasound Obstet Gynecol 1994;4:457–62. 37. Goldstein SR, Wolfson R. Endovaginal ultrasonographic measurement of early embryonic size as a means of assessing gestational age. J Ultrasound Med 1994;13:27–31. 38. Nyberg DA, Laing FC, Filly RA. Threatened abortion: sonographic distinction of normal and abnormal gestation sac. Radiology 1986;158:397–400. 39. Goldstein SR. Early detection of pathologic pregnancy by transvaginal ultrasonography. J Clin Ultrasound 1990;18:262–73. 40. Piantelli G, Sacchini C, Coltri A, Ludovici G, Paita Y, Gramellini D. Ultrasound dating-curve analysis in the assessment of gestational age. Clin Exp Obstet Gynecol 1994;2:108–18. 41. Saltved S, Almstrom H, Kublickas M. Ultrasound dating at 12-14 or 15-20 weeks of gestation? A prospective cross-validation of established dating formulae in a population of in-vitro fertilized pregnancies randomized to early or late dating scan. Ultrasound Obstet Gynecol 2004;24:42–50. 42. Sladkevicius P, Saltved S, Almstrom H, Kublickas M, Grunewald C, Valentin L, et al. Ultrasound dating at 12-14 weeks of gestation. A prospective cross-validation of established dating formulae in in-vitro fertilized pregnancies. Ultrasound Obstet Gynecol 2005;26:504–11. 43. Wu FS, Hwu YM, Lee RK, Li SH, Sun FJ, Lin MH, et al. First trimester ultrasound estimation of gestational age in pregnancies conceived after in vitro fertilization. Eur J Obstet Gynecol Reprod Biol 2012;160:151–5. 44. Chalouhi GE, Bernard JP, Benoist G, Nasr B, Ville Y, Salomon LJ. A comparison of first trimester measurements for prediction of delivery date. J Matern Fetal Neonatal Med 2011;24:51–7. 45. Coleman BG, Arger PH, Grumbach K, Menard MK, Mintz MC, Allen KS, et al. Transvaginal and transabdominal sonography: prospective comparison. Radiology 1988;168:639–43. 46. Jain KA, Hamper UM, Sanders RC. Comparison of transvaginal and transabdominal sonography in the detection of early pregnancy and its complications. AJR Am J Roentgenol 1988;151:1139–43. 47. Pennell RG, Needleman L, Pajak T, Baltarowich O, Vilaro M, Goldberg BB, et al. Prospective comparison of vaginal and abdominal sonography in normal early pregnancy. J Ultrasound Med 1991;10:63–7. 48. Lohr PA, Reeves MF, Creinin MD. A comparison of transabdominal and transvaginal ultrasonography for determination of gestational age and clinical outcomes in women undergoing early medical abortion. Contraception 2010;81:240–4. 49. Ferrazzi E, Garbo S, Sulpizio P, Ghisoni L, Levi SP, Buscaglia M. Miscarriage diagnosis and gestational age estimation in the early first trimester of pregnancy: transabdominal versus transvaginal sonography. Ultrasound Obstet Gynecol 1993;3:36–41.

50. Kaur A. Transvaginal ultrasonography in first trimester of pregnancy and its comparison with transabdominal ultrasonography. J Pharm Bioallied Sci 2011;3:329–38. 51. Gjerris AC, Loft A, Pinborg A, Tabor A, Christiansen M. First-trimester screening in pregnancies conceived by assisted reproductive technology: significance of gestational dating by oocyte retrieval or sonographic measurement of crown-rump length. Ultrasound Obstet Gynecol 2008;32:612–7. 52. Tunón K, Eik-Nes SH, Grøttum P, Von Düring V, Kahn JA. Gestational age in pregnancies conceived after in vitro fertilization: a comparison between age assessed from oocyte retrieval, crown-rump length and biparital diameter. Ultrasound Obstet Gynecol 2000;15(1):41–6. 53. Nyberg DA. Diagnostic imaging of fetal anomalies, 2nd ed. Philadelphia: Lippincott Williams Wilkins; 2003: pp 32–4. 54. Hadlock FP, Harrist RB, Martinez-Poyer J. How accurate is second trimester fetal dating? J Ultrasound Med 1991;10:557–61. 55. Hadlock FP, Deter RL, Harrist RB, Park SK. Fetal biparietal diameter: rational choice of plane section for sonographic measurement. AJR Am J Roentgenol 1982;138:871–4. 56. Hadlock FP, Deter RL, Harrist RB, Park SK. Fetal biparietal diameter: a critical re-evaluation of the relation to menstrual age by means of real-time ultrasound. J Ultrasound Med 1982;1:97–104. 57. Hadlock FP, Deter RL, Carpenter RJ, Park SK. Estimating fetal age: effect of head shape on BPD. AJR Am J Roentgenol 1981;137:83–5. 58. Law RG, MacRae KD. Head circumference as an index of fetal age. J Ultrasound Med 1982;1:281–8. 59. Hadlock FP, Deter RL, Harrist RB, Park SK. Fetal head circumference: relation to menstrual age. AJR Am J Roentgenol 1982;138:649–53. 60. Ott WJ. The use of ultrasonic fetal head circumference for predicting expected date of confinement. J Clin Ultrasound 1984;12:411–5. 61. Chervenak FA, Skupski DW, Romero R, Myers MK, Smith-Levitin M, Rosenwaks Z, et al. How accurate is fetal biometry in the assessment of fetal age? Am J Obstet Gynecol 1998;178:678–87. 62. Hadlock FP, Deter RL, Harrist RB, Park SK. Fetal abdominal circumference as a predictor of menstrual age. AJR Am J Roentgenol 1982;139:367–70. 63. Benson C, Doubilet PM. Sonographic prediction of gestational age: accuracy of second and third trimester fetal measurements. AJR Am J Roentgenol 1991;157:1275–7. 64. Shalev E, Feldman E, Weiner E, Zuckerman H. Assessment of gestational age by ultrasonic measurement of the femur length. Acta Obstet Gynecol Scand 1985;64:71–4. 65. Hadlock FP, Harrist RB, Deter RL, Park SK. A prospective evaluation of femur length as a predictor of gestational age. J Ultrasound Med 1983;2:111–2. 66. Yeh MN, Bracero L, Reilly KB, Murtha L, Aboulafia M, Barron BA. Ultrasonic measurement of the femur length as an index of fetal gestational age. Am J Obstet Gynecol 1982;144:519–22. 67. Hadlock FP, Harrist RB, Deter RL, Park SK. Fetal femur length as a predictor of menstrual age: sonographically measured. AJR Am J Roentgenol 1982;138:875–8. 68. Weisz B, David AL, Chitty L, Peebles D, Pandya P, Patel P, et al. Association of isolated short femur in the mid-trimester fetus with perinatal outcome. Ultrasound Obstet Gynecol 2008;31:512–6. 69. Papageorghiou AT, Fratelli N, Leslie K, Bhide A, Thilaganathan B. Outcome of fetuses with antenatally diagnosed short femur. Ultrasound Obstet Gynecol 2008;31:507–11.

FEBRUARY JOGC FÉVRIER 2014 l 179

SOGC Clinical Practice Guidelines

70. Hill LM, Guzick D, Hixson J, Peterson CS, Rivello DM. Composite assessment of gestational age: a comparison of institutionally derived and published regression equations. Am J Obstet Gynecol 1992;166:551–5. 71. Geirsson RT, Have G. Comparison of actual and ultrasound estimated second trimester gestational length in in-vitro fertilized pregnancies. Acta Obstet Gynecol Scand 1993;72:344–6. 72. Hadlock FP, Deter RL, Harrist RB, Park SK. Estimating fetal age: computer-assisted analysis of multiple fetal growth parameters. Radiology 1984;152:497–501. 73. Hadlock FP, Harrist RB, Shah YP, King DE, Park SK, Sharman RS. Estimating fetal age using multiple parameters: a prospective evaluation in a racially mixed population. Am.J Obstet Gynecol. 1987;156:955–57. 74. Mongelli M, Yuxin NG, Biswas A, Chew S. Accuracy of ultrasound dating formulae in the late second-trimester in pregnancies conceived with invitro fertilization. Acta Radiol 2003;44:452–5. 75. Mongelli M, Chew S, Yuxin NG, Biswas A. Third-trimester ultrasound dating algorithms derived from pregnancies conceived with artificial reproductive techniques. Ultrasound Obstet Gynecol 2005;26:129–31.

89. Goldstein I, Lockwood C, Belanger K, Hobbins J. Ultrasonographic assessment of gestational age with the distal femoral and proximal tibial ossification centers in the third trimester. Am J Obstet Gynecol 1988;158:127–30. 90. Gentili P, Trasimeni A, Giorlando C. Fetal ossification centers as predictors of gestational age in normal and abnormal pregnancies. J Ultrasound Med 1984;3:193–7. 91. Mahoney BS, Callen PW, Filly RA. The distal femoral epiphyseal ossification center in the assessment of third-trimester menstrual age: sonographic identification and measurement. Radiology 1985;155:201–4. 92. Mongelli M, Wilcox M, Gardosi J. Estimating the date of confinement: ultrasonographic biometry versus certain menstrual dates. Am J Obstet Gynecol 1996;174:278–81. 93. Rossavik IK, Fishburne JI. Conception age, menstrual age and ultrasound age: a second trimester comparison of pregnancies of known conception date with pregnancies dates from last menstrual period. Obstet Gynecol 1987;73:243–9.

76. Gottlieb AG, Galen HL. Nontraditional sonographic pearls in estimating gestational age. Semin Perinatol 2008;32:154–60.

94. Kramer MS, McLean FH, Boyd ME, Usher RH. The validity of gestational age estimation by menstrual dating in term, preterm, and postterm gestations. JAMA 1988;260:3306–8.

77. Jeanty P, Rodesch F, Delbeke D, Dumont JE. Estimation of gestational age from measurements of fetal long bones. J Ultrasound Med 1984;3:75–9.

95. Tunón K, Eik-Nes SH, Grøttum P. A comparison between ultrasound and a reliable last menstrual period as predictors of the day of delivery in 15,000 examinations. Ultrasound Obstret Gynecol 1996;8:178–85.

78. Yarkoni S, Schmidt W, Jeanty P, Reece EA, Hobbins JC. Clavicular measurement: a new biometric parameter for fetal evaluation. J Ultrasound Med 1985;4:467–70

96. Waldenström U, Axelsson O, Nilsson S. A comparison of the ability of a sonographically measured biparietal diameter and last menstrual period to predict the spontaneous onset of labor. Obstet Gynecol 1990;76:336–8.

79. Mercer BM, Sklar S, Shariatmadar A, Gillieson MS, D’Alton ME. Fetal foot length as a predictor of gestational age. Am J Obstet Gynecol 1987;156:350–5.

97. Kieler H, Axelsson O, Nilsson S, Waldenström U. Comparison of ultrasonic wseameasurement of biparietal diameter and last menstrual period as a predictor of day of delivery in women with regular 28 daycycles. Acta Obstet Gynecol Scand 1993;72:347–9.

80. Platt LD, Medearis AL, DeVore GR, Horenstein JM, Carlson DE, Brar HS. Fetal foot length: relationship to menstrual age and fetal measurements in the second trimester. Obstet Gynecol 1988;71:526–31. 81. Murao F, Shibukawa T, Takamiya O, Yamamoto K, Hasegawa K. Antenatal measurement of the scapula length using ultrasound. Gynecol Obstet Invest 1989;28:195–7. 82. Reece EA, Gabrielli S, Degennaro N, Hobbins JC. Dating through pregnancy: a measure of growing up. Obstet Gynecol Surv 1989;44:544–55. 83. Lee W, Barton S, Comstock CH, Bajorek S, Batton D, Kirk JS. Transverse cerebellar diameter: a useful predictor of gestational age for fetuses with asymmetric growth retardation. Am J Obstet Gynecol 1991;165(4 Pt 1):1044–50. 84. Sherer DM, Abramowicz JS, Plissinger MA, Woods JR Jr. Fetal sacral length in the ultrasonographic assessment of gestational age. Am J Obstet Gynecol 1993;168:626–33.

98. Backe B, Nakling J. Term prediction in routine ultrasound practice. Acta Obstet Gynecol Scand 1994;73:113–8. 99. Taipale P, Hiilesmaa V. Predicting delivery date by ultrasound and last menstrual period in early gestation. Obstet Gynecol 2001;97:189–94. 100. Blondel B, Morin I, Platt RW, Kramer MS, Usher R, Breart G. Algorithms for combining menstrual and ultrasound estimates of gestational age: consequences for rates of preterm and postterm birth. BJOG 2002;109:718–20. 101. Whitworth M, Bricker L, Neilson JP, Dowswell T. Ultrasound for fetal assessment in early pregnancy. Cochrane Database Syst Rev 2010;4:CD007058. 102. Benn PA, Borgida A, Horne D, Briganti S, Collins R, Rodis JF. Down syndrome and neural tube defect screening: the value of using gestational age by ultrasonography. Am J Obstet Gynecol 1997;176:1056–61.

85. Konje JC, Abrams KR, Bell SC, Taylor DJ. Determination of gestational age after the 24th week of gestation from fetal kidney length measurements. Ultrasound Obstet Gynecol 2002;19:592–7.

103. Wald NJ, Cuckle HS, Densem JW, Kennard A, Smith D. Maternal serum screening for Down’s syndrome: the effect of routine ultrasound scan determination of gestational age and adjustment for maternal weight. Br J Obstet Gynaecol 1992;99:144–9.

86. Drey EA, Kang MS, McFarland W, Taylor DJ. Improving the accuracy of fetal foot length to confirm gestation duration. Obstet Gynecol 2005;105:773–8.

104. Rahim RR, Cuckle HS, Sehmi IK, Jones RG. Compromise ultrasound dating policy in maternal serum screening for Down syndrome. Prenat Diagn 2002;22:1181–4.

87. Donne HD, Faúndes A, Tristão EG, de Sousa MH, Urbanetz AA. Sonographic identification and measurement of the epiphyseal ossification centers as markers of fetal gestational age. J Clin Ultrasound 2005;33:394–400.

105. Koster MP, Van Leeuwen-Spruijt M, Wortelboer EJ, Stoutenbeek P, Elvers LH, Loeber JG, et al. Lack of standardization in determining gestational age for prenatal screening. Ultrasound Obstet Gynecol 2008;32:607–11.

88. Goldstein I, Lockwood CJ, Reece, Hobbins JC. Sonographic assessment of the distal femoral and proximal tibial ossification centers in the prediction of pulmonic maturity in normal women and women with diabetes. Am J Obstet Gynecol 1988;159:72–6.

106. Wald NJ, Smith D, Kennard A, Palomaki GE, Salonen R, Holzgreve W, et al. Biparietal diameter and crown-rump length in fetuses with Down’s syndrome: implications for antenatal serum screening for Down’s syndrome. Br J Obstet Gynaecol 1993;100:430–5.

180 l FEBRUARY JOGC FÉVRIER 2014

Determination of Gestational Age by Ultrasound

107. Gardosi J, Francis A. Early pregnancy predictors of preterm birth: the role of a prolonged menstruation-conception interval. BJOG 2000;107:228–37. 108. Kallen K. Increased risk of perinatal/neonatal death in infants who were smaller than expected at ultrasound fetometry in early pregnancy. Ultrasound Obstet Gynecol 2004;24:30–4. 109. Nakling J, Backe B. Adverse obstetric outcome in fetuses that are smaller than expected at second trimester routine ultrasound examination. Acta Obstet Gynecol Scand 2002;81:846–51. 110. Tunón K, Eik-Nes SH, Grøttum P. Fetal outcome when the ultrasound estimate of the day of delivery is more than 14 days later than the last menstrual period estimate. Ultrasound Obstet Gynecol 1999;14:17–22. 111. Dietz PM, England LJ, Callaghan WM, Pearl M, Wier ML, Kharrazi M. A comparison of LMP-based and ultrasound-based estimates of gestational age using linked California livebirth and prenatal screening records. Paediatr Perinat Epidemiol 2007;21(Suppl 2):62–71. 112. Nguyen TH, Larsen T, Engholm G, Moller H. Increased adverse pregnancy outcomes with unreliable last menstruation. Obstet Gynecol. 2000;95:867–73. 113. Smith GC, Smith MF, McNay MB, Fleming JE. First-trimester growth and the risk of low birth weight. N Engl J Med 1998;339:1817–22.

114. Lynch CD, Zhang J. The research implications of the selection of a gestational age estimation method. Paediatr Perinat Epidemiol 2007;21(Suppl 2):86–96. 115. Crowther CA, Kornman L, O’Callaghan S, George K, Furness M, Willson K. Is an ultrasound assessment of gestational age at the first antenatal visit of value? A randomised clinical trial. Br J Obstet Gynaecol 1999;106:1273–9. 116. Bennett KA, Crane JM, O’Shea P, Lacelle J, Hutchens D, Copel JA. First trimester ultrasound screening is effective in reducing postterm labor induction rates: a randomized controlled trial. Am. J Obstet Gynecol 2004;190:1077–81. 117. Harrington DJ, MacKenzie IZ, Thompson K, Fleminger M, Greenwood C. Does a first trimester dating scan using crown rump length measurement reduce the rate of induction of labour for prolonged pregnancy? An uncompleted randomised controlled trial of 463 women. BJOG 2006;113:171–6. 118. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

FEBRUARY JOGC FÉVRIER 2014 l 181

SOGC CLINICAL PRACTICE GUIDELINE No. 307, May 2014 (Replaces No. 206, March 2008)

Diagnosis, Evaluation, and Management of the Hypertensive Disorders of Pregnancy: Executive Summary The guideline summarized here has been prepared by the Canadian Hypertensive Disorders of Pregnancy Working Group, reviewed and approved by the Hypertension Guideline Committee, reviewed by the Maternal Fetal Medicine and Family Physician Advisory committees, and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Laura A. Magee, MD, Vancouver BC Anouk Pels, MSc, Amsterdam, the Netherlands Michael Helewa, MD, Winnipeg MB Evelyne Rey, MD, Montreal QC Peter von Dadelszen, MBChB, Vancouver BC HYPERTENSION GUIDELINE COMMITTEE Laura A. Magee, MD (Chair), Vancouver BC Francois Audibert, MD, Montreal QC Emmanuel Bujold, MD, Quebec QC Anne-Marie Côté, MD, Sherbrooke QC Myrtle Joanne Douglas, MD, Vancouver BC Genevieve Eastabrook, MD, FRCSC, London ON Tabassum Firoz, MD, Vancouver BC Paul Gibson, MD, Calgary AB Andrée Gruslin, MD, Ottawa ON Jennifer Hutcheon, PhD, Vancouver BC Gideon Koren, MD, Toronto ON Ian Lange, MD, Calgary AB Line Leduc, MD, Montreal QC Alexander G. Logan, MD, Toronto ON Key Words: Hypertension, blood pressure, pregnancy, preeclampsia, maternal outcome, perinatal outcome, long-term prognosis

Karen L. MacDonell, PhD, Vancouver BC Jean-Marie Moutquin, MD, Sherbrooke QC Ilana Sebbag, MD, Vancouver BC Disclosure statements have been received from all of the committee. The literature searches and bibliographic for this guideline were undertaken by Becky Skidmore, Medical Research Analyst, Society of Obstetricians and Gynaecologists of Canada.

Abstract Objective: This executive summary presents in brief the current evidence assessed in the clinical practice guideline prepared by the Canadian Hypertensive Disorders of Pregnancy Working Group and published by Pregnancy Hypertension (http://www.pregnancyhypertension.org/article/S22107789(14)00004-X/fulltext) to provide a reasonable approach to the diagnosis, evaluation, and treatment of the hypertensive disorders of pregnancy. Evidence: Published literature was retrieved through searches of Medline, CINAHL, and The Cochrane Library in March 2012 using appropriate controlled vocabulary (e.g., pregnancy, hypertension, pre-eclampsia, pregnancy toxemias) and key words (e.g., diagnosis, evaluation, classification, prediction, prevention, prognosis, treatment, postpartum follow-up). Results were restricted to systematic reviews, randomized control trials, controlled clinical trials, and observational studies published in French or English between January 2006 and February 2012. Searches were updated on a regular basis and incorporated in the guideline to September 2013. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Values: The quality of evidence in the guideline summarized here was rated using the criteria described in the Report of the Canadian Task Force on Preventative Health Care (Table 1). J Obstet Gynaecol Can 2014;36(5):416–438

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

416 l MAY JOGC MAI 2014

Diagnosis, Evaluation, and Management of the Hypertensive Disorders of Pregnancy: Executive Summary

Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.39 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care.39

RECOMMENDATIONS

●

Antihypertensive Therapy for Severe Hypertension: 62–68

CHAPTER 1: DIAGNOSIS AND CLASSIFICATION OF THE MEASUREMENT OF BP FOR HDPs

●

Antihypertensive Therapy for Non-Severe Hypertension Without Comorbid Conditions: 69–73

●

For Non-Severe Hypertension (BP of 140–159/ 90–109 mmHg) With Comorbid Conditions: 74–76

●

Corticosteroids for Acceleration of Fetal Pulmonary Maturity: 77–80

●

BP Measurement: 1–10

●

Diagnosis of Hypertension: 11–17

●

Measurement of Proteinuria: 18–24

●

Classification of HDPs: 25–31

●

Timing of Delivery for Women With Preeclampsia: 81–88

●

Investigations to Classify HDPs: 32–37

●

Timing of Delivery for Women With Gestational Hypertension: 89, 90

●

Timing of Delivery for Women with Pre-existing Hypertension: 91

●

Mode of Delivery: 92–97

●

Anaesthesia: General Principles: 98–101

●

Anaesthesia: Fluid istration: 102–105

●

Monitoring: 106–108

●

Coagulation: 109, 110

●

Aspects of Care Specific to Women Wth Pre-Existing Hypertension: 111–115

●

Aspects of Care for Women With Preeclampsia: Magnesium Sulphate for Preventing or Treating Eclampsia: 116–123

●

Aspects of Care for Women With Preeclampsia: Plasma Volume Expansion: 124

CHAPTER 2: PREDICTION AND PREVENTION ●

Predicting Preeclampsia: 38–40

●

Preventing Preeclampsia and its Complications in Women at Low Risk: 41–46

●

Preventing Preeclampsia and its Complications in Women at Increased Risk: 47–54

CHAPTER 3: TREATMENT OF THE HDPs ●

Dietary and Lifestyle Changes: 55–59

●

Place of Care: 60, 61

ABBREVIATIONS BP

blood pressure

●

Therapies for HELLP Syndrome: 125–131

HDP

hypertensive disorder of pregnancy

●

Care in the 6 Weeks Postpartum: 132–142

HELLP hemolysis, elevated liver enzymes, low platelets

●

Care Beyond 6 Weeks Postpartum: 143–148

IUGR

intrauterine growth restriction

●

NICU

neonatal intensive care unit

Effects of Maternal Hypertension and its Therapies on Child Neurobehavioural Development: 149, 150

RCT

randomized control trial

RDS

respiratory distress syndrome

CHAPTER 4: PATIENT PERSPECTIVE: 151–153

MAY JOGC MAI 2014 l 417

SOGC CLINICAL PRACTICE GUIDELINE

INTRODUCTION

H

ypertensive disorders of pregnancy remain leading causes of maternal and perinatal morbidity and mortality.1,2 The guideline summarized here assesses the quality of the relevant existing evidence and provides a reasonable approach to the diagnosis, evaluation, and treatment of the HDP, focusing on Canadian context. Our purpose is to evidence-based maternity care of women who are planning pregnancy and are at risk of an HDP, have an HDP in the current pregnancy, or are postpartum and had an HDP. When necessary, we have provided expert opinion about reasonable clinical care. Our health intent and aim is to improve short- and longterm maternal, perinatal, and paediatric outcomes and the cost-effectiveness of related interventions in pregnancies complicated by an HDP. The expected benefit of this guideline is improved outcomes for mother, baby, and child through evidence-advised practice. Our target s are multidisciplinary maternity care providers from primary to tertiary levels of health care. The questions that this guideline seeks to address are: •• How, and in what setting, should BP be measured in pregnancy, and what is an abnormal BP? •• How should proteinuria be measured in pregnancy? What constitutes significant proteinuria? Is heavy proteinuria an indication for delivery? •• How should the HDPs be diagnosed and classified? What constitutes severe preeclampsia? •• What are the prognoses of pregnancies complicated by pre-existing hypertension, gestational hypertension, or preeclampsia? •• How can preeclampsia and its complications be predicted and/or prevented by lifestyle changes, medication, and/or care of a specific type or in a specific location? •• How should women with an HDP be managed regarding initial investigations, dietary and lifestyle changes, place of care, antihypertensive therapy, aspects of care specific to women with preeclampsia (such as magnesium sulphate), mode and timing of delivery, intrapartum care (including BP monitoring and analgesia/anaesthesia), and postpartum monitoring, treatment, and counselling regarding the impact of an HDP on both future pregnancy outcomes and longterm maternal and paediatric outcomes? •• What is the patient’s perspective on her diagnosis and evaluation?

418 l MAY JOGC MAI 2014

•• How can this guideline be implemented into clinical practice? This document presents a summary of the recommendations, along with ing text for the new classification of the HDPs, and all of the tables provided in the full guideline. Because of the breadth of the topic and the volume of material covered, the methods, ing text for all recommendations, and the full list of references, including those for the tables, have been published separately as an open-access article in Pregnancy Hypertension.3 Important changes affect all aspects of care covered in the 2008 guidelines. Notable examples include the addition of systolic BP in the definition of pregnancy hypertension, revised HDP classification, new information on prevention, more direction with respect to timing of delivery in women with any HDP, information about magnesium sulphate for fetal neuroprotection at < 32 weeks, a new gestational age cut-off (≤ 34+6 instead of ≤ 33+6 weeks) for istration of steroids, and a section on knowledge translation with links to useful tools for women and practitioners. CHAPTER 1: DIAGNOSIS OF HDP AND CLASSIFICATION OF BP MEASUREMENTS BP Measurement Recommendations

  1. Blood pressure should be measured with the woman in the sitting position with the arm at the level of the heart. (II-2A)   2. An appropriately sized cuff (i.e., length 1.5 times the circumference of the arm) should be used. (II-2A)   3. Korotkoff phase V should be used to designate diastolic blood pressure. (I-A)   4. If blood pressure is consistently higher in one arm, the arm with the higher values should be used for all blood pressure measurements. (III-B)   5. Blood pressure can be measured using a mercury sphygmomanometer, a calibrated aneroid device, or an automated blood pressure machine that has been validated for use in preeclampsia. (II-2A)   6. Automated blood pressure machines that have not been validated for use in women with preeclampsia may underestimate or overestimate blood pressure in those women; a comparison of readings using mercury sphygmomanometry or a calibrated aneroid device is recommended. (II-2A)

Diagnosis, Evaluation, and Management of the Hypertensive Disorders of Pregnancy: Executive Summary

  7. In the office setting, when blood pressure elevation is non-severe and preeclampsia is not suspected, ambulatory blood pressure monitoring or home blood pressure monitoring is useful to confirm persistently elevated blood pressure. (II-2C)   8. When home blood pressure monitoring is used, maternity care providers should ensure that patients have adequate training in measuring their blood pressure and interpreting the readings. (III-C)   9. The accuracy of all blood pressure measurement devices used in hospitals or offices should be checked regularly against a calibrated device. (II-3C) 10. The accuracy of all automated devices used for home blood pressure monitoring should be checked regularly against a calibrated device. (III-C) Diagnosis of Hypertension Recommendations

11. The diagnosis of hypertension should be based on office or in-hospital blood pressure measurements. (II-B) 12. Hypertension in pregnancy should be defined as an office (or in-hospital) systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg, based on the average of at least 2 measurements, taken at least 15 minutes apart, using the same arm. (II-2B) 13. Resistant hypertension should be defined as the need for 3 antihypertensive medications for blood pressure control at ≥ 20 weeks’ gestation. (III-C) 14. A transient hypertensive effect should be defined as an office systolic blood pressure ≥ 140 mmHg or a diastolic blood pressure ≥ 90 mmHg that is not confirmed after rest, on repeat measurement, on the same or on subsequent visits. (II-2B) 15. A white-coat hypertensive effect refers to blood pressure that is elevated in the office (i.e., systolic ≥ 140 mmHg or diastolic ≥ 90 mmHg), but < 135 mmHg (systolic) and < 85 mmHg (diastolic) on ambulatory or home blood pressure monitoring. (II-2B) 16. A masked hypertensive effect refers to blood pressure that is normal in the office (i.e., systolic < 140 mmHg and diastolic < 90 mmHg) but elevated on ambulatory or home blood pressure monitoring (i.e., systolic ≥ 135 mmHg or diastolic ≥ 85 mmHg). (II-2B) 17. Severe hypertension should be defined, in any setting, as a systolic blood pressure of ≥ 160 mmHg or a diastolic blood pressure of ≥ 110 mmHg based on the average of at least 2 measurements, taken at least 15 minutes apart, using the same arm. (II-2B)

Measurement of Proteinuria Recommendations

18. All pregnant women should be assessed for proteinuria. (II-2B) 19. Urinary dipstick testing (by visual or automated testing) may be used for screening for proteinuria when the suspicion of preeclampsia is low. (II-2B) 20. Significant proteinuria should be defined as ≥ 0.3 g/d in a complete 24-hour urine collection or ≥ 30 mg/mmol urinary creatinine in a spot (random) urine sample. (II-2B) 21. Significant proteinuria should be suspected when urinary dipstick proteinuria is ≥ 1+. (II-2A) 22. More definitive testing for proteinuria (by urinary protein:creatinine ratio or 24-hour urine collection) is encouraged when there is a suspicion of preeclampsia, including: ≥ 1+ dipstick proteinuria in women with hypertension and risingblood pressure and in women withnormal blood pressure, but symptoms or signs suggestive of preeclampsia. (II-2A) 23. Proteinuria testing does not need to be repeated once significant proteinuria of preeclampsia has been confirmed. (II-2A) 24. There is insufficient information to make a recommendation about the accuracy of the urinary albumin:creatinine ratio. (II-2L) Classification of HDPs Recommendations

25. Hypertensive disorders of pregnancy should be classified as pre-existing hypertension, gestational hypertension, preeclampsia, or “other hypertensive effects” on the basis of different diagnostic and therapeutic considerations. (II-2B) (Table 2) 26. The presence or absence of preeclampsia must be ascertained, given its clear association with more adverse maternal and perinatal outcomes. (II-2B) 27. In women with pre-existing hypertension, preeclampsia should be defined as resistant hypertension, new or worsening proteinuria, one or more adverse conditions, or one or more severe complications. (II-2B) 28. In women with gestational hypertension, preeclampsia should be defined as new-onset proteinuria, one or more adverse conditions, or one or more severe complications. (II-2B) 29. Severe preeclampsia should be defined as preeclampsia complicated by one or more severe complications. (II-2B) MAY JOGC MAI 2014 l 419

SOGC CLINICAL PRACTICE GUIDELINE

Table 2. Classification of the hypertensive disorders of pregnancy Disorder

Comments

Pre-existing (chronic) hypertension

This is defined as hypertension that develops either pre-pregnancy or at < 20+0 weeks' gestation

With comorbid condition(s)

Comorbid conditions (e.g., pre-gestational type I or II diabetes mellitus or kidney disease) warrant tighter BP control outside of pregnancy because of their association with heightened cardiovascular risk.

With evidence of preeclampsia

This is also known as superimposed preeclampsia, and is defined by the development of one or more of the following at ≥ 20 weeks: ●  resistant

hypertension, or

●  new

or worsening proteinuria, or

●  one

or more adverse conditions,* or

●  one

or more severe complications.*

Severe preeclampsia is defined as preeclampsia with one or more severe complications. Gestational hypertension

This is defined as hypertension that develops for the first time at ≥ 20+0 weeks' gestation.

With comorbid condition(s)

Comorbid conditions (e.g., pre-gestational type I or II diabetes mellitus or kidney disease) warrant tighter BP control outside of pregnancy because of their association with heightened cardiovascular risk.

With evidence of preeclampsia

Evidence of preeclampsia may appear only many weeks after the onset of gestational hypertension. Preeclampsia is defined as gestational hypertension with one or more of the following: ●  new

proteinuria, or

●  one

or more adverse conditions,* or

●  one

or more severe complications.*

Severe preeclampsia is defined as preeclampsia with one or more severe complications. Preeclampsia

Preeclampsia may arise de novo. It is defined as gestational hypertension with one or more of the following: ●  new

proteinuria, or

●  one

or more adverse conditions,* or

●  one

or more severe complications.*

Severe preeclampsia is defined as preeclampsia with one or more severe complications. Other hypertensive effects† Transient hypertensive effect

Elevated BP may be due to environmental stimuli, e.g., the pain of labour.

White-coat hypertensive effect

This is defined as BP that is elevated in the office (sBP ≥ 140 mmHg or dBP ≥ 90 mmHg), but consistently normal outside of the office (< 135/85 mmHg) by ABPM or HBPM

Masked hypertensive effect

This is defined as BP that is consistently normal in the office (sBP < 140 mmHg or dBP < 90 mmHg), but elevated outside of the office (≥ 135/85 mmHg) by ABPM or repeated HBPM.

sBP: systolic BP; dBP diastolic BP; ABPM: ambulatory BP monitoring; HBPM: home BP monitoring *Adverse conditions and severe complications of preeclampsia are defined in Table 3. †These may occur in women whose BP is elevated at < 20+0 or ≥ 20+0 weeks who are suspected of having pre-existing or gestational hypertension/ preeclampsia, respectively.

30. Severe preeclampsia, as defined in this guideline, warrants delivery. (II-2B) 31. The term PIH (pregnancy-induced hypertension) should be abandoned, as its meaning in clinical practice is unclear. (III-D) Definition of Preeclampsia

Preeclampsia is most commonly defined by new-onset proteinuria and, potentially, other end-organ dysfunction. Hypertension and proteinuria are discussed above under “Diagnosis of Hypertension”’ and “Management of Proteinuria.” Women with preeclampsia may have a 420 l MAY JOGC MAI 2014

diminished, or no, nocturnal BP decrease.4 Maternal end-organ dysfunction and fetal manifestations of preeclampsia illustrated in the Figure are all non-specific. In this model of its origins we describe preeclampsia that arises primarily through imperfect placentation (earlyonset or “placental” preeclampsia [pink]) or through either a lowered maternal threshold or excessive physiological placentation (late-onset or “maternal” preeclampsia [blue]). Some aspects of the preeclampsia process are specific to it, while others are shared with normotensive IUGR. A lowered maternal threshold may also influence the development of early-onset preeclampsia through

Diagnosis, Evaluation, and Management of the Hypertensive Disorders of Pregnancy: Executive Summary

The origins and consequences of preeclampsia

immunological factors

decidual immune cell EVT interactions

antigen exposure

• primigravidity ( ) / primipaternity ( ) • donor gamete(s) ( ) • duration of cohabitation ( ) • barrier contraception ( ) / fellatio ( ) • prior miscarriage ( ) • smoking ( )

(invasion & uteroplacental artery remodelling)

normal placentation

(late-onset pre-eclampsia) •macrosomia •multiple pregnancy •± lowered threshold

inadequate placentation (early-onset pre-eclampsia)

genetic factors • familial risks • SNPs • epigenetics

uteroplacental mismatch intervillous soup

lowered threshold

pre-eclampsia-specific •placental debris •innate immune activation •oxidative stress •eicosanoids •cytokines

• metabolic syndrome • chronic infection / inflammation • pre-existing hypertension • chronic kidney disease / DbM • high altitude

placental IUGR

(± maternal syndrome)

shared with IUGR •angiogenic imbalance

endothelial cell activation cardiorespiratory

•hypertension •ARDS •pulmonary oedema •cardiomyopathy / LV dysfunction •intravascular volume constriction •generalised oedema

CNS

•eclampsia •TIA / RIND / CVA •PRES •GCS<13

renal

•glomerular endotheliosis •proteinuria •ATN •AKI

hepatic

•periportal inflammation •hepatic dysfunction / failure •hepatic haematoma / rupture

haematological

•microangiopathic haemolysis •thrombocytopoenia •DIC

maternal syndrome

EVT: extravillous trophoblast; SNP: single nucleotide polymorphism; ARDS: acute respiratory distress syndrome; CNS: central nervous system; TIA: transient ischemic attack; RIND: reversible ischemic neurological deficit; CVA: cerebrovascular accident; PRES: posterior reversible encephalopathy syndrome; GCS: Glasgow Coma Scale; ATN: acute tubular necrosis; AKI: acute kidney injury; DIC: disseminated intravascular coagulation; DbM: diabetes mellitus; LV: left ventricle

direct endothelial cell activation. The consequences of endothelial cell activation that appear consistent between all women with preeclampsia include a variable impact on multiple vulnerable organ systems. Disease severity generally correlates with the degree and number of organ dysfunctions. Fetal manifestations may occur before, with, or in the absence of maternal manifestations.5 Table 3 outlines the end-organ dysfunctions of preeclampsia: adverse conditions and severe complications. Adverse conditions consist of maternal symptoms, signs, and abnormal laboratory results, and abnormal fetal monitoring results that may herald the development of severe maternal or fetal complications (including stillbirth). The adverse conditions are those that we wait for and respond to (e.g., low oxygen saturation) in an effort to avoid entirely the severe complications (e.g., pulmonary edema). That response could be more intensive maternal or fetal monitoring, specific treatment, or delivery. Severe maternal complications of preeclampsia warrant delivery.

The adverse conditions are manifestations of preeclampsia that increase the risk of adverse maternal or perinatal outcomes.6 Table 3 lists the adverse conditions by maternal organ system. Of particular importance are preterm preeclampsia, chest pain or dyspnea, and abnormality of one or more of oxygen saturation by pulse oximetry, platelet count, serum creatinine, or aspartate transaminase.6 Proteinuria predicts neither short-term adverse outcomes nor long-term maternal renal prognosis.7,8 HELLP syndrome is represented by its component parts (hemolysis, elevated liver enzymes, and low platelets), to which we react to by initiating delivery. How maternal adverse conditions may predict fetal or neonatal outcomes in preeclampsia is unclear. The perinatal literature suggests that abnormal fetal monitoring of various types may identify increased fetal risk. The biophysical profile has unproven utility in high risk women,9,10 and may falsely reassure with early-onset IUGR11 or preeclampsia.12 Currently, there is no single fetal monitoring test to accurately predict fetal compromise in women with MAY JOGC MAI 2014 l 421

SOGC CLINICAL PRACTICE GUIDELINE

Table 3. Adverse conditions and severe complications of preeclampsia Organ system affected

Adverse conditions (that increase the risk of severe complications)

Severe complications (that warrant delivery)

Central nervous system

Headache/visual symptoms

Eclampsia PRES Cortical blindness or retinal detachment Glasgow coma scale < 13 Stroke, TIA, or RIND

Cardiorespiratory

Chest pain/dyspnea

Uncontrolled severe hypertension (over a period of 12 h despite use of three antihypertensive agents)

Oxygen saturation < 97%

Oxygen saturation < 90%, need for ≥ 50% oxygen for > 1 h, intubation (other than for Caesarean section), pulmonary edema Positive inotropic Myocardial ischemia or infarction

Haematological

Elevated WBC count

Platelet count < 50 × 109/L

Elevated INR or aPTT

Transfusion of any blood product

Low platelet count Renal

Elevated serum creatinine

Acute kidney injury (creatinine > 150 µM with no prior renal disease)

Elevated serum uric acid Hepatic

New indication for dialysis Hepatic dysfunction (INR > 2 in absence of DIC or warfarin)

Nausea or vomiting RUQ or epigastric pain

Hepatic haematoma or rupture

Elevated serum AST, ALT, LDH, or bilirubin Low plasma albumin Feto-placental

Abnormal FHR

Abruption with evidence of maternal or fetal compromise

IUGR

Reverse ductus venosus A wave

Oligohydramnios

Stillbirth

Absent or reversed end-diastolic flow by Doppler velocimetry PRES: posterior reversible leukoencephalopathy syndrome; TIA: transient ischemic attack; RIND: reversible ischemic neurological deficit (< 48 hr); WBC: white blood cell; INR: international normalized ratio; aPTT: activated partial thromboplastin time; RUQ: right upper quadrant; AST: aspartate aminotransferase; ALT: alanine aminotransferase; LDH: lactate dehydrogenase; DIC: disseminated intravascular coagulation; FHR: fetal heart rate.

preeclampsia. Most experts suggest a combination of tests, with emphasis on umbilical artery Doppler when there is IUGR.9 Other non-specific risk factors for severe complications of preeclampsia are immigrant status, young maternal age, nulliparity, lower maternal weight, and in the index pregnancy, multiple pregnancy and early-onset preeclampsia.13 Definitions of severe preeclampsia vary, but most include multi-organ involvement14–16 We modified our definition of severe preeclampsia to preeclampsia associated with one or more severe complications. Severe preeclampsia now warrants delivery regardless of gestational age. Our definition excludes heavy proteinuria and HELLP syndrome, which are not absolute indications for delivery, and includes stroke17 and pulmonary edema, which are leading causes of maternal death in preeclampsia.2 422 l MAY JOGC MAI 2014

Other

A transient hypertensive effect is not associated with an increased risk of adverse outcomes. White-coat effect in early pregnancy (~30%) is common.18 Forty percent of women progress to persistent hypertension at ≥ 20 weeks (i.e., gestational hypertension) and 8% to preeclampsia. Women with white-coat effect have risks (e.g., severe hypertension, preterm delivery, and NICU ission) intermediate between normotension and either preexisting or gestational hypertension.19–24 Masked hypertension in early pregnancy (~30%) is also common,18 but associated perinatal risks are unknown. Outcomes with masked hypertension at ≥ 20 weeks (~10%) equate to those of gestational hypertension.25,26 Masked hypertension could be considered (and ambulatory or home BP monitoring performed) if there are unexplained maternal or perinatal complications typically associated with the HDPs.

Fibrinogen

INR and aPTT

Continued

Usually normal in TTP-HUS (ADAMTS13 vWF cleaving protein may be moderately decreased in HELLP, but ADAMTS13 antibody should be absent)

↓ more profound with AFLP than with HELLP

↓ with all causes of DIC including massive haemorrhage, genetic disorders

↑ is prominent in AFLP

↔↓

↑ is associated with adverse maternal outcome

Microangiopathy due to mechanical causes (e.g., cardiac valvopathy, cavernous haemangioma), DIC or other disorders of endothelial function (e.g., APS, TTP-HUS, vasculitis, malignant hypertension)

↓ with gestational, immune, or thrombotic thrombocytopenia, APS, AFLP, myelodysplasia

May be ↑ in APS or in DIC from other causes including sepsis, amniotic fluid embolism, stillbirth, massive haemorrhage, haemangiomas, or shock

RBC fragmentation

Blood film

↑ with corticosteroids

↑ with inflammation/infection

↑ due to neutrophilia of normal pregnancy

↓ with acute bleeding of any cause

↑ with DIC, which is usually associated with placental abruption

↓ associated with adverse maternal outcome)

Platelet count

Tests of coagulation*

↔

↓ if microangiopathic hemolysis from other cause ↓ with any chronic anemia (nutritional or myelodysplasia)

↑ due to volume depletion from any cause (e.g., vomiting)

↓ if microangiopathic hemolysis (with HELLP)

May be decreased in any cardiorespiratory complication (e.g., pulmonary embolism)

Proteinuria is usually absent in secondary causes of hypertension such as pheochromocytoma, hyperaldosteronism, thyrotoxicosis, coarctation of the aorta, and withdrawal syndromes

Bacteria: UTI or asymptomatic bacteruria

RBCs and/or casts are associated with other glomerular disease, with scleroderma renal crisis. and with about half of TTP-HUS

RBCs alone: renal stones, renal cortical necrosis (also associated with back pain and oliguria/anuria)

Hemoglobinuria (dipstick “hematuria” without RBCs): hemolytic anemia

Description in women with other conditions

↑ due to intravascular volume depletion

SpO2 < 97% associated with a heightened risk of severe complications (including non-respiratory)

Proteinuria without RBCs or casts

Description in women with preeclampsia

WBC and differential

Hemoglobin

CBC and blood film

Pulse oximetry

Oxygen saturation

Urinalysis (routine and microscopy with/ without additional tests for proteinuria)

Urine testing

MATERNAL TESTING

Investigations for diagnosis

Table 4. Investigations to diagnosis or monitor women with a hypertensive disorder of pregnancy

Diagnosis, Evaluation, and Management of the Hypertensive Disorders of Pregnancy: Executive Summary

MAY JOGC MAI 2014 l 423

424 l MAY JOGC MAI 2014

Oligohydramnios associated with adverse perinatal outcomes

Usually intrauterine fetal growth restriction (typically asymmetrical but can be symmetrical if early and/or severe)

Increased resistance, absent or reversed end-diastolic flow

Increased resistance, especially absent or reverse A wave

Cerebral redistribution (decreased resistance or “brain-sparing effect”). May be lost in extreme cases prior to fetal death

Deepest amniotic fluid pocket

Ultrasonographic assessment of fetal growth

Umbilical artery Doppler

Ductus venosus Doppler

Middle cerebral artery Doppler

‡Abnormal uterine artery Doppler velocimetry is practically defined at 22 to 24 weeks as bilateral notching with mean resistance index (RI) > 0.55 (i.e., > 50th centile), unilateral notching with mean RI > 0.65 (> 90th centile), or no notching with mean RI > 0.70 (> 95th centile).

†“PET imitators” include AFLP, catastrophic APS, TTP-HUS, malignant hypertension, and scleroderma renal crisis.

*Tests of coagulation are recommended if there is thrombocytopenia or placental abruption.

RBC: red blood cell; TTP-HUS: thrombotic thrombocytopenic purpur–hemolytic uremic syndrome; UTI: urinary tract infection; SpO2: oxygen saturation; CBC: complete blood count; HELLP: hemolysis, elevated liver enzyme, low platelet syndrome; WBC: white blood cell; APS: antiphopholipid antibody syndrome; AFLP: acute fatty liver of pregnancy; DIC: disseminated intravascular coagulation; INR international normalized ratio; aPTT: activated partial thromboplastin time; vWF: von Willebrand Factor; HCTZ: hydrochlorothiazide; AST: aspartate aminotransferase; ALT: alanine aminotransferase; PET: preeclampsia-eclampsia; LDH: lactate dehydrogenase; FHR: fetal heart rate

Abnormal or atypical FHR tracing (e.g., decreased variability)

↓ as negative acute phase reactant with acute severe illness, malnutrition, nephritic syndrome, crystalloid infusion

Fetal monitoring

↓ associated with adverse maternal and perinatal outcomes

Albumin

(early) ↑ in AFLP, ↑ with hemolytic anemia, other liver disease with dysfunction, genetic diseases

Unilateral/bilateral notching, or elevated pulsatility index or resistance index may a diagnosis of placental insufficiency including preeclampsia

↑ unconjugated from hemolysis or conjugated from liver dysfunction

Bilirubin

↑ LDH/AST ratio (> 22) with TTP-HUS

↑ with AFLP, intravascular hemolysis

Abnormalities are not specific to the cause of poor placentation and/or placental dysfunction

↑ may be prominent; the ↑ is associated with adverse maternal outcome

LDH

May be increased in other pregnancy-related conditions (e.g., intrahepatic cholestasis of pregnancy) or conditions not associated with pregnancy (e.g., viral hepatitis or cholecystitis)

↑ with AFLP and other PET imitators,† but to a lesser degree, and usually normal in TTP-HUS

↓ with AFLP, insulin therapy

Uterine artery Doppler velocimetry‡

↑ associated with adverse maternal outcome

AST or ALT

FETAL TESTING

↔

Glucose

↑ with dehydration, medication (e.g., HCTZ), genetic causes

Renal failure prominent in malignant hypertension, TTP-HUS (along with thrombocytopenia), AFLP (along with liver dysfunction)

↑ associated with adverse maternal outcome

↑ associated with adverse maternal outcome

↑ with other acute or chronic kidney disease

Description in women with other conditions

↑ due to hemoconcentration and/or renal failure

Description in women with preeclampsia

Serum uric acid

Serum creatinine

Serum chemistry

Investigations for diagnosis

Table 4. Continued

SOGC CLINICAL PRACTICE GUIDELINE

Diagnosis, Evaluation, and Management of the Hypertensive Disorders of Pregnancy: Executive Summary

Investigations to Classify HDPs Recommendations

32. For women with pre-existing hypertension, the following should be performed in early pregnancy (if not previously documented): serum creatinine, fasting blood glucose, serum potassium, and urinalysis (III-D), and EKG. (II-2C) 33. Among women with pre-existing hypertension or those with a strong clinical risk marker for preeclampsia, additional baseline laboratory testing may be based on other considerations deemed important by health care providers. (III-C) 34. Women with suspected preeclampsia should undergo the maternal laboratory (II-2B) and pertinent fetal (II-1B) testing. (Table 4) 35. Doppler velocimetry-based assessment of the fetal circulation may be useful to a placental origin for hypertension, proteinuria, and/or adverse conditions including intrauterine growth restriction, (II-2B) and for the timing of delivery. (I-A) 36. There is insufficient evidence to recommend use of the biophysical profile as part of a schedule of fetal testing in women with a hypertensive disorder of pregnancy. (II-2L) 37. If initial testing is reassuring, but there is ongoing concern about preeclampsia (e.g., change in maternal and/or fetal condition), maternal and fetal testing should be repeated. (III-C) Comments

Most abnormalities found in maternal and fetal testing are non-specific. When preeclampsia is suspected, interpretation relies on findings of multiple (not single) abnormalities. Preeclampsia imitators share manifestations with preeclampsia, but require different treatment.27–31 (Table 5) CHAPTER 2: PREDICTION AND PREVENTION Predicting Preeclampsia Recommendations

38. Women should be screened for clinical risk markers of preeclampsia from early pregnancy. (II-2C) (Table 6) 39. Consultation with an obstetrician or an obstetric inter­ nist, by telephone if necessary, should be con­sidered for women with a history of previous preeclampsia or another strong clinical marker of increased preeclampsia risk, particularly multiple pregnancy,

antiphospholipid antibody syndrome, significant proteinuria at first antenatal visit (usually early in pregnancy), or a pre-existing condition of hyper­ tension, diabetes mellitus, or renal disease. (II-2B) 40. Screening using biomarkers or Doppler ultrasound velocimetry of the uteroplacental circulation cannot be recommended routinely at present for women at low or increased risk of preeclampsia until such screening has been shown to improve pregnancy outcome. (II-2C) Preventing Preeclampsia and its Complications in Women at Low Risk

We based our recommendations on the need to prevent preeclampsia and/or its associated complications. Pregnant women are classified as being at either low or increased risk of preeclampsia, usually by the presence of one or more of the risk markers in Table 6 (see Predicting Preeclampsia). Preventative interventions may be best started before 16 weeks’ gestation when most of the physiologic transformation of uterine spiral arteries occurs. Such early intervention has the greatest potential to decrease early forms of preeclampsia.32 Women at low risk of preeclampsia have usually been from unselected populations of nulliparous and multiparous women. Recommendations

41. Calcium supplementation of at least 1 g/d, orally, is recommended for women with low dietary intake of calcium (< 600 mg/d). (I-A) 42. The following are recommended for other established beneficial effects in pregnancy: abstention from alcohol for prevention of fetal alcohol effects (II-2E), exercise for maintenance of fitness (I-A), periconceptual use of a folate-containing multivitamin for prevention of neural tube defects (I-A), and smoking cessation for prevention of low birthweight and preterm birth. (I-E) 43. Periconceptual and ongoing use of a folatecontaining multivitamin (I-B) or exercise (II-2B) may be useful in preventing preeclampsia. 44. Prostaglandin precursors and supplementation with magnesium or zinc are not recommended for preeclampsia prevention, but may be useful for prevention of other pregnancy complications. (I-C) 45. Dietary salt restriction during pregnancy (I-D), calorie restriction during pregnancy for overweight women (I-D), low-dose acetylsalicylic acid (I-E), vitamins C and E (based on current evidence) (I-E), and thiazide diuretics (I-E) are not recommended. MAY JOGC MAI 2014 l 425

SOGC CLINICAL PRACTICE GUIDELINE

Table 5. Preeclampsia imitators Pregnancy related

Not pregnancy related

Preeclampsia/HELLP syndrome

Malignant hypertension regardless of the cause

Acute fatty liver of pregnancy

Secondary causes of hypertension when associated with end-organ involvement (e.g., renal disease, pheochromocytoma) Disseminated intravascular coagulation (from any cause) Thrombotic thrombocytopenic purpura Hemolytic uremic syndrome Vasculitis or other systemic rheumatic condition (systemic lupus erythematous, scleroderma, cryoglobulinemia, catastrophic antiphospholipids syndrome) Sepsis Medications Cavernous hemangiomas Malignancy

46. There is insufficient evidence to make a recommendation about a heart-healthy diet (II-2L); workload or stress reduction (including bedrest) (II-2L); supplementation with iron with or without folate (I-L); vitamin D (I-L); pyridoxine (I-L); or food rich in flavonoids. (I-L) Preventing Preeclampsia and its Complications in Women at Increased Risk

Women at increased risk of preeclampsia are most commonly identified by a personal or family history of an HDP, chronic medical disease, and/or abnormal uterine artery Doppler before 24 weeks’ gestation. Combining clinical, biochemical, and/or ultrasonographic risk markers may better identify women at increased preeclampsia risk (see “Prediction”); however, no intervention trial has used such an approach to evaluate preventative therapy.33,34 Recommendations

47. Low-dose acetylsalicylic acid and calcium supplementation (of at least 1 g/d) for women with low calcium intake are recommended for preventions of preeclampsia in women at high risk. (I-A) 48. Acetylsalicylic acid should be: taken in a low dose (75–162 mg/d), (III-B) istered at bedtime, (I-B) initiated after diagnosis of pregnancy but before 16 weeks’ gestation, (I-B) and considered for continuation until delivery. (I-C) 49. Prophylactic doses of low-molecular-weight heparin may be discussed in women with previous placental complications (including preeclampsia) to prevent the recurrence of severe or early-onset preeclampsia, preterm delivery, and/or infants that are small for gestational age. (I-B)

426 l MAY JOGC MAI 2014

50. The following may be useful: L-arginine (I-B), increased rest at home in the third trimester (I-C), and reduction of workload or stress. (III-C) 51. The following may be useful for prevention of other pregnancy complications: prostaglandin precursors (I-B), magnesium supplementation (I-C), and heparin to prevent venous thromboembolic disease. (I-B) 52. The following are recommended for other established beneficial effects in pregnancy (as discussed for women at low risk of preeclampsia): abstention from alcohol (II-2E), periconceptual use of a folate-containing multivitamin (I-A), and smoking cessation. (I-E) 53. The following are not recommended: calorie restriction in overweight women during pregnancy (I-D), weight maintenance in obese women during pregnancy (III-D), antihypertensive therapy specifically to prevent preeclampsia (I-D), and vitamins C and E. (I-E) 54. There is insufficient evidence to make a recommendation about the usefulness of the following: the heart-healthy diet (III-L); exercise (I-L); selenium (I-L); garlic (I-L); zinc, pyridoxine, iron (with or without folate), vitamin D, or multivitamins with/without micronutrients. (III-L) CHAPTER 3: TREATMENT OF THE HDPs Dietary and Lifestyle Changes Recommendations

55. There is insufficient evidence to make a recommendation about the usefulness of the following: new severe dietary salt restriction for

Multiple pregnancy

Previous preeclampsia

Abnormal AFP, hCG, inhA, or E3# Excessive weight gain in pregnancy Infection during pregnancy (e.g., UTI, periodontal disease) Abnormal uterine artery Doppler** IUGR Investigational laboratory markers††

New partner Short duration of sexual relationship with current partner Reproductive technologies‖ Inter-pregnancy interval ≥ 10 years Booking† sBP ≥ 130 mmHg, or booking dBP ≥ 80 mmHg

Cocaine and metamphetamine use Previous miscarriage at ≤ 10 weeks with same partner

Non-smoking

Increased pre-pregnancy triglycerides

Heritable thrombophilias§

Abnormal PAPP-A or free βhCG

Gestational trophoblastic disease

Vaginal bleeding in early pregnancy

Elevated BP (gestational hypertension)¶

Lower maternal birthweight and/or preterm delivery First ongoing pregnancy

*Women at increased risk (who should be considered for specialty referral) are those with one of the bolded factors, or two or more of the unbolded markers.

††Investigational markers include, in the first trimester: PAPP-A, PlGF, PP-13, and in the second trimester: elevated sFlt-1/PlGF (soluble fms-like tyrosine kinase, placental growth factor), PAI-1/PAI-2 (plasminogen activator inhibitor) von Willebrand factor, and leptin.

**Abnormal uterine artery Doppler velocimetry is practically defined at 22 to 24 weeks as bilateral notching with mean resistance index (RI) > 0.55 (i.e., > 50th centile), unilateral notching with mean RI > 0.65 (> 90th centile), or no notching with mean RI > 0.70 (> 95th centile).

#Decreased first trimester PAPP-A ≤ 5th centile, 110 decreased first or second trimester placental growth factor, unexplained increased second trimester AFP, increased second trimester hCG, increased first or second trimester inhA, increased second trimester activin.

¶Elevated BP is defined as dBP ≥ 110 mmHg before 20 weeks, 2nd trimester mean arterial pressure of ≥ 85 mmHg, or a 2nd trimester sBP ≥ 120 mmHg. standardized cut-offs for 24-hour ambulatory BP or home BP monitoring have not been established.

‖Subfertility and its treatment (especially the use of donor eggs, sperm and/or gametes), after correction for multiple gestations.

§Heritable thrombophilia includes factor V Leiden gene mutation and protein S deficiency.

‡Maternal age was considered as a continuous variable in the SCOPE study.

†First antenatal visit, usually early in pregnancy.

Second or third trimester

Current pregnancy

Overweight/obesity

•  Pre-existing diabetes mellitus

•  Pre-existing renal disease or booking† •  proteinuria

•  Pre-existing hypertension or booking† •  diastolic BP ≥ 90 mmHg

Pre-existing medical condition(s)

Anti-phospholipid antibody syndrome

First trimester

Past medical or obstetric history*

AFP: alfafetoprotein; inhA: inhibin A; E3: estradiol; UTI: urinary tract infection; sBP: systolic BP; dBP: diastolic BP; PAPP-A: pregnancy-associated plasma protein A.

Family history of early-onset cardiovascular disease

Family history of preeclampsia (mother or sister)

Maternal age ≥ 40 years‡

Demographics and family history

Table 6. Risk markers for preeclampsia

Diagnosis, Evaluation, and Management of the Hypertensive Disorders of Pregnancy: Executive Summary

MAY JOGC MAI 2014 l 427

SOGC CLINICAL PRACTICE GUIDELINE

Table 7. The most commonly used agents for treatment of blood pressure ≥ 160/110 mmHg Agent

Dosage

Onset

Peak

Duration

Comments

Labetalol

Start with 20 mg IV; repeat 20 to 80 mg IV q 30 min, or 1 to 2 mg/min, max 300 mg (then switch to oral)

5 min

30 min

4 hr

Best avoided in women with asthma or heart failure. Neonatology should be informed if the woman is in labour, as parenteral labetalol may cause neonatal bradycardia.

Nifedipine

5 to 10 mg capsule to be swallowed, or bitten then swallowed, every 30 min

5 to 10 min

30 min

~6 hr

Staff should be aware of the distinction between short-acting nifedipine capsules used to treat severe hypertension and both the intermediate-acting PA tablet (which can be used for treatment of nonsevere or severe hypertension), and the slow-release tablets (XL) that are used for non-severe hypertension.

Hydralazine

Start with 5 mg IV; repeat 5 to 10 mg IV every 30 min, or 0.5 to 10 mg/hr IV, to a maximum of 20 mg IV (or 30 mg IM)

5 min

30 min

May increase the risk of maternal hypotension.

IV: intravenous; IM: intramuscular; PA: prolonged action; XL: slow release

women with any HDP, ongoing salt restriction among women with pre-existing hypertension, heart-healthy diet, and calorie restriction for obese women. (III-L) 56. There is insufficient evidence to make a recommendation about the usefulness of exercise, workload reduction, or stress reduction. (III-L) 57. For women with gestational hypertension (without preeclampsia), some bed rest in hospital (vs. unrestricted activity at home) may be useful to decrease severe hypertension and preterm birth. (I-B) 58. For women with preeclampsia who are hospitalized, strict bed rest is not recommended. (I-D) 59. For all other women with an HDP, the evidence is insufficient to make a recommendation about the usefulness of some bed rest, which may nevertheless be advised based on practical considerations. (III-C) The following recommendations apply to women with either pre-existing or gestational hypertension.

Antihypertensive Therapy for Severe Hypertension Recommendations

62. Blood pressure should be lowered to < 160 mmHg systolic and < 110 mmHg diastolic. (I-A) 63. Initial antihypertensive therapy in the hospital setting should be with nifedipine short-acting capsules, parenteral hydralazine, or parenteral labetalol. (I-A) (Table 7) 64. Alternative antihypertensive medications include a nitroglycerin infusion (I-B), oral methyldopa (I-B), oral labetalol (I-B), oral clonidine (III-B), or postpartum, oral captopril. (III-B) 65. Refractory hypertension may be treated with sodium nitroprusside. (III-B) 66. Nifedipine and magnesium sulphate can be used contemporaneously. (II-2B) 67. Magnesium sulphate is not recommended solely as an antihypertensive agent. (I-E) 68. Continuous fetal heart rate monitoring is advised until blood pressure is stable. (III-L)

Place of Care Recommendations

60. In-patient care should be provided for women with severe hypertension or severe preeclampsia. (II-2B). 61. A component of care through hospital day units or home care can be considered for women with nonsevere preeclampsia or non-severe pre-existing or gestational hypertension. (I-B, II-2B)

428 l MAY JOGC MAI 2014

Antihypertensive Therapy for Non-Severe Hypertension Without Comorbid Conditions Recommendations

69. Antihypertensive drug therapy may be used to keep systolic blood pressure at 130 to 155 mmHg and diastolic blood pressure at 80–105 mmHg. (I-B)

Diagnosis, Evaluation, and Management of the Hypertensive Disorders of Pregnancy: Executive Summary

Table 8. Doses of the most commonly used agents for treatment of blood pressures 149 to 159/90 to 105 mmHg Agent

Dosage

Comments

Methyldopa

250 to 500 mg po bid-qid (max 2 g/d)

There is no evidence to a loading dose of methyldopa.

Labetalol

100 to 400 mg po bid-tid (max 1200 mg/d)

Some experts recommend a starting dose of 200 mg po bid.

Nifedipine*

XL preparation (20 to 60 mg po OD, max 120 mg/d)

Ensure that the correct form of nifedipine has been prescribed so that the XL preparation is not confused with the capsules.

XL: slow release *The prolonged action nifedipine tablet is no longer available in Canada.

70. The choice of antihypertensive agent for initial treatment should be based on characteristics of the patient, contraindications to a particular drug, and physician and patient preference. (III-C) 71. Initial therapy in pregnancy can be with one of a variety of antihypertensive agents available in Canada: methyldopa (I-A), labetalol (I-A), other beta-blockers (acebutolol, metoprolol, pindolol, and propranolol), (I-B) and calcium channel blockers (nifedipine). (I-A) (Table 8) 72. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers should not be used during pregnancy. (II-2E) 73. Atenolol and prazosin are not recommended prior to delivery. (I-D) For Non-Severe Hypertension (BP of 140–159/ 90–109 mmHg) With Comorbid Conditions Recommendations

74. For women with comorbid conditions, antihypertensive drug therapy should be used to keep systolic blood pressure at < 140 mmHg and diastolic blood pressure at < 90 mmHg. (III-C) 75. Initial therapy in pregnancy can be with one of a variety of antihypertensive agents as listed for women without co-morbidities. (III-C) 76. Captopril, enalapril, or quinapril may be used postpartum, even during breastfeeding. (III-B) Corticosteroids for Acceleration of Fetal Pulmonary Maturity Recommendations

77. Antenatal corticosteroid therapy should be considered for all women who present with preeclampsia at ≤ 34+6 weeks’ gestation. (I-A) 78. Antenatal corticosteroid therapy should be considered for women who present at ≤ 34+6 weeks’ gestation with gestational hypertension (despite the absence of

proteinuria or adverse conditions) only if delivery is contemplated within the next 7 days. (III-L) 79. A rescue dose of corticosteroids may be considered for women at ≤ 34+6 weeks’ gestation who remain at high risk of preterm delivery 7 days or more after an initial course of antenatal corticosteroids. (I-C) 80. Antenatal corticosteroids may be considered for women delivered by elective Caesarean delivery at ≤ 38+6 weeks’ gestation to reduce respiratory morbidity. (I-B) Comments

When istered at ≤ 34+6 weeks’ gestation, antenatal corticosteroids accelerate fetal pulmonary maturity and decrease neonatal mortality and morbidity, including among women with HDPs.35 RCTs that istered steroids at 33+0 to 34+6 weeks resulted in reduced neonatal RDS.35 Prior to elective Caesarean section at ≤ 38+6 weeks’ gestation, antenatal corticosteroids decrease the excess neonatal respiratory morbidity and NICU issions.36,37 All subgroup analyses have not necessarily revealed such benefits following Caesarean or vaginal delivery.35 Timing of Delivery for Women With Preeclampsia

Delivery is the only intervention that initiates resolution of preeclampsia, and women with gestational hypertension or pre-existing hypertension may develop preeclampsia. Recommendations

81. Consultation with an obstetrician (by telephone if necessary) is mandatory in women with severe preeclampsia. (III-B) 82. All women with severe preeclampsia should be delivered immediately (either vaginally or by Caesarean), regardless of gestational age. (III-C) 83. For women with non-severe preeclampsia at < 24+0 weeks’ gestation, counselling should include, as an option, information about delivery within days. (II-2B) 84. For women with non-severe preeclampsia at 24+0 to 33+6 weeks’ gestation, expectant management

MAY JOGC MAI 2014 l 429

SOGC CLINICAL PRACTICE GUIDELINE

should be considered, but only in perinatal centres capable of caring for very preterm infants. (I-B) 85. For women with non-severe preeclampsia at 34+0 to 36+6 weeks’ gestation, there is insufficient evidence to make a recommendation about the benefits or risks of expectant management. (III-L) 86. For women with preeclampsia at ≥ 37+0 weeks’ gestation, immediate delivery is recommended. (I-A) 87. For women with non-severe preeclampsia complicated by hemolysis, elevated liver enzymes, low platelets syndrome at 24+0 to 34+6 weeks’ gestation, consider delaying delivery long enough to ister antenatal corticosteroids for acceleration of fetal pulmonary maturity if there is temporary improvement in maternal laboratory testing. (II-2B) 88. All women with hemolysis, elevated liver enzymes, low platelets syndrome at ≥ 35+0 weeks’ gestation should be considered for immediate delivery. (II-2B) Timing of Delivery for Women With Gestational Hypertension Recommendations

89. For women with gestational hypertension (without preeclampsia) at ≥ 37+0 weeks’ gestation, delivery within days should be discussed. (I-B) 90. For women with gestational hypertension (without preeclampsia) at < 37+0 weeks’ gestation, there is insufficient evidence to make a recommendation about the benefits or risks of expectant management. (III-L) Timing of Delivery for Women With Pre-Existing Hypertension Recommendation

91. For women with uncomplicated pre-existing hypertension who are otherwise well at ≥ 37+0 weeks’ gestation, delivery should be considered at 38+0 to 39+6 weeks’ gestation. (II-1B) Mode of Delivery Recommendations

92. For women with any hypertensive disorder of pregnancy, vaginal delivery should be considered unless a Caesarean delivery is required for the usual obstetric indications. (II-2B) 430 l MAY JOGC MAI 2014

93. If vaginal delivery is planned and the cervix is unfavourable, then cervical ripening should be used to increase the chance of a successful vaginal delivery. (1-A) 94. At a gestational age remote from term, women with a hypertensive disorder of pregnancy with evidence of fetal compromise may benefit from delivery by emergency Caesarean section. (II-2B) 95. Antihypertensive treatment should be continued throughout labour and delivery to maintain systolic blood pressure at < 160 mmHg and diastolic blood pressure at < 110 mmHg. (II-2B) 96. The third stage of labour should be actively managed with oxytocin, 5 units intravenous or 10 units intramuscular, particularly in the presence of thrombocytopenia or coagulopathy. (I-A) 97. Ergometrine maleate should not be istered to women with any hypertensive disorder of pregnancy, particularly preeclampsia or gestational hypertension; alternative oxytocics should be considered. (II-3D) Anaesthesia: General Principles Recommendations

  98. The anaesthesiologist should be informed when a woman with preeclampsia is itted to the delivery suite. (II-3B)   99. Early insertion of an epidural catheter (in the absence of contraindications) is recommended for control of labour pain. (I-A) 100. In the absence of contraindications, all of the following are acceptable methods of anaesthesia for women undergoing Caesarean delivery: epidural, spinal, combined spinal-epidural, and general anaesthesia. (I-A) 101. A routine fixed intravenous fluid bolus should not be istered prior to neuraxialanaesthesia. (I-E)

Anaesthesia: Fluid istration Recommendations

102. Intravenous and oral fluid intake should be minimized in women with preeclampsia, to avoid pulmonary edema. (II-2B) 103. Fluid should not be routinely istered to treat oliguria (< 15 mL/hr for 6 consecutive hours). (III-D) 104. For treatment of persistent oliguria, neither dopamine nor furosemide is recommended. (I-E)

Diagnosis, Evaluation, and Management of the Hypertensive Disorders of Pregnancy: Executive Summary

105. Phenylephrine or ephedrine may be used to prevent or treat hypotension during neuraxial anaesthesia. (I-A) Monitoring Recommendations

106. Arterial line insertion may be used for continuous arterial blood pressure monitoring when blood pressure control is difficult or there is severe bleeding. (II-3B) 107. Central venous pressure monitoring is not routinely recommended, and if a central venous catheter is inserted, it should be used to monitor trends and not absolute values. (II-2D) 108. Pulmonary artery catheterization is not recommended unless there is a specific associated indication (III-D), and then only in an intensive care unit setting. (III-B) Coagulation Recommendations

109. Upon ission to delivery suite, women with preeclampsia should have a platelet count done. (II-1A) 110. Neuraxial analgesia and/or anaesthesia are appropriate in women: a. with preeclampsia, provided there are no associated coagulation concerns (II-2E) (Table 9); b. with a platelet count ≥ 75 × 109/L, (II-2B); c. taking low-dose acetylsaliclylic acid in the presence of an adequate platelet count (I-A); d. receiving unfractionated heparin in a dose of ≤ 10 000 IU/d subcutaneously, 4 hours after the last dose and possibly immediately after the last dose without any delay (III-B); e. receiving unfractionated heparin in a dose > 10 000 IU/d subcutaneously if they have a normal activated partial thromboplastin time 4hours after the last dose (III-B); f. receiving intravenous heparin in a therapeutic dose if they have a normal activated partial thromboplastin time 4 hours after the last dose (III-B); or g. receiving low-molecular-weight heparin 10 to 12 hours after a prophylactic dose, or 24 hours after a therapeutic dose. (III-B)

Aspects of Care Specific to Women With Pre-Existing Hypertension Recommendations

111. Pre-conceptual counselling for women with pre-existing hypertension is recommended. (III-C) 112. The following antihypertensive drugs are all acceptable for use in the first trimester of pregnancy: methyldopa, labetalol, and nifedipine. (II-2B) 113. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers should be discontinued when planning pregnancy or as soon as pregnancy is diagnosed. (II-2D) 114. Atenolol should be discontinued when pregnancy is diagnosed. (I-D) 115. Planned changes in antihypertensive agent(s) for care in pregnancy should be made while the woman is planning pregnancy if the woman has uncomplicated pre-existing hypertension, or, if in the presence of comorbid conditions, she is likely to conceive easily (within 12 months). (III-L) Aspects of Care for Women With Preeclampsia: Magnesium Sulphate for Preventing or Treating Eclampsia Recommendations

116. Magnesium sulphate is recommended for first-line treatment of eclampsia. (I-A) 117. Magnesium sulphate is recommended as prophylaxis against eclampsia in women with severe preeclampsia. (I-A) 118. Magnesium sulphate may be considered as prophylaxis against eclampsia in women with non-severe preeclampsia but with severe hypertension, headaches/visual symptoms, right upper quadrant/epigastric pain, platelet count < 100 000 × 109/L, progressive renal insufficiency, and/or elevated liver enzymes, based on cost considerations. (I-C) 119. Magnesium sulphate should be used in standard dosing, usually 4 g intravenous loading dose followed by 1 g/hour. (I-A) 120. Routine monitoring of serum magnesium levels is not recommended. (I-E) 121. Phenytoin and benzodiazepines should not be used for eclampsia prophylaxis or treatment, unless there is a contraindication to magnesium sulphate or it is ineffective. (I-E) MAY JOGC MAI 2014 l 431

SOGC CLINICAL PRACTICE GUIDELINE

Table 9. Eligibility for neuraxial anaesthesia Treatment with ASA or heparin

Normal platelet count

Low platelet count (normal INR and aPTT)

None or low-dose ASA



 if platelet count > 75 × 109/L

Abnormal INR or aPTT (regardless of platelet count)*

Unclear if platelet count 50 to 75 × 109/L X if platelet count < 50 × 109/L UFH ≤ 10 000 IU/d (SC)†



Unclear

0 to 4 hr after last dose



Unclear

4 hr after last dose and a normal aPTT Therapeutic dose (IV)



Unclear

4 hr after last dose and a normal aPTT

X Contraindicated

> 10 000 IU/d (SC)‡

LMWH Prophylactic dose



Unclear

10 to 12 hr after last dose Therapeutic dose



Unclear

24 hr after last dose Low dose ASA + prophylactic UFH or LMWH§

Unclear║

Unclear

INR: international normalized ratio; aPTT: activated partial thromboplastin time; UFH: unfractionated heparin; SC: subcutaneous; IV: intravenous; LMWH: low-molecular-weight heparin Note: These recommendations are based on the absence of a rapidly falling platelet count or a known platelet dysfunction (e.g., von Willebrand’s disease). *Other than a lupus anticoagulant †Prophylactic dosing is defined as ≤ 10 000 IU/d ‡Therapeutic dosing (SC) is defined as > 10 000 IU/d §Prophylactic doses of UFH are defined as ≤ 10 000 IU/d ║Unless ASA is stopped 7 days or more before delivery

122. In women with pre-existing or gestational hypertension, magnesium sulphate should be considered for fetal neuroprotection in the setting of imminent preterm birth (within the next 24 hours) at ≤ 31+6 weeks. (1-A) 123. Delivery should not be delayed in order to ister antenatal magnesium sulphate for fetal neuroprotection if there are maternal and/or fetal indications of emergency delivery. (III-E) There is no international consensus on what defines severe preeclampsia. This document defines it as preeclampsia requiring delivery due to serious maternal end-organ involvement and/or fetal compromise (see “Classification of HDPs”). For eclampsia prevention in the setting of non-severe preeclampsia, we have added to the indication for magnesium sulphate (in Recommendation 120) the following symptoms/signs as these are included in the definition of severe preeclampsia by other organizations: 432 l MAY JOGC MAI 2014

severe hypertension, headaches/visual symptoms, right upper quadrant/epigastric pain, platelet count < 100 000 × 109/L, progressive renal insufficiency, and/or elevated liver enzymes. Aspects of Care for Women With Preeclampsia: Plasma Volume Expansion Recommendation

124. Plasma volume expansion is not recommended for women with preeclampsia. (I-E) Therapies for HELLP Syndrome Recommendations

125. Every obstetrical centre should be aware of the local delay between ordering and receiving platelets units. (III-B) 126. For a platelet count of < 20 × 109/L with hemolysis, elevated liver enzymes, low platelets

Diagnosis, Evaluation, and Management of the Hypertensive Disorders of Pregnancy: Executive Summary

Table 10. Recommendations for the transfusion of platelets related to mode of delivery in HELLP Mode of delivery Platelet count

Caesarean delivery

Vaginal delivery

< 20 × 10 /L

 

Consider in presence of:

9

20 to 49 × 109/L

 •  excessive active bleeding •  known platelet dysfunction •  platelet count falling rapidly • coagulopathy

≥ 50 × 10 /L 9

Regardless of the platelet count

Consider in presence of:

Consider in presence of:

•  excessive active bleeding

•  excessive active bleeding

•  known platelet dysfunction

•  known platelet dysfunction

•  platelet count falling rapidly

•  platelet count falling rapidly

• coagulopathy

• coagulopathy

No platelets should be transfused if there is a strong suspicion of HIT or TTP-HUS

HIT: heparin-induced thrombocytopenia; TTP-HUS: thrombotic thrombocytopenic purpura–hemolytic uremic syndrome

syndrome, platelet transfusion is recommended regardless of mode of delivery. (III-B) (Table 9) 127. For a platelet count of 20 × 109 to 49 × 109/L with hemolysis, elevated liver enzymes, low platelets syndrome, platelet transfusion is recommended prior to Caesarean delivery. (III-B) (Table 9) 128. For a platelet count of 20 × 109 to 49 × 109/L with hemolysis, elevated liver enzymes, low platelets syndrome, platelet transfusion should be considered prior to vaginal delivery if there is excessive active bleeding, known platelet dysfunction, a rapidly falling platelet count, or coagulopathy. (II-2D) (Table 10) 129. For a platelet count of ≥ 50 × 109/L with hemolysis, elevated liver enzymes, low platelets syndrome, platelet transfusion and/or packed red blood cells should be considered prior to either Caesarean or vaginal delivery only if there is excessive active bleeding, known platelet dysfunction, a rapidly falling platelet count, or coagulopathy. (III-B) 130. We do not recommend corticosteroids for treatment of hemolysis, elevated liver enzymes, low platelets syndrome until they have been proven to decrease maternal morbidity. (II-3L) 131. We recommend against plasma exchange or plasmapheresis for hemolysis, elevated liver enzymes, low platelets syndrome, particularly within the first 4 days postpartum. (II-3E)

Care in the 6 Weeks Postpartum Recommendations

132. Blood pressure should be measured during the time of peak postpartum blood pressure, at days 3 to 6 after delivery. (III-B) 133. Women with postpartum hypertension should be evaluated for preeclampsia (either arising de novo or worsening from the antenatal period). (II-2B) 134. Consideration should be given to continuing antihypertensive therapy postpartum, particularly in women with antenatal preeclampsia and those who delivered preterm. (II-2L) 135. Severe postpartum hypertension must be treated with antihypertensive therapy to keep systolic blood pressure < 160 mmHg and diastolic blood pressure < 110 mmHg. (I-A) 136. In women without co-morbidities, antihypertensive therapy should be considered to treat non-severe postpartum hypertension to keep blood pressure < 140/90 mmHg. (III-L) 137. Women with co-morbidities other than pre-gestational diabetes mellitus should be treated to keep blood pressure < 140/90 mmHg (III-C) 138. Women with pre-gestational diabetes mellitus should be treated to keep blood pressure < 130/80 mmHg. (III-C) 139. Antihypertensive agents generally acceptable for use in breastfeeding include the following: nifedipine XL, labetalol, methyldopa, captopril, and enalapril. (III-B)

MAY JOGC MAI 2014 l 433

SOGC CLINICAL PRACTICE GUIDELINE

140. There should be confirmation that end-organ dysfunction of preeclampsia has resolved. (III-C) 141. Non-steroidal anti-inflammatory drugs should not be given postpartum if hypertension is difficult to control, there is evidence of kidney injury (oliguria and/or creatinine≥ 90 µM), or platelets are < 50 to 109/L. (III-C) 142. Postpartum thromboprophylaxis should be considered in women with preeclampsia, particularly in the presence of other risk factors. (II-2B) Care Beyond 6 Weeks Postpartum Recommendations

143. Women with a history of severe preeclampsia (particularly those who presented or delivered before 34 weeks’ gestation) should be screened for pre-existing hypertension and underlying renal disease. (II-2B) 144. Referral for internal medicine or nephrology consultation (by telephone if necessary) should be considered for women with: (i) postpartum hypertension that is difficult to control, or (ii) women who had preeclampsia and have at 3-6 months postpartum either ongoing proteinuria, decreased estimated glomerular filtration rate (eGFR) (< 60 mL/min), or another indication of renal disease, such as abnormal urinary sediment. (III-A) 145. Women who are overweight should be encouraged to attain a healthy body mass index to decrease risk in future pregnancy (II-2A) and for long-term health. (I-A) 146. Women with pre-existing hypertension or persistent postpartum hypertension should undergo the following investigations (if not done previously) at least six weeks postpartum: urinalysis; serum sodium, potassium and creatinine; fasting glucose; fasting lipid profile; and standard 12-lead electrocardiography. (III-L) 147. Women who are normotensive but who have had a hypertensive disorder of pregnancy, may benefit from assessment of traditional cardiovascular risk markers. (II-2B) 148. All women who have had a hypertensive disorder of pregnancy should pursue a healthy diet and lifestyle. (I-B) 434 l MAY JOGC MAI 2014

Effects of Maternal Hypertension and Its Therapies on Child Neurobehavioural Development Recommendations

149. Clinicians should be aware that gestational hypertension and preeclampsia may each be associated with an increase in adverse paediatric neurodevelopmental effects, such as inattention and externalizing behaviours (e.g., aggressiveness). (II-2B). 150. Clinicians should be reassured that there is no compelling evidence that antihypertensive medications (specifically labetalol, nifedipine, or methyldopa) are themselves associated with clear adverse neurodevelopmental effects. (I-B) CHAPTER 4: PATIENT PERSPECTIVE Recommendations

151. Health care providers should be alert to symptoms of posttraumatic stress following a hypertensive disorder of pregnancy and refer women for appropriate evaluation and treatment. (II-2B) 152. Health care providers should inform their patients, antepartum and postpartum, about preeclampsia, its signs and symptoms, and the importance of timely reporting of symptoms to health care providers. (II-2B) 153. Information should be re-emphasized at subsequent visits. (III-C) CHAPTER 5: KNOWLEDGE TRANSLATION TOOLS AND IMPLEMENTATION OF THE GUIDELINE

The Appendix (Table 10 in the full document3) lists tools to the application of this guideline. Some websites provide general information about BP measurement for non-pregnant patients, but the recommendations are similar enough to those for pregnant women to be useful. Patients, their partners, and their care providers should be well educated about the HDP, and relevant sites are listed. Implementation of any evidence depends on individual knowledge and beliefs, as well as institutional culture. Strong recommendations should be incorporated into clinical practice. In well-resourced settings, almost all preeclampsiarelated maternal deaths involve substandard care.38 Some updates to the 2008 SOGC guidelines on the HDP may require additional effort to implement.

Diagnosis, Evaluation, and Management of the Hypertensive Disorders of Pregnancy: Executive Summary

Recommendation 9 states that all measurement devices used in hospitals or offices should be checked regularly against a calibrated device may not be possible for all Canadian hospitals and offices to do on a regular basis. Physicians should consider the category “other HDP” (white-coat and masked hypertension) as part of the classification of hypertensive women and consider using some form of out-of-office BP measurement to evaluate women with non-severe pre-existing or gestational hypertension. Health care providers should inform pregnant women about the symptoms and signs of the HDPs and refer them to appropriate knowledge translation tools. We recommend the use of corticosteroids for women ≤ 34+6 weeks’ gestation who are at high risk of delivery within the next seven days. This gestational age cut-off represents a fundamental change in practice that will require discussion. Physicians should be familiar with the blood bank policies of their own hospital. Physicians should be aware of postpartum signs of maternal posttraumatic stress disorder and the maternal and perinatal long-term effects of HDPs, especially at this vulnerable time in maternal care when the maternity care provider is often handing back care to the primary care physician. The reader is reminded to refer to the full open-access guideline published in Pregnancy Hypertension,3 which contains not only the recommendations and tables presented here, but also all explanatory text and additional references. REFERENCES 1. Health Canada. Special report on maternal mortality and severe morbidity in Canada. Enhanced surveillance: the path to prevention. Ottawa: Minister of Public Works and Government Services Canada; 2004. 2. Centre for Maternal and Child Enquiries. Saving mothers’ lives: reviewing maternal deaths to make motherhood safer: 2006–08. The eighth report on confidential enquiries into maternal deaths in the United Kingdom. BJOG 2011;118(Suppl 1):1–203. 3. Magee LA, Pels A, Helewa M, Rey E, Von Dadelszen P; Canadian Hypertensive Disorders of Pregnancy (HDP) Working Group. Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy. Pregnancy Hypertens 2014. Available at: http://www.pregnancyhypertension.org/article/S22107789(14)00004-X/fulltext. Accessed on February 28, 2014.

6. von Dadelszen P, Payne B, Li J, Ansermino JM, Broughton Pipkin F, Côté AM, et al.; PIERS Study Group. Prediction of adverse maternal outcomes in pre-eclampsia: development and validation of the fullPIERS model. Lancet 2011;377(9761):219–27. 7. Payne B, Magee LA, Menzies J, Côté AM, Hutcheon JA, Kyle P, et al.; PIERS Study Group. PIERS proteinuria: relationship with adverse maternal and perinatal outcome. J Obstet Gynaecol Can 2011;33:588–97. 8. Lampinen KH, Rönnback M, Groop PH, Kaaja RJ. Renal and vascular function in women with previous preeclampsia: a comparison of lowand high-degree proteinuria. Kidney Int 2006;70:1818–22. 9. Gruslin A, Lemyre B. Pre-eclampsia: fetal assessment and neonatal outcomes. Best Pract Res Clinl Obstet Gynaecol 2011;25:401–507. 10. Lalor JG, Fawole B, Alfirevic Z, Devane D. Biophysical profile for fetal assessment in high risk pregnancies. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD000038. 11. Kaur S, Picconi JL, Chadha R, Kruger M, Mari G. Biophysical profile in the treatment of intrauterine growth-restricted fetuses who weigh <1000 g. Am J Obstet Gynecol 2008;199:264.e1–4. 12. Payne BA, Kyle PM, Lim K, Lisonkova S, Magee LA, Pullar B, et al. An assessment of predictive value of the biophysical profile in women with preeclampsia using data from the full PIERS database. Pregnancy Hypertens 2013;3:166–71. 13. Urquia ML, Ying I, Glazier RH, Berger H, De Souza LR, Ray JG. Serious preeclampsia among different immigrant groups. J Obstet Gynaecol Can 2012;34:348–52. 14. Magee LA, Helewa M, Moutquin JM, von Dadelszen P; Hypertension Guideline Committee; Strategic Training Initiative in Research in the Reproductive Health Sciences (STIRRHS) Scholars. SOGC Clinical Practice Guidelines, No. 206, March 2008. Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy. J Obstet Gynaecol Can 2008;30(3 Suppl 1):S1–S48. 15. American College of Obstetricians and Gynecologists; Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy. Obstet Gynecol. 2013;122:1122–31. 16. Brown MA, Lindheimer MD, de Swiet M, Van Assche A, Moutquin JM. The classification and diagnosis of the hypertensive disorders of pregnancy: statement from the International Society for the Study of Hypertension in Pregnancy (ISSHP). Hypertens Pregnancy 2001;20(1):IX–XIV. 17. Why mothers die 2000–2002. The sixth report of the Confidential Enquiries into Maternal Deaths in the United Kingdom. London: RCOG Press; 2004. 18. Rey E, Morin F, Boudreault J, Pilon F, Vincent D, Ouellet D. Blood pressure assessments in different subtypes of hypertensive pregnant women: office versus home patient- or nurse-measured blood pressure. Hypertens Pregnancy 2009;28:168–77. 19. Brown MA, Mangos G, Davis G, Homer C. The natural history of white coat hypertension during pregnancy. BJOG 2005;112:601–6. 20. Magee LA, Ramsay G, von Dadelszen P. What is the role of out-ofoffice BP measurement in hypertensive pregnancy? Hypertens Pregnancy 2008;27:95–101.

4. Ogedegbe G, Pickering T. Principles and techniques of blood pressure measurement. Cardio Clin 2010; 28:571–86.

21. Saudan P, Brown MA, Buddle ML, Jones M. Does gestational hypertension become pre-eclampsia? Br J Obstet Gynaecol 1998;105:1177–84.

5. Redman CWG. The placenta, pre-eclampsia and chronic villitis. In: Redman CWG, Sargent IL SP, eds. The human placenta. Oxford: Blackwell Scientific; 1993:433–67.

22. Reinders A, Cuckson AC, Lee JT, Shennan AH. An accurate automated blood pressure device for use in pregnancy and pre-eclampsia: the Microlife 3BTO-A. BJOG 2005;112:915–20.

MAY JOGC MAI 2014 l 435

SOGC CLINICAL PRACTICE GUIDELINE

23. Villar J, Say L, Shennan A, Lindheimer M, Duley L, Conde-Agudelo A, et al. Methodological and technical issues related to the diagnosis, screening, prevention, and treatment of pre-eclampsia and eclampsia. Int J Gynaecol Obstet 2004;85(Suppl 1):S28–S41.

32. Ogge G, Chaiworapongsa T, Romero R, Hussein Y, Kusanovic JP, Yeo L, et al. Placental lesions associated with maternal underperfusion are more frequent in early-onset than in late-onset preeclampsia. J Perinat Med 2011;39:641–52. doi: 10.1515/JPM.2011.098.

24. Bellomo G, Narducci PL, Rondoni F, Pastorelli G, Stangoni G, Angeli G, et al. Prognostic value of 24-hour blood pressure in pregnancy. JAMA 1999;282:1447–52.

33. Akolekar R, Syngelaki A, Poon L, Wright D, Nicolaides KH. Competing risks model in early screening for preeclampsia by biophysical and biochemical markers. Fetal Diagn Ther 2013;33:8–15.

25. Hermida RC, Ayala DE, Iglesias M. Circadian rhythm of blood pressure challenges office values as the “gold standard” in the diagnosis of gestational hypertension. Chronobiol Int 2003;20:135–56.

34. Scazzocchio E, Figueras F, Crispi F, Meler E, Masoller N, Mula R, et al. Performance of a first-trimester screening of preeclampsia in a routine care low-risk setting. Am J Obstet Gynecol 2013;208(3):203.e1–203.e10.

26. Eguchi, Kazuo O, Akihide O, Takako H, Chikako T, Kayo S, et al. [abstracts of American Society of Hypertension 27th Annual Scientific Meeting and Exposition]. J Clin Hypertens 2012;14(Suppl 1):doi: 10.1111/j.1751-7176.2011.00665.x. 27. Sibai BM. Imitators of severe preeclampsia. Obstet Gynecol 2007;109:956–66. 28. Fesenmeier MF, Coppage KH, Lambers DS, Barton JR, Sibai BM. Acute fatty liver of pregnancy in 3 tertiary care centers. Am J Obstet Gynecol 2005;192:1416–9. 29. Erkan D, Espinosa G, Cervera R. Catastrophic antiphospholipid syndrome: updated diagnostic algorithms. Autoimmun Rev 2010;10:74–9. 30. Martin JN Jr, Bailey AP, Rehberg JF, Owens MT, Keiser SD, May WL. Thrombotic thrombocytopenic purpura in 166 pregnancies: 1955–2006. Am J Obstet Gynecol 2008;199:98–104. 31. Mouthon L, Berezne A, Bussone G, Noel LH, Villiger PM, Guillevin L. Scleroderma renal crisis: a rare but severe complication of systemic sclerosis. Clin Rev Allergy Immunol 2011;40:84–91.

35. Roberts D, Dalziel SR. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database of Systematic Reviews 2006;(3)CD004454. 36. Stutchfield P, Whitaker R, Russell I; Antenatal Steroids for Term Elective Caesarean Section (ASTECS) Research Team. Antenatal betamethasone and incidence of neonatal respiratory distress after elective caesarean section: pragmatic randomised trial. BMJ 2005;331:662. 37. Roberts D; Royal College of Obstetricians and Gynaecologists. Antenatal corticosteroids to reduce neonatal morbidity and mortality. Green-top Guideline No. 7. London: Royal College of Obstetricians and Gynaecologists; 2010. Available at: http://www.rcog.org.uk/files/ rcog-corp/GTG%207.pdf. Accessed on February 28, 2014. 38. Shennan AH, Redman C, Cooper C, Milne F. Are most maternal deaths from pre-eclampsia avoidable? Lancet 2012;379(9827):1686–7. 39. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

Appendix begins on next page

436 l MAY JOGC MAI 2014

Resource

https://ehealth.heartandstroke.ca/heartstroke/bpap.net/ vid_measure_bp.html http://hypertension.ca/measuring-blood-pressure

Heart and Stroke Foundation

Société Canadienne d/hypertension

Preeclampsia Foundation: Educational magnets and symptom Pads

Preeclampsia Foundation: Preeclampsia Education Tool

Preeclampsia awareness

American Heart Association document: Chronic Hypertension in Pregnancy

Impact of pre-existing hypertension on pregnancy

Heart and Stroke Foundation

http://www.preeclampsia.org/market-place

http://www.preeclampsia.org/market-place

https://circ.ahajournals.org/content/115/7/e188.full

http://www.heartandstroke.ca

http://www.RCOG.org.uk

Brochure

BP measurement and pre-existing hypertension

https://www.youtube.com/watch?v=eqajdX5XU9Y&feasture=pl

Canadian Hypertension Education Program (CHEP)

http://hypertension.ca/fr/mesures-dp1

http://www.heartfoundation.org.au/SiteCollectionDocuments/ Self-Management-BP.pdf

http://www.hypertension.ca/fr/mesures-dp1 (French)

http://www.hypertension.ca/measuring-blood-pressure (English)

PATIENT INFORMATION

National Heart Foundation of Australia

Canadian Hypertension Education Program (CHEP)

BP measurement by patients

Tool

APPENDIX. KNOWLEDGE TRANSLATION TOOLS FOR HDP

Continued

This website gives quick checklists of signs and symptoms of preeclampsia.

This tool explains the risks and symptoms of preeclampsia and how to act on them. This tool has shown to be effective in improving patient knowledge in an RCT (120 women).

This document explains in an understandable way how chronic hypertension and pregnancy influence each other and what the symptoms of preeclampsia that women should be aware of.

This website gives information about hypertension outside of pregnancy, blood pressure monitoring and medication.

This also includes your risk of recurrence.

This website gives detailed video on home BP measurement (outside pregnancy).

This website gives detailed information in English and French (with a poster in English) although the images are of older patients.

This link refers to a movie that gives instructions for self-measurement of BP.

This website gives information about the selfmeasurement of BP by patients and advice about buying a machine.

This website gives patients basic information about BP measurement and gives instructions on selfmeasurement.

Comment

Diagnosis, Evaluation, and Management of the Hypertensive Disorders of Pregnancy: Executive Summary

MAY JOGC MAI 2014 l 437

Tool

438 l MAY JOGC MAI 2014 http://www.dableducational.org/sphygmomanometers/devices_1_ clinical.html

Educational Trust

http://www.nice.org.uk/nicemedia/live/13098/50475/50475.pdf http://www.somanz.org/pdfs/somanz_guidelines_2008.pdf http://www.acog.org/~/media/Task%20Force%20and%20Work% 20Group%20Reports/HypertensioninPregnancy.pdf http://whqlibdoc.who.int/publications/2011/9789241548335_eng.pdf

NICE guidelines (UK, 2010)

Australasian guidelines (Australia and New Zealand, 2008)

College of Obstetricians and Gynecologists

WHO guidelines

Clinical practice guidelines from other countries

http://www.hypertension.ca/devices-endorsed-by-hypertensioncanada-dp1

http://www.who.int/reproductivehealth/publications/maternal_ perinatal_health/MSM_92_3_/en/index.html

HEALTH CARE PROVIDER INFORMATION

http://www.preeclampsia.org/market-place

http://biblio.hmr.qc.ca/Publications_pdf/H/hypertension_sfe080.pdf

http://www.preeclampsia.org/market-place

Resource

Canadian Hypertension Education Program (CHEP)

Approved BP measurement devices

WHO document: detecting preeclampsia, a practical guide, 2005

BP measurement

Preeclampsia Foundation; APEC: Educational pamphlet

Patient education after preeclampsia

Hôpital Maisonneuve-Rosemont, Centre affilié à l’Université de Montréal: Brochure on preeclampsia.

•  Preeclampsia and heart diseases

•  Preeclampsia FAQ

•  HELLP syndrome

Preeclampsia Foundation Brochures:

Patient education once preeclampsia develops

APPENDIX. Continued

Graded recommendations

Very practical but evidence not graded

Graded recommendations

This website gives an oversight of recommended blood pressure devices, outside of and during pregnancy.

This website gives an oversight of recommended blood pressure devices.

This document contains instructions how to measure blood pressure and proteinuria in pregnant women, and how to diagnose hypertensive disorders in pregnancy. This tool is for health care providers.

Educational brochure about cardiovascular risks associated with preeclampsia.

French brochure for patients about preeclampsia.

These are available in English and Spanish.

Comment

SOGC CLINICAL PRACTICE GUIDELINE

SOGC CLINICAL PRACTICE GUIDELINES No. 302, January 2014 (Replaces No. 173, February 2006)

Pregnancy Outcomes After Assisted Human Reproduction This clinical practice guideline has been prepared by the Genetics Committee, reviewed by the Reproductive Endocrinology and Infertility Committee and the Family Physicians Advisory Committee, and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Nanette Okun, MD, Toronto ON Sony Sierra, MD, Toronto ON GENETICS COMMITTEE R. Douglas Wilson (Chair), MD, Calgary AB Francois Audibert, MD, Montreal QC Jo-Ann Brock, MD, PhD, Halifax NS Carla Campagnolo, MSc, CCGC, London ON June Carroll, MD, Toronto ON Lola Cartier, MSc, CCGC, Montreal QC David Chitayat, MD, Toronto ON Alain Gagnon, MD, Vancouver BC Jo-Ann Johnson, MD, Calgary AB Sylvie Langlois, MD, Vancouver BC Lynn Murphy-Kaulbeck, MD, Moncton NB W. Kim MacDonald, MD, Halifax NS Nanette Okun, MD, Toronto ON Melanie Pastuck, RN, Cochrane AB

Abstract Objective: To review the effect of assisted human reproduction (AHR) on perinatal outcomes, to identify areas requiring further research with regard to birth outcomes and AHR, and to provide guidelines to optimize obstetrical management and counselling of prospective Canadian parents. Outcomes: This document compares perinatal outcomes of different types of AHR pregnancies with each other and with those of spontaneously conceived pregnancies. Clinicians will be better informed about the adverse outcomes that have been documented in association with AHR, including obstetrical complications, adverse perinatal outcomes, multiple gestations, structural congenital abnormalities, chromosomal abnormalities, and imprinting disorders. Evidence: Published literature was retrieved through searches of MEDLINE and the Cochrane Library from January 2005 to December 2012 using appropriate controlled vocabulary and key words (assisted reproduction, assisted reproductive technology, ovulation induction, intracytoplasmic sperm injection, embryo transfer, and in vitro fertilization). Results were not restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies; studies of all designs published in English from January 2005 to December 2012 were reviewed, and additional publications were identified from the bibliographies of these articles. Searches were updated on a regular basis and incorporated in the guideline to August 2013. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessmentrelated agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Values: The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1).

SPECIAL CONTRIBUTORS

Summary Statements

Lih Yeen Tan, MD, Toronto ON

01. There is increasing evidence that infertility or subfertility is an independent risk factor for obstetrical complications and adverse perinatal outcomes, even without the addition of assisted human reproduction. (II-2)

Valda Poplak, Toronto ON Helen Robson, MA, Toronto ON Disclosure statements have been received from all contributors.

Key Words: Assisted human reproduction, assisted reproductive technology, pregnancy outcomes, multiple gestation, imprinting, congenital anomalies, imprinting disorders.

02. The relative risk for an imprinting phenotype such as SilverRussell syndrome, Beckwith-Wiedemann syndrome, or Angelman syndrome is increased in the assisted reproduction population, but the actual risk for one of these phenotypes to occur in an assisted J Obstet Gynaecol Can 2014;36(1):64–83

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

64 l JANUARY JOGC JANVIER 2014

Pregnancy Outcomes After Assisted Human Reproduction

Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.176 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care.176

pregnancy is estimated to be low, at less than 1 in 5000. The exact biological etiology for this increased imprinting risk is likely heterogeneous and requires more research. (II-2) Recommendations 01. All men with severe oligozoospermia or azoospermia (sperm count < 5 million/hpf) should be offered genetic/ clinical counselling, karyotype assessment for chromosomal abnormalities, and Y-chromosome microdeletion testing prior to in vitro fertilization with intracytoplasmic sperm injection. (II-2A) 02. All men with unexplained obstructive azoospermia should be offered genetic/clinical counselling and genetic testing for cystic fibrosis prior to in vitro fertilization with intracytoplasmic sperm injection. (II-2A) 03. Multiple pregnancy is the most powerful predictive factor for adverse maternal, obstetrical, and perinatal outcomes. Couples should be thoroughly counselled about the significant risks of multiple pregnancies associated with all assisted human reproductive treatments. (II-2A) 04. The benefits and cumulative pregnancy rates of elective single embryo transfer a policy of using this protocol in couples with good prognosis for success, and elective single embryo transfer should be strongly encouraged in this population. (II-2A) 05. To reduce the incidence of multiple pregnancy, health care policies that public funding for assisted human reproduction, with regulations promoting best practice regarding elective single embryo transfer, should be strongly encouraged. (II-2A) 06. Among singleton pregnancies, assisted reproductive technology is associated with increased risks of preterm birth and low birth weight infants, and ovulation induction is associated with an increased risk of low birth weight infants. Until sufficient research has clarified the independent roles of infertility and treatment for infertility, couples should be counselled about the risks associated with treatment. (II-2B) There is a role for closer obstetric surveillance of women who conceive with assisted human reproduction. (III-L)

07. There is growing evidence that pregnancy outcomes are better for cryopreserved embryos fertilized in vitro than for fresh embryo transfers. This finding s a policy of elective single embryo transfer for women with a good prognosis (with subsequent use of cryopreserved embryos as necessary), and may reassure women who are considering in vitro fertilization. (II-2A) 08. Women and couples considering assisted human reproduction and concerned about perinatal outcomes in singleton pregnancies should be advised that (1) intracytoplasmic sperm injection does not appear to confer increased adverse perinatal or maternal risk over standard in vitro fertilization, and (2) the use of donor oocytes increases successful pregnancy rates in selected women, but even when ing for maternal age, can increase the risks of low birth weight and preeclampsia. (II-2B) 09. Any assisted reproductive technology procedure should be prefaced by a discussion of fetal outcomes and the slight increase in the risk of congenital structural abnormalities, with emphasis on known confounding factors such as infertility and body mass index. (II-2B) 10. In pregnancies achieved by artificial reproductive technology, routine anatomic ultrasound for congenital structural abnormalities is recommended between 18 and 22 weeks. (II-2A) 11. Pregnancies conceived by intracytoplasmic sperm injection may be at increased risk of chromosomal aberrations, including sex chromosome abnormalities. Diagnostic testing should be offered after appropriate counselling. (II-2A) 12. The possible increased risk for late onset cancer due to gene dysregulation for tumour suppression requires more long-term follow-up before the true risk can be determined. (III-A) 13. The clinical application of preimplantation genetic testing in fertile couples must balance the benefits of avoiding disease transmission with the medical risks and financial burden of in vitro fertilization. (III-B) 14. Preimplantation screening for aneuploidy is associated with inconsistent findings for improving pregnancy outcomes. Any discussion of preimplantation genetic screening with patients should clarify that there is no adequate information on the longterm effect of embryo single cell biopsy. (I-C)

JANUARY JOGC JANVIER 2014 l 65

SOGC Clinical Practice Guidelines

INTRODUCTION

A

lthough the definition varies, assisted reproductive technology is commonly defined as any procedure that involves handling eggs, sperm, or both outside the human body (in vitro). ART includes in vitro fertilization, with or without intracytoplasmic sperm injection, with fresh or frozen embryos (by cryopreservation or by vitrification and thawed embryo transfer) and IVF with donor oocytes, gamete intrafallopian transfer, zygote intrafallopian transfer, and assisted zona hatching. ART has expanded to include not only in vitro procedures, but also intrauterine insemination and OS with gonadotropin or ovarian stimulating medications1 ART s for 1.7% to 4% of pregnancies2 and has traditionally been used to address primary or secondary infertility.3 More recently, its use has expanded to allow ABBREVIATIONS AHR

assisted human reproduction

AHRC

Assisted Human Reproduction Canada

aOR

adjusted odds ratio

ART

assisted reproductive technology

ASRM

American Society for Reproductive Medicine

CARTR

Canadian Assisted Reproductive Technologies Registry

CBAVD

congenital bilateral absence of vas deferens

CFAS

Canadian Fertility and Andrology Society

DET

double embryo transfer

eSET

elective single embryo transfer

ESHRE

European Society of Human Reproduction and Embryology

ET

embryo transfer

FET

frozen embryo transfer

HFEA

Human Fertilisation and Embryology Authority

HR

hazard ratio

ISCI

intracytoplasmic sperm injection

IUI

intrauterine insemination

IVF

in vitro fertilization

LBW

low birth weight

MSAFP

maternal serum alpha-fetoprotein

PAPP-A

pregnancy-associated plasma protein-A

PGS

preimplantation genetic screening

RR

relative risk

OH

ovarian hyperstimulation

OI

ovulation induction

OS

ovarian stimulation

SART

Society for Assisted Reproduction Technologies

SGA

small for gestational age

TTP

time to pregnancy

66 l JANUARY JOGC JANVIER 2014

fertility preservation after gonadotoxic treatments in reproductive-age patients,4,5 to enable same-sex couples and single women and men to conceive and have biological children,6 and to facilitate the services of surrogate gestational carriers.7 The ethical and philosophical issues involved in AHR are complex and are handled differently in different countries, resulting in varying levels of regulation of these services.8–12 In Canada, the Assisted Human Reproduction Act,13 which covers topics including allowed (surrogacy, gamete donation) and prohibited (human cloning, buying or selling human reproductive material) processes, led to the creation of Assisted Human Reproduction Canada, an agency responsible for the licensing, monitoring, inspection, and enforcement of regulations for ART clinics. Following a 2010 Supreme Court decision resulting from a Charter challenge from Quebec, aspects of the Act relating to prohibitions (sex selection, selling of human reproductive material) have remained within the Federal Act, but much of the regulation of ART services will fall back under provincial jurisdiction.14 The 2012 Federal budget ordered the dissolution of AHRC in 2013, with its responsibilities redirected to Health Canada.4 Data for IVF clinics have been reported by the Canadian Assisted Reproductive Technologies Registry since 1999, under the auspices of the Canadian Fertility and Andrology Society.15 IVF clinics are accredited by Accreditation Canada.16 The availability of treatment for infertility and subfertility (a term generally used to name any grade of reduced fertility in couples unsuccessfully trying to conceive17) is important to the family health of Canadians.18 Obstetrical outcome data from pregnancies conceived by AHR and some long-term follow-up data on offspring suggest increased adverse outcomes related to AHR techniques. Care providers and prospective parents should be aware of these potential adverse outcomes. This guideline reviews the outcome data of AHR pregnancies using the Evaluation of Evidence criteria outlined in the Report of the Canadian Task Force on the Periodic Health Examination (Table 1). We searched the Cochrane Library and Ovid MEDLINE for English-language articles related to assisted reproduction and perinatal outcomes published from February 2005 to December 2012 (overlapping with the previous SOGC guideline). Well-conducted randomized controlled trials were considered evidence of the highest quality, followed by cohort studies. Key studies and ing data for each recommendation are referenced and summarized with evaluative comments.

Pregnancy Outcomes After Assisted Human Reproduction

OUTCOMES ASSOCIATED WITH UNTREATED INFERTILITY

OUTCOMES ASSOCIATED WITH MALE FACTOR INFERTILITY

Infertility, generally considered to be the inability to conceive after one year of attempting pregnancy,19 has been identified as a significant independent predictor of adverse obstetrical and perinatal outcomes.20–22 Unadjusted analyses suggest a 2-fold increased risk of preeclampsia, placental abruption, Caesarean section, and vacuum extraction, and a 5-fold increased risk of placenta previa in spontaneous singleton pregnancies in women with a history of infertility compared with women in the general population.23

Infertility is associated with male factor or abnormal sperm parameters in approximately 50% of cases.39 Studies have shown that 4.6% of oligozoospermic men and 13.7% of azoospermic men have constitutional chromosomal abnormalities, the most common being sex chromosomal abnormalities and autosomal translocations.40 Karyotype analysis of men with fewer than 5 million spermatozoa per milliliter of semen has been recommended as routine by the World Health Organization since 2000.41 As expected, infertile men with chromosomal abnormalities are more likely to have genetically abnormal spermatozoa and to father chromosomally abnormal pregnancies.42

Table 2 summarizes a number of studies documenting adjusted obstetrical, perinatal, and neonatal risks in populations of women with infertility or subfertility compared with control women.13,23–29 Some of these studies compared women with various delays in time to pregnancy who eventually conceived spontaneously to populations of women with short TTP, and found significant differences in a number of adverse outcomes, including preterm birth, LBW, and perinatal mortality. Other studies compared populations of women with delays in TTP with and without ART and found insignificant differences between these 2 groups, but increases in adverse outcomes between these 2 groups and a control group of women with no delay in TTP.30,31 Maternal factors related to an increased risk of infertility also have an independently associated risk of adverse obstetrical outcomes. Advancing maternal age is associated with both declining fertility and multiple adverse outcomes of ongoing pregnancy, as noted recently in an SOGC committee opinion on delayed childbearing.32 Research shows obesity impairs fertility, 33,34 although whether this effect is primarily ovarian or endometrial is controversial.35–37 Obesity is also independently related to adverse obstetrical outcomes, many of them similar to those associated with advancing maternal age38 and overlapping with those associated with AHR. Although there is little remaining debate about the association of infertility or subfertility with adverse obstetrical outcomes following AHR, more specific associations between ovarian/ovum or testicular/sperm factors, endometrial factors, or other factors and adverse outcomes are not well understood. Summary Statement

1. There is increasing evidence that infertility or subfertility is an independent risk factor for obstetrical complications and adverse perinatal outcomes, even without the addition of assisted human reproduction. (II-2)

Azoospermia can be classified as non-obstructive or obstructive. The most common cause of obstructive azoospermia is a congenital bilateral absence of vas deferens, a feature associated strongly with mutations in the cystic fibrosis transmembrane conductance regulator genes.43,44 In either presentation, a consultation with a urologist may lead to surgical extraction of sperm for use with IVF/ICSI. Microsurgical testis sperm extraction is estimated to be successful in 50% of attempts in non-obstructive azoospermia.45 Success with extracted sperm used in IVF/ICSI procedures has been documented with a pregnancy rate approaching 40%.46 A recently published systematic review summarized the potential reproductive outcomes of various male reproductive genetic abnormalities associated with azoospermia. (Table 3).47 Recommendations

1. All men with severe oligozoospermia or azoospermia (sperm count < 5 million/hpf) should be offered genetic/clinical counselling, karyotype assessment for chromosomal abnormalities, and Y-chromosome microdeletion testing prior to in vitro fertilization with intracytoplasmic sperm injection. (II-2A) 2. All men with unexplained obstructive azoospermia should be offered genetic/clinical counselling and genetic testing for cystic fibrosis prior to in vitro fertilization with intracytoplasmic sperm injection. (II-2A) OBSTETRICAL, PERINATAL, AND LONG-TERM OUTCOMES ASSOCIATED WITH ASSISTED REPRODUCTIVE TECHNOLOGY Multiple Pregnancy and Adverse Obstetrical and Perinatal Outcomes

Over the last 30 years, multiple birth rates have risen dramatically internationally, associated partly with increased maternal age at pregnancy, but mostly with infertility JANUARY JOGC JANVIER 2014 l 67

Maternal age Pre-pregnancy BMI Smoking Social status Gender of baby

Maternal age BMI Smoking Social class

Age Parity

Maternal age BMI Alcohol Smoking Occupational status

Maternal age Partiy Smoking

Maternal age Parity Offspring sex Year of birth Time from previous birth to conception

Basso and Baird 200326

Basso and Olsen 200527

Thomson et al. 200523

Zhu et al. 200628

Zhu et al. 200713

Romundstad et al. 200831

860 women with time to pregnancy > 12 months 6843 control subjects

Parity Smoking

68 l JANUARY JOGC JANVIER 2014 1 127 739 spontaneous conceptions 7474 ART conceptions 2204 women having one spontaneous conception and one ART conception (comparing outcomes in these pregnancies)

10 104 pregnancies with TTP > 12 months 51 041 pregnancies with TTP < 12 months

9727 pregnancies with TTP < 12 months 50 897 pregnancies with TTP < 12 months

1437 subfertile women 21 688 control subjects

4142 women with TTP > 12 months 16 305 women with TTP < 12 months

3899 (treated and untreated women with time to pregnancy > 1 year) 15 302 control subjects

Case-controlled study of 542 women with singleton or multiple perinatal deaths 972 randomly selected control subjects Examined treated and untreated infertility in each group

Population

Adjusted for

Potential confounders significant in logistic regression analysis

24

Draper et al. 199925

Henriksen et al. 1997

Study

SGA (< 2 SD below mean for GA and sex) Perinatal death

SGA < 5th percentile

Genital organ malformations

Preeclampsia Placenta previa Abruption Induction of labour Caesarean section Instrumental delivery LBW

Neonatal mortality within 28 days

GA < 37 weeks GA < 34 weeks Emergency Caesarean section

Perinatal mortality

Preterm birth < 37 weeks

Outcome

continued

1.26 (1.10 to 1.44) 1.31 (1.05 to 1.65) 0.99 (0.62 to 1.57) 0.36 (0.20 to 0.67) only significant if spontaneous conception preceded ART conception

1.24 (1.10 to 1.40) with no treatment 1.40 (1.23 to 1.60) with treatment

hazard ratio: 2.32 (1.24 to 4.35)

1.9 (1.5 to 2.5) 3.9 (2.2 to 7.0) 1.8 (1.1 to 3.0) 1.5 (1.3 to 1.6) 2.1 (1.8 to 2.4) 2.2 (1.8 to 2.6) 1.4 (1.3 to 1.7)

3.32 (1.47 to 7.53) with no treatment 2.21 (0.88 to 5.55) with treatment

1.38 (1.14 to 1.69) 1.51 (1.05 to 2.16) 1.15 (1.00 to 1.32)

2.9 (1.8 to 4.5)

1.7 (1.1 to 2.6) no difference with/without treatment

Odds ratio

Table 2. Controlled studies of obstetrical outcomes of women undergoing , compared with women conceiving spontaneously. after prolonged time to pregnancy

SOGC Clinical Practice Guidelines

Maternal age

1.19 (0.47 to 3.04) Low Apgar score

Multiple pregnancy is, arguably, the most important outcome issue associated with AHR. The increased incidence of adverse outcomes for fetuses and neonates of multiple pregnancies has been consistently reported, with preterm birth and its associated sequelae the most important. The increasing overall frequency of prematurity in Canada is related to a significant degree to the increased rate of multiple pregnancy.49 Much of this increase is confined to an increase in the proportion of infants born between 32 and 36 weeks’ gestation, but there has also been an increase in the frequency of preterm birth before 32 weeks, from 1% to 1.2%.49 In Canada, the proportion of preterm births secondary to multiple pregnancies has increased from approximately 30% in the 1970s to 58.4% in 2004.49 The risks of perinatal mortality, growth restriction, cerebral palsy, and congenital anomalies are also higher in multiples than in singletons, most notably in monochorionic, but also in dichorionic, twins.49,56,57

PE: preeclampsia

1.28 (0.88 to 1.88) Need for NICU

Although most multiple pregnancies following AHR are dichorionic twins, the incidence of monozygotic twins (most of whom have a monochorionic placentation) among all IVF pregnancies is estimated at 0.9% to 2%, compared with approximately 0.4% of live births from spontaneously conceived pregnancies.52–54 IVF pregnancies that occur after transferring blastocyst (5 days after fertilization) embryos are more often associated with monozygotic twinning (6%) than pregnancies that occur after transferring cleavagestage (2–3 days after fertilization) embryos (2%).55

Alcohol

0.95 (0.65 to 1.39) SGA

18 984 spontaneous pregnancies with TTP < 6 months Pre-pregnancy

treatments.48,49 Multifetal pregnancy follows ovulation induction or ovarian hyperstimulation alone at rates between 5% and 40%.50 The 2011 published rate of multiple pregnancies as a result of IVF reported by CARTR in Canada is approximately 30%.51

Smoking

1.28 (0.81 to 2.03) Preterm birth 928 spontaneous pregnancies with TTP > 2 years Prior abortion

Scarred uterus

1.21 (0.89 to 1.64) Caesarean section

BMI

1.56 (1.37 to 1.77) Caesarean section

1.37 (1.25 to 1.43) GA < 31 weeks

428 ART pregnancies with TTP > 2 years

2.19 (1.10 to 4.36) Perinatal death

Parity

1.41 (1.05 to 1.89) Antepartum hemorrhage 4363 spontaneous pregnancy control subjects Parity

Raatikainen et al. 201230

1.29 (1.02 to 1.61) Hypertension/PE 2171 singletons to subfertile women with no ART No. of previous abortions Jaques et al. 201029

Private/public hospital status

Odds ratio Outcome Population Adjusted for Study

Table 2. Continued

Pregnancy Outcomes After Assisted Human Reproduction

The risk of morbidity and mortality increases with each additional fetus in a multiple gestation.58 A recent twoyear study at one Quebec hospital showed that 17% of all NICU issions were from multiple pregnancies in women undergoing ART. Of these, 91% resulted from IVF, with 2 to 6 embryos transferred, and 9% from pregnancies conceived after OS.59 An Australian study similarly reported that 12.3 % of NICU issions between 1994 and 2005 resulted from assisted reproduction. Of those, 5% were singletons, 27% were twins, and 65% were triplets.60 There is no doubt that the increasing use of AHR has led to increased perinatal morbidity and mortality secondary to an increase in the incidence of multiple pregnancy. Whether AHR multiples pose more risk than spontaneous multiples for perinatal adverse outcomes is less clear. Controlled studies of perinatal outcomes comparing JANUARY JOGC JANVIER 2014 l 69

SOGC Clinical Practice Guidelines

Table 3. Potential reproductive outcomes of various male reproductive genetic abnormalities associated with azoospermia Test

Finding

Adverse consequences

Y-chromosome microdeletion

AZFc microdeletion

Male offspring with severe spermatogenetic failure/ sterility

AZFc microdeletions with aberrations in pseudoautosomal regions (PARs)

Male offspring with severe spermatogenetic failure/ sterility; possible skeletal or other anomalies

gr/gr microdeletion

Male offspring with severe spermatogenetic failure/ sterility; possible skeletal or other anomalies

47, XXY (Klinefelter syndrome)

Hypogonadism, slightly increased rate of autosomal and sex chromosomal disomy in sperm; offspring with 46XX or 46XY karyotype with no genetic anomalies

Isodicentric Y chromosome

Possible offspring with 45X, Turner’s syndrome, or mixed gonadal dysgenesis (45,X/46,XY)

Chromosome translocations

Depends on chromosomes involved; recurrant pregnancy loss or aneuploidy of offspring

CF mutation analysis

Congenital bilateral absence of vas deferens

Offspring with possible mild cystic fibrosis disease spectrum if partner is a carrier; renal abnormalities if no CFTR mutation identified

Sperm morphology

Structural aberrations of the spermatozoon (e.g. Globozoospermia, dysplasia of the fibrous sheath)

No obvious congenital anomalies in offspring reported but possible higher rates of embryo aneuploidy

Karyotype analysis

CFTR: Cystic fibrosis transmembrane conductance regulator Adapted from Harnisch and Oates, 2012.47

twin pregnancies conceived after AHR with those of spontaneously conceived twins,61–67 as well as 2 systematic reviews,68,69 reveal data that are somewhat conflicting. The study quality is hampered by several factors, including small sample size, retrospective design, and inability to accurately identify pregnancies conceived by ART (IVF or IVF/ICSI) versus other forms of AHR (OI, OH, or OI/OH–IUI), with some studies likely incorrectly classifying the latter in the “spontaneous” group. As well, the known effects of chorionicity and subfertility themselves are inconsistently controlled. Finally, the fact that women undergoing AHR treatments generally attend prenatal care earlier, and are followed more closely, could confound the results. With these limitations in mind, recent studies have suggested very little independent influence of ART on adverse outcome between these 2 comparison groups, with some showing better outcomes within the ART group. Joy et al. found an increase in preterm birth, lower birth weight, and congenital anomalies among the spontaneously conceived twins, but these findings were negated when the monochorionic twins were removed.70 Morcel et al. found that differences in outcomes were related to chorionicity and method of AHR, with higher risk among pregnancies conceived by OI than by ART,66 and Verstraelen et al. suggest that subfertility itself plays a significant role in adverse outcomes.64 Maternal complications are more common in multiple pregnancies than in singletons. Anemia, gestational hypertension,71 preeclampsia, gestational diabetes, operative 70 l JANUARY JOGC JANVIER 2014

risks from Caesarean section, and postpartum hemorrhage are of increased concern with multiple pregnancy.72 As well as medical complications, multiple births generate significant economic and psychosocial costs.73–75 Interestingly, a recent study found, among parents of both ART and spontaneous pregnancies, that the mental health of both parents was more adversely affected by multiples than by singletons, but that ART did not have an additional adverse effect.76 Multifetal reduction can be very emotionally difficult for couples who have gone through fertility treatment, particularly when the procedure may result in the loss of the entire pregnancy.77 Although some studies document a risk of long-term adverse emotional consequences for the couple,78–80 current evidence s multifetal pregnancy reduction of higher order multiples to twins in order to improve pregnancy outcomes.81,82 Compared with spontaneously conceived twin pregnancies, twin pregnancies remaining after fetal reduction continue to have an increased risk of preterm birth, LBW, very low birth weight, and fetal growth restriction.62,83 Because of these maternal and perinatal risks, there has been significant international effort to reduce the incidence of multiple pregnancy associated with AHR. Transfer of fewer embryos per cycle will reduce multiple pregnancy rates, but this beneficial effect may be accompanied by a less than acceptable pregnancy rate.

Pregnancy Outcomes After Assisted Human Reproduction

Two recent systematic reviews examined this topic. A 2009 Cochrane review compared the live birth rate of elective DET with that of elective single, triple, or quadruple embryo transfer. The review concluded that a single cycle of eSET resulted in a lower live birth rate than DET, but that the cumulative live birth rate in a fresh eSET cycle followed by a frozen eSET was not significantly different from a single DET cycle.84

of number of embryos transferred, and the current recommendations93 suggest that individual IVF-ET programs should evaluate their own data to identify patientspecific, embryo-specific, and cycle-specific determinants of implantation and live birth in deciding on the number of embryos to transfer. Updated recommendations will likely consider the age of the woman or the egg donor to be paramount in this decision-making process.

A second meta-analysis by Grady et al. in 2012 compared perinatal outcomes between DET and eSET pregnancies. They found an RCT-based relative risk of 0.37 (0.25 to 0.55) for preterm birth < 37 weeks, and a RCT-based RR of 0.25 (0.15 to 0.45) for birth weight < 2500 g in the eSET group.85 Upon consideration of these results, it appears likely that with a policy of fresh eSET followed, as necessary, by a cycle of frozen eSET, the cumulative live birth rate would be very similar to DET.

Internationally, in some jurisdictions the proportion of eSET has increased and the multiple birth rate has fallen. The 2010 US data report an approximate 15% eSET rate94 (twice that of 2000), while 2011 data from the UK report a 16.8% eSET rate.95 The 2011 UK data show a significantly lower (20.6%) multiple pregnancy rate95 than the 2010 US rate of 31%.94

Many clinicians differentiate between live birth rates and perinatal outcomes with IVF in women under and over 40 years of age, but these 2 studies did not. A recent observational UK study of 33 514 live births in 124 148 IVF cycles examined these outcomes according to whether 1, 2, or ≥ 3 embryos were transferred in women aged < 40 or ≥ 40. The study found that the overall live birth rate was better in the < 40 age group, that the live birth rate was higher for DET than for SET in both age groups, that perinatal outcomes were worse in both age groups for DET than for SET, but, notably, that the difference in adverse perinatal outcomes in DET versus SET was less in the > 40 age group. This large observational study s consideration of DET for women ≥ 40. The study showed that transferring more than 2 embryos did not increase live birth rates in either age group, and it discouraged transferring 3 or more embryos at any stage.86 The potential impact of a policy of eSET in appropriately selected women on perinatal and maternal outcomes is significant, and such a policy could result in substantial cost savings. One modelling study examined the cost utility of this policy,87 and a multi-centre cohort examining the longterm effects and cost implications of the Dutch policy of eSET is ongoing.88 Based on this research, ESHRE,89 HFEA,90 ASRM,91 and SOGC and CFAS (tly)92 have modified their guidelines and recently endorsed a policy of eSET for women with clinical factors predictive of a high chance of success for cumulative live birth in centres with a good cryopreservation facility. However, there is no current specific predictive model to facilitate broad policy recommendations in

Recently, AHRC analyzed the current international and national state of AHR policy on embryo transfer. An overriding factor that surfaced as a barrier to a broader practice of eSET was active government legislation, often linked to reimbursement. Those jurisdictions with legislation and funded programs had much higher rates of eSET; Belgium, Finland, and Australia approach 50% eSET rates, with funded programs and linked legislation promoting maximal use of eSET. In Canada, an expert in Ontario has recommended consideration of legislation and public funding for higher rates of eSET.96 As of August 5, 2010, the provincial government of Quebec began funding 3 cycles of IVF with OS or up to 6 cycles of natural or modified natural cycles of IVF, with IVF funding tied to eSET for clinically favourable situations. An initial report on the first 3 months of the program in 2009 found an increase in the rate of eSET from 1.6% to 50%, and a reduction in the multiple pregnancy rate from 25.6% to 3.7%.97 The most recent report indicates an eSET rate of 49%, a 5.2% multiple pregnancy rate, and a predicted cumulative pregnancy rate of 60% per cycle.”98 Although most of the attention in reducing multiple pregnancy rates has been directed at strategies related to IVF, studies are increasingly addressing strategies related to OI and OH with gonadotropin medications. This latter literature is complicated by heterogeneity in both the patient population and the medication regimens aimed at OI or OH, with or without IUI. In addition, unlike ART/ IVF, there is even less regulation and capture of data on treatment outcomes in this population, as it is not subject to either mandatory or voluntary AHR reporting in North America or Europe. JANUARY JOGC JANVIER 2014 l 71

SOGC Clinical Practice Guidelines

A recent review99 and ASRM committee opinion on ways to reduce multiple pregnancy rates following OI/OS reviews several strategies that have been studied, including longer initial treatment with clomiphene citrate prior to gonadotropin use, lower doses of gonadotropins, and monitoring and altering cycle management on the basis of estradiol levels and follicle size. The committee concludes that useful work has been done, but larger, prospective studies are needed prior to the issue of a formal guideline on this issue.100 Recommendations

3. Multiple pregnancy is the most powerful predictive factor for adverse maternal, obstetrical, and perinatal outcomes. Couples should be thoroughly counselled about the significant risks of multiple pregnancies associated with all assisted human reproductive treatments. (II-2A) 4. The benefits and cumulative pregnancy rates of elective single embryo transfer a policy of using this protocol in couples with good prognosis for success, and elective single embryo transfer should be strongly encouraged in this population. (II-2A) 5. To reduce the incidence of multiple pregnancy, health care policies that public funding for assisted human reproduction, with regulations promoting best practice regarding elective single embryo transfer, should be strongly encouraged. (II-2A) Singleton Pregnancies and Perinatal Outcome

AHR resulting in singleton pregnancies has also been shown to be associated with adverse obstetrical and perinatal outcomes, but this is challenging literature to analyze. There are many individual factors that can independently and significantly contribute to adverse outcomes, but they are difficult to isolate as they are interrelated with the couple’s clinical profile (reason for infertility/subfertility) and treatment regime. The quality of studies has improved as accumulated data from large registries have been published, but these still do not allow the isolation of likely important but interrelated clinical details, such as maternal and paternal background factors and individual factors within the treatment regimes. Different forms of OI versus OH, donor versus own eggs, timing and/or method of aspiration of eggs, maturation in an artificially high hormonal milieu in the mother (OH) or in the laboratory (in vitro maturation), fresh or frozen embryos, method of freezing embryos or eggs, origin of sperm (ejaculated, testicular, epididymal), quality of sperm, number of embryos formed, number of embryos transferred, stage of transfer (cleavage vs. blastocyst 72 l JANUARY JOGC JANVIER 2014

stage), and the effect of “vanishing” fetuses are some of the factors that could affect perinatal, obstetrical, and longterm outcomes in different but significant ways. There are, however, some evolving trends that continue to the association between AHR and increased risk of adverse obstetrical and perinatal outcomes among singleton pregnancies. Preterm Birth

Along with multiple pregnancy, preterm birth and LBW are the most commonly examined measures of adverse perinatal outcome in singleton pregnancies conceived after AHR.101,102 Table 4 summarizes these data.96–99,101,103 Several studies have found an increased risk of preterm birth, whether defined as birth before 37 weeks, at 32 to 36 weeks, or before 32 weeks, in IVF versus spontaneous singleton pregnancies. Adjusted odds ratios/relative risks are between 1.95 and 3.22.104–108 It is not as convincing that OI alone increases the risk of preterm birth once other factors are controlled,109,110 although one recent large Finnish cohort study found an independent effect on preterm birth in all categories of gestational age cut-offs.111 Low Birth Weight

In almost all studies of singleton pregnancies resulting from any type of AHR, LBW is found more often than in spontaneous pregnancies. As in preterm birth, all systematic reviews have associated IVF with reduced birth weight, as indicated in Table 4.69,82,105–108 LBW in these cases reflects not only decreased gestational age, but also less than optimal growth for a given gestational age. OI is also quite consistently associated with LBW.109–111 Exposure to gonadotropic stimulation, which produces increased physiologic levels of circulating estradiol combined with in vitro culture may be cumulatively detrimental to normal embryo growth.112 Many emerging studies are attempting to isolate the causative factors responsible for growth disturbance in women undergoing AHR by comparing outcomes in various subsets within cohort studies of the AHR population and with outcomes in spontaneous pregnancies. Consistent with the data on the contribution of the diagnosis and causes of infertility itself, Sasanova et al. performed logistic regression analysis on 8941 singleton pregnancies after IVF to determine predictive factors for preterm birth and LBW. They found that primiparity, smoking, BMI, and the vanishing twin phenomenon increased the risk of preterm birth, and that maternal age, smoking, BMI, and duration of infertility increased the risk of LBW.113

Pregnancy Outcomes After Assisted Human Reproduction

Table 4. Controlled studies of preterm birth and LBW among singleton pregnancies after AHR, compared with spontaneously conceived pregnancies Perinatal outcomes Preterm delivery < 37 weeks

RR ovulation induction alone (95% CI)

RR IVF (95% CI) 1.98 (1.77 to 2.22)97 2.00 (1.70 to 2.20)

1.32 (1.15 to 1.50)104

98

1.93 (1.36 to 2.74)99 1.84 (1.54 to 2.21)100 1.91 (1.31 to 2.80)101 Preterm delivery 32–36 weeks or < 32 weeks

2.3 (1.00 to 5.28)99

1.52 (1.13 to 2.04)104

Low birth weight < 2500 g

1.40 (1.01 to 1.95)99

1.43 (1.23 to 1.67)104

2.20 (1.55 to 3.13)

103

1.40 (1.01 to 1.95)100 Very low birth weight < 1500 g SGA < 10th percentile

3.78 (2.49 to 5.75)99

3.1 (1.0 to 10.4)102

2.7 (1.8 to 4.1)102

1.78 (1.33 to 2.38)104

1.98 (1.21 to 3.24)

1.71 (1.09 to 2.69)103

A number of studies that compared IVF cycles with fresh versus frozen (cryopreserved) embryos found that frozen embryo transfers result in higher birth weights, a lower chance of SGA infants, and a lower rate of preterm birth.114–116 A large Australian cohort study performing regression analysis to determine predictive factors for LBW reports a significant increase in LBW with fresh versus FET, with an aOR of 1.9 (95% CI 1.6 to 2.4).117 A systematic review on the topic also reports that the preterm birth rate is either unchanged or decreased, and the LBW/ SGA rate is unchanged or improved with cryopreserved versus fresh IVF cycles.118 A recent American cohort study of 24 334 singleton fresh IVF pregnancies compared with 13 806 singleton FET IVF pregnancies found no significant increase in aORs for preterm birth with FET, but an increase in the overall rate of LBW, with an aOR of 1.35 (95% CI 1.20 to 1.51) among pregnancies of fresh IVF cycles. In donor oocyte cycles with no OS, the rate of LBW was not increased.119 These findings suggest that changes in the uterine environment associated with multiple follicle production increases the risk of LBW. An interesting Danish cohort study of sibling singleton births comparing 5 groups of successive pregnancies •• fresh IVF-ISCI vs. spontaneous, •• fresh IVF-ICSI vs. FET, •• FET vs. FET, •• fresh IVF-ICSI vs. fresh IVF-ICSI, •• spontaneous vs. spontaneous

103

found a higher risk of LBW and lower mean birth weight in fresh IVF-ICSI pregnancies than in FET, and an overall lower birth weight with any ART than with spontaneous pregnancy.120 The most recent data from a cohort of 25 777 births documents a significant difference in birth weight of 90.9 g in singletons conceived in frozen versus fresh transfer cycles.121 There is speculation that the endometrial environment may be improved by the lower doses of OS agents required for FET, or that better quality embryos are recruited and persevere through cryopreservation procedures. However, another cohort study of 32 416 singleton IVF or ICSI pregnancies found no independent relationship between the parameters of OS used in these cycles and birth weight.122 An interesting study of 292 singletons examined serum estradiol levels during IVF cycles found that adjusted for patient age, BMI, parity, number of embryos transferred, day of transfer, and gonadotropin dose, high serum estradiol levels (> 3450 pg/mL or > 90th percentile) were associated with preeclampsia (OR 4.8; 95% CI 1.6 to 14.8) and SGA (OR 9.4; 95% CI 3.2 to 27.5).123 Other studies have compared pregnancies conceived after ICSI/IVF to spontaneous pregnancies with regard to preterm birth and LBW. Two small studies (N = 41 ICSI/147 control subjects124; N = 276 ICSI/273 control subjects125) comparing IVF/ICSI pregnancies with JANUARY JOGC JANVIER 2014 l 73

SOGC Clinical Practice Guidelines

spontaneous pregnancies did not find an increase in LBW or preterm birth. A study comparing 81 singleton ICSI pregnancies to 81 matched-control IVF pregnancies did not find any significant difference in preterm birth or low birth weight.126 A Canadian study comparing ICSI (n = 104), IVF (n = 133) and in vitro ovum maturation (n = 31) did not find any significant differences in rates of preterm birth or LBW.127 The source of sperm for ICSI (ejaculated, epididymal, or testicular) does not appear to influence birth weight parameters.128,129 ICSI itself does not appear to adversely affect preterm birth or LBW rates. Use of donor, versus autologous, oocytes has been reported to increase the risk of preterm birth and LBW. A small case-controlled study comparing 81 IVF donor cycles to 77 autologous oocyte IVF cycles found an increased aOR of 2.6 (95% CI 1.04 to 6.3) for preterm birth.130 A SART report comparing 60 037 standard IVF cycles with 10 176 donor egg cycles and 1180 gestational carrier cycles found aORs of 1.21 (95% CI 1.13 to 1.30) for birth weight < 2500 g and 1.28 (95% CI 1.10 to 1.49) for birth weight < 1500 g when comparing donor egg with autologous egg IVF cycles.37 Other Obstetrical Outcomes

There has been some question of whether AHR leads to placental abnormalities as a mediating factor for some adverse outcomes, such as LBW, preeclampsia, abnormal implantation, placenta accreta, antepartum hemorrhage, and postpartum hemorrhage. Possible early placental abnormalities are consistent with the finding of altered levels of maternal serum marker levels for Down syndrome and open neural tube defects in the first and second trimester. Several studies, including that reported from the Danish cohort, found a significantly lower PAPP-A level among ART pregnancies (except those with FET) of 0.8 MoM131 and an elevated total hCG.132 Several studies report an increased risk of preeclampsia with AHR. Calhoun reports an aOR of 2.2 (95% CI 1.03 to 4.72), when controlling for factors including multiple gestation, for preeclampsia with AHR; the risk was greatest for IVF (aOR 5.3; 95% CI 1.74 to 15.89), and there was no reported association between IUI and preeclampsia.133 Two separate cohort studies from the same Ontario database report somewhat contradictory findings. Sun et al. found a non-significant increased risk of a composite outcome of placenta-mediated complications (stillbirth, growth restriction, preeclampsia, and abruption) with IUI (OR 1.30; 95% CI 0.94 to 1.80) but not with IVF or OI in a matched-control study in singletons.134 Another analysis on 74 l JANUARY JOGC JANVIER 2014

an overlapping cohort from the same database controlling for, but not excluding, multiples, reports an increased risk for preeclampsia with IVF (OR 1.78; 95% CI 1.05 to 3.06), but not for IUI or OI.135 Small studies have linked donor oocytes with an increased risk of preeclampsia over autologous oocytes.130,136 Other placental complications reported to occur with increased frequency with ART include placenta previa, placental abruption, and antepartum and postpartum hemorrhage. In a review of 42 placenta accreta cases, the OR for IVF versus spontaneous pregnancies was 13.2 (95% CI 6.7 to 25.8).137 A large Australian cohort study of 6730 IVF/ICSI pregnancies compared with 24 619 spontaneous pregnancies found an aOR of 2.0 (95% CI 1.8 to 2.3) for antepartum hemorrhage, 2.3 (95% CI 1.9 to 2.9) for placenta previa, 2.1 (95% CI 1.4 to 3.0) for abruption, and 1.3 (95% CI 1.2 to 1.4) for postpartum hemorrhage.138 A recent systematic review of 13 studies did not indicate an increased risk of postpartum depression associated with ART.139 The timing of the transfer of the embryo in IVF or IVF/ ICSI may influence the outcome. Optimal timing has evolved from the cleavage-stage to the blastocyst stage, as the success rate after blastocyst transfer is higher, resulting in a higher live birth rate.140 In a meta-analysis of 4 studies of 1102 blastocyst transfer cycles versus 1485 cleavage-stage cycles, the ratio of males to females was higher (OR 1.29; 95% CI 1.10 to 1.51) in blastocyst transfer cycles. In the same report a meta-analysis of 7 studies of 9316 blastocyst cycles versus 31 601 cleavagestage cycles found the rate of monozygotic twinning to be increased with blastocyst transfer (OR 3.04; 95% CI 1.54 to 6.01).141 In another study of 1311 blastocyst transfer cycles versus 12 562 cleavage-stage cycles, the rate of birth < 37 weeks was slightly increased in the blastocyst transfer group (OR 1.35; 95% CI 1.07 to 1.71), but the LBW rate was unchanged.142 Long-Term Child Outcomes

Several large registry-based studies examining long-term child outcomes have been published recently. There appears to be little, if any, increased risk of significant neurodevelopmental or behavioural adverse outcomes at 2-year124 or 5-year125,143 follow-ups. A 10-year follow-up study found no significant difference between ICSI and spontaneously conceived children.144 Physical health, thus far, appears equal, although there has been a reported increase in undescended testes and resulting urogenital surgery in boys after ICSI.145 Although small studies reported an increase in certain childhood cancers, registry data do not this relationship.146

Pregnancy Outcomes After Assisted Human Reproduction

Recommendations

6. Among singleton pregnancies, assisted reproductive technology is associated with increased risks of preterm birth and low birth weight infants, and ovulation induction is associated with an increased risk of low birth weight infants. Until sufficient research has clarified the independent roles of infertility and treatment for infertility, couples should be counselled about the risks associated with treatment. (II-2B) There is a role for closer obstetric surveillance for women who conceive with assisted human reproduction. (III-L) 7. There is growing evidence that pregnancy outcomes are better for cryopreserved embryos fertilized in vitro than for fresh embryo transfers. This finding s a policy of elective single embryo transfer for women with a good prognosis (with subsequent use of cryopreserved embryos as necessary), and may reassure women who are considering in vitro fertilization. (II-2A) 8. Women and couples considering assisted human reproduction and concerned about perinatal outcomes in singleton pregnancies should be advised that (1) intracytoplasmic sperm injection does not appear to confer increased adverse perinatal or maternal risk over standard in vitro fertilization, and (2) the use of donor oocytes increases successful pregnancy rates in selected women, but even when ing for maternal age, can increase the risk of low birth weight and preeclampsia. (II-2B) FETAL STRUCTURAL, CHROMOSOMAL, AND IMPRINTING ABNORMALITIES ASSOCIATED WITH ASSISTED HUMAN REPRODUCTION Structural Abnormalities (Malformations, Deformations, and Disruptions)

Previous studies of the association between ART and structural congenital malformations have reported an elevated risk, but were limited by small sample sizes, varying definitions of congenital anomalies, and lack of data on potential confounding variables.147–149 A longitudinal study of the Danish national birth cohort found that singletons born to couples with a history of infertility, but who conceived naturally or with ART treatment had a higher prevalence of congenital malformations (HR 1.20; 95% CI 1.07 to 1.35) than babies born spontaneously with no delay in time to conception. Babies born of ART in infertile couples had an increased prevalence of genital organ malformations (HR 2.32; 95% CI 1.24 to 4.35).27

The National Birth Defects Prevention Study provided a casecontrolled analysis of ed live-born infants versus those born through ART for congenital defects. Adjustments for confounders included maternal race, maternal age, smoking, and parity. ART was associated with septal heart defects (aOR 2.1; 95% CI 1.1 to 4.0); esophageal atresia (aOR 4.5; 95% CI 1.9 to 10.5), and anorectal atresia (aOR 3.7; 95% CI 1.5 to 9.1). Among multiple births, there was no significant association between ART and birth defects.150 The findings of a recent retrospective cohort study of IVF/ ICSI patients in a Canadian centre suggest there is a higher prevalence of infants with congenital heart defects in infants conceived by IVF/ICSI (1.1%) than in spontaneously conceived infants (0.4%) (P < 0.01). A maternal BMI of > 30 kg/m2 was found to increase this prevalence of birth defects.151 More recent registry data demonstrate a higher risk for major congenital abnormalities in infants following both IVF and IVF-ICSI than in spontaneous conceptions, after adjusting for appropriate confounding factors.152 IVF-ICSI has been shown to have a 2-fold increased risk for major malformations in singletons (8.9%), compared with spontaneous conceptions (6.0%), and a 2-fold risk for major malformations in one or both newborns among twin gestations following IVF-ICSI, compared with singletons following IVF-ICSI.149,153 A meta-analysis reviewing data from 46 different studies, including 124 468 infants conceived with ART, compared with spontaneously conceived children, showed that the total adjusted RR for ART procedures versus spontaneous conception was 1.36 (95% CI 1.26 to 1.48), with no difference seen between IVF and IVF/ICSI.154 Davies et al.38 compared the incidence of birth defects, including births and terminations of pregnancy, in patients in South Australia undergoing IVF (with or without ICSI) with those of spontaneous pregnancies. Among the total IVF cases (± ICSI), the aOR for IVF ± ICSI was 1.28 (95% CI 1.16 to 1.41). Comparing IVF alone to spontaneous pregnancies resulted in the loss of any significant effect of ART, while IVF/ICSI remained a significant risk factor, with an aOR of 1.57 (95% CI 1.30 to 1.90). In the same population (N = 308 974), the incidence of birth defects with a history of infertility, with or without ART, was higher than among spontaneous pregnancies without a history of infertility.2 Recommendations

9. Any assisted reproductive technology procedure should be prefaced by a discussion of fetal outcomes and the slight increase in the risk of congenital structural abnormalities, with emphasis

JANUARY JOGC JANVIER 2014 l 75

SOGC Clinical Practice Guidelines

Table 5. Human phenotypes identified and associated with imprinted genes Syndrome

Chromosome location

1.

Beckwith-Wiedemann

2.

Angelman

15q11-q12 maternal

3.

Prader-Willi

15q11-q12 paternal

4.

Silver-Russell

5.

Transient neonatal diabetes mellitus

6q24

6.

McCune Albright

20q13

7.

Familial nonchromaffin paraganglioma

11q13

8.

Maternal and paternal uniparental disomy

9.

Turner

on known confounding factors such as infertility and body mass index. (II-2B) 10. In pregnancies achieved by assisted reproductive technology, routine anatomic ultrasound for congenital structural abnormalities is recommended between 18 and 22 weeks. (II-2A) Chromosomal Disorders

The incidence of any chromosomal abnormality in births and induced terminations, after adjusting for maternal age and parity, following IVF (0.7%) has been shown to be similar to those in spontaneously conceived pregnancies (0.2%), but significantly higher following IVF-ICSI (1.0%).149 Significantly more de novo chromosomal aberrations have been diagnosed prenatally in children conceived by IVF-ICSI than the general newborn population155 A prospective clinical observation study156 analyzed peripheral and umbilical cord blood samples of male children born to fathers with normal spermatogenesis. De novo Y-chromosome microdeletions were identified in 5.3% of 19 IVF offspring and in 16.7% of 18 ICSI offspring; both techniques were statistically significantly associated with a higher rate of de novo Y-chromosome microdeletions than in male children conceived naturally. As in spontaneously conceived pregnancies, options for prenatal diagnosis of aneuploidy (chorionic villus sampling or amniocentesis) in patients who conceive after AHR should be determined by results of prenatal screening tests for aneuploidy,156 except for those resulting from IVF-ICSI.154 Most studies find no significant differences between nuchal translucency measurements in IVF and IVF-ICSI pregnancies and in spontaneously conceived pregnancies.158 PAPP-A levels have been found to be significantly lower after ART.159 MSAFP is not a reliable marker for neural tube defects following fetal reduction.160 Elevated MSAFP levels have been observed in pregnancies conceived with donor oocytes.161 76 l JANUARY JOGC JANVIER 2014

11p15

7p11-p13, 7q31-qter, 11p15

2, 14, 16 X

Recommendation

11. Pregnancies conceived by intracytoplasmic sperm injection may be at increased risk of chromosomal aberrations, including sex chromosome abnormalities. Diagnostic testing should be offered after appropriate counselling. (II-2A) Imprinting Disorders

Pregnancies using ART are increasing with the availability of the technology and with patient needs and choices, and recent estimates indicate that in industrialized and developed countries 1.7% to 4.0% of all children are born after ART.2 The first live-born offspring after IVF, FET, and ICSI were reported in 1978, 1984, and 1992.162–164 The association between adverse pregnancy outcomes and genetic imprinting errors with the identification of epimutations is rare, but understanding of the mechanisms through animal and human research is quickly expanding. Genomic imprinting is a process of epigenetic modification which allows genes to be expressed in a parent-of-origin– specific manner. These genetic loci are important for normal growth and development. Imprinting is found predominately in placental mammals and may have evolved as a mechanism to balance the allocation of parental resources to the offspring.16,46 Epigenetics is the modification of the “complete” DNA structure by methylation or histones that results in the gene becoming non-transcribed in a timespecific period or a tissue-specific fashion, but with no alteration of the actual DNA coding sequence in the gene. Nine human phenotypes have been identified and associated with an imprinted gene (Table 5).165,166 The imprinting loci/epimutations in phenotypes that have been strongly associated with children conceived with ART are Beckwith-Wiedemann syndrome, Silver-

Pregnancy Outcomes After Assisted Human Reproduction

Russell syndrome, and Angelman syndrome. The reported evidence of association between these imprinting phenotypes and various ART techniques, including IVF and ICSI, have been confined to epimutations. There are a number of potential mechanisms by which ART could contribute to the creation of epimutations. The composition/culture of the media environment, disruption of maternally-imprinted genes with superovulation, hypomethylation of paternal or maternal genes, or, as with the other potential adverse outcomes perhaps incorrectly associated with ART, the underlying condition responsible for infertility, could all be associated with imprinting abnormalities.17 While the association between imprinting and ART has biological plausibility and strong data from animal and human species, the overall risk for a child to be born with an imprinting defect following ART is low. The probable increased imprinting-associated ART risks are related to the phenotypes Silver-Russell syndrome and BeckwithWiedemann syndrome, with less evidence ing the association with Angelman syndrome and Prader-Willi syndrome. Studies have proposed that ART children are at a greater risk of later malignancy, with a possible etiology of reduced imprinted gene activity leading to dysregulation in tumour suppression.168 Large follow-up studies suggest an increased cancer risk in ART children, but other confounding factors, such as prematurity and asphyxia, may be in play.169 Further studies are required, as the majority of the ART cohort is under age 30.169 A 2009 review concluded that “epigenetic aberrations can result in outcomes as specific as Beckwith-Wiedemann syndrome or as diffuse as growth restriction.”167 Substantial evidence exists from animal and human studies that gametogenesis and preimplantation are vulnerable to epimutations. Whether ART introduces epigenetic aberrations during these critical times, or whether epimutations are more frequent in individuals with infertility, remains unresolved.167 Summary Statement

2. The relative risk for an imprinting phenotype such as Silver-Russell syndrome, Beckwith-Wiedemann syndrome, or Angelman syndrome is increased in the assisted reproduction population, but the actual risk for one of these phenotypes to occur in an assisted pregnancy is estimated to be low, at less than 1 in 5000. The exact biological etiology for this imprinting risk increase is likely heterogeneous and requires more research. (II-2)

Recommendation

12. The possible increased risk for late onset cancer due to gene dysregulation for tumour suppression requires more long-term follow-up before the true risk can be determined. (III-A) Preimplantation Genetic Screening

Recently, more ART cycles have incorporated preimplantation genetic screening for aneuploidy or random genetic error at the stage of the embryo to increase the chance of a successful live birth. The process includes the microscopic biopsy of embryos at 72 hours of age to isolate a blastomere or trophectoderm tissue at the blastocyst stage of development. Genomic analysis is then done using traditional fluorescent in situ hybridization analysis of 5 to 7 chromosomes or, more recently, whole genome analysis using comparative genomic hybridization.170,171 Indications for the application include advanced maternal age, repeated IVF failure, recurrent miscarriage, and testicular sperm extraction. The literature remains controversial with respect to the testing’s proven benefit in of a healthy live birth as an outcome and, more specifically, with respect to the well-being of that infant. A recent report of a series of 581 children born after PGS found that birth weight and major malformation rates were not statistically different from those of other IVF/ICSI children.172 The same study also reported the misdiagnosis rate was less than 1%. A further prospective blinded follow-up study of children born to women randomly assigned to receive PGS or not found that the technique was not associated with impaired mental, psychomotor, or behavioural outcomes by age 2 years, although there was a suggestion that with detailed neurological testing, PGS was associated with a less “optimal” neurological testing score.173 More recently the same group reported on the follow-up of the same cohort at 4 years of age. They found no effect of PGS on singletons in the cohort, but a significant negative difference in neurological testing scores among twins after PGS.174 Thus the effects of preimplantation genetic screening on long-term outcomes are unclear. A recently published technical update has reviewed preimplantation screening and diagnosis in more detail.175 Recommendations

13. T he clinical application of preimplantation genetic testing in fertile couples must balance the benefits of avoiding disease transmission with the medical risks and financial burden of in vitro fertilization. (III-B)

JANUARY JOGC JANVIER 2014 l 77

SOGC Clinical Practice Guidelines

14. Preimplantation screening for aneuploidy is associated with inconsistent findings for improving pregnancy outcomes. Any discussion of preimplantation genetic screening with patients should clarify that there is no adequate information on the long-term effect of embryo single cell biopsy. (I-C) SUMMARY

As with knowledge of outcomes in other emerging and developing technologies, there continue to be gaps in our knowledge of the association of AHR with maternal, perinatal, and childhood outcomes. A recent discussion paper prepared for AHRC on reproductive outcomes after AHR has emp hasized the importance of comprehensive outcomes surveillance systems that build on the current CARTR database, with personalized health information, measurable outcomes including long-term and developmental outcomes, and the ability to link to other relevant national and international databases.1 There has been an improvement in the quality of data with the accumulation and accuracy of large population databases and improved linkage of AHR parameters to birth and early childhood outcomes, but ongoing efforts in this area are critical to further specify the differential association of underlying infertility factors and details of AHR on outcomes. The majority of pregnancies resulting from AHR are uncomplicated and result in the birth of healthy children. However, it is also clear that when TTP are greater than one year, a higher proportion of AHR pregnancies than spontaneous pregnancies are associated with obstetrical and perinatal complications, whether it be a result primarily of underlying parental factors leading to infertility or of specific AHR techniques. The majority of obstetric and pediatric problems after AHR arise as a result of multiple pregnancies. Much new evidence has accumulated to encourage the use of eSET where appropriate and, when applied, this has been shown to markedly reduce the multiple pregnancy rate. Counselling of prospective parents should incorporate this knowledge. REFERENCES 1. Walker MEL. Measurement of assisted human reproduction outcomes in Canada. A discussion paper prepared for participants of the 2010 Outcomes Roundtable. Available at: http://publications.gc.ca/collections/collection_2011/pac-ahrc/ H1–9–27–2011-eng.pdf. Accessed on September 14, 2013. 2. Talaulikar VS, Arulkumaran S. Reproductive outcomes after assisted conception. Obstet Gynecol Surv 2012;67:566–83.

78 l JANUARY JOGC JANVIER 2014

3. European Society of Human Reproduction and Embryology. ART fact sheet. Available at: http://www.eshre.eu/ESHRE/English/ Guidelines-Legal/ART-fact-sheet/page.aspx/1061. Accessed on November 5, 2012. 4. Fertile future. Available at: http://fertilefuture.ca. Accessed April 15, 2012. 5. Rodriguez-Wallberg KA, Oktay K. Fertility preservation medicine: options for young adults and children with cancer. J Pediatr Hematol Oncol 2010;32:390–6. 6. Buckett W. Infertility treatment for non-traditional families. 2011. Available at: http://www.iaac.ca/en/632–613-infertility-treatmentfor-non-traditional-families-by-william-buckett-md-mrcog-fall-2011. Accessed on September 14, 2011. 7. Surrogacy in Canada online: information, referral and since 2001. Available at: http://www.surrogacy.ca. Accessed on April 15, 2012. 8. Centers for Disease Control and Prevention. ART reports and resources. 2013. Available at: http://www.cdc.gov/art/ARTReports.htm. Accessed on February 25, 2013. 9. Society for Assisted Reproductive Technology. IVF success rate reports. Available at: http://www.sart.org. Accessed on February 25, 2013. 10. New York State Department of Health Task Force on Life and Law. Executive summary of assisted reproductive technologies: analysis and recommendations for public policy. 2011. Available at: http://www.health.ny.gov/regulations/task_force/reports_publications/ execsum.htm. Accessed on February 25, 2013. 11. European Society of Human Reproduction and Embryology. Comparative analysis of medically assisted reproduction in the EU: regulation and technologies (SANCO/2008/C6/051). Final report. 2008. Available at: http://www.eshre.eu/Guidelines-and-Legal/Legislation-forMAR-treatments.aspx. Accessed on September 14, 2013. 12. Australian Government National Health and Medical Research Council. Ethical guidelines on the use of assisted reproductive technology in clinical practice and research (2007). 2007. Available at: http://www.nhmrc.gov.au/guidelines/publications/e78. Accessed on February 25, 2013. 13. Zhu JL, Obel C, Hammer Bech B, Olsen J, Basso O. Infertility, infertility treatment, and fetal growth restriction. Obstet Gynecol 2007;110:1326–34. 14. Assisted Human Reproduction Canada. Available at: http://www.hc-sc.gc.ca/dhp-mps/brgtherap/legislation/reprod/ index-eng.php. Accessed September 14, 2013. 15. Canadian Fertility and Andrology Society. ART live birth rates. Available at: http://www.cfas.ca/index.php?option=com_ content&view=article&id=260&Itemid=460. Accessed on February 25, 2013. 16. Accreditation Canada. Assisted reproductive technology standards for clinical services. Available at: http://www.accreditation.ca/en/ content.aspx?pageid=203&=assisted+reproductive. Accessed on February 25, 2013. 17. Jenkins J, Daya S, Kremer J, Balasch J, Barratt C, Cooke I, et al. European Classification of Infertility Taskforce (ECIT) response to Habbema et al., “Towards less confusing terminology in reproductive medicine: a proposal.” Human Reproduction 2004;19:2687–8. 18. Royal Commission on New Reproductive Technologies, Government of Canada. Proceed with care: final report of the Royal Commission on New Reproductive Technologies. Ottawa: Minister of Government Services Canada; 1993. 19. Lobo R, Mishell DR, Davajan V. Mishell’s textbook of infertility, contraception, and reproductive endocrinology. Philadelphia: Mosby Elsevier; 1997. 20. Joffe M, Li Z. Association of time to pregnancy and the outcome of pregnancy. Fertil Steril 1994;62:71–5.

Pregnancy Outcomes After Assisted Human Reproduction

21. Sutcliffe AG, Ludwig M. Outcome of assisted reproduction. Lancet 2007;370:351–9. 22. Reddy UM, Wapner RJ, Rebar RW, Tasca RJ. Infertility, assisted reproductive technology, and adverse pregnancy outcomes: executive summary of a National Institute of Child Health and Human Development workshop. Obstet Gynecol 2007;109:967–77. 23. Thomson F, Shanbhag S, Templeton A, Bhattacharya S. Obstetric outcome in women with subfertility. BJOG 2005;112:632–7. 24. Henriksen TB, Baird DD, Olsen J, Hedegaard M, Secher NJ, Wilcox AJ. Time to pregnancy and preterm delivery. Obstet Gynecol 1997;89:594–9. 25. Draper ES, Kurinczuk JJ, Abrams KR, Clarke M. Assessment of separate contributions to perinatal mortality of infertility history and treatment: a case-control analysis. Lancet 1999;353:1746–9.

39. Palermo GD, Neri QV, Monahan D, Kocent J, Rosenwaks Z. Development and current applications of assisted fertilization. Fertil Steril 2012;97:248–59. 40. Johnson MD. Genetic risks of intracytoplasmic sperm injection in the treatment of male infertility: recommendations for genetic counseling and screening. Fertil Steril 1998;70:397–411. 41. Rowe PJ, Comhaire FH, Hargreave TB, Mahmoud AMA; World Health Organization. WHO manual for the standardized investigation, diagnosis and management of the infertile male. Cambridge: Cambridge University Press; 2000. 42. Shi Q, Martin RH. Aneuploidy in human spermatozoa: FISH analysis in men with constitutional chromosomal abnormalities, and in infertile men. Reproduction 2001;121:655–66.

26. Basso O, Baird DD. Infertility and preterm delivery, birthweight, and Caesarean section: a study within the Danish National Birth Cohort. Hum Reprod 2003;18:2478–84.

43. Bareil C, Guittard C, Altieri JP, Templin C, Claustres M, des Georges M. Comprehensive and rapid genotyping of mutations and haplotypes in congenital bilateral absence of the vas deferens and other cystic fibrosis transmembrane conductance regulator-related disorders. J Mol Diagnos 2007;9:582–8.

27. Basso O, Olsen J. Subfecundity and neonatal mortality: longitudinal study within the Danish national birth cohort. BMJ 2005;330:393–4.

44. Walsh TJ, Pera RR, Turek PJ. The genetics of male infertility. Semin Reprod Med 2009;27:124–36.

28. Zhu JL, Basso O, Obel C, Bille C, Olsen J. Infertility, infertility treatment, and congenital malformations: Danish national birth cohort. BMJ 2006;333:679.

45. Schlegel PN. Testicular sperm extraction: microdissection improves sperm yield with minimal tissue excision. Hum Reprod 1999;14:131–5.

29. Jaques AM, Amor DJ, Baker HW, Healy DL, Ukoumunne OC, Breheny S, et al. Adverse obstetric and perinatal outcomes in subfertile women conceiving without assisted reproductive technologies. Fertil Steril 2010;94:2674–9. 30. Raatikainen K, Kuivasaari-Pirinen P, Hippelainen M, Heinonen S. Comparison of the pregnancy outcomes of subfertile women after infertility treatment and in naturally conceived pregnancies. Hum Reprod 2012;27:1162–9. 31. Romundstad LB, Romundstad PR, Sunde A, Von Düring V, Skjaerven R, Gunnell D, et al. Effects of technology or maternal factors on perinatal outcome after assisted fertilisation: a population-based cohort study. Lancet 2008;372:737–43. 32. Johnson JA, Tough S; SOGC Genetics Committee. Delayed child-bearing. Society of Obstetricians and Gynaecologist of Canada Committee Opinion, No. 271, January 2012. J Obstet Gynaecol Can 2012;34:80–93.

46. Kahraman S, Ozgür S, Alataş C, Aksoy S, Balaban B, Evrenkaya T, et al. High implantation and pregnancy rates with testicular sperm extraction and intracytoplasmic sperm injection in obstructive and non-obstructive azoospermia. Hum Reprod 1996;11:673–6. 47. Harnisch B, Oates R. Genetic disorders related to male factor infertility and their adverse consequences. Semin Reprod Med 2012;30:105–15. 48. Blondel B, Kaminski M. Trends in the occurrence, determinants, and consequences of multiple births. Semin Perinatol 2002;26:239–49. 49. Liu S, Allen A, Fraser W. Preterm birth rate. In: Canadian Perinatal Health Report; 2008. Ottawa: Minister of Public Works and Government Services; 2008. pp. 123–6. 50. Fa BC, Devroey P, Macklon NS. Multiple birth resulting from ovarian stimulation for subfertility treatment. Lancet 2005;365:1807–16. 51. Gunby J, Bissonnette F, Librach C, Cowan L. Assisted reproductive technologies (ART) in Canada: 2007 results from the Canadian ART . Fertil Steril 2011;95:542–7. e541–e510.

33. Maheshwari A, Stofberg L, Bhattacharya S. Effect of overweight and obesity on assisted reproductive technology—a systematic review. Hum Reprod Update 2007;13:433–44.

52. Blickstein I. Estimation of iatrogenic monozygotic twinning rate following assisted reproduction: pitfalls and caveats. Am J Obstet Gynecol 2005;192:365–8.

34. Bellver J, Ayllon Y, Ferrando M, Melo M, Goyri E, Pellicer A, et al. Female obesity impairs in vitro fertilization outcome without affecting embryo quality. Fertil Steril 2010;93:447–54.

53. Vela G, Luna M, Barritt J, Sandler B, Copperman AB. Monozygotic pregnancies conceived by in vitro fertilization: understanding their prognosis. Fertil Steril 2011;95:606–10.

35. Metwally M, Tuckerman EM, Laird SM, Ledger WL, Li TC. Impact of high body mass index on endometrial morphology and function in the peri-implantation period in women with recurrent miscarriage. Reprod Biomed Online 2007;14:328–334.

54. Vitthala S, Gelbaya TA, Brison DR, Fitzgerald CT, Nardo LG. The risk of monozygotic twins after assisted reproductive technology: a systematic review and meta-analysis. Hum Reprod Update 2009;1545–55.

36. Metwally M, Cutting R, Tipton A, Skull J, Ledger WL, Li TC. Effect of increased body mass index on oocyte and embryo quality in IVF patients. Reprod Biomed Online 2007;15(5):532–5.

55. Milki AA, Jun SH, Hinckley MD, Behr B, Giudice LC, Westphal LM. Incidence of monozygotic twinning with blastocyst transfer compared to cleavage-stage transfer. Fertil Steril 2003;79:503–6.

37. Gibbons WE, Cedars M, Ness RB. Toward understanding obstetrical outcome in advanced assisted reproduction: varying sperm, oocyte, and uterine source and diagnosis. Fertil Steril 2011;95:1645–9 e1641.

56. Alexander GR, Slay Wingate M, Salihu H, Kirby RS. Fetal and neonatal mortality risks of multiple births. Obstet Gynecol Clin North Am 2005;32:1–16. vii.

38. Davies GA, Maxwell C, McLeod L; SOGC Maternal Fetal Medicine Committee; SOGC Clinical Practice Obstetrics. Obesity in pregnancy. Society of Obstetricians and Gynaecologists of Canada Clinical Practice Guideline, No. 239, February 2010. J Obstet Gynaecol Can 2010;32:165–73.

57. Pharoah PO. Risk of cerebral palsy in multiple pregnancies. Clin Perinatol 2006;33:301–13. 58. Salihu HM, Aliyu MH, Rouse DJ, Kirby RS, Alexander GR. Potentially preventable excess mortality among higher-order multiples. Obstet Gynecol 2003;102:679–84.

JANUARY JOGC JANVIER 2014 l 79

SOGC Clinical Practice Guidelines

59. Janvier A, Spelke B, Barrington KJ. The epidemic of multiple gestations and neonatal intensive care unit use: the cost of irresponsibility. J Pediatr 2011;159:409–13. 60. Garg P, Abdel-Latif ME, Bolisetty S, Bajuk B, Vincent T, Lui K. Perinatal characteristics and outcome of preterm singleton, twin and triplet infants in NSW and the ACT, Australia (1994–2005). Arch Dis Child Fetal Neonatal Ed 2010;95:F20-F24. 61. Nassar AH, Usta IM, Rechdan JB, Harb TS, Adra AM, Abu-Musa AA. Pregnancy outcome in spontaneous twins versus twins who were conceived through in vitro fertilization. Am J Obstet Gynecol 2003;189:513–8. 62. Luke B, Brown MB, Nugent C, Gonzalez-Quintero VH, Witter FR, Newman RB. Risk factors for adverse outcomes in spontaneous versus assisted conception twin pregnancies. Fertil Steril 2004;81:315–9. 63. Smithers PR, Halliday J, Hale L, Talbot JM, Breheny S, Healy D. High frequency of cesarean section, antepartum hemorrhage, placenta previa, and preterm delivery in in-vitro fertilization twin pregnancies. Fertil Steril 2003;80:666–8. 64. Verstraelen H, Goetgeluk S, Derom C, Vansteelandt S, Derom R, Goetghebeur E, et al. Preterm birth in twins after subfertility treatment: population based cohort study. BMJ 2005;331:1173. 65. Delbaere I, Goetgeluk S, Derom C, De Bacquer D, De Sutter P, Temmerman M. Umbilical cord anomalies are more frequent in twins after assisted reproduction. Hum Reprod 2007;22:2763–7. 66. Morcel K, Lavoue V, Beuchee A, Le Lannou D, Poulain P, Pladys P. Perinatal morbidity and mortality in twin pregnancies with dichorionic placentas following assisted reproductive techniques or ovarian induction alone: a comparative study. Eur J Obstet Gynecol Reprod Biol 2010;153:138–42. 67. Vasario E, Borgarello V, Bossotti C, Libanori E, Biolcati M, Arduino S, et al. IVF twins have similar obstetric and neonatal outcome as spontaneously conceived twins: a prospective follow-up study. Reprod Biomed Online 2010;21:422–8. 68. Helmerhorst FM, Perquin DA, Donker D, Keirse MJ. Perinatal outcome of singletons and twins after assisted conception: a systematic review of controlled studies. BMJ 2004;328:261. 69. McDonald S, Murphy K, Beyene J, Ohlsson A. Perinatal outcomes of in vitro fertilization twins: a systematic review and meta-analyses. Am J Obstet Gynecol 2005;193:141–52. 70. Joy J, McClure N, Cooke IE. A comparison of spontaneously conceived twins and twins conceived by artificial reproductive technologies. J Obstet Gynaecol 2008;28:580–5. 71. Thomopoulos C, Tsioufis C, Michalopoulou H, Makris T, Papademetriou V, Stefanadis C. Assisted reproductive technology and pregnancy-related hypertensive complications: a systematic review. J Hum Hypertens 2013;27:148–57. 72. Ombelet W, De Sutter P, Van der Elst J, Martens G. Multiple gestation and infertility treatment: registration, reflection and reaction—the Belgian project. Hum Reprod Update 2005;11:3–14. 73. Garel M, Blondel B. Assessment at 1 year of the psychological consequences of having triplets. Hum Reprod 1992;7:729–32. 74. Garel M, Salobir C, Blondel B. Psychological consequences of having triplets: a 4-year follow-up study. Fertil Steril 1997;67:1162–5. 75. Chambers GM, Chapman MG, Grayson N, Shanahan M, Sullivan EA. Babies born after ART treatment cost more than non-ART babies: a cost analysis of inpatient birth-ission costs of singleton and multiple gestation pregnancies. Hum Reprod 2007;22:3108–15. 76. Vilska S, Unkila-Kallio L, Punamäki RL, Poikkeus P, Repokari L, Sinkkonen J, et al. Mental health of mothers and fathers of twins conceived via assisted reproduction treatment: a 1-year prospective study. Hum Reprod 2009;24:367–7.

80 l JANUARY JOGC JANVIER 2014

77. Evans MI, Berkowitz RL, Wapner RJ, Carpenter RJ, Goldberg JD, Ayoub MA, et al. Improvement in outcomes of multifetal pregnancy reduction with increased experience. Am J Obstet Gynecol 2001;184:97–103. 78. Collopy KS. “I couldn’t think that far”: infertile women’s decision making about multifetal reduction. Res Nurs Health 2004;27:75–86. 79. Bergh C, Moller A, Nilsson L, Wikland M. Obstetric outcome and psychological follow-up of pregnancies after embryo reduction. Hum Reprod 1999;14:2170–5. 80. Schreiner-Engel P, Walther VN, Mindes J, Lynch L, Berkowitz RL. First-trimester multifetal pregnancy reduction: acute and persistent psychologic reactions. Am J Obstet Gynecol 1995;172(2 Pt 1):541–7. 81. Stone J, Ferrara L, Kamrath J, Getrajdman J, Berkowitz R, Moshier E, et al. Contemporary outcomes with the latest 1000 cases of multifetal pregnancy reduction (MPR). Am J Obstet Gynecol 2008;199:406. e401–e404. 82. Skiadas CC, Missmer SA, Benson CB, Acker D, Racowsky C. Spontaneous reduction before 12 weeks’ gestation and selective reduction similarly extend time to delivery in in vitro fertilization of trichorionic-triamniotic triplets. Fertil Steril 2011;95:596–9. 83. Cheang CU, Huang LS, Lee TH, Liu CH, Shih YT, Lee MS. A comparison of the outcomes between twin and reduced twin pregnancies produced through assisted reproduction. Fertil Steril 2007;88:47–52. 84. Pandian Z, Bhattacharya S, Ozturk O, Serour G, Templeton A. Number of embryos for transfer following in-vitro fertilisation or intra-cytoplasmic sperm injection. Cochrane Database Syst Rev. 2009(2):CD003416. 85. Grady R, Alavi N, Vale R, Khandwala M, McDonald SD. Elective single embryo transfer and perinatal outcomes: a systematic review and metaanalysis. Fertil Steril 2012;97:324–331. 86. Lawlor DA, Nelson SM. Effect of age on decisions about the numbers of embryos to transfer in assisted conception: a prospective study. Lancet 2012;379:521–7. 87. Scotland GS, McLernon D, Kurinczuk JJ, McNamee P, Harrild K, Lyall H, et al. Minimising twins in in vitro fertilisation: a modelling study assessing the costs, consequences and cost-utility of elective single versus double embryo transfer over a 20-year time horizon. BJOG 2011;118:1073–83. 88. van Heesch MM, Bonsel GJ, Dumoulin JC, Evers JL, van der Hoeven MA, Severens JL, et al. Long term costs and effects of reducing the number of twin pregnancies in IVF by single embryo transfer: the TwinSing study. BMC Pediatr 2010;10:75. 89. European Society of Human Reproduction and Embryology. Good clinical treatment in assisted reproduction. An ESHRE position paper. Available at: http://www.eshre.eu/~/media/emagic%20files/ Guidelines/Position%20Papers/GCT%20in%20ART.pdf. Accessed on February 27, 2013. 90. Association of Clinical Embryologists, Bliss, British Fertility Society, British Infertility Counselling Association, Donor Conception Network, Endometriosis UK, et al. Multiple births from fertility treatment in the UK: a consensus statement. Hum Fertil (Camb) 2011;14:151–3. 91. Practice Committee of Society for Assisted Reproductive Technology, Practice Committee of American Society for Reproductive Medicine. Elective single-embryo transfer. Fertil Steril 2012;97:835–42. 92. Min JK, Hughes E, Young D, Gysler M, Hemmings R, Cheung AP, et al; t SOGC-CFAS Clinical Practice Guidelines Committee. Elective single embryo transfer following in vitro fertilization. Society of Obstetricians and Gynaecologists Canada Clinical Practice Guideline, No. 241, April 2010. J Obstet Gynaecol Can 2010;32:363–77. 93. t SOGC-CFAS. Guidelines for the number of embryos to transfer following in vitro fertilization No. 182, September 2006. Int J Gynaecol Obstet 2008;102:203–16.

Pregnancy Outcomes After Assisted Human Reproduction

94. Centers for Disease Control and Prevention. 2010 Assisted reproductive technology national summary report. Available at: http://www.cdc.gov/art/ART2010/NationalSummary_index.htm. Accessed on September 15, 2013. 95. Human Fertilisation & Embryology Authority. Fertility treatment in 2011: trends and figures. 2011. Available at: http://www.hfea.gov.uk/docs/ HFEA_Fertility_Trends_and_Figures_2011_-_Annual__ Report.pdf. Accessed on September 15, 2013. 96. Raising expectations: recommendations of the expert on infertility and adoption. 2009. Available at http://www.children.gov.on.ca/htdocs/ english/documents/infertility/RaisingExpectationsEnglish.pdf. Accessed on September 15, 2013. 97. Bissonnette F, Phillips SJ, Gunby J, Holzer H, Mahutte N, St-Michel P, et al. Working to eliminate multiple pregnancies: a success story in Quebec. Reprod Biomed Online 2011;23:500–4. 98. Bissonnette F. The first 6 months of IVF funding-Quebec. Available at: http://www.cfas.ca/index.php?option=com_content&view=article&id= 1123%3Afirst6-qc-en&catid=1014%3Aquebec&Itemid=691. Accessed on May 8, 2012. 99. Diamond MP, Singh M. Use of gonadotropins for initiation of singleton gestations in non-assisted reproductive technology cycles. Fertil Steril 2012;97:810–2. 100. Practice Committee of American Society for Reproductive Medicine. Multiple gestation associated with infertility therapy: an American Society for Reproductive Medicine Practice Committee opinion. Fertil Steril 2012:825–34. 101. Branum AM, Schoendorf KC. Changing patterns of low birthweight and preterm birth in the United States, 1981–98. Paediatr Perinat Epidemiol 2002;16:8–15. 102. Welmerink DB, Voigt LF, Daling JR, Mueller BA. Infertility treatment use in relation to selected adverse birth outcomes. Fertil Steril 2010;94:2580–6. 103. Government of the United Kingdom. Fertility treatment in 2010— trends and figures by the Human Fertilisation and Embryology Authority. 2010. Available at: http://data.gov.uk/dataset/human-fertilisationand-embryology-authority-fertility-treatment-2010-data. Accessed on September 15, 2013. 104. McGovern PG, Llorens AJ, Skurnick JH, Weiss G, Goldsmith LT. Increased risk of preterm birth in singleton pregnancies resulting from in vitro fertilization-embryo transfer or gamete intrafallopian transfer: a meta-analysis. Fertil Steril 2004;82:1514–20. 105. Jackson RA, Gibson KA, Wu YW, Croughan MS. Perinatal outcomes in singletons following in vitro fertilization: a meta-analysis. Obstet Gynecol 2004;103:551–63. 106. McDonald SD, Murphy K, Beyene J, Ohlsson A. Perinatal outcomes of singleton pregnancies achieved by in vitro fertilization: a systematic review and meta-analysis. J Obstet Gynaecol Can 2005;27(5):449–59. 107. McDonald SD, Han Z, Mulla S, Murphy KE, Beyene J, Ohlsson A. Preterm birth and low birth weight among in vitro fertilization singletons: a systematic review and meta-analyses. Eur J Obstet Gynecol Reprod Biol 2009;146:138–8. 108. Klemetti R, Sevon T, Gissler M, Hemminki E. Health of children born as a result of in vitro fertilization. Pediatrics 2006;118:1819–27. 109. Kapiteijn K de Bruijn CS, de Boer E, de Craen AJ, Burger CW, van Leeuwen FE, et al. Does subfertility explain the risk of poor perinatal outcome after IVF and ovarian hyperstimulation? Hum Reprod 2006;21:3228–34. 110. D’Angelo DV, Whitehead N, Helms K, Barfield W, Ahluwalia IB. Birth outcomes of intended pregnancies among women who used assisted reproductive technology, ovulation stimulation, or no treatment. Fertil Steril 2011;96:314–20.e2.

111. Klemetti R, Sevon T, Gissler M, Hemminki E. Health of children born after ovulation induction. Fertil Steril 2010;93:1157–68. 112. Phillips DP, Talaulikar D, Hawkins CA, Hickman PE. Utilisation of sFLC assays—how well do we comply with guidelines? Int J Lab Hematol 2012; 35:200–10. 113. Sazonova A, Kallen K, Thurin-Kjellberg A, Wennerholm UB, Bergh C. Factors affecting obstetric outcome of singletons born after IVF. Hum Reprod 2011;26:2878–86. 114. Belva F, Henriet S, Van den Abbeel E, Camus M, Devroey P, Van der Elst J, et al. Neonatal outcome of 937 children born after transfer of cryopreserved embryos obtained by ICSI and IVF and comparison with outcome data of fresh ICSI and IVF cycles. Hum Reprod 2008;23:2227–38. 115. Pinborg A, Loft A, Aaris Henningsen AK, Rasmussen S, Andersen AN. Infant outcome of 957 singletons born after frozen embryo replacement: the Danish National Cohort Study 1995–2006. Fertil Steril 2010;94:1320–7. 116. Pelkonen S, Koivunen R, Gissler M, Nuojua-Huttunen S, Suikkari AM, Hydén-Granskog C, et al. Perinatal outcome of children born after frozen and fresh embryo transfer: the Finnish cohort study 1995–2006. Hum Reprod 2010;25:914–23. 117. Shih W, Rushford DD, Bourne H, Garrett C, McBain JC, Healy DL, et al. Factors affecting low birthweight after assisted reproduction technology: difference between transfer of fresh and cryopreserved embryos suggests an adverse effect of oocyte collection. Hum Reprod 2008;23:1644–53. 118. Wennerholm UB, Söderström-Anttila V, Bergh C, Aittomäki K, Hazekamp J, Nygren KG, et al. Children born after cryopreservation of embryos or oocytes: a systematic review of outcome data. Hum Reprod 2009;24:2158–72. 119. Kalra SK, Ratcliffe SJ, Coutifaris C, Molinaro T, Barnhart KT. Ovarian stimulation and low birth weight in newborns conceived through in vitro fertilization. Obstet Gynecol 2011;118:863–71. 120. Henningsen AK, Pinborg A, Lidegaard O, Vestergaard C, Forman JL, Andersen AN. Perinatal outcome of singleton siblings born after assisted reproductive technology and spontaneous conception: Danish national sibling-cohort study. Fertil Steril 2011;95:959–63. 121. Nakashima A, Araki R, Tani H, Ishihara O, Kuwahara A, Irahara M, et al. Implications of assisted reproductive technologies on term singleton birth weight: an analysis of 25,777 children in the national assisted reproduction registry of Japan. Fertil Steril 2013;99:450–5. 122. Griesinger G, Kolibianakis EM, Diedrich K, Ludwig M. Ovarian stimulation for IVF has no quantitative association with birthweight: a registry study. Hum Reprod 2008;23:2549–54. 123. Imudia AN, Awonuga AO, Doyle JO, Kaimal AJ, Wright DL, Toth TL, et al. Peak serum estradiol level during controlled ovarian hyperstimulation is associated with increased risk of small for gestational age and preeclampsia in singleton pregnancies after in vitro fertilization. Fertil Steril 2012;97:1374–9. 124. Agarwal P, Loh SK, Lim SB, Sriram B, Daniel ML, Yeo SH, et al. Two-year neurodevelopmental outcome in children conceived by intracytoplasmic sperm injection: prospective cohort study. BJOG 2005;112:1376–83. 125. Ludwig A, Katalinic A, Thyen U, Sutcliffe AG, Diedrich K, Ludwig M. Neuromotor development and mental health at 5.5 years of age of singletons born at term after intracytoplasmatic sperm injection ICSI: results of a prospective controlled single-blinded study in . Fertil Steril 2009;91:125–32. 126. Knoester M, Helmerhorst FM, Vandenbroucke JP, van der Westerlaken LA, Walther FJ, Veen S; Leiden Artificial Reproductive Techniques Follow-up Project (L-art-FUP). Perinatal outcome, health, growth, and medical care utilization of 5- to 8-year-old intracytoplasmic sperm injection singletons. Fertil Steril 2008;89:1133–46.

JANUARY JOGC JANVIER 2014 l 81

SOGC Clinical Practice Guidelines

127. Buckett WM, Chian RC, Holzer H, Dean N, Usher R, Tan SL. Obstetric outcomes and congenital abnormalities after in vitro maturation, in vitro fertilization, and intracytoplasmic sperm injection. Obstet Gynecol 2007;110:885–91.

145. Ludwig AK, Katalinic A, Thyen U, Sutcliffe AG, Diedrich K, Ludwig M. Physical health at 5.5 years of age of term-born singletons after intracytoplasmic sperm injection: results of a prospective, controlled, single-blinded study. Fertil Steril 2009;91:115–24.

128. Belva F, De Schrijver F, Tournaye H, Liebaers I, Devroey P, Haentjens P, et al. Neonatal outcome of 724 children born after ICSI using nonejaculated sperm. Hum Reprod 2011;26:1752–8.

146. Brinton LA, Krüger Kjaer S, Thomsen BL, Sharif HF, Graubard BI, Olsen JH, et al. Childhood tumor risk after treatment with ovulationstimulating drugs. Fertil Steril 2004;81:1083–91.

129. Tsai CC, Huang FJ, Wang LJ, Lin YJ, Kung FT, Hsieh CH, et al. Clinical outcomes and development of children born after intracytoplasmic sperm injection (ICSI) using extracted testicular sperm or ejaculated extreme severe oligo-astheno-teratozoospermia sperm: a comparative study. Fertil Steril 2011;96:567–71.

147. Schieve LA, Rasmussen SA, Buck GM, Schendel DE, Reynolds MA, Wright VC. Are children born after assisted reproductive technology at increased risk for adverse health outcomes? Obstet Gynecol 2004;103:1154–63.

130. Klatsky PC, Delaney SS, Caughey AB, Tran ND, Schattman GL, Rosenwaks Z. The role of embryonic origin in preeclampsia: a comparison of autologous in vitro fertilization and ovum donor pregnancies. Obstet Gynecol 2010;116:1387–92. 131. Gjerris AC, Loft A, Pinborg A, Christiansen M, Tabor A. First-trimester screening markers are altered in pregnancies conceived after IVF/ICSI. Ultrasound Obstet Gynecol 2009;33:8–17. 132. Weisz B, Rodeck CH. An update on antenatal screening for Down’s syndrome and specific implications for assisted reproduction pregnancies. Hum Reprod Update 2006;12:513–8. 133. Calhoun KC, Barnhart KT, Elovitz MA, Srinivas SK. Evaluating the association between assisted conception and the severity of preeclampsia. ISRN Obstet Gynecol 2011;2011:928592. doi: 10.5402/2011/928592. 134. Sun LM, Walker MC, Cao HL, Yang QY, Duan T, Kingdom J. Assisted reproductive technology and placenta-mediated adverse pregnancy outcomes. Obstet Gynecol 2009;114:818–24. 135. Chen XK, Wen SW, Bottomley J, Smith GN, Leader A, Walker MC. In vitro fertilization is associated with an increased risk for preeclampsia. Hypertens Pregnancy 2009;28:1–12. 136. Wiggins DA, Main E. Outcomes of pregnancies achieved by donor egg in vitro fertilization—a comparison with standard in vitro fertilization pregnancies. Am J Obstet Gynecol 2005;192:2002–6. 137. Esh-Broder E, Ariel I, Abas-Bashir N, Bdolah Y, Celnikier DH. Placenta accreta is associated with IVF pregnancies: a retrospective chart review. BJOG 2011;118:1084–9. 138. Healy DL, Breheny S, Halliday J, Jaques A, Rushford D, Garrett C, et al. Prevalence and risk factors for obstetric haemorrhage in 6730 singleton births after assisted reproductive technology in Victoria Australia. Hum Reprod 2010;25:265–74. 139. Ross LE, McQueen K, Vigod S, Dennis CL. Risk for postpartum depression associated with assisted reproductive technologies and multiple births: a systematic review. Hum Reprod Update 2011;17:96–106. 140. Blake DA, Farquhar CM, Johnson N, Proctor M. Cleavage stage versus blastocyst stage embryo transfer in assisted conception. Cochrane Database Syst Rev 2007(4):CD002118. 141. Chang HJ, Lee JR, Jee BC, Suh CS, Kim SH. Impact of blastocyst transfer on offspring sex ratio and the monozygotic twinning rate: a systematic review and meta-analysis. Fertil Steril 2009;91:2381–90. 142. Kallen B, Finnstrom O, Lindam A, Nilsson E, Nygren KG, Olausson PO. Blastocyst versus cleavage stage transfer in in vitro fertilization: differences in neonatal outcome? Fertil Steril 2010;94:1680–3. 143. Ponjaert-Kristoffersen I, Tjus T, Nekkebroeck J, Squires J, Verté D, Heimann M, et al. Psychological follow-up study of 5-year-old ICSI children. Hum Reprod 2004;19:2791–7. 144. Leunens L, Celestin-Westreich S, Bonduelle M, Liebaers I, Ponjaert-Kristoffersen I. Follow-up of cognitive and motor development of 10-year-old singleton children born after ICSI compared with spontaneously conceived children. Hum Reprod 2008;23:105–11.

82 l JANUARY JOGC JANVIER 2014

148. Ericson A, Kallen BA. Nonsteroidal anti-inflammatory drugs in early pregnancy. Reprod Toxicol 2001;15:371–5. 149. Wennerholm UB, Bergh C, Hamberger L, Lundin K, Nilsson L, Wikland M, et al. Incidence of congenital malformations in children born after ICSI. Hum Reprod 2000;15:944–8. 150. Reefhuis J, Honein MA, Schieve LA, Correa A, Hobbs CA, Rasmussen SA. Assisted reproductive technology and major structural birth defects in the United States. Hum Reprod 2009;24:360–6. 151. Wen SW, Leader A, White RR, Léveillé MC, Wilkie V, Zhou J, et al. A comprehensive assessment of outcomes in pregnancies conceived by in vitro fertilization/intracytoplasmic sperm injection. Eur J Obstet Gynecol Reprod Biol 2010;150:160–5. 152. Hansen M, Kurinczuk JJ, Bower C, Webb S. The risk of major birth defects after intracytoplasmic sperm injection and in vitro fertilization. N Engl J Med 2002;346:725–30. 153. Katalinic A, Rösch C, Ludwig M; German ICSI Follow-Up Study Group. Pregnancy course and outcome after intracytoplasmic sperm injection: a controlled, prospective cohort study. Fertil Steril 2004;81:1604–16. 154. Chen T, McDonald A, Shadbolt B, Talaulikar D. Precision of histological bone marrow staging in follicular lymphoma and diffuse large B-cell lymphoma. Clin Invest Med 2012;35:E358. 155. Bonduelle M, Van Assche E, Joris H, Keymolen K, Devroey P, Van Steirteghem A, et al. Prenatal testing in ICSI pregnancies: incidence of chromosomal anomalies in 1586 karyotypes and relation to sperm parameters. Hum Reprod 2002;17:2600–14. 156. Feng C, Wang LQ, Dong MY, Huang HF. Assisted reproductive technology may increase clinical mutation detection in male offspring. Fertil Steril 2008;90:92–6. 157. Chitayat D, Langlois S, Wilson RD; SOGC Genetics Committee; CCMG Prenatal Diagnosis Committee. Prenatal screening for fetal aneuploidy in singleton pregnancies. Society of Obstetricians and Gynaecologists of Canada Clinical Practice Guideline, No. 261, July 2011. J Obstet Gynaecol Can 2011;33:736–50. 158. Ranta JK, Raatikainen K, Romppanen J, Pulkki K, Heinonen S. Increased time-to-pregnancy and first trimester Down’s syndrome screening. Hum Reprod 2010;25:412–7. 159. Amor DJ, Xu JX, Halliday JL, Francis I, Healy DL, Breheny S, et al. Pregnancies conceived using assisted reproductive technologies (ART) have low levels of pregnancy-associated plasma protein-A (PAPP-A) leading to a high rate of false-positive results in first trimester screening for Down syndrome. Hum Reprod 2009;24:1330–8. 160. Shulman LP, Phillips OP, Cervetti TA. Maternal serum analyte levels after first-trimester multifetal pregnancy reduction. Am J Obstet Gynecol 1996;174:1072–4. 161. Shulman A, Maymon R. Mid-gestation Down syndrome screening test and pregnancy outcome among unstimulated assisted-conception pregnancies. Prenat Diagn 2003;23:625–8.

Pregnancy Outcomes After Assisted Human Reproduction

162. Steptoe PC, Edwards RG. Birth after the reimplantation of a human embryo. Lancet 1978;2:366. 163. Zeilmaker GH, Alberda AT, van Gent I, Rijkmans CM, Drogendijk AC. Two pregnancies following transfer of intact frozen-thawed embryos. Fertil Steril 1984;42:293–6. 164. Palermo G, Joris H, Devroey P, Van Steirteghem AC. Pregnancies after intracytoplasmic injection of single spermatozoon into an oocyte. Lancet 1992;340:17–8. 165. Ishida M, Moore GE. The role of imprinted genes in humans. Mol Aspects Med 2013;34:826–40. 166. Iliadou AN, Janson PC, Cnattingius S. Epigenetics and assisted reproductive technology. J Intern Med 2011;270:414–20.

171. Fiorentino F, Spizzichino L, Bono S, Biricik A, Kokkali G, Rienzi L, et al. PGD for reciprocal and Robertsonian translocations using array comparative genomic hybridization. Hum Reprod 2011;26:1925–35. 172. Liebaers I, Desmyttere S, Verpoest W, De Rycke M, Staessen C, Sermon K, et al. Report on a consecutive series of 581 children born after blastomere biopsy for preimplantation genetic diagnosis. Hum Reprod 2010;25:275–82. 173. Middelburg KJ, van der Heide M, Houtzager B, Jongbloed-Pereboom M, Fidler V, Bos AF, et al. Mental, psychomotor, neurologic, and behavioral outcomes of 2-year-old children born after preimplantation genetic screening: follow-up of a randomized controlled trial. Fertil Steril 2011;96:165–9.

168. Lim DH, Maher ER. Genomic imprinting syndromes and cancer. Adv Genet 2010;70:145–75.

174. Schendelaar P, Middelburg KJ, Bos AF, Heineman MJ, Kok JH, La Bastide-Van Gemert S, et al. The effect of preimplantation genetic screening on neurological, cognitive and behavioural development in 4-year-old children: follow-up of a RCT. Hum Reprod 2013;28:1508–18.

169. Savage T, Peek J, Hofman PL, Cutfield WS. Childhood outcomes of assisted reproductive technology. Hum Reprod 2011;26:2392–400.

175. Audibert F; SOGC Genetics Committee. Preimplantation genetic testing. Society of Obstetricians and Gynaecologists Canada, Technical Update No. 232, August 2009. J Obstet Gynaecol Can 2009;31:761–75.

170. Colls P, Escudero T, Fischer J, Cekleniak NA, Ben-Ozer S, Meyer B, et al. Validation of array comparative genome hybridization for diagnosis of translocations in preimplantation human embryos. Reprod Biomed Online 2012;24:621–9.

176. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

167. Wilkins-Haug L. Epigenetics and assisted reproduction. Curr Opin Obstet Gynecol 2009;21:201–6.

JANUARY JOGC JANVIER 2014 l 83

SOGC CLINICAL PRACTICE GUIDELINE No. 309, July 2014 (Replaces No. 123, February 2003)

Prenatal Invasive Procedures in Women With Hepatitis B, Hepatitis C, and/or Human Immunodeficiency Virus Infections This guideline has been prepared by the Genetics Committee, reviewed by the Infectious Disease Committee, and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS

Abstract Objective: To review the risk of in utero infection through prenatal invasive procedures in women with hepatitis B, hepatitis C, and/or human immunodeficiency virus (HIV) infections. Outcomes: Fetal and neonatal morbidity and mortality.

Jo-Ann Brock, MD, Halifax NS

Evidence: Published literature was retrieved through searches of Medline, CINAHL, and the Cochrane Library using appropriate controlled vocabulary (amniocentesis, chorionic villus sampling, cordocentesis, fetal and neonatal infection) and key words (hepatitis B, hepatitis C, HIV). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies from 2002 to 2012 published in English or French. (Studies from 1966 to 2002 were previously reviewed in Clinical Practice Guideline No. 123.) Searches were updated on a regular basis and incorporated in the guideline to February 2014.

Carla Campagnolo, MSc, CCGC, London ON



Alain Gagnon, MD, FRCSC, Vancouver BC Gregory Davies, MD, FRCSC, Kingston ON R. Douglas Wilson, MD, FRCSC, Calgary AB GENETICS COMMITTEE R. Douglas Wilson (Chair), MD, Calgary AB Francois Audibert, MD, Montreal QC

June Carroll, MD, Toronto ON David Chitayat, MD, Toronto ON Alain Gagnon, MD, Vancouver BC Jo-Ann Johnson, MD, Calgary AB William MacDonald, MD, Halifax NS Lynn Murphy-Kaulbeck, MD, Moncton NB Nanette Okun, MD, Toronto ON Melanie Pastuck, RN, Cochrane AB Disclosure statements have been received from all contributors.

Key Words: Pregnancy, genetics, amniocentesis, chorionic villus sampling, viral hepatitis, human immunodeficiency virus, prenatal diagnosis

Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies.

Values: The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table). Recommendations 1. For women infected with hepatitis B, hepatitis C, and/or human immunodeficiency virus, the use of non-invasive methods of prenatal risk assessment is recommended, using tests with high sensitivity and low false-positive rates, such as serum screening combined (or not) with nuchal translucency, anatomic ultrasound, and non-invasive molecular prenatal testing. (III-B)

J Obstet Gynaecol Can 2014;36(7):648–653

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

648 l JULY JOGC JUILLET 2014

Prenatal Invasive Procedures in Women With Hepatitis B, Hepatitis C, and/or Human Immunodeficiency Virus Infections

Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.35 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care.35

2. For women infected with hepatitis B, hepatitis C, and/or human immunodeficiency virus undergoing an amniocentesis, every effort should be made to avoid inserting the needle through, or very close to, the placenta. (II-2B) 3. Little information is available on other prenatal diagnostic and therapeutic invasive procedures; the risks and benefits of such procedures should therefore be assessed prior to their use. (III-C) 4. The rate of neonatal hepatitis B infection attributable to amniocentesis ranges up to 1.4% in newborns of mothers positive for hepatitis B surface antigen. However, the rate of neonatal infection attributable to amniocentesis in newborns of mothers with a positive hepatitis B e antigen status may be as high as 16%. Although there is no statistically significant difference between the rates of infection in newborns exposed to amniocentesis or not exposed to amniocentesis in these two maternal populations, knowledge of the mother’s hepatitis B e antigen status may be valuable in counselling women about the risks associated with amniocentesis. (II-2A) 5. Amniocentesis in women infected with hepatitis C does not appear to significantly increase the risk of vertical transmission, but women should be counselled that very few studies have properly addressed this possibility (II-2C). More research on this topic is recommended. (III-L) 6. Amniocentesis in women infected with human immunodeficiency virus on combination antiretroviral therapy does not appear to significantly increase the risk of vertical transmission, particularly if the viral load is undetectable, but women should be counselled that data on this issue is limited. (II-2B) 7. For women not on combined antiretroviral therapy, the risk of vertical transmission is increased by performing an amniocentesis. When possible, combined antiretroviral therapy should be initiated and the procedure postponed until the viral load is undetectable. Other case management should be individualized in consultation with infectious diseases specialists and obstetricians. (III-B)

INTRODUCTION

T

hese guidelines are designed to address the risks of in utero infection (vertical transmission) through prenatal invasive procedures in women infected with hepatitis B, hepatitis C, and/or HIV so that obstetric care providers may better counsel these women about their options. ASSESSMENT OF RISK AND AMNIOCENTESIS

For women infected with hepatitis B, hepatitis C, or HIV, the addition of non-invasive methods of prenatal risk screening, such as serum screening combined (or not) with nuchal translucency, and anatomic ultrasound, provide the best risk assessment possible to properly inform women of their risk of chromosomal anomalies. The best available test should be used to keep the false-positive rate to a minimum. None of these infections seems to be associated with a significant increase in vertical transmission when amniocentesis is performed in the settings described below. The use of NIPT using cell-free DNA technology could be based on the same indications as in women without these chronic infections. Women whose risk of vertical transmission is significantly higher than in those not exposed to an invasive procedure (such as HIV-infected women not on cART) should be considered for NIPT prior to any confirmatory invasive testing, after being counselled on the benefits and limitations of the test. NIPT provides higher sensitivity (close to 100%) and a lower false-positive rate (around 1%) when screening for trisomy 13, 18, or 21 in a highrisk population than the most frequently used screening JULY JOGC JUILLET 2014 l 649

SOGC CLINICAL PRACTICE GUIDELINE

methods (such as serum based screening or first trimester screening). Because of its lower false-positive rate, it can therefore reduce the number of amniocenteses performed. Currently NIPT does not routinely screen for other chromosomal anomalies that are found more often in women who screen positive with the first-line screening approaches. It is often used as a secondary test prior to invasive testing or as a primary test in a high-risk population based on age or previous history.1 Data on the accuracy of the test in a general population is limited. It has not been studied specifically in a population with a chronic viral infection or on antiretroviral medications. In planning for an amniocentesis for women infected with hepatitis B, hepatitis C, and/or HIV undergoing amniocentesis, every effort should be made to avoid inserting the needle through the placenta, as was the case in all the series described in this guideline. Limited information is available on procedures other than amniocentesis in this population, therefore this guideline focuses specifically on that procedure. Recommendations

1. For women infected with hepatitis B, hepatitis C, and/or human immunodeficiency virus, the use of non-invasive methods of prenatal risk assessment is recommended, using tests with high sensitivity and low false-positive rates, such as serum screening combined (or not) with nuchal translucency, anatomic ultrasound, and non-invasive molecular prenatal testing. (III-B) 2. For women infected with hepatitis B, hepatitis C, and/or human immunodeficiency virus undergoing an amniocentesis, every effort should be made to avoid inserting the needle through, or very close to, the placenta. (II-2B) 3. Little information is available on other prenatal diagnostic and therapeutic invasive procedures; the risks and benefits of such procedures should therefore be assessed prior to their use. (III-C)

ABBREVIATIONS cART

combined antiretroviral therapy

CVS

chorionic villus sampling

DNA

deoxyribonucleic acid

HBeAg hepatitis B e antigen HBsAg hepatitis B surface antigen HCV

hepatitis C virus

HIV

human immunodeficiency virus

NIPT

non-invasive molecular prenatal testing

RNA

ribonucleic acid

650 l JULY JOGC JUILLET 2014

HEPATITIS B

In women presenting for prenatal care, hepatitis B has a prevalence of 0.34% to 1.1%.2–4 The rate of vertical transmission in HBsAg-positive women without immunoprophylaxis is approximately 15%, and may be as high as 90% in those women who are HBsAg- and HBeAgpositive. With appropriate immunoprophylaxis, the rate of vertical transmission drops to 1.5% for women who are HBsAg-positive and to 10% for women who are HBsAg- and HBeAg-positive.5 Genetic amniocentesis has been reported in 115 HBsAg positive-women.6–9 Most amniocenteses were performed with care to avoid a transplacental approach. All the infants of these pregnancies received hepatitis B vaccination and immunoprophylaxis commencing at birth. The overall rate of vertical transmission was 2.9%. This rate of immunoprophylaxis failure is consistent with rates seen in women who have not undergone amniocentesis.10 In one series, 3 infants (30%) of mothers who were HBeAgpositive demonstrated postnatal seroconversion following an amniocentesis, compared with 14% for those whose HBeAgpositive mothers did not have an amniocentesis (P > 0.05).9 These findings would suggest that the risk of fetal hepatitis B infection through amniocentesis is low. However, knowledge of the mother’s HBeAg-status may be valuable when counselling on the risks associated with amniocentesis, as the transmission rate may be higher in HBeAg-positive women. No available studies report on vertical transmission in this population using other prenatal invasive procedures (such as CVS or fetal blood sampling) or assess preventive strategies (such as hepatitis B immunoglobulin and antiviral therapies) prior to invasive prenatal procedures. Recommendation

4. The rate of neonatal hepatitis B infection attributable to amniocentesis ranges up to 1.4% in newborns of mothers positive for hepatitis B surface antigen. However, the rate of neonatal infection attributable to amniocentesis in newborns of mothers with a positive hepatitis B e antigen status may be as high as 16%. Although there is no statistically significant difference between the rates of infection in newborns exposed to amniocentesis or not exposed to amniocentesis in these two maternal populations, knowledge of the mother’s hepatitis B e antigen status may be valuable in counselling women about the risks associated with amniocentesis. (II-2A) HEPATITIS C

The prevalence of hepatitis C varies greatly between populations. Generally, the prevalence in women of

Prenatal Invasive Procedures in Women With Hepatitis B, Hepatitis C, and/or Human Immunodeficiency Virus Infections

reproductive age is 1% to 2%.11,12 A British Columbia study reported a prevalence of HCV infection of around 0.9% in the pregnant population, although only half of those women would have been detected through testing based on risk-factors.13 In women in the Canadian federal penitentiary system, however, the prevalence is 40%,14 and in antenatal clinics in Scotland it is 0.6%.14 The rate of vertical transmission is approximately 5% to 10%.15–18 The exact timing of vertical transmission is unknown, but elective Caesarean section does not appear to be preventive.18 The risk of vertical transmission appears to be increased in women whose hepatitis C is associated with active liver disease, in those whose level of HCV RNA is greater than 106/mL, and in women co-infected with HIV.15,18 Only a few series discuss the use of amniocentesis in pregnant women infected with HCV. One series reported the use of amniocentesis in 22 women with hepatitis C, of whom 16 had HCV RNA identified in their serum. All women (median age 39 years) underwent amniocentesis in the 4th month of pregnancy.19 The amniotic fluid samples were tested using polymerase chain reaction for HCV RNA. Of the 16 viremic women, HCV RNA was detected in the amniotic fluid of only one, whose placenta was anterior. On postnatal testing, none of the children from these pregnancies, including the child from the pregnancy with HCV RNA-positive amniotic fluid, was found to be HCV RNA-positive.19 A case–control study, published as an abstract only, of factors involved in vertical transmission reported a similar rate of amniocentesis in infected (8/51) and non-infected (28/110) children.20 In contrast, a case series of 44 vertically infected children reported a history of amniocentesis in 10 (22.5%) of the pregnancies, a rate higher than seen in the general population.21 Finally, Minola et al. reported a case of a twin pregnancy in which only one sac was sampled, and only that one fetus was infected at 12 months of age.22 Although the 2 best studies are somewhat reassuring, little is learned from these series, as the various methodologies do not allow for a metaanalysis. In summary, amniocentesis in women infected with hepatitis C does not significantly increase the risk of vertical transmission, but women should be counselled that very few studies have properly addressed this possibility, nor have factors that could affect the transmission rate been well studied. There are no studies available on other prenatal invasive procedures such as CVS or fetal blood sampling. Recommendation

5. Amniocentesis in women infected with hepatitis C does not appear to significantly increase the risk of vertical transmission, but women should

be counselled that very few studies have properly addressed this possibility (II-2C). More research on this topic is recommended (III-L). HUMAN IMMUNODEFICIENCY VIRUS

The prevalence of HIV in an obstetric population varies greatly, depending on the population studied. The reported prevalence in British Columbia is 0.03%, while in some inner city populations in the United States, the prevalence is as high as 1.5%.23,24 The AIDS Clinical Trials Group 076 study clearly demonstrated a 26% vertical transmission rate, which was lowered to 8% in patients who received antepartum, intrapartum, and neonatal zidovudine therapy.25 Many HIV-positive women are now taking cART.26 In those, the vertical transmission rate has decreased to less than 1%.27 In a French series of 1632 HIV-positive women, of whom only 5% received antenatal zidovudine therapy, the rate of vertical transmission was 19%.28 Amniocentesis was performed on 13 women and amnioscopy on 26 women, with a vertical transmission rate of 36%. This rate was significantly higher than that observed in women who did not have invasive needling procedures (18%). Five series reporting on a total of 159 women on cART provide contemporary data on this topic. No case of vertical transmission was reported in those series for women having undergone an amniocentesis while on cART.29 A contemporaneous French cohort of 2528 women on cART who had not had an amniocentesis had a reported 1.2% transmission rate.30 With this reassuring data, experts now suggest that indicated amniocentesis should not be avoided in women with HIV who are on cART, particularly if their viral loads are low, but that the best non-invasive screening available should be used prior to invasive testing by amniocentesis. López and Coll suggest that 2 weeks of cART prior to the amniocentesis were sufficient to provide the therapy’s observed benefit of reduced vertical transmission.29 Others recommend waiting for an undetectable viral load before proceeding.31 These factors should be considered in the choice of antiretroviral, which should be made in consultation with infectious diseases specialists and obstetrical care providers. For example, raltegravir could be used to rapidly decrease a high maternal viral load before the amniocentesis.32 Somigliana et al. reported in their series 3 women having undergone CVS and 4 having undergone a cordocentesis, all while on cART.33 No cases of vertical transmission were reported in those 7 women. With such limited data, however, the use of these procedures cannot be recommended if amniocentesis is an option, because more data is available on amniocentesis. JULY JOGC JUILLET 2014 l 651

SOGC CLINICAL PRACTICE GUIDELINE

Recommendations

6. Amniocentesis in women infected with human immunodeficiency virus on combination antiretroviral therapy does not appear to significantly increase the risk of vertical transmission, particularly if the viral load is undetectable, but women should be counselled that limited data is available on this issue. (II-2B) 7. For women not on combined antiretroviral therapy, the risk of vertical transmission is increased by performing an amniocentesis. When possible, combined antiretroviral therapy should be initiated and the procedure postponed until the viral load is undetectable. Other case management should be individualized in consultation with infectious diseases specialists and obstetricians. (III-B) RISK OF AMNIOTIC FLUID CONTAMINATION AT AMNIOCENTESIS

Contamination of the fetal amniotic cavity with maternal blood during amniocentesis is common.34 In a study by Giorlandino et al., 20 women underwent a second amniocentesis 2 weeks after the original amniocentesis because of cell culture contamination.34 At the second amniocentesis all 20 were found to have maternal blood contamination in the amniotic fluid based on red blood cell and hemoglobin concentrations.34 The amniotic fluids of women undergoing their first amniocentesis were used as matched control subjects and no maternal blood contamination was found at the onset of the procedure. The amount of maternal blood in the amniotic fluid was significantly increased when an anterior placenta was present.34 CONCLUSION

There is a critical lack of evidence to determine the impact of prenatal invasive procedures on the risk of vertical transmission in women with hepatitis B, hepatitis C, and/or HIV. For this reason, non-invasive methods of prenatal risk screening that provide the highest sensitivity with the lowest false-positive rate should be used to minimize the number of amniocenteses performed. The available evidence suggests the risk of vertical transmission through amniocentesis in women infected with hepatitis B and hepatitis C is not greatly increased if present at all. In contrast, the risk of vertical transmission of HIV appears to be increased through amniocentesis for women not on cART. For women with HIV treated on cART for at least 2 weeks, the risk of vertical transmission associated with amniocentesis appears to be negligible if present at all. Efforts should be made in all cases to avoid inserting the needle through the placenta. 652 l JULY JOGC JUILLET 2014

REFERENCES 1. Langlois S, Brock J-A; SOCG Genetics Committee. Current status in non-invasive prenatal detection of Down syndrome, trisomy 18, and trisomy 13 using cell-free DNA in maternal plasma. SOGC Committee Opinion, No. 287, February 2013. J Obstet Gynaecol Can 2013;35:177–81. 2. Delage G, Montplaisir S, Remy-Prince S, Pierri E. Prevalence of hepatitis B virus infection in pregnant women in the Montreal area. Can Med Assoc J 1986;134:897–901. 3. Healy CM, Cafferkey MT, Butler KM, Cahill I, McMorrow J, Philbin M, et al. Antenatal hepatitis B screening – is there a need for a national policy? Ir Med J 2001;94:111–2, 114. 4. Miranda AE, Alves MC, Neto RL, Areal KR, Gerbase AC. Seroprevalence of HIV, hepatitis B virus, and syphilis in women at their first visit to public antenatal clinics in Vitoria, Brazil. Sex Transm Dis 2001;28:710–3. 5. Centers for Disease Control and Prevention. Protection against viral hepatitis. Recommendations of the Immunization Practices Advisory Committee. Morb Mortal Wkly Rep 1990;39:1–26. 6. Towers CV, Asrat T, Rumney P. The presence of hepatitis B surface antigen and deoxyribonucleic acid in amniotic fluid and cord blood. Am J Obstet Gynecol 2001;184:1514–8. 7. Alexander JM, Ramus R, Jackson G, Sercely B, Wendel GD Jr. Risk of hepatitis B transmission after amniocentesis in chronic hepatitis B carriers. Infect Dis Obstet Gynecol 1999;7:283–6. 8. Grosheide PM, Quartero HW, Schalm SW, Heijtink RA, Christiaens GC. Early invasive prenatal diagnosis in HbsAg-positive women. Prenat Diagn 1994;14:553–8. 9. Ko TM, Tseng LH, Chang MH, Chen DS, Hsieh FJ, Chuang SM, et al. Amniocentesis in mothers who are hepatitis B virus carriers does not expose the infant to an increased risk of hepatitis B virus infection. Arch Gynecol Obstet 1994;255:25–30. 10. Centers for Disease Control. Hepatitis B virus: a comprehensive strategy for eliminating transmission in the United States through universal vaccination: recommendations of the Advisory Committee on Immunization Practices (ACIP). Part 1: immunization of infants, children, and adolescents. Morb Mortal Wkly Rep 1991;40(RR-13):1–19. 11. Healy CM, Cafferkey MT, Conroy A, Dooley S, Hall WW, Beckett M, et al. Hepatitis C infection in an Irish antenatal population. Ir J Med Sci 2000;169:180–2. 12. Ford PM, White C, Kaufmann H, MacTavish J, Pearson M, Ford S, et al. Voluntary anonymous linked study of the prevalence of HIV infection and hepatitis C among inmates in a Canadian federal penitentiary for women. CMAJ 1995;153:1605–9. 13. Blasig A, Wagner EC, Pi D, Bigham M, Remple VP, Craib KJP, et al. Hepatitis C infection among pregnant women in British Columbia: reported prevalence and critical appraisal of current prenatal screening methods. Can J Public Health 2011;102:98–102. 14. Goldberg D, McIntyre PG, Smith R, Appleyard K, Dunlop J, Taylor A, et al. Hepatitis C virus among high and low risk pregnant women in Dundee: unlinked anonymous testing. Br J Obstet Gynaecol 2001;108:365–70. 15. Ohto H, Terazawa S, Sasaki N, Sasaki N, Hino K, Ishiwata C, et al. Transmission of hepatitis C virus from mothers to infants. The Vertical Transmission of Hepatitis C Virus Collaborative Study Group. N Engl J Med 1994;330:744–50. 16. Hillemanns P, Dannecker C, Kimmig R, Hasbargen U. Obstetric risks and vertical transmission of hepatitis C virus infection in pregnancy. Acta Obstet Gynecol Scand 2000;79:543–7.

Prenatal Invasive Procedures in Women With Hepatitis B, Hepatitis C, and/or Human Immunodeficiency Virus Infections

17. Conte D, Fraquelli M, Prati D, Colucci A, Minola E. Prevalence and clinical course of chronic hepatitis C virus (HCV) infection and rate of HCV vertical transmission in a cohort of 15,250 pregnant women. Hepatology 2000;31:751–5.

27. Loutfy MR, Margolese S, Money DM, Gysler M, Hamilton S, Yudin MH; Canadian HIV Pregnancy Planning Guideline Development Team. SOGC Clinical Practice Guideline, No. 278, June 2012. J Obstet Gynaecol Can 2012;34:575–90.

18. European Paediatric Hepatitis C Virus Network. Effects of mode of delivery and infant feeding on the risk of mother-to-child transmission of hepatitis C virus. Br J Obstet Gynaecol 2001;108:371–7.

28. Mandelbrot L, Mayaux MJ, Bongain A, Berrebi A, Moudoub-Jeanpetit Y, Benifla JL, et al. Obstetric factors and mother-to-child transmission of human immunodeficiency virus type 1: the French perinatal cohorts. SEROGEST French Pediatric HIV Infection Study Group. Am J Obstet Gynecol 1996;175:661–7.

19. Delamare C, Carbonne B, Heim N, Berkane N, Petit JC, Uzan S, et al. Detection of hepatitis C virus RNA (HCV RNA) in amniotic fluid: a prospective study. J Hepatol 1999;31:416–20. 20. Poiraud S, Cohen J, Amiot X, Berkane N, Flahauif A, Dussaix E, et al. Mother to child transmission of hepatitis C virus: a case-control study of risk factors. Gastroenterology 2001;(Suppl A):A–366. 21. Cohen J, Dessaix E, Bernard O. Transmission du virus de l’hépatite C de la mère à l’enfant: une étude de 44 enfants. Gastroenterol Biol Clin 1998;22:A179. 22. Minola E, Maccabruni A, Martinetti M. Amniocentesis as a possible risk factor for mother-to-infant transmission of hepatitis C virus. Hepatology 2001;33:1341–42. 23. Patrick DM, Money DM, Forbes J, Dobson SR, Rekart ML, Cook DA, et al. Routine prenatal screening for HIV in a low-prevalence setting. CMAJ 1998;159:942–7. 24. Guinan ME, Hardy A. Epidemiology of AIDS in women in the United States. 1981 through 1986. J Am Med Assoc 1987;257:2039–42. 25. Connor EM, Sperling RS, Gelber R, Kiselev P, Scott G, O’Sullivan MJ, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med 1994;331:1173–80. 26. Carpenter CC, Fischl MA, Hammer SM, Hirsch MS, Jacobsen DM, Katzenstein DA, et al. Antiretroviral therapy for HIV infection in 1998: updated recommendations of the International AIDS Society-USA . JAMA 1998;280:78–86.

29. López M, Coll O. Chronic viral infections and invasive procedures: risk of vertical transmission and current recommendations. Fetal Diagn Ther 2010;28:1–8. 30. Ducarme G, Ceccaldi PF, Bernuau J, Luton D. Amniocentesis and viral risk (hepatitis B, C and HIV). J Gynecol Obstet Biol Reprod 2009;38:469–473. 31. Low-Beer NM, Penn ZJ. Management of HIV in pregnancy. RCOG Green-top Guideline No. 39. London: Royal College of Obstetricians and Gynaecologists; 2010. 32. Westling K, Pettersson K, Kaldma A, Navér L. Rapid decline in HIV viral load when introducing raltegravir-containing antiretroviral treatment late in pregnancy. AIDS Patient Care STDS 2012;26:714–7. 33. Somigliana E, Bucceri AM, Tibaldi C, Alberico S, Ravizza M, Savasi V, et al. Early invasive diagnostic techniques in pregnant women who are infected with the HIV: a multicenter case series. Am J Obstet Gynecol 2005;193:437–42. 34. Giorlandino C, Gambuzza G, D’Alessio P, Santoro ML, Gentili P, Vizzone A. Blood contamination of amniotic fluid after amniocentesis in relation to placental location. Prenat Diagn 1996;16:180–2. 35. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

JULY JOGC JUILLET 2014 l 653

SOGC CLINICAL PRACTICE GUIDELINE No. 314, October 2014 (Replaces No. 261, July 2011)

Prenatal Screening, Diagnosis, and Pregnancy Management of Fetal Neural Tube Defects This clinical practice guideline has been prepared by the Genetics Committee, reviewed by Family Physician Advisory and Diagnostic Imaging Committees, and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRIMARY AUThOR

Abstract Objective: To provide obstetrical and genetic health care practitioners with guidelines and recommendations for prenatal screening, diagnosis, and obstetrical management of fetal open and closed Options: This review includes prenatal screening and diagnostic including maternal serum alpha fetoprotein screening, ultrasound, fetal magnetic resonance imaging, and amniocentesis.

SOGC GENETICS COMMITTEE

Outcomes: To improve prenatal screening, diagnosis, and obstetrical

Francois Audibert, MD, Montreal QC Evidence: Published literature was retrieved through searches

Lola Cartier, MSc, CCGC, Montreal QC

neural tube defects, alpha fetoprotein, ultrasound scan, magnetic reviews, randomized control trials/controlled clinical trials, and observational studies published in English from 1977 to 2012. Searches were updated on a regular basis and incorporated in

practice guideline collections, clinical trial registries, and national health care practitioners was also reviewed. Values: criteria described in the Report of the Canadian Task Force on . SPECIAL CONTRIBUTOR

This review will provide health care practitioners with a better understanding of the available risks associated with each technique to allow evidenced-based management.

Key words: prenatal screening, congenital anomalies, neural tube defects, alpha fetoprotein, ultrasound scan, magnetic resonance

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

OCTOBER JOGC OCTOBRE 2014

927

SOGC CLINICAL PRACTICE GUIDELINE

Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive health Care A. There is good evidence to recommend the clinical preventive action controlled trial II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

more than one centre or research group D. There is fair evidence to recommend against the clinical preventive action places with or without the intervention. Dramatic results in E. There is good evidence to recommend against the clinical preventive action III:

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees decision-making

Preventive Health Care.109 on Preventive Health Care.109

RECOMMENDATIONS Screening Evaluation abnormalities including open/closed neural tube defects

estimated risk of recurrence, and prediction of long-term neonatal and childhood outcomes of open/closed neural tube

anatomical ultrasound with detailed fetal intracranial and spinal

of

closed neural tube defects screening should be discontinued with the limited clinical exceptions of pregnant women with a 2 or when geographical

screening, maternal serum alpha fetoprotein can be used as a 4. Positive screening results for open/closed neural tube defect referral to appropriate experienced providers for genetic review,

Diagnostic Evaluation 5. If the second trimester screening fetal ultrasound indicates a probable diagnosis of neural tube defects, the women should be for a more detailed ultrasound examination looking for the 6. Prenatal magnetic resonance imaging can be considered as an additional fetal imaging technique if further detailed fetal

maternal–fetal medicine, and pediatric neurosurgical counselling

Pregnancy Management 10. Following the detection of an isolated open/closed neural tube management options after diagnostic and genetic testing results are available. Options should include information about or fetal contraindications for prenatal repair at 20–26 weeks’ prognosis, and

request. For an encephalocele, individualized counselling is

Invasive Prenatal Diagnostic Methods considered in selected MMC vertex presentation cases that have

928

OCTOBER JOGC OCTOBRE 2014

Prenatal Screening, Diagnosis, and Pregnancy Management of Fetal Neural Tube Defects

oral folic acid supplementation of 5 mg within a multivitamin preparation should be recommended to the female partner,

INTRODUCTION

O

CNTDs are congenital abnormalities or malformations of the neuraxis. Structural developmental malformations can affect the thoracic, is declined, fetal magnetic resonance imaging should be considered to better evaluate fetal abnormalities either in utero or after postnatal death. If genetic studies have not been completed prior to the termination, at the minimum,

not performed. This procedure will maximize information for

Pregnancy Follow-up 14. Follow-up consultation is recommended when postnatal genetic and pathologic studies are complete, to provide the woman with

presumed folic acid-sensitive open/closed neural tube defect

(anencephaly or encephalocele). Secondary co-anomalies (disruption or deformation) can involve the lower limb, bowel, bladder, cerebellum, and cerebral cortex or cerebral ventricles (for myelomeningocele).1–3 The human neural tube normally closes during the 3rd and 4th weeks of embryonic development (correlating with 5–6 weeks’ gestation from LMP). The primary method of preventing the majority of OCNTDs is with increased red blood cell folate by supplementation, but this increased maternal folate strategy must occur before conception and continue new cell production during rapid cell division.4–6 This biological folic acid factor is important because embryogenesis has certain folic acid-sensitive anomalies

ABBREVIATIONS

trimester development. With the introduction of folic acid supplementation (1991–1992), there has been a

AFP

alpha fetoprotein

FPR

false positive rate

LMP

last menstrual period

MC

meningocele

MRI

magnetic resonance imaging

MSAFP

maternal serum alpha fetoprotein

of OCNTDs in Canada. This reduction and new clinical prenatal surgical outcomes for OCNTD highlighted the need for new clinical care protocols and recommendations to be developed for prenatal screening, diagnosis, and management of OCNTDs. Since the introduction of ONTD screening methods in the 1970s, the total number of reported cases has increased, most likely because of advances in prenatal screening and early detection.2,7–14 A decrease in birth prevalence is the result of both primary prevention, in the form of folic prevention methods (prenatal screening and termination of an affected pregnancy).4,6,13,14

OR

odds ratio

RCT

randomized controlled trial

OCNTD screening and diagnosis are carried out by MSAFP measurement, fetal imaging techniques (ultrasound imaging and MRI), and amniocentesis. It is recommended that prenatal screening be offered and undertaken in the second trimester between 15 and 22 weeks’ gestation to OCTOBER JOGC OCTOBRE 2014

929

SOGC CLINICAL PRACTICE GUIDELINE

maximize testing accuracy, achieve a low FPR, and allow optimal management of affected pregnancies.4,10,15–27 Factors that have been reported to affect the accuracy and interpretation of OCNTD screening results include type of NTD malformation, gestational age, maternal weight, maternal insulin-dependent diabetes, multiple gestations, ethnicity, environmental factors (prescription and non-prescription medications), and concurrent fetal anomalies.1,9,13,17,22 Early prenatal screening for ONTD gives parents and health care practitioners the ability to evaluate the anomaly and the overall health of the fetus during the second trimester. This guideline focuses on NTD screening, diagnosis, and post-diagnostic pregnancy management. GENETICS OF NTD

In humans, the neural tube closes between 21 to 28 days of embryonic development, and abnormal closure is characterized by the improper fusion of the neural tube in the developing embryo.1,2,7 NTD prevalence ranges from 1 in 300 to 1 in 1000 pregnancies and is affected by ethnic, genetic, and dietary factors, with the highest NTD rates in the United Kingdom and the United States and the lowest rates in Japan.9,10,28–31 Certain chronic maternal medical conditions will increase the risk of NTDs, including poorly controlled maternal insulindependent diabetes (OR 11.5), antiepileptic medications (valproic acid, carbamazepin), therapy with folic acid antagonists, and maternal obesity (OR 3.5).28–31 NTDs are described by their anatomical location and neural content type as follows:

16.3% incidence.33–37 Syndromes or sequences associated with NTDs include amniotic band syndrome, cloacal extrophy, limb body wall complex, OEIS (omphalocele, extrophy, imperforate anus, spinal) syndrome, cerebrocostomandibular syndrome, and caudal regression.38 Other syndromic OCNTDs are associated with single gene disorders such as (cranial ONTD and holoprosencephaly) genes. Other single gene disorders reported include Waardenburg syndrome and Curarino syndrome.38 There are reports of gene mutations or alterations of gene expression leading to ONTDs, such as polymorphisms or SNPs in genes responsible for folate transport, the methionine/homocysteine metabolic cycle, methylation, and nucleotide biosynthesis. Rare mechanisms contributing autoantibodies to the folate receptors, and infertility or assisted reproductive technology therapy.39–42 NON-INVASIVE NTD SCREENING TEChNIQUES Ultrasound Screening

Ultrasound is the non-invasive screening modality of choice for the detection of fetal anomalies including NTDs because 4,21,22,43,44

The current generation of ultrasound machines allow for highly detailed fetal imaging. National screening policy documents cite detection rates of approximately 68% to 94% for NTDs,9,22,45–47 with EUROCAT reporting a 68% 48 and British Columbia an 86% detection rate (1997–1999).4

4. inencephaly/craniorachischisis (abnormal skull and upper spine development) 1.5%.32

A second trimester screening ultrasound should be offered to all pregnant women, as recommended in a number of SOGC guidelines43,49,50 for the detection of congenital anomalies from 18 to 22 weeks’ gestation, avoiding the need for a second trimester MSAFP screening test.15,43,45,47,48 Ultrasound is recommended routinely in all second trimester pregnancies and is a more effective screen for OCNTD (improved sensitivity with lower FPR although more expensive) than MSAFP screening, and diagnostically it is safer than amniocentesis which carries the risk of infection or spontaneous abortion.9,11,45,47,51–53 In addition, ultrasound has the major advantage of screening for multiple congenital anomalies at a single ultrasound imaging visit. The factors that may affect ultrasound screening for NTDs include

Seventy percent of NTDs related to genetic abnormalities are isolated, non-syndromic anomalies or malformations, and with current genetic knowledge, are considered to have a multi-factorial inheritance. Chromosomal abnormalities associated with an “apparently isolated” NTD have a 2.4% to

of fetuses, and maternal BMI. Other factors to consider are parental ethnicity, “at risk” maternal medication use, maternal diabetic status, and personal, pregnancy, and family histories.1,15,43,54–61 In a fetus with an OCNTD, features visible by ultrasound in the second trimester include anencephaly

93% ONTDs (neural placode at the base of the NTD) and 7% CNTDs (MC = dural sac only; MMC = neural elements attached to the dural sac); 2. anencephaly (closure failure of caudal NT folds causing failure of brain development) 40%; 3. encephalocele (outpouching of the brain through a bony skull defect; occipital is most common, with anterior and lateral locations) 8.5%; and

930

OCTOBER JOGC OCTOBRE 2014

Prenatal Screening, Diagnosis, and Pregnancy Management of Fetal Neural Tube Defects

dysmorphology), open spinal anomalies (abnormal skull shape [lemon sign], abnormal appearance and possible increased width of the cerebral ventricles, abnormal appearance of the posterior fossa/cerebellum [banana sign], and abnormal or incomplete appearance of the posterior vertebral arches in thoracic, lumbar, or sacral locations), and closed spinal anomalies (with the possible absence of the lemon and banana signs and a thick appearing MMC sac protruding from the posterior vertebral opening). Abnormal lower limb movement and positioning of the foot or feet may also be present.43,49,50 Preliminary research for NTD at 11 to 13 weeks’ gestation, assessing structural developmental variation, such as the absence of intracranial translucency, decreased frontomaxillary facial angle, partial or complete cisterna magna obliteration (brainstem diameter decreased intracranial CSF volume. NTD imaging should be conducted under a research protocol at the present time. 61–65

The experience of the sonographer and up-to-date and well-maintained equipment are important in screening evaluation.7,15 The importance of these factors is highlighted in the recent publication from the rural areas of China,7 where researchers found that ultrasound did not meet its full potential as a method of secondary screening of NTDs; ultrasound was a satisfactory screening method, but NTD detection rate was low. This study did not report that ultrasound was a poor method for screening, but rather that the ultrasound screening skills of the were not optimal for the detection of NTD anomalies.7

contrast and spatial resolution, and single-shot rapid acquisition with relaxation enhancements for decreasing fetal movement effects,22,69–71 there is no established standard imaging reference because MRI is not used as a screening modality.22,67,70,72 by MRI emphasizes the importance of correct imaging methods and radiologic interpretation. Many new techniques under development are already commonly used in the neonatal period, when anatomical structures order to use them safely during pregnancy.66–70 Operator interpretation of the MRI requires a thorough knowledge of normal and abnormal fetal anatomy. As the option of fetal NTD surgery becomes available in perinatal CNS evaluation.70,73,74 MRI is considered safe for the fetus, but there are hypothetical concerns about teratogenesis and acoustic damage.67,70 While additional fetal MRI research with neonatal follow-up is needed, an SOGC Diagnostic Imaging Committee Guideline75 reports that fetal MRI is safe at 1.5 tesla magnet exposure during the second and third trimesters. Ultrasound has the advantage over MRI of easier patient access to imaging services; it is not hampered by fetal movement, it is less expensive than MRI, and it provides good spatial resolution. MRI, however, is not limited by contrast, and performs well regardless of oligohydramnios, maternal obesity, or fetal lie.22,27,70,73,74

Fetal MRI

Obstetric application of MRI began approximately 20 years ago, 10 years after its discovery and initial use.66,67 The main use of fetal MRI is as an adjunct to the primary ultrasound detail could be obtained for management planning and counselling.68–70 Fetal MRIs are usually conducted between the late second and early third trimesters, between 23 and 32 weeks’ gestation.21,59,70 This gestational age allows for optimal imaging of the entire fetal brain and subarachnoid space15,21,67,71; however, late gestation MRI can delay decisions regarding pregnancy management, including termination of pregnancy. The use of fetal MRI, primarily known for its superior brain imaging capabilities, has now been expanded to detect non-CNS abnormalities.22,27,67,70 Although there have been many advances in MRI technology such as the use of T2-weighted sequences, which allow for better

additional anomalies,76 but its expense, lack of a standard of reference for imaging, and limited availability are factors that continue to favour ultrasound as the imaging choice for the detection of OCNTDs.77,78 Maternal serum AFP

MSAFP screening was once considered the gold standard of prenatal ONTD screening, but with advances in technology, research, and knowledge, MSAFP screening now has limited value when reliable second trimester ultrasound (screening and diagnostic) is available. Since the mid-1970s, non-invasive MSAFP has been used for the detection of ONTDs.10,11,19,27,51,79 MSAFP levels rise early in the pregnancy, and ONTD screening was optimized to discern normal from abnormal MSAFP results in the second trimester between 15 and 18 weeks’ gestation.14,15,18,45 MSAFP levels are measured in multiples of the median, using unaffected pregnancies of the same gestational age as OCTOBER JOGC OCTOBRE 2014

931

SOGC CLINICAL PRACTICE GUIDELINE

the control value.11,14,18 To interpret results, it is important to correctly identify the gestational age, number of fetuses, maternal ethnicity, and maternal weight. Furthermore, such factors as a personal or family history of OCNTD, any maternal “at risk for NTD” medications (epilepsy control [valproic acid, carbamazepine] or folate antagonists), or certain chronic medical conditions, such as diabetes, must be taken into consideration.14,18 First trimester MSAFP (11 to 13 gestational weeks) levels in normal pregnancies are affected by maternal race, weight, smoking status, and method of contraception (oral birth control).46 Second trimester MSAFP detects 71% to 90% of NTDs, with an FPR of 1% to 3% percent.11,14,18 Elevated levels of MSAFP can be associated with other conditions, such as fetal skin disorders, abdominal wall defects, fetal demise, fetal nephrosis, and pregnancies at an increased risk for placenta-related adverse events.14,17,19 First trimester MSAFP 10%,55 and it is not recommended of NTD screening. A detailed fetal structural ultrasound at 18 to 22 gestational weeks and amniocentesis (AFAFP, AFAChE, and chromosome karyotype analysis) is recommended as a diagnostic follow-up with an elevated second trimester MSAFP level (screen-positive result). A second trimester detailed ultrasound (at 18 to 22 gestational weeks) is recommended as the standard of care for all pregnancies to determine the approximate gestational age, (not usually detected by MSAFP screening), or screen for other congenital anomalies.43,49,50 Earlier ultrasound imaging for dating or evaluating the pregnancy may be required, based on clinical care factors as determined by the primary obstetrical provider. First trimester dating by crown–rump length has a ± 3 to 5 day standard deviations for estimating the gestational age, compared to the ± 7 day standard deviations for the 18 to 22 gestational weeks’ ultrasound. Many recent retrospective studies have shown that with present screening approaches and new technology measuring MSAFP is no longer practical for the detection selecting women for diagnostic testing, such as ultrasound or amniocentesis.14,16,19,20,51,79

Recommendations Screening Evaluation

1. The primary screening test for the detection of fetal structural abnormalities including open/closed neural tube defects (anencephaly, anatomical ultrasound with detailed fetal intracranial and spinal imaging and assessment. (II-2A) 2. The primary use of maternal serum alpha fetoprotein for open/closed neural tube defects screening should be discontinued with the limited clinical exceptions of pregnant women with a pre2 or when geographical or clinical access factors limit timely and good quality ultrasound screening at 18 to 22 weeks’ gestation. (II-2A) 3. When used as a component in maternal serum genetic aneuploidy screening, maternal serum alpha fetoprotein can be used as a secondary screening tool in the second trimester. (II-2A) 4. Positive screening results for open/closed neural tube defect (ultrasound ± maternal serum alpha fetoprotein) require timely referral to appropriate experienced providers for genetic review, diagnosis, and counselling. (II-2A) Diagnostic Evaluation

5. If the second trimester screening fetal ultrasound indicates a probable diagnosis of neural tube defects, the women should be referred to a tertiary or regional centre with ultrasound expertise for a more detailed ultrasound examination looking for the features associated with a neural tube defect sequence. (II-2A) 6. Prenatal magnetic resonance imaging can be considered as an additional fetal imaging technique if further detailed fetal central nervous system assessment is required for diagnostic or management counselling. (II-2A) INVASIVE PRENATAL DIAGNOSTIC METhODS (NTD SCREENING/TESTING) Amniocentesis

AFP from the fetal yolk sac initially and subsequently

MSAFP screening for ONTDs is less costly than ultrasound or amniocentesis,11,52 but its cost advantage must be weighed detect closed NTDs, and the requirement of further testing that includes detailed second trimester ultrasound when second trimester screening MSAFP levels are elevated. 932

OCTOBER JOGC OCTOBRE 2014

only AFP is present in maternal blood.5,14,17,80 Elevated levels of AFAFP and AFAChE are present is fetuses 14,18,80

Prenatal Screening, Diagnosis, and Pregnancy Management of Fetal Neural Tube Defects

An amniocentesis is most often performed for the detection of chromosomal aneuploidy or genetic the detection of NTDs.18,23,74,81–84 The procedure is usually conducted between the 15th and 20th gestational weeks.6,17,45,85–88 karyotype, chromosomal microarray, and AFAFP and AFAChE levels. When amniocentesis is performed with a suspicion of OCNTD, the information from the karyotype, chromosomal microarray, AFAFP, and the AFAChE levels with counselling regarding prognosis. If amniocentesis is being performed for aneuploidy AChE is not routinely required. aneuploidy still require a routine second trimester screening ultrasound for fetal congenital anomalies, including NTD screening if a complete ultrasound anatomic assessment is Risks associated with amniocentesis include spontaneous abortion (estimated procedural risk of 0.5% to 1.0% added to the no-procedure background spontaneous risk of pregnancy loss), post-procedure spotting, infections, rupture of membranes, and fetal damage or loss.48,86–88 Amniocentesis for genetic testing is especially important when considering prenatal or postnatal repair of congenital fetal genetic factors is important as these factors may interfere with the neonatal outcome.73,74,81–83 Although an amniocentesis is an important diagnostic option for high-risk pregnancies in the detection of chromosomal abnormalities and ONTDs, amniocentesis should not be used as a method for laboratory NTD (AFAFP, AFAChE) screening because of the risks and cost associated with the test. Recommendations Invasive Prenatal Diagnostic Methods

amniocentesis (following the ultrasound detection

risk of recurrence, and prediction of long-term neonatal and childhood outcomes of open/closed neural tube defect for family counselling. (II-2A) 8. When a routine diagnostic amniocentesis indicates only a risk anomalies, it is not necessary to take an amniotic fetoprotein and acetylcholinesterase testing to screen for open neural tube defects. (II-2E) an open/closed neural tube defect (isolated or in a more complex multiple-anomaly grouping) requires referral for comprehensive genetic, maternal–fetal medicine, and pediatric neurosurgical counselling for complete patient-focused care. (II-2A) PREGNANCY MANAGEMENT Counselling Information for Continuing Pregnancies

Counselling should be based on the recognition of the personal impact that a physical or mental disability could have on a child and its family. One of the major questions a family asks when their fetus is given an isolated, non-syndromic, non-chromosomal myelomeningocele diagnosis is “What will the quality of life be for my child?” Król et al. reported a followup study of 33 children (19 female; 14 male) with a myelomeningocele at ages 5 to 20 years. They were evaluated in 2 age groups: 5 to 12 (n = 17) and 13 to 20 (n = 16) using the Health-Related Quality of Life in study reported good, very good, and average QoL in 64%, 30%, and 6% of participants respectively. None of the participants felt their QoL was poor. Issues of visual perception in the younger group and ambulation in the older group were related to lower QoL scores. The vast majority of children had a history of good specialist care. The most common medical issues were related to hydrocephalus and neurogenic bladder.89 In a larger study of 119 patients with hydrocephalus and MMC, Barf et al. reported a near equal overall QoL in the study group (76%) as in an age-matched peer group (72%),

suspected open/closed neural tube defect), should be evaluated for a fetal karyotype (and, if indicated and available, a chromosomal microarray),

life, but less satisfaction with their sex lives and abilities to

acetylcholinesterase. These test results will allow comprehensive evaluation of the etiology, estimated

In a retrospective cohort study Hunt and Oakeshott reported on 117 open MMC patients. The cohort had had 54%

that the severity of disease and the level of the lesion had little bearing on self-reported QoL.90

OCTOBER JOGC OCTOBRE 2014

933

SOGC CLINICAL PRACTICE GUIDELINE

mortality and, at evaluation, had an average age of 35 years. Among the survivors, 40% were independent in activities of daily living, meeting medical needs, transportation, and continence care.91 Bowman et al. reported a 25-year follow-up of 118 MMC patients in which 75% lived to early adult age, 85% had high school or college education, 80% were able to maintain social bladder continence with catheterization, 90% reported acceptable levels of bowel continence, and 86% of long-term survivors were shunt-dependent. childhood or early adulthood was an unrecognized shunt malfunction.92 For more complete counselling knowledge, the health care provider could consider an economic assessment of the cost of continuing care for the MMC patient. Yi et al. reported across all.93 The lifetime direct medical costs for being for inpatient care, treatment at initial diagnosis in childhood, and co-morbidities in adult life. The caregiver Continuing Pregnancy Surveillance and Method of Delivery

Pregnancy surveillance and delivery recommendations for fetuses with OCNTDs are controversial because increased pregnancy termination has limited the study of the MMC delivery model for more than 2 decades. The ACOG Practice Bulletin94 reports that most pregnancies complicated by MMC will deliver with appropriate lung maturity at term, and there is no evidence that antenatal fetal heart rate testing for an MMC indication improves outcome. It is recognized that anomalous fetuses frequently interpret.95 Serial ultrasounds for fetal growth, head size, and ventricular size may be helpful in continued prognosis counselling and delivery planning. The fetus should be delivered at a centre with a level III NICU and pediatric neurosurgery services.90 A latex-free delivery and surgical repair plan should be considered because individuals with MMC are at an increased risk of developing a severe and life-threatening allergy to latex.96 The mode of delivery for an MMC-affected fetus with a vertex presentation remains controversial. There are no RCTs, but at least 5 studies representing a total of 400 patients suggested vaginal delivery does not adversely affect neonatal outcome, and one large study of 200 patients suggested Caesarean 934

OCTOBER JOGC OCTOBRE 2014

sections as a safer method of delivery for the MMC-affected fetus.97–102 Breech presentation is common in the MMCaffected fetus as a result of decreased lower limb neurologic function and megacephaly, and hence requires delivery by Caesarean section. Prenatal in Utero Repair of MMC

The Randomized Trial of Prenatal versus Postnatal Repair of Myelomeningocele74 showed that prenatal fetal surgery for MMC reduced the need for ventricular peritoneal shunting (40% vs. 82%) and showed improved lower limb motor outcomes at 30 months of age. However, the surgery was associated with maternal and fetal risks. Additional improvement in the child composite score for mental development and motor function at 30 months of age was score: prenatal surgery [n = 64] 148.6 ± 57.5; postnatal surgery [n = 70] 122.6 ± 57.2; P = 0.007). Improved hindbrain herniation at 12 months and ambulation at 30 months was also reported. This landmark study provides an important treatment option for parents because it clearly surgery, albeit at the cost of increased maternal risks for the index and subsequent pregnancies.74 An accompanying editorial counselled caution regarding the initiation of this new prenatal treatment in multiple fetal therapy/treatment centres and emphasized that most women who expressed an interest in the experimental trial were either ineligible or declined to participate, with only 15% of screened women participating in the study.103 A legal and ethical opinion that drew attention to prioritizing the fetus stated that: unlike a born child, a fetus is not a patient in the real sense, but only a metaphor. However, it would be unethical if a care provider, without the woman’s informed consent, promoted the interests of the fetus over those of the woman.104 When considering the consent to fetal surgery the parents have clear legal responsibilities to provide or consent to their born children’s necessary medical care but the maternal duties to fetuses in utero are not generally recognized.”104 Regarding whether this study was research or a therapeutic innovation they stated that: the research component of the study was not in the prenatal surgical and postnatal management of each child but in the systematic control of each case according to the research protocol and the retrospective comparative review for all the outcome data.104

Prenatal Screening, Diagnosis, and Pregnancy Management of Fetal Neural Tube Defects

Their conclusion was that “women, diagnosed with a fetal MMC and where open fetal surgery is available, will have to be informed of this treatment option.”104 This prenatal repair option needs therefore to be presented to families in Canada as part of the informed consent process because although it is not available here, it is available in the United States.104 Postnatal Repair of MMC

The decision to perform postnatal repair is the most likely clinical scenario in Canada for the MMC fetus or neonate because only mothers who have travelled to in utero MMC treatment centres in the United States will have received in utero MMC repair. The postnatal group in the Randomized Trial of Prenatal 74 is used as the clinical outcome for comparison because the RCT study was done in selected Children’s Hospital facilities with organized and comprehensively controlled pediatric neurosurgery services. The placement of a shunt within the group (82%, compared to prenatal group 40%; P = 0.001). Other abnormal cranial and brain features were higher in the postnatal group than in the prenatal repair group (degree of hindbrain herniation, P = 0.001; brainstem kinking, P = 0.001; abnormal location of the 4th ventricle, P = 0.002). lower with postnatal repair than with prenatal repair, but this was mainly due to differences in motor function between the spinal anatomical levels of the defects (P = 0.001); the Bayley (P independently with prenatal repair and 21% with postnatal repair (relative risk 2.01 ([95% CI 1.16–3.48]; P = 0.01). lower WeeFIM scores for self-care (P = 0.02) and mobility (P = 0.003), but not for cognitive ability (P = 0.67). Immediate postnatal care for MMC is required whether the birth was by Caesarean section or vaginal delivery. Neonatology specialists should attend in the labour room for MMC protection and care, probable neonatal prematurity (less than 37 weeks’ gestation), and planning and performing subsequent primary neurosurgical MMC closure within 24 hours of delivery, especially if the MMC is open or the MMC sac was ruptured at delivery Termination of Pregnancy

Over the last 3 decades an estimated 70% to 80% of women and couples with a fetus affected by OCNTD have chosen termination of the pregnancy.4,105,106

For families choosing to terminate a pregnancy because of an MMC, anencephaly, or encephalocele, the health care provider should discuss fetal autopsy and chromosomal provide important information about the etiology for the NTD and the recurrence risk.107 Measures to prevent recurrence, including maternal supplementation with 5 mg of preconception folic, are recommended in subsequent pregnancies because folic acid supplementation has been shown in an RCT to reduce the isolated recurrence risk of NTD by 72%, with a resulting reduction of the non-supplementation prevalence rate of 3% to a post supplementation recurrence rate of 1%.5,108 Recommendations Pregnancy Management

10. Following the detection of an isolated open/closed neural tube defect, families should be offered a choice of 3 obstetrical care management options after diagnostic and genetic testing results are available. Options should include information about prenatal myelomeningocele repair and prognosis (if there are no maternal or fetal contraindications for prenatal repair at 20–26 weeks’ gestation), postnatal myelomeningocele surgical repair and prognosis, and pregnancy termination with autopsy. Because anencephaly is a lethal condition, pregnancy with anencephaly may be interrupted at any gestational age on the woman’s request. For an encephalocele, individualized counselling is recommended because of the possibly unique circumstances of the anomaly. (II-2A) 11. Caesarean section is the most common method of delivery for a fetus with a myelomeningocele (MCC) in either vertex or breech presentation, but is it with intrapartum fetal heart rate monitoring can be considered in selected MMC vertex presentation cases that have no macrocephaly related to gestational age and a small or no MMC sac. (II-2A) 12. Delivery management for a fetus with complex multiple anomalies including a neural tube defect will need to be individually determined by the multidisciplinary health care providers at the anticipated delivery centre based on the differential testing results, prenatal care requirements, anticipated neonatal morbidity or mortality, and family consultation and requests. (III-A) 13. Autopsy is recommended for all cases of prenatal and postnatal open/closed neural tube defect (isolated or complex) following either termination

OCTOBER JOGC OCTOBRE 2014

935

SOGC CLINICAL PRACTICE GUIDELINE

of pregnancy or prenatal/postnatal death. Induction of labour may be the preferred method for pregnancy termination, allowing for a more complete autopsy evaluation of the fetal central nervous system. If autopsy is declined, fetal magnetic resonance imaging should be considered to better evaluate fetal abnormalities either in utero or after postnatal death. If genetic studies have not been completed prior to the termination, at the minimum, chromosomal karyotyping and/or chromosomal microarray should be considered or encouraged, even if a full autopsy is not performed. This procedure will maximize information for postnatal review and counselling. (II-2A) Pregnancy Follow-up

14. Follow-up consultation is recommended when postnatal genetic and pathologic studies are complete, to provide the woman with information related to the etiology, risk of recurrence, recurrence prevention, and the possible impact on other family of the congenital isolated or complex anomaly. (II-2A) 15. When a previous pregnancy history is complicated by a presumed folic acid-sensitive open/closed neural tube defect (i.e., no karyotype, chromosomal etiology) for either member of the couple, or if either member of the couple planning the pregnancy is personally affected with an isolated neural tube disorder, oral folic acid supplementation of 5 mg within a multivitamin preparation should be recommended to the female partner, starting at least 3 months prior to pregnancy conception and

Although it may be cost effective, the MSAFP screen can detect only open NTDs; it has poor sensitivity and used as an adjunct to ultrasound when more detail of the CNS is required or when fetal therapy is being considered. MRI is more expensive and is not as readily available as ultrasound; further research is necessary to ensure its reported safety and to allow the creation of reference standards. Amniocentesis is an invasive diagnostic procedure that is accurate in the detection of ONTDs and in analyses for chromosomal or genetic abnormalities. With the use of ultrasound for guidance, amniocentesis performed by experienced hands, can greatly reduce the risks of miscarriage, infection, and harm to the fetus. However, although amniocentesis has a greater than 99% detection rate for ONTD, it is neither cost effective nor necessary for the detection of ONTD unless performed for the Improved prenatal screening and diagnosis will enable mothers or couples to obtain precise information about detected anomalies so they can make informed decisions about whether to continue or interrupt the pregnancy and what their options are for fetal or postnatal repair. Our current knowledge and experience indicates that pregnant woman should be offered 2 prenatal screening approaches: 1. risk screening for fetal aneuploidy and fetal anomalies, using a combination of non-invasive techniques that includes ultrasound (fetal anatomic and structural detail) and 2. maternal serum testing for placental biochemical

SUMMARY

NTDs occur early in embryologic development, secondary to failure of fusion of the neural groove and formation of the neural tube. NTDs include malformations or disruptions in the lower spine and upper cranium and occur in approximately 1 in 1000 live births. There are 2 methods of prevention: primary prevention with

trimester screening approaches) or for placental cellfree fetal DNA (for future direct fetal molecular DNA screening or diagnostic testing). REFERENCES 1. Frey L, Ha WA. Epidemiology of neural tube defects. Epilepsia 2003;44(3):4–13.

and secondary prevention with prenatal screening and pregnancy interruption.

2. Gucciardi E, Pietrusiak M, Reynolds DL, Rouleau J. Incidence of neural tube defects in Ontario 1986-1999. CMAJ 2002;167(3):237–40.

Ultrasound is presently the best screening method for prenatal detection of fetal anomalies including NTDs because of its safety, availability, accuracy, and costeffectiveness. MSAFP screening should be used in limited clinical scenarios as an additional screening method.

FZD6 is a novel gene for human neural tube defects. Human Mutation 2011;3:384–90.

936

OCTOBER JOGC OCTOBRE 2014

Chambers GK, et al. The impact of prenatal diagnosis on neural tube defect (NTD) pregnancy versus birth incidence in British Columbia. J Appl Genet 2006;47:151–58.

Prenatal Screening, Diagnosis, and Pregnancy Management of Fetal Neural Tube Defects

Preconceptional vitamin/folic acid supplementation 2007: the use of folic acid in combination with a multivitamin supplement for the prevention of neural tube defects and other congenital anomalies. J Obstet Gynaecol Can 2007;29:1003–26.

N Engl J Med 2007;357(2):135–42. 7. Lu QB, Wang ZP, Gong R, Sun XH, Gao LJ, Zhao ZT. Investigation of in rural areas of China. Public Health 2011;125:639–44. 8. Kokalj TS, Rejc B, Gersak K. Incidence and prevention of neural tube defects in Slovenia. Eur J Obstet Gynecol 2011;156:119–20. 9. Cameron M, Moran P. Prenatal screening and diagnosis of neural tube defects. Prenatal Diagnosis 2009;29:402–11. 10. Bamforth FJ. Laboratory screening for genetic disorders and birth defects. Clin Biochem 1994;27:333–42.

25. Ewigman BG, Crane JP, Frigoletto FD, LeFevre ML, Bain RP, McNellis D. Effect of prenatal ultrasound screening on perinatal outcome. N Engl J Med 1993;329:821–7. 26. Saari-Kemppainen A, Karjalainen O, Ylostalo P, Heinonen O. Ultrasound screening and perinatal mortality: Controlled trial of systematic one-stage screening in pregnancy. Int J Gynaecol Obstet 1991;35:100. 27. Saleem SN, Said AH, Abdel-Raouf M, El-Kattan EA, Zaki MS, Madkour N, et al. Fetal MRI in the evaluation of fetuses referred for sonographically suspected neural tube defects (NTDs)—impact on diagnosis and management decision. Neuroradiology 2009;51:761–72. 28. Boulet SL, Yang Q, Mai C, Kirby RS, Collins JS, Robbins JM, et al; National Birth Defects Prevention Network. Trends in the United States. Birth Defects Res A Clin Mol Teratol 2008;82:527–32. 29. Shurtleff DB, Luthy DA, Nyberg DA, Benedetti TJ, Mack LA. Meningomyelocele: management in utero and post natum. Ciba Found Symp 1994;181:270–86. Neurol 1997;39:568.

concentration of second-trimester maternal serum a-fetoprotein. Am J Obstet Gynecol 1999;180:1227–33. 12. Harris RA, Washington AE, Nease RF, Kupperman M. Cost utility of prenatal diagnosis and the risk-based threshold. Lancet 2004;363:276–82. 13. EUROCAT Working Group. Prevalence of neural tube defects in 20 regions of Europe and the impact of prenatal diagnosis, 1980-1986. Epistemiol Community Health 1991;4552–8. 14. Cuckle HS, Wald NJ, Cuckle PM. Prenatal screening and diagnosis of neural tube defects in England and Wales in 1985. Prenat Diagnos 1989;9:393–400. 15. Roberts N, Bhide A. Ultrasound prenatal diagnosis of structural abnormalities. Obstet Gynaecol Reprod Med 2007;17:1–8. 16. Norem CT, Schoen EJ, Walton DL, Krieger RC, O’Keefe J, To TT, et al. Routine ultrasonography compared with maternal serum alpha-fetoprotein for neural tube defect screening. Obstet Gynecol 2005;106:747–52. 17. Driscoll DA, Gross SJ. Screening for fetal aneuploidy and neural tube defects. Genet Med 2009;11:818–21. 18. Chodirker BN, Cadrin C, Davies GAL, Summers AM, Wilson RD, Winsor EJT, et al. Canadian guidelines for prenatal diagnosis. Part 1: genetic indicators for prenatal diagnosis. SOGC Clinical Practice Guidelines, No. 105, June 2001. J Obstet Gynaecol Can 2001;23:525–31. 19. Johnson JA, Summers A. Prenatal genetic screening for Down syndrome and open neural tube defects using maternal serum marker screening. J Obstet Gynaecol Can 1999;21:887–91. 20. Wald NJ, Hackshaw A, Stone R, Densem J. Serum alpha-fetoprotein 1993;13:1047–50. 21. Sohn YS, Kim MJ, Kwon JY, Kim YH, Park YW. The usefulness of fetal MRI for prenatal diagnosis. Yonsei Med J 2007;48:671–7. 22. Pugash D, Brugger PC, Bettelheim D, Prayer D. Prenatal ultrasound and fetal MRI: the comparative value of each modality in prenatal diagnosis. Eur J Radiol 2008; 68:214–26. 23. Delisle M, Wilson RD. First trimester prenatal diagnosis: amniocentesis. Semin Perinatol 1999;23:414–23. 24. Zambelli H, Carelli E, Honorato D, Marba S, Coelho G, Carnevalle A, et al. Assessment of neurosurgical outcome in children prenatally diagnosed with myelomeningocele and development of a protocol for fetal surgery to prevent hydrocephalus. Childs Nerv Syst 2007;23:421–5.

31. Manning SM, Jennings R, Madsen JR. Pathophysiology, prevention and potential treatment of neural tube defects. Ment Retard Dev Disabil Res Rev 2000;6:6–14. 32. Ghi T, Pilu G, Falco P, Segata M, Carletti A, Cocchi G, et al. Prenatal 2006;28:899–903. 33. Kanit H, Özkan AA, Öner SR, Ispahi C, Endrikat JS, Ertan K. Chromosomal abnormalities in fetuses with ultrasonographically detected neural tube defects. Clin Dysmorphol 2012;20:190–3. 34. Drugan A, Johnson MP, Dvorin E, Moody J, Krivchenia EL, Schwartz D, et al. Aneuploidy with neural tube defects: another reason for complete evaluation in patients with suspected ultrasound anomalies or elevated maternal serum alpha-fetoprotein. Fetal Diagn Ther 1989;4:88–92. 35. Harmon JP, Hiett Ak, Palmer CG, Golichowski AM. Prenatal ultrasound detection of isolated neural tube defects is cytogenetic evaluation warranted? Obstet Gynecol 1995:86:595–9. 36. Hume RF, Drugan A, Reichler A, Lampinen J, Martin LS, Johnson MP, et al. Aneuploidy among prenatally detected neural tube defects. Am J Med Genet 1996;61:171-173. 37. Kennedy D, Chitayat D, Winsor EJ, Silver M, Toi A. Prenatally diagnosed neural tube defects: ultrasound, chromosome, and autopsy or postnatal 38. Chen, . Syndromes, disorders and maternal risk factors associated with

human neural tube defects: genetic causes and prevention. Biofactors 2011;37;261–8. 40. Alfarra HY, Alfarra SR, Sadiq MF. Neural tube defects between folate metabolism and genetics. Ind J Hum Genet 2011;17(3):126–31. 41. Aneji CN, Northrup H, Au KS. Deep sequencing study of the MTHFR gene to identify variants associated with myelomeningocele. Birth Defects Res A Clin Mol Teratol 2012;94:84–90. 42. Wang XW, Luo YL, Wang W, Zhang Y, Chen Q, Cheng LY. Association between MTHFR A1298C polymorphism and neural tube defect susceptibility: a meta-analysis. Am J Obstet Gynecol 2012;251:e1–e7. 43. Cargill Y, Morin L; Society of Obstetricians and Gynaecologists of Canada. Diagnostic Imaging Committee. Content of a complete routine second trimester obstetrical ultrasound examination and report. SOGC Clinical Practice Guidelines, No. 223, March 2009. J Obstet Gynaecol Can 2009;31:272–5.

OCTOBER JOGC OCTOBRE 2014

937

SOGC CLINICAL PRACTICE GUIDELINE

44. Dashe JS, Twickler DM, Santos-Ramos R, McIntire DD, Ramus RM. Alpha-fetoprotein detection of neural tube defects and the impact of standard ultrasound. Am J Obstet Gynecol 2006;195:1623–8.

63. Scheier M, Lachmann R, Petros M, Nicolaides KH. Three-dimensional

45. Benn PA, Borgida A, Home D, Briganti S, Collins R, Rodis JF. Down syndrome and neural tube defect screening—the value of using gestational age by ultrasonography. Am J Obstet Gynecol 1997;176:1056–61.

64. Lachmann R, Chaoui R, Moratalla J, Picciarelli G, Nicolaides KH.

11-13 weeks’ gestation. Ultrasound Obstet Gynecol 2011;38:625–9.

Diagn 2011;31:103–6. 65. Loureiro T, Ushakov F, Montenegro N, Gielchinsky Y, Nicolaides KH.

46. Lee W, Chaiworapongsa T, Romero R, Williams R, McNie B, Johnson A, weeks’ gestation. Ultrasound Obstet Gynecol 2012;39:620–4. dimensional ultrasonography. J Ultrasound Med 2002;21:619–26. 47. Malhotra N, Rao JP, Malhotra J, Malhotra N. Ultrasound for screening fetal malformations—has 3-D made a difference? J SAFOG 2012;2:7–10. 48. Garne E, Dolk H, Loane M, Boyd PA. EUROCAT website data on prenatal detection rates of congenital anomalies. J Med Screen 2010;17:97–8. SOGC Imaging Committee.. Fetal soft markers in obstetric ultrasound. SOGC Clinical Practice Guidelines, No. 162, June 2005. J Obstet Gynaecol Can 2005; 27:592–612. Society of Obstetricians and Gynaecologists of Canada. Evaluation of prenatally diagnosed structural congenital anomalies. SOGC Committee Opinion, No. 234, Sept 2009. J Obstet Gynaecol Can 2009;31:875–81. 51. Wald NJ, Cuckle H, Brock JH, Peto R, Polani PE, Woodford FP. Maternal serum-alpha-fetoprotein measurement in antenatal screening Collaborative Study on Alpha-fetoprotein in Relation to Neural-tube Defects. Lancet 1977;309:1323–32. of prenatal maternal serum alpha-feto protein screening. Med Care 1988;26:1185–202. and chorionic villus sampling for prenatal genetic testing. Med Care 1994;32:863–80. 54. Bredaki FE, Wright D, Akolekar R, Cruz G, Nicolaides KH. Maternal serum alpha-fetoprotein in normal pregnancy at 11-13 weeks’ gestation. Fetal Diagn Ther 2011;30:274–9. 55. Bredaki FE, Poon LC, Birdir C, Escalante D, Nicolaides KH. Firsttrimester screening for neural tube defects using alpha-fetoprotein. Fetal Diagn Ther 2012;31:109–14. 56. Stratmeyer ME, Greenleaf JF, Dalecki D, Salvesen KA. Fetal ultrasound: mechanical effects. J Ultrasound Med 2008;27:597–605.

Fetal MRI: a developing technique for the developing patient. AJR Am J Roentgenology 2004;182:243–52. 67. Garel C. Fetal MRI: what is the future? Ultrasound Obstet Gynecol 2008;31:123–8. 68. Glenn OA, Cuneo AA, Barkovich AJ, Hashemi Z, Bartha AI, Xu D. Malformations of cortical development- diagnostic accuracy of fetal MR imaging. Radiology 2012;263(3):843–55. 69. Girard N, Chaumoitre K, Chapon F, Pineau S, Barberet M, Brunel H. Fetal magnetic resonance imaging of acquired and developmental brain anomalies. Semin Perinatol 2009;33:234–50. 70. Ljubic A, Cetkovic A, Mikic AN, Stamenkovic JD, Jovanovic I, Opincal TS, et al. Ultrasound vs MRI in diagnosis of fetal and maternal complications. Ultrasound Review 2001;5(2/3):231–42. 71. Cannie M, Jani J, Dymarkowski S, Deprest J. Fetal magnetic resonance imaging: luxury or necessity? Ultrasound Obstet Gynecol 2006;27:471–6. 72. Al-Mukhtar A, Kasprian G, Schmook MT, Brugger PC, Prayer D. Diagnostic pitfalls in fetal brain MRI. Semin Perinatol 2009;33:251–8. 73. Sutton LN. Fetal surgery for neural tube defects. Best Pract Res Clin Obstet Gynaecol 2008;22:175–88. 74. Adzick NS, Thom EA, Spong CY, Brock JW, Burrows PK, Johnson MP, et al. A randomized trial of prenatal versus postnatal repair of myelomeningocele. N Engl J Med 2011;364:993–1004. 75. Patenaude Y, Pugash D, Lim K, Morin L; SOGC Diagnostic Imaging Committee. The use of Magnetic Resonance Imaging in the obstetric patient. SOGC Clinical Practice Guidelines, No. 306, April 2014. J Obstet Gynaecol Can 2014;36:349–355. 76. Bulas D. Fetal magnetic resonance imaging as a complement to fetal ultrasonography. Ultrasound Q 2007;23:3–22. Clin Radiol 2013;68:e715-e722. 78. Ben-Sira L, Garel C, Malinger G, Constantini S. Prenatal diagnosis of spinal dysraphism. Childs Nerv Syst 2013;29:1541–52.

Review 2005;5:297–303. 58. Roberts CJ, Hibbard BM, Roberts EE, Ecans KT, Laurence KM, Robertson IB. Diagnostic effectiveness of ultrasound in detection of neural tube defect: the South Wales experience of 2509 scans (1977-1982) in high-risk mothers. Lancet 1983;2:1068–9.

et al. Maternal serum alpha-fetoprotein screening for neutal tube defects and other disorders using an ultramicro-ELISA. Collaborative study in Cuba and in the German Democratic Republic. Hum Genet 1986;73:60–3.

59. Hosny IA, Elghawabi HS. Ultrafast MRI of the fetus: an increasingly important tool in prenatal diagnosis of congenital anomalies. Magn Reson Imaging 2010;28:1431–9.

Acta Obstet Gynecol Scand 2007;86:67–71.

60. Cameron M, Moran P. Prenatal screening and diagnosis of neural tube defects. Prenat Diagn 2009;29:402–11. 61. Chaoui R, Benoit B, Mitkowska-Wozniak H, Heling KS, Nicolaides KH. Assessment of intracranial translucency (IT) in the detection 2009;34:249–52.

81. Wapner RJ, Martin CL, Levy B, Ballif BC, Eng CM, Zachary JM, et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med 2012;367:2175–84. et al. Karyotype versus microarray testing for genetic abnormalities after stillbirth. N Engl J Med 2012;367:2185–93.

62. Lachmann R, Picciarelli G, Moratalla J, Greene N, Nicholaides KH. gestation. Ultrasound Obstet Gynecol 2010;36:268–71.

938

OCTOBER JOGC OCTOBRE 2014

Connolly S, et al. Clinical diagnosis by whole-genome sequencing of a prenatal sample. N Engl J Med 2012;367:2226–32.

Prenatal Screening, Diagnosis, and Pregnancy Management of Fetal Neural Tube Defects

84. Shumway JB, Greenspoon JS, Khouzami AN, Platt LD, Blakemore KJ. fetoprotein (MSAFP) in abdominal pregnancies: correlation with extent and site of placental implantation and clinical implications. J Matern Fetal Med 1996;5:120–3. 85. Laurence KM, Elder G, Evans KT, Hibbard BM, Hooles M, Roberts CJ. Should women at high risk of neural tube defect have an amniocentesis? J Med Genet 1985;22:457–61. 86. Nizard J. Amniocentesis: technique and education. Curr Opin Obstet Gynecol 2010;22:152–4. 87. Wilson RD, Langlois S, Johnson JA; Genetics Committee and CCMG Prenatal Diagnosis Committee of the Society of Obstetricians and Gynaecologists of Canada. Mid-trimester amniocentesis fetal loss rate. SOGC Committee Opinion, No. 194, July 2007. J Obstet Gynaecol Can 2007;29:586–90. 88. Kooper AJ, de Bruijn D, van Ravenwaaij-Arts CMA, Faas BHW, Creemers JWT, Thomas CMG, et al. Fetal anomaly scan potentially will replace routine AFAFP assays for the detection of neural tube defects. Prenat Diagn 2007;27:29–33.

97. Cochrane D, Aronyk K, Sawatzky B, Wilson D, Steinbok P. The effects of labour and delivery on spinal cord function and ambulation in patients with meningomyelocele. Child Nerv Syst 1991;7:312–5. section delivery improve diagnosis? Obstet Gynecol 1988;71:532–4. 99. Sakala EP, Andree I. Optimal route of delivery for meningomyelocele. Obstet Gynecol Surv 1990;45:209–12. 100. Hill AE, Beattie F. Does caesarean section delivery improve neurological 101. Merrill DC, Goodwin P, Burson JM, Sato Y, Williamson R, Weiner . The optimal route of delivery for fetal meningomyelocele. Am J Obstet Gynecol 1998;179:235–40. 102. Luthy DA, Wardinsky T, Shurtleff DB, Hollenback KA, Hickok DE, Nyberg DA, et al. Cesarean section before the onset of labor and subsequent motor function in infants with meningomyelocele diagnosed antenatally. N Engl J Med 1991;324:662–6. 103. Simpson JL, Greene MF. Fetal surgery for myelomeningocele? N Engl J Med 2011;364: 1076–7. 104. Dickens BM, Cook RJ. Ethical and legal issues in reproductive health. Legal and ethical issues in fetal surgery. Int J Gynaecol Obstet 2011;115:80–3.

Child Neurol 2007;49:458–63. 35: prospective community based cohort study. BMJ 2003;326:1365–6. outcome: a 25-year prospective. Pediatr Neurosurg 2001;34:114-120. 93. Yi Y, Lindemann M, Colligs A, Snowball C. Economic burden of neural tube defects and impact of prevention with folic acid: a literature review. Eur J Pediatr 2011;170:1391–400. 94. ACOG Committee on Practice Bulletins. Neural tube defects. ACOG Practice Bulletin. Clinical Management Guidelines for ObstetricianGynecologists. No 44, July 2003 (Replaces Committee Opinion Number 252, March 2001). Obstet Gynecol 2003;102:203–13. behavior in fetuses with congenital abnormalities. Ultrasound Obstet Gynecol 1997;9:302–9. outcome: a 25-year prospective. Pediatr Neurosurg 2001;34:114–20.

105. Barry S. Quality of life and myelomeningocele: an ethical and evidence-based analysis of the Groningen protocol. Pediatr Neurosurg 2010;46:409–14. EUROCAT working group. Survey of prenatal screening policies in Europe for structural malformations and chromosome anomalies, and their impact on detection and termination rates for neural tube defects and Down’s syndrome. BJOG 2008;115:689–96. Committees of the Society of Obstetricians and Gynaecologists of Canada. Fetal and perinatal autopsy in prenatally diagnosed fetal abnormalities with normal karyotype. SOGC Technical Update, No. 267, October 2011. J Obstet Gynaecol Can 2011;33:1047–57. 108. Miller EC, Liu N, Wen SW, Walker M. Why do Canadian women fail to achieve optimal pre-conceptional folic acid supplementation? An observational study. J Obstet Gynaecol Can 2011;33:1116–23. 109. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

OCTOBER JOGC OCTOBRE 2014

939

SOGC CLINICAL PRACTICE GUIDELINE No. 315, November 2014

The Prevention of Ovarian Hyperstimulation Syndrome This clinical practice guideline has been prepared by the Reproductive Endocrinology Infertility Committee and approved by Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Shannon Corbett, MD, Ottawa ON Doron Shmorgun, MD, Ottawa ON Paul Claman, MD, Ottawa ON

Abstract Objective: To review the clinical aspects of ovarian hyperstimulation syndrome and provide recommendations on its prevention. Options: Preventative measures, early recognition, and prompt systematic ive care will help avoid poor outcomes. Outcomes: Establish guidelines to assist in the prevention of ovarian hyperstimulation syndrome, early recognition of the condition when it occurs, and provision of appropriate ive measures in the correct setting.

James Graham, MD, Calgary AB

Evidence: Published literature was retrieved through searches of Medline, Embase, and the Cochrane Library from 2011 to 2013 using appropriate controlled vocabulary ([OHSS] ovarian hyperstimulation syndrome and: agonist IVF, antagonist IVF, metformin, HCG, gonadotropin, coasting, freeze all, agonist trigger, progesterone) and key words (ovarian hyperstimulation syndrome, ovarian stimulation, gonadotropin, human chorionic gonadotropin, prevention). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies published in English. There were no date restrictions. Searches were updated on a regular basis and incorporated in the guideline to February 2013.

Jon Havelock, MD, Burnaby BC



REPRODUCTIVE ENDOCRINOLOGY INFERTILITY COMMITTEE Anthony Cheung, MD (Co-chair), Vancouver BC Sony Sierra, MD (Co-chair), Toronto ON Belina Carranza-Mamane, MD, Sherbrooke QC Allison Case, MD, Saskatoon SK Cathie Dwyer, RN, Toronto ON

Sarah Healey, MD, St. John’s NL Robert Hemmings, MD, Montreal QC Kimberly Liu, MD, Toronto ON Tarek Motan, MD, Edmonton AB Ward Murdock, MD, Fredericton NB David Smithson, MD, London ON Tannys Vause, MD, Ottawa ON Benjamin Wong, MD, Calgary AB SPECIAL CONTRIBUTOR Mathias Gysler, MD, Oakville ON

Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technologyrelated agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies.

Values: The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). Summary Statements 1. The particular follicle-stimulating hormone formulation used for ovarian stimulation does not affect the incidence of ovarian hyperstimulation syndrome. (I) 2. Coasting may reduce the incidence of severe ovarian hyperstimulation syndrome. (III)

Disclosure statements have been received from all contributors.

J Obstet Gynaecol Can 2014;36(11):1024–1033

Key Words: Ovarian hyperstimulation syndrome, ovarian stimulation, gonadotropin, human chorionic gonadotropin, prevention

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

1024 l NOVEMBER JOGC NOVEMBRE 2014

The Prevention of Ovarian Hyperstimulation Syndrome

Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.65 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care.65

3. Coasting for longer than 3 days reduces in vitro fertilization pregnancy rates. (II-2) 4. The use of either luteinizing hormone or human chorionic gonadotropin for final oocyte maturation does not influence the incidence of ovarian hyperstimulation syndrome. (I) 5. There is no clear published evidence that lowering the human chorionic gonadotropin dose will result in a decrease in the rate of ovarian hyperstimulation syndrome. (III) 6. Cabergoline starting from the day of human chorionic gonadotropin reduces the incidence of ovarian hyperstimulation syndrome in patients at higher risk and does not appear to lower in vitro fertilization pregnancy rates. (II-2)

7. Avoiding pregnancy by freezing all embryos will prevent severe prolonged ovarian hyperstimulation syndrome in patients at high risk. (II-2) 8. Pregnancy rates are not affected when using gonadotropinreleasing hormone (GnRH) agonists in GnRH antagonist protocols for final egg maturation when embryos are frozen by vitrification for later transfer. (II-2) Recommendations 1. The addition of metformin should be considered in patients with polycystic ovarian syndrome who are undergoing in vitro fertilization because it may reduce the incidence of ovarian hyperstimulation syndrome. (I-A) 2. Gonadotropin dosing should be carefully individualized, taking into the patient’s age, body mass, antral follicle count, and previous response to gonadotropins. (II-3B)

ABBREVIATIONS ART

assisted reproductive technology

CI

confidence interval

FSH

follicle-stimulating hormone

GnRH

gonadotropin-releasing hormone

hCG

human chorionic gonadotropin

HES

hydroxyethyl starch

IVF

in vitro fertilization

LH

luteinizing hormone

LPS

luteal phase

OHSS

ovarian hyperstimulation syndrome

OR

odds ratio

PCOS

polycystic ovary syndrome

RCT

randomized control study

SC

subcutaneously

VEGF

vascular endothelial growth factor

3. Cycle cancellation before istration of human chorionic gonadatropin is an effective strategy for the prevention of ovarian hyperstimulation syndrome, but the emotional and financial burden it imposes on patients should be considered before the cycle is cancelled. (III-C) 4. Gonadotropin-releasing hormone (GnRH) antagonist stimulation protocols are recommended in patients at high risk for ovarian hyperstimulation syndrome (OHSS). The risk of severe OHSS in patients on GnRH antagonist protocols who have a very robust ovarian stimulation response can be reduced by using a GnRH agonist as a substitute for human chorionic gonadotropin to trigger final oocyte maturation. (I-B) 5. A gonadotropin-releasing hormone (GnRH) antagonist protocol with a GnRH agonist trigger for final oocyte maturation is recommended for donor oocyte and fertility preservation cycles. (III-C) 6. Albumin or other plasma expanders at the time of egg retrieval are not recommended for the prevention of ovarian hyperstimulation syndrome. (I-E) 7. Elective single embryo transfer is recommended in patients at high risk for ovarian hyperstimulation syndrome. (III-C)

NOVEMBER JOGC NOVEMBRE 2014 l 1025

SOGC Clinical Practice Guideline

8. Progesterone, rather than human chorionic gonadotropin, should be used for luteal phase . (I-A)

Table 2. Classification of OHSS

9. Outpatient culdocentesis should be considered for the prevention of disease progression in severe ovarian hyperstimulation syndrome. (II-2B)

Grade

Symptoms

Mild OHSS

Abdominal bloating Mild abdominal pain Ovarian size usually < 8 cm

INTRODUCTION

O

HSS is a iatrogenic complication of exogenous gonadotropin therapy used to mature multiple follicles for assisted reproductive treatments. The syndrome is only rarely observed with clomiphene citrate treatment but has been reported even after spontaneous ovulation.1 Published guidelines already exist on the management of patients suffering from severe OHSS.2 The goal of this guideline is to provide a practical, evidence-based framework for the prevention of OHSS. After gonadotropin stimulation for IVF, the reported incidence of moderate OHSS is 3% to 6%, and for severe OHSS it is 0.1% to 2%.3,4 The mild form, which has little clinical consequence, occurs in about 20% to 33% of IVF cycles3,5 and is of little clinical concern. However, fatalities have been reported in the most severe cases.6 Except during rare events, OHSS occurs only after ovulation (i.e. after exposure to an endogenous LH surge, to exogenous LH or hCG, or to endogenous hCG of pregnancy).7 Early OHSS symptoms may begin as soon as 24 hours after hCG istration, but become most severe 7 to 10 days after hCG; severe OHSS is usually associated with the rise of endogenous hCG from an early pregnancy8 (see Table 2). Physicians prescribing ovarian stimulation need to identify patients at increased risk for OHSS in order to apply preventive and active management strategies to minimize morbidity from this complication of fertility treatment. Pathophysiology of OHSS

OHSS is a systemic disease thought to result from vasoactive peptides released from the granulosa cells in hyperstimulated ovaries.7 The fundamental physiological change in severe OHSS is an increase in vascular perme­ ability, resulting in a fluid shift from the intravascular spaces to third-space compartments such as the peritoneal and thoracic cavities, often resulting in hemoconcentration.9,10 The most important mediator in this process is thought to be VEGF.11 ing evidence comes from studies showing that serum VEGF levels correlate with OHSS severity. Additionally, hCG has been shown to increase VEGF expression in human granulosa cells, which in turn raises serum VEGF concentration.12,13 A new body of clinical data demonstrates how the istration of dopamine agonist drugs decreases VEGF activity, which in 1026 l NOVEMBER JOGC NOVEMBRE 2014

Moderate OHSS

Moderate abdominal pain Nausea with/without vomiting Ultrasound evidence of ascites Ovarian size usually 8–12 cm

Severe OHSS

Clinical ascites (occasionally pleural effusion) Oliguria Hemoconcentration hematocrit (> 45%) Hypoproteinemia Ovarian size usually > 12 cm

Critical OHSS

Tense ascites or large pleural effusion Hematocrit (> 55%) White cell count > 25 000/L Oligo/anuria Thromboembolism Acute respiratory distress syndrome

Reproduced with permission of the British Fertility Society.1

turn decreases the clinical burden of OHSS.14 Numerous other mediators have been implicated in the disease process such as angiotensin II, insulin-like growth factor 1 and interleukin-6.2 Risk Factors

Several factors have been demonstrated to independently increase the risk of developing OHSS. These include •• age < 30 years,15 •• polycystic ovaries (i.e., > 24 antral follicles present on baseline ultrasound examination),16,17 •• high serum estradiol at hCG trigger or rapidly rising serum estradiol,15 •• previous episodes of OHSS,18 •• large number of small follicles (8 to 12 mm) seen on ultrasound during ovarian stimulation,17 •• use of hCG, as opposed to progesterone, for luteal phase after IVF,18 •• large number of oocytes retrieved (> 20),19 and •• high anti-müllerian hormone (> 3.36 ng/mL).20 PREVENTION

Physicians providing ART treatment must balance the competing interests of trying to sufficiently stimulate the

The Prevention of Ovarian Hyperstimulation Syndrome

ovary to optimize the chance of achieving a pregnancy and minimizing the risk of severe OHSS. To achieve both of these goals both primary and secondary preventative measures have been shown to be useful.1 Primary prevention involves identifying risk factors for OHSS and choosing an appropriate ovarian stimulation regimen. Secondary prevention involves recognizing patients who are over-responsive to gonadotropins and intervening to reduce the risk of OHSS while still trying to salvage the treatment cycle. A meta-analysis of 5 RCTs showed a significant reduction in the incidence of OHSS with the use of metformin in women with PCOS undergoing IVF (12/216 vs. 44/210; OR 0.21, 95% CI 0.11 to 0.41, P < 0.01).21 These findings were later corroborated in a Cochrane review from the same group.22 Interestingly, a recent RCT showed that women with polycystic ovarian morphology that does not meet the criteria for PCOS do not incur the same protective benefit from metformin of reduced OHSS.23 Metformin should ideally be started 8 weeks before planned gonadotropin stimulation to be effective in OHSS prevention. To minimize gastrointestinal side effects we recommend starting Metformin at a low dose of 500 mg HS and slowly increasing the dose until the effective dose of 500 mg × 3 (1500 mg) daily is reached. Metformin should continue until egg retrieval. Two separate meta-analyses of RCTs comparing recombinant FSH and urinary FSH showed no difference in the incidence of OHSS.24,25 There is no linear positive correlation between gonadotropin dose and the incidence of severe OHSS. On the contrary, patients developing OHSS tend to be those who respond robustly to gonadotropins and are often prescribed lower than average doses of these drugs than other women undergoing IVF. Young, thin women, especially those with polycystic ovaries on ultrasound (i.e., > 12 antral follicles seen on each ovary) are at higher risk for OHSS and should receive a lower starting dose of gonadotropin than would be given to other women.26 Careful monitoring of these patients during stimulation is prudent to allow for a decrease in the dose of gonadotropins if a very robust response is detected early in the treatment cycle.18 Summary Statement

1. The particular follicle-stimulating hormone formulation used for ovarian stimulation does not affect the incidence of ovarian hyperstimulation syndrome. (I)

Recommendations

1. The addition of metformin should be considered in patients with polycystic ovarian syndrome who are undergoing in vitro fertilization because it may reduce the incidence of ovarian hyperstimulation syndrome. (I-A) 2. Gonadotropin dosing should be carefully individualized, taking into the patient’s age, body mass, antral follicle count, and previous response to gonadotropins. (II-3B) Coasting

Coasting involves withholding gonadotropins while maintaining pituitary suppression with a gonadotropinreleasing hormone agonist or antagonist. istering hCG to trigger oocyte maturation once estrogen levels plateau or drop is thought to reduce the risk for OHSS. Larger follicles have a lower requirement for FSH than smaller follicles. Once follicles are > 12 mm in diameter, stopping all gonadotropins still allows for larger follicles to continue their growth and maturation, while smaller follicles undergo atresia, which may result in reduced production of vasoactive peptides such as VEGF.27 It has been shown that coasting on a GnRH agonist for up to 3 days does not adversely affect pregnancy rates.28 The same criteria for coasting can be applied to GnRH antagonist cycles as to GnRH agonist cycles with similar IVF outcomes.29 In a systematic review of 12 retrospective studies examining the benefit of coasting, the coasted patients had a 2.5% incidence of hospitalization for OHSS, which is lower than expected for patients at high risk for OHSS.30 Previous studies have shown a significant drop in pregnancy rate with longer than 3 to 4 days of coasting.28,31 Therefore, cycle cancellation should be considered if estradiol levels do not start to fall by the fourth day of coasting. A meta-analysis of 3 RCTs comparing recombinant LH with urinary hCG for triggering final oocyte maturation and 11 RCTs comparing recombinant hCG with urinary LH did not show any difference in the risk of OHSS.32 Summary Statements

2. Coasting may reduce the incidence of severe ovarian hyperstimulation syndrome. (III) 3. Coasting for longer than 3 days reduces in vitro fertilization pregnancy rates. (II-2) 4. The use of either luteinizing hormone or human chorionic gonadotropin for final oocyte maturation does not influence the incidence of ovarian hyperstimulation syndrome. (I)

NOVEMBER JOGC NOVEMBRE 2014 l 1027

SOGC Clinical Practice Guideline

The degree of hCG exposure has been associated with the risk of OHSS.18 It is recognized that hCG has no direct effect on the vascular system33; however, vasoactive substances such as VEGF are released in the ovary in response to hCG istration and are most likely responsible for inducing vascular hyperpermeability and third-spacing in high-risk women.34 A retrospective series of 94 IVF cycles showed that when hCG doses were lowered, both pregnancy rates and the rate of severe OHSS remained unchanged.35 However, a lower incidence of severe OHSS has been observed with the use of lower doses of hCG for final oocyte maturation in an at-risk population. Because serum levels of hCG are dependent on body mass,36,37 one Canadian fertility centre uses hCG 5000 IU SC to trigger final egg maturation in patients at risk for OHSS who have a BMI < 28 kg/m2, despite the lack of published data. Women with a BMI ≥ 28 kg/m2 are all given hCG 10 000 IU SC for final egg maturation because yields of mature eggs have been observed to be lower with a dose reduction in this population.36 Summary Statement

5. There is no clear published evidence that lowering human chorionic gonadotropin dose will result in a decrease in the rate of ovarian hyperstimulation syndrome. (III) Cabergoline

VEGF produced by granulosa cells of developing follicles is thought to be a key mediator in both hCG-dependent ovarian angiogenesis and the pathophysiology of OHSS.38 Recently, the dopamine agonist cabergoline has been introduced as a secondary prevention strategy in women deemed to be at high risk for OHSS because of a very robust gonadotropin response at the end of a controlled ovarian stimulation cycle. Dopamine agonists show similar effects to anti-angiogenic drugs on vascular permeability, and except for occasional nausea, they appear not to have undesirable side effects.33,39 Evidence from animal models shows that cabergoline blocks VEGF-mediated increase in vascular permeability without affecting angiogenesis.33 Carbergoline’s postulated mechanism of action is partial inhibition of the phosphorylation of its associated receptor, the VEGF receptor 2.40 A recent Cochrane review included 2 RCTs addressing cabergoline and OHSS. In the RCT conducted by Alvarez et al. on oocyte donors at risk for OHSS (20 to 30 follicles at > 12 mm and > 20 eggs retrieved), in which the treatment group received oral cabergoline 0.5 mg daily for 8 days starting on the day of hCG and the control group received a placebo, the incidence of moderate OHSS was significantly reduced in the cabergoline group (20% vs. 1028 l NOVEMBER JOGC NOVEMBRE 2014

43.8%, P = 0.04).14 The same first author also showed that pregnancy rates are not compromised in patients given cabergoline.41 The second RCT by Carriza et al. randomized women who were undergoing IVF and at high risk for OHSS (estradiol ≥ 14 700 pmol/L on day of hCG trigger) into two groups: the study group received 20 grams of prophylactic intravenous albumin and 0.5 mg of Cabergoline orally once daily for 3 weeks commencing the day after oocyte retrieval and the control group received only albumin.42 The risk of early OHSS (occurring within the first 9 days after hCG trigger) decreased significantly (P < 0.001) in the cabergoline group; none of the patients who had taken cabergoline progressed to early OHSS, but 15.0% of the control group did. The risk of late OHSS did not decrease. In both of the RCTs examined, the use of cabergoline did not affect the pregnancy outcome (clinical pregnancy rate or miscarriage rate), nor was it associated with an increased risk of adverse events.43 Two published abstracts have demonstrated the safety and efficacy of using cabergoline at even smaller doses: 0.5 mg twice weekly for 6 doses44 and 0.5 mg twice weekly for 3 doses.45 Clinicians at one Canadian fertility centre use a dose of cabergoline 0.5 mg every 3 days to a total of 4 doses starting on the day of oocyte maturation trigger and a significant reduction in the incidence of severe OHSS has been anecdotally observed since the introduction of cabergoline into the prevention strategies for OHSS. Although still somewhat preliminary, current data suggest that cabergoline is associated with a reduction in moderate OHSS in patients at high risk and has no adverse effect on the pregnancy rate. Summary Statement

6. Cabergoline starting from the day of human chorionic gonadotropin reduces the incidence of ovarian hyperstimulation syndrome in patients at higher risk and does not appear to lower in vitro fertilization pregnancy rates. (II-2) Cycle Cancellation

OHSS will not develop in the absence of exposure to exogenous hCG or LH or to an endogenous LH surge as long as a pregnancy does not develop. Therefore, withholding hCG in cycles at risk for OHSS and cancelling the cycle is the most effective method of preventing OHSS. This prevention strategy is especially important in agonist cycles in which the option to substitute an agonist trigger for hCG does not exist. However, because the emotional and financial costs of cancellation are significant, other prevention strategies should be exhausted before cycle cancellation is considered.

The Prevention of Ovarian Hyperstimulation Syndrome

Recommendation

3. Cycle cancellation before the istration of human chorionic gonadotropin is an effective strategy for the prevention of ovarian hyperstimulation syndrome, but the emotional and financial burden it imposes on patients should be considered before the cycle is cancelled. (III-C) PROTOCOLS

Assisted reproductive technologies, especially IVF protocols, generally use GnRH agonists or antagonists to prevent an endogenous LH surge from occurring before follicular maturation. A Cochrane review of 29 RCTs showed a significantly lower incidence of OHSS in GnRH antagonist cycles than in GnRH agonist cycles (OR 0.43; 95% CI 0.33 to 0.57). Differences in rates of pregnancy or live births were not observed between the two protocols.46 One important benefit of using GnRH antagonist protocols in patients at risk for OHSS (e.g., PCOS patients) is that final oocyte maturation can be achieved using a GnRH agonist instead of hCG. In a GnRH antagonist protocol, a GnRH agonist trigger will displace the GnRH antagonist from the GnRH receptor to induce a controlled surge of endogenous LH and FSH. This GnRH agonistinduced LH has a shorter half-life than exogenous hCG, resulting in a less sustained luteotrophic stimulation and hence a lower risk for OHSS.47 GnRH agonist triggering may prevent early OHSS. OHSS is rarely encountered in IVF egg donors when GnRH agonist is used to trigger final oocyte maturation.47 An important potential concern when using a GnRH agonist trigger during GnRH antagonist IVF cycles is the possible risk of having an inadequate luteal phase. A single dose of GnRH agonist induces an endogenous LH surge that has a much shorter half-life than hCG, resulting in compromised corpus luteum formation48 and a shorter duration of the luteal phase.49 Initial reports showed poor clinical outcomes with a higher incidence of early pregnancy loss and compromised pregnancy rates when a GnRH agonist was used for final oocyte maturation.50,51 Subsequent transfer of frozen-thawed embryos from patients with a GnRH agonist trigger showed improved pregnancy rates and spontaneous abortion rates similar to those in patients using an hCG trigger. These data suggest that the etiology of the observed lower success rates in fresh cycles triggered with GnRH agonist is due to endometrial problems in the luteal phase rather than to an effect on embryo quality.52

More recent studies have addressed these concerns by employing a more comprehensive LPS protocol after final oocyte maturation with GnRH agonists. Using the more aggressive LPS protocol, IVF success rates with a GnRH agonist trigger were comparable to those observed when hCG was used for final egg maturation. In 2011 Humaidan et al. reviewed 6 recent RCTs employing a protocol of more aggressive LPS (3 RCTs with aggressive high dose progesterone and estrogen supplementation LPS, 2 RCTs with the addition of low-dose hCG LPS, and one RCT with progesterone and recombinant LH LPS). Importantly, the live birth rate per fresh IVF embryo transfer cycle improved significantly when modified luteal was used. There were no cases of severe OHSS reported after GnRH agonist triggering, but a 4.6% incidence of severe OHSS was observed in the hCG trigger group for a risk difference of 5% (95% CI −0.07 to 0.02).53 These results GnRH agonist triggering as an alternative to hCG triggering when a fresh embryo transfer is planned, resulting in a reduction of OHSS and the potential to preserve IVF success rates with adequate LPS. It is not yet clear whether using a GnRH agonist trigger with aggressive LPS results in the same pregnancy rate with fresh embryo transfer as using hCG to trigger final oocyte maturation. Although the optimal protocol of luteal supplementation has not yet been defined, 2 approaches to luteal phase in agonist-triggered cycles have been proposed. The first approach is to use aggressive steroid supplementation with progesterone and estrogen, allowing the corpus luteum to degenerate and reduce the risk of OHSS.54 The second approach is to attempt rescue of the corpus luteum by istering a low dose of hCG on the day of oocyte retrieval in addition to standard LPS with vaginal progesterone and oral estrogen.55,56 The latter approach may need fine tuning because hCG may exacerbate the risk of OHSS and has mostly been examined in a population that was not at high risk for OHSS.52 For cycles in which an oocyte donor is stimulated or for fertility preservation cycles in which embryo transfer is not going to occur, a GnRH antagonist pituitary suppression protocol is recommended. This will offer an option for a GnRH agonist trigger to help obviate OHSS risk without affecting pregnancy rates, because a compromised luteal phase is not a concern when embryos are not being transferred into the patient being stimulated. For oocyte donors Lupron 3 mg (0.6 mL) intramuscular 36 hours prior to oocyte retrieval, followed by a repeat dose 10 hours later may be used. NOVEMBER JOGC NOVEMBRE 2014 l 1029

SOGC Clinical Practice Guideline

Recommendations

4. Gonadotropin-releasing hormone (GnRH) antagonist stimulation protocols are recommended in patients at high risk for ovarian hyperstimulation syndrome (OHSS). The risk of severe OHSS in patients on GnRH antagonist protocols who have a very robust ovarian stimulation response can be reduced by using a GnRH agonist as a substitute for human chorionic gonadotropin to trigger final oocyte maturation. (I-B) 5. A gonadotropin-releasing hormone (GnRH) antagonist protocol with a GnRH agonist trigger for final oocyte maturation is recommended for donor oocyte and fertility preservation cycles. (III-C) Prolonged hospitalization with severe OHSS tends to occur more commonly in pregnancy cycles. Cryopreservation of all embryos prevents the possibility of pregnancy in that cycle. The strategy of freezing all embryos in a patient at risk for severe OHSS can prevent prolonged hospitalization, yet still offer hope for a pregnancy with a subsequent transfer of thawed embryos. Avoiding the risk of OHSS needs to be balanced against the possibility of having poor embryo survival, a reduced chance of success after thawing, and a later embryo transfer. However, since vitrification has become available at many treatment centres, the efficiency of cryopreservation programs has increased dramatically, with significantly increased embryo survival rates and higher ongoing pregnancy rates than slow freezing techniques.57,58 A trial comparing cryopreservation of all embryos with fresh embryo transfer alone found a lower incidence of OHSS in the group in which all embryos were cryopreserved than in the fresh embryo transfer group (0/58 vs. 4/67), although this difference did not reach statistical significance.59 Garcia-Velasco et al. compared their experience with agonist triggering and oocyte vitrification in patients at high risk of developing OHSS with coasting in 248 patients undergoing IVF who were at risk for OHSS.47 Ninety-six patients were triggered with the agonist, with their eggs vitrified and then transferred after thawing and fertilization in a subsequent cycle, and 152 were coasted and then had a fresh embryo transfer.47 The clinical pregnancy and implantation rates were significantly higher with transfer of frozen-thawed embryos in a subsequent cycle than with fresh embryo transfer after coasting (50% vs. 29.5%, and 32.1% vs. 19.2%, respectively). There were no cases of OHSS in the cryopreservation and subsequent embryo transfer group, but an 18.7% rate of moderate OHSS in those women who were coasted, with additional cases that were cancelled for being at extremely high risk for OHSS even after coasting. 1030 l NOVEMBER JOGC NOVEMBRE 2014

In patients at high risk for OHSS on a GnRH antagonist protocol, GnRH agonist trigger followed by embryo cryopreservation of all embryos is a good option for preventing OHSS. Summary Statements

7. Avoiding pregnancy by freezing all embryos will prevent severe prolonged ovarian hyperstimulation syndrome in patients at high risk. (II-2) 8. Pregnancy rates are not affected when using gonadotropin-releasing hormone (GnRH) agonists in GnRH antagonist protocols for final egg maturation when embryos are frozen by vitrification for later transfer. (II-2) A number of clinical trials have yielded conflicting results on the use of intravenous fluids such as albumin, HES, Haemaccel, and dextran at the time of egg retrieval as a possible way to prevent the severe form of OHSS. It has been speculated that prophylactic intravenous fluid istration may interrupt the development of OHSS by increasing the plasma oncotic pressure, restorating intravascular volume, and deactivating ovarian mediators involved in the pathogenesis of OHSS.60 Intravenous istration of fluids such as human albumin, HES, Haemaccel, and dextran infusion immediately post oocyte retrieval or shortly thereafter have also been reported.60 In 2011 a Cochrane review of 8 RCTs comparing human albumin and placebo in 1660 patients and HES and placebo in 487 patients at risk for OHSS found a borderline statistically significant decrease in the incidence of severe OHSS with the istration of human albumin (8 RCTs; OR 0.67; 95% CI 0.45 to 0.99).60 Although there was also some ive evidence for the use of HES in preventing OHSS, the safety of HES has not been established and more studies are needed to fully address its use. No RCT compared either dextran or Haemaccel with placebo or no treatment. The cumulative literature does not the use of intravenous albumin around the time of egg retrieval for the prevention of OHSS. Recommendation

6. Albumin or other plasma expanders at the time of egg retrieval are not recommended for the prevention of ovarian hyperstimulation syndrome. (I-E) Elective Single Embryo Transfer

It is well-known that endogenous hCG levels are significantly higher in multiple pregnancies than in singleton pregnancies.61 If an embryo transfer is being planned in a young patient who is thought to be at significant risk for OHSS based on underlying risk factors, elective single

The Prevention of Ovarian Hyperstimulation Syndrome

embryo transfer should be advised. This may decrease the risk of multiple gestations and should in turn decrease the risk of severe OHSS. Recommendation

7. Elective single embryo transfer is recommended in patients at high risk for ovarian hyperstimulation syndrome. (III-C) In patients undergoing controlled superovulation with pituitary suppression and oocyte retrieval, luteal phase hormonal supplementation is needed to maximize the chance of pregnancy.53 HCG is effective at providing LPS, however, it plays a vital role in precipitating OHSS and may worsen established OHSS. In a meta-analysis of RCTs, progesterone was established as being equally effective as hCG for LPS and it is associated with a lower risk of OHSS.62 Recommendation

8. Progesterone, rather than human chorionic gonadotropin, should be used for luteal phase . (I-A) Culdocentesis

Active outpatient intervention in the early stages of OHSS can minimize associated complications.63 Culdocentesis may alleviate patient discomfort and function to precipitate diuresis in women who are oliguric.64 Culdocentesis can be offered in an attempt to prevent disease progression in severe OHSS and eliminate the need for hospital ission.63 Recommendation

9. Outpatient culdocentesis should be considered for the prevention of disease progression in severe ovarian hyperstimulation syndrome. (II-2B) SUMMARY

Risk-factors and response to ovarian stimulation are limited in their ability to assist in the prediction of OHSS disease occurrence. This becomes evident as some OHSS cases occur in patients not thought to be at significant risk, while the majority of high-risk cases do not result in OHSS.1 Experience with controlled ovarian stimulation and knowledge of OHSS pathophysiology, risk factors, and clinical presentation remains essential for the prevention of severe OHSS. In spite of limited understanding of the pathophysiology of OHSS, there is now good evidence that preventive strategies can profoundly reduce the incidence of severe OHSS. Prior to the start of controlled ovarian stimulation,

the addition of metformin in patients with PCOS undergoing IVF should be considered as it may reduce the incidence of OHSS. During the treatment cycle, clinical risk factors should be used in judging the starting doses of gonadotropins. In patients with a very robust response to gonadotropins, coasting should be considered to prevent later OHSS. At the time of hCG trigger, the use of Cabergoline has been shown to reduce the risk for severe OHSS in patients at risk for this complication. There is no strong evidence to hCG trigger dose as an effective means to decrease the risk of OHSS. Cycle cancellation by withholding hCG has consistently been shown to obviate the risk of OHSS. Avoiding pregnancy by freezing all embryos will prevent severe prolonged OHSS in patients at high risk. Evidence also suggests that a GnRH agonist trigger followed by cryopreservation of all embryos is comparable to cycle cancellation in its efficacy at preventing OHSS with little compromise in success rates in those IVF centres that have a good embryo cryopreservation program. Finally, progesterone should be used for LPS rather than hCG. Continued research is required to gain a better appreciation of the pathophysiology of OHSS, which may advance our ability to predict and prevent this potentially serious illness. REFERENCES 1. Mathur R, Kailasam C, Jenkins J. Review of the evidence base of strategies to prevent ovarian hyperstimulation syndrome. Hum Fertil 2007;10:75–85. 2. Shmorgun D, Claman P, et al.; t SOGC–CFAS Clinical Practice Guidelines Committee. The diagnosis and management of ovarian hyperstimulation syndrome. SOGC Clinical Practice Guidelines, No. 268, November 2011. J Obstet Gynaecol Can 2011;33:1156–62. 3. Golan A, Ron-El R, Herman A, Soffer Y, Weinraub Z, Caspi E. Ovarian hyperstimulation syndrome: an update review. Obstet Gynecol Surv 1989;44:430–40. 4. Serour GI, Aboulghar M, Mansour R, Sattar MA, Amin Y, Aboulghar H. Complications of medically assisted conception in 3,500 cycles. Fertil Steril 1998;70:638–42. 5. Morris RS, Miller C, Jacobs L, Miller K. Conservative management of ovarian hyperstimulation syndrome. J Reprod Med 1995;40:711–4. 6. Semba S, Moriya T, Youssef EM, Sasano H. An autopsy case of ovarian hyperstimulation syndrome with massive pulmonary edema and pleural effusion. Pathol Int 2000;50:549–52. 7. Delvigne A, Rozenberg S. Epidemiology and prevention of ovarian hyperstimulation syndrome (OHSS): a review. Hum Reprod Update 2002;8;559–77. 8. Delvigne A, Rozenberg S. Review of clinical course and treatment of ovarian hyperstimulation syndrome (OHSS). Hum Reprod Update 2003;9:77–96. 9. Tollan A, Holst N, Forsdahl F, Fadnes HO, Oian P, Maltau JM. Transcapillary fluid dynamics during ovarian stimulation for in vitro fertilization. Am J Obstet Gynecol 1990;162:554–8.

NOVEMBER JOGC NOVEMBRE 2014 l 1031

SOGC Clinical Practice Guideline

10. Goldsman MP, Pedram A, Dominguez CE, Ciuffardi I, Levin E, Asch RH. Increased capillary permeability induced by human follicular fluid: a hypothesis for an ovarian origin of the hyperstimulation syndrome. Fertil Steril 1995;63:268–72.

26. The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004a;81:19–25.

11. Geva E, Jaffe RE. Role of vascular endothelial growth factor in ovarian physiology and pathology. Fertil Steril 2000;74;429–38.

27. Benadiva CA, Davis O, Kigman I, Moomjy M, Liu HC, Rosenwaks Z. Withholding gonadotrophin istration is an effective alternative for the prevention of ovarian hyperstimulation syndrome. Fertil Steril 1997;67:724–7.

12. Neulen J, Yan Z, Raczek S, Weindel K, Keek C, Weich HA, et al. Human chorionic gonadotripin-dependent expression of vascular endothelial growth factor/vascular permeability factor in human granulose cells: importance in ovarian hyperstimulation syndrome. J Clin Endocrinol Metab 1995;80:1967–71.

28. Mansour R, Alboulghar M, Serour G, Amin Y, Abou-Setta AM. Criteria of a successful coasting protocol for the prevention of severe ovarian hyperstimulation syndrome. Hum Reprod 2005;20:3167–72.

13. Pellincer A, Albert C, Mercander A, Bonilla-Musoles F, Remohi J, Simon C. The pathogenesis of ovarian hyperstimulation syndrome: in vitro studies investigating the role of interleukin-1β, interleukin-6, and vascular endothelial growth factor. Fertil Steril 1999;71:482–89.

29. Farhi J, Ben-Haroush A, Lande Y, Sapir O, Pinkas H, Fisch B. In vitro fertilization cycle outcome after coasting in gonadotropin-releasing hormone (GnRH) agonist versus GnRH antagonist protocols. Fertil Steril 2009;91:377–82.

14. Alvarez C, Marti-Bonmati L, Novella-Maestre E, Sanz R, Gomez R, Fernandez-Sanchez M, et al. Dopamine agonist cabergoline reduces hemoconcentration and ascites in hyperstimulated women undergoing assisted reproduction. J Clin Endocrinol Metab 2007;92:2931–7.

30. Delvigne A, Rozenberg S. Preventive attitude of physicians to avoid OHSS in IVF patients. Hum Reprod 2001;16:2491–5.

15. Navot D, Relou A, Birkenfield A, Rabinowitz R, Brzezinski A, Margalioth EJ. Risk factors and prognostic variables in the ovarian hyperstimulation syndrome. Am J Obstet Gynecol 1988;159:210–5. 16. Brinsden PR, Wada I, Tan SL, Balen A, Jacobs HS. Diagnosis, prevention and management of ovarian hyperstimulation syndrome. Br J Obstet Gynaecol 1995;102:767–72. 17. Enskog A, Henriksson M, Unander M, Nilsson L, Brannstrom M. Prospective study of the clinical and laboratory parameters of patients in whom ovarian hyperstimulation syndrome developed during controlled ovarian hyperstimulation for in vitro fertilization. Fertil Steril 1999;71:808–14. 18. Navot D, Bergh PA, Laufer N. Ovarian hyperstimulation syndrome in novel reproductive technologies: prevention and treatment. Fertil Steril 1992;58:249–61. 19. Asch R, Li H-P, Balmaceda JP, Weckstein LN, Stone SC. Severe ovarian hyperstimulation syndrome in assisted reproductive technology: definition of high risk groups. Hum Reprod 1991;6:1395–9. 20. Lee TH, Liu CH, Huang CC, Wu YL, Shih YT, Ho HN, et al. Serum anti-Müllerian hormone and estradiol levels as predictors of ovarian hyperstimulation syndrome in assisted reproduction technology cycles. Hum Reprod 2008;23:160–7. 21. Costello MF, Chapman M, Conway U. A review and meta-analysis of randomized controlled trials on metformin co-istration during gonadotrophin ovulation induction or IVF in women with polycystic ovary syndrome. Hum Reprod 2006;21:1387–99. 22. Tso LO, Costello MF, Albuquerque LE, Andriolo RB, Freitas V. Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome. Cochrane Database Syst Rev 2009 Apr 15;(2):CD006105. 23. Swanton A, Lighten A, Granne I, McVeigh E, Lavery S, Trew G, et al. Do women with ovaries of polycystic morphology without any other features of PCOS benefit from short-term metformin co-treatment during IVF? A double-blind, placebo-controlled, randomized trial. Hum Reprod 2011;26:2178–84. 24. Daya S. Updated meta-analysis of recombinant follicle stimulating hormone (FSH) versus urinary FSH for ovarian stimulation in assisted reproduction. Fertil Steril 2002;77:711–4. 25. Coomarasamy A, Afnan M, Cheema D, van der Veen F, Bossuyt PM, van Wely M. Urinary hMG versus recombinant FSH for controlled ovarian hyperstimulation following an agonist long down-regulation protocol in IVF or ICSI treatment: a systematic review and meta-analysis. Hum Reprod 2008;23:310–5.

1032 l NOVEMBER JOGC NOVEMBRE 2014

31. García-Velasco JA, Isaza V, Quea G, Pellicer A. Coasting for the prevention of ovarian hyperstimulation syndrome: much ado about nothing? Fertil Steril 2006;85:547–54. 32. Youssef MA, Al-Inany HG, Aboulghar M, Mansour R, Abou-Setta AM. Recombinant versus urinary human chorionic gonadotrophin for ovulation induction in assisted conception. Cochrane Database Syst Rev 2011;13(4):CD003719. 33. Gomez R, Gonzalez-Izquierdo M, Zimmerman RC, Novella-Maestre E, Alonso-Muriel I, Sanchez-Criado J, et al. Low dose dopamine agonist istration blocks VEGF mediated vascular permeability without altering VEGFR-2 dependent luteal angiogenesis in a rat ovarian hyperstimulated model. Endocrinology 2006;147:5400–11. 34. Soares SR, Gomez R, Simon C, Garcia-Velasco JA, Pellicer A. Targeting the vascular endothelial growth factor system to prevent ovarian hyperstimulation syndrome. Human Reprod Update 2008;14:321–33. 35. Schmidt DW, Maier DB, Nulsen JC, Benadiva CA. Reducing the dose of human chorionic gonadotropin in high responders does not affect the outcomes of in vitro fertilization. Fertil Steril 2004;82:841–6. 36. Salha O, Dada T, Sharma V. Influence of body mass index and selfistration of hCG on the outcome of IVF cycles: a prospective cohort study. Hum Fertil (Camb) 2001;4:37–42. 37. Kahraman S, Karlikaya G, Kavrut M, Karagozoglu H. A prospective, randomized, controlled study to compare two doses of recombinant human chorionic gonadotropin in serum and follicular fluid in woman with high body mass index. Fertil Steril 2010;93:2084–7. 38. Bates DO, Harper SJ. Regulation of vascular permeability by vascular endothelial growth factors. Vascul Pharmacol 2002;39:225–37. 39. Garcia-Velasco J. How to avoid ovarian hyperstimulation syndrome: a new indication for dopamine agonists. Reprod Biomed Online 2009;18(Suppl 2):71–5. 40. Kumar P, Sait SF, Sharma A, Kumar M. Ovarian hyperstimulation syndrome. J Hum Reprod Sci 2011;4:70–5. 41. Alvarez C, Alonso-Muriel I, García G, Crespo J, Bellver J, Simón C, et al. Implantation is apparently unaffected by the dopamine agonist Cabergoline when istered to prevent ovarian hyperstimulation syndrome in women undergoing assisted reproduction treatment: a pilot study. Hum Reprod 2007;22:3210–4. 42. Carizza C, Abdelmassih V, Abdelmassih S, Ravizzini P, Salgueiro L, Salgueiro PT, et al.. Cabergoline reduces the early onset of ovarian hyperstimulation syndrome: a prospective randomized study. Reprod Biomed Online 2008;17:751–5. 43. Tang H, Hunter T, Hu Y, Zhai SD, Sheng X, Hart RJ. Cabergoline for preventing ovarian hyperstimulation syndrome. Cochrane Database Syst Rev 2012;15(2):CD008605.

The Prevention of Ovarian Hyperstimulation Syndrome

44. Faghih M, DiPaolo L, Willoughby K, Karnis M, Hughes E, Neal M. Dostinex use for OHSS prevention does not affect IVF success. Fertil Steril 2008;90(Suppl):P–379. 45. Bhangoo R, Karunis M, Ballas J, San Roman GA, Stelling JR. Cabergoline decreases risk of ovarian hyperstimulation syndrome and has no effect on pregnancy rate during in vitro fertilization. Fertil Steril 2008;90(Suppl):P–387. 46. Al-Inany HG, Youssef MA, Aboulghar M, Broekmans F, Sterrenburg M, Smit JAM, et al. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database Syst Rev 2011;11(5):CD001750. 47. Garcia-Velasco JA. Agonist trigger: what is the best approach? Agonist trigger with vitrification of oocytes or embryos. Fertil Steril 2012;97:527–8. 48. Itskovitz J, Boldes R, Levron J, Erlik Y, Kahana L, Brandes JM. Induction of preovulatory luteinizing hormone surge and prevention of ovarian hyperstimulation syndrome by gonadotropin-releasing hormone agonist. Fertil Steril 1991;56:213–20. 49. Beckers NG, Macklon NS, Eijkemans MJ, Ludwig M, Felberbaum RE, Diedrich K, et al. Nonsupplemented luteal phase characteristics after the istration of recombinant human chorionic gonadotropin, recombinant luteinizing hormone, or gonadotropin-releasing hormone (GnRH) agonist to induce final oocyte maturation in in vitro fertilization patients after ovarian stimulation with recombinant follicle-stimulating hormone and GnRH antagonist cotreatment. J Clin Endocrinol Metab 2003;88:4186–92. 50. Kolibianakis EM, Schultze-Mosgau A, Schroer A, van Steirteghem A, Devroey P, Diedrich K, et al. A lower ongoing pregnancy rate can be expected when GnRH agonist is used for triggering final oocyte maturation instead of HCG in patients undergoing IVF with GnRH antagonists. Hum Reprod 2005;20:2887–92. 51. Humaidan P, Ejdrup BH, Bungum L, Bungum M, Grondahl ML, Westergaard L. GnRH agonist or hCG for ovulation induction in GnRH antagonist IVF/ICSI cycles: a prospective randomized study. Hum Reprod 2005;20:1213–20. 52. Garcia-Velasco JA, Motta L, López A, Mayoral M, Cerrillo M, Pacheco A. Low-dose human chorionic gonadotropin versus estradiol/progesterone luteal phase in gonadotropin-releasing hormone agonist-triggered assisted reproductive technique cycles: understanding a new approach. Fertil Steril 2010;94:2820–3. 53. Humaidan P, Kol S, Papanikolaou EG; Copenhagen GnRH Agonist Triggering Workshop Group. GnRH agonist for triggering of final oocyte maturation: time for a change of practice? Hum Reprod Update 2011;17:510–24. 54. Engmann L, DiLuigi A, Schmidt D, Nulsen J, Maier D, Benadiva C. The use of gonadotropin-releasing hormone (GnRH) agonist to induce

oocyte maturation after cotreatment with GnRH antagonist in high-risk patients undergoing in vitro fertilization prevents the risk of ovarian hyperstimulation syndrome: a prospective randomized controlled study. Fertil Steril 2008;89:84–91. 55. Humaidan P, Bungum L, Bungum M, Yding Andersen C. Rescue of corpus luteum function with peri-ovulatory HCG supplementation in IVF/ICSI GnRH antagonist cycles in which ovulation was triggered with a GnRH agonist: a pilot study. Reprod Biomed Online 2006;13:173–8. 56. Humaidan P, Ejdrup Bredkjaer H, Westergaard LG, Yding Andersen C. 1,500 IU human chorionic gonadotropin istered at oocyte retrieval rescues the luteal phase when gonadotropin-releasing hormone agonist is used for ovulation induction: a prospective, randomized, controlled study. Fertil Steril 2010;93:847–54. 57. Balaban B, Urman B, Ata B, Isiklar A, Larman MG, Hamilton R, et al. A randomised controlled study of human day 3 embryo cryopreservation by slow freezing or vitrification: vitrification is associated with higher survival, metabolism and blastocyst formation. Hum Reprod 2008;23:1976–82. 58. AbdelHafez FF, Desai N, Abou-Setta AM, Falcone T, Goldfarb J. Slow freezing, vitrification and ultra-rapid freezing of human embryos: a systematic review and meta-analysis. Reprod Biomed Online 2010;20:209–22. 59. Ferraretti AP, Gianaroli L, Magli C, Fortini D, Selman H, Feliciani E. Elective cryopreservation of all pronucleate embryos in women at risk of ovarian hyperstimulation syndrome :efficiency and safety. Hum Reprod 1999;14:1457–60. 60. Youssef MA, Al-Inany HG, Aboulghar M, Mansour R, Abou-Setta AM. Recombinant versus urinary human chorionic gonadotrophin for ovulation induction in assisted conception. Cochrane Database Syst Rev 2011;13(4):CD003719. 61. Kumbak B, Oral E, Karlikaya G, Lacin S, Kahraman S. Serum oestradiol and β-HCG measurements after day 3 or 5 embryo transfers in interpreting pregnancy outcome. Rep Bio Med Online 2006;13:459–64. 62. van der Linden M, Buckingham K, Farquhar C, Kremer JA, Metwally M. Luteal phase for assisted reproduction cycles. Cochrane Database Syst Rev 2011;5(10):CD009154. 63. Fluker M, Copeland J, Yuzpe A. An ounce of prevention: outpatient management of ovarian hyperstimulation syndrome. Fertil Steril 2000;73:821–4. 64. Borenstein R, Elhalah U, Lunenfeld B, Schwartz ZS. Severe ovarian hyperstimulation syndrome: a re-evaluated therapeutic approach. Fertil Steril 1989;51:791–5. 65. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

NOVEMBER JOGC NOVEMBRE 2014 l 1033

SOGC CLINICAL PRACTICE GUIDELINE No. 315, November 2014

The Prevention of Ovarian Hyperstimulation Syndrome This clinical practice guideline has been prepared by the Reproductive Endocrinology Infertility Committee and approved by Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Shannon Corbett, MD, Ottawa ON Doron Shmorgun, MD, Ottawa ON Paul Claman, MD, Ottawa ON

Abstract Objective: To review the clinical aspects of ovarian hyperstimulation syndrome and provide recommendations on its prevention. Options: Preventative measures, early recognition, and prompt systematic ive care will help avoid poor outcomes. Outcomes: Establish guidelines to assist in the prevention of ovarian hyperstimulation syndrome, early recognition of the condition when it occurs, and provision of appropriate ive measures in the correct setting.

James Graham, MD, Calgary AB

Evidence: Published literature was retrieved through searches of Medline, Embase, and the Cochrane Library from 2011 to 2013 using appropriate controlled vocabulary ([OHSS] ovarian hyperstimulation syndrome and: agonist IVF, antagonist IVF, metformin, HCG, gonadotropin, coasting, freeze all, agonist trigger, progesterone) and key words (ovarian hyperstimulation syndrome, ovarian stimulation, gonadotropin, human chorionic gonadotropin, prevention). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies published in English. There were no date restrictions. Searches were updated on a regular basis and incorporated in the guideline to February 2013.

Jon Havelock, MD, Burnaby BC



REPRODUCTIVE ENDOCRINOLOGY INFERTILITY COMMITTEE Anthony Cheung, MD (Co-chair), Vancouver BC Sony Sierra, MD (Co-chair), Toronto ON Belina Carranza-Mamane, MD, Sherbrooke QC Allison Case, MD, Saskatoon SK Cathie Dwyer, RN, Toronto ON

Sarah Healey, MD, St. John’s NL Robert Hemmings, MD, Montreal QC Kimberly Liu, MD, Toronto ON Tarek Motan, MD, Edmonton AB Ward Murdock, MD, Fredericton NB David Smithson, MD, London ON Tannys Vause, MD, Ottawa ON Benjamin Wong, MD, Calgary AB SPECIAL CONTRIBUTOR Mathias Gysler, MD, Oakville ON

Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technologyrelated agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies.

Values: The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). Summary Statements 1. The particular follicle-stimulating hormone formulation used for ovarian stimulation does not affect the incidence of ovarian hyperstimulation syndrome. (I) 2. Coasting may reduce the incidence of severe ovarian hyperstimulation syndrome. (III)

Disclosure statements have been received from all contributors.

J Obstet Gynaecol Can 2014;36(11):1024–1033

Key Words: Ovarian hyperstimulation syndrome, ovarian stimulation, gonadotropin, human chorionic gonadotropin, prevention

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

1024 l NOVEMBER JOGC NOVEMBRE 2014

The Prevention of Ovarian Hyperstimulation Syndrome

Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.65 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care.65

3. Coasting for longer than 3 days reduces in vitro fertilization pregnancy rates. (II-2) 4. The use of either luteinizing hormone or human chorionic gonadotropin for final oocyte maturation does not influence the incidence of ovarian hyperstimulation syndrome. (I) 5. There is no clear published evidence that lowering the human chorionic gonadotropin dose will result in a decrease in the rate of ovarian hyperstimulation syndrome. (III) 6. Cabergoline starting from the day of human chorionic gonadotropin reduces the incidence of ovarian hyperstimulation syndrome in patients at higher risk and does not appear to lower in vitro fertilization pregnancy rates. (II-2)

7. Avoiding pregnancy by freezing all embryos will prevent severe prolonged ovarian hyperstimulation syndrome in patients at high risk. (II-2) 8. Pregnancy rates are not affected when using gonadotropinreleasing hormone (GnRH) agonists in GnRH antagonist protocols for final egg maturation when embryos are frozen by vitrification for later transfer. (II-2) Recommendations 1. The addition of metformin should be considered in patients with polycystic ovarian syndrome who are undergoing in vitro fertilization because it may reduce the incidence of ovarian hyperstimulation syndrome. (I-A) 2. Gonadotropin dosing should be carefully individualized, taking into the patient’s age, body mass, antral follicle count, and previous response to gonadotropins. (II-3B)

ABBREVIATIONS ART

assisted reproductive technology

CI

confidence interval

FSH

follicle-stimulating hormone

GnRH

gonadotropin-releasing hormone

hCG

human chorionic gonadotropin

HES

hydroxyethyl starch

IVF

in vitro fertilization

LH

luteinizing hormone

LPS

luteal phase

OHSS

ovarian hyperstimulation syndrome

OR

odds ratio

PCOS

polycystic ovary syndrome

RCT

randomized control study

SC

subcutaneously

VEGF

vascular endothelial growth factor

3. Cycle cancellation before istration of human chorionic gonadatropin is an effective strategy for the prevention of ovarian hyperstimulation syndrome, but the emotional and financial burden it imposes on patients should be considered before the cycle is cancelled. (III-C) 4. Gonadotropin-releasing hormone (GnRH) antagonist stimulation protocols are recommended in patients at high risk for ovarian hyperstimulation syndrome (OHSS). The risk of severe OHSS in patients on GnRH antagonist protocols who have a very robust ovarian stimulation response can be reduced by using a GnRH agonist as a substitute for human chorionic gonadotropin to trigger final oocyte maturation. (I-B) 5. A gonadotropin-releasing hormone (GnRH) antagonist protocol with a GnRH agonist trigger for final oocyte maturation is recommended for donor oocyte and fertility preservation cycles. (III-C) 6. Albumin or other plasma expanders at the time of egg retrieval are not recommended for the prevention of ovarian hyperstimulation syndrome. (I-E) 7. Elective single embryo transfer is recommended in patients at high risk for ovarian hyperstimulation syndrome. (III-C)

NOVEMBER JOGC NOVEMBRE 2014 l 1025

SOGC Clinical Practice Guideline

8. Progesterone, rather than human chorionic gonadotropin, should be used for luteal phase . (I-A)

Table 2. Classification of OHSS

9. Outpatient culdocentesis should be considered for the prevention of disease progression in severe ovarian hyperstimulation syndrome. (II-2B)

Grade

Symptoms

Mild OHSS

Abdominal bloating Mild abdominal pain Ovarian size usually < 8 cm

INTRODUCTION

O

HSS is a iatrogenic complication of exogenous gonadotropin therapy used to mature multiple follicles for assisted reproductive treatments. The syndrome is only rarely observed with clomiphene citrate treatment but has been reported even after spontaneous ovulation.1 Published guidelines already exist on the management of patients suffering from severe OHSS.2 The goal of this guideline is to provide a practical, evidence-based framework for the prevention of OHSS. After gonadotropin stimulation for IVF, the reported incidence of moderate OHSS is 3% to 6%, and for severe OHSS it is 0.1% to 2%.3,4 The mild form, which has little clinical consequence, occurs in about 20% to 33% of IVF cycles3,5 and is of little clinical concern. However, fatalities have been reported in the most severe cases.6 Except during rare events, OHSS occurs only after ovulation (i.e. after exposure to an endogenous LH surge, to exogenous LH or hCG, or to endogenous hCG of pregnancy).7 Early OHSS symptoms may begin as soon as 24 hours after hCG istration, but become most severe 7 to 10 days after hCG; severe OHSS is usually associated with the rise of endogenous hCG from an early pregnancy8 (see Table 2). Physicians prescribing ovarian stimulation need to identify patients at increased risk for OHSS in order to apply preventive and active management strategies to minimize morbidity from this complication of fertility treatment. Pathophysiology of OHSS

OHSS is a systemic disease thought to result from vasoactive peptides released from the granulosa cells in hyperstimulated ovaries.7 The fundamental physiological change in severe OHSS is an increase in vascular perme­ ability, resulting in a fluid shift from the intravascular spaces to third-space compartments such as the peritoneal and thoracic cavities, often resulting in hemoconcentration.9,10 The most important mediator in this process is thought to be VEGF.11 ing evidence comes from studies showing that serum VEGF levels correlate with OHSS severity. Additionally, hCG has been shown to increase VEGF expression in human granulosa cells, which in turn raises serum VEGF concentration.12,13 A new body of clinical data demonstrates how the istration of dopamine agonist drugs decreases VEGF activity, which in 1026 l NOVEMBER JOGC NOVEMBRE 2014

Moderate OHSS

Moderate abdominal pain Nausea with/without vomiting Ultrasound evidence of ascites Ovarian size usually 8–12 cm

Severe OHSS

Clinical ascites (occasionally pleural effusion) Oliguria Hemoconcentration hematocrit (> 45%) Hypoproteinemia Ovarian size usually > 12 cm

Critical OHSS

Tense ascites or large pleural effusion Hematocrit (> 55%) White cell count > 25 000/L Oligo/anuria Thromboembolism Acute respiratory distress syndrome

Reproduced with permission of the British Fertility Society.1

turn decreases the clinical burden of OHSS.14 Numerous other mediators have been implicated in the disease process such as angiotensin II, insulin-like growth factor 1 and interleukin-6.2 Risk Factors

Several factors have been demonstrated to independently increase the risk of developing OHSS. These include •• age < 30 years,15 •• polycystic ovaries (i.e., > 24 antral follicles present on baseline ultrasound examination),16,17 •• high serum estradiol at hCG trigger or rapidly rising serum estradiol,15 •• previous episodes of OHSS,18 •• large number of small follicles (8 to 12 mm) seen on ultrasound during ovarian stimulation,17 •• use of hCG, as opposed to progesterone, for luteal phase after IVF,18 •• large number of oocytes retrieved (> 20),19 and •• high anti-müllerian hormone (> 3.36 ng/mL).20 PREVENTION

Physicians providing ART treatment must balance the competing interests of trying to sufficiently stimulate the

The Prevention of Ovarian Hyperstimulation Syndrome

ovary to optimize the chance of achieving a pregnancy and minimizing the risk of severe OHSS. To achieve both of these goals both primary and secondary preventative measures have been shown to be useful.1 Primary prevention involves identifying risk factors for OHSS and choosing an appropriate ovarian stimulation regimen. Secondary prevention involves recognizing patients who are over-responsive to gonadotropins and intervening to reduce the risk of OHSS while still trying to salvage the treatment cycle. A meta-analysis of 5 RCTs showed a significant reduction in the incidence of OHSS with the use of metformin in women with PCOS undergoing IVF (12/216 vs. 44/210; OR 0.21, 95% CI 0.11 to 0.41, P < 0.01).21 These findings were later corroborated in a Cochrane review from the same group.22 Interestingly, a recent RCT showed that women with polycystic ovarian morphology that does not meet the criteria for PCOS do not incur the same protective benefit from metformin of reduced OHSS.23 Metformin should ideally be started 8 weeks before planned gonadotropin stimulation to be effective in OHSS prevention. To minimize gastrointestinal side effects we recommend starting Metformin at a low dose of 500 mg HS and slowly increasing the dose until the effective dose of 500 mg × 3 (1500 mg) daily is reached. Metformin should continue until egg retrieval. Two separate meta-analyses of RCTs comparing recombinant FSH and urinary FSH showed no difference in the incidence of OHSS.24,25 There is no linear positive correlation between gonadotropin dose and the incidence of severe OHSS. On the contrary, patients developing OHSS tend to be those who respond robustly to gonadotropins and are often prescribed lower than average doses of these drugs than other women undergoing IVF. Young, thin women, especially those with polycystic ovaries on ultrasound (i.e., > 12 antral follicles seen on each ovary) are at higher risk for OHSS and should receive a lower starting dose of gonadotropin than would be given to other women.26 Careful monitoring of these patients during stimulation is prudent to allow for a decrease in the dose of gonadotropins if a very robust response is detected early in the treatment cycle.18 Summary Statement

1. The particular follicle-stimulating hormone formulation used for ovarian stimulation does not affect the incidence of ovarian hyperstimulation syndrome. (I)

Recommendations

1. The addition of metformin should be considered in patients with polycystic ovarian syndrome who are undergoing in vitro fertilization because it may reduce the incidence of ovarian hyperstimulation syndrome. (I-A) 2. Gonadotropin dosing should be carefully individualized, taking into the patient’s age, body mass, antral follicle count, and previous response to gonadotropins. (II-3B) Coasting

Coasting involves withholding gonadotropins while maintaining pituitary suppression with a gonadotropinreleasing hormone agonist or antagonist. istering hCG to trigger oocyte maturation once estrogen levels plateau or drop is thought to reduce the risk for OHSS. Larger follicles have a lower requirement for FSH than smaller follicles. Once follicles are > 12 mm in diameter, stopping all gonadotropins still allows for larger follicles to continue their growth and maturation, while smaller follicles undergo atresia, which may result in reduced production of vasoactive peptides such as VEGF.27 It has been shown that coasting on a GnRH agonist for up to 3 days does not adversely affect pregnancy rates.28 The same criteria for coasting can be applied to GnRH antagonist cycles as to GnRH agonist cycles with similar IVF outcomes.29 In a systematic review of 12 retrospective studies examining the benefit of coasting, the coasted patients had a 2.5% incidence of hospitalization for OHSS, which is lower than expected for patients at high risk for OHSS.30 Previous studies have shown a significant drop in pregnancy rate with longer than 3 to 4 days of coasting.28,31 Therefore, cycle cancellation should be considered if estradiol levels do not start to fall by the fourth day of coasting. A meta-analysis of 3 RCTs comparing recombinant LH with urinary hCG for triggering final oocyte maturation and 11 RCTs comparing recombinant hCG with urinary LH did not show any difference in the risk of OHSS.32 Summary Statements

2. Coasting may reduce the incidence of severe ovarian hyperstimulation syndrome. (III) 3. Coasting for longer than 3 days reduces in vitro fertilization pregnancy rates. (II-2) 4. The use of either luteinizing hormone or human chorionic gonadotropin for final oocyte maturation does not influence the incidence of ovarian hyperstimulation syndrome. (I)

NOVEMBER JOGC NOVEMBRE 2014 l 1027

SOGC Clinical Practice Guideline

The degree of hCG exposure has been associated with the risk of OHSS.18 It is recognized that hCG has no direct effect on the vascular system33; however, vasoactive substances such as VEGF are released in the ovary in response to hCG istration and are most likely responsible for inducing vascular hyperpermeability and third-spacing in high-risk women.34 A retrospective series of 94 IVF cycles showed that when hCG doses were lowered, both pregnancy rates and the rate of severe OHSS remained unchanged.35 However, a lower incidence of severe OHSS has been observed with the use of lower doses of hCG for final oocyte maturation in an at-risk population. Because serum levels of hCG are dependent on body mass,36,37 one Canadian fertility centre uses hCG 5000 IU SC to trigger final egg maturation in patients at risk for OHSS who have a BMI < 28 kg/m2, despite the lack of published data. Women with a BMI ≥ 28 kg/m2 are all given hCG 10 000 IU SC for final egg maturation because yields of mature eggs have been observed to be lower with a dose reduction in this population.36 Summary Statement

5. There is no clear published evidence that lowering human chorionic gonadotropin dose will result in a decrease in the rate of ovarian hyperstimulation syndrome. (III) Cabergoline

VEGF produced by granulosa cells of developing follicles is thought to be a key mediator in both hCG-dependent ovarian angiogenesis and the pathophysiology of OHSS.38 Recently, the dopamine agonist cabergoline has been introduced as a secondary prevention strategy in women deemed to be at high risk for OHSS because of a very robust gonadotropin response at the end of a controlled ovarian stimulation cycle. Dopamine agonists show similar effects to anti-angiogenic drugs on vascular permeability, and except for occasional nausea, they appear not to have undesirable side effects.33,39 Evidence from animal models shows that cabergoline blocks VEGF-mediated increase in vascular permeability without affecting angiogenesis.33 Carbergoline’s postulated mechanism of action is partial inhibition of the phosphorylation of its associated receptor, the VEGF receptor 2.40 A recent Cochrane review included 2 RCTs addressing cabergoline and OHSS. In the RCT conducted by Alvarez et al. on oocyte donors at risk for OHSS (20 to 30 follicles at > 12 mm and > 20 eggs retrieved), in which the treatment group received oral cabergoline 0.5 mg daily for 8 days starting on the day of hCG and the control group received a placebo, the incidence of moderate OHSS was significantly reduced in the cabergoline group (20% vs. 1028 l NOVEMBER JOGC NOVEMBRE 2014

43.8%, P = 0.04).14 The same first author also showed that pregnancy rates are not compromised in patients given cabergoline.41 The second RCT by Carriza et al. randomized women who were undergoing IVF and at high risk for OHSS (estradiol ≥ 14 700 pmol/L on day of hCG trigger) into two groups: the study group received 20 grams of prophylactic intravenous albumin and 0.5 mg of Cabergoline orally once daily for 3 weeks commencing the day after oocyte retrieval and the control group received only albumin.42 The risk of early OHSS (occurring within the first 9 days after hCG trigger) decreased significantly (P < 0.001) in the cabergoline group; none of the patients who had taken cabergoline progressed to early OHSS, but 15.0% of the control group did. The risk of late OHSS did not decrease. In both of the RCTs examined, the use of cabergoline did not affect the pregnancy outcome (clinical pregnancy rate or miscarriage rate), nor was it associated with an increased risk of adverse events.43 Two published abstracts have demonstrated the safety and efficacy of using cabergoline at even smaller doses: 0.5 mg twice weekly for 6 doses44 and 0.5 mg twice weekly for 3 doses.45 Clinicians at one Canadian fertility centre use a dose of cabergoline 0.5 mg every 3 days to a total of 4 doses starting on the day of oocyte maturation trigger and a significant reduction in the incidence of severe OHSS has been anecdotally observed since the introduction of cabergoline into the prevention strategies for OHSS. Although still somewhat preliminary, current data suggest that cabergoline is associated with a reduction in moderate OHSS in patients at high risk and has no adverse effect on the pregnancy rate. Summary Statement

6. Cabergoline starting from the day of human chorionic gonadotropin reduces the incidence of ovarian hyperstimulation syndrome in patients at higher risk and does not appear to lower in vitro fertilization pregnancy rates. (II-2) Cycle Cancellation

OHSS will not develop in the absence of exposure to exogenous hCG or LH or to an endogenous LH surge as long as a pregnancy does not develop. Therefore, withholding hCG in cycles at risk for OHSS and cancelling the cycle is the most effective method of preventing OHSS. This prevention strategy is especially important in agonist cycles in which the option to substitute an agonist trigger for hCG does not exist. However, because the emotional and financial costs of cancellation are significant, other prevention strategies should be exhausted before cycle cancellation is considered.

The Prevention of Ovarian Hyperstimulation Syndrome

Recommendation

3. Cycle cancellation before the istration of human chorionic gonadotropin is an effective strategy for the prevention of ovarian hyperstimulation syndrome, but the emotional and financial burden it imposes on patients should be considered before the cycle is cancelled. (III-C) PROTOCOLS

Assisted reproductive technologies, especially IVF protocols, generally use GnRH agonists or antagonists to prevent an endogenous LH surge from occurring before follicular maturation. A Cochrane review of 29 RCTs showed a significantly lower incidence of OHSS in GnRH antagonist cycles than in GnRH agonist cycles (OR 0.43; 95% CI 0.33 to 0.57). Differences in rates of pregnancy or live births were not observed between the two protocols.46 One important benefit of using GnRH antagonist protocols in patients at risk for OHSS (e.g., PCOS patients) is that final oocyte maturation can be achieved using a GnRH agonist instead of hCG. In a GnRH antagonist protocol, a GnRH agonist trigger will displace the GnRH antagonist from the GnRH receptor to induce a controlled surge of endogenous LH and FSH. This GnRH agonistinduced LH has a shorter half-life than exogenous hCG, resulting in a less sustained luteotrophic stimulation and hence a lower risk for OHSS.47 GnRH agonist triggering may prevent early OHSS. OHSS is rarely encountered in IVF egg donors when GnRH agonist is used to trigger final oocyte maturation.47 An important potential concern when using a GnRH agonist trigger during GnRH antagonist IVF cycles is the possible risk of having an inadequate luteal phase. A single dose of GnRH agonist induces an endogenous LH surge that has a much shorter half-life than hCG, resulting in compromised corpus luteum formation48 and a shorter duration of the luteal phase.49 Initial reports showed poor clinical outcomes with a higher incidence of early pregnancy loss and compromised pregnancy rates when a GnRH agonist was used for final oocyte maturation.50,51 Subsequent transfer of frozen-thawed embryos from patients with a GnRH agonist trigger showed improved pregnancy rates and spontaneous abortion rates similar to those in patients using an hCG trigger. These data suggest that the etiology of the observed lower success rates in fresh cycles triggered with GnRH agonist is due to endometrial problems in the luteal phase rather than to an effect on embryo quality.52

More recent studies have addressed these concerns by employing a more comprehensive LPS protocol after final oocyte maturation with GnRH agonists. Using the more aggressive LPS protocol, IVF success rates with a GnRH agonist trigger were comparable to those observed when hCG was used for final egg maturation. In 2011 Humaidan et al. reviewed 6 recent RCTs employing a protocol of more aggressive LPS (3 RCTs with aggressive high dose progesterone and estrogen supplementation LPS, 2 RCTs with the addition of low-dose hCG LPS, and one RCT with progesterone and recombinant LH LPS). Importantly, the live birth rate per fresh IVF embryo transfer cycle improved significantly when modified luteal was used. There were no cases of severe OHSS reported after GnRH agonist triggering, but a 4.6% incidence of severe OHSS was observed in the hCG trigger group for a risk difference of 5% (95% CI −0.07 to 0.02).53 These results GnRH agonist triggering as an alternative to hCG triggering when a fresh embryo transfer is planned, resulting in a reduction of OHSS and the potential to preserve IVF success rates with adequate LPS. It is not yet clear whether using a GnRH agonist trigger with aggressive LPS results in the same pregnancy rate with fresh embryo transfer as using hCG to trigger final oocyte maturation. Although the optimal protocol of luteal supplementation has not yet been defined, 2 approaches to luteal phase in agonist-triggered cycles have been proposed. The first approach is to use aggressive steroid supplementation with progesterone and estrogen, allowing the corpus luteum to degenerate and reduce the risk of OHSS.54 The second approach is to attempt rescue of the corpus luteum by istering a low dose of hCG on the day of oocyte retrieval in addition to standard LPS with vaginal progesterone and oral estrogen.55,56 The latter approach may need fine tuning because hCG may exacerbate the risk of OHSS and has mostly been examined in a population that was not at high risk for OHSS.52 For cycles in which an oocyte donor is stimulated or for fertility preservation cycles in which embryo transfer is not going to occur, a GnRH antagonist pituitary suppression protocol is recommended. This will offer an option for a GnRH agonist trigger to help obviate OHSS risk without affecting pregnancy rates, because a compromised luteal phase is not a concern when embryos are not being transferred into the patient being stimulated. For oocyte donors Lupron 3 mg (0.6 mL) intramuscular 36 hours prior to oocyte retrieval, followed by a repeat dose 10 hours later may be used. NOVEMBER JOGC NOVEMBRE 2014 l 1029

SOGC Clinical Practice Guideline

Recommendations

4. Gonadotropin-releasing hormone (GnRH) antagonist stimulation protocols are recommended in patients at high risk for ovarian hyperstimulation syndrome (OHSS). The risk of severe OHSS in patients on GnRH antagonist protocols who have a very robust ovarian stimulation response can be reduced by using a GnRH agonist as a substitute for human chorionic gonadotropin to trigger final oocyte maturation. (I-B) 5. A gonadotropin-releasing hormone (GnRH) antagonist protocol with a GnRH agonist trigger for final oocyte maturation is recommended for donor oocyte and fertility preservation cycles. (III-C) Prolonged hospitalization with severe OHSS tends to occur more commonly in pregnancy cycles. Cryopreservation of all embryos prevents the possibility of pregnancy in that cycle. The strategy of freezing all embryos in a patient at risk for severe OHSS can prevent prolonged hospitalization, yet still offer hope for a pregnancy with a subsequent transfer of thawed embryos. Avoiding the risk of OHSS needs to be balanced against the possibility of having poor embryo survival, a reduced chance of success after thawing, and a later embryo transfer. However, since vitrification has become available at many treatment centres, the efficiency of cryopreservation programs has increased dramatically, with significantly increased embryo survival rates and higher ongoing pregnancy rates than slow freezing techniques.57,58 A trial comparing cryopreservation of all embryos with fresh embryo transfer alone found a lower incidence of OHSS in the group in which all embryos were cryopreserved than in the fresh embryo transfer group (0/58 vs. 4/67), although this difference did not reach statistical significance.59 Garcia-Velasco et al. compared their experience with agonist triggering and oocyte vitrification in patients at high risk of developing OHSS with coasting in 248 patients undergoing IVF who were at risk for OHSS.47 Ninety-six patients were triggered with the agonist, with their eggs vitrified and then transferred after thawing and fertilization in a subsequent cycle, and 152 were coasted and then had a fresh embryo transfer.47 The clinical pregnancy and implantation rates were significantly higher with transfer of frozen-thawed embryos in a subsequent cycle than with fresh embryo transfer after coasting (50% vs. 29.5%, and 32.1% vs. 19.2%, respectively). There were no cases of OHSS in the cryopreservation and subsequent embryo transfer group, but an 18.7% rate of moderate OHSS in those women who were coasted, with additional cases that were cancelled for being at extremely high risk for OHSS even after coasting. 1030 l NOVEMBER JOGC NOVEMBRE 2014

In patients at high risk for OHSS on a GnRH antagonist protocol, GnRH agonist trigger followed by embryo cryopreservation of all embryos is a good option for preventing OHSS. Summary Statements

7. Avoiding pregnancy by freezing all embryos will prevent severe prolonged ovarian hyperstimulation syndrome in patients at high risk. (II-2) 8. Pregnancy rates are not affected when using gonadotropin-releasing hormone (GnRH) agonists in GnRH antagonist protocols for final egg maturation when embryos are frozen by vitrification for later transfer. (II-2) A number of clinical trials have yielded conflicting results on the use of intravenous fluids such as albumin, HES, Haemaccel, and dextran at the time of egg retrieval as a possible way to prevent the severe form of OHSS. It has been speculated that prophylactic intravenous fluid istration may interrupt the development of OHSS by increasing the plasma oncotic pressure, restorating intravascular volume, and deactivating ovarian mediators involved in the pathogenesis of OHSS.60 Intravenous istration of fluids such as human albumin, HES, Haemaccel, and dextran infusion immediately post oocyte retrieval or shortly thereafter have also been reported.60 In 2011 a Cochrane review of 8 RCTs comparing human albumin and placebo in 1660 patients and HES and placebo in 487 patients at risk for OHSS found a borderline statistically significant decrease in the incidence of severe OHSS with the istration of human albumin (8 RCTs; OR 0.67; 95% CI 0.45 to 0.99).60 Although there was also some ive evidence for the use of HES in preventing OHSS, the safety of HES has not been established and more studies are needed to fully address its use. No RCT compared either dextran or Haemaccel with placebo or no treatment. The cumulative literature does not the use of intravenous albumin around the time of egg retrieval for the prevention of OHSS. Recommendation

6. Albumin or other plasma expanders at the time of egg retrieval are not recommended for the prevention of ovarian hyperstimulation syndrome. (I-E) Elective Single Embryo Transfer

It is well-known that endogenous hCG levels are significantly higher in multiple pregnancies than in singleton pregnancies.61 If an embryo transfer is being planned in a young patient who is thought to be at significant risk for OHSS based on underlying risk factors, elective single

The Prevention of Ovarian Hyperstimulation Syndrome

embryo transfer should be advised. This may decrease the risk of multiple gestations and should in turn decrease the risk of severe OHSS. Recommendation

7. Elective single embryo transfer is recommended in patients at high risk for ovarian hyperstimulation syndrome. (III-C) In patients undergoing controlled superovulation with pituitary suppression and oocyte retrieval, luteal phase hormonal supplementation is needed to maximize the chance of pregnancy.53 HCG is effective at providing LPS, however, it plays a vital role in precipitating OHSS and may worsen established OHSS. In a meta-analysis of RCTs, progesterone was established as being equally effective as hCG for LPS and it is associated with a lower risk of OHSS.62 Recommendation

8. Progesterone, rather than human chorionic gonadotropin, should be used for luteal phase . (I-A) Culdocentesis

Active outpatient intervention in the early stages of OHSS can minimize associated complications.63 Culdocentesis may alleviate patient discomfort and function to precipitate diuresis in women who are oliguric.64 Culdocentesis can be offered in an attempt to prevent disease progression in severe OHSS and eliminate the need for hospital ission.63 Recommendation

9. Outpatient culdocentesis should be considered for the prevention of disease progression in severe ovarian hyperstimulation syndrome. (II-2B) SUMMARY

Risk-factors and response to ovarian stimulation are limited in their ability to assist in the prediction of OHSS disease occurrence. This becomes evident as some OHSS cases occur in patients not thought to be at significant risk, while the majority of high-risk cases do not result in OHSS.1 Experience with controlled ovarian stimulation and knowledge of OHSS pathophysiology, risk factors, and clinical presentation remains essential for the prevention of severe OHSS. In spite of limited understanding of the pathophysiology of OHSS, there is now good evidence that preventive strategies can profoundly reduce the incidence of severe OHSS. Prior to the start of controlled ovarian stimulation,

the addition of metformin in patients with PCOS undergoing IVF should be considered as it may reduce the incidence of OHSS. During the treatment cycle, clinical risk factors should be used in judging the starting doses of gonadotropins. In patients with a very robust response to gonadotropins, coasting should be considered to prevent later OHSS. At the time of hCG trigger, the use of Cabergoline has been shown to reduce the risk for severe OHSS in patients at risk for this complication. There is no strong evidence to hCG trigger dose as an effective means to decrease the risk of OHSS. Cycle cancellation by withholding hCG has consistently been shown to obviate the risk of OHSS. Avoiding pregnancy by freezing all embryos will prevent severe prolonged OHSS in patients at high risk. Evidence also suggests that a GnRH agonist trigger followed by cryopreservation of all embryos is comparable to cycle cancellation in its efficacy at preventing OHSS with little compromise in success rates in those IVF centres that have a good embryo cryopreservation program. Finally, progesterone should be used for LPS rather than hCG. Continued research is required to gain a better appreciation of the pathophysiology of OHSS, which may advance our ability to predict and prevent this potentially serious illness. REFERENCES 1. Mathur R, Kailasam C, Jenkins J. Review of the evidence base of strategies to prevent ovarian hyperstimulation syndrome. Hum Fertil 2007;10:75–85. 2. Shmorgun D, Claman P, et al.; t SOGC–CFAS Clinical Practice Guidelines Committee. The diagnosis and management of ovarian hyperstimulation syndrome. SOGC Clinical Practice Guidelines, No. 268, November 2011. J Obstet Gynaecol Can 2011;33:1156–62. 3. Golan A, Ron-El R, Herman A, Soffer Y, Weinraub Z, Caspi E. Ovarian hyperstimulation syndrome: an update review. Obstet Gynecol Surv 1989;44:430–40. 4. Serour GI, Aboulghar M, Mansour R, Sattar MA, Amin Y, Aboulghar H. Complications of medically assisted conception in 3,500 cycles. Fertil Steril 1998;70:638–42. 5. Morris RS, Miller C, Jacobs L, Miller K. Conservative management of ovarian hyperstimulation syndrome. J Reprod Med 1995;40:711–4. 6. Semba S, Moriya T, Youssef EM, Sasano H. An autopsy case of ovarian hyperstimulation syndrome with massive pulmonary edema and pleural effusion. Pathol Int 2000;50:549–52. 7. Delvigne A, Rozenberg S. Epidemiology and prevention of ovarian hyperstimulation syndrome (OHSS): a review. Hum Reprod Update 2002;8;559–77. 8. Delvigne A, Rozenberg S. Review of clinical course and treatment of ovarian hyperstimulation syndrome (OHSS). Hum Reprod Update 2003;9:77–96. 9. Tollan A, Holst N, Forsdahl F, Fadnes HO, Oian P, Maltau JM. Transcapillary fluid dynamics during ovarian stimulation for in vitro fertilization. Am J Obstet Gynecol 1990;162:554–8.

NOVEMBER JOGC NOVEMBRE 2014 l 1031

SOGC Clinical Practice Guideline

10. Goldsman MP, Pedram A, Dominguez CE, Ciuffardi I, Levin E, Asch RH. Increased capillary permeability induced by human follicular fluid: a hypothesis for an ovarian origin of the hyperstimulation syndrome. Fertil Steril 1995;63:268–72.

26. The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004a;81:19–25.

11. Geva E, Jaffe RE. Role of vascular endothelial growth factor in ovarian physiology and pathology. Fertil Steril 2000;74;429–38.

27. Benadiva CA, Davis O, Kigman I, Moomjy M, Liu HC, Rosenwaks Z. Withholding gonadotrophin istration is an effective alternative for the prevention of ovarian hyperstimulation syndrome. Fertil Steril 1997;67:724–7.

12. Neulen J, Yan Z, Raczek S, Weindel K, Keek C, Weich HA, et al. Human chorionic gonadotripin-dependent expression of vascular endothelial growth factor/vascular permeability factor in human granulose cells: importance in ovarian hyperstimulation syndrome. J Clin Endocrinol Metab 1995;80:1967–71.

28. Mansour R, Alboulghar M, Serour G, Amin Y, Abou-Setta AM. Criteria of a successful coasting protocol for the prevention of severe ovarian hyperstimulation syndrome. Hum Reprod 2005;20:3167–72.

13. Pellincer A, Albert C, Mercander A, Bonilla-Musoles F, Remohi J, Simon C. The pathogenesis of ovarian hyperstimulation syndrome: in vitro studies investigating the role of interleukin-1β, interleukin-6, and vascular endothelial growth factor. Fertil Steril 1999;71:482–89.

29. Farhi J, Ben-Haroush A, Lande Y, Sapir O, Pinkas H, Fisch B. In vitro fertilization cycle outcome after coasting in gonadotropin-releasing hormone (GnRH) agonist versus GnRH antagonist protocols. Fertil Steril 2009;91:377–82.

14. Alvarez C, Marti-Bonmati L, Novella-Maestre E, Sanz R, Gomez R, Fernandez-Sanchez M, et al. Dopamine agonist cabergoline reduces hemoconcentration and ascites in hyperstimulated women undergoing assisted reproduction. J Clin Endocrinol Metab 2007;92:2931–7.

30. Delvigne A, Rozenberg S. Preventive attitude of physicians to avoid OHSS in IVF patients. Hum Reprod 2001;16:2491–5.

15. Navot D, Relou A, Birkenfield A, Rabinowitz R, Brzezinski A, Margalioth EJ. Risk factors and prognostic variables in the ovarian hyperstimulation syndrome. Am J Obstet Gynecol 1988;159:210–5. 16. Brinsden PR, Wada I, Tan SL, Balen A, Jacobs HS. Diagnosis, prevention and management of ovarian hyperstimulation syndrome. Br J Obstet Gynaecol 1995;102:767–72. 17. Enskog A, Henriksson M, Unander M, Nilsson L, Brannstrom M. Prospective study of the clinical and laboratory parameters of patients in whom ovarian hyperstimulation syndrome developed during controlled ovarian hyperstimulation for in vitro fertilization. Fertil Steril 1999;71:808–14. 18. Navot D, Bergh PA, Laufer N. Ovarian hyperstimulation syndrome in novel reproductive technologies: prevention and treatment. Fertil Steril 1992;58:249–61. 19. Asch R, Li H-P, Balmaceda JP, Weckstein LN, Stone SC. Severe ovarian hyperstimulation syndrome in assisted reproductive technology: definition of high risk groups. Hum Reprod 1991;6:1395–9. 20. Lee TH, Liu CH, Huang CC, Wu YL, Shih YT, Ho HN, et al. Serum anti-Müllerian hormone and estradiol levels as predictors of ovarian hyperstimulation syndrome in assisted reproduction technology cycles. Hum Reprod 2008;23:160–7. 21. Costello MF, Chapman M, Conway U. A review and meta-analysis of randomized controlled trials on metformin co-istration during gonadotrophin ovulation induction or IVF in women with polycystic ovary syndrome. Hum Reprod 2006;21:1387–99. 22. Tso LO, Costello MF, Albuquerque LE, Andriolo RB, Freitas V. Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome. Cochrane Database Syst Rev 2009 Apr 15;(2):CD006105. 23. Swanton A, Lighten A, Granne I, McVeigh E, Lavery S, Trew G, et al. Do women with ovaries of polycystic morphology without any other features of PCOS benefit from short-term metformin co-treatment during IVF? A double-blind, placebo-controlled, randomized trial. Hum Reprod 2011;26:2178–84. 24. Daya S. Updated meta-analysis of recombinant follicle stimulating hormone (FSH) versus urinary FSH for ovarian stimulation in assisted reproduction. Fertil Steril 2002;77:711–4. 25. Coomarasamy A, Afnan M, Cheema D, van der Veen F, Bossuyt PM, van Wely M. Urinary hMG versus recombinant FSH for controlled ovarian hyperstimulation following an agonist long down-regulation protocol in IVF or ICSI treatment: a systematic review and meta-analysis. Hum Reprod 2008;23:310–5.

1032 l NOVEMBER JOGC NOVEMBRE 2014

31. García-Velasco JA, Isaza V, Quea G, Pellicer A. Coasting for the prevention of ovarian hyperstimulation syndrome: much ado about nothing? Fertil Steril 2006;85:547–54. 32. Youssef MA, Al-Inany HG, Aboulghar M, Mansour R, Abou-Setta AM. Recombinant versus urinary human chorionic gonadotrophin for ovulation induction in assisted conception. Cochrane Database Syst Rev 2011;13(4):CD003719. 33. Gomez R, Gonzalez-Izquierdo M, Zimmerman RC, Novella-Maestre E, Alonso-Muriel I, Sanchez-Criado J, et al. Low dose dopamine agonist istration blocks VEGF mediated vascular permeability without altering VEGFR-2 dependent luteal angiogenesis in a rat ovarian hyperstimulated model. Endocrinology 2006;147:5400–11. 34. Soares SR, Gomez R, Simon C, Garcia-Velasco JA, Pellicer A. Targeting the vascular endothelial growth factor system to prevent ovarian hyperstimulation syndrome. Human Reprod Update 2008;14:321–33. 35. Schmidt DW, Maier DB, Nulsen JC, Benadiva CA. Reducing the dose of human chorionic gonadotropin in high responders does not affect the outcomes of in vitro fertilization. Fertil Steril 2004;82:841–6. 36. Salha O, Dada T, Sharma V. Influence of body mass index and selfistration of hCG on the outcome of IVF cycles: a prospective cohort study. Hum Fertil (Camb) 2001;4:37–42. 37. Kahraman S, Karlikaya G, Kavrut M, Karagozoglu H. A prospective, randomized, controlled study to compare two doses of recombinant human chorionic gonadotropin in serum and follicular fluid in woman with high body mass index. Fertil Steril 2010;93:2084–7. 38. Bates DO, Harper SJ. Regulation of vascular permeability by vascular endothelial growth factors. Vascul Pharmacol 2002;39:225–37. 39. Garcia-Velasco J. How to avoid ovarian hyperstimulation syndrome: a new indication for dopamine agonists. Reprod Biomed Online 2009;18(Suppl 2):71–5. 40. Kumar P, Sait SF, Sharma A, Kumar M. Ovarian hyperstimulation syndrome. J Hum Reprod Sci 2011;4:70–5. 41. Alvarez C, Alonso-Muriel I, García G, Crespo J, Bellver J, Simón C, et al. Implantation is apparently unaffected by the dopamine agonist Cabergoline when istered to prevent ovarian hyperstimulation syndrome in women undergoing assisted reproduction treatment: a pilot study. Hum Reprod 2007;22:3210–4. 42. Carizza C, Abdelmassih V, Abdelmassih S, Ravizzini P, Salgueiro L, Salgueiro PT, et al.. Cabergoline reduces the early onset of ovarian hyperstimulation syndrome: a prospective randomized study. Reprod Biomed Online 2008;17:751–5. 43. Tang H, Hunter T, Hu Y, Zhai SD, Sheng X, Hart RJ. Cabergoline for preventing ovarian hyperstimulation syndrome. Cochrane Database Syst Rev 2012;15(2):CD008605.

The Prevention of Ovarian Hyperstimulation Syndrome

44. Faghih M, DiPaolo L, Willoughby K, Karnis M, Hughes E, Neal M. Dostinex use for OHSS prevention does not affect IVF success. Fertil Steril 2008;90(Suppl):P–379. 45. Bhangoo R, Karunis M, Ballas J, San Roman GA, Stelling JR. Cabergoline decreases risk of ovarian hyperstimulation syndrome and has no effect on pregnancy rate during in vitro fertilization. Fertil Steril 2008;90(Suppl):P–387. 46. Al-Inany HG, Youssef MA, Aboulghar M, Broekmans F, Sterrenburg M, Smit JAM, et al. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database Syst Rev 2011;11(5):CD001750. 47. Garcia-Velasco JA. Agonist trigger: what is the best approach? Agonist trigger with vitrification of oocytes or embryos. Fertil Steril 2012;97:527–8. 48. Itskovitz J, Boldes R, Levron J, Erlik Y, Kahana L, Brandes JM. Induction of preovulatory luteinizing hormone surge and prevention of ovarian hyperstimulation syndrome by gonadotropin-releasing hormone agonist. Fertil Steril 1991;56:213–20. 49. Beckers NG, Macklon NS, Eijkemans MJ, Ludwig M, Felberbaum RE, Diedrich K, et al. Nonsupplemented luteal phase characteristics after the istration of recombinant human chorionic gonadotropin, recombinant luteinizing hormone, or gonadotropin-releasing hormone (GnRH) agonist to induce final oocyte maturation in in vitro fertilization patients after ovarian stimulation with recombinant follicle-stimulating hormone and GnRH antagonist cotreatment. J Clin Endocrinol Metab 2003;88:4186–92. 50. Kolibianakis EM, Schultze-Mosgau A, Schroer A, van Steirteghem A, Devroey P, Diedrich K, et al. A lower ongoing pregnancy rate can be expected when GnRH agonist is used for triggering final oocyte maturation instead of HCG in patients undergoing IVF with GnRH antagonists. Hum Reprod 2005;20:2887–92. 51. Humaidan P, Ejdrup BH, Bungum L, Bungum M, Grondahl ML, Westergaard L. GnRH agonist or hCG for ovulation induction in GnRH antagonist IVF/ICSI cycles: a prospective randomized study. Hum Reprod 2005;20:1213–20. 52. Garcia-Velasco JA, Motta L, López A, Mayoral M, Cerrillo M, Pacheco A. Low-dose human chorionic gonadotropin versus estradiol/progesterone luteal phase in gonadotropin-releasing hormone agonist-triggered assisted reproductive technique cycles: understanding a new approach. Fertil Steril 2010;94:2820–3. 53. Humaidan P, Kol S, Papanikolaou EG; Copenhagen GnRH Agonist Triggering Workshop Group. GnRH agonist for triggering of final oocyte maturation: time for a change of practice? Hum Reprod Update 2011;17:510–24. 54. Engmann L, DiLuigi A, Schmidt D, Nulsen J, Maier D, Benadiva C. The use of gonadotropin-releasing hormone (GnRH) agonist to induce

oocyte maturation after cotreatment with GnRH antagonist in high-risk patients undergoing in vitro fertilization prevents the risk of ovarian hyperstimulation syndrome: a prospective randomized controlled study. Fertil Steril 2008;89:84–91. 55. Humaidan P, Bungum L, Bungum M, Yding Andersen C. Rescue of corpus luteum function with peri-ovulatory HCG supplementation in IVF/ICSI GnRH antagonist cycles in which ovulation was triggered with a GnRH agonist: a pilot study. Reprod Biomed Online 2006;13:173–8. 56. Humaidan P, Ejdrup Bredkjaer H, Westergaard LG, Yding Andersen C. 1,500 IU human chorionic gonadotropin istered at oocyte retrieval rescues the luteal phase when gonadotropin-releasing hormone agonist is used for ovulation induction: a prospective, randomized, controlled study. Fertil Steril 2010;93:847–54. 57. Balaban B, Urman B, Ata B, Isiklar A, Larman MG, Hamilton R, et al. A randomised controlled study of human day 3 embryo cryopreservation by slow freezing or vitrification: vitrification is associated with higher survival, metabolism and blastocyst formation. Hum Reprod 2008;23:1976–82. 58. AbdelHafez FF, Desai N, Abou-Setta AM, Falcone T, Goldfarb J. Slow freezing, vitrification and ultra-rapid freezing of human embryos: a systematic review and meta-analysis. Reprod Biomed Online 2010;20:209–22. 59. Ferraretti AP, Gianaroli L, Magli C, Fortini D, Selman H, Feliciani E. Elective cryopreservation of all pronucleate embryos in women at risk of ovarian hyperstimulation syndrome :efficiency and safety. Hum Reprod 1999;14:1457–60. 60. Youssef MA, Al-Inany HG, Aboulghar M, Mansour R, Abou-Setta AM. Recombinant versus urinary human chorionic gonadotrophin for ovulation induction in assisted conception. Cochrane Database Syst Rev 2011;13(4):CD003719. 61. Kumbak B, Oral E, Karlikaya G, Lacin S, Kahraman S. Serum oestradiol and β-HCG measurements after day 3 or 5 embryo transfers in interpreting pregnancy outcome. Rep Bio Med Online 2006;13:459–64. 62. van der Linden M, Buckingham K, Farquhar C, Kremer JA, Metwally M. Luteal phase for assisted reproduction cycles. Cochrane Database Syst Rev 2011;5(10):CD009154. 63. Fluker M, Copeland J, Yuzpe A. An ounce of prevention: outpatient management of ovarian hyperstimulation syndrome. Fertil Steril 2000;73:821–4. 64. Borenstein R, Elhalah U, Lunenfeld B, Schwartz ZS. Severe ovarian hyperstimulation syndrome: a re-evaluated therapeutic approach. Fertil Steril 1989;51:791–5. 65. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

NOVEMBER JOGC NOVEMBRE 2014 l 1033

SOGC CLINICAL PRACTICE GUIDELINE No. 308, June 2014 (Replaces No. 95, September 2000)

Venous Thromboembolism and Antithrombotic Therapy in Pregnancy This clinical practice guideline has been prepared by the VTE in Pregnancy Guideline Working Group, reviewed by Maternal Fetal Medicine and Family Physician Advisory committees, and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Wee-Shian Chan, MD, Vancouver BC Evelyne Rey, MD, Montreal QC Nancy E. Kent, MD, Vancouver BC VTE IN PREGNANCY GUIDELINE WORKING GROUP Wee-Shian Chan, MD (Co-Chair), Vancouver BC Nancy E. Kent, MD (Co-Chair), Vancouver BC Evelyne Rey, MD (Co-Chair), Montreal QC Thomas Corbett, MD, Edmonton AB Michèle David, MD, Montreal QC M. Joanne Douglas, MD, Vancouver BC Paul S. Gibson, MD, Calgary AB Laura Magee, MD, Vancouver BC Marc Rodger, MD, Ottawa ON Reginald E. Smith, Pharm D, Victoria BC Disclosure statements have been received from all contributors.

Abstract Objective: To present an approach, based on current evidence, for the diagnosis, treatment, and thromboprophylaxis of venous thromboembolism in pregnancy and postpartum. Evidence: Published literature was retrieved through searches of PubMed, Medline, CINAHL, and The Cochrane Library from

Key Words: Venous thromboembolism, deep vein thrombosis, pulmonary embolism, thromboprophylaxis, assisted reproductive technology, heparin, neuraxial analgesia, adverse pregnancy outcomes, pregnancy or puerperal complications

November 2011 to July 2013 using appropriate controlled vocabulary (e.g. pregnancy, venous thromboembolism, deep vein thrombosis, pulmonary embolism, pulmonary thrombosis) and key words (e.g., maternal morbidity, pregnancy complications, thromboprophylaxis, antithrombotic therapy). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies published in English or French. There were no date restrictions. Grey (unpublished) literature was identified through searching the websites of clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Values: The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventative Health Care (Table 1). Recommendations 01. Objective testing is required following clinical suspicion of deep vein thrombosis or pulmonary embolism. (II-2A) 02. For the diagnosis of deep vein thrombosis, ultrasonography is recommended, and should be repeated at least once over 7 days if the initial study is negative. For each examination, the entire length of the venous system from the external iliac to the popliteal vein must be visualized and compression manoeuvres performed from the femoral to the popliteal vein. (II-2B) 03. For the diagnosis of pulmonary embolism, either ventilationperfusion scan or computed tomographic angiography can be used. (II-2A) In pregnant women, a ventilation-perfusion scan is the preferred test. (III-B) 04. Neither D-dimer alone nor clinical prediction rules should be used to rule out venous thromboembolism in pregnant women without objective testing. (III-D) 05. Pregnant women diagnosed with acute venous thromboembolism should be hospitalized or followed closely as outpatients for the first 2 weeks after the initial diagnosis. (III-C) 06. Low molecular weight heparin is the preferred pharmacologic agent over unfractionated heparin for the treatment of venous thromboembolism in pregnancy. (II-2A) 07. Heparin-induced thrombocytopenia in pregnant women is extremely rare. Consultation with a hematologist or thrombosis specialist is recommended to consider the use of heparanoids for treatment of venous thromboembolism if it occurs. (II-3B) J Obstet Gynaecol Can 2014;36(6):527–553

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

JUNE JOGC JUIN 2014 l 527

SOGC CLINICAL PRACTICE GUIDELINE

Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.187 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care.187

08. Vitamin K antagonists should only be considered in exceptional circumstances for the treatment of venous thromboembolism in pregnancy. (II-2A) 09. We recommend against the use of oral Xa inhibitors and oral direct thrombin inhibitors for the treatment of venous thromboembolism in pregnancy. (III-D) 10. For the treatment of acute venous thromboembolism in pregnancy we recommend adhering to the manufacturer’s recommended dosing for individual low molecular weight heparins based on the woman’s current weight. (II-1A) Low molecular weight heparin can be istered once or twice a day depending on the agent selected. (III-C) 11. For pregnant women initiated on therapeutic low molecular weight heparin, baseline platelet counts should be done and repeated a week later to screen for heparin-induced thrombocytopenia. (III-C) 12. For pregnant women with an acute venous thromboembolism we recommend therapeutic anticoagulation for a minimum of 3 months. (I-A) 13. Following initial treatment, anticoagulation intensity can be decreased to intermediate or prophylactic dose for the remainder of the pregnancy and for at least 6 weeks postpartum. (III-C)

18. Therapeutic dose anticoagulation should be initiated for confirmed cerebral venous thrombosis. (II-2A) 19. Thromboprophylaxis should be considered in future pregnancies following a cerebral venous thrombosis. (II-1C) 20. For superficial thrombophlebitis, compression ultrasound should be performed to exclude deep vein thrombosis (II-2A), and it should be repeated if proximal extension is suspected based on worsening phlebitis. (III-C) 21. Prophylactic or intermediate dose low molecular weight heparin for 1 to 6 weeks is recommended for women with bilateral superficial thrombophlebitis, for very symptomatic women, and for superficial thrombophlebitis located ≤ 5 cm from the deep venous system (saphenofemoral and saphenopopliteal junctions) or affecting ≥ 5 cm of vein. (I-A) 22. Observation alone is recommended in women with superficial thrombophlebitis at low risk of deep vein thrombosis and for those who do not require symptom control. Clinical follow-up of these women should occur within 7 to 10 days, with a repeat compression ultrasound within one week. (I-A) 23. Computed tomography and/or magnetic resonance imaging (with or without angiography) are the definitive imaging modalities to rule out ovarian vein thrombosis. (II-2A)

14. In pregnant women with acute proximal leg deep vein thrombosis, the use of graded compression stockings can be considered for relief of symptoms. (III-C)

24. For confirmed ovarian vein thrombosis, we recommend parenteral broad-spectrum antibiotics, continued for at least 48 hours after defervescence and clinical improvement. (II-2A) Longer antibiotic therapy is necessary for septicemia or complicated infections. (III-C)

15. Thrombolytic therapy in pregnancy should only be considered in limb-threatening deep vein thrombosis or massive pulmonary embolism. (III-C)

25. For confirmed ovarian vein thrombosis, therapeutic dose anticoagulation could be considered for 1 to 3 months. (III-C)

16. Vena cava filters should only be used in pregnant women with acute pulmonary embolism or deep vein thrombosis and contraindications to anticoagulation. (III-C) 17. Computed tomographic venography and/or magnetic resonance imaging should be performed to rule out cerebral venous thrombosis if suspected. (I-C)

528 l JUNE JOGC JUIN 2014

26. Routine screening for all inherited thrombophilias in all women with a first episode of venous thromboembolism diagnosed in pregnancy is not indicated. (III-C) 27. Testing for protein S, protein C, and antithrombin deficiencies is indicated following a venous thromboembolism in pregnancy if there is a family history of these particular thrombophilias, or if thrombosis occurs in an unusual site. (III-C)

Venous Thromboembolism and Antithrombotic Therapy in Pregnancy

28. Testing for antiphospholipid antibodies is indicated if the results would affect the duration of anticoagulation. (III-C) 29. Individual risk assessment for venous thromboembolism should be performed prior to all pregnancies, once pregnancy is achieved, and repeated throughout pregnancy as new clinical situations arise. The woman’s preferences and values should be taken into when considering the use of antepartum thromboprophylaxis. (III-B) 30. Women at increased risk should be advised of the symptoms and signs of venous thromboembolism. (III-B) 31. Low molecular weight heparin is the preferred pharmacologic agent over unfractionated heparin for antepartum thromboprophylaxis. (III-A) Low molecular weight heparin doses should be used as per the manufacturer’s recommendation. (III-C) 32. Routine anti-Xa medication and platelet-level monitoring are not recommended when a patient is on a prophylactic dose of thromboprophylaxis. (II-2E)

33. We recommend therapeutic thromboprophylaxis during pregnancy in the following situations: a. long-term therapeutic anticoagulation used prior to pregnancy for a persistent indication; (III-B) b. personal history of multiple previous venous thromboembolism. (III-B) 34. We recommend intermediate or therapeutic thromboprophylaxis during pregnancy in the following situation: a. personal history of a previous venous thromboembolism and a high-risk thrombophilia (antithrombin deficiency, antiphospholipid syndrome) not previously on anticoagulation. (III-B) 35. We recommend prophylactic dose thromboprophylaxis during pregnancy in the following situations (absolute risk > 1%): a. personal history of a previous unprovoked venous thromboembolism; (II-2A) b. personal history of a previous venous thromboembolism related to oral contraceptives or pregnancy; (II-2A)

ABBREVIATIONS

c. personal history of a previous provoked venous thromboembolism and any low risk thrombophilia; (I-A)

APLS

antiphospholipid syndrome

d. asymptomatic homozygous factor V Leiden; (II-2A)

aPTT

activated partial thromboplastin time

ART

assisted reproductive technology

e. asymptomatic homozygous prothrombin gene mutation 20210A; (III-B)

AT

antithrombin

ASA

acetylsalicylic acid

ASRA

American Society of Regional Anesthesia

BMI

body mass index

CT

computed tomography

CTA

CT angiography

CUS

compression ultrasound

CVT

cerebral venous thrombosis

DVT

deep vein thrombosis

FVL

factor V Leiden

HIT

heparin-induced thrombocytopenia

IUGR

intrauterine growth restriction

LDA

low-dose ASA

LMWH low molecular weight heparin MRI

magnetic resonance imaging

NSAID non-steroidal anti-inflammatory drug OHSS

ovarian hyperstimulation syndrome

OVT

ovarian vein thrombosis

PGM

prothrombin gene mutation 20210A

PC

protein C

PE

pulmonary embolism

PS

protein S

SGA

small for gestational age

SLE

systemic lupus erythematosus

ST

superficial thrombophlebitis

UH

unfractionated heparin

VQ

ventilation/perfusion

VTE

venous thromboembolism

f. asymptomatic combined thrombophilia; (III-B) g. asymptomatic antithrombin deficiency; (III-B) h. non-obstetrical surgery during pregnancy, with the duration of thromboprophylaxis being procedure- and patientdependent; (III-B) i. strict antepartum bedrest for ≥ 7 days in a woman with a body mass index of > 25 kg/m2 at her first antenatal visit. (II-2B) 36. Antepartum thromboprophylaxis for isolated pregnancy-related risk factors is not recommended. (III-E) 37. Antepartum thromboprophylaxis should be considered in the presence of multiple clinical or pregnancy-related risk factors where the overall absolute risk of venous thromboembolism is estimated to be > 1%, especially in women itted to hospital for bed rest. (II-2B) 38. Routine thromboprophylaxis is not required for all women undergoing ovulation induction. (III-C) 39. If severe ovarian hyperstimulation syndrome occurs with assisted reproductive technology, we recommend thromboprophylaxis with low molecular weight heparin for at least 8 to 12 weeks after resolution of the syndrome. (III-B) 40. Thromboprophylaxis with low molecular weight heparin should be considered for any women at increased risk for venous thromboembolism undergoing assisted reproductive technology at the time of ovarian stimulation. (III-B) 41. Women who develop a venous thromboembolism in association with the use of assisted reproductive technology but who do not conceive in that cycle should be treated with therapeutic anticoagulation for a minimum of 3 months. (II-3A) Those who conceive in that assisted reproductive technology cycle should be treated as per recommendations 12 and 13 for acute venous thromboembolism in pregnancy. (I-A, III-C) 42. Women on prophylactic dose, intermediate dose, or therapeutic anticoagulation should have a discussion about options for analgesia/anaesthesia prior to delivery. (III-B)

JUNE JOGC JUIN 2014 l 529

SOGC CLINICAL PRACTICE GUIDELINE

43. Switching from thromboprophylactic low molecular weight heparin to a prophylactic dose of unfractionated heparin at term (37 weeks) may be considered to allow for more options with respect to labour analgesia. (III-L) 44. Discontinue prophylactic or intermediate dose low molecular weight heparin or unfractionated heparin upon the onset of spontaneous labour or the day prior to a planned induction of labour or Caesarean section. (II-3B) 45. A recent platelet count should be available on ission in labour or before Caesarean delivery in women who have been, or are, on anticoagulants. (III-B)

postpartum risk factors after every delivery and repeat as new clinical situations arise. (II-2B) 57. Low molecular weight heparin is the preferred pharmacologic agent over unfractionated heparin for postpartum thrombo­ prophylaxis. (III-A) Low molecular weight heparin doses should be used as per the manufacturer’s recommendation. (III-C) 58. Pharmacologic thromboprophylaxis postpartum is recommended in the following situations:

a. history of any prior venous thromboembolism; (II-2A)

46. For women on low molecular weight heparin, neuraxial anaesthesia can be istered as a:

b. any high-risk thrombophilia: antiphospholipid syndrome, antithrombin deficiency, homozygous factor V Leiden or prothrombin gene mutation 20210A, or combined thrombophilia; (II-2B)

a. prophylactic dose: a minimum of 10 to 12 hours after the last dose; (III-B) b. therapeutic dose: after 24 hours since the last dose. (III-B)

c. strict bedrest prior to delivery for 7 days or more; (II-2B)

47. For women on unfractionated heparin, neuraxial anaesthesia can be istered as a:

d. peripartum or postpartum blood loss of > 1 litre or blood product replacement, and concurrent postpartum surgery; (II-2B)

a. prophylactic dose (maximum 10 000 U/day): after no delay; (III-B) b. therapeutic intravenous infusion: at least 4 hours after stopping the infusion and when the activated partial thromboplastin time is normal; (III-B) c. therapeutic subcutaneous unfractionated heparin: when the activated partial thromboplastin time is normal. This may be 12 hours or longer after the last injection. (III-B) 48. Neuraxial anaesthesia must be avoided in a woman who is fully anticoagulated or in whom there is evidence of altered coagulation. (II-3A)

Any 1 of the following risk factors (each with an absolute risk of venous thromboembolism > 1%):

e. peripartum/postpartum infection. (II-2B) 59. Postpartum thromboprophylaxis should be considered in the presence of multiple clinical or pregnancy-related risk factors when the overall absolute risk is estimated to be greater than 1% drawn from the following groupings: a. any 2 of the following risk factors (each with an absolute risk of venous thromboembolism < 1% in isolation):

i. body mass index ≥ 30 kg/m2 at first antepartum visit; (II-2B)

49. Removal of a neuraxial catheter left in situ postpartum should only be done 4, 10 to 12, or 24 hours following the istration of prophylactic dose unfractionated heparin (maximum 10 000 U/day), prophylactic low molecular weight heparin (single daily dose), or therapeutic dose low molecular weight heparin, respectively, or in the case of therapeutic unfractionated heparin, when the activated partial thromboplastin time is normal. (II-3B)



ii. smoking > 10 cigarettes/day antepartum; (II-2B)



iii. preeclampsia; (II-2B)



iv. intrauterine growth restriction; (II-2B)



v. placenta previa; (II-2B)



vi. emergency Caesarean section; (II–2B)

50. Prophylactic dose low molecular weight heparin (single daily dose) may be started or restarted 4 hours after neuraxial catheter removal, providing there is full neurological recovery and no evidence of active bleeding or coagulopathy. (III-B)



vii. peripartum or postpartum blood loss of > 1 litre or blood product replacement; (II-2B)



viii. any low risk thrombophilia: PC or PS deficiency, heterozygous factor V Leiden, or prothrombin gene mutation 20210A; (III-B)

51. Therapeutic low molecular weight heparin may be started or restarted at least 24 hours after a single injection neuraxial block and a minimum of 4 hours after neuraxial catheter removal, providing there is full neurological recovery and no evidence of active bleeding or coagulopathy. (III-B) 52. Subcutaneous unfractionated heparin may be started or restarted at least 1 hour after a single injection neuraxial block, providing there is full neurological recovery and no evidence of active bleeding or coagulopathy. (III-B) 53. Do not ister antiplatelet agents (acetylsalicylic acid or nonsteroidal anti-inflammatory drugs) concomitantly with heparin if a neuraxial catheter is left in situ postpartum. (III-D) 54. Women on therapeutic anticoagulation who have received neuraxial anesthesia should be monitored closely for the development of a spinal hematoma. (III-B) 55. Universal postpartum thromboprophylaxis is not recommended. (III-D) 56. Assess women for increased risk of postpartum venous thromboembolism based on antepartum, intrapartum, and

530 l JUNE JOGC JUIN 2014



ix. maternal cardiac disease, SLE, sickle cell disease, inflammatory bowel disease, varicose veins, gestational diabetes; (III-B)



x. preterm delivery; (III-B)



xi. stillbirth. (III-B) b. Any 3 or more of the following risk factors (each with an absolute risk of venous thromboembolism < 1%):



i. age > 35 years; (II-2B)



ii. parity ≥ 2; (II-2B)



iii. any assisted reproductive technology; (II-2B)



iv. multiple pregnancy; (II-2B)



v. placental abruption; (II-2B)



vi. premature rupture of membranes; (II-2B)



vii. elective Caesarean section; (II-2B)



viii. maternal cancer. (III-B)

Venous Thromboembolism and Antithrombotic Therapy in Pregnancy

60. Intermittent or sequential pneumatic compression devices are alternatives in women when heparin is contraindicated postpartum. When the risk of postpartum venous thromboembolism is high they may be used in combination with low molecular weight heparin or unfractionated heparin. (III-B)

the existing evidence that s the recommendations, and it is meant to be complementary to other international guidelines on this topic.8–15

61. Women with ongoing and persistent risk factors should receive postpartum thromboprophylaxis for a minimum of 6 weeks postpartum. (II-3B)

ACUTE VENOUS THROMBOEMBOLISM IN PREGNANCY

62. Women with transient antepartum or intrapartum risk factors should receive postpartum thromboprophylaxis until discharged from hospital or up to 2 weeks postpartum. (III-C)

Due to hormonal influences on vascular tone and compressive effects on veins by the enlarging uterus, DVT in pregnancy generally presents in the lower extremities, with a predisposition for the left leg (70 to 80%).16,17 In contrast to their presentation in non-pregnant patients, DVTs are often isolated to the iliac and/or femoral vein during pregnancy (61%).18 Consequently diagnostic approaches advocated for use in non-pregnant patients require modification in pregnancy.8

63. Universal screening for thrombophilias in women experiencing adverse pregnancy outcomes (severe preeclampsia, intrauterine growth restriction, stillbirth) is not indicated. (II-2D) 64. Women with recurrent miscarriage or late pregnancy loss should be screened for antiphospholipid syndrome. (I-B) 65. Low-dose acetylsalicylic acid or low-dose acetylsalicylic acid plus low molecular weight heparin is recommended in pregnancy in women with confirmed antiphospholipid syndrome. (I-C) 66. Low-dose acetylsalicylic acid plus low molecular weight heparin is not recommended for women with a history of recurrent miscarriage in the absence of confirmed antiphospholipid syndrome. (I-E) 67. Low molecular weight heparin should not be used routinely to reduce the risk of recurrent placenta-mediated complications in women with or without thrombophilia (excluding antiphospholipid syndrome). (I-C)

INTRODUCTION

T

his guideline summarizes the available data and the quality of the evidence to provide practical approaches to the diagnosis, management, and prevention of VTE in pregnancy. VTE remains an important cause of maternal morbidity and mortality in Canada with an overall incidence of DVT and PE of 12.1 per 10 000 and 5.4 per 10 000 pregnancies, respectively.1 VTE occurs at a rate of 5.4 per 10 000 antepartum, 7.2 per 10 000 peripartum, and 4.3 per 10 000 pregnancies postpartum.1 These rates are consistent with published literature from around the world.2–4 The first and second trimesters of pregnancy convey similar risks for DVT, with a higher risk in the third trimester and the first 3 weeks postpartum.5,6 PE occurs more commonly postpartum, decreasing in incidence after the first 6 weeks.3,7 This guideline sequentially reviews key components in reducing the risk VTE in pregnancy, which include accurate diagnosis and treatment of DVT and PE, antepartum thromboprophylaxis in appropriate patients, peripartum management of anticoagulants, and postpartum thromboprophylaxis, and concludes with a discussion of the use of heparin to prevent adverse pregnancy outcomes. Making decisions about the management of individual patients can be challenging and complex. Wherever possible, this guideline attempts to summarize and organize

Diagnosis of VTE in Pregnancy

In non-pregnant patients, diagnostic approaches for VTE use a combination of validated structured clinical prediction rules with or without the use of D-dimer testing, followed by objective testing with CUS.8 Extrapolating the same approach to pregnancy is difficult because: 1. structured prediction rules have not been validated in pregnant women, 2. the anatomic presentation of lower extremity DVT in pregnant women could affect the sensitivity of CUS,18 and 3. current validated D-dimer level cut-off points are of limited utility.19,20 The potential use of a pregnancy-specific structured prediction rule and pregnancy-specific D-dimer thresholds has been reported,21–23 but currently neither test should be used alone or in combination to diagnose or exclude VTE without further validation studies. Our recommended diagnostic algorithm for DVT in pregnancy is shown in Figure 1. When a pregnant woman presents with a suspected DVT, she should undergo an ultrasound including direct visualization of the entire proximal venous system from the iliac to the popliteal vein.24 Doppler studies should be performed at the level of the iliac vein to ensure that flow is present. Compression manoeuvers should be performed along the entire venous system from the femoral to the popliteal vein. The sensitivity and negative predictive value of this method are 90.9% (95% CI 69.4 to 98.4) and 98.9% (95% CI 95.5 to 99.8), respectively.24 Published evidence is currently insufficient to the safety of performing a single ultrasound examination in pregnant women with suspected DVT. Hence, we would recommend repeat testing with CUS and JUNE JOGC JUIN 2014 l 531

SOGC CLINICAL PRACTICE GUIDELINE

Figure 1. Algorithm for the diagnosis of deep venous thrombosis in pregnant patients Suspected DVT Compression ultrasound of entire proximal venous system from iliac to popliteal vein and Doppler examination of external iliac vein Consider MRI if isolated iliac vein DVT is suspected based on symptoms and Doppler examination of external iliac vein

DVT not diagnosed

DVT diagnosed

Repeat above ultrasound examination within 7 days

DVT diagnosed

DVT not diagnosed

Clinical follow-up

Doppler imaging as above at least once again over the next 7 days if the initial study is negative. If isolated iliac vein obstruction (i.e. absence of flow) is suspected on Doppler examination, two options are available: 1. institute therapeutic anticoagulation followed by repeat CUS in 2 to 3 days, or 2. proceed with MRI. The option chosen depends on patient preference, availability of expertise, and access to imaging. The specificity and sensitivity of MRI and the specific technique used to diagnose DVT in pregnancy remains uncertain.25,26 When PE is suspected clinically, definitive diagnosis requires diagnostic imaging. Several factors should be considered in the choice of VQ scan or CTA: 1. the maternal and fetal risks associated with the tests (radiation and contrast agent), 2. the sensitivity of the tests, and 3. their availability. For both VQ scan and CTA the calculated radiation risk to the fetus is low, with levels below the threshold of 50 mGy 532 l JUNE JOGC JUIN 2014

for subsequent childhood malignancy.27–29 The calculated minimum radiation dose to each breast for an average 60 kg woman is 20 to 35 mGy from CTA and 0.28 mGy from VQ scan.30,31 While little is known about the long-term effects of radiation exposure to breast tissue during pregnancy, there are data linking imaging procedures to an increased risk of breast cancer.32 The iodinated contrast agent required for computed tomographic angiography to diagnosis PE crosses the placenta and can theoretically result in fetal or neonatal hypothyroidism. However, this risk was not significant in an observational study of over 300 pregnancies.33 In pregnancy the observed sensitivity and negative predictive values of CTA and VQ scan appears to be high, using clinical outcome as a surrogate measure.34–38 The specificity of a CTA in pregnancy cannot be ascertained, but studies in non-pregnant patients suggest CTA might be less specific in younger patients.39 The decision to use CTA or VQ scan is also dictated by local availability and expertise. The CTA technique used to diagnose PE in nonpregnant patients should be modified as 5% to 36% of scans can be inadequate in pregnancy due to physiological changes.32,40–42 We currently advocate the use of the VQ scan as the diagnostic test in pregnancy whenever possible

Venous Thromboembolism and Antithrombotic Therapy in Pregnancy

Figure 2. Algorithm for the diagnosis of pulmonary embolism in pregnant patients using the preferred VQ scan Suspected PE

Bilateral ultrasound examination of lower extremity* DVT diagnosed

DVT not diagnosed

Start treatment

VQ scan

Normal

Non-diagnostic

Low pretest†

Serial ultrasound exams of lower extremity*

High probability

High/moderate pretest†

Spiral CTA scan‡

PE diagnosed

*Bilateral US should include examination of the iliac veins with Doppler manoeuvers †Pretest determined by clinician’s subjective assessment ‡Modification in spiral CT protocol should be considered for pregnant patients

for the reasons listed above. However, if CTA is used, it is important to counsel patients regarding breast radiation and ensure local awareness for technique modification. As illustrated in Figure 2, initial testing for PE should reasonably begin with bilateral CUS. Although the likelihood of asymptomatic DVT is low, if a DVT is diagnosed in the presence of unexplained chest pain, shortness of breath or tachycardia, a PE can be assumed and ventilation-perfusion scanning avoided. If CUS is negative or if the initial bilateral leg CUS examination is not available, a ventilationperfusion scan should be performed. If the scan is normal, no further testing is needed; if the scan is high probability, anticoagulation should be initiated. For non-diagnostic scans, either CTA or serial CUS testing, based on clinical suspicion and the presence of risk factors, should be done. If CTA is selected, a negative scan will rule out a PE while a positive scan will be diagnostic. When the CTA is inconclusive or inadequate, serial whole leg ultrasound examination or repeat testing with a VQ scan is recommended.43

Recommendations

1. Objective testing is required following clinical suspicion of deep vein thrombosis or pulmonary embolism. (II-2A) 2. For the diagnosis of deep vein thrombosis, ultrasonography is recommended, and should be repeated at least once over 7 days if the initial study is negative. For each examination, the entire length of the venous system from the external iliac to the popliteal vein must be visualized and compression manoeuvres performed from the femoral to the popliteal vein. (II-2B) 3. For the diagnosis of pulmonary embolism, either ventilation-perfusion scan or computed tomographic angiography can be used. (II-2A) In pregnant women, a ventilation-perfusion scan is the preferred test. (III-B) 4. Neither D-dimer alone nor clinical prediction rules should be used to rule out venous thromboembolism in pregnant women without objective testing. (III-D) JUNE JOGC JUIN 2014 l 533

SOGC CLINICAL PRACTICE GUIDELINE

Table 2. Incidence of side effects related to low molecular weight heparins in pregnancy Therapeutic dose

Prophylactic dose

Any dose

References

Antepartum bleeding

0% to 0.57%

0.42%

0% to 0.43%

51, 171 to 173

Postpartum bleeding

1.15% to 5.6%

0.92%

0.94% to 1.6%

51, 171 to 173

Wound hematoma

1.39%

0%

0.5% to 0.61%

51, 171 to 173

Major skin reaction/allergy

1.15%

0.96%

0.5% to 1.8%

51, 173

Osteoporosis

0%

0.26%

0.04% to 0.2%

51, 173

HIT

0%

0%

0%

51, 173

TREATMENT OF ACUTE VTE Setting

Once an acute VTE is confirmed, therapeutic anti­ coagulation should be instituted promptly. There are no studies confirming the safety of outpatient management in pregnancy for women with acute VTE. Given the additional fetal concerns, pregnant women with an acute PE and/or a large proximal DVT should be considered for hospitalization or followed closely as outpatients in the initial two weeks following diagnosis if they remain hemodynamically stable. Recommendation

5. Pregnant women diagnosed with acute venous thromboembolism should be hospitalized or followed closely as outpatients for the first 2 weeks after the initial diagnosis. (III-C) Choice of anticoagulant

Vitamin K antagonists, such as warfarin, should not be considered for the treatment of VTE in pregnancy except in exceptional circumstances. They cross the placenta, and first trimester exposure can cause warfarin embryopathy (midfacial and limb hypoplasia, stippled bone epiphyses).44,45 They are also associated with pregnancy loss and fetal anticoagulation at the time of delivery.46 UH and LMWH do not cross the placenta and do not cause teratogenicity or fetal bleeding.47–52 HIT occurs in 3% of non-pregnant patients receiving UH. It has never been reported in a pregnancy with LMWH, 51 and outside of pregnancy HIT has been reported only in rare cases.53 Due to its lower side-effect profile and ease of dosing, LMWH is recommended over UH for use in pregnant women. Table 2 outlines the pooled risk estimates of side effects associated with LMWH use in pregnancy. The specific LMWH preparation used depends on availability and costs. There is no current evidence to 534 l JUNE JOGC JUIN 2014

suggest the superiority of one preparation of LMWH over another. Danaparoid and fondaparinux are heparanoid molecules that do not cross-react with HIT antibodies. Both are treatment options for pregnant women with evidence of HIT or allergic reactions to heparins.54,55 These agents should only be used after consultation with an appropriate specialist. There are currently no data on the safety in pregnancy of the oral direct thrombin inhibitors (dabigatran) and factor Xa inhibitors (rivaroxaban and apixaban). Given their very low molecular weights, they are likely to cross the placenta and should be avoided. Recommendations

6. Low molecular weight heparin is the preferred pharmacologic agent over unfractionated heparin for the treatment of venous thromboembolism in pregnancy. (II-2A) 7. Heparin-induced thrombocytopenia in pregnant women is extremely rare. Consultation with a hematologist or thrombosis specialist is recommended to consider the use of heparanoids for treatment of venous thromboembolism if it occurs. (II-3B) 8. Vitamin K antagonists should only be considered in exceptional circumstances for the treatment of venous thromboembolism in pregnancy. (II-2A) 9. We recommend against the use of oral Xa inhibitors and oral direct thrombin inhibitors for the treatment of venous thromboembolism in pregnancy. (III-D) Anticoagulant dosing and monitoring

Recommended doses for anticoagulation medications are presented in Table 3. The specific LMWH dosing is as per the manufacturer’s recommendation, based on the woman’s weight at the time of presentation.

Venous Thromboembolism and Antithrombotic Therapy in Pregnancy

Table 3. Dosing of anticoagulants UH

Prophylactic dose

Intermediate dose

Therapeutic dose

5000 U SC twice daily

10 000 U SC twice daily

IV: 80 U/kg bolus (max 5000 U) followed by 18 U/kg and adjusted according to local nomogram

Obesity: 7500 U SC twice daily

SC: 150 to 200 U/kg twice daily A lower dose should be considered in women weighing less than 50 kg175 Target aPTT 1.5 to 2.5 × baseline Dalteparin

100 U/kg SC daily or 5000 U SC twice daily

200 U/kg daily or 100 U/kg SC twice daily

40 mg SC twice daily

1 mg/kg SC twice daily or 1.5 mg/kg SC daily

2850 U SC daily

Not applicable

171 U/kg SC daily

4500 U SC daily

4500 U SC twice daily or 9000 U SC daily

175 U/kg SC daily

Obesity: 75 U/kg daily 750 U SC twice daily

Not applicable

2000 U SC twice daily

5000 U SC daily or twice daily > 20 weeks Obesity: 7500 U SC daily

Enoxaparin

40 mg SC daily or 30 mg SC twice daily Obesity: 60 mg SC daily

Nadroparin Tinzaparin Danaparoid SC: subcutaneously

There are uncertainties surrounding dosing regimens; the need for monitoring and dose increases with weight gain associated with therapeutic LMWH use in pregnancy.56 While LMWH is istered as a single daily dose for non-pregnant patients, twice a day dosing is often used in pregnancy, especially for the first month when the risk of recurrence is greatest. This practice stems from the altered renal elimination of LMWH and the impact of weight gain, both of which affect anti-Xa activity in pregnant women.9,14,50,52,57–59 Hence, for the treatment of acute VTE, especially major proximal VTE and PE, consideration should be given to initial monitoring of anti-Xa activity, during the first month of treatment only, to target a level of 0.6 to 1.0 U/mL 4 hours after injection, bearing in mind that target levels will vary with the LMWH used. However, the cost of the assay, the lack of correlation with clinical events, and the variability between assays makes the utility of monitoring anti-FXa activity in pregnancy controversial.9 If UH is selected for initial treatment, it should be istered initially as a bolus followed by a continuous infusion, using a weight-based nomogram to estimate required doses, and adjusting the infusion to keep the aPTT at 1.5 to 2.5 times baseline. After initial treatment, a switch to therapeutic subcutaneous LMWH or UH can be made. If UH is selected, it should be istered subcutaneously twice daily with doses adjusted to maintain the aPTT at 1.5 to 2.5 times pregnancy baseline at the mid-dosing interval (i.e., 6 hours after the last dose). For women with significant renal impairment (GFR < 30 mL/minute) we recommend UH over LMWH.

Recommendations

10. For the treatment of acute venous thromboembolism in pregnancy we recommend adhering to the manufacturer’s recommended dosing for individual low molecular weight heparins based on the woman’s current weight. (II-1A) Low molecular weight heparin can be istered once or twice a day depending on the agent selected. (III-C) 11. For pregnant women initiated on therapeutic low molecular weight heparin, baseline platelet counts should be taken and repeated a week later to screen for heparin-induced thrombocytopenia. (III-C) Duration of therapeutic anticoagulation

If an acute VTE is diagnosed early in pregnancy, reducing the anticoagulation intensity after 3 months to intermediate or prophylactic (low) dose LMWH for the duration of the pregnancy is an option, although evidence confirming or disputing the safety of this option is unavailable. In the postpartum period, both LMWH and warfarin can be used. Recommendations

12. For pregnant women with an acute venous thromboembolism we recommend therapeutic anticoagulation for a minimum of 3 months. (I-A) 13. Following initial treatment, anticoagulation intensity can be decreased to intermediate or prophylactic dose for the remainder of the pregnancy and for at least 6 weeks postpartum. (III-C) JUNE JOGC JUIN 2014 l 535

SOGC CLINICAL PRACTICE GUIDELINE

Prevention of post-thrombotic syndrome

Post-thrombotic syndrome is a constellation of symptoms (chronic leg swelling, discoloration, pain on walking or standing) occurring in 20% to 40% of nonpregnant patients who develop a proximal DVT.60 Graded compression stockings with 30 to 40 mmHg pressure at the ankles for 2 years were previously felt to reduce this rate.61 A recent large placebo-controlled RCT (N = 803) showed that compression stockings did not prevent postthrombotic syndrome, nor did they influence the severity or rate of recurrence after a first proximal DVT in an older non-pregnant population.62 Observational studies are limited in pregnancy, therefore the need for prolonged use of graded compression stockings in pregnant women is uncertain and we recommend them for symptom relief alone. Recommendation

14. In pregnant women with acute proximal leg deep vein thrombosis, the use of graded compression stockings can be considered for relief of symptoms. (III-C) Thrombolytic therapy

Thrombolytic therapy has been used successfully in pregnant women who present with massive PE and hemodynamic instability.63,64 Streptokinase, r-tPA, and urokinase do not appear to have direct placental transfer. The risk of catastrophic bleeding with their use needs to be weighed against the risk of maternal and fetal death. The only indication for thrombolytic therapy in pregnancy is limb-threatening DVT or a massive PE.8 Recommendation

15. Thrombolytic therapy in pregnancy should only be considered in limb-threatening deep vein thrombosis or massive pulmonary embolism. (III-C) Vena cava filters

Vena cava filters are rarely required in pregnancy.65–68 Placement of a retrievable filter can be considered if a patient presents with an acute PE within 2 weeks of delivery or if anticoagulation therapy has to be interrupted due to major bleeding concerns. Careful planning of filter insertion with interventional radiology is necessary to minimize fetal exposure to radiation. Recommendation

16. Vena cava filters should only be used in pregnant women with acute pulmonary embolism or deep vein thrombosis and contraindications to anticoagulation. (III-C) 536 l JUNE JOGC JUIN 2014

CEREBRAL VENOUS THROMBOSIS

The incidence of CVT ranges from 0.01% to 0.04% in Western countries.69 Pregnancy and the puerperium, Caesarean section, dehydration, anemia, thrombophilia, and hypertension are identified risk factors.69–71 Symptoms and signs include diffuse headache, altered consciousness, seizures, and focal neurological deficits. CT venography and/or MRI studies should be performed in suspected CVT if initial imaging modalities without contrast are negative or inconclusive. Once CVT is diagnosed, therapeutic dose anticoagulation should be initiated. In addition to haematologists and thrombosis specialists, other medical and surgical subspecialists may be required depending on neurological complications. Recommendations

17. Computed tomographic venography and/or magnetic resonance imaging should be performed to rule out cerebral venous thrombosis if suspected. (I-C) 18. Therapeutic dose anticoagulation should be initiated for confirmed cerebral venous thrombosis. (II-2A) 19. Thromboprophylaxis should be considered in future pregnancies following a cerebral venous thrombosis. (II-1C) SUPERFICIAL THROMBOPHLEBITIS

Superficial thrombophlebitis is inflammation with or without thrombosis of a superficial vein, isolated or associated with peripheral or central catheters. The incidence in pregnancy is 0.068%.72 ST is usually selflimiting, but it can extend into the deep venous system and/or recur. Factors associated with DVT include bilateral ST, ST presenting near the deep venous system (saphenofemoral and saphenopopliteal junctions), systemic infection, absence of varicose veins, and a previous history of DVT.73,74 Concurrent PE is diagnosed in 4% of individuals with ST affecting ≥ 5 cm of a vein.75 The preferred treatment of ST is uncertain in pregnant women. A recent trial in non-pregnant patients showed that fondaparinux (2.5 mg daily for 45 days) significantly reduced the incidence of DVT and the extension and recurrence of the ST.76 A recent Cochrane meta-analysis showed that LMWH (prophylactic and therapeutic doses) and NSAIDS for 8 to 12 days were more effective than placebo in reducing the extension or recurrence of ST, but without decreasing the occurrence of symptomatic DVT.77 Since safety data on fondaparinux use is limited and

Venous Thromboembolism and Antithrombotic Therapy in Pregnancy

extended NSAID use is discouraged in pregnancy after 26 to 28 weeks’ gestation, we recommend prophylactic or intermediate dose LMWH for 1 to 6 weeks in symptomatic women and in women with bilateral ST, ST of 5 cm or more, or ST located less than 5 cm from the deep venous system. Observation alone is recommended in women with ST who are at low risk of DVT and for those who do not require symptom control. Clinical follow-up of these women should occur within 7 to 10 days, with a repeat CUS within one week. Recommendations

20. For superficial thrombophlebitis, compression ultrasound should be performed to exclude deep vein thrombosis (II-2A), and it should be repeated if proximal extension is suspected based on worsening phlebitis. (III-C) 21. Prophylactic or intermediate dose low molecular weight heparin for 1 to 6 weeks is recommended for women with bilateral superficial thrombophlebitis, for very symptomatic women, and for superficial thrombophlebitis located ≤ 5 cm from the deep venous system (saphenofemoral and saphenopopliteal junctions) or affecting ≥ 5 cm of vein. (I-A) 22. Observation alone is recommended in women with superficial thrombophlebitis at low risk of deep vein thrombosis and for those who do not require symptom control. Clinical follow-up of these women should occur within 7 to 10 days, with a repeat compression ultrasound within one week. (I-A) OVARIAN VEIN THROMBOSIS

Ovarian vein thrombosis is an uncommon event, complicating 0.05% to 0.18% of pregnancies and affecting the right vein in up to 90% of cases.78,79 Risk factors include Caesarean section, multiple gestation, and infection.79 Complications include extension of the thrombus into the vena cava and/or renal veins, and sepsis. PE occurs in 13% of cases.80 Symptoms and signs of OVT include nausea, vomiting, guarding, constant lower abdominal or flank pain, palpable sausage-shaped tender abdominal masses, fever, rigors, and leukocytosis in the first 15 days after a delivery, abortion, or ruptured ectopic pregnancy. A pelvic ultrasound should be done initially, followed by CT and/or MRI in the case of a negative or equivocal result.81 Broad-spectrum parenteral antibiotics should be initiated with the diagnosis of OVT and continued for at least 48 hours after defervescence and clinical improvement.82,83 A longer treatment course is required in the presence

of septicemia. Even though a small randomized study (N = 14) did not report a difference in the resolution of the fever with antibiotics alone versus antibiotics plus UH,78 concurrent anticoagulation is often recommended.79,82–84 We recommend anticoagulation for 1 to 3 months. There are no studies to guide the risk of recurrence of OVT and the need for thromboprophylaxis in subsequent pregnancies. The risk is likely low.84 Recommendations

23. Computed tomography and/or magnetic resonance imaging (with or without angiography) are the definitive imaging modalities to rule out ovarian vein thrombosis. (II-2A) 24. For confirmed ovarian vein thrombosis, we recommend parenteral broad-spectrum antibiotics, continued for at least 48 hours after defervescence and clinical improvement. (II-2A) Longer antibiotic therapy is necessary for septicemia or complicated infections. (III-C) 25. For confirmed ovarian vein thrombosis, therapeutic dose anticoagulation could be considered for 1 to 3 months. (III-C) THROMBOPHILIA SCREENING AFTER THE DIAGNOSIS OF ACUTE VTE

There is no consensus as to whether or not patients require thrombophilia testing following the diagnosis of an acute VTE in the non-pregnant state. The acute management of the current or subsequent pregnancies is generally not altered by knowledge of the thrombophilia status, nor is counselling regarding subsequent risks of VTE. However, patients with VTE and a known family history of PS, PC, or AT deficiency would benefit from screening, as these might affect the duration of anticoagulation required for the initial episode.85 Screening for other inherited thrombophilias is unnecessary because the presence of these will not change management.86,87 Screening for acquired thrombophilia, i.e. APLS, has been advocated for non-pregnant patients, since a persistently positive screen (over 12 weeks) could affect the duration of anticoagulation.86 There are concerns about applying this to pregnant women: 1. the risk of a false positive, leading to patient anxiety, is significant, 2. the need to prolong anticoagulation beyond the usual recommended duration for pregnant patients with APLS is uncertain, and 3. repeat testing is required 8 to 12 weeks after delivery. JUNE JOGC JUIN 2014 l 537

SOGC CLINICAL PRACTICE GUIDELINE

We therefore recommend against routine screening for APLS during pregnancy, unless thrombosis occurs in an unusual site or if the results would affect the duration of anticoagulation. Recommendations

26. Routine screening for all inherited thrombophilias in all women with a first episode of venous thromboembolism diagnosed in pregnancy is not indicated. (III-C) 27. Testing for protein S, protein C, and antithrombin deficiencies is indicated following a venous thromboembolism in pregnancy if there is a family history of these particular thrombophilias, or if thrombosis occurs in an unusual site. (III-C) 28. Testing for antiphospholipid antibodies is indicated if the results would affect the duration of anticoagulation. (III-C) MANAGEMENT OF ANTICOAGULATION THERAPY IN PREGNANT WOMEN WITH MECHANICAL HEART VALVES

For management of anticoagulation therapy in these patients, we would refer clinicians to the guidelines published by American College of Chest Physicians.9 ANTEPARTUM THROMBOPROPHYLAXIS

Recognizing that the pregnant state confers an increased risk for VTE is only the first step in determining which women will benefit from thromboprophylaxis during pregnancy. Although there is a 10-fold increase over baseline, the absolute risk of VTE during pregnancy remains low (0.5 per 1000 pregnancies),1 and LMWH is not a risk-free medication (see Table 2). Hence, the difficulty in clinical practice is reconciling the low absolute risk of VTE with the low risk of side effects associated with thromboprophylaxis. Determining a reasonable level of absolute risk of VTE for recommending a need for thromboprophylaxis was the first step in the development of this guideline. Most experts would agree that pregnant women with an estimated absolute risk of VTE above 10% should receive thromboprophylaxis, while those with an estimated VTE risk of less than 1% might not. When the risk falls between 1% and 10% the decision to offer thromboprophylaxis would depend on the magnitude of VTE risk, the consequences of having a DVT or PE, the risks associated with thromboprophylaxis, and the patient’s and physician’s preferences.88 In this guideline we leaned 538 l JUNE JOGC JUIN 2014

towards the avoidance of VTE during pregnancy, while minimizing the number of women who would experience heparin side effects. Hence, we recommend antepartum thromboprophylaxis when the overall estimated absolute risk of VTE is greater than 1%. Unfortunately, the magnitude to which additional biological factors in the antepartum period increase the risk for a given patient is imprecisely reported in the literature (see Table 4). Involvement of appropriate specialists should be considered in cases of clinical uncertainty. Previous objectively documented VTEs which were unprovoked or related to hormonal therapy or pregnancy confer the highest risk of recurrence during pregnancy and warrant antepartum thromboprophylaxis.89–92 Unprovoked or idiopathic VTEs are those occurring in the absence of clinical risk factors such as surgery, hospitalization or plaster cast immobilization within one month, and cancer. Thrombophilias, whether inherited or acquired, have varying propensities for VTE. High-risk thrombophilias include AT deficiency, APLS, homozygous FVL or PGM, and combined thrombophilias.93,94 The more prevalent inherited thrombophilias, such as heterozygote FVL and PGM, confer a lower risk of VTE than the rarer ones, such as PS and PC deficiency.95,96 Since data to guide the use of thromboprophylaxis in uncommon asymptomatic thrombophilia are sparse, our recommendations for these conditions are based on estimated absolute risks for VTE in the general population97–99 rather than on data from retrospective family studies,100–103 especially for PC deficiency. Note that a recent task force on APLS recommended the use of hydroxychloroquine for thromboprophylaxis in patients with both SLE and APLS,104 although the benefit of this recommendation has not been proven in pregnancy. Screening for thrombophilia in women with a previous VTE should only be done if the result will modify management in the current pregnancy, in the presence of a family history of a high-risk inherited thrombophilia, and if the woman is fully counselled about the implications of a positive result prior to testing. Screening specifically for APLS should be considered in women with a previous unprovoked VTE or VTEs in unusual sites. A family history of VTE alone, in the absence of a personal history or other risk factors for VTE, does not increase the personal risk of VTE sufficiently to warrant antepartum thromboprophylaxis.105 The contribution of various clinical and pregnancyrelated risk factors for VTE has been derived from several population-based observational studies.2,3,106–108 (Table 5)

Venous Thromboembolism and Antithrombotic Therapy in Pregnancy

Table 4. Literature review of incidence of symptomatic VTE antepartum without prophylaxis according to various biological and clinical risk factors Incidence of symptomatic VTE* < 1%

1% to 5%

> 5% to 10%

••91,92

•89

> 10%

Personal history of previous VTE Single unprovoked

•

Pregnancy-related O-related Single provoked (Other than O- or pregnancy-related)

•

FVL (hetero- and homozygosity)

•100

92

•91

•92

•91

••

91

•90

89,90

•89 •100

FVL homozygosity

•94

Combined FVL and PGM heterozygosity

••

AT deficiency

176,177

Asymptomatic thrombophilia

••••101,178,181,182

FVL homozygosity

•••96,98,179 •96

PGM homozygosity Combined FVL and PGM heterozygosity

••

AT deficiency

••179,183

FVL heterozygosity PGM heterozygosity PC deficiency PS deficiency

•••••••

•••

98,182

94,96,179

••99,174

••98,103

••177,183

96–99,178–180

••••96,98,101,179 •••

98,99,179

•94 ••

•••103,183,185

102,185

••176,183 •176

Family history of symptomatic thrombophilia and unknown status FVL

•••97,101,178

PGM

••102,184

PC deficiency

••99,103

PS deficiency

•••103,183,185

Combined pregnancy-related risk factors

•109

Strict bed rest ≥ 7 days + BMI ≥ 25 kg/m2 at first antenatal visit O: oral contraceptive pill *Each dot represents one study; the superscript numerals are references to those studies.

However, a large case–control study of 613 232 births with 559 cases of antepartum and postpartum VTE (overall incidence of 1/1000 live births) showed that most previously identified pregnancy-related risk factors in isolation did not increase the absolute risk of antepartum VTE above 1%.109 This has recently been ed by a large populationbased cohort study from the UK.4 For example, although maternal obesity has been identified as a risk factor, the absolute risk of VTE associated with maternal obesity alone would not warrant the use of thromboprophylaxis, even ing for various definitions of increased BMI presented in the literature.107,110 Notably, the combination of antenatal bedrest for ≥ 7 days (defined as > 90% of the time in bed) and a booking (first antenatal visit) BMI of ≥ 25 kg/m2 increased the risk of antenatal VTE to

approximately 6% in the large case–control study,109 warranting antepartum thromboprophylaxis with this combination of clinical factors (see Table 4). While we recognize that strict bedrest is rarely indicated in hospitalized obstetrical patients today, the significant increase in risk of VTE incurred when it is instituted cannot be overemphasized. Hence, antepartum thromboprophylaxis should be considered in the presence of multiple clinical or pregnancy-related risk factors when the overall absolute risk of VTE is estimated to be greater than 1%, especially in patients who are in hospital, where bedrest is often prescribed. Due to its lower side-effect profile, LMWH is the preferred pharmacologic agent over UH for antepartum thromboprophylaxis. Table 3 presents the doses of JUNE JOGC JUIN 2014 l 539

SOGC CLINICAL PRACTICE GUIDELINE

Table 5. Literature review of incidence of symptomatic VTE antepartum without prophylaxis according to various clinical or pregnancy-related risk factors Incidence of symptomatic VTE* < 0.3%

0.3% to 0.5%

> 0.5% to < 1.0%

Maternal pre-pregnancy risk factors Age > 35 years BMI > 30 kg/m2 or weight > 90 kg at first antenatal visit

••••2,4,108,109 •••••4,106,108–110

•107 •

Weight > 120 kg at first antenatal visit Parity ≥ 2

••••

Smoking >10 cigarettes/day or current versus never smoked

•••••

2,4,106,109

110

•108

2,4,107–109

•4

Pre-existing diabetes

•4

Inflammatory bowel disease Varicose veins

•

Cancer

•4

4

Risk factors related to present pregnancy Multiple pregnancy

•••2,4,109

••3,109

ART (singleton)

Preeclampsia/pre-existing hypertension

•109 •109

ART (twins) Strict bedrest ≥ 7 days + BMI < 25 kg/m2 at first antenatal visit

•106

•186 ••

•109

4,109

IUGR

•109

Preeclampsia + IUGR

•109

Gestational diabetes

••3,109

*Each dot represents one study; the superscript numerals are references to those studies.

the heparins currently available in Canada, as per the manufacturers’ recommendations. However, some women may need a dose adjustment because of their weight, and weight increases as pregnancy progresses. Women who are known to require antepartum thromboprophylaxis should start LMWH once the decision is made and the patient becomes pregnant. For others, ongoing evaluation of the need for antepartum thromboprophylaxis should be made throughout pregnancy, taking into the patient’s risk factors and preferences and the side-effects associated with LMWH. Antepartum thromboprophylaxis should be continued until the onset of labour, and restarted after delivery (see relevant sections). Recommendations

29. Individual risk assessment for venous thromboembolism should be performed prior to all pregnancies, once pregnancy is achieved, and repeated throughout pregnancy as new clinical situations arise. The woman’s preferences and values should be taken into when considering the use of antepartum thromboprophylaxis. (III-B) 540 l JUNE JOGC JUIN 2014

30. Women at increased risk should be advised of the symptoms and signs of venous thromboembolism. (III-B) 31. Low molecular weight heparin is the preferred pharmacologic agent over unfractionated heparin for antepartum thromboprophylaxis. (III-A) Low molecular weight heparin doses should be used as per the manufacturer’s recommendation. (III-C) 32. Routine anti-Xa and platelet level monitoring are not recommended when a patient is on a prophylactic dose of thromboprophylaxis. (II-2E) 33. We recommend therapeutic thromboprophylaxis during pregnancy in the following situations: a. long-term therapeutic anticoagulation used prior to pregnancy for a persistent indication; (III-B) b. personal history of multiple previous venous thromboembolism. (III-B) 34. We recommend intermediate or therapeutic thromboprophylaxis during pregnancy in the following situation: a. personal history of a previous venous thromboembolism and a high-risk thrombophilia (antithrombin deficiency, antiphospholipid

Venous Thromboembolism and Antithrombotic Therapy in Pregnancy

syndrome) not previously on anticoagulation. (III-B) 35. We recommend prophylactic dose thromboprophylaxis during pregnancy in the following situations (absolute risk > 1%): a. personal history of a previous unprovoked venous thromboembolism; (II-2A) b. personal history of a previous venous thromboembolism related to oral contraceptives or pregnancy; (II-2A) c. personal history of a previous provoked venous thromboembolism and any low risk thrombophilia; (I-A) d. asymptomatic homozygous factor V Leiden; (II-2A) e. asymptomatic homozygous prothrombin gene mutation 20210A; (III-B) f. asymptomatic combined thrombophilia; (III-B) g. asymptomatic antithrombin deficiency; (III-B) h. non-obstetrical surgery during pregnancy, with the duration of thromboprophylaxis procedureand patient-dependent; (III-B) i. strict antepartum bedrest for ≥ 7 days in a woman with a body mass index of > 25 kg/m2 at her first antenatal visit. (II-2B) 36. Antepartum thromboprophylaxis for isolated pregnancy-related risk factors is not recommended. (III-E) 37. Antepartum thromboprophylaxis should be considered in the presence of multiple clinical or pregnancy-related risk factors where the overall absolute risk of venous thromboembolism is estimated to be > 1%, especially in women itted to hospital for bedrest. (II-2B) ASSISTED REPRODUCTIVE TECHNOLOGY

The risk of VTE in women undergoing ART is estimated to be 0.11% per cycle of in vitro fertilization111; however, in the presence of severe OHSS it is as high as 0.78%.112 Additionally, up to 70% of VTEs in OHSS involve the upper extremity, a much higher incidence than expected.113,114 VTE associated with ART and OHSS may also present weeks or even months after the resolution of the OHSS.115 There is currently little to guide clinicians in the use of thromboprophylaxis in women undergoing ART. Extrapolating from the observational data from studies in pregnant women, we believe that in women at high risk for VTE (those identified in Table 4), instituting thromboprophylaxis at the start of ovarian stimulation, and maintaining it for the duration of the ART, would be sensible. If pregnancy is achieved, thromboprophylaxis should be continued in the antepartum period.

For women undergoing IVF with no risk factors for VTE, routine thromboprophylaxis is unnecessary. However, for women who develop severe OHSS, thromboprophylaxis should be considered for at least 8 to 12 weeks after resolution of the OHSS. Ongoing need for thromboprophylaxis would depend on whether pregnancy is achieved in that cycle and on the presence of other antepartum risk factors (such as those in Table 5). Recommendations

38. Routine thromboprophylaxis is not required for all women undergoing ovulation induction. (III-C) 39. If severe ovarian hyperstimulation syndrome occurs with assisted reproductive technology we recommend thromboprophylaxis with low molecular weight heparin for at least 8 to 12 weeks after resolution of the syndrome. (III-B) 40. Thromboprophylaxis with low molecular weight heparin should be considered for any women at increased risk for venous thromboembolism undergoing assisted reproductive technology at the time of ovarian stimulation. (III-B) 41. Women who develop a venous thromboembolism in association with the use of assisted reproductive technology but who do not conceive in that cycle should be treated with therapeutic anticoagulation for a minimum of 3 months. (II-3A) Those who conceive in that assisted reproductive technology cycle should be treated as per recommendations 12 and 13 for acute venous thromboembolism in pregnancy. (I-A, III-C) PERIPARTUM ANTICOAGULATION AND NEURAXIAL ANAESTHESIA Management Before Delivery and Neuraxial Anaesthesia

Current consensus guidelines on the use of neuraxial (epidural, spinal, combined spinal/epidural) analgesia or anaesthesia in patients on anticoagulants largely refer to the management of non-obstetric patients.10,116,117 Similar recommendations for obstetric patients are extrapolated from recommendations for non-obstetric patients and “weak” evidence (e.g. case reports, case series, pharmacokinetic studies), and do not take into the physiological changes of pregnancy. These changes generally alter the pharmacokinetics of heparin (both LMWH and UH) in the third trimester such that a “prophylactic dose” in the third trimester may be greater than that used early in pregnancy. The recommendations in this document are taken mainly from those of the ASRA.10 It is important to note that guidelines from other JUNE JOGC JUIN 2014 l 541

SOGC CLINICAL PRACTICE GUIDELINE

Table 6. Recommended timing for neuraxial procedures in relation to anticoagulation dosing in pregnant patients. Prophylactic dose

Therapeutic dose

Delay between last dose of anticoagulation and neuraxial anesthesia UH

LMWH

Maximum 10 000 IU/d

> 4 hours after stopping IV infusion, when aPTT is normal.

No delay unless evidence of abnormal coagulation10

When aPTT is normal after stopping subcutaneous UH, may be > 12 hours.

10 to 12 hours10

> 24 hours10

Delay between last dose of anticoagulant and removal of neuraxial catheter UH

4 hours

When aPTT is normal

LMWH

Minimum 10 to 12 hours

Minimum 24 hours

Delay between neuraxial anaesthesia and restarting anticoagulant UH

1 to 8 hours120

1 to 8 hours120

LMWH

6 to 8 hours after initiation of neuraxial technique

> 24 hours after initiation of neuraxial technique

> 24 hours if bleeding during the neuraxial block > 4 hours after removal of the neuraxial catheter10,120

societies may differ117 and that the recommendations regarding timing may not apply to all types of LMWH. Early consultation with an anaesthesiologist to assess risks and benefits will inform the patient of her options for intrapartum anaesthesia. Full informed consent must be obtained for neuraxial analgesia and the reasons for deciding whether or not to proceed must be documented. Whenever possible, women should withhold their thromboprophylaxis at the onset of labour or after their dose on the day prior to a planned induction of labour or Caesarean section. For women on therapeutic anticoagulation, a planned date and mode of delivery is recommended to help simplify their peripartum management. Switching from thromboprophylactic LMWH to a prophylactic dose of UH at term (37 weeks) may allow for more options with respect to labour analgesia, since neuraxial anaesthesia is contraindicated for at least 10 to 12 hours after LMWH but there is no recommended delay after a maximum dose of 10 000 units of UH per day.118 Although the ASRA Guidelines suggest no delay following up to 10 000 units of UH per day, many anaesthesiologists prefer to wait a minimum of 4 hours. For women on an intermediate or therapeutic LMWH dose, the risks and benefits of discontinuing subcutaneous LMWH and changing to therapeutic subcutaneous or intravenous UH to allow for neuraxial anaesthesia once the aPTT is normal could be considered. The switch is not necessarily advantageous, however, as at these doses coagulation may be impaired for a duration similar to that with either heparin. Although not required with women on 10 000 542 l JUNE JOGC JUIN 2014

> 4 hours after removal of the neuraxial catheter120

units of UH or less, some anaesthesiologists would check an aPTT prior to neuraxial anaesthesia in all women on UH. Recommendations for the interval delay between the last istered dose of heparin and the insertion or removal of a neuraxial blockade or catheter are shown in Table 6. A recent platelet count should be available in the labour suite or before Caesarean section for women on anticoagulants. In the exceptional situation of a pregnant woman who has had a VTE within the past 2 to 4 weeks, peripartum use of intravenous UH during the latent stage of labour may be necessary. In these women the risk of stopping the heparin should be weighed against the benefit of a neuraxial anaesthesia, based on the anticipated duration of labour and mode of delivery. In this situation, neuraxial anaesthesia could be considered 4 hours after discontinuation of intravenous UH if the platelet count and aPTT are normal. Although a spinal hematoma is a rare complication (estimated incidence is < 1:150 000 with epidural anaesthesia and < 1:220 000 with spinal anaesthetics in healthy patients119), it can result in permanent neurological dysfunction.10,120 If a spinal hematoma is suspected (new onset or progressive neurological signs, back pain, or bowel/bladder dysfunction), early confirmation by MRI should be done and surgical intervention undertaken, if warranted, to achieve better outcomes.10,121,122 In women on heparin, the co-existence of any factors that can increase the risk of spinal hematoma (e.g. NSAIDs, LDA in combination with heparin, thrombocytopenia, multiple neuraxial attempts, traumatic tap) should prompt a

Venous Thromboembolism and Antithrombotic Therapy in Pregnancy

re-evaluation of the istration of neuraxial anaesthesia, independent of these guidelines. ASA alone does not appear to increase the risk of neuraxial hematomas. However epidural hematomas have been reported in the non-obstetric literature when patients have received a combination of heparin and ASA, even with an 81 mg dose.123 Neuraxial anaesthesia must be avoided in women who are fully anticoagulated or when there is evidence of altered coagulation (e.g., petechiae, bruising, altered aPTT without APLS, disseminated intravascular coagulation in patients with HELLP syndrome). Recommendations

42. Women on prophylactic dose, intermediate dose, or therapeutic anticoagulation should have a discussion about options for analgesia/anaesthesia prior to delivery. (III-B) 43. Switching from thromboprophylactic low molecular weight heparin to a prophylactic dose of unfractionated heparin at term (37 weeks) may be considered to allow for more options with respect to labour analgesia. (III-L) 44. Discontinue prophylactic or intermediate dose low molecular weight heparin or unfractionated heparin upon the onset of spontaneous labour or the day prior to a planned induction of labour or Caesarean section. (II-3B) 45. A recent platelet count should be available on ission in labour or before Caesarean delivery in women who have been, or are, on anticoagulants. (III-B) 46. For women on low molecular weight heparin, neuraxial anaesthesia can be istered as a: a. prophylactic dose: a minimum of 10 to 12 hours after the last dose; (III-B) b. therapeutic dose: after 24 hours since the last dose. (III-B) 47. For women on unfractionated heparin, neuraxial anaesthesia can be istered as a: a. prophylactic dose (maximum 10 000 U/day): after no delay; (III-B) b. therapeutic intravenous infusion: at least 4 hours after stopping the infusion and when the activated partial thromboplastin time is normal; (III-B) c. therapeutic subcutaneous unfractionated heparin: when the activated partial thromboplastin time is normal. This may be 12 hours or longer after the last injection. (III-B) 48. Neuraxial anaesthesia must be avoided in a woman who is fully anticoagulated or in whom there is evidence of altered coagulation. (II-3A)

Postpartum Management of Anticoagulation After Neuraxial Anaesthesia

After delivery, prophylactic heparin can be initiated or resumed in women who had neuraxial anesthesia once hemostasis is confirmed, there are no signs of neurological complications, and after a minimum of 4 hours following neuraxial catheter removal (see Table 6 for timing intervals). For women on intermediate or therapeutic dose LMWH, the first postpartum dose should be given no sooner than 24 hours postpartum and a minimum of 4 hours following neuraxial catheter removal. Federal Drug istration recommendations for the timing of the first dose of LMWH following removal of a neuraxial catheter.124 The neuraxial catheter must be removed before the first LMWH dose.10 For women requiring ongoing therapeutic heparin our recommendations would be (1) intravenous UH: restart, without a bolus, at a rate of 18 U/kg/hour and monitor aPTT every 6 hours, or (2) subcutaneous LMWH: restart with a low dose (5000 U) at a minimum of 4 hours after removal of the neuraxial catheter and increase to therapeutic dose LMWH after 24 hours. Assessment of the risks and benefits of anticoagulation in these patients should be ongoing within the multidisciplinary team. Intermittent pneumatic compression devices postpartum should be considered for these women at higher risk for venous thrombosis. Recommendations

49. Removal of a neuraxial catheter left in situ postpartum should only be done 4, 10 to 12, or 24 hours following the istration of prophylactic dose unfractionated heparin (maximum 10 000 U/day), prophylactic low molecular weight heparin (single daily dose), or therapeutic dose low molecular weight heparin, respectively, or in the case of therapeutic unfractionated heparin, when the activated partial thromboplastin time is normal. (II-3B) 50. Prophylactic dose low molecular weight heparin (single daily dose) may be started or restarted 4 hours after neuraxial catheter removal, providing there is full neurological recovery and no evidence of active bleeding or coagulopathy. (III-B) 51. Therapeutic low molecular weight heparin may be started or restarted at least 24 hours after a single injection neuraxial block and a minimum of 4 hours after neuraxial catheter removal, providing there is full neurological recovery and no evidence of active bleeding or coagulopathy. (III-B) 52. Subcutaneous unfractionated heparin may be started or restarted at least 1 hour after a single injection neuraxial block, providing there is full JUNE JOGC JUIN 2014 l 543

SOGC CLINICAL PRACTICE GUIDELINE

Table 7. Literature review of incidence of postpartum thromboprophylaxis recommended for single risk factors in isolation Incidence of symptomatic VTE* 1% to 5%

> 5%

Personal history of previous VTE

••89,140

Single Asymptomatic thrombophilia

••96,181

FVL homozygosity

•183

•140

APLS Risk factors related to present pregnancy

•109

Strict antepartum bedrest ≥ 7 days Risk factors related to delivery and postpartum period > 1 L postpartum hemorrhage + postpartum surgery

•109

Peripartum and/or postpartum infection

•109

Incidence of symptomatic VTE postpartum without prophylaxis is > 1% *Each dot represents one study; the superscript numerals are references to those studies.

neurological recovery and no evidence of active bleeding or coagulopathy. (III-B) 53. Do not ister antiplatelet agents (acetylsalicylic acid or non-steroidal anti-inflammatory drugs) concomitantly with heparin if a neuraxial catheter is left in situ postpartum. (III-D) 54. Women on therapeutic anticoagulation who have received neuraxial anesthesia should be monitored closely for the development of a spinal hematoma. (III-B) POSTPARTUM THROMBOPROPHYLAXIS

Postpartum PE is a leading cause of maternal mortality in Canada, with up to 17 maternal deaths each year.125 The “per day” risk is 15- to 35-fold greater in the 6 weeks following delivery than in non-pregnant age-matched control subjects, with the highest risk being in the first 3 weeks.3,5–7 It is generally agreed that universal postpartum thromboprophylaxis is neither cost-effective nor recommended.126,127 In weighing the risks of treatment, specifically heparin (see Table 2), versus the potential for a devastating outcome, it seems reasonable again to use an absolute VTE risk of greater than 1% in considering postpartum thromboprophylaxis (Table 7). It is important to carefully evaluate the need for thromboprophylaxis immediately after every delivery and re-evaluate it over the puerperium as additional risk factors present themselves. Women who have been on antepartum thromboprophylaxis will usually require ongoing heparin postpartum, but the reasons for continuing

544 l JUNE JOGC JUIN 2014

should be revisited. Ideally, the plan for postpartum thromboprophylaxis will have been reviewed with these women prior to delivery. Many women, however, will require thromboprophylaxis for the first time postpartum. The risk versus benefits should be continually weighed in the decision making process.

Observational studies have demonstrated differing biological and clinical risk factors for antenatal versus postpartum VTE.3,4,106,129 In the case–control study by Jacobsen et al.,109 most postpartum risk factors, aside from strict antepartum bedrest for 7 days or more, had minimal impact in isolation (Tables 8 and 9). The strongest associations were seen with combined risks. Table 8 lists the factors of sufficient risk to warrant thromboprophylaxis when 2 are present. Table 9 lists weaker associations, warranting 3 or more to raise the absolute VTE risk postpartum to > 1%. Operative vaginal delivery, prolonged labour, extensive perineal trauma, or prolonged repairs have been flagged as risk factors in other guidelines.11,13 Evidence to this is lacking and there are no RCTs assessing thromboprophylaxis following vaginal deliveries. RCTs of heparin after Caesarean section do exist with 236 women randomized over 4 trials.130–133 A Cochrane systematic review concluded that there was insufficient evidence of the benefit or harm associated with thromboprophylaxis after Caesarean section due to the small numbers and different comparisons.134 Overall the risk associated with any Caesarean section is modest.4,106,109,129 Hence, we recommend against thromboprophylaxis following a Caesarean section in the absence of at least one other risk factor in the case of an emergency, and at least two other risk factors for elective Caesarean sections.

Venous Thromboembolism and Antithrombotic Therapy in Pregnancy

Table 8. Literature review of incidence of postpartum thromboprophylaxis recommended for any two risk factors Incidence of symptomatic VTE* < 0.3%

0.3% to 0.5%

BMI > 30 kg/m2 at first antenatal visit

•••106,107,109

••4,140

Smoking > 10 cigarettes/day or current versus never smoked

••••

> 0.5% to > 1.0%

Maternal pre-pregnancy risk factors

•109

2,4,107,129

•••4,106,140

Maternal cardiac disease

••4,140

SLE

•140

Sickle cell disease Inflammatory bowel disease

•

Varicose veins

•4

4

Risk factors related to present pregnancy Preeclampsia

•4

•••2,3,109

Preterm birth

•

•129

4

IUGR

•109

Gestational diabetes

•109

Placenta previa

•3

Stillbirth

•4

Risk factors related to delivery and postpartum period

••3,109

Emergency Caesarean section Any Caesarean section

••••4,106,129,140

>1 L postpartum haemorrhage or transfusion postpartum

•

•2 •

4

•170 ••

109

129,140

Combined risk factors

• 109

Preeclampsia + IUGR Incidence of symptomatic VTE postpartum without prophylaxis < 1% in isolation. *Each dot represents one study; the superscript numerals are references to those studies.

Table 9. Literature review of incidence of postpartum thromboprophylaxis recommended for three or more risk factors Incidence of symptomatic VTE* < 0.2%

0.2% to 0.3%

Maternal pre-pregnancy risk factors

•4

Cancer

••4,109

Parity ≥ 2 Age > 35 years

•2

•••••2,4,5,106,109

Risk factors related to present pregnancy

•109

ART Multiple pregnancy

••••

2,4,109,140

•3

Placental abruption PROM

•

Elective Caesarean section

•109

109

•3

Incidence of symptomatic VTE postpartum without prophylaxis < 1% in isolation *Each dot represents one study; the superscript numerals are references to those studies.

JUNE JOGC JUIN 2014 l 545

SOGC CLINICAL PRACTICE GUIDELINE

As the puerperium is inherently a higher risk period for VTE than the non-pregnant state, good hydration and mobilization should be encouraged for every woman postpartum.



Recommendations

55. Universal postpartum thromboprophylaxis is not recommended. (III-D) 56. Assess women for increased risk of postpartum venous thromboembolism based on antepartum, intrapartum, and postpartum risk factors after every delivery and repeat as new clinical situations arise. (II-2B) 57. Low molecular weight heparin is the preferred pharmacologic agent over unfractionated heparin for postpartum thromboprophylaxis. (III-A) Low molecular weight heparin doses should be used as per the manufacturer’s recommendation. (III-C) 58. Pharmacologic thromboprophylaxis postpartum is recommended in the following situations: Any 1 of the following risk factors (each with an absolute venous thromboembolism risk > 1%): a. history of any prior venous thromboembolism; (II-2A) b. any high-risk thrombophilia: antiphospholipid syndrome, antithrombin deficiency, homozygous factor V Leiden or prothrombin gene mutation 20210A, combined thrombophilia; (II-2B) c. strict bed rest prior to delivery for 7 days or more; (II-2B) d. peripartum or postpartum blood loss of > 1 litre or blood product replacement, and concurrent postpartum surgery; (II-2B) e. peripartum/postpartum infection. (II-2B) 59. Postpartum thromboprophylaxis should be considered in the presence of multiple clinical or pregnancy-related risk factors when the overall absolute risk is estimated to be greater than 1% drawn from the following groups: a. any 2 of the following risk factors (each with an absolute risk of venous thromboembolism < 1% in isolation): i. body mass index ≥ 30 kg/m2 at first antepartum visit; (II-2B) ii. smoking > 10 cigarettes/day antepartum; (II-2B) iii. preeclampsia; (II-2B) iv. intrauterine growth restriction; (II-2B) v. placenta previa; (II-2B) vi. emergency Caesarean section; (II-2B) vii. peripartum or postpartum blood loss of > 1 litre or blood product replacement; (II-2B)

546 l JUNE JOGC JUIN 2014





viii. any low risk thrombophilia: PC or PS deficiency, heterozygous factor V Leiden, or prothrombin gene mutation 20210A; (III-B) ix. maternal cardiac disease, SLE, sickle cell disease, inflammatory bowel disease, varicose veins, gestational diabetes; (III-B) x. preterm delivery; (III-B) xi. stillbirth. (III-B) b. any 3 or more of the following risk factors (each with an absolute risk of venous thromboembolism < 1% in isolation): i. age > 35 years; (II-2B) ii. parity ≥ 2; (II-2B) iii. any assisted reproductive technology; (II-2B) iv. multiple pregnancy; (II-2B) v. placental abruption; (II-2B) vi. premature rupture of the membranes; (II-2B) vii. elective Caesarean section; (II-2B) viii maternal cancer. (III-B)

Mechanical Compression Devices

Mechanical methods of thromboprophylaxis include both graded compression stockings and intermittent pneumatic compression devices. Older evidence suggested that graded compression stockings were beneficial in reducing post-operative VTE, leading to their widespread use.135 However, their benefit has recently been challenged by two large trials in stroke patients (N = 5632). Thigh-high stockings did not reduce symptomatic VTE or proximal DVT,136 and knee-high stockings increased the risk of thrombosis.137 In light of this new evidence we do not advocate the routine use of graded compression stockings in postpartum women to reduce the risk of VTE. Intermittent pneumatic compression devices have not been studied in pregnancy. Following major gynaecologic surgery associated with a high risk of VTE, they are effective if left on for 5 days or until hospital discharge, but not if removed the day after surgery.138 In general surgery trials, they are associated with fewer major bleeding episodes than heparin but have a lower VTE risk reduction rate.9 Most of these RCTs were underpowered to prove efficacy in preventing PE or mortality postoperatively.139 When pharmacologic treatment is not possible, such as with active bleeding, thrombocytopenia, known heparin allergy or HIT, intermittent pneumatic compression devices are a good alternative. In women at very high risk for VTE postpartum (> 10%), combined mechanical and pharmacologic thromboprophylaxis is recommended. Recommendation

60. Intermittent or sequential pneumatic compression devices are alternatives in women when heparin

Venous Thromboembolism and Antithrombotic Therapy in Pregnancy

is contraindicated postpartum. When the risk of postpartum venous thromboembolism is high they may be used in combination with low molecular weight heparin or unfractionated heparin. (III-B) Postpartum Thromboprophylaxis: Duration of Anticoagulation

Up to 60% of postpartum PE occurs in the 4 to 6 weeks after delivery.3,5,7 The duration of thromboprophylaxis varies with the underlying risk factors. Women with prior VTE have the highest risk and require a minimum of 6 weeks.89,140 Women with persistent risks that will be present throughout the puerperium (e.g. high risk thrombophilia or prolonged immobility), should also have extended thromboprophylaxis for a full 6 weeks. There is no evidence to guide the duration of treatment in women having only transient antepartum or intrapartum risks. Given the logistics involved in discharging women on heparin injections, individual institutions and practitioners may vary with respect to the duration of postpartum thromboprophylaxis they choose in these cases. Other guidelines recommend both options: until discharge from hospital fully mobile as a minimum54,118 or up to 1 to 2 weeks postpartum.11,15 Recommendation

61. Women with ongoing and persistent risk factors should receive postpartum thromboprophylaxis for a minimum of 6 weeks postpartum. (II-3B) 62. Women with transient antepartum or intrapartum risk factors should receive postpartum thromboprophylaxis until discharged from hospital or up to 2 weeks postpartum. (III-C) THROMBOPROPHYLAXIS TO PREVENT ADVERSE PREGNANCY OUTCOMES Adverse Pregnancy Conditions: Screening

In the 1990s reports of an increase in placenta-mediated pregnancy complications (e.g. recurrent miscarriage, late fetal loss, preeclampsia, placental abruption, and intrauterine growth restriction) in women with thrombophilia appeared in the literature.141–144 Whereas these early studies suggested a weak association between inherited thrombophilia and placenta-mediated pregnancy complications, subsequent prospective cohort studies suggested no association between most thrombophilia and preeclampsia or SGA infants.127,145–149 Women with APLS do have an increased risk of recurrent and late pregnancy loss.127,150 However, there is only a weak association between these complications and FVL and no association with PGM.149 Hence, universal thrombophilia screening

in women experiencing adverse pregnancy outcomes is not indicated.148 What remains unknown is whether more severe placenta-mediated pregnancy complications (e.g. severe or early-onset preeclampsia, SGA < 3rd percentile, major abruption) are more strongly associated with specific thrombophilia and potentially improved with antenatal thromboprophylaxis. Recommendations

63. Universal screening for thrombophilias in women experiencing adverse pregnancy outcomes (severe preeclampsia, intrauterine growth restriction, stillbirth) is not indicated. (II-2D) 64. Women with recurrent miscarriage or late pregnancy loss should be screened for antiphospholipid syndrome. (I-B) LMWH to Prevent Recurrent Adverse Pregnancy Conditions

The benefit of heparin plus LDA in women with APLS and recurrent miscarriage or late fetal loss (variably defined in the different studies) is controversial.151–154 A meta-analysis looking at 5 trials (N = 334) showed that LMWH plus LDA significantly increased the live birth rate (74.3%) compared to LDA alone (55.8%) with a number needed to treat of 5.6, but with significant heterogeneity.155 This evidence modestly s screening women with recurrent miscarriage or late pregnancy loss for APLS and using LMWH alone or with LDA to prevent recurrent miscarriage when APLS is confirmed. Recent RCTs, however, showed no benefit of LMWH alone or LMWH plus LDA versus no treatment or LDA alone to prevent recurrent miscarriage in women without APLS.156–161 Although there were no significant complications related to LMWH use in these trials, there were reports of injection site bruising and skin reactions highlighting the fact that heparin is not a benign treatment and should not be prescribed in the absence of evidence to its use. Given that placental thrombosis is a part of the common pathophysiology of placenta-mediated pregnancy complications, it is plausible that LDA alone, heparin alone, or the combination of LDA plus LMWH might prevent recurrence of adverse pregnancy outcomes in subsequent pregnancies for women with and without thrombophilia.162–168 A review of 6 trials (N = 848 women) showed that LMWH, compared to no treatment, reduced the risk of early-onset preeclampsia (RR 0.16, 95% CI 0.07 to 0.36), birth before 37 weeks (RR 0.77, 95% CI 0.62 to 0.96), and SGA infants (RR 0.42, 95% CI 0.29 to 0.59) without any significant effect on perinatal mortality. JUNE JOGC JUIN 2014 l 547

SOGC CLINICAL PRACTICE GUIDELINE

There was an overall reduction in a composite outcome of complications (preeclampsia, abruption, SGA infants, or fetal loss after 12 weeks) from 42.9% to 18.7% (RR 0.52, 95% CI 0.32 to 0.86).169 A 2013 Cochrane review of 9 trials (N = 979) concluded that prophylactic dose heparin (UH or LMWH), compared to no treatment, decreased perinatal mortality (RR 0.40, 95% CI 0.20 to 0.78), preterm delivery < 34 weeks (RR 0.46, 95% CI 0.29 to 0.73) and SGA infants (RR 0.41, 95% CI 0.27-0.61) in women at high risk.170 Although this data appears promising, given that LMWH is not risk free, it should not be used routinely to reduce the risk of recurrence of all placenta-mediated complications in women, with or without thrombophilia, pending the publication of larger trials or individual patient data meta-analysis. APLS has been considered the exception in many centers, extrapolating from experience with recurrent miscarriage. However, despite the common usage of LMWH and LDA to prevent other adverse pregnancy outcomes in women with APLS, there are no published trials that this practice. Recommendations

65. Low-dose acetylsalicylic acid or low-dose acetylsalicylic acid plus low molecular weight heparin is recommended in pregnancy in women with confirmed antiphospholipid syndrome. (I-C) 66. Low-dose acetylsalicylic acid plus low molecular weight heparin is not recommended for women with a history of recurrent miscarriage in the absence of confirmed antiphospholipid syndrome. (I-E) 67. Low molecular weight heparin should not be used routinely to reduce the risk of recurrent placenta-mediated complications in women with or without thrombophilia (excluding antiphospholipid syndrome). (I-C) FUTURE DIRECTIONS

As we now better understand the appropriate diagnosis of DVT in pregnant women, studies elucidating diagnostic strategies for PE during pregnancy which minimize both fetal and maternal radiation exposure are still required. Even as LMWH replaces UH as the anticoagulant of choice in pregnancy, questions surrounding appropriate dosing regimens or the need for monitoring anti-Xa activity still remain. As we unequivocally accept that VTE prevention is an important strategy to reduce maternal morbidity and mortality, we also recognize that thromboprophylaxis is not without maternal side-effects or costs. In determining the factors associated with an increased risk of VTE, in 548 l JUNE JOGC JUIN 2014

isolation or in combination, which supersede the risk of thromboprophylaxis, we extrapolated data mostly from retrospective studies. Data from further large prospective registries could yield more information on the absolute risks associated with various biologic and clinical factors, or combination of factors, which would warrant thromboprophylaxis. We anticipate data from further prospective studies will become available which will shed light on the effectiveness of LMWH, plus or minus LDA, in preventing recurrent adverse pregnancy outcomes in women with or without inherited thrombophilia. REFERENCES 1. Liu S, Rouleau J, Joseph KS, Sauve R, Liston R, Young D, et al. Epidemiology of pregnancy-associated venous thromboembolism: a population-based study in Canada. J Obstet Gynaecol Can 2009;31:611–20. 2. Lindqvist P, Dahlback B, Marsal K. Thrombotic risk during pregnancy: a population study. Obstet Gynecol 1999;94:595–9. 3. Jacobsen AF, Skjeldestad FE, Sandset PM. Incidence and risk patterns of venous thromboembolism in pregnancy and puerperium—a based case-control study. Am J Obstet Gynecol 2008;198:233.e1–233.e7. 4. Sultan AA, Tata L, West J, Fiaschi L, Fleming K, Nelson-Piercy C, et al. Risk factors for first venous thromboembolism around pregnancy: a population-based cohort study from the United Kingdom. Blood 2013;121:3953–61. 5. Sultan AA, West J, Tata LJ, Fleming K, Nelson-Piercy C, Grainge MJ. Risk of first venous thromboembolism in and around pregnancy: a population-based cohort study. BJH 2011;156:366–73. 6. Virkus RA, Lokkegaard ECL, Bergholt T, Mogensen U, Langhoff-Roos J, Lidegaard O. Venous thromboembolism in pregnant and puerperal women in Denmark 1995–2005. Thromb Haemost 2011;106:304–9. 7. Heit JA, Kobbervig CE, James AH, Petterson TM, Bailey KR, Melton LJ. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med 2005;143:697–706. 8. Bates SM, Jaeschke R, Stevens SM, Goodacre S, Wells PS, Stevenson MD, et al. Diagnosis of DVT. Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141:e351S–e418S. 9. Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO. VTE, thrombophilia, antithrombotic therapy, and pregnancy: antithrombotic therapy and prevention of thrombosis, 9th ed.: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141;e691S–e736S. 10. Horlocker TT, Wedel DJ, Rowlingson JC, Enneking FK, Kopp SL, Benzon HT, et al. Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine evidence-based guidelines (third edition). Reg Anesth Pain Med 2010;35:64–101. 11. Nelson-Piercy C, MacCallum P, Mackillop L. Reducing the risk of thrombosis and embolism during pregnancy and the puerperium. Green-top guideline no. 37a. London: Royal College of Obstetricians and Gynaecologists; 2009.

Venous Thromboembolism and Antithrombotic Therapy in Pregnancy

12. Greer IA, Thomson AJ. The acute management of thrombosis and embolism during pregnancy and the puerperium. Green-top guideline no. 37b. London: Royal College of Obstetricians and Gynaecologists; 2007. 13. .McLintock C, Brighton T, Chunilal S, Dekker G, McDonnell N, McRae S, et al.; Councils of the Society of Obstetric Medicine of Australia and New Zealand; Australasian Society of Thrombosis and Haemostasis. Recommendations for the prevention of pregnancyassociated venous thromboembolism. Aust N Z J Obstet Gynaecol 2012;52:3–13. 14. McLintock C, Brighton T, Chunilal S, Dekker G, McDonnell N, McRae S, et al.; Councils of the Society of Obstetric Medicine of Australia and New Zealand; Australasian Society of Thrombosis and Haemostasis. Recommendations for the diagnosis and treatment of deep venous thrombosis and pulmonary embolism in pregnancy and the postpartum period. Aust N Z J Obstet Gynaecol 2012;52:14–22. 15. Lindqvist PG, Hellgren, M. Obstetric thromboprophylaxis: the Swedish guidelines. Adv Hematol 2011;2011:1–6. doi:10.1155/2011/157483. 16. Macklon NS, Greer IA, Bowman AW. An ultrasound study of gestational and postural changes in the deep venous system of the leg in pregnancy. Br J Obstet Gynecol 1997;104:191–7.

29. Hurwitz LM, Yoshizumi T, Reiman RE, Goodman PC, Paulson EK, Frush DP, et al. Radiation dose to the fetus from body MDCT during early gestation. Am J Roentgenol 2006;186:871–6. 30. Cook JV, Kyriou J. Radiation from CT and perfusion scanning in pregnancy. BMJ 2005;331:350. 31. Parker MS, Hui FK, Camacho MA, Chung JK, Broga DW, Sethi NN. Female breast radiation exposure during CT pulmonary angiography. Am J Roentgenol 2005;185:1228–33. 32. Berrington de Gonzalez A, Darby S. Risk of cancer from diagnostic X-rays: estimates for the UK and 14 other countries. Lancet 2004;363:345–51. 33. Bourjeily G, Chalhoub M, Phornphutkul C, Alleyne TC, Woodfield CA, Chen KK. Neonatal thyroid function: effect of a single exposure to iodinated contrast medium in utero. Radiology 2010;256:744–50. 34. Chan WS, Ray JG, Murray S, Coady GE, Coates G, Ginsberg JS. Suspected pulmonary embolism in pregnancy: clinical presentation, results of lung scanning, and subsequent maternal and pediatric outcomes. Arch Intern Med 2002;162:1170–5. 35. Scarsbrook AF, Bradley KM, Gleeson FV. Perfusion scintigraphy: diagnostic utility in pregnant women with suspected pulmonary embolic disease. Eur Radiol 2007;17:2554–60.

17. Ray JG, Chan WS. Deep vein thrombosis during pregnancy and the puerperium: a meta-analysis of the period of risk and the leg of presentation. Obstet Gynecol Surv 1999;54:265–71.

36. Cahill AG, Stout MJ, Macones GA, Bhalla S. Diagnosing pulmonary embolism in pregnancy using computed-tomographic angiography or ventilation-perfusion. Obstet Gynecol 2009;114:124–9.

18. Chan WS, Spencer FA, Ginsberg JS. Anatomic distribution of deep vein thrombosis in pregnancy. CMAJ 2010;182(7):657–60.

37. Shahir K, Goodman LR, Tali A, Thorsen KM, Hellman RS. Pulmonary embolism in pregnancy: CT pulmonary angiography versus perfusion scanning. Am J Roentgenol 2010;195:214–20.

19. To MS, Hunt BJ, Nelson-Piercy C. A negative D-dimer does not exclude venous thromboembolism in pregnancy. J Obstet Gynaecol 2008;28:222–3. 20. Damodaram M, Kaladindi M, Luckit J, Yoong W. D-dimers as a screening test for venous thromboembolism in pregnancy: is it of any use? J Obstet Gynaecol 2009;29:101–3. 21. Chan WS, Chunilal S, Lee A, Crowther M, Rodger M, Ginsberg JS. A red blood cell agglutination D-dimer test to exclude deep venous thrombosis in pregnancy. Ann Intern Med 2007;147:165–70. 22. Chan WS, Lee A, Spencer FA, Crowther M, Rodger M, Ramsay T, et al. Predicting deep venous thrombosis in pregnancy: out in “LEFt” field? Ann Intern Med 2009;151:85–92. Erratum in: Ann Intern Med 2009;151:516. 23. Chan WS, Lee A, Spencer FA, Chunilal S, Crowther M, Wu W, et al. D-dimer testing in pregnant patients: towards determining the next ‘level’ in the diagnosis of deep vein thrombosis. J Thromb Haemost 2010;8:1004–11. 24. Le Gal G, Kercret G, Ben Yahmed K, Bressollette L, Robert-Ebadi H, Riberdy L, et al.; EDVIGE Study Group. Diagnostic value of single complete compression ultrasonography in pregnant and postpartum women with suspected deep vein thrombosis: a prospective study. BMJ 2012;344:e2635. doi:10.1136/bmj.e2635. 25. Fraser DG, Moody AR, Morgan PS, Martel AL, Davidson I. Diagnosis of lower-limb deep venous thrombosis: a prospective blinded study of magnetic resonance direct thrombus imaging. Ann Intern Med 2002;136:89–98. 26. Sampson FC, Goodacre SW, Thomas SM, van Beek EJ. The accuracy of MRI in diagnosis of suspected deep vein thrombosis: systematic review and meta-analysis. Eur Radiol 2007;17:175–81. 27. Ginsberg JS, Hirsh J, Rainbow RJ, Coates G. Risks to the fetus of radiologic procedures used in the diagnosis of maternal thromboembolic disease. Thromb Haemost 1989;61:189–96. 28. Doll R, Wakefield R. Risk of childhood cancer from fetal radiation. Br J Rad 1997;70:130–9.

38. Bourjeily G, Khalil H, Raker C, Martin S, Auger P, Chalhoub M, et al. Outcomes of negative multidetector computed tomography with pulmonary angiography in pregnant women suspected of pulmonary embolism. Lung 2012;190:105–11. 39. Anderson DR, Kahn SR, Rodger MA, Kovacs MJ, Morris T, Hirsch A, et al. Computed tomographic pulmonary angiography vs ventilationperfusion lung scanning in patients with suspected pulmonary embolism: a randomized controlled trial. JAMA 2007;298:2743–53. 40. U-King-Im JM, Freeman SJ, Boylan T, Cheow HK. Quality of CT pulmonary angiography for suspected pulmonary embolus in pregnancy. Eur Radiol 2008;18:2709–15. 41. Ridge CA, McDermott S, Freyne BJ, Brennan DJ, Collins CD, Skehan SJ. Pulmonary embolism in pregnancy: comparison of pulmonary CT angiography and lung scintigraphy. Am J Roentgenol 2009;193:1223–7. 42. Ridge CA, Mhuircheartaigh JN, Dodd JD, Skehan SJ. Pulmonary CT angiography protocol adapted to the hemodynamic effects of pregnancy. Am J Roentgenol 2011;197:1058–63. 43. Bourjeily G, Paidas M, Khalil H, Rosene-Montella K, Rodger M. Pulmonary embolism in pregnancy. Lancet 2010;375:500–12. 44. Ginsberg JS, Hirsch J, Turner DC, Levine MN, Burrows R. Risks to the fetus of anticoagulant therapy during pregnancy. Thromb Haemost 1989;61:197–203. 45. Pauli RM, Haun J. Intrauterine effects of coumarin derivatives. Dev Brain Dysfunct 1993;6:229–47. 46. Chan WS, Anand S, Ginsberg JS. Anticoagulation of pregnant women with mechanical heart valves: a systemic review of the literature. Arch Intern Med 2000;160:191–6. 47. Flessa HC, Kapstrom AB, Glueck HI, Will JJ. Placental transport of heparin. Am J Obstet Gynecol 1965;93;570–3. 48. Forestier F, Daffos F, Capella-Pavlovsky M. Low molecular weight heparin (PK10169) does not cross the placenta during second trimester of pregnancy; study by direct fetal blood sampling under ultrasound. Thromb Res 1984;34;557–60.

JUNE JOGC JUIN 2014 l 549

SOGC CLINICAL PRACTICE GUIDELINE

49. Lepercq J, Conard J, Borel-Derlon A, Darmon JY, Boudignat O, Francoual C, et al Venous thromboembolism during pregnancy: a retrospective study of enoxaparin safety in 624 pregnancies. BJOG 2001;108:1134–40.

66. Aburahma AF, Mullins DA. Endovascular caval interruption in pregnant patients with deep vein thrombosis of the lower extremity. J Vasc Surg 2001;33:375–8.

50. Rodie VA, Thomson AJ, Stewart FM, Quinn AJ, Walker ID, Greer IA. Low molecular weight heparin for the treatment of venous thromboembolism in pregnancy: a case series. BJOG 2001;109:1020–4.

67. Kawamata K, Chiba Y, Tanaka R, Higashi M, Nishigami K. Experience of temporary inferior vena cava filters inserted in the perinatal period to prevent pulmonary embolism in pregnant women with deep vein thrombosis. J Vasc Surg 2005;41:652–6.

51. Greer IA, Nelson-Piercy C. Low-molecular weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systemic review of safety and efficacy. Blood 2005;106:401–7.

68. Milford W, Chadha Y, Lust K. Use of a retrievable vena cava filter in term pregnancy: case report and review of the literature. Aust N Z J Obstet Gynaecol 2009;49:331–3.

52. Ni Ainle FN, Wong A, Appleby N, Byrne B, Regan C, Tayyaba H, et al. Efficacy and safety of once daily low molecular weight heparin (tinzaparin sodium) in high risk pregnancy. Blood Coagul Fibrinolysis 2008;19:689–92. 53. Linkins L-A, Dans AL, Moores LK, Bona R, Davidson BL, Schulmans S, et al. Treatment and prevention of heparin-induced thrombocytopenia. Chest 2012;141:e495S–e530S.

69. Lanska DJ, Kryscio RJ. Risk factors for peripartum and postpartum stroke and intracranial venous thrombosis. Stroke 2000;31:1274–82. 70. Cantu-Brito C, Arauz A, Aburto Y, Barinagarrementeria F, Ruiz-Sandoval JL, Baizabal-Carvallo JF. Cerebrovascular complications during pregnancy and postpartum: clinical and prognosis observations in 240 Hispanic women. Eur J Neurol 2011;18:819–25.

54. Schindewolf M, Mosch G, Bauersachs RM, Lindhoff-Last E. Safe anticoagulation with danaparoid in pregnancy and lactation. Thromb Haemost 2004;92:211.

71. Saposnik G, Barinagarrementeria F, Brown RD Jr., Bushnell CD, Cucchiaron B, Cushman M, et al. Diagnosis and management of cerebral venous thrombosis: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011;42:1158–92.

55. Mazzolai L, Hohlfeld P, Spertini F, Hayoz D, Schapira M, Duchosal MA. Fondaparinux is a safe alternative in case of heparin intolerance during pregnancy. Blood 2006;108:1569–70.

72. McColl MD, Ramsay JE, Tait RC, Walker ID, McCall F, Conkie JA, et al. Superficial vein thrombosis: incidence in association with pregnancy and prevalence of thrombophilic defects. Thromb Haemost 1998;79:741–2.

56. Sarig G, Brenner B. Monitoring of low molecular weight heparin (LMWH) in pregnancy. Thrombosis Res 2005;115(Suppl 1):84–6.

73. Lutter KS, Kerr TM, Roedersheimer LR, Lohr JM, Sampson MG, Cranley JJ. Superficial thrombophlebitis diagnosed by duplex scanning. Surgery 1991;110:42–6.

57. Barbour LA, Oja JL, Schultz LK. A prospective trial that demonstrates that dalteparin requirements increase in pregnancy to maintain therapeutic levels of anticoagulation. Am J Obstet Gynecol 2004;191:1024–9. 58. Norris LA, Bonnar J, Smith MP, Steer PJ, Savidge G. Low molecular weight heparin (tinzaparin) therapy for moderate risk thromboprophylaxis during pregnancy: a pharmacokinetic study. Thromb Haemost 2004;92:791–6.

74. Gorty S, Patton-Adkins J, DaLanno M, Starr J, Dean S, Satiani B. Superficial venous thrombosis of the lower extremities: analysis of risk factors, and recurrence and role of anticoagulation. Vasc Med 2004;9:1–6. 75. Wichers IM, Di Nisio M, Buller HR, Middeldorp S. Treatment of superficial vein thrombosis to prevent deep vein thrombosis and pulmonary embolism: a systematic review. Haematologica 2005;90:672–7.

59. Smith MP, Norris LA, Steer PJ, Savidge GF, Bonnar J. Tinzaparin sodium for thrombosis treatment and prevention during pregnancy. Am J Obstet Gynecol 2004;190:495–501.

76. Decousus H, Prandoni P, Mismetti P, Bauersachs R, Boda Z, Brenner B, et al. Fondaparinux for the treatment of superficial-vein thrombosis in the legs. N Engl J Med 2010;363:1222–32.

60. Kahn SR, Ginsberg JS. The post thrombotic syndrome: current knowledge, controversies, and directions for future research. Blood Rev 2002;16:155–65.

77. Di Nisio M, Wichers IM, Middeldorp S. Treatment for superficial thrombophlebitis of the leg. Cochrane Database Syst Rev 2012;3:CD004982.

61. Kearon C, Akl EA, Comerota AJ, Prandoni, P, Bounameaux H, Goldhaber SZ, et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed.: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141:e419S–e494S.

78. Brown CE, Stettler RW, Twickler D, Cunningham FG. Puerperal septic pelvic thrombophlebitis: incidence and response to heparin therapy. Am J Obstet Gynecol 1999;181:143–8.

62. Kahn SR, Shapiro S, Wells PS, Rodger MA, Kovacs MJ, Anderson DR, et al. A multicenter randomized placebo controlled trial of compression stockings to prevent the post-thrombotic syndrome after proximal deep venous thrombosis: The S.O.X. Trial. Blood (ASH Annual Meeting Abstracts), 2012;120:393. 63. Turrentine MA, Braema G, Ramirez MM. Use of thrombolytics for the treatment of thromboembolic disease during pregnancy. Obstet Gynecol Surv 1995;50:534–1. 64. Leonhardt G, Gaul C, Nietsch HH, Buerke M, Schleussner E. Thrombolytic therapy in pregnancy. J Thromb Thrombolysis 2006;21:271–6. 65. Decousus H, Leizorovicz A, Parent F, Page Y, Tardy B, Girard P, et al. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. Prévention du risque d’embolie pulmonaire par Interruption Cave Study Group. N Engl J Med 1998;338:409–15.

550 l JUNE JOGC JUIN 2014

79. Salomon O, Dulitzky M, Apter S. New observations in postpartum ovarian vein thrombosis: experience of single center. Blood Coagul Fibrinolysis 2010;21:16–9. 80. Dunnihoo DR, Gallaspy JW, Wise RB, Otterson WN. Postpartum ovarian vein thrombophlebitis: a review. Obstet Gynecol Surv 1991;46:415–27. 81. Twickler DM, Setiawan AT, Evans RS, Erdman WA, Stettler RW, Brown CE, et al. Imaging of puerperal septic thrombophlebitis: prospective comparison of MR imaging, CT, and sonography. Am J Roentgenol 1997;169:1039-1043. 82. Garcia J, Aboujaoude R, Apuzzio J, Alvarez JR. Septic pelvic thrombophlebitis: diagnosis and management. Infect Dis Obstet Gynecol 2006;2006:15614. 83. Chen KT. Septic pelvic thrombophlebitis. Available at: http://www.uptodate.com. Accessed on September 15, 2012. 84. Kominiarek MA, Hibbard JU. Postpartum ovarian vein thrombosis: an update. Obstet Gynecol Surv 2006;61:337–42.

Venous Thromboembolism and Antithrombotic Therapy in Pregnancy

85. Ho WK, Hankey GJ, Eikelboom JW. Should adult patients be routinely tested for heritable thrombophilia after an episode of venous thromboembolism? Med J Aust 2011;195:139–42. 86. Dalen JE. Should patients with venous thromboembolism be screened for thrombophilia? Am J Med 2008;121:458–63. 87. Middeldorp S. Evidence-based approach to thrombophilia testing. J Thromb Thrombolysis 2011;31:275–81. 88. Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, et al. Prevention of venous thromboembolism: American College of Chest Physicians evidence-based clinical practive guidelines (8th Edition). Chest 2008;133:381S–453S. 89. Brill-Edwards P, Ginsberg JS, Gent M, Hirsh J, Burrows R, Kearon C, et al. Safety of withholding heparin in pregnant women with a history of venous thromboembolism. Recurrence of clot in this pregnancy study group. N Engl J Med 2000;343:1439–44. 90. Pabinger I, Grafenhofer H, Kaider A, Kyrle PA, Quehenberger P, Mannhalter C, et al. Risk of pregnancy-associated recurrent venous thromboembolism in women with a history of venous thrombosis. J Thromb Haemost 2005;3:949–54. 91. De Stefano V, Martinelli I, Rossi E, Battaglioli T, Za T, Mannuucci PM, et al. The risk of recurrent venous thromboembolism in pregnancy and puerperium without antithrombotic prophylaxis. Br J Haematol 2006;135:386–91. 92. White RH, Chan WS, Zhou H, Ginsberg JS. Recurrent venous thromboembolism after pregnancy-associated versus unprovoked thromboembolism. Thromb Haemost 2008;100:246–52. 93. Meinardi JR, Middeldorp S, de Kam PJ, Koopman MM, van Pampus ECM, Hamulyak K, et al. Risk of venous thromboembolism in carriers of factor V Leiden with a concomitant inherited thrombophilic defect: a retrospective analysis. Blood Coagul Fibrinolysis 2001;12:713–20. 94. Samama MM, Rached RA, Horellou MH, Aquilanti S, Mathieux VG, Plu-Burean G, et al. Pregnancy-associated venous thromboembolism (VTE) in combined heterozygous factor V Leiden (FVL) and prothrombin (FII) 20210 A mutation and in heterozygous FII single gene mutation alone. Br J Haematol 2003;123:327–34. 95. Rodeghiero F, Tosetto A. The epidemiology of inherited thrombophilia: the VITA Project. Vicenza Thrombophilia and Atherosclerosis Project. Thromb Haemost 1997;78:636–40. 96. Jacobsen AF, Dahm A, Bergrem A, Jacobsen EM, Sandset PM. Risk of venous thrombosis in pregnancy among carriers of the factor V Leiden and the prothrombin gene G20210A polymorphisms. J Thromb Haemost 2010;8:2443–9. 97. Middeldorp S, Henkens CMA, Koopman MMW, van Pampus ECM, Hamulyak K, Van der Meer J, et al. The incidence of venous thromboembolism in family of patients with Factor V Leiden mutation and venous thrombosis. Ann Intern Med 1998;128:15–20. 98. Zotz RB, Gerhardt A, Scharf RE. Inherited thrombophilia and gestational venous thromboembolism. Best Pract Res Clin Haematol 2003;16:243–59. 99. McColl MD, Ramsay JE, Tait RC, Walker ID, McCall F, Conkie JA, et al. Risk factors for pregnancy associated venous thromboembolism. Thromb Haemost 1997;78:1183–8. 100. Pabinger I, Nemes L, Rintelen C, Koder S, Lechler E, Loreth R, et al. Pregnancy-associated risk for venous thromboembolism and pregnancy outcome in women homozygous for factor V Leiden. Hematol J 2000;1:37–41. 101. Middeldorp S, Libourel EJ, Hamulyak K, Van der Meer J, Buller HR. The risk of pregnancy-related venous thromboembolism in women who are homozygous for factor V Leiden. Br J Haematol 2001;113:553–5. 102. Martinelli I, Battaglioli T, De Stefano V, Tormene D, Valdre L, Grandone E, et al. The risk of first venous thromboembolism during

pregnancy and puerperium in double heterozygotes for factor V Leiden and prothrombin G20210A. J Thromb Haemost 2008;6:494–8. 103. Folkeringa N, Brouwer JLP, Korteweg FJ, Veeger NJGM, Erwich JJHM, Van Der Meer J. High risk of pregnancy-related venous thromboembolism in women with multiple thrombophilic defects. Br J Haematol 2007;138:110–6. 105. Hron G, Eichinger S, Weltermann A, Minar E, Bialonczyk C, Hirschl M, et al. Family history for venous thromboembolism and the risk for recurrance. Am J Med 2006;119:50–3. 104. Ruiz-Irastorza G, Cuadrado M, Ruiz-Arruza I, Brey R, Crowther M, Derksen R, et al. Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid antibodypositive patients: report of a task force at the 13th International Congress on Antiphospholipid Antibodies. Lupus 2011;20:206–18. 106. Simpson EL, Lawrenson RA, Nightingale AL, Farmer RD. Venous thromboembolism in pregnancy and the puerperium: incidence and additional risk factors from a London perinatal database. BJOG 2001;108:56–60. 107. Larsen TB, Sorensen HT, Gislum M, Johnsen SP. Maternal smoking, obesity, and risk of venous thromboembolism during pregnancy and the puerperium: a population-based nested case-control study. Thromb Res 2007;120:505–9. 108. Knight M. Antenatal pulmonary embolism: risk factors, management and outcomes. BJOG 2008;115:453–61. 109. Jacobsen AF, Skjeldestad FE, Sandset PM. Ante- and postnatal risk factors of venous thrombosis: a hospital-based case–control study. J Thromb Haemost 2008;6:905–12. 110. Robinson HE, O’Connell CM, Joseph KS, McLeod NL. Maternal outcomes in pregnancies complicated by obesity. Obstet Gynecol 2005;106:1357–64. 111. Nelson SM, Greer IA. Artificial reproductive technology and the risk of venous thromboembolic disease. Haemostasis 2006;4:1661–3. 112. Mára M, Koryntová D, Rezábek K, Kaprál A, Drbohlav P, Jirsová S, et al. Thromboembolic complications in patients undergoing in vitro fertilization: retrospective clinical study. Ceska Gynekol 2004;69:312–6. 113. Rao AK, Chitkara U, Milki AA. Subclavian vein thrombosis following IVF and ovarian hyperstimulation: a case report. Hum Reprod 2005;20:3307–12. 114. Salomon O, Schiby G, Heiman Z, Avivi K, Sigal C, Levran D, et al. Combined jugular and subclavian vein thrombosis following assisted reproductive technology—new observation. Fertil Steril 2009;92:620–5. 115. Chan WS, Dixon ME. The “ART” of thromboembolism: a review of assisted reproductive technology and thromboembolic complications. Thromb Res 2008;121:713–26. 116. Moen V, Dahlgren N, Irestedt L. Severe neurological complications after central neuraxial blockades in Sweden 1990-1999. Anesthesiology 2004;101:950–9. 117. Breivik H, Bang U, Jalonen J, Vigfússon G, Alahuhta S, Lagerkranser M. Nordic guidelines for neuraxial blocks in disturbed haemostasis from the Scandinavian Society of Anaesthesiology and Intensive Care Medicine. Acta Anaesthesiol Scand 2010;54:16–41. 118. Harnett MJ, Walsh ME, McElrath TF, Tsen LC. The use of central neuraxial techniques in parturients with Factor V Leiden mutation. Anesth Analg 2005;101:1821–3. 119. Vandermeulen EP, Van Aken H, Vermylen J. Anticoagulants and spinalepidural anesthesia. Anesth Analg 1994;79:1165–77. 120. Butwick AJ, Carvalho B. Neuraxial anesthesia in obstetric patients receiving anticoagulant and antithrombotic drugs. Int J Obstet Anesth 2010;19:193–201.

JUNE JOGC JUIN 2014 l 551

SOGC CLINICAL PRACTICE GUIDELINE

121. Horlocker TT. What’s a nice patient like you doing with a complication like this? Diagnosis, prognosis and prevention of spinal hematoma. Can J Anesth 2004;51:527–34. 122. Lee LA, Posner KL, Domino KB, Caplan RA, Cheney FW. Injuries associated with regional anesthesia in the 1980s and 1990s: a closed claims analysis. Anesthesiology 2004;101:143–52. 123. Bateman BT, Mhyre JM, Ehrenfeld J, Kheterpal S, Abbey KR, Argalious M, et al. The risk and outcomes of epidural hematomas after perioperative and obstetric epidural catheterization: a report from the multicenter Perioperative Outcomes Group Research Consortium. Anesth Analg 2013;116:1380–5. 124. US Food and Drug istration. FDA drug safety communication: updated recommendations to decrease risk of spinal column bleeding and paralysis in patients on low molecular weight heparins. Silverspring (MD): US FDA; 2013. November 6, 2013. Available at: http://www.fda.gov/ Drugs/DrugSafety/ucm373595.htm. Accessed on January 30, 2014. 125. Rodger M. Evidence base for the management of venous thromboembolism in pregnancy. Hematology 2010;1:173–80. 126. Robertson L, Wu O, Langhorne P, Twaddle S, Clark P, Lowe GO, et al. Thrombophilia in pregnancy: a systematic review. Br J Haematol 2005;132:171–96. 127. James AH. Prevention and management of venous thromboembolism in pregnancy. Am J Med 2007;120:S26–S34. 128. Accreditation Canada. Required organizational practices handbook 2014. Ottawa: Accreditation Canada; 2014. Available at: http://www.accreditation.ca/sites/default/files/rop-handbook2014-en.pdf. Accessed on February 28, 2014. 129. Danilenko-Dixon DR, Heit JA, Silverstein MD, Yawn BP, Petterson TM, Lohse CML, et al. Risk factors for deep vein thrombosis and pulmonary embolism during pregnancy or post partum: a population-based casecontrol study. Am J Obstet Gynecol 2001;184:104–10. 130. Gibson JL, Ekevall K, Walker I, Greer IA. Puerperal thromboprophylaxis: comparison of the anti-Xa activity of enoxaparin and unfractionated heparin. Br J Obstet Gynaecol 1998;105:795–7. 131. Burrows RF, Gan ET, Gallus AS, Wallace EM, Burrows EA. A randomized double-blind placebo controlled trial of low molecular weight heparin as prophylaxis in preventing venous thromboembolic events after caesarean section: a pilot study. Br J Obstet Gynaecol 2001;108:835–9. 132. Ellison J, Thomson AJ, Conkie JA, McCall F, Walker D, Greer IA. Thromboprophylaxis following caesarean section - a comparison of the antithrombotic properties of three low molecular weight heparins dalteparin, enoxaparin and tinazaparin. Thromb Haemost 2001;86:1374–8. 133. Gates S, Brocklehurst P, Ayers S, Bowler U. Thromboprophylaxis and pregnancy: two randomized controlled pilot trials that used lowmolecular-weight heparin. Am J Obstet Gynecol 2004;191:1296–303. 134. Tooher R, Gates S, Dowswell T, Davis LJ. Prophylaxis for venous thromboembolic disease in pregnancy and the early postnatal period. Cochrane Database Syst Rev 2010;5:CD001689. 135. Sachdeva A, Dalton M, Amaragiri SV, Lees T. Elastic compression stockings for prevention of deep vein thrombosis. Cochrane Database Syst Rev 2010;7:CD001484. 136. Dennis M, Sandercock PA, Reid J, Graham C, Murray G, Venable G, et al.; for the CLOTS Trial Collaboration. Effectiveness of thigh-length graduated compression stockings to reduce the risk of deep vein thrombosis after stroke (CLOTS trial 1): a multicentre, randomized controlled trial. Lancet 2009;373:1958–65. 137. Dennis M, Sandercock PA, Reid J, Graham C, Murray G, Venables G, et al.; for the CLOTS Trial Collaboration. Thigh-length versus below-knee stockings for deep venous thrombosis prophylaxis after stroke: a randomized trial. Ann Intern Med 2010;153:553–62.

552 l JUNE JOGC JUIN 2014

138. Clarke-Pearson DL, Creasman WT, Coleman RE, Synan IS, Hinshaw WM. Perioperative external pneumatic calf compression as thromboembolism prophylaxis in gynecologic oncology: report of a randomized controlled trial. Gynecol Oncol 1984;18:226–32. 139. Clarke-Pearson DL, Abaid N. Prevention of venous thromboembolic events after gynecologic surgery. Obstet Gynecol 2012;119:155–67. 140. James AH, Jamison MG, Brancazio LR, Myers ER. Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality. Am J Obstet Gynecol 2006;194:1311–5. 141. Dekker GA, de Vries JI, Doelitzsch PM, Huijgens PC, von Blomberg BME, Jakobs C, et al. Underlying disorders associated with severe early-onset preeclampsia. Am J Obstet Gynecol 1995;173:1042–8. 142. Rai RS, Clifford K, Cohen H, Regan L. High prospective fetal loss rate in untreated pregnancies of women with recurrent miscarriage and antiphospholipid antibodies. Hum Reprod 1995;10:3301–4. 143. Kupferminc MJ, Eldor A, Steinman N, Many A, Bar-Am A, Jaffa A, et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Eng J Med 1999;340:9–13. 144. Kupferminc MJ, Fait G, Many A, Gordon D, Eldor A, Lessing JB. Severe preeclampsia and high frequency of genetic thrombophilic mutations. Am J Obstet Gynecol 2000;96:45–9. 145. Alfirevic Z, Roberts D, Martlew V. How strong is the association between maternal thrombophilia and adverse pregnancy outcomes? A systematic review. Eur J Obstet Gynecol Reprod Biol 2002;101:6–14. 146. Rey E, Khan SR, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 2003;361:901–8. 147. Howley H, Walker M, Rodger M. A systematic review of the association between factor V Leiden or prothrombin gene variant and intrauterine growth restriction. Am J Obstet Gynecol 2005;192:694–708. 148. Wu O, Robertson L, Twaddle S, Lowe GD, Clark P, Greaves M, et al. Screening for thrombophilia in high-risk situations: systematic review and cost-effectiveness analysis. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) study. Health Technol Assess 2006;10:1–110. 149. Rodger MA, Betancourt MT, Clark P, Lindqvist PG, Dizon-Townson D, Said J, et al. The association of factor V leiden and prothrombin gene mutation and placenta-mediated pregnancy complications: a systematic review and meta-analysis of prospective cohort studies. PLoS Med 2010;7:e1000292. 150. Abou-Nassar K, Carrier M, Ramsay T, Rodger MA. The association between antiphospholipid antibodies and placenta mediated complications: a systematic review and meta-analysis. Thromb Res 2011;128:77–85. 151. Kuttah WH. Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone. Am J Obstet Gynecol 1996;174:1584–9. 152. Rai R, Cohen H, Dave M, Regan L. Randomized controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ 1997;314:253–7. 153. Farquharson RG, Quenby S, Greaves M. Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment. Obstet Gynecol 2002;100:408–13. 154. Laskin CA, Spitzer KA, Clark CA, Crowther MR, Ginsberg JS, Hawker GA, et al. Low molecular weight heparin and aspirin for recurrent pregnancy loss: results from the randomized controlled HepASA trial. J Rheumatol 2009;36:279–87.

Venous Thromboembolism and Antithrombotic Therapy in Pregnancy

155. Mak A, Cheung MW, Cheak AA, Ho RC. Combination of heparin and aspirin is superior to aspirin alone in enhancing live birth in patients with recurrent pregnancy loss and positive anti-phospholipid antibodies: a meta-analysis of randomized controlled trials and meta-regression. Rheumatology 2010;49:281–8. 156. Dolitzky M, Inbal A, Segal Y, Weiss A, Brenner B, Carp H. A randomized study of thromboprophylaxis in women with unexplained consecutive recurrent miscarriages. Fertil Steril 2006;86:362–6. 157. Badawy AM, Khiary M, Sherif LS, Hassan M, Ragab A, Abdelall I. Low-molecular weight heparin in patients with recurrent early miscarriages of unknown aetiology. J Obstet Gynaecol 2008;28:280–4. 158. Fawzy M, Shokeir T, El-Tatongy M, Warda O, El-Refaiey AA, Mosbah A. Treatment options and pregnancy outcome in women with idiopathic recurrent miscarriage: a randomized placebo-controlled study. Arch Gynecol Obstet 2008;278:33–8. 159. Clark P, Walker ID, Langhome P, Crichton L, Thomson A, Greaves M, et al. SPIN (Scottish Pregnancy Intervention) study: a multicenter, randomized controlled trial of low molecular weight heparin and low-dose aspirin in women with recurrent miscarriage. Blood 2010;115:4162–7. 160. Kaandorp SP, Goddijn M, van der Post JA, Hutten BA, Verhoeve HR, Hamulyak K, et al. Aspirin plus heparin or aspirin alone in women with recurrent miscarriage. N Engl J Med 2010;362:1586–96. 161. Visser J, Ulander V-M, Helmerhost FM, Lampinen K, Morin-Papunen L, Bloemenkamp KWM, et al. Thromboprophylaxis for recurrent miscarriage in women with or without thrombophilia. Thromb Haemost 2011;105:295–301. 162. Leduc L, Dubois E, Tasker L, Rey E, David M. Dalteparin and low-dose aspirin in the prevention of adverse obstetric outcomes in women with inherited thrombophilia. J Obstet Gynaecol Can 2007;29:787–93. 163. Rey E, Garneau P, David M, Gauthier R, Leduc L, Michon N, et al. Dalteparin for the prevention of recurrence of placental-mediated complications of pregnancy in women without thrombophilia: a pilot randomized controlled trial. J Thromb Haemost 2009;7:58–64. 164. Gris J-C, Chauleur C, Faillie J-L, Baer G, Mares P, Fabbro-Peray P, et al. Enoxaparin for the secondary prevention of placental vascular complications in women with abruption placentae (NOH-AP trial). Thromb Haemost 2010;104:771–9. 165. Gris J-C, Chaleur C, Molinari N, Mares P, Fabbro-Peray P, Quere I, et al. Addition of enoxaparin to aspirin for the secondary prevention of placental vascular complications in women with severe pre-eclampsia (NOH-PE trial). Thromb Haemost 2011;106:1053–61. 166. Kupferminc MJ, Rimon E, Many A, Maslovitz S, Lessing JB, Gamzu R. Low molecular weight heparin treatment during subsequent pregnancies of women with inherited thrombophilia and previous severe pregnancy complications. J Matern Fetal Neonatal Med 2011;24:1042–5. 167. De Vries JI, van Pampus MG, Hague WM, Bezemer PD, Joosten JH; on behalf of FRUIT investigators. Low-molecular-weight heparin added to aspirin in the prevention of recurrent early-onset pre-eclampsia in women with inheritable thrombophilia: the FRUIT-RCT. J Thromb Haemost 2012;10:64–72. 168. Martinelli I, Ruggenenti P, Cetin I, Pardi G, Perna A, Vergani P. et al. Heparin in pregnant women with previous placenta-mediated pregnancy complications: a prospective, randomized, multicenter, controlled clinical trial. Blood 2012; 119:3269–75.

171. Blanco-Molina A, Trujillo-Santos J, Criado J, Lopez L, Lecumberria R, Guiterrez R, et al. Venous thromboembolism during pregnancy or postpartum: findings from the RIETE Registry. Thromb Haemost 2007;97:186–90. 172. Bauersachs RM, Dudenhausen J, Faridi A, Fischer T, Fung S, Geisen U, et al. Risk stratification and heparin prophylaxis to prevent venous thromboembolism in pregnant women. Thromb Haemost 2007;98:1237–45. 173. Nelson-Piercy C, Powrie R, Borg JY, Rodger M, Talbot D, Stinson J, et al. Tinzaparin use in pregnancy: an international, retrospective study of the safety and efficacy profile. Eur J Obstet Gynecol Reprod Biol 2011;159:293–9. 174. Blanco-Molina A, Rota L, Di Micco P, Brenner B, Trujillo-Santos J, Ruiz-Gamietea A, et al; for the RIETE Investigators. Venous thromboembolism during pregnancy, postpartum or during contraceptive use. Thromb Haemost 2010;103:306–11. 175. Clark NP, Delate T, Cleary SJ, Witt DM. Analysis of unfractionated heparin dose requirements to target therapeutic anti-Xa intensity during pregnancy. Thromb Res 2010;125:402–5. 176. Pabinger I, Schneider B. Thrombotic risk in hereditary antithrombin III, protein C, or protein S deficiency: a cooperative, retrospective study. Arterioscler Thromb Vasc Biol 1996;16:742–8. 177. van Boven HH, Vandenbroucke JP, Briët E, Rosendaal FR. Gene-gene and gene-environment interactions determine risk of thrombosis in families with inherited antithrombin deficiency. Blood 1999;94:2590–4. 178. Tormene D, Simioni P, Prandoni P, Luni S, Zerbirati P, Sartor D, et al. Factor V Leiden mutation and the risk of venous thromboembolism in pregnant women. Haematologica 2001;86:1305–9. 179. Gerhardt A, Scharf RE, Beckmann MW, Struve S, Bender HG, Pillny M, et al. Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium. N Engl J Med 2000;342:374–80. 180. Hiltunen L, Rautanen A, Rasi V, Kaaja R, Kere J, Krusius T, et al. An unfavorable combination of Factor V Leiden with age, weight, and blood group causes high risk of pregnancy-associated venous thrombosis: a population-based nested case-control study. Thromb Res 2007;119:423–32. 181. Procare G. Risk of venous thromboembolism during pregnancy in homozygous carriers of the Factor V Leiden mutation: are there any predictive factors? J Thromb Haemost 2004;2:359–60. 182. Martinelli I, Legnani C, Bucciarelli P, Grandone E, De Stefano V, Mannucci PM. Risk of pregnancy-related venous thrombosis in carriers of severe inherited thrombophilia. Thromb Haemost 2001;86:800–3. 183. Conard J, Horellou MH, Van Dreden P, Lecompte T, Samama M. Thrombosis and pregnancy in congenital deficiencies in AT III, protein C or protein S: study of 78 women. Thromb Haemost 1990;63:319–20. 184. Tormene D, De Stefano V, Grandone E, Za T, Perlati M, Rossi M, et al. The G20210A prothrombin variant and the risk of venous thromboembolism or fetal loss in pregnant women: a family study. J Thromb Haemost 2007;5:2193–6. 185. Friederich PW, Sanson BJ, Simioni P, Zanadari S, Huisman MV, Kindt I, et al. Frequency of pregnancy-related venous thromboembolism in anticoagulant factor-deficient women: implications for prophylaxis. Ann Intern Med 1996;125:955–60.

169. Rodger MA, Carrier M, Le Gal G, Martinelli I, Perna A, Rey E, et al. Meta-analysis of low molecular weight heparin to prevent recurrent placenta-mediated complications. Blood 2013;123:822–8.

186. Carr MH, Towers CV, Eastenson AR, Pircon RA, Iriye BK, Adashek JA. Prolonged bedrest during pregnancy: does the risk of deep vein thrombosis warrant the use of routine heparin prophylaxis? J Matern Fetal Med 1997;6:264–7.

170. Dodd JM, McLeod A, Windrim RC, Kingdom J. Antithrombotic therapy for improving maternal or infant health outcomes in women considered at risk of placental dysfunction. Cochrane Database Syst Rev 2013 24;7:CD00678.

187. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

JUNE JOGC JUIN 2014 l 553

SOGC CLINICAL PRACTICE GUIDELINE No. 288, March 2013

Cancer Chemotherapy and Pregnancy This clinical practice guideline has been prepared by the Chemotherapy During Pregnancy Working Group and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Gideon Koren, MD, Toronto ON Nathalie Carey, BSc, Toronto ON Robert Gagnon, MD, Montreal QC Cynthia Maxwell, MD, Toronto ON Irena Nulman, MD, Toronto ON Vyta Senikas, MD, Ottawa ON Disclosure statements have been received from all authors.

assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and from national and international medical specialty societies. Values: The quality of evidence is rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). Benefits, harms, and costs: This guideline highlights the need to prevent pregnancy in women who are being treated for cancer and informs health care professionals treating pregnant women with chemotherapy of the potential risks of the therapy or ameliorated treatment protocols. J Obstet Gynaecol Can 2013;35(3):263–278

SUMMARY STATEMENTS AND RECOMMENDATIONS Summary Statements

Abstract

1. As women are postponing child-bearing, more of them are experiencing cancer in pregnancy. (II-2)

Objective: To promote careful education, istration, monitoring and restricted distribution when prescribing and dispensing chemotherapeutic and potentially teratogenic medications, as well as to develop clinical recommendations for the use of cancer chemotherapy in pregnant women and women of child-bearing age.

2. Chemotherapeutic agents used to combat cancer cross the placenta and may adversely affect embryogenesis by affecting cell division. (II-1)

Outcomes: To ensure that women of child-bearing age receiving chemotherapy can be appropriately counselled on the risks of becoming pregnant during treatment, and to provide guidance for health care practitioners treating pregnant women with antineoplastic agents. Evidence: Published literature was retrieved through searches of PubMed or Medline, CINAHL, and The Cochrane Library in 2011, using appropriate controlled vocabulary (e.g., antineoplastic agents, neoplasms, pregnancy) and key words (e.g., cancer, neoplasms, pregnancy, chemotherapy, antineoplastic agents). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. Studies were restricted to those with available English abstracts or text. Searches were updated on a regular basis and incorporated in the guideline to October 2011. Grey (unpublished) literature was identified through searching the websites of health technology

3. Exposure to such agents after the first trimester of pregnancy has not been associated with increased risk of malformations but is associated with increased risk of stillbirth, intrauterine growth restriction, and fetal toxicities. (II-2) Recommendations 1. The health care provider should examine the patient’s risk of pregnancy and desire to prevent pregnancy during chemotherapy. (I-A) 2. Decisions about the best course of management in pregnancy, including timing of delivery, should balance maternal and fetal risks. Most authorities concur that maternal health and well-being must prevail. (I-A) 3. Women diagnosed with cancer in pregnancy should be optimally managed by a multidisciplinary team that includes oncologists and/or hematologists (depending on the malignancy), perinatologists, family physicians, psychologists, social workers, and spiritual advisors, if sought by the family. (I-A)

Key Words: Pregnancy prevention, cancer, neoplasms, pregnancy, chemotherapy, antineoplastic agents

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

MARCH JOGC MARS 2013 l 263

SOGC CLINICAL PRACTICE GUIDELINE

Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.88 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care.88

INTRODUCTION

I

n Canada, over 9% of the 1.2 million cancers diagnosed annually in adults are diagnosed in those aged 20 to 44 years, and almost two thirds of these diagnoses are in women. This is likely because of the tendency for sexspecific cancers, such as breast and cervical cancer, to occur at younger ages than other cancers. Demonstrably, breast and cervical cancers are the 2 most common cancers to occur in young women, with rates of 34% and 10%, respectively. Thyroid cancer is the third most common at around 9%.1 A diagnosis of cancer during this stage of life may postpone or complicate child-bearing. Almost all chemotherapeutic agents are teratogenic in animals. For some drugs only experimental data exist. Women diagnosed with cancer during their childbearing years should therefore be made aware of the risks associated with the use of cancer chemotherapy in pregnancy. Information must be provided by the woman’s health care providers, including the obstetrician, who can

ABBREVIATIONS ABD

doxorubicin, bleomycin, dacarbazine

ABVD

doxorubicin, bleomycin, vinblastine, dacarbazine

AVD

doxorubicin, vinblastine, dacarbazine

CNS

central nervous system

FAC

5-fluorouracil, doxorubicin, cyclophosphamide

IUGR

intrauterine growth restriction

MOPP

mechlorethamine, vincristine, procarbazine, prednisone

264 l MARCH JOGC MARS 2013

engage in an active discussion, answer questions, and provide any additional clarification required. Research conducted by Santucci et al.2 suggested that women want their health care providers to initiate discus­ sions regarding the potential teratogenic/reproductive risks of exposure to medications. The following are important principles of effective teratogenic counselling: 1. Timely provision of information 2. Provision of data on all potential effects on a fetus 3. Provision of clear information 4. Repetition of important information 5. Avoidance of assumptions about women’s pregnancy intentions 6. Explanation of why health care providers are asking about sexual activity and pregnancy intentions 7. Discussion of consequences for reproductive health.2 These discussions are best conducted by multidisciplinary teams that include the woman’s family physician, hematologist and/or oncologist, and obstetrician-gynaecologist. Providing women with detailed and updated information about pregnancy-related risks before they begin chemotherapy is necessary to reduce the risk of fetal exposure. Since nearly one half of pregnancies are unplanned, the use of effective methods of contraception during chemotherapy should be discussed. To date, no cases of fetal exposure to lenalidomide have been reported, highlighting the effectiveness of the RevAid program,3 and ing the use of such methods.

Cancer Chemotherapy and Pregnancy

The occurrence of cancer in pregnancy is a rare and challenging event, complicating up to 0.02% to 0.1% of pregnancies annually.4,5 Because of the rise in delayed childbearing, the rates of cancer in pregnancy are expected to rise with the increased incidence of several age-dependent malignancies.5 The cancers most commonly diagnosed during pregnancy are breast cancer, cervical cancer, thyroid cancer, Hodgkin’s lymphoma, and non-Hodgkin’s lymphoma.4 Although surgery is generally considered safe during pregnancy, there is little information regarding the safety of cytotoxic agents, which are often required in the optimal management of cancer.4,6 Anticancer drugs aim, through different mechanisms, to arrest cell division and cell growth. By doing so, they pose direct risk to the developing embryo during the first trimester of pregnancy. Knowledge of pregnancy outcomes following cancer treatment has been limited by the low prevalence of cancer during pregnancy, high rates of pregnancy terminations in women with cancer, and the decision not to treat during critical fetal periods. The scarce evidence regarding the fetal safety of maternal chemotherapy during pregnancy is limited to small retrospective studies and case reports that are often underpowered, making their results difficult to interpret and generalize. Additionally, because cytotoxic agents are usually istered in multiple-drug regimens, it is difficult to estimate the potential teratogenic effects of each individual drug.7 In contrast to this paucity of information, there is a plethora of animal studies showing high rates of teratogenicity for most cancer chemotherapeutics. The main problem in interpreting these experimental data is the substantially higher dose per kg (or m2) used in the animal experiments, and inability to extrapolate these data to human experience. Several issues highlight the problems of drug therapy facing pregnant women. An estimated 50% of pregnancies are unplanned, so many women are exposed to teratogens before they realize they are pregnant.8 Also, women may decline treatment, even for life-threatening conditions, for fear of being exposed to medication that could harm their fetus.9 Following a diagnosis of cancer in pregnancy, the pregnant woman, her family, and her medical team are required to make complex treatment decisions, often in the absence of definitive evidence. Without standardized guidelines concerning chemotherapy in pregnant women, a woman may compromise her health or the health of the developing fetus. PREGNANCY PREVENTION

The detrimental impact of thalidomide worldwide in the late 1950s and early 1960s1 provides clear evidence of the need for careful education, istration, monitoring and restricted distribution in prescribing and dispensing

chemotherapeutic and potentially teratogenic medications. The devastating effects of fetal exposure to teratogenic drugs are not limited to thalidomide: diethylstilbestrol was withdrawn from the Canadian market, and isotretinoin capsules are available only through a company-sponsored pregnancy prevention program.2,4,5,10 Beyond awareness and education, the health care professional and the patient must examine the patient’s risk of pregnancy, including fertility and/or menopausal status (with consideration of previous chemotherapy and age), frequency or potential of sexual activity with a male partner, and desire to prevent pregnancy. After completing a pregnancy risk assessment, the patient and health care provider must fully discuss methods of contraception, giving careful consideration to the efficacy and availability of contraceptive options, the patient’s previous choices and her motivation to adhere to a contraceptive regimen, the rate of adherence, ease of use, cost, sideeffect profile (considering disease state and chemotherapy regimen), and access to emergency contraception. While a contraceptive plan may be in place, health care providers should check frequently with the patient to assess adherence and satisfaction with the chosen methods. Additional considerations may be necessary for higher risk populations, including teenage patients. This additional and optimal prevention of fetal exposure to teratogens for all women of child-bearing age can be achieved with the implementation of an effective controlled distribution program such as RevAid.3 DEFINING TERATOLOGY Physiological Background

Teratogenesis is defined as the structural or functional dysgenesis of fetal organs.11 Broadly, exposures that irreversibly affect the normal growth, structure, or function of a developing embryo or fetus are defined as teratogenic.12 Known teratogens include environmental factors such as radiation, certain viruses such as rubella, chemicals such as alcohol, and therapeutic drugs such as thalidomide and isotretinoin.9 Teratogenic effects vary widely in severity and range, and include death (miscarriage or stillbirth), malformations, impaired organ functioning, impaired fertility, and mutagenicity.8 Congenital malformations, defined as defects in organ structure or function, occur in 1% to 3% of the general population.9 Of the major defects, about 25% are of genetic origin and 65% are of unknown etiology.9 Only 2% to 3% of malformations are believed to be associated with drug treatment.8 The teratogenic potential of any drug depends on a variety of factors that include the extent of its placental transfer, MARCH JOGC MARS 2013 l 265

SOGC CLINICAL PRACTICE GUIDELINE

the dose istered, the duration of exposure, the genetic variability in drug metabolism of the mother and the fetus, and the timing of exposure. Teratogens must reach the fetus in sufficient amounts and during critical time windows to cause adverse fetal effects.8,9 Most drugs reach the fetus through the maternal bloodstream, and several factors can affect the fetus’s exposure to the drug Most molecules with molecular weights smaller than 500 Da easily diffuse across the placenta, whereas large molecules with molecular weights greater than 1000 Da do not easily cross the placental barrier.8,9 Additionally, factors such as lipid solubility, polarity, maternal and fetal pH, protein binding, and maternal drug metabolism profile can affect the amount of drug reaching the developing fetus.8,9 The timing of the exposure is critical, as the effect produced by a teratogen depends on the developmental stage.8,9 The all-or-none period The all-or-none period includes the time from conception until somite formation (on average 8 to 14 days from conception). Insult during this phase typically results in fetal death and miscarriage, or intact survival. Teratogen exposure at this stage may interrupt processes that facilitate implantation, leading to miscarriages. However, if implantation is successful despite teratogen exposure, the fetus is expected to develop normally. This is due to the presence of totipotent cells found in the undifferentiated embryo at this time; these cells enable repair and recovery of damaged tissue. In general, exposure during this period does not cause congenital malformations unless the insult persists beyond this stage.9 Organogenesis The most sensitive period of drug exposure is during organogenesis, which occurs roughly 2 to 8 weeks postconception during the embryonic period.9 Especially during gastrulation, which occurs 3 to 5 weeks post-conception, tissues are differentiating rapidly, and damage becomes vast and irreparable. Additionally, each organ system has a period of maximum vulnerability. For example, the neural tube, heart, and limbs are affected earlier than the palate and ears. Following organogenesis, the genitals, eyes, CNS, and hematopoietic system continue to be sensitive to teratogenic insult.8,9 The fetal phase The fetal phase, from the end of the embryonic stage to term, is characterized by growth and functional maturation of formed organs and systems. Exposures during this later stage of pregnancy can result in IUGR and low birth weight, and may affect the size or function of several organs.8,9 266 l MARCH JOGC MARS 2013

In summary, the teratogenic potential of a drug is dynamic, affected by the timing, the dose, and the molecular properties of the teratogens, and by cumulative exposure. HISTORICAL PERSPECTIVE

The consequences of thalidomide use in the late 1950s and early 1960s dramatically changed the public perception regarding fetal exposures during pregnancy, leading to fear and resistance against pharmacotherapy, as well as to extensive research in the field. Before this, it was generally believed that the placenta served as a barrier to prevent adverse effects of drugs from reaching the fetus.8 Thalidomide, although originally marketed as a safe and effective sedative and anti-emetic for the management of nausea and vomiting in pregnancy, was found to cause malformations at a frequency of 15% to 100%, particularly when taken between 27 and 50 days post-conception.13,14 Although the rates of malformation for thalidomide were high and followed a characteristic pattern (phocomelia and CNS dysmorphology), its teratogenicity was not suspected for several years. In Canada, 115 children were born with malformations after exposure to the drug.15 As a result, thalidomide was withdrawn from Canadian markets on March 2, 1962, although some pharmacies continued to have the drug available as late as May 1962.13,14 AVOIDING TERATOLOGICAL RISKS

Although the teratological risks of thalidomide are clear, this drug and lenalidomide are currently indicated in treating multiple myeloma. Their effectiveness in treating this disorder suggests there is a need for them. However, their high risk for teratogenicity, combined with the high occurrence of unplanned pregnancies, demands safety measures in their distribution to ensure they are not used during pregnancy. These requirements led to the establishment of the RevAid program,3 which carefully and effectively controls the distribution of thalidomide and lenalidomide. Only prescribers ed with the RevAid program are able to prescribe lenalidomide and thalidomide to patients. Physicians ed with RevAid are informed of the risks of these medications, and especially the risks they pose during pregnancy. In ing, the physicians must comply with the requirements of the program, which include an obligation to inform patients considering treatment with these drugs of all the risks and benefits of the drugs and requirements of the RevAid program. All patients and physicians are required to complete a RevAid Patient-Physician agreement form. In addition, only RevAid certified pharmacists may dispense thalidomide or lenalidomide. These specially trained pharmacists must also agree to comply with the requirements of the program.

Cancer Chemotherapy and Pregnancy

The conditions that must be met for access to thalidomide or lenalidomide are the most stringent for women of childbearing age. Women must be warned of the potential for birth defects and that, because of the risk to others, they must never share their medication or give blood up to 4 weeks after ceasing to take the medication. To ensure prevention of pregnancy, the RevAid program requires that women use 2 methods of contraception in parallel, starting 4 weeks before they begin taking the medication and continuing until 4 weeks after cessation of therapy. In addition, they must consent to regular pregnancy tests before and during treatment. Two pregnancy tests are given before the first prescriptions; a pregnancy test is done weekly during the first 4 weeks of therapy; and, with regular therapy, pregnancy tests are performed every 4 weeks with both regular or no periods, and every 2 weeks if periods are irregular. The RevAid program represents a safe, controlled way to provide these useful drugs to people who are not at risk of suffering their negative effects. As many chemotherapeutic agents are potentially teratogenic, and as women of childbearing age often require prompt pharmacological intervention, guidelines like those of the RevAid program are necessary to prevent pregnancy during chemotherapy treatment. In Canada, a program similar to RevAid outlines the use of isotretinoin.10 Women are informed of fetal risks, are prescribed 2 contraceptive methods in parallel, and sign a document attesting to compliance. However, unlike the RevAid program, it does not require registration and has no mandatory follow-up. The lack of these measures has resulted in unplanned pregnancies and fetal exposures to this teratogen, highlighting the importance of thorough guidelines outlining the distribution of all teratogenic substances in women of child-bearing age. Currently, no guidelines exist for the use of chemotherapy in non-pregnant women of child-bearing age. The development of a program similar to RevAid to monitor the distribution of chemotherapeutic agents and follow-up on all women enrolled in the program are needed to ensure pregnancy prevention during chemotherapy treatment. Additional guidelines are necessary to address the use of chemotherapy when it is indicated during pregnancy. The importance of these guidelines is 2-fold. First, they would give health care providers a conclusive resource on which to base their treatment plans. Second, they would help to dispel common misconceptions patients have about the use of chemotherapy during pregnancy; this will encourage pregnant women to pursue care that ensures the best longterm outcome for themselves and their infants.

CANCER AND PREGNANCY

The diagnosis of cancer during pregnancy poses difficult dilemmas for the pregnant patient, her family, and the medical team. Cancer in pregnancy is rare, complicating up to 0.02% to 0.1% of pregnancies annually.4,5,16 The cancers most commonly diagnosed in pregnancy are breast cancer, cervical cancer, thyroid cancer, Hodgkin’s lymphoma, and non-Hodgkin’s lymphoma. See Table 2 for details on particular cancers during pregnancy. ANTINEOPLASTIC AGENTS AND PREGNANCY

The main challenge in managing cancer during pregnancy is treating the patient with the optimal anti-cancer regimen without harming the developing fetus. Critically, for the best chance at survival for the mother, chemotherapy cannot always be postponed until the end of the pregnancy, and no current regimen has been confirmed (by studies with sufficient statistical power) safe for use during gestation. Because of their relatively low molecular weight, most cytotoxic agents cross the placenta and reach the fetus.17,18 The pharmacology of various anti-cancer drugs may be altered by the normal physiological changes that occur during pregnancy, such as increased plasma volume, enhanced renal and hepatic elimination, and decreased albumin concentration. Dosing similar to that of nonpregnant women of the same weight may lead to undertreatment of pregnant women with cancer.18 However, it is still not clear whether pregnant women should be treated with different doses of chemotherapy, and no studies have addressed the effectiveness of treatment regimens in pregnancy. Chemotherapy during the first trimester may increase the risk of spontaneous abortions, fetal death, and major congenital malformations. The teratogenic effects depend on the dosage, time of istration, and cumulative exposure to the chemotherapeutic agent. Fetal malformations reflect the gestational age at exposure, and the most vulnerable period is during weeks 2 to 8, when organogenesis occurs. The eyes, ears, teeth-palate, genitalia, hematopoietic system, and CNS remain vulnerable to chemotherapy beyond organogenesis.17 Almost all chemotherapeutic agents are teratogenic in animals. For many chemotherapeutic agents, the risk of teratogenesis in humans is unknown. However, the risk of teratogenesis in humans following cancer treatment appears to be lower than is commonly estimated from animal data because of the proportionately larger doses used in animals First trimester exposure to chemotherapy has been estimated to have a 10% to 20% risk for major malformations. It has been suggested that this risk may decline to about 6% MARCH JOGC MARS 2013 l 267

Unknown

0.01% to 0.3%

0.0015% to 0.012%

Unknown

0.016% to 0.1%

Unknown

Breast

Cervical

Hepatocellular carcinoma

Hodgkin’s Lymphoma

Intracranial tumours

Frequency in pregnancy

Bone malignancies

Cancer

Table 2. Cancers during pregnancy

268 l MARCH JOGC MARS 2013 •  Headache •  Nausea and vomiting •  Nonspecific symptoms to focal neurologic deficits such as hemiparesis and visual field defects. •  Pregnancy can exacerbate neurology with the patient presenting with impending or actual cerebral herniation. •  Common symptoms of intracranial pressure can potentially be confused with routine pregnancy-related conditions.

•  Painless lymph node enlargement •  Lymph node biopsy

•  Right upper quadrant pain or distention and weight loss.

•  Papanicolaou smear •  Abnormal cytology •  Colposcopy

•  Often delayed in pregnancy, 9 to 15 months •  Ultrasound •  Excisional biopsy (palpable mass) •  Incisional mass (large mass)

•  Pain •  t dysfunction •  Pathological fractures

Diagnosis

•  MRI

•  Physical exam •  Blood tests •  Bone marrow biopsy •  Abdominal ultrasonography or chest X-ray with abdominal shielding •  MRI

•  Liver sonography •  MRI •  Fine liver aspiration

•  Clinical examination •  Biopsy or cone histology •  Ultrasound and MRI •  Stage I (79%) •  Stage II/III (21%)

•  Clinical examination •  Biopsy •  Ultrasound or MRI •  Stage II/III (65% to 90%)

•  MRI •  Ultrasound •  Biopsy

Staging

—

•  Nodular sclerosis most common. •  Histological subtypes are the same as in non-pregnant women < 40 years.

—

•  Squamous carcinoma (> 80%) •  Adenocarcinoma •  Neuroendocrine

•  Invasive ductal carcinoma (75% to 90%) •  Inflammatory breast cancer (1.5% to 4%)

—

Pathology

continued

•  Very limited data suggest that pregnancy does not exacerbate tumour growth or affect the outcome of the patients.

•  Survival rates found to be similar to that of non-pregnant control matched for age, stage and treatment protocol.

•  Small number of published cases precludes any firm conclusions.

•  Higher proportion of early stage tumours likely due to increased screening performed routine antenatal care. •  No differences in survival of matched pregnant and nonpregnant women.

•  No differences found in survival between pregnant and nonpregnant women with breast cancer of same nodal status. •  However, pregnant women have 2.5-fold higher risk for metastases because of delays in diagnosis.

•  Limited data suggest that pregnancy does not exacerbate tumour growth or affect the patient outcome.

Prognosis

SOGC CLINICAL PRACTICE GUIDELINE

Frequency in pregnancy

0.001%

Unknown

0.014% to 0.28%

0.016%

Cancer

Leukemia

Lung

Malignant melanoma

Non-Hodgkin’s Lymphoma

Table 2. Continued

•  Painless lymph node enlargement •  Lymph node biopsy

•  Changes to the shape or colour of existing moles or any pigmented lesion, or the appearance of a new lump anywhere on the skin.

•  Symptoms such as bloodstreaked sputum, persistent cough or change in cough pattern, wheezing, decreased appetite with poor weight gain, along with other loco-regional symptoms are commonly seen. •  Delays in diagnosis may occur because of low index of suspicion, tendency to attribute symptoms such as fatigue and dyspnea on the pregnant state and the reluctance to order chest radiography during pregnancy.

•  Blood work •  Bone marrow biopsy

Diagnosis

•  Physical exam •  Blood tests •  Bone marrow biopsy •  Abdominal ultrasonography or chest X-ray with abdominal shielding •  MRI

•  Assessment of tumour site. •  Ultrasound •  Fine needle aspiration biopsy. •  Lymphatic mapping with blue dye or radio-labelled tracer injected at tumour site plus sentinel lymph node biopsy. •  MRI

•  Anteroposterior and lateral chest radiographs. •  Ultrasound •  MRI •  Sputum cytology •  Fine needle aspiration biopsy •  Bronchoscopy with biopsy •  Bronchoalveolar lavage

•  Ultrasounds •  MRI

Staging

•  Degrees of severity from indolent to very aggressive. •  Histological subtypes in pregnancy appear to be aggressive with diffuse large B-cell or peripheral T-cell lymphomas being the most common.

•  Superficial spreading melanomas most common (41%).

•  Non-small cell lung cancers, in order of most to least frequent: adenocarcinoma, squamous cell, large cell, and bronchoalveolar. •  Small cell lung cancer.

•  Acute myeloid leukemia •  Acute lymphoblastic leukemia •  Chronic myeloid leukemia •  Chronic lymphocytic leukemia

Pathology

continued

•  Survival rates found to be similar to that of non-pregnant control matched for age, stage and treatment protocol. •  There may be a trend toward lower birth weight infants born to mothers who had non-Hodgkin’s lymphoma in pregnancy.

•  Malignant melanoma is the most frequent cancer that metastasizes to the placenta or fetus, ing for 31% of reported cases. •  When matched for age, anatomic site and stage, most studies have not demonstrated a difference in survival between pregnant and non-pregnant women.

•  No evidence that pregnancy alters the prognosis of lung cancer. •  Maternal outcome for both small cell and non-small cell lung cancer has been poor and is a reflection of the advanced stage at diagnosis.

•  Spontaneous abortion, prematurity, IUGR, and death have been associated with maternal leukemia. •  Survival rates found to be similar to that of non-pregnant control matched for age, stage and treatment protocol.

Prognosis

Cancer Chemotherapy and Pregnancy

MARCH JOGC MARS 2013 l 269

•  Survival rates found to be similar to that of non-pregnant control matched for age, stage and treatment protocol. •  Differentiated thyroid cancer, subtypes papillary and follicular, are most common. •  Medullary thyroid cancer s for only 5% to 10% of all thyroid cancers. •  New thyroid nodule or enlargement of a pre-existing nodule •  Pain in the neck region, hoarseness •  Horner’s syndrome may be present 0.0036% to 0.014% Thyroid

•  Thyroid function test •  Fine needle aspiration biopsy •  Ultrasound

•  Survival rates found to be similar to that of non-pregnant control matched for age, stage and treatment protocol. •  Vast majority of adnexal masses are benign and are diagnosed at an early stage. •  Surface epithelial-stromal tumour (50.6%) •  Germ cell tumours (dysgerminomas and malignant teratomas) (39%) •  Pelvic ultrasounds. •  MRI •  Significant numbers of patients are asymptomatic. •  Adnexal masses. 0.002% to 0.008%

Pathology

Ovarian

Table 2. Continued

Diagnosis Frequency in pregnancy Cancer

Staging

Prognosis

SOGC CLINICAL PRACTICE GUIDELINE

270 l MARCH JOGC MARS 2013

when folate antagonists (which are considered the most teratogenic anti-cancer drugs) are excluded.17,19 The istration of chemotherapy during the second and third trimesters has not been associated with major congenital malformations but may increase the risk for IUGR, low birth weight, and stillbirth. A review of 376 cases of fetuses exposed to chemotherapy in utero, most after organogenesis, demonstrated 5% fetal death rate and 1% neonatal death rate. Other complications included preterm delivery (5%), IUGR (7%), and transient myelosuppression (4%).17 A recent American registry of 152 women exposed to chemotherapy mostly after the first trimester demonstrated only a single case of intrauterine fetal death and a single case of neonatal death.20 The malformation rate was 3.8%, with a 7.6% risk for IUGR. Only 2 of the 159 live born infants suffered transient myelosuppression. A European study compared the rates of adverse pregnancy outcomes in patients exposed to chemotherapy (117 pregnancies) during the second and third trimesters and in healthy control patients (58 pregnancies).21 Although the incidences of major and minor malformations had not increased compared with previous reports, the small size of the control group prevents extensive conclusions. The rate of low birth weight was higher in the chemotherapy group (17.9%) than in the control group (8.6%). Most of the infants with low birth weight were born to mothers treated for hematological malignancies.21 For cancer diagnosis made late in pregnancy, consideration can be given to delaying initiation of chemotherapy balanced against gestational age and possible delivery before treatment. The major message is that most fetuses whose exposure is limited to the second and third trimester of pregnancy are born healthy. Specific Cytotoxic Groups

Alkylating agents Alkylating agents are commonly used for the treatment of a variety of cancers. These compounds act directly on cell DNA to prevent rapidly replicating cells from reproducing. Their action is not specific to a particular phase of the cell cycle. Cyclophosphamide, dacarbazine, ifosfamide, mechlorethamine, and procarbazine are among those commonly used.22 Cyclophosphamide is commonly used for the treatment of breast cancer, ovarian cancer, and non-Hodgkin’s lymphoma. Avilés et al.,23 reported healthy pregnancy outcomes in 11 patients treated during the first trimester with cyclophosphamide-containing protocols.23 A further 5 reported exposures in the first trimester resulted in several congenital malformations including absent big toes, single coronary artery, imperforate anus, umbilical hernia, cleft palate, multiple eye defects, and esophageal

Cancer Chemotherapy and Pregnancy

atresia.24–28 Included in this, one set of twin infants in which the male twin, born with congenital anomalies, later developed thyroid cancer at age 11 and stage III neuroblastoma at age13.28 His twin sister was unaffected by the exposure and was developing normally at the time of the study, suggesting differential pharmacogenetic effects on the drug metabolism into the active form of the drug. Cyclophosphamide exposures in the second and third trimester of pregnancy are more frequent. One study examined the outcomes of 61 patients treated for different malignancies during the second and third trimester and found 59 infants were born with no malformations.21 One infant whose mother was treated also with doxorubicin was born with hip subluxation and another infant who was exposed to the EFC protocol (epirubicin, cisplatin,  fluorouracil) was born with rectal atresia. Another 110 patients exposed during the second and third trimesters to an assortment of multidrug protocols, including cyclophosphamide, resulted in 105 normal births and 5 congenital malformations: 1 intrauterine death with normal autopsy, 1 neonatal death due to autoimmune disorder, 1 infant with IgA deficiency, 1 with pyloric stenosis, and 1 with holoprosencephaly.20 Intrauterine growth restriction occurred in 7 cases (6%). An additional 81 women who were treated with the FAC regimen for breast cancer during the second to third trimesters demonstrated 3 congenital abnormalities, including 1 case of Down syndrome, 1 infant with ureteral reflux, and another with talipes.29,30 Finally, 28 patients treated for breast cancer with different cyclophosphamide-containing regimens during the second and third trimesters all had normal deliveries and outcomes.31 This information suggests that second and third trimester exposure to cyclophosphamide may not increase the risk for adverse effects. Dacarbazine exposures occur most frequently in pregnancy during istration of ABVD protocols, or in combination MOPP, ABVD or MOPP/AVD protocols. In 19 patients treated for lymphoma with ABVD after the first trimester, 17 healthy infants were born, and 2 with congenital malformations: 1 infant with plagiocephaly, and 1 infant with fourth and fifth syndactyly.20 In another 12 reports of lymphoma patients treated with ABVD (83.3%), MOPP/ABVD (8.3%), or MOPP/ABD (8.3%) protocols, all resulted in normal deliveries and healthy outcomes.32 Through this limited information, it appears that exposure to dacarbazine during the later stages of pregnancy is not associated with a specific set of malformations. Use in the first trimester cannot be recommended. Two case reports of ifosfamide treatment, combined with doxorubicin for Ewing sarcoma in pregnancy were located.33,34 One exposure occurred during the second trimester and the other in the third trimester. Both pregnancies had normal outcomes. Scarcity of information regarding ifosfamide is a recommendation for using a better-studied alternative.

MOPP treatment, involving exposure to alkylating agents mechlorethamine and procarbazine was reported in 14 patients.21,32,34,35 One patient treated during the first trimester delivered an infant with hydrocephaly that died 4 hours after birth.35 A second trimester exposure to MOPP/ABV resulted in bilateral partial syndactyly of second and third digits in the fetus.21 Twelve exposures to MOPP/ABV or ABVD described by Avilés et al., with an unspecified amount occurring in the first trimester, all resulted in normal outcomes.32 These data suggest mechlorethamine and procarbazine are not associated with an increased risk in the second and third trimesters. Platinum compounds Platinum compounds form DNA adducts that result in DNA crosslinking. DNA crosslinks inhibit replication, transcription, and other nuclear functions. The combination of these events arrests cell proliferation and ultimately tumour growth. Cisplatin and carboplatin are among the most commonly used platinum compounds. Cisplatin exposure in the second and third trimesters has been frequently described. Four patients who had cervical cancer during pregnancy and who were treated in the second trimester with cisplatin all delivered healthy infants with no congenital malformations.36–39 Another 3 patients treated for small cell lung carcinoma and 2 treated for ovarian cancer delivered healthy infants after exposures to cisplatin.40–42 Finally, 6 of 7 infants born to 7 patients exposed to cisplatin in various regimens for different malignancies were healthy. Only 1 infant was born with a congenital malformation, hearing loss that was attributed to genetic factors from the parents.20 Cisplatin use in the second and third trimesters of pregnancy has not been found to be associated with any pattern or increased risk of adverse fetal effects. Carboplatin exposure occurred during the second and third trimesters of 5 patients. Four were women with ovarian cancer, all of whom delivered healthy infants. The 1 case of CNS malignancy was the only report of an adverse pregnancy outcome, with a spontaneous abortion of a fetus with gastroschisis, as reported by Cardonick et al.20 Although evidence is limited, carboplatin exposure in the second and third trimesters does not appear to increase the risk for major malformations. Antimetabolites Antimetabolites are small compounds used to treat leukemia, lymphoma, and breast cancer. They act as false substrates during DNA or RNA synthesis, resulting in inhibition of cellular metabolism. This process occurs independently of the phase of the cell cycle. Common examples of chemotherapeutic agents of this drug class are methotrexate, 5-fluorouracil, aminopterin, cytarabine, tioguanine, and mercaptopurine.22 MARCH JOGC MARS 2013 l 271

SOGC CLINICAL PRACTICE GUIDELINE

Methotrexate exposure during the first trimester of pregnancy has been associated with malformations similar to the aminopterin syndrome, including cranial dysostosis with delayed ossification, hypertelorism, wide nasal bridge, micrognathia, and ear anomalies.43 In a series of 20 exposures during the first trimester, 7 infants developed this pattern of anomalies.44–52 In addition, there were 5 cases of miscarriage and 1 case of skeletal abnormalities with ambiguous genitalia. Exposure to methotrexate (together with cyclophosphamide and 5-fluorouracil) in the second and third trimesters in 12 patients did not show the same pattern of malformations: all infants were born healthy.31 Because of the suspected teratogenicity of methotrexate, it should not be considered a first-line therapy, and should not be used at any stage of pregnancy. One study reported on 53 exposures to 5-fluorouracil, with 5 occurring in the first trimester.17 One of these patients spontaneously miscarried, and there were 6 cases of IUGR. The rest of the infants had normal outcomes. A further 12 patients exposed to 5-fluorouracil, along with cyclophosphamide and methotrexate, in the second and third trimesters had normal outcomes.31 Similarly, 18 patients treated with 5-fluorouracil for breast and colorectal cancers during the second and third trimester all had normal pregnancy outcomes.20 Hahn et al. reported 3 congenital malformations out of 35 exposures to 5-fluorouracil in an FAC protocol during the second and third trimesters for the treatment of breast cancer.29 One infant was born with Down syndrome, 1 with clubfoot, and 1 with congenital bilateral ureteral reflux. As these are fairly common congenital abnormalities, the authors compared these rates with expected population frequencies and determined that the chemotherapy may not have been the cause. As an antimetabolite, 5-fluorouracil is not one of the first-line agents recommended, but it has not been associated with any increased risk for malformation in the second and third trimesters. Capecitabine exposure in 1 patient treated during the first trimester for colorectal cancer resulted in a normal pregnancy with a healthy outcome.20 Evidence is insufficient for conclusions to be made about the safety of capecitabine. In 9 patients treated with various regimens including cytosine arabinoside for leukemia, 5 of them during the first trimester, no congenital malformations were reported.23 Two more patients treated during the second and third trimesters with this antimetabolite for non-Hodgkin’s lymphoma and acute myeloid leukemia also had healthy pregnancy outcomes.20 Although information is limited, there is so far no evidence to indicate that istration of cytosine arabinoside in pregnancy results in fetal malformations. One patient treated with gemcitabine for a pancreatic tumour during the second and third trimesters had a normal 272 l MARCH JOGC MARS 2013

pregnancy and healthy outcome.20 A second patient treated for non-small cell lung cancer delivered prematurely, at 28 weeks, but with no congenital malformations.53 Anti-tumour antibiotics Microorganisms produce these cytotoxic agents that interact directly with DNA resulting in anti-cancer activity. The manner in which antibiotics interact with DNA differs considerably between agents. Bleomycin creates DNA breaks and is commonly used in the ABVD protocol. Cardonick et al.20 reported on 23 exposures to bleomycin in pregnancy, with varying malignancies and regimens.20 Twenty of the women were being treated for lymphoma, while the remaining 3 had ovarian cancer. Treatment occurred during the second and third trimesters, and 3 congenital malformations resulted. One infant was born with plagiocephaly and another with fourth and fifth finger syndactyly. A third infant was born with genetic hearing loss, of which his parents were both genetic carriers.20 Another patient treated with bleomycin (in combination with etoposide and cisplatin) for teratoma during the third trimester had a normal delivery and healthy infant.42 Bleomycin therapy in the second and third trimesters of pregnancy was not associated with any grouping of malformations. Topoisomerase inhibitors Anthracyclines Anthracyclines commonly used are doxorubicin, daunoru­ bicin, epirubicin, idarubicin, and mitoxantrone. Van Calsteren et al. reported on a number of pregnant patients treated with topoisomerase inhibitors.18 A total of 36 patients treated for various malignancies with doxorubicin during the second and third trimester were evaluated. One infant, also exposed to cyclophosphamide, was born with hip subluxation. A second infant exposed to FAC regimen was born with doubled cartilage rings in both ears. The rest of the infants (34/36) had normal outcomes. Another 25 patients in this series were exposed to daunorubicincontaining treatments for various malignancies during the second and third trimesters. Two infants had congenital malformations: 1 with bilateral partial syndactyly of second and third digits, and the other with rectal atresia. The remaining 23 outcomes were normal. Cardonick et al. detailed the pregnancy outcomes of 118 patients treated for breast cancer (98) and lymphoma (20) with various topoisomerase inhibitor-containing regimens, all during the second and third trimesters.20 A total of 5 abnormal outcomes were observed: 1 infant with IgA deficiency, 1 neonatal death due to autoimmune disorder, 1 infant with pyloric stenosis, 1 infant with holoprosencephaly, and 1 intrauterine demise with normal autopsy. In another series of 11 patients treated with doxorubicin together with

Cancer Chemotherapy and Pregnancy

cyclophosphamide during the second and third trimesters of pregnancy, all infants had normal outcomes.31 Epirubicin exposure was noted in 5 patients concomitant with cyclophosphamide during the second and third trimesters. No congenital malformations were reported.31 In 1 case, a patient treated for acute myeloid leukemia was exposed to idarubicin together with all-trans retinoic acid during the first trimester and had a normal pregnancy outcome. 54 A further 9 cases of patients treated for various malignancies during the second and third trimesters, however, resulted in 4 congenital malformations,32,55–59 including 1 case of transient dilated cardiomyopathy and 2 cases of permanent dilated cardiomyopathy.55–57 As data on possible effects to the fetal heart are inconclusive, caution should be exercised with respect to the use of idarubicin during pregnancy. One patient treated for teratoma with mitoxantrone and bleomycin and cisplatin during the third trimester had a normal delivery, and the infant had no congenital malformations.42 Plant alkaloids and taxanes Plant alkaloids and natural products, such as taxanes, may inhibit mitosis or inhibit enzymes needed for reproduction of the cell. These agents are specific to the M phase of the cell. They include paclitaxel, docetaxel, etoposide, vinblastine, and vincristine.22 In 19 patients, 2 in the first trimester, exposed to docetaxel for the treatment of breast cancer, 3 congenital malformations were noted.60 Two infants had cerebral ventriculomegaly; however, in both cases the diagnosis was made before istration of chemotherapy. The only malformation potentially related to cytotoxicity is 1 case of pyloric stenosis in an infant whose mother was exposed to doxorubicin, cyclophosphamide, paclitaxel, and docetaxel. Therefore, the use of docetaxel appears to be safe in the second and third trimesters. Exposures to paclitaxel in multi-drug therapies for various malignancies in 19 patients resulted in 1 congenital malformation and 1 intrauterine or postnatal demise.20 Pyloric stenosis was reported in an infant exposed to paclitaxel, docetaxel, cyclophosphamide, and doxorubicin as discussed above. In a patient treated with doxorubicin, vincristine, cyclophosphamide, prednisone, and rituximab for nonHodgkin’s lymphoma, intrauterine fetal demise occurred at 30 weeks. The autopsy results were normal. Twenty-four more cases of exposure to paclitaxel for the treatment of breast cancer in the second and third trimester resulted in 23 healthy outcomes. The 1 congenital malformation was the case of pyloric stenosis following multi-drug exposure reported previously. Finally, 1 patient treated with paclitaxel weekly from 20 weeks’ gestation delivered a healthy infant

with no congenital malformations.61 These data suggest that paclitaxel may be compatible with therapy in the second and third trimesters of pregnancy. Vincristine exposures in 11 patients treated for various cancers during the second and third trimesters resulted in healthy outcomes for 10 infants.20 As previously noted, 1 infant exposed to vincristine, doxorubicin, cyclophosphamide, prednisone, and rituximab died in utero at 30 weeks, and the autopsy results were normal. These limited exposures suggest that vincristine therapy does not increase risk for malformation during the second and third trimesters. Of 20 patients treated in the second and third trimesters for Hodgkin’s lymphoma and non-Hodgkin’s lymphoma with varying vinblastine-containing regimens, 2 had infants with malformations.20 After in utero exposure to doxorubicin, bleomycin, dacarbazine, and vinblastine throughout second and third trimesters for Hodgkin’s lymphoma, there was 1 case of plagiocephaly. Another infant exposed to the same regimen was born with fourth and fifth finger syndactyly. Although evidence to date suggests there is not a significant concern with unique vinblastine treatment in the second and third trimesters, more research is needed. Etoposide exposure in 6 patients during the second and third trimesters did not appear to cause any congenital malformations.20,40,42 One infant was born with genetic hearing loss ruled unrelated to exposure to etoposide, cisplatin, and bleomycin. Although there is only limited experience with etoposide, there were no patterns of congenital malformations noted with etoposide exposure in the later stages of pregnancy. Molecularly targeted agents Recently, the choice of treatment for the pregnant patient with cancer has become even more complicated because of the increasing use of targeted anti-cancer therapies. The benefit of the targeted agents has been well demonstrated for various malignancies; however, their safety during pregnancy has not been established. Currently, significant experience with exposure during pregnancy is available only for the tyrosine kinase inhibitor, imatinib and the monoclonal antibody, rituximab. The largest report regarding exposure to imatinib during pregnancy included 180 pregnant women with chronic myeloid leukemia. Outcome data were available for 125 patients.62 Congenital malformations were identified in 12 infants, 3 of whom had strikingly similar complex malformations (a combination of omphalocele with severe renal and skeletal malformations) that are clearly cause for concern. All congenital malformations were associated with first trimester exposure to imatinib. It appears that although most pregnancies exposed to imatinib are likely to have a successful outcome, this exposure may result in serious fetal MARCH JOGC MARS 2013 l 273

SOGC CLINICAL PRACTICE GUIDELINE

malformations. These concerns suggest that imatinib should not be istered during the first trimester.62,63 Rituximab is an anti-CD20 monoclonal B-cell antibody indicated mainly for diffuse large B cell and follicular non-Hodgkin’s lymphomas. Recently it has been also istered to patients with several autoimmune diseases. A 2011 report described 231 pregnancies associated with maternal rituximab exposure.64 Most cases were confounded by the concomitant use of potentially teratogenic medications (most commonly methotrexate). Of the 153 pregnancies with outcome data, 90 resulted in live births. First trimester miscarriages were reported in 33 (21%) cases, and 28 pregnancies were electively terminated. Twenty-two infants were born prematurely, and there was 1 neonatal death. Eleven neonates had hematological abnormalities without corresponding infections. Two congenital malformations were identified: 1 case of talipes, and 1 of cardiac malformation (a combination of ventricular septal defect, persistent foramen ovale, and persistent ductus arteriosus). The limited experience to date suggests that the istration of rituximab may be considered safe during the second and third trimesters. TREATMENT GUIDELINES

Patients with a slowly growing cancer diagnosed during the first trimester may be followed at short intervals for signs of disease progression without treatment until the second trimester. However, when aggressive, advanced, or progressive disease is diagnosed in the first trimester, a delay in therapy may adversely affect maternal survival.3,63–67 Therefore, treatment with appropriate, often combination, chemotherapy should be given promptly. However, this should be accompanied by detailed counselling to ensure that the woman and her family understand the potential teratogenic effects of chemotherapy in the first trimester. In specific cases, the treatment with singleagent chemotherapy (preferably a vinca alkaloid or an anthracycline) during the first trimester followed by conventional multi-agent therapy at the beginning of the second trimester may be considered. Such therapeutic approaches appear to be safe; however, data regarding their efficacy for the maternal cancer is lacking. Most multi-drug protocols may be istered during the second and third trimesters without an apparent increase in the risk for severe malformations. Regimens based on a combination of cyclophosphamide and an anthracycline istered to women with breast cancer or lymphoma have been most commonly used during pregnancy, and their istration after the end of the first trimester found to be safe. Weekly fractionated-dose chemotherapy may be preferred to allow ease of pregnancy monitoring, and interruption of treatment if necessary.6 274 l MARCH JOGC MARS 2013

Treatment during the second and third trimesters does not carry a risk for morphological congenital malformation; however, infants may be born earlier than expected and small for gestational age, and some of the agents used in treatment are neurotoxins, which may theoretically affect brain development. The timing of delivery should be planned to avoid myelosuppression, but no long-term developmental sequelae have been reported. If possible, delivery should be postponed for 2 to 3 weeks following anti-cancer treatment to allow bone marrow recovery.4,69 Furthermore, neonates, especially preterm infants, have limited capacity to metabolize and eliminate drugs because of liver and renal immaturity. The delay of delivery after chemotherapy will allow fetal drug excretion by the placenta. POSTPARTUM CARE Breastfeeding

As a rule, women using cancer chemotherapeutic agents after delivery should not be breastfeeding as neither shortterm nor long-term safety has been established. Exceptions include azathioprine, with which repeated measures failed to show accumulation in milk. If the lactating mother requires drug therapy, safety of breastfed infants is a concern because almost all drugs the mother ingests are excreted into milk. Of many factors that determine magnitude of drug excretion into milk, plasma protein binding, ionization characteristics and lipophilicity of drug are the most important.70 Recently, expression and function of carrier-mediated drug transport in the mammary gland have been elucidated. For example, the lactating mammary gland highly expresses breast cancer resistant protein (BCRP: ABCG2), which carries its substrates from maternal circulation into milk. Initially, its role as a toxin transporter was perplexing as it appeared to actively contaminate mother’s milk. However, it was later shown that breast cancer resistant protein in the mammary gland is a major vitamin B2 transporter.71 Some organic cation transporters carry both xenobiotics and nutrients, and mammary gland drug transporters have a nutrient carrier function that is taken over by maternal xenobiotics. In addition to the above mentioned attributes of drugs, such as protein binding and ionization characteristics, transporter affinity as a substrate is another important factor for defining milk excretion of drugs.70 Risk assessment of drug therapy, including cancer chemotherapy, during lactation must consider several factors that are distinct from those of pregnancy. First, average levels of drug exposure in the infant are usually an order of magnitude lower in lactation-mediated exposure than in transplacental exposure. Second, the mother has an option to discontinue, or temporarily interrupt, breastfeeding if the risk is perceived to be high. Third, cancer chemotherapy schedules may allow breastfeeding women to store their

Cancer Chemotherapy and Pregnancy

own milk for near-future use. In addition, women with cancer who are being treated with chemotherapy may perceive the importance of breastfeeding and the risks associated with it differently from women who are taking non-cancer related medications. Published clinical studies on excretion of cancer chemotherapy agents into milk, and resultant infant plasma levels, are very limited. Breastfeeding-related information is available for the following chemotherapeutic agents in cancer treatment, but levels of evidence are not high enough to make firm recommendations. Cisplatin There are 3 published case reports on use of cisplatin in lactating women with cancer.72–74 At various post-dose time points, plasma cisplatin concentrations were measured as platinum. The maternal plasma levels ranged from 0.8 mg/ mL to about 3 mg/mL when measured and expressed as plasma platinum levels, but the maternal plasma ratio varied widely from nearly zero (milk levels were below the detection limit of platinum) to 1.1. Cisplatin pharmacokinetic studies in non-lactating patients indicate that average plasma platinum concentrations after 100 mg/m2 dosing (a high therapeutic dose) are about 3.91 ± 1.41 mg/mL.75 Assuming maternal plasma ratio to be the reported highest (1.1), the infant would receive 4.3 mg/kg/day of platinum. Taken together, evidence of cisplatin safety/toxicity in breastfeeding is weak. Because of the relatively long half-life of cisplatin, most experts recommend discontinuation of breastfeeding, but emerging data on benefits of breastfeeding and lack of clear toxicity data may require revisiting the current recommendation. Cyclophosphamide Three case reports of use of cyclophosphamide during breastfeeding exist; however, there are no quantitative data on cyclophosphamide levels in milk.76–78 In one case, a woman with leukemia received weekly intravenous doses of cyclophosphamide 800 mg and vincristine 2 mg over a 6-week period, in addition to prednisolone (30 mg/day). Her 4-month-old infant was breastfed during this treatment cycle and found to be neutropenic at the end of the treatment, but returned to normal after breastfeeding was discontinued.76 Another patient with Burkitt lymphoma received daily cyclophosphamide 6 mg/kg intravenously. At 23 days of life, her infant developed neutropenia and thrombocytopenia over a 3-day period. The limited information from these reports suggests that cyclophosphamide is not compatible with breastfeeding.77 Doxorubicin In milk samples of a woman receiving doxorubicin 70 mg/m2 (an intravenous dose of 90 mg), the drug and its active metabolite, doxorubicinol, were detected. The peak

milk concentrations of doxorubicin and doxorubicinol were 128 mg/L (0.24 mM) and 111 mg/L (0.20 mM), respectively, 24 hours after the dose.72 Anthracyclines may not be absorbed orally, and the dose to the infant, based on the peak levels, may be in the low range of 2% of the weight-adjusted dose. However, safety data are too scant to make a firm recommendation at this point. A 28-year-old woman with acute promyelocytic leukemia received chemotherapy during pregnancy and breastfeeding.79 After first consolidation therapy, she delivered healthy baby at 34 weeks’ gestation. After delivery she received second consolidation therapy. Then she was treated with intravenous etoposide (80 mg/m2/day: days 1 to 5) and other drugs including mitoxantrone (6 mg/m2/day: days 1 to 3) and cytarabine (170 mg/m2/day: days 1 to 5) as third consolidation therapy. The post-infusion peak milk concentrations of etoposide ranged from 580 mg/L to 800 mg/L, which quickly declined and became undetectable in 24 hours. Breastfeeding was resumed 3 weeks after the end of the therapy without incident. In the same woman described above, mitoxantrone milk concentration reached 120 mg/mL immediately after the third dose. Mitoxantrone milk concentrations decreased to about 20 mg/mL by 7 days after the last (third) dose, and remained at that level 4 weeks after the last dose.79 After maternal oral doses of imatinib (400 mg/day), milk concentrations are approximately in the range of 0.5 mg/mL to 3.2 mg/mL. Its active metabolite is also in a similar range of concentrations (1 mg/mL to 2.5 mg/mL). One infant was breastfed during the maternal imatinib treatment without incident.80–83 Methotrexate A 25-year-old woman with choriocarcinoma received methotrexate 22.5 mg orally (15 mg/m2/day). Peak methotrexate concentrations in milk samples were 2.6 ng/mL on 2 different dosing occasions.84 In the case of a woman who received a single dose of 65 mg of methotrexate intramuscularly (50 mg/m2) for ectopic pregnancy, 6 milk samples taken over the following 24-hour period did not show detectable levels of the drug.85 Studies on excretion of cancer chemotherapeutic agents into human milk are scarce, but accumulating evidence is overwhelmingly ive of the tangible benefit of human milk for many aspects of infant development. Given the nature of the maternal diseases in question, risk-benefit assessment of breastfeeding during maternal chemotherapy needs to be carefully individualized. Follow-Up

While treating pregnant women during the second and third trimesters, it is important to bear in mind that the CNS is still developing and that treatment can have long-term MARCH JOGC MARS 2013 l 275

SOGC CLINICAL PRACTICE GUIDELINE

side effects on the child’s development. Long-term followup data on children born to mothers treated for leukemia during pregnancy have been published.32 The children’s psychological, physical, and neurological development were reported as normal. The grandchildren of exposed pregnant women were also followed up in the same study. Even those children had normal neurological and psychological development. No congenital malformations were reported. One review included 111 children born to women treated during pregnancy, who were followed for up to 19 years. All the children had normal neurological development.86 Another concern is the possibility of secondary malignancies in exposed children. Avilés and Neri followed 84 children to a median age of 18 years: no secondary malignancies and no fertility issues were reported.32 Yet, in a case of twin exposure to cyclophosphamide, 1 infant developed 2 different cancers (neuroblastoma and thyroid) over his lifetime.28 To date, there is no other large-scale follow-up. A recent registry reported on well-being of infants born to treated mothers, but the follow-up period is only a few years.20 Ongoing observation is underway to provide a full and detailed report in the coming years. At birth, the placenta should be examined for invasion of malignant cells. Any infant with placental involvement should be considered high risk and subsequently monitored. Cardonick et al. recommend follow-up every 6 months for at least 2 years, with a focus on the primary malignancy. A physical examination, blood chemistry, and chest X-ray may also be of value.20 ETHICAL CONSIDERATIONS

When considering the treatment of cancer during pregnancy with chemotherapeutic agents, it is important to balance maternal and fetal interests Decisions about the management of cancer in pregnancy should be made individually for each patient after careful consideration of cancer type, cancer stage, gestational age, maternal and fetal risks, and possible treatment alternatives. Termination of pregnancy may be indicated but will not be acceptable in all cases for social and sometimes religious reasons. Furthermore, most evidence does not suggest increased maternal survival following therapeutic abortion.87 If the patient desires the pregnancy, and termination is not an option, the decision to start chemotherapy during pregnancy should be weighed against the potential impact on maternal survival.17 Physicians should discuss the situation with the pregnant patient and her family, providing all the information available regarding the malignancy, possible treatment alternatives, and both maternal and fetal risks.17 A multidisciplinary team, which includes 276 l MARCH JOGC MARS 2013

the family physician, hematologist and/or oncologist, obstetrician, social worker, psychologist, and in some cases religious advisors, should be assembled whenever possible to optimize the physical and mental well-being of the woman, her baby, and her family. SUMMARY STATEMENTS AND RECOMMENDATIONS Summary Statements

1. As women are postponing child-bearing, more of them are experiencing cancer in pregnancy. (II-2) 2. Chemotherapeutic agents used to combat cancer cross the placenta and may adversely affect embryogenesis by affecting cell division. (II-1) 3. Exposure to such agents after the first trimester of pregnancy has not been associated with increased risk of malformations but is associated with increased risk of stillbirth, intrauterine growth restriction, and fetal toxicities. (II-2) Recommendations

1. The health care provider should examine the patient’s risk of pregnancy and desire to prevent pregnancy during chemotherapy. (I-A) 2. Decisions about the best course of management in pregnancy, including timing of delivery, should balance maternal and fetal risks. Most authorities concur that maternal health and well-being must prevail. (I-A) 3. Women diagnosed with cancer in pregnancy should be optimally managed by a multidisciplinary team that includes oncologists and/or hematologists (depending on the malignancy), perinatologists, family physicians, psychologists, social workers, and spiritual advisors, if sought by the family. (I-A) REFERENCES 1. Cancer Care Ontario, Cancer in young adults in Canada. Toronto: Cancer Care Ontario; 2006. May 2006. Available at: http://www.cancercare.on.ca and http://www.cancer.ca. Accessed December 27, 2012. 2. Santucci AK, Gold MA, Akers AY, Borrero S, Schwarz EB. Women’s perspectives on counseling about risks for medication-induced birth defects. Birth Defects Res A Clin Mol Teratol 2009;88:64–9. 3. RevAid [website]. Available at: http://www.revaid.ca/revaid. Accessed January 3, 2013. 4. Pereg D, Koren G, Lishner M. Cancer in pregnancy: gaps, challenges and solutions. Cancer Treat Rev 2008;34:302–12. 5. Koren G, Lishner M, Santiago S, eds. The Motherisk guide to pregnancy and lactation. 2nd ed. Toronto: Motherisk Program; 2005. 6. Azim HA, Peccatori FA. Managing cancer during pregnancy: what evidence do we have? Pol Arch Med Wewn 2011;121:29–34.

Cancer Chemotherapy and Pregnancy

7. Leslie KK. Chemotherapy and pregnancy. Clin Obstet Gynecol 2002;45(1):153–64. 8. Koren G, Pastuszak A, Ito S. Drugs in pregnancy. N Engl J Med 1998;338(16):1128–37. 9. Koren G. Fetal risks of maternal pharmacotherapy: identifying signals. Handb Exp Pharmacol 2011;205:285–94. 10. iPledge [website]. Available at: https://www.ipledgeprogram.com/ Default.aspx. Accessed January 3, 2013. 11. Moore KL. The developing human: clinically oriented embryology. 4th ed. Philadelphia: W.B. Saunders;1988:131. 12. Buhimschi CS, Weiner . Medications in pregnancy and lactation: part 1. Teratology. Obstet Gynecol 2009;113(1):166–88. 13. Laffitte E, Revuz J. Thalidomide: an old drug with new clinical applications. Expert Opin Drug Saf 2004;3(1):47–56. 14. Thalidomide Victims Association of Canada. The Canadian tragedy. 2011. Available at: http://www.thalidomide.ca/the-canadian-tragedy. Accessed December 27, 2012. 15. CBC News. In depth health: thalidomide. Nov 22, 2007. Available at: http://www.cbc.ca/news/background/health/thalidomide.html. Accessed December 27, 2012. 16. Pavlidis NA. Coexistence of pregnancy and malignancy. Oncologist 2002;7:279–87. 17. Cardonick E, Iacobucci A. Use of chemotherapy during human pregnancy. Lancet Oncol 2004;5:283–91. 18. Van Calsteren K, Verbesselt R, Ottevanger N, Halaska M, Heyns L, Van Bree R, et al. Pharmacokinetics of chemotherapeutic agents in pregnancy: a preclinical and clinical study. Acta Obstet Gynecol Scand 2010;89:1338–45. 19. Doll DC, Ringenberg QS, Yarbro JW. Antineoplastic agents and pregnancy. Semin Oncol 1989;16:337–46. 20. Cardonick E, Usmami A, Ghaffar S. Perinatal outcomes of a pregnancy complicated by cancer, including neonatal follow-up after in utero exposure to chemotherapy. Am J Clin Oncol 2010;33:221–8. 21. Van Calsteren K, Heyns L, De Smet F, Van Eycken L, Gziri MM, Van Gemert W, et al. Cancer during pregnancy: an analysis of 215 patients emphasizing the obstetrical and the neonatal outcomes. J Clin Oncol 2010;28:683–9.

29. Hahn KM, Johnson PH, Gordon N, Kuerer H, Middleton L, Ramirez M, et al. Treatment of pregnant breast cancer patients and outcomes of children exposed to chemotherapy in utero. Cancer 2006;106:1219–26. 30. Berry DL, Theriault RL, Holmes FA, Parisi VM, Booser DJ, Singletary SE, et al. Management of breast cancer during pregnancy using a standardized protocol. J Clin Oncol 1999;17(3):855–61. 31. Ring AE, Smith IE, Jones A, Shannon C, Galani E, Ellis PA. Chemotherapy for breast cancer during pregnancy: an 18-year experience from five London teaching hospitals. J Clin Oncol 2005;23:4192–7. 32. Avilés A, Neri N. Hematological malignancies and pregnancy: a final report of 84 children who received chemotherapy in utero. Clin Lymph 2001;2(3):173–7. 33. Nakajima W, Ishida A, Takahashi M, Hirayama M, Washino N, Ogawa M, et al. Good outcome for infant of mother treated with chemotherapy for Ewing sarcoma at 25 to 30 weeks’ gestation. J Pediatr Hematol Oncol 2004;26:308–11. 34. Merimsky O, Le Chevalier T, Missenard G, Lepechoux C,  Cojean-Zelek I, Mesurolle B, et al. Management of cancer in pregnancy: a case of Ewing’s sarcoma of the pelvis in the third trimester. Ann Oncol 1999;10:345–50. 35. Lishner M, Zemlickis D, Degendorfer P, Panzarella T, Sutcliffe SB,  Koren G. et al. Maternal and foetal outcome following Hodgkin’s disease in pregnancy. Br J Cancer 1992;65:114–7. 36. Giacalone PL, Laffargue F, Benos P, Rousseau O, Hedon B. Cisplatin neoadjuvant chemotherapy in a pregnant woman with invasive carcinoma of the uterine cervix. Br J Obstet Gynaecol 1996;103(9):932–4. 37. Caluwaerts S, Van Calsteren K, Mertens L, Lagae L, Moerman P, Hanssens M, et al. Neoadjuvant chemotherapy followed by radical hysterectomy for invasive cervical cancer diagnosed during pregnancy: report of a case and review of the literature. Int J Gynecol Cancer 2006;16:905–8. 38. Benhaim Y, Pautier P, Bensaid C, Lhommé C, Haie-Meder C, Morice P. Neoadjuvant chemotherapy for advanced stage cervical cancer in a pregnant patient: report of one case with rapid tumor progression. Eur J Obstet Gynecol Reprod Biol 2008;136(2):267–8. 39. Palaia I, Pernice M, Graziano M, Bellati F, Panici PB. Neoadjuvant chemotherapy plus radical surgery in locally advanced cervical cancer during pregnancy: a case report. Am J Obstet Gynecol 2007;197(4):e5–6.

22. Missailidis S, ed. Anticancer therapeutics. 1st ed. Chichester, GB: John Wiley & Sons, Ltd.; 2008.

40. Kluetz PG, Edelman MJ. Successful treatment of small cell lung cancer during pregnancy. Lung Cancer 2008;61(1):129–30.

23. Avilés A, Díaz-Maqueo JC, Talavera A, Guzmán R, García EL. Growth and development of children of mothers treated with chemotherapy during pregnancy: current status of 43 children. Am J Hematol 1991;36(4):243–8.

41. Ferrandina G, Distefano M, Testa A De Vincenzo R, Scambia G. Management of an advanced ovarian cancer at 15 weeks of gestation: Case report and literature review. Gynecol Oncol 2005; 97:693–6.

24. Greenberg LH, Verdes P, Tanaka KR. Congenital anomalies probably induced by cyclophosphamide. JAMA 1964;188(5):423–6. 25. Toledo TM, Harper RC, Moser RH. Fetal effects during cyclophosphamide and irradiation therapy. Ann Intern Med 1971;74:87–91. 26. Murray CL, Reichert JA, Anderson J, Twiggs LB. Multimodal cancer therapy for breast cancer in the first trimester of pregnancy. JAMA 1984;252:2607–8. 27. Kirshon B, Wasserstrum N, Willis R, Herman GE, McCabe ER. Teratogenic effects of first-trimester cyclophosphamide therapy. Obstet Gynecol 1988;72(3 Pt2):462–4. 28. Zemlickis D, Lishner M, Erlich R, Koren G. Teratogenicity and carcinogenicity in a twin exposed in utero to cyclophosphamide. Teratog Carcinog Mutagen 1993;13(3):139–43.

42. Karimi-Zarchi M, Behtash N, Modares Gilani M. Good pregnancy outcome after prenatal exposure to bleomycin, etoposide and cisplatin for ovarian immature teratoma: a case report and literature review. Arch Gynecol Obstet 2008;277:75–8. 43. Warkany J. Aminopterin and methotrexate: folic acid deficiency. Teratology 1978;17(3):353–7. 44. Bawle EV, Conard JV, Weiss L. Adult and two children with fetal methotrexate syndrome. Teratology 1998;7:51–5. 45. Buckley LM, Bullboy CA, Leichtman L, Marquez M. Multiple congenital anomalies associated with weekly low dose methotrexate treatment of the mother. Arthritis Rheum 1997;40:971–3. 46. Diniz EM, Corradini HB, Ramos JL, Brock R. Effect of the fetus of methotrexate (amethopterin) istered to the mother. Presentation of a case [article in Portuguese]. Rev Hosp Clin Fac Med Sao Paulo 1978;33:286–90.

MARCH JOGC MARS 2013 l 277

SOGC CLINICAL PRACTICE GUIDELINE

47. Milunsky A, Greaf JW, Gaynor MF Jr. Methotrexate induced congenital malformations. J Pediatr 1968;72:790–5. 48. Powell HR, Ekert H. Methotrexate induced congenital malformations. Med J Aust 1971;2:1076–1077. 49. Dara P, Slater LM, Armentrout SA. Successful pregnancy during chemotherapy for acute leukemia. Cancer 1981;47:845–6. 50. Feliu J, Juarez S, Ordoñez A, Garcia-Paredes ML, Gonzalez-Baron M, Montero JM. Acute leukemia and pregnancy. Cancer 1988;61:580–4.

67. Lishner M. Cancer in pregnancy. Ann Oncol 2003;14(3):iii31–iii36. 68. Pereg D, Koren G, Lishner M. The treatment of Hodgkin and non-Hodgkin’s lymphoma. Haematologica 2007;92:1230–7. 69. Shapira T, Pereg D, Lishner M. How I treat acute and chronic leukemia in pregnancy. Blood Rev 2008;22(5):247–9. 70. Ito S. Drug therapy for breast-feeding women. N Eng J Med 2000;343:118–26.

51. Addar MH. Methotrexate embryopathy in a surviving intrauterine fetus after presumed diagnosis of ectopic pregnancy: a case report. J Obstet Gynaecol Can 2004;26:1001–3.

71. Van Herwaarden AE, Wagenaar E, Merino G, Jonker JW, Rosing H,  Beijnen JH, et al. Multidrug transporter ABCG2/Breast cancer resistance protein secretes riboflavin (vitamin B2) into milk. Mol Cell Biol 2007;27(4):1247–53.

52. Kozlowski RD, Steinbrunner JV, MacKenzie AH, Clough JD, Wilke WS,  Segal AM. Outcome of first trimester exposure to low dose methotrexate in eight patients with rheumatic disease. Am J Med 1990;88:589–92.

72. Egan PC, Costanza ME, Dodion P, Egorin MJ, Bachur NR. Doxorubicin and cisplatin excretion into human milk. Cancer Treat Rep 1985;69:1387–9.

53. Gurumurthy M, Koh P, Sing R, Bhide A, Satodia P, Hocking M, et al. Metastatic non-small-cell lung cancer and the use of gemcitabine during pregnancy. J Perinatol 2009;29:63–5.

73. Gilad BB, Joseph M. Cisplatin excretion in human milk. J Natl Cancer Inst 1992;84: 451–2.

54. Valappl S, Kurkar M, Howell R. Outcome of pregnancy in women treated with all-trans retinoic acid: a case report and review of literature. Hematology 2007;12(5):415–8. 55. Niedermeier DM, Frei-Lahr DA, Hall PD. Treatment of acute myeloid leukemia during the second trimester of pregnancy. Pharmacotherapy 2005;25:1134–40.

74. De Vries EG, van der Zee AG, Uges DR, Sleijfer DT. Excretion of platinum into breast milk. Lancet 1989;1(8636):497. 75. Urien S, Brain E, Bugat R, et al. Pharmacokinetics of platinum after oral or intravenous cisplatin; a phase 1 study in 32 adult patients. Cancer Chemother Pharmacol 2005;55:55–60. 76. Amato D, Niblett JS. Neutropenia from cyclophosphamide in breast milk. Med J Aust 1977;1(11):383–4.

56. Siu BL, Alonzo MR, Varga TA, Ferich AL. Transient dilated cardiomyopathy in a newborn exposed to idarubicin and all-trans-retinoic acid (ATRA) early in the second trimester of pregnancy. Int J Gynecol Cancer 2002;12:399–402.

77. James ID. istration of cyclophosphamide during late pregnancy and early lactation: a case report. J Natl Med Assoc 1979;71:165–6.

57. Achtari C, Hohlfield P. Cardiotoxic transplacental effect of idarubicin istered during the second trimester of pregnancy. Am J Obstet Gynecol 2000;183:511–2.

79. Azuno Y, Kaku K, Fujita N, Okubo M, Kaneko T, Matsumoto N. Mitoxantrone and etoposide in breast milk. Am J Hematol 1995;48:131–2.

58. Claahsen HL, Semmekrot BA, van Dongen PW, Mattijssen V. Successful outcome after exposure to idarubicin and cytosine-arabinoside during second trimester of pregnancy—a case report. Am J Perinatol 1998;15:295–7. 59. Matsuo K, Shimoya K, Ueda S, Wada K, Koyama M, Murata Y. Idarubicin istered during pregnancy: its effect on the fetus. Gynecol Obstet Invest 2004;58:186–8. 60. Mir O, Berveiller P, Goffinet F, Treluyer JM, Serreau R, Goldwasser F,  et al. Taxanes for breast cancer during pregnancy: a systematic review. Ann Oncol 2010;21:425–33. 61. Gonzalez-Angulo AM, Walters RS, Carpenter RJ Jr, Ross MI, Perkins GH, Gwyn K, et al. Paclitaxel chemotherapy in a pregnant patient with bilateral breast cancer. Clin Breast Cancer 2004;5(4):317–9. 62. Pye SM, Cortes J, Ault P, Hatfield A, Kantarjian H, Pilot R, et al. The effects of imatinib on pregnancy outcome. Blood 2008;111:5505–8. 63. Cole S, Kantarjian H, Ault P, Cortes JE. Successful completion of pregnancy in patient with CML without active intervention: a case report and review of the literature. Clin Lymphoma Myeloma 2009;9(4):324–7.

78. Wiernik PH, Duncan JH. Cyclophosphamide in human milk. Lancet 1971;1:912.

80. Kronenberger R, Schleyer E, Bornhä M, Ehninger G, Gattermann N, Blum S. Imatinib in breast milk. Ann Hematol 2009;88:1265–6. 81. Ali R, Ozkalemkas F, Kimya Y, Koksal N, Ozkocaman V, Gulten T, et al. Imatinib use during pregnancy and breast feeding: a case report and review of the literature. Arch Gynecol Obstet 2009;280:169–75. 82. Russell MA, Carpenter MW, Akhtar MS, Lagattuta TF, Egorin MJ. Imatinib mesylate and metabolite concentrations in maternal blood, umbilical cord blood, placenta and breast milk. J Perinatol 2007;27:241–3. 83. Gambacorti-erini CB, Tornaghi L, Marangon E, et al. Imatinib concentrations in human milk. Blood 2007;109:1790. 84. Johns DG, Rutherford L, Leighton PC, Vogel CL. Secretion of methotrexate into human milk. Am J Obstet Gynecol 1972;112:978–80. 85. Tanaka T, Walsh W, Verjee Z, et al. Methotrexate use in a lactating woman with an ectopic pregnancy [abstract]. Birth Defects Res A Clin Mol Teratol 2009;85:494. 86. Nulman I, Laslo D, Fried S, Uleryk E, Lishner M, Koren G. Neurodevelopment of children exposed in utero to treatment of maternal malignancy. Br J Cancer 2001;85:1611–8.

65. Pentheroudakis G. Cancer and pregnancy. Ann Oncol 2008;19(5):v38–v39.

87. Azim HA Jr, Paclidis N, Peccatori FA. Treatment of the pregnant mother with cancer: a systematic review on the use of cytotoxic, endocrne, targeted agents and immunotherapy during pregnancy. Part I and II. Cancer Treat Rev 2010;36:101–21.

66. Pentheroudakis G, Orecchia R, Hoekstra HJ, Pavlidis N; ESMO Guidelines Working Group.et al. Cancer, fertility and pregnancy: ESMO Clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010;21(5):v266–v273.

88. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

64. Chakravarty EF, Murray ER, Kelman A, Farmer P. Pregnancy outcomes after maternal exposure to rituximab. Blood 2011;117(5):1499–506.

278 l MARCH JOGC MARS 2013

SOGC CLINICAL PRACTICE GUIDELINES No. 301, December 2013

Cervical Insufficiency and Cervical Cerclage This clinical practice guideline has been prepared by the Maternal Fetal Medicine Committee, reviewed by the Clinical Practice Obstetrics Committee, and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Richard Brown, MD, Montreal QC Robert Gagnon, MD, Montreal QC Marie- Delisle, MD, Vancouver BC MATERNAL FETAL MEDICINE COMMITTEE Robert Gagnon, MD (Chair), Montreal QC Emmanuel Bujold, MD (Co-Chair), Quebec QC Melanie Basso, RN, Vancouver BC Hayley Bos, MD, London ON Richard Brown, MD, Montreal QC Stephanie Cooper, MD, Calgary AB Joan Crane, MD, St John’s NL Gregory Davies, MD, Kingston ON Katy Gouin, MD, Quebec QC Savas Menticoglou, MD, Winnipeg MB William Mundle, MD, Windsor ON Christy Pylypjuk, MD, Saskatoon SK Anne Roggensack, MD, Calgary AB Frank Sanderson, MD, Saint John NB Vyta Senikas, MD, Ottawa ON Disclosure statements have been received from all contributors. The literature searches and bibliographic for this guideline were undertaken by Becky Skidmore, Medical Research analyst, Society of Obstetricians and Gynaecologists of Canada.

Key words: Cervical insufficiency, cervical incompetence, cervical cerclage, preterm delivery, prematurity, Shirodkar cerclage, MacDonald cerclage, abdominal cerclage, rescue cerclage, cervical shortening, trans-vaginal ultrasound, cervical length

Abstract Objective: The purpose of this guideline is to provide a framework that clinicians can use to determine which women are at greatest risk of having cervical insufficiency and in which set of circumstances a cerclage is of potential value. Evidence: Published literature was retrieved through searches of PubMed or MEDLINE, CINAHL, and The Cochrane Library in 2012 using appropriate controlled vocabulary (e.g., uterine cervical incompetence) and key words (e.g., cervical insufficiency, cerclage, Shirodkar, cerclage, MacDonald, cerclage, abdominal, cervical length, mid-trimester pregnancy loss). Results were restricted to systematic reviews, randomized control trials/ controlled clinical trials, and observational studies. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to January 2011. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technologyrelated agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Values: The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table). Recommendations 01. Women who are pregnant or planning pregnancy should be evaluated for risk factors for cervical insufficiency. A thorough medical history at initial evaluation may alert clinicians to risk factors in a first or index pregnancy. (III-B) 02. Detailed evaluation of risk factors should be undertaken in women following a mid-trimester pregnancy loss or early premature delivery, or in cases where such complications have occurred in a preceding pregnancy. (III-B) 03. In women with a history of cervical insufficiency, urinalysis for culture and sensitivity and vaginal cultures for bacterial vaginosis should be taken at the first obstetric visit and any infections so found should be treated. (I-A) 04. Women with a history of three or more second-trimester pregnancy losses or extreme premature deliveries, in whom no specific cause other than potential cervical insufficiency is identified, should be offered elective cerclage at 12 to 14 weeks of gestation. (I-A)

J Obstet Gynaecol Can 2013;35(12):1115–1127

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

DECEMBER JOGC DÉCEMBRE 2013 l 1115

SOGC Clinical Practice Guidelines

Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.156 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care.156

05. In women with a classic history of cervical insufficiency in whom prior vaginal cervical cerclage has been unsuccessful, abdominal cerclage can be considered in the absence of additional mitigating factors. (II-3C) 06. Women who have undergone trachelectomy should have abdominal cerclage placement. (II-3C) 07. Emergency cerclage may be considered in women in whom the cervix has dilated to < 4 cm without contractions before 24 weeks of gestation. (II-3C) 08. Women in whom cerclage is not considered or justified, but whose history suggests a risk for cervical insufficiency (1 or 2 prior mid-trimester losses or extreme premature deliveries), should be offered serial cervical length assessment by ultrasound. (II-2B) 0 9. Cerclage should be considered in singleton pregnancies in women with a history of spontaneous preterm birth or possible cervical insufficiency if the cervical length is ≤ 25 mm before 24 weeks of gestation. (I-A) 10. There is no benefit to cerclage in a woman with an incidental finding of a short cervix by ultrasound examination but no prior risk factors for preterm birth. (II-1D) 11. Present data do not the use of elective cerclage in multiple gestations even when there is a history of preterm birth; therefore, this should be avoided. (I-D) 12. The literature does not the insertion of cerclage in multiple gestations on the basis of cervical length. (II-1D)

INTRODUCTION

C

ervical insufficiency may be present in up to 1% of obstetric populations, and it therefore represents a concern frequently enough that a guideline to address the dilemmas in its management is overdue. Despite having been part of obstetric practice for over a century, both the

1116 l DECEMBER JOGC DÉCEMBRE 2013

role of cervical cerclage and indications for it remain illdefined and controversial, with wide practice variations in different clinical settings. In part, the lack of clarity that surrounds cerclage is fostered by uncertainty in identifying those patients who will truly benefit from its use (i.e., those with true cervical insufficiency or truly increased risk of early preterm delivery).1,2 Cervical insufficiency has no consistent definition, but is usually characterized by dilatation and shortening of the cervix before the 37th week of gestation in the absence of preterm labour, and is most classically associated with painless, progressive dilatation of the uterine cervix in the second or early third trimester resulting in membrane prolapse, premature rupture of the membranes, midtrimester pregnancy loss, or preterm birth.3,4 Cervical insufficiency arises from the woman’s inability to a full-term pregnancy due to a functional or structural defect of the cervix.1 The incidence of true cervical insufficiency is estimated at less than 1% of the obstetric population. In Denmark from 1980 to 1990, cervical insufficiency was diagnosed in 4.6 per 1000 women,2 and it is estimated to occur in 8% of women with recurrent mid-trimester losses.5 A variety of risk factors have been identified and are divided here into those that may be identified from prior maternal history and those that may arise in the index pregnancy itself. The classic history that raises the suspicion of cervical insufficiency is that of recurrent mid-trimester

Cervical Insufficiency and Cervical Cerclage

pregnancy losses. A previous preterm pre-labour rupture of membranes at less than 32 weeks should be noted, as should a prior pregnancy with a cervical length measurement of less than 25 mm prior to 27 weeks of gestation.6 Any history of prior cervical trauma (e.g. repeated therapeutic abortion, repetitive cervical dilatation, cone biopsy, cervical tears and lacerations, trachelectomy) should also be noted. A risk factor reducing in incidence is that of the mother herself having been exposed to diethylstilbestrol in utero. 6 A variety of other maternal risk factors include the presence of a congenital uterine anomaly or a maternal connective tissue disease or abnormalities, e.g. Ehlers-Danlos syndrome,7 that impacts upon the integrity of normal collagen development and function. Recently, polycystic ovarian syndrome has been suggested as a risk factor for cervical insufficiency, especially in women of South Asian or Black origin.8 In many cases, especially when clinical features and findings lead to suspicion of the diagnosis in the first pregnancy, these risk factors may not be present and the cause may remain idiopathic.9–12 In the index pregnancy, findings indicative of possible cervical insufficiency include cervical funnelling, cervical shortening,12 and overt cervical dilatation.13 Even in the absence of funnelling, a cervical length determined by ultrasound to be < 25 mm prior to 27 weeks10,11 increases the risk of pregnancy loss or preterm birth. Up to 85% of the cervix’s dry weight is collagen. Petersen and Uldbjerg examined cervical collagen in non-pregnant women with previous cervical insufficiency and found that they had markedly lower median cervical hydroxyproline concentrations than parous women without cervical insufficiency.14 The causes of this have yet to be ascertained, but this seems to be a key factor in understanding the mechanism of cervical failure in such cases. In addition to its mechanical strength, the cervix may also play a role in protecting the uterine contents from ascending infection,4,15 with one key factor in this being the role of the cervical mucous as a barrier between the uterus and ascending infection. Data suggest that 80% of cases of acute cervical insufficiency may be associated with intra-amniotic infection.16 DIAGNOSIS OF CERVICAL INSUFFICIENCY

There is no diagnostic test for cervical insufficiency. Although many tests have been reported or are used (assessment of the cervical canal width by hysterosalpingogram, assessment of the ease of insertion of cervical dilators [size 9 Hegar] without resistance, the

force required to withdraw an inflated Foley catheter through the internal os, the force required to stretch the cervix using an intracervical balloon) none of these meet the criteria required for a diagnostic test.17–21 Part of the diagnosis is based upon the exclusion of other causes of preterm delivery or mid-trimester pregnancy loss. In recent practice, transvaginal ultrasonography has been increasingly used as a demonstrably valid and reproducible method of cervical assessment, and cervical shortening correlates with the risk of preterm delivery.12,22–25 Without a reliable diagnostic test, it becomes necessary to screen for or to predict the likelihood of cervical insufficiency. This process is based upon the identification and recognition of key risk factors in the woman’s history and in the index pregnancy. The most common factors in the patient history that indicate she may be at risk are a prior second trimester pregnancy loss or a prior preterm birth. It should be noted, however, that although in some situations there may be a continuum between cervical insufficiency and preterm labour and delivery, in others these are distinct and unrelated processes. A history of preterm labour or the identification of factors that increase the risk for preterm birth do not always necessarily indicate risk for cervical insufficiency.26,27 A history of prior cervical surgery, e.g. loop electrosurgical excision procedure (LEEP), may also present a risk for cervical insufficiency. In such patients there may also be a role for cervical length assessment by ultrasound. In patients who have had a prior LEEP, a 30 mm cervical length has a positive predictive value for preterm birth of 54%, but a negative predictive value of 95%.23 However, because of the low overall frequency of cervical insufficiency even in this group, some data do not the routine use of mid-trimester ultrasound in such women.23 Other forms of cervical trauma, for example cervical tears, may also be significant.28 Less frequent in current practice is the identification of women who were exposed to diethylstilboestrol when in utero themselves.29–31 The key finding in the current pregnancy is the identification of cervical shortening. Cervical length assessment by ultrasound is an established means of assessing the risk for preterm labour and delivery (cervical length < 25 mm).11,12,22,25,32,33 Patients may also be found to have cervical dilatation rather than just shortening, or they may present with preterm membrane rupture. Identification of cervical dilatation in DECEMBER JOGC DÉCEMBRE 2013 l 1117

SOGC Clinical Practice Guidelines

the absence of a maternal history of contractions, with or without membrane rupture, is considered tantamount to a diagnosis of cervical insufficiency. Models based on the recognition of these two main risk factors (cervical shortening and cervical dilatation) have been described and may be of value in determining which patients are at greatest risk, but further assessment of such screening tools is required.34 Recommendations

1. Women who are pregnant or planning pregnancy should be evaluated for risk factors for cervical insufficiency. A thorough medical history at initial evaluation may alert clinicians to risk factors in a first or index pregnancy. (III-B) 2. Detailed evaluation of risk factors should be undertaken in women following a mid-trimester pregnancy loss or early premature delivery, or in cases where such complications have occurred in a preceding pregnancy. (III-B) MANAGEMENT OF CERVICAL INSUFFICIENCY

The management of cervical insufficiency can be viewed as falling broadly into two main types: those in which it is clear that surgical intervention in the form of cerclage is indicated, and those in which a conservative path will be pursued. Indications for the insertion of a cerclage may arise from the clinical history or the finding of cervical shortening and/or dilatation in the index pregnancy, and therefore may be divided into prophylactic cerclage versus therapeutic cerclage. Alternatives to cerclage include the cervical pessary; some data suggest this may be of benefit in some cases, but these data are sparse and conflicting. Further investigation of such techniques is required before they can be considered as part of a guideline for the management of cervical insufficiency.35 Prophylactic Transvaginal Cerclage

Consider elective cerclage if there appears to be a high risk of cervical insufficiency based on the woman’s obstetric history. The level of risk is typically determined by identifying and assessing the significance of the risk factors described in the “Diagnosis of Cervical Insufficiency” section. Most frequently the assessment of risk will be founded upon a history of second-trimester pregnancy losses or early preterm deliveries in the absence of other mitigating risk factors.36–38 Therefore a detailed evaluation of risk factors should be undertaken in women presenting with a history of a mid-trimester pregnancy loss or early premature delivery. 1118 l DECEMBER JOGC DÉCEMBRE 2013

Data from the UK  MRC/RCOG  RCT36 did not demonstrate the benefit of cerclage after 1 or 2 prior deliveries preceding 33 weeks’ gestation; however, the numbers were small and this might have had an impact on the observed effect, particularly in the case of midtrimester losses as opposed to premature deliveries. The benefit of cerclage after 2 or 3 mid-trimester losses alone, as opposed to losses and deliveries up to and including 33 weeks, is undefined. The findings of this UK study might be influenced by the inclusion of cases in which the treating obstetrician was unsure that the cerclage would be of benefit. However, other smaller studies also failed to demonstrate the benefit of cerclage.37,38 A recent Cochrane review analyzed data from 12 studies of women considered at sufficient risk to justify cerclage who were randomized to cerclage, alternative treatments (e.g., progesterone), or no treatment. This analysis presents somewhat conflicting findings in reporting that cerclage has a statistically significant effect on reducing gestational age at delivery and no significant impact on perinatal morbidity and mortality, but it is associated with increased maternal morbidity and Caesarean section rates (the latter perhaps also ing for a non-significant increase in respiratory morbidity amongst infants born to women with a cerclage).39 A prophylactic cerclage is normally placed between 12 and 14 weeks’ gestation. Although placement can be delayed, the gestational age of prior pregnancy losses should be taken into , particularly in women whose losses present at progressively earlier gestations. Prerequisites for prophylactic cerclage placement

Prior to placement of a cerclage it is essential to confirm the viability of the pregnancy by ultrasound. It is wise therefore, at the same time to exclude significant malformations and determine whether there is a significantly elevated aneuploidy risk by first trimester ultrasound nuchal translucency screening, if possible combined with serum marker screening. In cases found to be at elevated risk for aneuploidy or with fetal malformations, placement may be delayed until after karyotype results are obtained (using chorionic villus sampling for earlier karyotype determination than amniocentesis, where available) or until a more detailed ultrasound assessment is performed. Before ission for cerclage, urinalysis for culture and sensitivity and vaginal cultures for bacterial vaginosis should be taken and any infections found should be treated.16,40–46 Microbial invasion of the amniotic cavity has been reported to occur in around 50% of women with cervical insufficiency and exposed fetal membranes.45,47 Amniocentesis has therefore been suggested for evaluating and treating such colonization

Cervical Insufficiency and Cervical Cerclage

prior to cerclage placement; however, no clear benefit in prolonging pregnancy has been shown for amniocentesis over cerclage alone, and therefore its routine use is not advised.48 Cerclage techniques and materials

The two main techniques of transvaginal cerclage involve the MacDonald approach and the Shirodkar approach. In the McDonald approach the suture is inserted as close as possible to the junction of the cervix with the vagina, with no dissection of tissue planes.49 In the Shirodkar approach a subepithelial suture is inserted above the junction of the cervix with the vagina with dissection of the bladder and rectum; this allows for higher placement (closer to the internal cervical os) of the suture than the McDonald approach.50 There are no data to indicate an advantage of one technique over another, so the choice between a McDonald approach or modification thereof or a Shirodkar approach or modification thereof should be left to the discretion and skills of the surgeon.51–55 Both techniques, influenced by patient selection, are associated with an increased Caesarean section rate, which is perhaps marginally higher following the Shirodkar approach, although this data has not been replicated.56 Two forms of double cerclage are also described. The first simply involves the insertion of two cervical cerclages in an attempt to buttress the cervix more strongly. This has been shown to be of no benefit.57 In the second double cerclage, a second occlusive suture is placed at the external os to retain the mucous plug and help the cervix maintain itself as a barrier to infection. Only limited data regarding this are available at present.58 No data indicate any advantage or disadvantage of particular suture materials. The most frequently used is a braided Mersilene tape, although some surgeons use Prolene. Meshes are also reportedly used, but no comparisons have been made with existing techniques.59,60 There are data indicating that delayed absorbable suture materials may also be used, but the benefits or disadvantages of different materials still require greater evaluation.61 Unless it is contraindicated, regional anaesthesia is usually preferred to general anaesthesia in light of its lesser associated risks.62,63 It should be noted that for prophylactic cerclage, no randomized trials have presented findings free of confounding variables to the routine use of tocolytics,64,65 corticosteroids, or antibiotics,66–68 although for cerclages placed in gestations close to fetal viability, corticosteroid usage should be considered. Similarly, data on the use of progesterone in women who have a

cerclage in place are limited. The use of progesterone with cerclage is not new, but despite more recent data for the use of progesterone therapy in women at risk of preterm delivery, overall data do not presently this approach. Although one early study implied a benefit to progesterone, it was an uncontrolled cohort study,69 and a contemporaneous controlled cohort evaluation demonstrated a reduction in hospital ission, but not in the rate of pregnancy loss.70 A more recent study of 17-alpha-hydroxyprogesterone caproate in women with cerclage essentially demonstrated no advantage, although this study was retrospective and the criteria for cerclage placement were ill-defined.71 Two further studies also indicated that 17-alpha-hydroxyprogesterone caproate injections do not provide additional benefit for the prevention of preterm birth in women who received an ultrasound-indicated cerclage.72,73 There are no specific data comparing the efficacy of systemic and vaginal progesterones in women with a cerclage in place. Complications

Three randomized clinical trials have shown that cerclage is associated with increased medical interventions and doubles the risk of puerperal pyrexia.36–38 The use of tocolytics increases with cerclage, as does the rate of hospital issions, and one study found a higher rate of Caesarean sections.37 However, the risk and nature of complications is influenced by whether the cerclage is inserted electively or as an emergency with membranes bulging through the cervix. The complications reported with cerclage include sepsis, premature rupture of membranes, premature labour, cervical dystocia, cervical laceration at delivery (11% to 14%),74–76,77 and hemorrhage. However, meta-analysis of a number of studies has not confirmed higher rates of chorioamnionitis or preterm pre-labour membrane rupture in women managed with cerclage than in those managed by other means.78 Although cervical dystocia is frequently cited as a complication of cerclage due to cervical scarring,79 data do not its being truly attributable to cerclage80; the increased risk of cervical laceration, however, although it appears to be unrelated to the timing of the removal of the cerclage, can be attributed to the cerclage.74–76,81 Recommendations

3. In women with a history of cervical insufficiency, urinalysis for culture and sensitivity and vaginal cultures for bacterial vaginosis should be taken at the first obstetric visit and any infections so found should be treated. (I-A)

DECEMBER JOGC DÉCEMBRE 2013 l 1119

SOGC Clinical Practice Guidelines

4. Women with a history of three or more second trimester pregnancy losses or extreme premature deliveries, in whom no specific cause other than potential cervical insufficiency is identified, should be offered elective cerclage at 12 to 14 weeks of gestation. (I-A) Cerclage follow-up

Lengthening of the cervix following cerclage has been observed, and the immediate assessment of the cervix following suture placement may correlate with gestational age at delivery82–84; however, the data are inconsistent on the efficacy of continued cervical length assessment post cerclage in determining when delivery might occur.85,86 This is somewhat ed by the inconsistency in studies evaluating whether the placement of a second suture is beneficial in women whose cervix is found to shorten further post cerclage placement, with two studies demonstrating contradictory effects of such a measure.87,88 Therefore at present routine post-cerclage follow-up by ultrasound is not recommended. The positive predictive value of fibronectin as a predictor of preterm delivery appears to be adversely affected by a cerclage, although the negative predictive value is not.89 Removal of cerclage

The cerclage is generally removed electively at 36 to 38 weeks’ gestation. Removal can usually be performed without anaesthesia or with only short-acting narcotics, such as Fentanyl istered intravenously. The onset of premature labour unresponsive to tocolysis and or a strong suspicion of sepsis are indications for emergency removal of the cerclage. A number of studies have addressed the question of cerclage removal with premature membrane rupture and no associated contractions. Meta-analysis has shown an increased neonatal mortality rate with delayed removal, with sepsis the principal cause; therefore a policy of removal within 48 hours (allowing time for corticosteroid istration if appropriate) is advocated.90–93 C-reactive protein estimation may be used as a predictor of chorioamnionitis following preterm membrane rupture and may therefore aid the decision between immediate or delayed (< 48 hours) suture removal.94,95 Incidentally, it should be noted that clear documentation of the cerclage placement, specifically knot placement and number, will facilitate the removal of the cerclage prior to delivery. Prophylactic Transabdominal Cerclage

In women with a good history of cervical insufficiency in whom prior vaginal cerclage has been unsuccessful, abdominal cerclage can be considered in the absence of 1120 l DECEMBER JOGC DÉCEMBRE 2013

additional mitigating factors.96–100 This should also be considered for women who have undergone trachelectomy or who have had an effective trachelectomy.101,102 The placement of an abdominal suture may be undertaken by either laparoscopic or open surgical techniques. The former is generally preferred in current practice,103,104 although both techniques are associated with higher maternal morbidity than a transvaginal cerclage approach. Abdominal cerclage should be undertaken by a surgeon experienced in the placement of such sutures. A prophylactic abdominal cerclage is often inserted at the same time as a trachelectomy is performed in women of reproductive age who plan to pursue the option of childbirth.105 Recommendations

5. In women with a classic history of cervical insufficiency in whom prior vaginal cerclage has been unsuccessful, abdominal cerclage can be considered in the absence of additional mitigating factors. (II-3C) 6. Women who have undergone trachelectomy should have abdominal cerclage placement. (II-3C) Emergency Cerclage

An emergency (or salvage or rescue) cerclage is typically one placed in a woman whose cervix is already dilated. Emergency should be considered when there is clinical or sonographic identification of a cervix dilated > 1 to 2 cm with no perceived uterine contractions (with or without membranes bulging through the external os).106,107 It is important to note that there must be no clinical evidence of chorioamnionitis. Although some groups advocate amniocentesis prior to emergency cerclage in order to both exclude infection and aid in reducing intrauterine pressure, no randomized studies confirm the effect of this approach.108,109 A small randomized clinical trial has shown prolongation of pregnancies by 4 weeks with emergency cerclage placement,110 and other observational studies have reported pregnancy prolongation of between 6 and 9 weeks with emergency cerclage placement compared with under 4 weeks with conservative management (bed rest).111–114 Scoring systems have been considered to evaluate which cases will benefit from emergency cerclage (based on cervical effacement, dilatation, and membrane prolapse).115,116 The benefit of cerclage even with cervical dilatation to 4 cm has been shown and should be considered, and the scoring systems can be used to counsel patients about the likely outcome of undergoing emergency cerclage. Adjunctive measures

The istration of a course of indomethacin prior to cerclage placement might reduce protruding membranes

Cervical Insufficiency and Cervical Cerclage

through its effect on reducing fetal urine production (thereby reducing intrauterine pressure) and through its tocolytic value.110 Bed rest with or without Trendelenburg may further help to reduce bulging membranes and facilitate suture placement, as may using a Foley balloon inserted into the cervix and then inflated to mechanically reduce the membranes.117 Broad-spectrum antibiotic coverage is usually prescribed, although there are no data to this. Amniocentesis may have a greater role to play in emergency cerclage than in prophylactic cerclage. The first potential benefit of amniocentesis in emergency cases is in identifying those women who may not benefit from cerclage, based upon evidence of infection109 or on a more complex evaluation of proteonomic markers that investigates infection as well as other factors believed to affect the efficacy of cerclage.109,118 Its second benefit is in removing a larger volume of amniotic fluid (cf. amniodrainage), permitting bulging membranes to withdraw into the cervix by reducing intrauterine pressure and thereby facilitating cerclage placement.119–121 Cerclage removal

The criteria for removal of an emergency cerclage are the same as for a prophylactic cerclage. Recommendation

7. Emergency cerclage may be considered in women in whom the cervix has dilated to < 4 cm without contractions before 24 weeks of gestation. (II-3C) Cervical Pessary

The use of pessaries in the management of cervical insufficiency or preterm delivery is not new, with the use of a glass pessary having first been described in 1977.122 Since then various designs and materials have been used and reported.123–129 Although many of these reports and reviews showed promise, a Cochrane review found no studies suitable for inclusion in an analysis of the benefits of this technique.35 Since then a number of studies have been undertaken, some of which are still in progress. Two recent studies have again suggested a benefit of cervical pessaries in the management of cervical insufficiency, preterm delivery, or short cervix.130,131 However, to date the data ing such techniques in the routine management of cervical insufficiency remain insufficient. CONSERVATIVE OBSERVATIONAL MANAGEMENT

A conservative strategy including cervical length assess­ ment may be adopted in the management of women considered to have cervical insufficiency, but whose

history is not considered to indicate enough risk to warrant immediate prophylactic cerclage.132 In such women, ultrasound cervical length assessment will identify a cohort who is at increased risk of a further pregnancy loss or preterm delivery, some of whom may then benefit from the subsequent placement of a cerclage. Conservative management should be based on and include the following steps: 1. Urine for culture and sensitivity and vaginal cultures for bacterial vaginosis40–42 should be taken at the first obstetric visit, and any infections found should be treated.16,40–46 2. Serial transvaginal ultrasonography should be performed every 7 to 14 days from 16 weeks of gestation or at least 2 weeks prior to the gestational age of the earliest preceding pregnancy loss.133 3. Consider advising the patient to reduce physical activity, especially those with physical employment, prolonged periods of standing, or frequent and repetitive lifting, although there are no data to confirm or deny the efficacy of bed rest in such cases.134 4. Strongly encourage the cessation of smoking with referral to programs. 5. Beyond 23 weeks consider the prophylactic use of corticosteroids if there are signs or symptoms suggestive of an increased risk of preterm delivery. Ultrasound assessment of cervical length

Ultrasound has been shown reliably and reproducibly to allow estimation of cervical length. The length of the cervix as measured by ultrasound has in turn been demonstrated to be a useful tool in the prediction of the risk of preterm delivery.12,25,33,135 Transvaginal ultrasonography is the gold standard technique of assessment, but if this cannot be performed then an assessment may be made either abdominally or transperineally.136 Assessment of the cervix typically reports the cervical length and identifies any evidence of cervical funnelling. Although funnelling is typically reported when the cervix is assessed, it should be noted that data do not the placement of a cerclage on the basis of funnelling, but rather on residual cervical length.12 Transfundal pressure created by applying fundal pressure in the direction of the uterine axis for 15 seconds is more effective than coughing or standing in eliciting cervical changes and signs of progressive second trimester cervical shortening during active assessment of the cervix.137–139 DECEMBER JOGC DÉCEMBRE 2013 l 1121

SOGC Clinical Practice Guidelines

Flow diagram

Women with prior history suggestive of cervical insufficiency or presenting with cervical shortening or dilatation in the absence of contractions

Women presenting in the first or early second trimester with 3 or more mid-trimester losses or preterm births

Vaginal cerclage

Consider abdominal suture if previous vaginal cerclage unsuccessful or if inadequate cervical tissue to place cerclage

Cervix more than 1 cm dilated

1 or 2 mid-trimester losses or pretem deliveries

Expectant management Serial cervical length assessment

If no chorioamnionitis or contractions consider emergency cerclage Consider steroids depending on gestational age

If contracting manage as threatened preterm labour Consider tocolysis and steroids depending on the gestational age

If cervical length below 2.5 cm at less than 24 weeks, consider cervical cerclage OR progesterone therapy

Recommendations

8. Women in whom cerclage is not considered or justified, but whose history suggests a risk for cervical insufficiency (1 or 2 prior mid-trimester losses or extreme premature deliveries), should be offered serial cervical length assessment by ultrasound. (II-2B) Cerclage Based on Ultrasound Measurement of Cervical Length

Data do not the placement of a cerclage in women in whom there is an incidental finding by ultrasound of cervical shortening (≤ 25 mm) and who are not otherwise considered to be at risk of mid trimester loss or of preterm delivery.140–142 Women considered to be at risk (because, e.g., of a history of mid-trimester loss or early preterm delivery) should be offered cerclage if their cervical length is ≤ 25 mm before 24 weeks of gestation.140,143–147 Recommendations

9. Cerclage should be considered in singleton pregnancies in women with a history of spontaneous preterm birth or possible cervical

1122 l DECEMBER JOGC DÉCEMBRE 2013

insufficiency if the cervical length is ≤ 25 mm before 24 weeks of gestation. (I-A) 10. There is no benefit to cerclage in a woman with an incidental finding of a short cervix by ultrasound examination but no prior risk factors for preterm birth. (II-1D) Progesterone

Progesterones have been used historically and more recently in the prevention of preterm birth. The possible efficacy of progesterones in cervical insufficiency has often been extrapolated from that in preterm birth, but this may not be appropriate. At present no data the use of progesterone together with cerclage. The data comparing cerclage and progesterone in isolation are limited and perhaps inapplicable to the question of using progesterones for cervical insufficiency. One study reported no significant difference in the rate of preterm birth between women treated with progesterone or by cerclage; however, the indication for intervention was a short cervix on ultrasound screening, and by the criteria presented in this guideline, cerclage would not have been

Cervical Insufficiency and Cervical Cerclage

indicated in many of the cases included.148 However, a study evaluating the effects of progesterone on cervical length in women considered at risk of preterm birth suggests that progesterone helps preserve cervical length,70 and thereby reduces the risk of preterm birth; this finding also s the use of vaginal progesterones.149,150 The role of progesterone in mid-trimester loss remains unclear, therefore its routine use is not recommended and further evaluation is needed. Further information regarding the use of progesterones to prevent preterm birth may be found in the SOGC guideline, “The Use of Progesterone for Prevention of Preterm Birth.”151 Multiple Gestations

Because twins and higher-order multiple gestations are at increased risk of preterm delivery, it has been speculated that cerclage placement may improve their perinatal outcomes. However, elective cerclage placement in multiple pregnancies without additional risk factors has not been shown to benefit pregnancy outcomes in this group.152 Furthermore, although ultrasound cervical length assessment in this group may predict an increased risk of early delivery,153 in contrast to singleton gestations, data have shown no benefit in the placement of cerclage in multiple gestations with ultrasound-identified cervical shortening.143,154,155 Indeed, a meta-analysis has shown a relative risk increase of 2.15 for preterm delivery (< 35 weeks) in such pregnancies with an ultrasound-indicated (cervical length < 25 mm) cerclage.143 Recommendations

11. Present data do not the use of elective cerclage in multiple gestations even when there is a history of preterm birth; therefore, this should be avoided. (I-D) 12. The literature does not the insertion of cerclage in multiple gestations on the basis of cervical length. (II-1D) SUMMARY

The decision on how best to minimize the risk of recurrent mid-trimester pregnancy loss (loss between 14 and 26 weeks) or extreme preterm birth in women who are deemed at increased risk, either by virtue of their medical history or the findings of a short or dilated cervix, should be personalized, based on the clinical circumstances, the skills and expertise of the clinical team, and the woman’s informed consent (Figure). REFERENCES 1. Rand L, Norwitz ER. Current controversies in cervical cerclage. Semin Perinatol 2003;27:73–85.

2. Lidegaard O. Cervical incompetence and cerclage in Denmark 1980-1990. A based epidemiological survey. Acta Obstet Gynecol Scand 1994;73:35–8. 3. McDonald IA. Incompetence of the cervix. Aust N Z J Obstet Gynaecol 1978;18:34-7. 4. Shennan A, Jones B. The cervix and prematurity: aetiology, prediction and prevention. Semin Fetal Neonatal Med 2004;9:471–9. 5. Drakeley AJ, Roberts D, Alfirevic Z. Cervical stitch (cerclage) for preventing pregnancy loss in women. Cochrane Database Syst Rev. 2003:CD003253. 6. Althuisius SM, Dekker GA, Hummel P, Bekedam DJ, van Geijn HP. Final results of the Cervical Incompetence Prevention Randomized Cerclage Trial (CIPRACT): therapeutic cerclage with bed rest versus bed rest alone. Am J Obstet Gynecol 2001;185:1106–12. 7. De Vos M, Nuytinck L, Verellen C, De Paepe A. Preterm premature rupture of membranes in a patient with the hypermobility type of the Ehlers-Danlos syndrome. A case report. Fetal Diagn Ther 1999;14:244–7. 8. Feigenbaum SL, Crites Y, Hararah MK, Yamamoto MP, Yang J, Lo JC. Prevalence of cervical insufficiency in polycystic ovarian syndrome. Hum Reprod 2012;27:2837–42. 9. Drakeley AJ, Quenby S, Farquharson RG. Mid-trimester loss—appraisal of a screening protocol. Hum Reprod 1998;13:1975–80. 10. Odibo AO, Talucci M, Berghella V. Prediction of preterm premature rupture of membranes by transvaginal ultrasound features and risk factors in a high-risk population. Ultrasound Obstet Gynecol 2002;20:245–51. 11. Owen J, Yost N, Berghella V, Thom E, Swain M, Dildy GA 3rd, et al. Mid-trimester endovaginal sonography in women at high risk for spontaneous preterm birth. JAMA 2001;286:1340–8. 12. To MS, Skentou C, Liao AW, Cacho A, Nicolaides KH. Cervical length and funneling at 23 weeks of gestation in the prediction of spontaneous early preterm delivery. Ultrasound Obstet Gynecol 2001;18:200–3. 13. Leitich H, Brunbauer M, Kaider A, Egarter C, Husslein P. Cervical length and dilatation of the internal cervical os detected by vaginal ultrasonography as markers for preterm delivery: a systematic review. Am J Obstet Gynecol 1999;181:1465–72. 14. Petersen LK, Uldbjerg N. Cervical collagen in non-pregnant women with previous cervical incompetence. Eur J Obstet Ggynecol Reprod Biol 1996;67:41–5. 15. Ugwumadu A. Chorioamnionitis and mid-trimester pregnancy loss. Gynecol Obstet Invest 2010;70:281–5. 16. Lee SE, Romero R, Park CW, Jun JK, Yoon BH. The frequency and significance of intraamniotic inflammation in patients with cervical insufficiency. Am J Obstet Gynecol 2008;198:633e1–e8. 17. Block MF, Rahhal DK. Cervical incompetence. A diagnostic and prognostic scoring system. Obstet Gynecol 1976;47:279–81. 18. Toaff R, Toaff ME, Ballas S, Ophir A. Cervical incompetence: diagnostic and therapeutic aspects. Isr J Med Sci 1977;13:39–49. 19. Zlatnik FJ, Burmeister LF, Feddersen DA, Brown RC. Radiologic appearance of the upper cervical canal in women with a history of premature delivery. II. Relationship to clinical presentation and to tests of cervical compliance. J Reprod Med 1989;34:525–30. 20. Zlatnik FJ, Burmeister LF. Interval evaluation of the cervix for predicting pregnancy outcome and diagnosing cervical incompetence. J Reprod Med 1993;38:365–9. 21. Anthony GS, Walker RG, Robins JB, Cameron AD, Calder AA. Management of cervical weakness based on the measurement of cervical resistance index. Eur J Obstet Gynecol Reprod Biol 2007;134:174–8. 22. Domin CM, Smith EJ, Terplan M. Transvaginal ultrasonographic measurement of cervical length as a predictor of preterm birth: a systematic review with meta-analysis. Ultrasound Q 2010;26:241–8.

DECEMBER JOGC DÉCEMBRE 2013 l 1123

SOGC Clinical Practice Guidelines

23. Fischer RL, Sveinbjornsson G, Hansen C. Cervical sonography in pregnant women with a prior cone biopsy or loop electrosurgical excision procedure. Ultrasound Obstet Gynecol 2010;36:613–7.

44. Hassan S, Romero R, Hendler I, Gomez R, Khalek N, Espinoza J, et al. A sonographic short cervix as the only clinical manifestation of intraamniotic infection. J Perinat Med 2006;34:13–9.

24. Rust OA, Atlas RO, Reed J, van Gaalen J, Balducci J. Revisiting the short cervix detected by transvaginal ultrasound in the second trimester: why cerclage therapy may not help. Am J Obstet Gynecol 2001;185:1098–105.

45. Bujold E, Morency AM, Rallu F, Ferland S, Tetu A, Duperron L, et al. Bacteriology of amniotic fluid in women with suspected cervical insufficiency. J Obstet Gynaecol Can 2008;30:882–7.

25. Visintine J, Berghella V, Henning D, Baxter J. Cervical length for prediction of preterm birth in women with multiple prior induced abortions. Ultrasound Obstet Gynecol 2008;31:198–200. 26. Iams JD, Johnson FF, Sonek J, Sachs L, Gebauer C, Samuels P. Cervical competence as a continuum: a study of ultrasonographic cervical length and obstetric performance. Am J Obstet Gynecol 1995;172:1097–103; discussion 104–6. 27. Vidaeff AC, Ramin SM. From concept to practice: the recent history of preterm delivery prevention. Part I: cervical competence. Am J Perinatol 2006;23:3–13. 28. Lees DH, Sutherst JR. The sequelae of cervical trauma. Am J Obstet Gynecol 1974;120:1050–4. 29. Berger MJ, Goldstein DP. Impaired reproductive performance in DES-exposed women. Obstet Gynecol 1980;55:25–7. 30. Ludmir J, Landon MB, Gabbe SG, Samuels P, Mennuti MT. Management of the diethylstilbestrol-exposed pregnant patient: a prospective study. Am Obstet Gynecol 1987;157:665–9. 31. Singer MS, Hochman M. Incompetent cervix in a hormone-exposed offspring. Obstet Gynecol 1978;51:625–6. 32. Moragianni VA, Aronis KN, Craparo FJ. Biweekly ultrasound assessment of cervical shortening in triplet pregnancies and the effect of cerclage placement. Ultrasound Obstet Gynecol 2011;37:617–8. 33. Owen J, Yost N, Berghella V, Maherson C, Swain M, Dildy GA 3rd, et al. Can shortened midtrimester cervical length predict very early spontaneous preterm birth? Am J Obstet Gynecol 2004;191:298–303. 34. Odibo AO, Farrell C, Macones GA, Berghella V. Development of a scoring system for predicting the risk of preterm birth in women receiving cervical cerclage. J Perinatol 2003;23:664–7. 35. Abdel-Aleem H, Shaaban OM, Abdel-Aleem MA. Cervical pessary for preventing preterm birth. Cochrane Database Syst Rev. 2010:CD007873. 36. Final report of the Medical Research Council/Royal College of Obstetricians and Gynaecologists multicentre randomised trial of cervical cerclage. MRC/RCOG Working Party on Cervical Cerclage. Br J Obstet Gynaecol 1993;100:516–23. 37. Lazar P, Gueguen S, Dreyfus J, Renaud R, Pontonnier G, Papiernik E. Multicentred controlled trial of cervical cerclage in women at moderate risk of preterm delivery. Br J Obstet Gynaecol 1984;91:731–5. 38. Rush RW, Isaacs S, Mherson K, Jones L, Chalmers I, Grant A. A randomized controlled trial of cervical cerclage in women at high risk of spontaneous preterm delivery. Br J Obstet Gynaecol 1984;91:724–30. 39. Alfirevic Z, Stampalija T, Roberts D, Jorgensen AL. Cervical stitch (cerclage) for preventing preterm birth in singleton pregnancy. Cochrane Database Syst Rev. 2012;4:CD008991. 40. Leitich H, Bodner-Adler B, Brunbauer M, Kaider A, Egarter C, Husslein P. Bacterial vaginosis as a risk factor for preterm delivery: a meta-analysis. Am J Obstet Gynecol 2003;189:139–47. 41. Leitich H, Brunbauer M, Bodner-Adler B, Kaider A, Egarter C, Husslein P. Antibiotic treatment of bacterial vaginosis in pregnancy: a meta-analysis. Am J Obstet Gynecol 2003;188:752–8. 42. Matijevic R, Grgic O, Knezevic M. Vaginal pH versus cervical length in the mid-trimester as screening predictors of preterm labor in a low-risk population. Int J Gynaecol Obstet 2010;111:41–4. 43. Ankirskaia AS, Demidova EM, Zemlianaia AA, Nikonov AP. [Genital mycoplasma as a risk factor of obstetric and perinatal pathology]. Vestnik Akademii meditsinskikh nauk SSSR 1991:17–9.

1124 l DECEMBER JOGC DÉCEMBRE 2013

46. Oh KJ, Lee SE, Jung H, Kim G, Romero R, Yoon BH. Detection of ureaplasmas by the polymerase chain reaction in the amniotic fluid of patients with cervical insufficiency. J Perinat Med 2010;38:261–8. 47. Romero R, Gonzalez R, Sepulveda W, Brandt F, Ramirez M, Sorokin Y, et al. Infection and labor. VIII. Microbial invasion of the amniotic cavity in patients with suspected cervical incompetence: prevalence and clinical significance. Am J Obstet Gynecol 1992;167:1086–91. 48. Airoldi J, Pereira L, Cotter A, Gomez R, Berghella V, Prasertcharoensuk W, et al. Amniocentesis prior to physical exam-indicated cerclage in women with midtrimester cervical dilation: results from the expectant management compared to physical exam-indicated cerclage international cohort study. Am J Perinatol 2009;26:63–8. 49. McDonald IA. Suture of the cervix for inevitable miscarriage. J Obstet Gynaecol Br Emp 1957;64:346–50. 50. Shirodkar VN. A new method of operative treatment for habitual abortion in the second trimester of pregnancy. Antiseptic 1955;52:299–300. 51. The Shirodkar stitch. Lancet. 1977;2:691–2. 52. Branch DW. Operations for cervical incompetence. Clin Obstet Gynecol 1986;29:240–54. 53. Caspi E, Schneider DF, Mor Z, Langer R, Weinraub Z, Bukovsky I. Cervical internal os cerclage: description of a new technique and comparison with Shirodkar operation. Am J Perinatol 1990;7:347–9. 54. Druzin ML, Berkeley AS. A simplified approach to Shirodkar cerclage procedure. Surg Gynecol Obstet 1986;162:375–6. 55. Odibo AO, Berghella V, To MS, Rust OA, Althuisius SM, Nicolaides KH. Shirodkar versus McDonald cerclage for the prevention of preterm birth in women with short cervical length. Am J Perinatol 2007;24:55–60. 56. Harger JH. Comparison of success and morbidity in cervical cerclage procedures. Obstet Gynecol 1980;56:543–8. 57. Woensdregt K, Norwitz ER, Cackovic M, Paidas MJ, Illuzzi JL. Effect of 2 stitches vs 1 stitch on the prevention of preterm birth in women with singleton pregnancies who undergo cervical cerclage. Am J Obstet Gynecol 2008;198:396e1–e7. 58. Secher NJ, McCormack CD, Weber T, Hein M, Helmig RB. Cervical occlusion in women with cervical insufficiency: protocol for a randomised, controlled trial with cerclage, with and without cervical occlusion. BJOG 2007;114:649e1–e6. 59. Brodman ML, Friedman F Jr., Morrow JD, Stone J. Wide-band transabdominal cerclage for a foreshortened, incompetent cervix. Obstet Gynecol 1994;84:704–6. 60. Luznik M. Use of mesh cerclage in prevention of early preterm delivery: a promising new surgical method for women with dilated cervix and membrane herniation? Wiener klinische Wochenschrift. 006;118(Suppl 2):76–9. 61. Abdelhak YE, Sheen JJ, Kuczynski E, Bianco A. Comparison of delayed absorbable suture v nonabsorbable suture for treatment of incompetent cervix. J Perinat Med 1999;27:250–2. 62. Goodman S. Anesthesia for nonobstetric surgery in the pregnant patient. Semin Perinatol 2002;26:136–45. 63. Paech M. Regional analgesia and anaesthesia. In: Russell R, editor. Anaesthesia for obstetrics and gynaecology. London: BMJ Publishing Group; 2008. p. 109–77. 64. Locci M, Nazzaro G, Merenda A, Pisaturo ML, Laviscio P, Poppiti R, et al. Atosiban vs ritodrine used prophylactically with cerclage in ICSI pregnancies to prevent pre-term birth in women identified as being at high risk on the basis of transvaginal ultrasound scan. J Obstet Gynaecol 2006;26:396–401.

Cervical Insufficiency and Cervical Cerclage

65. Visintine J, Airoldi J, Berghella V. Indomethacin istration at the time of ultrasound-indicated cerclage: is there an association with a reduction in spontaneous preterm birth? Am J Obstet Gynecol. 2008;198:643e1–e3.

86. Andersen HF, Karimi A, Sakala EP, Kalugdan R. Prediction of cervical cerclage outcome by endovaginal ultrasonography. Am J Obstet Gynecol 1994;171:1102–6.

66. Charles D, Edwards WR. Infectious complications of cervical cerclage. Am J Obstet Gynecol 1981;141:1065–71.

87. Baxter JK, Airoldi J, Berghella V. Short cervical length after historyindicated cerclage: is a reinforcing cerclage beneficial? Am J Obstet Gynecol 2005;193:1204–7.

67. Kessler I, Shoham Z, Lancet M, Blickstein I, Yemini M, Miskin A, et al. Complications associated with genital colonization in pregnancies with and without cerclage. Int J Gynaecol Obstet 1988;27:359–63. 68. Shiffman RL. Continuous low-dose antibiotics and cerclage for recurrent second-trimester pregnancy loss. J Reprod Med 2000;45:323–6. 69. Ayers JW, Peterson EP, Ansbacher R. Early therapy for the incompetent cervix in patients with habitual abortion. Fertil Steril 1982;38:177–81. 70. Zakut H, Lanciano A. The influence of progesterone treatment on the course and outcome of pregnancies following suture of the cervix for cervical incompetence. Clin Exp Obstet Gynecol. 1981;8:1–5. 71. Rebarber A, Cleary-Goldman J, Istwan NB, Rhea DJ, Desch C, Russo-Stieglitz K, et al. The use of 17 alpha-hydroxyprogesterone caproate (17p) in women with cervical cerclage. Am J Perinatol 2008;25:271–5. 72. Berghella V, Figueroa D, Szychowski JM, Owen J, Hankins GD, Iams JD, et al. 17-alpha-hydroxyprogesterone caproate for the prevention of preterm birth in women with prior preterm birth and a short cervical length. Am J Obstet Gynecol 2010;202:351e1–e6. 73. Rafael TJ, Mackeen AD, Berghella V. The effect of 17-alphahydroxyprogesterone caproate on preterm birth in women with an ultrasound-indicated cerclage. Am J Perinatol 2011;28:389–94. 74. Melamed N, Ben-Haroush A, Chen R, Kaplan B, Yogev Y. Intrapartum cervical lacerations: characteristics, risk factors, and effects on subsequent pregnancies. Am J Obstet Gynecol. 2009;200:388 e1–e4. 75. Parikh R, Brotzman S, Anasti JN. Cervical lacerations: some surprising facts. Am J Obstet Gynecol 2007;196:e17–e18. 76. Landy HJ, Laughon SK, Bailit JL, Kominiarek MA, Gonzalez-Quintero VH, Ramirez M, et al. Characteristics associated with severe perineal and cervical lacerations during vaginal delivery. Obstet Gynecol 2011;117:627–35. 77. Bonfadini Bossi E, Migliavacca AE, Fagnani D, Salini P, Rella R, Garone G, et al. [Treatment of segmental cervical incompetence in pregnancy. Surgical indications, technic and results of 128 cervical cerclage operations]. Minerva Ginecol 1981;33:385–8. 78. Jorgensen AL, Alfirevic Z, Tudur Smith C, Williamson PR; Cerclage IPD Meta-analysis Group. Cervical stitch (cerclage) for preventing pregnancy loss: individual patient data meta-analysis. BJOG 2007;114:1460–76. 79. Bassaw B, Roopnarinesingh S. The efficacy of cervical cerclage. West Indian Med J 1990;39:39–42. 80. Weissman A, Jakobi P, Zahi S, Zimmer EZ. The effect of cervical cerclage on the course of labor. Obstet Gynecol 1990;76:168–71. 81. Abdelhak YE, Aronov R, Roque H, Young BK. Management of cervical cerclage at term: remove the suture in labor? J Perinat Med 2000;28:453–7. 82. Funai EF, Paidas MJ, Rebarber A, O’Neill L, Rosen TJ, Young BK. Change in cervical length after prophylactic cerclage. Obstet Gynecol 1999;94:117–9. 83. Guzman ER, Houlihan C, Vintzileos A, Ivan J, Benito C, Kappy K. The significance of transvaginal ultrasonographic evaluation of the cervix in women treated with emergency cerclage. Am J Obstet Gynecol 1996;175:471–6. 84. Althuisius SM, Dekker GA, van Geijn HP, Hummel P. The effect of therapeutic McDonald cerclage on cervical length as assessed by transvaginal ultrasonography. Am J Obstet Gynecol 1999;180:366–9. 85. Dijkstra K, Funai EF, O’Neill L, Rebarber A, Paidas MJ, Young BK. Change in cervical length after cerclage as a predictor of preterm delivery. Obstet Gynecol 2000;96:346–50.

88. Fox R, Holmes R, James M, Tuohy J, Wardle P. Serial transvaginal ultrasonography following McDonald cerclage and repeat suture insertion. Aust N Z J Obstet Gynaecol 1998;38:27–30. 89. Duhig KE, Chandiramani M, Seed PT, Briley AL, Kenyon AP, Shennan AH. Fetal fibronectin as a predictor of spontaneous preterm labour in asymptomatic women with a cervical cerclage. BJOG 2009;116:799–803. 90. Jenkins TM, Berghella V, Shlossman PA, McIntyre CJ, Maas BD, Pollock MA, et al. Timing of cerclage removal after preterm premature rupture of membranes: maternal and neonatal outcomes. Am J Obstet Gynecol 2000;183:847–52. 91. Ludmir J, Bader T, Chen L, Lindenbaum C, Wong G. Poor perinatal outcome associated with retained cerclage in patients with premature rupture of membranes. Obstet Gynecol 1994;84:823–6. 92. McElrath TF, Norwitz ER, Lieberman ES, Heffner LJ. Management of cervical cerclage and preterm premature rupture of the membranes: should the stitch be removed? Am J Obstet Gynecol 2000;183:840–6. 93. Giraldo-Isaza MA, Berghella V. Cervical cerclage and preterm PROM. Clin Obstet Gynecol 2011;54:313–20. 94. Trochez-Martinez RD, Smith P, Lamont RF. Use of C-reactive protein as a predictor of chorioamnionitis in preterm prelabour rupture of membranes: a systematic review. BJOG 2007;114:796–801. 95. Wiwanitkit V. Maternal C-reactive protein for detection of chorioamnionitis: an appraisal. Infect Dis Obstet Gynecol 2005;13:179–81. 96. Friedli I, Stamm J, Beguin F. [Cerclage by the abdominal route]. J Gynecol Obstet Biol Reprod (Paris) 1987;16:951–4. 97. Gesson-Paute A, Berrebi A, Parant O. [Transabdominal cervico-isthmic cerclage in the management of cervical incompetence in high risk women]. J Gynecol Obstet Biol Reprod (Paris) 2007;36:30–5. 98. Benson RC, Durfee RB. Transabdominal cervico uterine cerclage during pregnancy for the treatment of cervical incompetency. Obstet Gynecol 1965;25:145–55. 99. Zaveri V, Aghajafari F, Amankwah K, Hannah M. Abdominal versus vaginal cerclage after a failed transvaginal cerclage: a systematic review. Am J Obstet Gynecol 2002;187:868–72. 100. Davis G, Berghella V, Talucci M, Wapner RJ. Patients with a prior failed transvaginal cerclage: a comparison of obstetric outcomes with either transabdominal or transvaginal cerclage. Am J Obstet Gynecol 2000;183:836–9. 101. Lotgering FK, Gaugler-Senden IP, Lotgering SF, Wallenburg HC. Outcome after transabdominal cervicoisthmic cerclage. Obstet Gynecol 2006;107:779–84. 102. Jolley JA, Battista L, Wing DA. Management of pregnancy after radical trachelectomy: case reports and systematic review of the literature. Am J Perinatol 2007;24:531–9. 103. Dubuisson J, Jardon K, Botchorishvili R, Rabischong B, Tran X, Bourdel N, et al. [How I perform... a laparoscopic transabdominal isthmic cerclage]. Gynecol Obstet Fertil 2008;36:459–60. 104. Carter JF, Soper DE, Goetzl LM, Van Dorsten JP. Abdominal cerclage for the treatment of recurrent cervical insufficiency: laparoscopy or laparotomy? Am J Obstet Gynecol 2009;201:111.e1–e4. 105. Shepherd JH, Milliken DA. Conservative surgery for carcinoma of the cervix. Clin Oncol (R Coll Radiol) 2008;20:395–400. 106. Benifla JL, Goffinet F, Darai E, Proust A, De Crepy A, Madelenat P. Emergency cervical cerclage after 20 weeks’ gestation: a retrospective study of 6 years’ practice in 34 cases. Fetal Diagn Ther 1997;12:274–8.

DECEMBER JOGC DÉCEMBRE 2013 l 1125

SOGC Clinical Practice Guidelines

107. Olatunbosun OA, Dyck F. Cervical cerclage operation for a dilated cervix. Obstet Gynecol 1981;57:166–70. 108. Ochi M, Ishikawa K, Itoh H, Miwa S, Fujimura Y, Kimura T, et al. [Aggressive management of prolapsed fetal membranes earlier than 26 weeks’ gestation by emergent McDonald cerclage combined with amniocentesis and bladder overfilling]. Nihon Sanka Fujinka Gakkai Zasshi 1994;46:301–7. 109. Mays JK, Figueroa R, Shah J, Khakoo H, Kaminsky S, Tejani N. Amniocentesis for selection before rescue cerclage. Obstet Gynecol 2000;95:652–5. 110. Althuisius SM, Dekker GA, Hummel P, van Geijn HP. Cervical incompetence prevention randomized cerclage trial: emergency cerclage with bed rest versus bed rest alone. Am J Obstet Gynecol 2003;189:907–10. 111. Daskalakis G, Papantoniou N, Mesogitis S, Antsaklis A. Management of cervical insufficiency and bulging fetal membranes. Obstet Gynecol 2006;107:221–6. 112. Stupin JH, David M, Siedentopf JP, Dudenhausen JW. Emergency cerclage versus bed rest for amniotic sac prolapse before 27 gestational weeks. A retrospective, comparative study of 161 women. EurJ Obstet Gynecol Reprod Biol 2008;139:32–7. 113. Schorr SJ, Morales WJ. Obstetric management of incompetent cervix and bulging fetal membranes. J Reprod Med 1996;41:235–8. 114. Olatunbosun OA, al-Nuaim L, Turnell RW. Emergency cerclage compared with bed rest for advanced cervical dilatation in pregnancy. Int Surg 1995;80:170–4. 115. Kokia E, Dor J, Blankenstein J, Seidman DS, Lipitz S, Serr DM, et al. A simple scoring system for the treatment of cervical incompetence diagnosed during the second trimester. Gynecol Obstet Invest 1991;31:12–6. 116. Terkildsen MF, Parilla BV, Kumar P, Grobman WA. Factors associated with success of emergent second-trimester cerclage. Obstet Gynecol 2003;101:565–9. 117. Tsatsaris V, Senat MV, Gervaise A, Fernandez H. Balloon replacement of fetal membranes to facilitate emergency cervical cerclage. Obstet Gynecol 2001;98:243–6.

127. Acharya G, Eschler B, Gronberg M, Hentemann M, Ottersen T, Maltau JM. Noninvasive cerclage for the management of cervical incompetence: a prospective study. Arch Gynecol Obstet 2006;273:283–7. 128. Dharan VB, Ludmir J. Alternative treatment for a short cervix: the cervical pessary. Semin Perinatol. 2009;33:338–42. 129. Grzonka DT, Kazmierczak W, Cholewa D, Radzioch J. [Herbich cervical pessary--method of therapy for cervical incompetence and prophylaxis of prematurity]. Wiad Lek 2004;57(Suppl 1):105–7. 130. Kimber-Trojnar Z, Patro-Malysza J, Leszczynska-Gorzelak B, Marciniak B, Oleszczuk J. Pessary use for the treatment of cervical incompetence and prevention of preterm labour. J Matern Fetal Neonatal Med 2010;23:1493–9. 131. Goya M, Pratcorona L, Merced C, Rodo C, Valle L, Romero A, et al. Cervical pessary in pregnant women with a short cervix (PECEP): an open-label randomised controlled trial. Lancet 2012;379:1800–6. 132. Berghella V, Haas S, Chervoneva I, Hyslop T. Patients with prior secondtrimester loss: prophylactic cerclage or serial transvaginal sonograms? Am J Obstet Gynecol 2002;187:747–51. 133. To MS, Palaniappan V, Skentou C, Gibb D, Nicolaides KH. Elective cerclage vs. ultrasound-indicated cerclage in high-risk pregnancies. Ultrasound Obstet Gyneco 2002;19:475–7. 134. Sosa C, Althabe F, Belizan J, Bergel E. Bed rest in singleton pregnancies for preventing preterm birth. Cochrane Database Syst Rev 2004:CD003581. 135. Simcox R, Seed PT, Bennett P, Teoh TG, Poston L, Shennan AH. A randomized controlled trial of cervical scanning vs history to determine cerclage in women at high risk of preterm birth (CIRCLE trial). Am J Obstet Gynecol 2009;200:623e1–e6. 136. Hertzberg BS, Bowie JD, Weber TM, Carroll BA, Kliewer MA, Jordan SG. Sonography of the cervix during the third trimester of pregnancy: value of the transperineal approach. AJR Am J Rroentgenol 1991;157:73–6.

118. Weiner , Lee KY, Buhimschi CS, Christner R, Buhimschi IA. Proteomic biomarkers that predict the clinical success of rescue cerclage. Am J Obstet Gynecol 2005;192:710–8.

137. Guzman ER, Pisatowski DM, Vintzileos AM, Benito CW, Hanley ML, Ananth CV. A comparison of ultrasonographically detected cervical changes in response to transfundal pressure, coughing, and standing in predicting cervical incompetence. Am J Obstet Gynecol 1997;177:660–5.

119. Locatelli A, Vergani P, Bellini P, Strobelt N, Arreghini A, Ghidini A. Amnioreduction in emergency cerclage with prolapsed membranes: comparison of two methods for reducing the membranes. Am J Perinatol 1999;16:73–7.

138. Guzman ER, Vintzileos AM, McLean DA, Martins ME, Benito CW, Hanley ML. The natural history of a positive response to transfundal pressure in women at risk for cervical incompetence. Am J Obstet Gynecol 1997;176:634–8.

120. Cerqui AJ, Olive E, Bennett MJ, Challis D. Emergency cervical cerclage. Is there a role for amnioreduction? Aust N Z J Obstet Gynaecol 1999;39:155–8.

139. Guzman E, Rosenberg J, Houlihan C, Ivan J, Waldron R, Knuppel R. A new method using vaginal ultrasound and transfundal pressure to evaluate the asymptomatic incompetent cervix. Obstet Gynecol 1994;83:248–52.

121. Makino Y, Makino I, Tsujioka H, Kawarabayashi T. Amnioreduction in patients with bulging prolapsed membranes out of the cervix and vaginal orifice in cervical cerclage. J Perinat Med 2004;32:140–8. 122. Jiratko K, Baran P, Zabransky F. [Our experiences with Mayer-Ring pessary in the prevention of premature labour]. Zentralbl Gynakol 1977;99:220–8. 123. Quaas L, Hillemanns HG, du Bois A, Schillinger H. [The Arabin cerclage pessary—an alternative to surgical cerclage]. Geburtshilfe Frauenheilkd 1990;50:429–33. 124. Leduc L, Wasserstrum N. Successful treatment with the Smith-Hodge pessary of cervical incompetence due to defective connective tissue in Ehlers-Danlos syndrome. Am J Perinatol 1992;9:25–7. 125. Newcomer J. Pessaries for the treatment of incompetent cervix and premature delivery. Obstet Gynecol Surv 2000;55:443–8. 126. Arabin B, Halbesma JR, Vork F, Hubener M, van Eyck J. Is treatment with vaginal pessaries an option in patients with a sonographically detected short cervix? J Perinat Med 2003;31:122–33.

1126 l DECEMBER JOGC DÉCEMBRE 2013

140. Berghella V, Keeler SM, To MS, Althuisius SM, Rust OA. Effectiveness of cerclage according to severity of cervical length shortening: a meta-analysis. Ultrasound Obstet Gynecol 2010;35:468–73. 141. Incerti M, Ghidini A, Locatelli A, Poggi SH, Pezzullo JC. Cervical length < or = 25 mm in low-risk women: a case control study of cerclage with rest vs rest alone. Am J Obstet Gynecol 2007;197:315e1–e4. 142. To MS, Alfirevic Z, Heath VC, Cicero S, Cacho AM, Williamson PR, et al. Cervical cerclage for prevention of preterm delivery in women with short cervix: randomised controlled trial. Lancet 2004;363:1849–53. 143. Berghella V, Odibo AO, To MS, Rust OA, Althuisius SM. Cerclage for short cervix on ultrasonography: meta-analysis of trials using individual patientlevel data. Obstet Gynecol 2005;106:181–9. 144. Berghella V, Rafael TJ, Szychowski JM, Rust OA, Owen J. Cerclage for short cervix on ultrasonography in women with singleton gestations and previous preterm birth: a meta-analysis. Obstet Gynecol 2011;117:663–71.

Cervical Insufficiency and Cervical Cerclage

145. Heath VC, Souka AP, Erasmus I, Gibb DM, Nicolaides KH. Cervical length at 23 weeks of gestation: the value of Shirodkar suture for the short cervix. Ultrasound Obstet Gynecol 1998;12:318–22.

151. Farine D, Mundle WR, Dodd J, Basso M, Delisle MF, Farine D, et al. The use of progesterone for prevention of preterm birth. J Obstet Gynaecol Can 2008;30:67–77.

146. Hibbard JU, Snow J, Moawad AH. Short cervical length by ultrasound and cerclage. J Perinatol 2000;20:161–5.

152. Dor J, Shalev J, Mashiach S, Blankstein J, Serr DM. Elective cervical suture of twin pregnancies diagnosed ultrasonically in the first trimester following induced ovulation. Gynecol Obstet Invest 1982;13:55–60.

147. Owen J, Hankins G, Iams JD, Berghella V, Sheffield JS, Perez-Delboy A, et al. Multicenter randomized trial of cerclage for preterm birth prevention in high-risk women with shortened midtrimester cervical length. Am J Obstet Gynecol 2009;201:375 e1-e8. 148. Keeler SM, Kiefer D, Rochon M, Quinones JN, Novetsky AP, Rust O. A randomized trial of cerclage vs. 17 alpha-hydroxyprogesterone caproate for treatment of short cervix. J Perinat Med 2009;37:473–9. 149. Hassan SS, Romero R, Vidyadhari D, Fusey S, Baxter JK, Khandelwal M, et al. Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol 2011;38:18–31. 150. Romero R, Nicolaides K, Conde-Agudelo A, Tabor A, O’Brien JM, Cetingoz E, et al. Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and meta-analysis of individual patient data. Am J Obstet Gynecol 2012;206:124 e1–e19.

153. Yang JH, Kuhlman K, Daly S, Berghella V. Prediction of preterm birth by second trimester cervical sonography in twin pregnancies. Ultrasound Obstet Gynecol 2000;15:288–91. 154. Newman RB, Krombach RS, Myers MC, McGee DL. Effect of cerclage on obstetrical outcome in twin gestations with a shortened cervical length. Am J Obstet Gynecol 2002;186:634–40. 155. Zucchini S, Borghesani F, Soffriti G, Chirico C, Vultaggio E, Di Donato P. Transvaginal ultrasound diagnosis of twin reversed arterial perfusion syndrome at 9 weeks’ gestation. Ultrasound Obstet Gynecol 1993;3:209–11. 156. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

DECEMBER JOGC DÉCEMBRE 2013 l 1127

Clinical Practice Guidelines No. 299, November 2013

Female Genital Cutting This clinical practice guideline has been prepared by the Social Sexual Issues Committee and the Ethics Committee, and reviewed by the Clinical Practice Gynaecology Committee, the Canadian Paediatric and Adolescent Gynaecology and Obstetricians Committee, and the Family Physicians Advisory Committee, and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Liette Perron, MSW, Ottawa ON Vyta Senikas, MD, Ottawa ON

Erin Nelson, LLB, LLM, Edmonton AB Marianne Pierce, MD, Halifax NS Deborah Robertson, MD, Toronto ON Anne Simmonds, RN, PhD, Scotsburn NS Disclosure statements have been received from all of the committees. The literature searches and bibliographic for this guideline were undertaken by Becky Skidmore, Medical Research Analyst, Society of Obstetricians and Gynaecologists of Canada.

Margaret Burnett, MD, Winnipeg MB Victoria Davis, MD, Scarborough ON

Abstract

SOCIAL SEXUAL ISSUES COMMITTEE

Objective: To strengthen the national framework for care of adolescents and women affected by female genital cutting (FGC) in Canada by providing health care professionals with: (1) information intended to strengthen their knowledge and understanding of the practice; (2) directions with regard to the legal issues related to the practice; (3) clinical guidelines for the management of obstetric and gynaecological care, including FGC related complications; and (4) guidance on the provision of culturally competent care to adolescents and women with FGC.

Margaret Burnett, MD (Chair), Winnipeg MB Anjali Aggarwal, MD, Toronto ON Jeanne Bernardin, MD, Moncton NB Virginia Clark, MD, Golden BC Victoria Davis, MD, Scarborough ON William Fisher, BA, MS, PhD, London ON Rosana Pellizzari, MD, Peterborough ON Viola Polomeno, RN, PhD, Ottawa ON Maegan Rutherford, MD, Halifax NS Jeanelle Sabourin, MD, Edmonton AB ETHICS COMMITTEE Jodi Shapiro, MD (Chair), Toronto ON Saima Akhtar, MD, London ON Bruno Camire, MD, Quebec QC Jan Christilaw, MD, Vancouver BC Julie Corey, RM, St Jacobs ON

Key words: Female genital cutting, female genital mutilation, female circumcision, pregnancy, gynecological care, adolescents, Canada.

Evidence: Published literature was retrieved through searches of PubMed, CINAHL, and The Cochrane Library in September 2010 using appropriate controlled vocabulary (e.g., Circumcision, Female) and keywords (e.g., female genital mutilation, clitoridectomy, infibulation). We also searched Social Science Abstracts, Sociological Abstracts, Gender Studies Database, and ProQuest Dissertations and Theses in 2010 and 2011. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to December 2011. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Values: The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1).

J Obstet Gynaecol Can 2013;35(11):e1–e18

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

NOVEMBER JOGC NOVEMBRE 2013 l e1

Clinical Practice Guidelines

Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.59 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care.59

Summary Statements 01. Female genital cutting is internationally recognized as a harmful practice and a violation of girls’ and women’s rights to life, physical integrity, and health. (II-3) 02. The immediate and long-term health risks and complications of female genital cutting can be serious and life threatening. (II-3) 03. Female genital cutting continues to be practised in many countries, particularly in sub-Saharan Africa, Egypt, and Sudan. (II-3) 04. Global migration patterns have brought female genital cutting to Europe, Australia, New Zealand, and North America, including Canada. (II-3) 05. Performing or assisting in female genital cutting is a criminal offense in Canada. (III) 06. Reporting to appropriate child welfare protection services is mandatory when a child has recently been subjected to female genital cutting or is at risk of being subjected to the procedure. (III) 07. There is concern that female genital cutting continues to be perpetuated in receiving countries, mainly through the act of re-infibulation. (III)

ABBREVIATIONS BMA

British Medical Association

FGC

female genital cutting

FGM

female genital mutilation

FIWG

Federal Interdepartmental Working Group (on Female Genital Mutilation)

HIV

human immunodeficiency virus

IUD

intrauterine device

SERC

Sexuality Education Resource Centre (Manitoba)

e2 l NOVEMBER JOGC NOVEMBRE 2013

08. There is a perception that the care of women with female genital cutting is not optimal in receiving countries. (III) 09. Female genital cutting is not considered an indication for Caesarean section. (III) Recommendations 01. Health care professionals must be careful not to stigmatize women who have undergone female genital cutting. (III-A) 02. Requests for re-infibulation should be declined. (III-B) 03. Health care professionals should strengthen their understanding and knowledge of female genital cutting and develop greater skills for the management of its complications and the provision of culturally competent care to adolescents and women who have undergone genital cutting. (III-A) 04. Health care professionals should use their knowledge and influence to educate and counsel families against having female genital cutting performed on their daughters and other family . (III-A) 05. Health care professionals should advocate for the availability of and access to appropriate and counselling services. (III-A) 06. Health care professionals should lend their voices to communitybased initiatives seeking to promote the elimination of female genital cutting. (III-A) 07. Health care professionals should use interactions with patients as opportunities to educate women and their families about female genital cutting and other aspects of women’s health and reproductive rights. (III-A) 08. Research into female genital cutting should be undertaken to explore women’s perceptions and experiences of accessing sexual and reproductive health care in Canada. (III-A) The perspectives, knowledge, and clinical practice of health care professionals with respect to female genital cutting should also be studied. (III-A). 09. Information and guidance on female genital cutting should be integrated into the curricula for nursing students, medical

Female Genital Cutting

students, residents, midwifery students, and students of other health care professions. (III-A) 10. Key practices in providing optimal care to women with female genital cutting include: a. determining how the woman refers to the practice of female genital cutting and using this terminology throughout care; (III-C) b. determining the female genital cutting status of the woman and clearly documenting this information in her medical file; (III-C) c. ensuring the availability of a well-trained, trusted, and neutral interpreter who can ensure confidentiality and who will not exert undue influence on the patient–physician interaction when providing care to a woman who faces language challenges; (III-C) d. ensuring the proper documentation of the woman’s medical history in her file to minimize the need for repeated medical histories and/or examinations and to facilitate the sharing of information; (III-C) e. providing the woman with appropriate and well-timed information, including information about her reproductive system and her sexual and reproductive health; (III-C) f. ensuring the woman’s privacy and confidentiality by limiting attendants in the room to those who are part of the health care team; (III-C) g. providing woman-centred care focused on ensuring that the woman’s views and wishes are solicited and respected, including a discussion of why some requests cannot be granted for legal or ethical reasons; (III-C) h. helping the woman to understand and navigate the health system, including access to preventative care practices; (III-C) i. using prenatal visits to prepare the woman and her family for delivery; (III-C) j. when referring, ensuring that the services and/or practitioners who will be receiving the referral can provide culturally competent and sensitive care, paying special attention to concerns related to confidentiality and privacy. (III-C)

Epub ahead of print. This document will be published in: J Obstet Gynaecol Can 2013;35(11)

of the communities that practice FGC. In French, FGC is often referred to as “excision”—a general term covering all types of the practice. The term “female genital cutting” was chosen for this document because it is considered medically correct, neutral, and culturally sensitive. When reference material or direct quotations from other authors are used, their original terminology is retained. Definition of Female Genital Cutting

WHO defines female genital mutilation as “all procedures involving partial or total removal of the external female genitalia or injury to the female genital organs for nonmedical reasons.”1 Genital tattooing, piercing, hair removal, and labiaplasty could technically be included in the WHO definition of Type IV FGM, but for the purpose of this document, we define FGC as WHO Types I, II, and III. Glossary

Cultural competence: “A set of congruent behaviors, attitudes, and policies that come together in a system, agency, or among professionals that enables the system or professionals to work effectively in cross-cultural situations.”2 Defibulation: Incision of the vulva to open the vagina of a woman who has undergone infibulation. Infibulation: Excision of part of the external genitalia and stitching of the vulvovaginal opening to partially cover the vaginal opening. Medicalization: The “situations in which FGM is practiced by any category of trained healthcare provider, whether in a public or a private clinic, at home or elsewhere. It also includes the surgical procedure of reinfibulation at any time in a woman’s life.” (WHO, 2010).3 Re-infibulation: The re-suturing of the vulvar opening that has been opened with defibulation. Classification

INTRODUCTION

T

here is no international consensus on what to call the practice of physically altering girls’ and women’s genitals. The current most commonly used in the literature are “female circumcision,” “female genital mutilation,” and “female genital cutting.” Although “female circumcision” is used in many communities where FGC is prevalent, it is problematic because it tends to equate the practice with male circumcision. “Female genital mutilation,” formally adopted and used in advocacy documents by the UN and WHO, calls attention to the gravity and harm of the act, but some consider the term judgemental and stigmatizing, especially

WHO classifies FGM procedures into 4 types (Table 2).1 The types of procedure vary considerably across countries, within countries, and between ethnic groups. It is estimated that most women with FGC are subjected to clitorectomy (Type I), excision (Type II), or “nicking,” in which no flesh is removed (Type IV).1 Approximately 10% of women are subjected to infibulation (Type III), the most severe form of the procedure, practiced in Djibouti, Eritrea, Ethiopia, Somalia, and Sudan.4 WHO recognizes that the definition of Type IV raises a number of unresolved issues because some of the NOVEMBER JOGC NOVEMBRE 2013 l e3

Clinical Practice Guidelines

Table 2. WHO modified typology, 2007 Type I

Partial or total removal of the clitoris and/or the prepuce (clitoridectomy). When it is important to distinguish between the major variations of Type 1 mutilation, the following subdivisions are proposed: Type Ia, removal of the clitoral hood or prepuce only; Type Ib, removal of the clitoris with the prepuce.

Type II

Partial or total removal of the clitoris and the labia minora, with or without excision of the labia major (excision). When it is important to distinguish between the major variations of Type II that have been documented, the following subdivision are proposed: Type IIa, removal of the labia minora only; Type IIb, partial or total removal of the clitoris and labia minora; Type IIc, partial or total removal of the clitoris, the labia minora, and the labia majora.

Type III

Narrowing of the vaginal orifice with creation of a covering seal by cutting and appositioning the labia minora and/or the labia majora, with or without excision of the clitoris (infibulations). When it is important to distinguish between variations in infibulations, the following subdivisions are proposed: Type IIIa, removal and apposition of the labia minora; Type IIIb, removal and apposition of the labia majora.

Type IV

Unclassified: all other harmful procedures to the female genitalia for non-medical purposes (e.g., pricking, piercing, incising, scraping, and cauterization).

Reproduced with permission from the World Health Organization (WHO. Eliminating female genital mutilation: an interagency statement. Geneva: WHO; 2008: p 24).

practices listed are legally accepted and not generally considered FGM in many countries (e.g., genital cosmetic surgery, hymen repair, piercing). WHO recommends that in determining whether genital practices should be categorized as FGM, human rights principles should be applied, including the right of health, the rights of children, and the right to non-discrimination on the basis of sex.1 Prevalence in Canada

Although the magnitude of the practice of FGC in Canada remains unknown, literature from as early as the 1990s confirms that FGC has been found among certain immigrant communities.5–11 Table 3 brings together two sets of data: 1. a list of countries in which FGC of Types I, II, III, and IV has been documented as a traditional practice,1 and 2. Canadian immigration data related to the number of permanent and temporary residents received in Canada from 2005 to 2009 from countries in which FGC has been documented.12 Although the Canadian immigration data should be considered with caution, it provides insight into the continual arrival in Canada of newcomers from countries where the practice is prevalent, including adolescents and women who may have undergone FGC and girls who may be at risk. e4 l NOVEMBER JOGC NOVEMBRE 2013

While there is no evidence that any type of FGC is practiced in Canada, there is concern that girls from practising communities may still be at risk. In their exploratory study of the perceptions of Somali women of their earlier experience of FGC, Chalmers and Omer-Hashi13 found that only one third of respondents ed the Canadian law prohibiting the practice, while two thirds reported ambivalent feelings. Furthermore, when asked “whether or not they would (hypothetically) wish to have [their daughters] circumcised,” almost half said they would. In their study exploring FGC as it relates to gender identity and the acculturation process in Canada, Vissandjée et al. were unable to determine whether these practices had been abandoned by new arrivals to Canada; their findings suggested that “the need to maintain a status equal to that of the country of origin potentially increased the risk of the practices being performed [on girls].”11 Finally, SERC Manitoba, in their work with immigrants affected by FGC, reported that women were split in their opinions of the issue; although some women strongly ed discontinuation of the practice, others either ed it or remained conflicted about what should be done about it.14 These findings are ed by a number of European studies that show the practice is not necessarily abandoned with migration and that girl children remain at risk.15–17 Summary Statement

1. Female genital cutting is internationally recognized as a harmful practice and a violation of girls’ and women’s rights to life, physical integrity, and health. (II-3)

Female Genital Cutting

Table 3. Countries in which female genital mutilation of Types I, II, III, and IV has been documented as a traditional practice, and number of permanent and temporary residents (both sexes) received in Canada from those countries in the years 2005 to 2009

Country

Year*

Estimated prevalence of FGM in girls and women 15 to 49 years %

Benin

2001

16.8

815

Burkina Faso

2005

72.5

632 3790

Residents received in Canada (2005 to 2009)12

Cameroon

2004

1.4

Central African

2005

25.7

88

Chad

2004

44.9

481

Cote d’Ivoire

2005

41.7

2766

Djibouti

2006

93.1

313

Egypt

2005

95.8

10 482

Eritrea

2002

88.7

2391

Ethiopia

2005

74.3

7126

Gambia

2005

78.3

178

Ghana

2005

3.8

4071

Guinea

2005

95.6

1643

Guinea-Bissau

2005

44.5

N/A

Kenya

2003

32.2

3389

Liberia†

45.0

424

Mali

2001

91.6

629

Mauritania

2001

71.3

272

Niger

2006

2.2

298

Nigeria

2003

19.0

11 259

Senegal

2005

28.2

1878

Sierra Leone

2005

94.0

406

Somalia

2005

97.9

4596

Sudan, Northern (approx. 80% of total population in survey)

2000

90.0

3752

Togo

2005

5.8

701

Tanzania

2004

14.6

1115

Uganda

2006

0.6

1113

Yemen

1997

22.6

888

*Year of national data reports from which the data were derived. †Estimate derived from a variety of local and sub-national studies. Columns 1, 2, and 3 reproduced with permission of the World Health Organization. (WHO. Eliminating female genital mutilation: an interagency statement. Geneva: WHO; 2008: p 29).

NOVEMBER JOGC NOVEMBRE 2013 l e5

Clinical Practice Guidelines

Table 4. Recognized complications and risks of female genital cutting1 Immediate risks of Types I, II, and III

Long-term risks of Types I, II, and III

Additional risks associated with Type III

Pain due to the cutting of the nerves and sensitive genital tissues

Chronic pain due to trapped or unprotected nerves

Shock caused by pain and/or hemorrhage

Epithelial inclusion cysts

Surgery to enable penetration during sexual intercourse and for childbirth, and sometimes re-infibulation

Excessive bleeding

Infections (i.e. abscesses and genital ulcers; chronic pelvic infections; urinary tract infections)

Difficulty in ing urine/ ing feces Infections Increased risk of blood borne viral infections including hepatitis and HIV due to the use of unsterilized and shared instruments Death Psychological consequences Unintended labial fusion Re-infibulation due to unsuccessful healing

Keloid formation Sexually transmitted infections, especially genital herpes Increased risk of blood-borne viral infections including hepatitis and HIV due to genital trauma during intercourse (especially for Type III) Sexual dysfunction (i.e. decreased sexual pleasure, pain during sex) Vulvar or vaginal lacerations with intercourse or childbirth

Inability to have intercourse Infertility Dysmenorrhea due to outflow obstruction Endometriosis Difficulty voiding Difficulty using tampons, diaphragms, pessaries, etc. Difficulty with speculum examinations Difficulty accessing Pap smear screening and other gynaecological procedures requiring vaginal access (cervical cultures, endometrial biopsy, IUD placement, etc.)

Increased Caesarean section rates, obstructed labour Psychological consequences (i.e. fear of sexual intercourse, post traumatic stress disorder, anxiety, depression and memory loss)

Immediate and Long-term Complications

FGC is usually performed on girls between the ages of 5 and 12, although infants and adult women are sometimes subjected to the procedure. Typically, the child is forcibly held while the excision is done using a razor blade, piece of broken glass, or knife. Infibulation may involve stitching or pinning the labia. The girl’s legs are usually bound together to promote closure of the cut edges of the incision(s). Anaesthetic is not typically used, and the struggles of the child may aggravate the genital trauma. It should be noted that many women do not experience any long-term complications from the procedure. The immediate health risks and consequences of FGC can, however, be serious and life-threatening to girls and women. Complications vary according to the type of procedure conducted and the conditions under which FGC is performed (e.g., hygienic conditions, instruments used, experience of the practitioner).1,18 Table 4 provides a synopsis of the immediate and long-term health complications of FGC/FGM from types I, II, and III as compiled by WHO.1 Health care professionals in receiving countries tend to address the long-term complications of FGC, especially those related to Types II and III.18 e6 l NOVEMBER JOGC NOVEMBRE 2013

Impact on Women and Adolescents Living in Receiving Countries

While the health and psychological effects of FGC have been documented in sub-Saharan Africa, research on the impact of the practice on women’s well-being and health outcomes in countries of migration is limited. Berggren et al.19 found that women who had undergone FGC and were now living in Sweden “expressed a double shame at being different”: shame in their countries of origin if they had not undergone the procedure, but also shame in Sweden if they had been subjected to it. These feelings of shame contributed to their increased sense of vulnerability in their encounters with Swedish maternity care and to their further negative experiences in accessing care. In a study exploring the birthing experiences of Somali women in Ontario, Chalmers and Omer-Hashi reported a Caesarean section rate of over 50%.13 Vangen et al., in reviewing the Norwegian Medical Registry data, found the frequency of emergency Caesarean section among ethnic Somalis (15%) was triple that of ethnic Norwegians.20 Other perinatal complications in immigrant Somali women in Norway included induction of labour, fetal distress, secondary arrest, prolonged second stage of labour, and perinatal death. Although both authors recognized difficulties in ascertaining whether the adverse birth outcomes were

Female Genital Cutting

caused by FGC or other factors, their findings suggested that Somali women represented a higher risk group in obstetrics.20 Finally, Bragg,21 in reviewing the results of the 2003–2005 UK Confidential Enquiry into Maternal and Children Health noted that maternal mortality was 6 times higher in black African women than in white women in the United Kingdom. Among the new factors documented as potential contributing causes were unsatisfactory arrangements for interpretation and lack of health care provider awareness of FGC. Little is known of how FGC affects the psychological well-being of girls and adolescents.22,23 Anecdotal evidence suggests that the girls and/or adolescents’ concerns about the practice “are very much intertwined with other concerns common to all adolescents regarding sexuality, body image, attractiveness, identity, belonging and conforming with peers.”22 Traditional and Cultural Beliefs, Values, and Attitudes Upholding the Practice

The practice continues to be perpetuated due to an array of complex social, religious, and cultural reasons intrinsically linked to traditional beliefs, values, and attitudes related to women’s sexuality and the perceived need to control their sexual and reproductive capacity.24 Parents submit their daughters to FGC not as means of punishment or abuse, but as a way to protect them and give them “the best possible chance to have a future that will ensure [their] social acceptance and economic security.”25 FGC is performed in order to prepare girls for adulthood and marriage, to ensure their virginity until marriage, to ensure their fidelity in marriage, to make them clean, beautiful, and pure, and to maintain the family’s honour. In certain communities, it is seen as a rite of age or an initiation into a secret women’s society; in others it is thought to increase fertility and to enhance the sexual pleasure of men. FGC is often performed by “older women who carry on the tradition and make sure girls in their family undergo the practice.”15 Men play a role by remaining ive and not intervening in matters related to the practice, by preferring to marry a woman who has undergone FGC, or by insisting that it is performed on their daughters.11,15,26 Summary Statements

2. The immediate and long-term health risks and complications of female genital cutting can be serious and life threatening. (II-3) 3. Female genital cutting continues to be practised in many countries, particularly in sub-Saharan Africa, Egypt, and Sudan. (II-3)

4. Global migration patterns have brought female genital cutting to Europe, Australia, New Zealand, and North America, including Canada. (II-3) Recommendations

1. Health care professionals must be careful not to stigmatize women who have undergone female genital cutting. (III-A) 2. Requests for re-infibulation should be declined. (III-B) 3. Health care professionals should strengthen their understanding and knowledge of female genital cutting and develop greater skills for the management of its complications and the provision of culturally competent care to adolescents and women who have undergone genital cutting. (III-A) Legal Issues Related to FGC in Canada

FGC is illegal in Canada and anyone who performs or assists with the practice can be criminally charged and convicted. The Criminal Code also makes it a crime for parents or family to take a girl out of Canada for the purpose of having FGC/FGM performed elsewhere. Appendix 1 provides the main sections of the Canadian Criminal Code that state that anyone who “wounds” or “maims” a female person by excision, infibulation, or mutilation of the labia or clitoris is committing aggravated assault. Exceptions are made for surgery conducted for legitimate medical reasons. Although not explicitly mentioned in any Canadian provincial child welfare legislation, the Federal Interdepartmental Working Group on Female Genital Mutilation considered FGC “a form of child physical abuse and as such, any child suspected of being at risk of the practice would justify intervention by child protection authorities.”8 Because FGC is a recognized violation of human rights, a child or woman at risk for FGC has a legitimate claim for asylum.8 Statements and Policies of Provincial Medical Organizations in Canada

Appendix 2 provides information related to the position statements or directives issued by provincial medical organizations that have addressed the subject of FGC. These professional organizations have consistently condemned the practice of FGC and make it clear that a physician who engages in this practice is guilty of professional misconduct. Challenges in Responding to the Health Needs of Women and Adolescents with FGC

In a study exploring the birthing experience of Somali women in Ontario, Chalmers and Omer-Hashi found NOVEMBER JOGC NOVEMBRE 2013 l e7

Clinical Practice Guidelines

that although not all women had negative experiences in accessing health care, many considered the care not optimal, and further reported that “they were treated in ways that they perceived harsh and even offensive to [their] cultural values.”13 Women’s reported concerns were mainly with lack of services and care including assistance with baby care, especially when they were in pain due to their FGC; warm, caring, and sympathetic staff; privacy during labour and in the wards; confidence in the capacity of the clinicians to provide adequate care; and appropriate clinical care, including the ability to refuse what they considered unwarranted Caesarean sections. A consultation process undertaken in 2000 by the FIWG with community and health care providers identified the following as key health care issues affecting women with FGC in Canada: their lack of knowledge of the health consequences of the practice and the relation of FGC to their own health symptoms; differences in their healthseeking behaviours and practices from those of other women in Canada; their reluctance to seek health care due to lack of knowledge of how the system works; their distrust of authority figures (especially if they have experienced political prosecution); past adverse experience with health care providers; preference for women physicians; financial barriers; difficult and traumatic experiences in accessing care due to language and cultural barriers; lack of confidentiality and health care providers’ lack of training of in how to deal with complications of FGC; and issues related to what affected women considered the high Caesarean section rate at childbirth.8 These factors deter women with FGC and their families from seeking care until absolutely necessary.8,10,27 Studies exploring the perceptions of women with FGC in the United States, Europe, and Australia of the perinatal care they received report similar findings.28–33 Recent European studies shed light on the experiences and clinical practices of health providers providing care to women with FGC and how these contribute to the quality of care provided. Vangena et al. (2002)28 found that health care providers in Norway faced difficulties initiating discussion about the practice with women; lacked clinical skills in how and when to defibulate women and in determining the extent of repair after delivery; and at times performed Caesarean sections because they lacked knowledge related to care management. Widmark et al.34 and Johansen35 reported that health care providers found providing care to infibulated women at childbirth especially stressful and emotionally challenging. Of particular concern were the strong emotional and sometimes contradictory feelings of health providers, which included “deep empathy, protectiveness and the desire to treat the e8 l NOVEMBER JOGC NOVEMBRE 2013

circumcised women with extra care”, but also anger and hatred “towards tradition, religion, men and especially the husbands.”34 Significant gaps in both theoretical knowledge and practice related to FGC were found among health professionals in United Kingdom, Sweden, Spain, and the United States.36–39 Summary Statements

5. Performing or assisting in female genital cutting is a criminal offense in Canada. (III) 6. Reporting to appropriate child welfare protection services is mandatory when a child has recently been subjected to female genital cutting or is at risk of being subjected to the procedure. (III) 7. There is concern that female genital cutting continues to be perpetuated in receiving countries, mainly through the act of re-infibulation. (III) 8. There is a perception that the care of women with female genital cutting is not optimal in receiving countries. (III) CLINICAL MANAGEMENT OF WOMEN LIVING WITH FGC Gynaecologic Care

Women experiencing distressing symptoms related to vaginal obstruction or mass effect, or those considering intercourse or pregnancy can be offered surgery, defibulation, or excision. For defibulation, under general anaesthesia, the infibulated scar is incised in the midline from the neo-introitus to the level of the urethral orifice using scissors, coagulation/ cutting, or laser.40 The labial edges may need interrupted sutures to ensure hemostasis and/or approximation of the ipsilateral labial edges. Postoperatively, topical analgesic gels can help with pain relief, as can generous application of lubricants and frequent sitz baths. Estrogen cream and topical antibiotic ointment may also be helpful. Unfortunately, because FGC is not reversible some of its complications may not be amenable to therapy. Vaginal dilators may be appropriate for some women. Vaginal calibre is best sustained, postoperatively, when the woman is willing to use gentle vaginal dilation to help prevent re-stenosis of the introitus. Additional guidance related to defibulation is available in the online WHO document entitled Management of Pregnancy, Childbirth and the Postpartum Period in the Presence of Genital Mutilation.41 Contraceptive measures remain the same as for other women. Infertility rates may be higher in women who have undergone FGC.42 The incidence of infertility appears to be related to the extent of FGC. Introital stenosis can make intercourse difficult or impossible, and there may be tubal damage from infection or endometriosis. Artificial

Female Genital Cutting

reproductive technologies can be more challenging in a woman with FGC because of the need for a vaginal approach (hysterosonogram, intrauterine insemination, trans-vaginal ovum retrieval). It is important for health care professionals to avoid verbal and non-verbal reactions to women with FGC that may make the women feel stigmatized. Well-woman examinations and cervical screening need to be fully explained so the woman understands the need for the tests. A wide variety of small, narrow specula should be available to perform the exam with the least amount of discomfort. The use of a lubricant is encouraged. Obstetrical Care

Most forms of FGC do not directly impact obstetrical care. Infibulation may cause obstructed labour and is associated with an increased risk of vaginal/vulvar lacerations. When treating pregnant and labouring women it is important to demonstrate a professional and nonjudgemental approach to FGC. Many of these women originate from communities where FGC is the norm. They are used to the way their genitals feel and look. They may be fearful of the changes that may occur as a result of the delivery, particularly if the delivery is conducted by someone who is not familiar with FGC. If defibulation will be necessary to allow vaginal birth, it can be performed in advance or at the time of delivery. There may be medical indications to offer defibulation in advance to decrease the incidence of Caesarean section.43 However, many women prefer to wait until delivery and have defibulation only if absolutely necessary to facilitate the birth.44 If defibulation is performed intrapartum, an episiotomy performed at the same time facilitates delivery and minimizes vaginal tearing. Possible scenarios should be discussed in advance so the woman has ample opportunity to state her views, ask questions, and understand the reasoning behind common interventions such as analgesia in labour, defibulation, episiotomy, and Caesarean section. It is advisable to discuss hospital policies on labour companions, rooming in, and visiting hours because local practices may be at odds with the expectations of the woman and her family. Sympathetic post-delivery care, good analgesia, and assistance with care of the newborn are essential given the likelihood of vulvar pain experienced by women with FGC.13 It is vital that women who have had FGC are treated with respect and sensitivity. In some communities, it is customary to re-infibulate the genitals after each childbirth.45 WHO and other international health organizations strongly oppose all medicalization of FGC including re-infibulation because it may legitimize the practice of FGC/M in general.3 Re-infibulation is not specifically prohibited

by the Canadian Criminal Code; however, requests for re-infibulation should be declined on medical grounds because repetitive cutting and suturing of the vulva is likely to increase scar tissue, thus causing or perpetuating dyspareunia or voiding difficulties. If incisions are made or tearing occurs during childbirth, it is reasonable to repair defects in a way that will promote good hemostasis, vaginal , and normal appearance. Typically, high vaginal tears should be sought and sutured first; it is important to keep in mind that obstructed labour secondary to infibulation may be associated with “blow out” lacerations of the vagina and vulva. Episiotomy incisions and perineal tears may then be repaired in the usual manner. Infibulated tissue may be tough and relatively avascular. A small anterior tear or incision may not require suturing. In other cases, re-approximation of the cut edges may be appropriate. Alternatively, the raw edges can be over-sewn with interrupted, delayed absorbable suture in an effort to preserve the capacity of the vulvar opening. The vulvar tissues have a tendency to heal together as the raw edges sit in apposition. Gentle self-dilatation after defibulation may be required while the edges heal in the postpartum period. It is common for women to be concerned about the appearance of their genitals and to request that their appearance be preserved or restored as much as possible. Reassurance and information sharing are important. A patient-centred approach requires us to hear our patients’ requests and to be sensitive to the cultural context in which these requests are made. The health care professional should a culturally competent approach in which the autonomy of the patient is honoured as much as possible without compromising her health or breaching the ethical principle of non-maleficence. Caesarean section seems to be more common in women with FGC than in the general population. Caesarean section rates in low-resource countries tend to be considerably lower than in North America and cultural differences exist in women’s acceptance of Caesarean. Health care professionals should be aware that FGC is not an indication for Caesarean delivery. Frequency of Caesarean delivery may be reduced if defibulation is performed antenatally.43 Population studies have suggested that women with FGC have statistically increased risks of perinatal mortality, postpartum hemorrhage, and fetal distress. Currently there is insufficient data to determine whether these findings are related to FGC or to socioeconomic factors affecting health care access and quality of care.46 Summary Statement

9. Female genital cutting is not considered an indication for Caesarean section. (III) NOVEMBER JOGC NOVEMBRE 2013 l e9

Clinical Practice Guidelines

Sexual Health

Sexual function may be normal in women with FGC even in the absence of the clitoris and/or labia, especially in those women with Type I or II FGC (Table 2). Currently accepted treatment for sexual dysfunction should be considered for those women with FGC. Women with Type III FGC are significantly affected in of sex drive, arousal, and orgasm.47 There is some evidence that defibulation can improve sexual function in the domains of desire, arousal, satisfaction, and pain, but not lubrification and orgasm.48 The use of lubricants, self-stimulation, and dilators may improve sexual function. The need for defibulation may be considered, by some cultural groups, an indication of male sexual dysfunction. In cultures that practice Type III FGC the husband may be instructed in how to open (cut) or stretch the introitus to facilitate intercourse. Sexual dysfunction may occur in men secondary to the association of sex causing pain in their wife and their own physical discomfort when attempting intercourse.19,49 Adolescent Care

The physical complications and management of FGC in adolescents are the same as those in adult women. Some adolescents request revision of their FGC to feel more “normal” or less “different.” This should not be denied as long as there is a full discussion of the risks and benefits, both physical and psychological (the risk of alienation from her society). Young women often have no recollection of FGC performed at an early age; however, once integrated into Canadian society they may feel self-conscious when they realize that they were subjected to the practice as children. One study suggests significantly higher rates of post-traumatic stress disorder (30%) and other psychiatric syndromes (48%) in women living with FGC than in the general population.50 As in relations with all adolescents, the health care provider should be sensitive to sexual issues that may be exacerbated by FGC. Discussion about healthy sexual choices, contraception, and avoidance of sexually transmitted infections is always important, as is attention to any self-destructive behaviours (sexual promiscuity, substance abuse, eating disorders, suicidality). Well-woman examinations should also be discussed. Working with Families with Daughters at Risk

All health professionals providing care to families from communities that practise FGC should educate the parents about the illegality of the practice in Canada and its harmful effects. This is especially true when parents are suspected to be planning to have the procedure carried out on their daughter or are struggling with the decision. It is also important to that health care professionals have legal responsibilities to protect children, and thus to report their e10 l NOVEMBER JOGC NOVEMBRE 2013

suspicions of a child at risk of FGC to provincial child welfare agencies. Practical guidance for health care professionals can be found in the BMA’s latest guideline related to FGM.45 SERC Manitoba has developed more information for professionals on how to provide culturally sensitive counselling when working with families with young daughters.51 Recommendations

4. Health care professionals should use their knowledge and influence to educate and counsel families against having female genital cutting performed on their daughters and other family . (III-A) 5. Health care professionals should advocate for the availability of and access to appropriate and counselling services. (III-A) 6. Health care professionals should lend their voices to community-based initiatives seeking to promote the elimination of female genital cutting. (III-A) 7. Health care professionals should use interactions with patients as opportunities to educate women and their families about female genital cutting and other aspects of women’s health and reproductive rights. (III-A) 8. Research into female genital cutting should be undertaken to explore women’s perceptions and experiences of accessing sexual and reproductive health care in Canada. (III-A) The perspectives, knowledge, and clinical practice of health care professionals with respect to female genital cutting should also be studied. (III-A). 9. Information and guidance on female genital cutting should be integrated into the curricula for nursing students, medical students, residents, midwifery students, and students of other health care professions. (III-A) PROVIDING CULTURALLY COMPETENT CARE TO WOMEN AND ADOLESCENTS WITH FEMALE GENITAL CUTTING Preamble

The experience of FGC/FGM is only one event in a woman’s life, which may or may not be affecting her currently.51

The SOGC recognizes that the experience of a woman living with FGC must be considered within her experience as an immigrant and/or a visible minority women living in Canada, and possibly a refugee or asylum seeker. FGC (with or without complication) is but one of many issues and concerns a woman faces in her attempt to establish a life for herself and her family in Canada. Her experience will vary from other women depending on a number of factors

Female Genital Cutting

including her race, nationality, socioeconomic background, length of time in Canada or in other Western countries, education, religion, and sexual orientation. If she is a refugee or an asylum seeker, her experience may also differ from immigrant women by the possibility that she left her home under extreme circumstances, may be separated from her family, and may have been subjected to significant personal trauma such as rape or other violence. Consequently, in their interaction with women with FGC, health care professionals’ focus should be directed towards addressing the woman’s health concerns as a priority and taking a holistic approach.

•• Do you have any problems ing your urine? Does it take you a long time to urinate? (Note that women with obstruction may take several minutes to urine.)

Key Care Practices in Providing Care to Women with FGC

Communication Effective communication is considered paramount in the provision of culturally competent care to women with FGC and their families. Not only will it ensure that women have access to the information needed to make an informed choice about their health and the care they need, but it will also enhance their care experience and may positively influence their “perceptions of themselves, their bodies and their decision to seek future health care.”22 Communication within health care teams is also essential to ensure continuity of care and care that meets the women’s needs.

The following provides a summary of 10 key care practices which may assist health care professionals in the provision of culturally competent care to women with FGC. These are not meant to be prescriptive and are presented as good practices to guide you in your work with women who have undergone the FGC. The following have been adapted from a number of sources.18,22,23,30,34,52–56 Terminology when providing care Women who have undergone the practice of FGC may not see themselves as different or mutilated, and many may be offended by the use of the term “female genital mutilation.” The term “female circumcision” is frequently used by practicing communities and may be the terminology of choice of the woman and her family.57 The health care professional in interaction with a woman with FGC should determine how the woman refers to the practice and then, use the woman’s choice of terminology throughout care. Identification of the woman’s FGC status Identifying as early as possible the FGC status of women will ensure the delivery of effective care, especially maternity care. Determining the place of origin of women can provide insight into their potential status. When completing the medical history of a woman potentially at risk of having undergone the practice, the health care professional should sensitively enquire if she has had genital surgery or if she has been cut. Further to the pelvic examination, the health care professional should document the type of FGC clearly in the medical file, using diagrams if necessary. Examples of simple and sensitive questions to discover whether a woman has undergone FGC and is experiencing any complications related to the practice54 •• Many women from your country have been circumcised or “closed” as children. If you do not mind telling me, were you circumcised or closed as a child?

•• Do you have any pain with menstruation? Does your menstrual blood get stuck? •• Do you have any itching or burning or discharge from your pelvic area? •• (If sexually active) Do you have any pain or difficulty when having relations?

In interactions with a woman with FGC, the health care professional should (if necessary, possible, and appropriate), ensure the availability of a well-trained, trusted, and neutral female interpreter who can ensure confidentiality and who will not exert undue influence on the patient–physician interaction. If interpretation services are not available, choose an adult family member (preferably a female); avoid using the women’s children as interpreters. If a child is the only option possible, avoid discussing very sensitive issues at the first encounter and inquire whether she can bring an adult (preferably female) at her next visit. It is important also to that facial expressions, body language, and tone of voice play an important role in establishing effective communications. When working in a health care team, the health care professional should be sure to document findings in detail to minimize the need for repeated medical histories and/or examinations and to facilitate the sharing of information. Care should also be taken to ensure that all case discussions are conducted in a professional manner and that no language is used that can be construed as insensitive or patronizing. Providing women with appropriate and well-timed information Women from countries where FGC is practiced may not have been exposed to reproductive care discussions and be unfamiliar with their anatomy, in particular their reproductive organs, and they may never have had a NOVEMBER JOGC NOVEMBRE 2013 l e11

Clinical Practice Guidelines

physical, breast, or internal examination. As in all health professional–patient interactions, the way the information is shared (i.e., what is said and how it is said) will influence the outcome of the treatment. Communicating in a professional manner can contribute to creating a safe environment for women who find obstetrical and gynaecological care difficult and stressful. To ensure adequate information is provided to the woman, the health care professional should be sure to speak slowly and clearly and to use simple but accurate . If the woman’s knowledge of reproductive care is limited, the health care professional should make use of the interaction to share information with her. Pictures, diagrams, or anatomical models may be used to facilitate these discussions. Consideration should also be given to making longer appointments available. Confidentiality and privacy In many countries where FGC is practiced, sex and sexuality including issues related to FGC are considered very private matters and are not openly discussed. Some women refrain from seeking care because of their fear of being humiliated and judged when they disclose that they have undergone the practice. Finally, many women may experience embarrassment when asked to disrobe and uncover their bodies in front of a health care practitioner. In many cultures affected by FGC women prefer to be cared for by female attendants. The health care professional should ensure the woman’s privacy and confidentiality by limiting the attendants in the room (including delivery room) to those who are part of the health care team. Respect of a woman’s wish for modesty can be expressed by offering her a long-sleeved gown, knocking and waiting before entering the room, and draping the woman carefully when examining her. Care should be taken to ensure that the examination is done using a gentle touch, especially when examining the woman’s sensitive areas. Telling her what you are about to do, what you are doing, and what you have observed (good or bad) can be calming and reassuring for her. Finally, it is important to ensure that the woman is not part of a teaching session unless informed consent has been obtained. Trainees should be introduced and the reasons for their presence and their role in the health care of the woman should be explained. Woman-centred care In many cultures where FGC is practiced, women who seek care may be accompanied by their husbands and other family such as mothers-in-law and male relatives and these may expect to be involved in the decisione12 l NOVEMBER JOGC NOVEMBRE 2013

making process. In some other cultures, birth is considered women’s business and consequently, men are not expected to participate in the pregnancy nor the birth, nor are they the birth companion of choice of many women.58 The health care professional in his/her interactions with the woman should explore and assess the decisionmaking process of the woman and her family and be sure to solicit the woman’s views and wishes. The health care professional should also enquire who the woman’s choice of birth companion is, and respect it. Health-seeking behaviours and practices and preventative care The health-seeking behaviours and practices of many immigrant women, including women with FGC, often vary from Canadian norms. They may be unfamiliar with health services for screening and illness prevention and be more accustomed to seeking care when ill. They may also continue to use traditional medicine or health methods in their health care practices. Many may find our health care services difficult to understand and navigate, and frightening and intimidating, especially if they do not speak English or French. The health care professional should assist the woman in understanding how the health system works and help her navigate it. Every opportunity should be taken to educate the woman about preventive care practices important for herself and potentially for her daughters. Culturally appropriate educational pamphlets should also be made available. Preparation for delivery In many countries where FGC is practiced, prenatal care similar to that in Canada may not be available, and many births take place without skilled attendants. Health care may only be sought when complications arise. Many women with FGC prefer natural childbirth and fear Caesarean section and other unfamiliar medical procedures. The health care professional should take advantage of the prenatal visits to properly prepare the woman and her family for the delivery. The focus should be on developing a detailed birth plan with her and her family. Attention should be given to sharing information verbally and in other formats (if available) about when to come to the hospital, ission procedures, hospital policies, what to expect in the delivery room, who will be part of the health care team, the care she can expect from hospital nurses and staff, how interpreters are used at the hospital, length of stay, etc. Providing information about when and why defibulation will take place, when and why Caesarean sections are performed,

Female Genital Cutting

the pain medication options available (during and after labour), other medical procedures that might be necessary, and the call schedule also help the woman prepare for delivery. Referrals Referrals to other health care professionals and/or services are integral to the provision of quality and comprehensive care. Many women, however, may consider referrals for counselling to be foreign, not beneficial, and a waste of their time. When referring a woman, the health care professional should ensure that the services and/or practitioners who receive the referral can provide culturally appropriate and sensitive care to women with FGC. The professional should also explain to the woman beforehand why and where the referral has been made. A woman should be referred to counselling when she requests the referral, when the health care professional feels that counselling is necessary for a favourable outcome of treatment (e.g. when an infibulated pregnant woman shows signs of anxiety about defibulation and may be experiencing flashbacks of her FGC), or when the presenting symptoms are primarily psychological or sexual in nature. Recommendation

10. Key practices in providing optimal care to women with female genital cutting include: a. determining how the woman refers to the practice of female genital cutting and using this terminology throughout care; (III-C) b. determining the female genital cutting status of the woman and clearly documenting this information in her medical file; (III-C) c. ensuring the availability of a well-trained, trusted, and neutral interpreter who can ensure confidentiality and who will not exert undue influence on the patient–physician interaction when providing care to a woman who faces language challenges; (III-C) d. ensuring the proper documentation of the woman’s medical history in her file to minimize the need for repeated medical histories and/ or examinations and to facilitate the sharing of information; (III-C) e. providing the woman with appropriate and welltimed information, including information about her reproductive system and her sexual and reproductive health; (III-C) f. ensuring the woman’s privacy and confidentiality by limiting attendants in the room to those who are part of the health care team; (III-C)

g. providing woman-centred care focused on ensuring that the woman’s views and wishes are solicited and respected, including a discussion of why some requests cannot be granted for legal or ethical reasons; (III-C) h. helping the woman to understand and navigate the health system, including access to preventative care practices; (III-C) i. using prenatal visits to prepare the woman and her family for delivery; (III-C) j. when referring, ensuring that the services and/ or practitioners who will be receiving the referral can provide culturally competent and sensitive care, paying special attention to concerns related to confidentiality and privacy. (III-C) REFERENCES 1. World Health Organization, Department of Reproductive Health and Research. Eliminating female genital mutilation: an interagency statement. Geneva: WHO; 2008. Available at: http://www.who.int/ reproductivehealth/publications/fgm/9789241596442/en/index.html. Accessed on July 25, 2013. 2. Nova Scotia Department of Health. A cultural competence guide for primary health care professionals in Nova Scotia. Halifax: Nova Scotia Department of Health; 2005. Available at: http://www.healthteamnovascotia.ca/cultural_competence/ Cultural_Competence_guide_for_Primary_Health_Care_ Professionals.pdf. Accessed on July 25, 2013. 3. UNAIDS, UNDP, UNFPA, UNHCR, UNICEF, UNIFEM, et al. Global strategy to stop health care providers from performing female genital mutilation. Geneva: World Health Organization; 2010. Available at: http://www.who.int/reproductivehealth/publications/ fgm/rhr_10_9/en/index.html. Accessed on March 11, 2011. 4. Yoder PS, Khan S; USAID. Numbers of women circumcised in Africa: the production of a total. DHS Working Paper 39. Claverton MD: Macro International; 2004. Available at: http://www.measuredhs.com/ pubs/pdf/WP39/WP39.pdf. Accessed on July 25, 2013. 5. Lalonde A. Clinical management of female genital mutilation must be handled with understanding, comion. CMAJ 1995;152(6):949–50. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1337778/ pdf/cmaj00066-0153.pdf. Accessed on July 25, 2013. 6. MacLeod TL. Female genital mutilation. J SOGC 1995;17:333–42. 7. Omer-Hashi K, Entwistle MR. Female genital mutilation. Can J Public Health 1997;88(2):137. 8. Federal Interdepartmental Working Group on Female Genital Mutilation. FGM and health care: current situation and legal status—recommendations to improve health care of affected women. Ottawa: Health Canada; 2000. Available at: http://www.cwhn.ca/en/resource_en/results/FGM. Accessed on August 20, 2013. 9. Ontario Human Rights Commission. Policy on female genital mutilation (FGM). Toronto: OHRC: Toronto; 2000. Available at: http://www.ohrc.on.ca/en/resources/Policies/PolicyFGM2/pdf. Accessed on August 20, 2013. 10. Chalmers B, Hashi KO. 432 Somali women’s birth experiences in Canada after earlier female genital mutilation. Birth 2000;27:227–34.

NOVEMBER JOGC NOVEMBRE 2013 l e13

Clinical Practice Guidelines

11. Vissandjée B, Kantiebo M, Levine A, N’Dejuru R. The cultural context of gender, identity: female genital excision and infibulation. Health Care Women Int 2003;24(2):115–24.

29. Herrel N, Olevitch L, DuBois DK, Terry P, Thorp D, Kind E, et al. Somali refugee women speak out about their needs for care during pregnancy and delivery. J Midwifery Womens Health 2004;49:345–9.

12. Citizenship and Immigration Canada. Canada—facts and figures (immigration overview—permanent and temporary residents). Ottawa: CIC; 2009. Available at: http://www.cic.gc.ca/English/ resources/statistics/menu-fact.asp#tphp idtphp. Accessed on August 2, 2013.

30. Theirfelder C, Tanner C M, Bodiang K. Female genital mutilation in the context of migration: experience of African women with the Swiss health care system. Eur J Public Health 2005;15(1):86–90.

13. Chalmers B, Omer-Hashi K. What Somali women say about giving birth in Canada. J Reprod Infant Psychol 2002;20:267–82. 14. Sexuality Education Resource Center (SERC). Our selves, our daughters: community-based education addressing female genital cutting (FGC) with refugee and immigrant women in Winnipeg—final activity and evaluation report. Winnipeg: SERC; 2010. 15. Almroth L, Elmusharaf S. Genital mutilation of girls. Womens Health (Lond Engl) 2007;3:475–85. 16. Dorkenoo E, Morison L, Macfarlane A; Foundation for Women’s Health, Research and Development (FORWARD); The London School of Hygiene and Tropical Medicine; The Department of Midwifery, City University. A statistical study to estimate the prevalence of female genital mutilation in England and Wales: summary report. London: FORWARD; 2007. Available at: http://www.forwarduk.org.uk/ /96. Accessed on August 13, 2013. 17. Litorp H, Franck M, Almroth L. Female genital mutilation among antenatal care and contraceptive advice attendees in Sweden. Acta Obstet Gynecol Scand 2008;87:716–22. 18. Nour NM. Female genital cutting: clinical and cultural guidelines. Obstet Gynecol Surv 2004;59(4):272–9. 19. Berggren V, Musa Ahmed S, Hernlund Y, Johansson E, Habbani B, Edberg A-K. Being victims or beneficiaries? Perspectives on female genital cutting and reinfibulation in Sudan. Afr J Reprod Health 2006;10(2):24–36. 20. Vangen S, Stollenberg C, Johansen REB, Sundby J, Stray-Perderson B. Perinatal complications among ethnic Somalis in Norway. Acta Obstet Gynecol Scand 2002;81:317–22. 21. Bragg R. Maternal deaths and vulnerable migrants. Lancet 2008;371:879–81. Available at: http://www.uic.edu/orgs/womenshealth/ Maternal%20deaths%20and%20Vulnerable%20migrants.pdf. Accessed on August 3, 2013. 22. Toubia N. Caring for women with circumcision: a technical manual for health care providers. New York: Rainbow Publications; 1999. 23. Strickland JL. Female circumcision/female genital mutilation. J Pediatr Adolesc Gynecol 2001;14(3):109–12. 24. UNICEF Office of Research. Changing a harmful social convention: female genital mutilation/cutting. New York: UNICEF; 2005. Available at: http://www.unicef-irc.org/publications/396. Accessed on August 3, 2013. 25. UNICEF Office of Research. The Dynamics of social change: towards the abandonment of FGM/C in five African countries. New York: UNICEF; 2010. Available at: http://www.unicef-irc.org/publications/618. Accessed on August 3, 2013. 26. Morison LA, Dirir A, Elmi S, Warsame J, Dirir S. How experiences and attitudes relating to female circumcision vary according to age on arrival in Britain: a study among young Somalis in London. Ethn Health 2004;9:75–100. 27. Buckland RL. The everyday experience of Somali women in Canada: implications for health. Thesis. Ottawa: University of Ottawa; 1997. 28. Vangena S, Johansen RE, Sundby J, Traeen B, Stray-Pedersen B. Qualitative study of perinatal care experiences among Somali women and local health care professionals in Norway. Eur J Obstet Gynecol Reprod Biol 2004;15;112:29–35.

e14 l NOVEMBER JOGC NOVEMBRE 2013

31. Murray L, Windsor C, Parker E, Tewifik O. The experiences of african women giving birth in Brisbane, Australia. Health Care Women Int 2010;31:458–72. 32. Lundberg P, Gerezgiher A. Experiences from pregnancy and childbirth related to female genital mutilation among Eritrean immigrant women in Sweden. Midwifery 2008;24:214–25. 33. Upvall MJ, Mohammed K, Dodge PD. Perspectives of Somali Bantu refugee women living with circumcision in the United States. Int J Nurs Stud 2009;46:360–8. 34. Widmarck C, Tishelman C, Ahlberg BM. A study of Swedish midwives’ encounters with infibulated African women in Sweden. Midwifery 2002;1:113–25. 35. Johansen REB. Care for infibulated women giving birth in Norway: an anthropological analysis of health workers’ management of a medically and culturally unfamiliar issue. Med Anthropol Q 2006;20:516–44. 36. Zaidi N, Khalil A, Roberts C, Browne M. Knowledge of female genital mutilation among healthcare professionals. Contemp Nurse 2007;25:22–30. 37. Widmark C, Levál A, Tishelman C, Ahlberg BM. Obstetric care at the intersection of science and culture: Swedish doctors’ perspectives on obstetrical care of women who have undergone female genital cutting. J Obstet Gynaecol 2010;30:553–8. 38. Kaplan-Marcusán A, Fernández del Rio N, Moreno-Navarro J, Castany Fàbregas MJ, Muñoz-Ortiz L. Perception of primary health professionals about female genital mutilation: from healthcare to intercultural competence. BMC Health Services Research; 2009;9:11. 39. Hess R, Neinland J, Saalinger N. Knowledge of female genital cutting and experience with women who are circumcised: a survey of nurse-midwives in the United States. J Midwifery Womens Health 2010;55:45–54. 40. Abdulcadir J, Margairaz C, Boulvain M, Irion O. Care of women with female genital mutilation / cutting. Swiss Med Wkly 2011;140:w13137. 41. World Health Organization, Department of Reproductive Health and Research. Management of pregnancy, childbirth and the postpartum period in the presence of genital mutilation. Available at: http://www.who.int/reproductivehealth/publications/ maternal_perinatal_health/RHR_01_13_/en/index.html. Accessed on August 3, 2013. 42. Almroth L, Elmusharaf S, El Hadi N, Obeid A, El Sheikh MA, Elfadil SM, et al. Primary infertility after genital mutilation in girlhood in Sudan: a case-control study. Lancet 2005;366:385–91. 43. Raouf SB, Ball T, Hughes A, Holder R, Papaioannou S. Obstetric and neonatal outcomes for women with reversed and non-reversed type III female genital mutilation. Int J Gynaecol Obstet 2011;113:141–3. 44. Wuest S, Rajo L, Wyssmueller MD, Muller M, Stadlmaryr W, Surbek DV, et al. Effects of female genital mutilation on birth outcomes in Switzerland. BJOG 2009;116:1204–9. 45. BMA Ethics. Female genital mutilation: caring for patients and safeguarding children. BMA Guideline. 2011. Available at: http://bma.org.uk/search?query=Female%20genital%20mutilation. Accessed on August 3, 2013. 46. Ndiaye P, Diongue M, Faye A. Ouedraogo D, Tal Dia A. [Female genital mutilation and complications in childbirth in the province of Gourma (Burkina Faso)]. Sante Publique 2010;22:563–70.

Female Genital Cutting

47. Okonofu FE, Larsen U, Oronsaye F, Snow RC, Slanger TE. The association between female genital cutting and correlates of sexual and gynaecological morbidity in Edo State, Nigeria. BJOG 2002;109:1089–96. 48. Krause E, Brandner S, Mueller MD, Kuhn A. Out of Eastern Africa: defibulation and sexual function in woman with female genital mutilation. J Sex Med 2011;8:1420–5. 49. Almroth L, Almroth-Bergren V, Hassanein OM, Al-Said SSE, Hasan SSA, Lithell UB, et al. Male complications of female genital mutilation. Soc Sci Med 2001;53:1455–60. 50. Berendt A, Moritz S. Post-traumatic stress disorder and memory problems after female genital mutilation. Am J Psychiatry 2005;162:1000–2. 51. Sexuality Education Resource Centre Manitoba. Working with women and girls who have experienced female genital cutting/female genital mutilation. Winnipeg: SERC; 2000. Available at: http://www.serc.mb.ca/content/dload/ WorkingWithWomenAnd GirlsWhoHaveExperiencedFemaleGenital CuttingFemaleGenitalMutiliationCulturallySensitiveCounselling/file. Accessed on March 13, 2011. 52. Adamson F. Female genital mutilation: a counselling guide for professionals. London: FORWARD; 1995.

53. Horowitz C, Jackson JC. Female “circumcision”: African women confront American medicine. J Gen Intern Med 1997;12:513–5. 54. Carroll J, Epstein R, Fiscella K, Gipson T, Volpe E, Jean-Pierre P. Caring for Somali women: implications for clinician–patient communication. Patient Educ Couns 2007;66:337–45. 55. Turner D. Female genital cutting: implications for nurses. Nurs Womens Health 2007;11:366–72. 56. London Safeguarding Children Board. London FGM resource pack. London: London Safeguarding Children Board; 2009. Available at: http://www.londonscb.gov.uk/fgm. Accessed on August 20, 2013. 57. Omer-Hashi K. Commentary: female genital mutilation: perspectives from a Somalian midwife. Birth 1994;21:224–6. 58. Ford AR, Legault P, Russell J, Van Wagner V; Equity Committee of the Interim Regulatory Council on Midwifery. Midwifery care for immigrant and refugee women in Ontario. Can Womens Stud 1994;14:83. 59. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

Appendices begin on next page

NOVEMBER JOGC NOVEMBRE 2013 l e15

Clinical Practice Guidelines

APPENDIX 1. Criminal Code of Canada Sections of the Criminal Code of Canada that address or could be used to address FGC (Criminal Code of Canada, December 14, 2011)1

Aggravated assault

268. (1)

Every one commits an aggravated assault who wounds, maims, disfigures or endangers the life of the complainant.

Punishment (2) Every one who commits an aggravated assault is guilty of an indictable offence and liable to imprisonment for a term not exceeding fourteen years. Excision (3) For greater certainty, in this section, “wounds” or “maims” includes to excise, infibulate or mutilate, in whole or in part, the labia majora, labia minora or clitoris of a person, except where (a) a surgical procedure is performed, by a person duly qualified by provincial law to practise medicine, for the benefit of the physical health of the person or for the purpose of that person having normal reproductive functions or normal sexual appearance or function; or (b) the person is at least eighteen years of age and there is no resulting bodily harm. Consent (4) For the purposes of this section and section 265, no consent to the excision, infibulation or mutilation, in whole or in part, of the labia majora, labia minora or clitoris of a person is valid, except in the cases described in paragraphs (3)(a) and (b).

Removal of child from Canada 273.3 (1) No person shall do anything for the purpose of removing from Canada a person who is ordinarily resident in Canada and who is (a) under the age of 16 years, with the intention that an act be committed outside Canada that if it were committed in Canada would be an offence against section 151 or 152 or subsection 160(3) or 173(2) in respect of that person; (b) 16 years of age or more but under the age of eighteen years, with the intention that an act be committed outside Canada that if it were committed in Canada would be an offence against section 153 in respect of that person; or (c) under the age of eighteen years, with the intention that an act be committed outside Canada that if it were committed in Canada would be an offence against section 155 or 159, subsection 160(2) or section 170, 171, 267, 268, 269, 271, 272 or 273 in respect of that person.

Criminal negligence

219. (1)

Every one is criminally negligent who (a) in doing anything, or (b) in omitting to do anything that it is his duty to do, shows wanton or reckless disregard for the lives or safety of other persons.

Accessory after the fact

23. (1)

An accessory after the fact to an offence is one who, knowing that a person has been a party to the offence, receives, comforts or assists that person for the purpose of enabling that person to escape.

Duty of persons to provide necessaries

215. (1) Every one is under a legal duty (a) as a parent, foster parent, guardian or head of a family, to provide necessaries of life for a child under the age of sixteen years; (b) to provide necessaries of life to their spouse or common-law partner; and (c) to provide necessaries of life to a person under his charge if that person (i) is unable, by reason of detention, age, illness, mental disorder or other cause, to withdraw himself from that charge, and (ii) is unable to provide himself with necessaries of life

REFERENCE 1. Department of Justice. Consolidation Criminal Code (R.S.C., 1985, c. C-48). Act current to 2011-12-14. Available at: http://laws-lois.justice.gc.ca/eng/ acts/C-46. Accessed on August 2, 2013.

e16 l NOVEMBER JOGC NOVEMBRE 2013

Female Genital Cutting

APPENDIX 2. Statements and Policies Provided by Provincial Medical Bodies The Provincial Medical Board of Nova Scotia During the past few years, attention has been drawn to the practice of female genital mutilation (FGM). There has been an increase in immigration to Canada from those areas of the world which allow this practice. Female genital mutilation is irreversible and imposed on young girls without their consent. While this practice is entertained for cultural reasons, there are severe long-term physical and psychological complications for these young girls. Many groups, including UNICEF, WHO, and African women’s groups have spoken forcefully against FGM. In 1992, the College of Physicians and Surgeons of British Columbia and Alberta endorsed the World Health Organization position which condemns militating procedures. The Provincial Medical Board of Nova Scotia (PMB) would like to add its voice to these groups. The Board considers the practice of FGM such as excision of female genitalia, female circumcision, and infibulation as unacceptable medical procedures. FGM is an inhumane practice and physicians in Nova Scotia are advised not to perform this surgery nor to attempt to reconstruct the infibulations after a vaginal delivery. The PMB considers FGM outside the acceptable standards of medical care in Nova Scotia and Canada. In addition, the practice of FGM is illegal according to Canada’s Criminal Code as advised by the Federal Minister of Justice (1994). (Statement provided by College of Physicians and Surgeons of Nova Scotia on November 30, 2010.)

Le Collège des médecins du Québec Notice published in the BULLETIN, Vol. XXXIV, No. 3 – September 1994. In the last few years, female genital cutting has made headlines around the world. Canada has recently welcomed immigrants and refugees originating from regions where female genital cutting is practiced. Female genital cutting is irreversible. Some cultures may view it as an important ritual, but it nevertheless results in long-term physical and psychological traumas for young women. It’s not the first time that this topic has been debated. Such a practice is unacceptable, particularly in view of articles 2.03.01, 2.03.14, 2.03.17, and 2.03.23 of the Code of ethics of physicians. It is also proscribed by the Criminal Code. The Corporation wishes to remind its that they must refuse to collaborate or participate in such procedures. Physicians called upon to treat victims of such mutilations must show these patients respect and empathy. (Statement provided by Le Collège des médecins du Québec representative on November 29, 2010.)

The College of Physicians and Surgeons of Ontario Female Cutting (Mutilation)1 PRINCIPLES The practice of medicine is guided by the values of comion, service, altruism and trustworthiness. These values form the basis of professionalism. The physician–patient relationship is the foundation of the practice of medicine and a physician has the duty to always act in the patient’s best interest. Good communication is a fundamental component of a trusting physician–patient relationship. Physicians should demonstrate cultural sensitivity in their communication with patients and families. [3] POLICY Physicians must not perform any FGC/M procedures. Further, physicians must not refer patients to any person for the performance of FGC/M procedures. The performance of, or referral for, FGC/M procedures by a physician will be regarded by the College as professional misconduct. Where there is doubt if a procedure is considered to be FGC/M physicians should seek advice from the Canadian Medical Protective Association and/or legal counsel. During the course of a vaginal delivery of a woman who has been previously subjected to an FGC/M procedure, a physician may find it necessary to surgically disrupt the scar tissue resulting from the earlier procedure. In this circumstance, at the conclusion of the delivery, the physician must confine activities to repairing the surgical incision or laceration required during the delivery, and must not, for example, endeavour to reconstruct an infibulation. Wherever possible, the physician should advise the patient of this limitation prior to delivery; ideally this conversation should be had prior to pregnancy and during the course of prenatal care. Reporting The performance of FGC/M procedures on a female under the age of 18 by any person may constitute child abuse. Physicians who have reasonable grounds to believe than an FGC/M procedure has been performed on, or is being contemplated for, any female under the age of 18, must notify the appropriate child protection authorities, regardless of where the procedure has been or will be undertaken. [4] In the event that a physician has reasonable grounds to believe that another physician is performing FGC/M procedures, the matter should immediately be brought to the attention of the College. This expectation is based in professionalism and ethics, and is distinct from the legal obligation to report child abuse discussed above. Continued NOVEMBER JOGC NOVEMBRE 2013 l e17

Clinical Practice Guidelines

APPENDIX 2. Continued Care of Patients As appropriate, physicians should provide culturally sensitive counseling regarding the dangers related to performing FGC/M procedures. As part of their commitment to treat patients with comion, physicians who encounter patients subjected to FGC/M procedures should educate themselves on the appropriate management of possible complications, in order to provide appropriate counsel and care. Endnotes 3. See the SO’s Practice Guide at http://www.so.on.ca under Policies and Publications. 4. Pursuant to Child and Family Services Act, R.S.O. 1990, c.C11, s.72(1) and the Criminal Code, R.S.C. 1985, c. C-46, s 273(1) and the SO’s Mandatory Reporting policy.

The College of Physicians and Surgeons of Manitoba Female Circumcision (Revised 2001)2 Female circumcision is not an appropriate medical practice under any circumstance and if performed by a physician, represents professional misconduct. If a physician is aware of a proposal to perform female circumcision on a child, the incident must be reported pursuant to the requirement to report child abuse set forth in The Child and Family Services Act.

The College of Physicians and Surgeons of Alberta Directive provided by the Council to its (1994) THAT physicians, as well as other providers of women’s health care, be made aware of the issues involved in Female Genital Mutilation (FGM). Specifically, physicians must not perform FGM. Where physicians encounter medical complications of FGM, they shall manage these in a culturally sensitive and ethical manner; this may require individualized consideration of secondary reconstruction of the previous FGM. (Statement provided by SA representative on December 1, 2010.)

The College of Physicians and Surgeons of British Columbia College’s Position3 The College endorses the position of the World Health Organizational (WHO), and many other medical organizations, regarding female genital mutilation, as having no health benefits, and both immediate and long-term negative health consequences. – A physician must decline to perform female genital mutilation and must not make a referral for the purpose of female genital mutilation. – An adult parent or guardian cannot consent to the excision, infibulation or mutilation of the labia majora, labia minora or clitoris on behalf of a child, except in the circumstances described under section 268(3) of the Criminal Code. – Urgent action must be taken if a physician considers that a child may be at risk of female genital mutilation. Duty to Report3 A physician must report to the College and the Ministry of Children and Family Development if: – A physicians learns of another physician performing female genital mutilation; – A physician is requested to perform female genital mutilation or learns that these procedures may be performed on a child or person under 18 years of age; or – A physician considers that a child may be at risk in relation to the practice of female genital mutilation.

REFERENCES 1. The College of Physicians and Surgeons of Ontario. Female genital cutting (mutilation). Policy #2-11. Available at: http://www.so.on.ca/policies/policies/default.aspx?ID=1596. Accessed on August 2, 2013. 2. The College of Physicians and Surgeons of Manitoba. Female circumcision (2011 rev.) Statement 111. Available at: http://sm.mb.ca/cjj39alckF30a/wp-content/s/st111.pdf. Accessed on August 2, 2013. 3. College of Physicians and Surgeons of British Columbia. Professional standards and guidelines: female genital mutilation. Available at: https://www.sbc.ca/files/u6/Female-Genital-Mutilation.pdf. Accessed on August 2, 2013.

e18 l NOVEMBER JOGC NOVEMBRE 2013

SOGC CLINICAL PRACTICE GUIDELINE SOGC CLINICAL PRACTICE GUIDELINE

No. 209, July 2008

Guideline for the Management of Postoperative Nausea and Vomiting This guideline has been approved by Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Geoff McCracken, MB, BCh, Toronto ON Patricia Houston, MD, Toronto ON Guylaine Lefebvre, MD, Toronto ON

2. When the choice is available, patients should be advised that the risk of PONV decreases when regional rather than general anaesthesia is istered. (III-A) 3. The perioperative use of opioids should be minimized. Surgeons should evaluate the risks/benefits of opioid istration in light of the increased risk of PONV. (III-B) 4. Prophylactic antiemetics should be istered to patients with moderate or high risk of developing PONV. (II-1A) 5. In patients with a high risk of developing PONV, combination antiemetic therapy should be considered. (III-B)

Abstract Objective: To provide recommendations for the management of postoperative nausea and vomiting (PONV), which may affect as many as 30% of patients. Methods and Evidence: Medline, PubMed, and the Cochrane Database were searched for articles published in English from 1995 to 2007. Recognizing that we must work as a team to optimize the care of our patients perioperatively, this guideline was written in partnership with anaesthesiologists.

6. Acupoint electrical stimulation may be used as an alternative or adjuvant therapy for prevention of PONV. (II-1A) 7. For patients with PONV who did not receive prophylaxis or in whom prophylaxis failed, antiemetic treatment should be istered as soon as feasible. (III-A) 8. When prophylaxis with one drug has failed, a repeat dose of this drug should not be initiated as a rescue therapy; instead, a drug from a different class of antiemetic drugs should be istered. (III-A)

Options: The areas of clinical practice considered in formulating this guideline are prevention and prophylaxis, treatment, both medical and alternative, and patient education.

9. As patients who undergo surgery in surgical daycare units may have PONV after they are discharged, they should be given instructions for its management. (III-B)

Outcomes: Implementation of this guideline should optimize the prevention of and prophylaxis against PONV and the prompt treatment of women who suffer from PONV following gynaecologic surgery. Increased awareness of options for management should help minimize the effects of PONV.

10. Patients at high risk of developing PDNV should be provided with rescue treatment. (III-B)

Benefits, Harms, and Costs: PONV results not only in increased patient discomfort and dissatisfaction but also in increased costs related to length of hospital stay. Cost of medications to prevent and treat PONV must be weighed against improved surgical experience for the patient and decreased costs to the system. Values: Recommendations were made according to the guidelines developed by the Canadian Task Force on Preventive Health Care. Recommendations 1. Physicians should be aware of the risk factors associated with PONV, and the baseline risks should be reduced whenever possible. (III-A)

Key Words: Postoperative nausea, postoperative vomiting

J Obstet Gynaecol Can 2008;30(7):600–607

INTRODUCTION

ostoperative nausea and vomiting, defined as nausea and/or vomiting occurring within 24 hours after surgery, affects between 20% and 30% of patients.1–4 As many as 70% to 80% of patients at high risk may be affected.5 The etiology of PONV is thought to be multifactorial, involving individual, anaesthetic, and surgical risk factors.2,5,6 PONV results in increased patient discomfort and dissatisfaction6 and in increased costs related to length of hospital stay. One study revealed that the time to discharge was increased by 25% in patients with PONV.7 Serious medical complications such as pulmonary aspiration, although uncommon, are also associated with vomiting.6

P

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

600

l JULY JOGC JUILLET 2008

Guideline for the Management of Postoperative Nausea and Vomiting

Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of Evidence Assessment*

Classification of Recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case-control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

D. There is fair evidence to recommend against the clinical preventive action E. There is good evidence to recommend against the clinical preventive action L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.75 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the The Canadian Task Force on Preventive Health Care.75

PONV is a significant problem for patients: in one study, patients were more concerned about PONV than about postoperative pain8; in another, patients were willing to spend up to US $100 for an effective antiemetic treatment.9 Several thousand studies examining PONV have been published, and several hundred new papers are published each year on the topic. Guidelines for the prevention and management of PONV have been published by anaesthetic journals and societies.10–12 Management of PONV for gynaecological patients in most hospitals continues to be on an ad hoc basis. The aim of these guidelines is to provide information on the management of PONV in gynaecological patients.

afferent pathways involved in stimulating the vomiting centre are: 1. the chemoreceptor triggering zone, 2. the vagal mucosal pathway in the gastrointestinal system, 3. neuronal pathways from the vestibular system, 4. reflex afferent pathways from the cerebral cortex C2,3, and 5. midbrain afferents. Stimulation of one of these afferent pathways can activate the vomiting centre via cholinergic (muscarinic), dopaminergic, histaminergic, or serotonergic receptors.

PHYSIOLOGY OF NAUSEA AND VOMITING

MANAGEMENT OF PONV

Primary control of nausea and vomiting arises from the vomiting centre, located in the medulla. The five primary

Reduction in Baseline Risk Factors

ABBREVIATIONS CTZ

chemoreceptor triggering zone

NK-1

neurokinin-1 receptor antagonist

NNT

number needed to treat

NSAIDs nonsteroidal anti-inflammatory drugs

Blanket use of PONV prophylaxis is not cost-effective and unnecessarily risks drug-related adverse effects. Most guidelines are in agreement that patients at low risk for PONV are unlikely to benefit from prophylaxis and that it should be reserved for patients at moderate to high risk. Patients with no more than one risk factor are considered low risk. Identifying patient risks remains a challenge. Apfel et al.13 devised a simplified risk score for predicting PONV. They concluded that there are 4 main risk factors:

PDNV

post-discharge nausea and vomiting

1. female sex,

PONV

postoperative nausea and vomiting

2. prior history of motion sickness or PONV, JULY JOGC JUILLET 2008 l

601

SOGC CLINICAL PRACTICE GUIDELINE

3. non-smoker, and

Recommendations

4. the use of postoperative opioids.

2. When the choice is available, patients should be advised that the risk of PONV decreases when regional rather than general anaesthesia is istered. (III-A)

The estimated probability of PONV was 10%, 21%, 39%, and 78% with 0, 1, 2, 3, and 4 risk factors, respectively. Risk Factors for PONV

These can de divided into 3 main groups: • Patient-specific: female sex8,13; non-smoker13,14; history of PONV or motion sickness.13–15 • Anaesthetic: use of volatile anaesthetics within 0 to 2 hours16; use of nitrous oxide17; use of intraoperative and postoperative opioids13,18–21; high doses of neostigmine. • Surgical: duration of surgery, with each 30-minute increase in duration increasing the risk of PONV by 60%.22 Recommendation 1. Physicians should be aware of the risk factors associated with PONV, and the baseline risks should be reduced whenever possible. (III-A) Optimization in the Perioperative Period A number of perioperative factors have been shown to reduce the risk of PONV. When possible, regional anaesthetic should be istered as general anaesthetic is associated with an 11-fold increased risk of PONV.22 When general anaesthetic is required, the use of propofol as the induction agent is effective in reducing early PONV incidence when compared with other induction agents. The number needed to treat with propofol to reduce PONV is approximately 5.23 Avoidance of intraoperative and postoperative opioids has been shown to reduce PONV. Moiniche et al. showed that treatment with NSAIDs as compared with opioids decreased the risk of PONV.20 The use of supplemental oxygen perioperatively has been shown to reduce PONV by 50%.24,25 possibly by reducing gastrointestinal hypoxia. However, there is conflicting evidence, and a recent study by Turan et al. demonstrated no benefit associated with supplemental oxygen.26 Perioperative intravenous fluid istration has been shown to reduce PONV.27,28 The mechanism is unclear but may be related to the release of serotonin due to decreased intestinal perfusion, which can be caused by the drop in systolic blood pressure seen with some induction agents. Neostigmine, a reversal agent for non-depolarising muscle relaxants, is associated with increased PONV, especially in large doses (> 2.5 mg),29 and should be avoided if possible. 602

l JULY JOGC JUILLET 2008

3. The perioperative use of opioids should be minimized. Surgeons should evaluate the risks/benefits of opioid istration in light of the increased risk of PONV. (III-B) Pharmacological Prophylaxis

Prophylactic doses and timing for the istration of antiemetics are shown in Table 2. Serotonin (5-HT3) receptor antagonists exert their effects in the chemoreceptor trigger zone and at vagal afferents in the gastrointestinal tract. Ondansetron was the first of this class of drug to be marketed; others include dolasetron, tropisetron, and granisetron. In 2003, an expert agreed that there was no evidence of any difference in the efficacy and safety profiles of the different 5-HT3 receptor antagonists in the prophylaxis against PONV.10 Ondansetron 4 mg has a NNT of 7 for the prevention of nausea and 6 for the prevention of vomiting. The number needed to harm with a single dose of ondansetron is 36 for headache, 31 for increased liver enzymes, and 23 for constipation.30 Dexamethasone, a corticosteroid, istered at a dose of 8–10 mg IV, prevents PONV with a NNT of 4.38 Smaller doses of 2.5–5 mg have been shown to be as effective13,40 The precise mode of action is not well understood, but may be due to the release of endorphins that elevate mood and stimulate appetite.16 There are no reports of adverse effects in the doses used for the management of PONV.38 Droperidol blocks dopamine receptors in the CTZ. The efficacy of droperidol is equivalent to that of ondansetron, with a NNT of 5 for prevention of PONV. The FDA issued a “black box” warning about droperidol, stating that it may cause death associated with QT prolongation and torsades de pointes. In Canada, droperidol is still available but its use is limited by Health Canada.48 Metoclopramide blocks dopamine receptors in the CTZ and vomiting centre. It also shortens bowel transit time and in high doses blocks serotonin receptors. When used in standard clinical doses of 10 mg, metoclopramide was found to be ineffective for PONV prophylaxis.49 A dose of 50 mg intravenous metoclopramide has been shown to significantly reduce late (> 12 hours) PONV, but the side effect profile is unsatisfactory.47 The guidelines produced by Gan et al. do not recommend metoclopramide as a perioperative antiemetic.10 Dimenhydrinate, a commonly used antihistaminic, has similar efficacy to 5-HT3 receptor antagonists.43 Its efficacy is

Guideline for the Management of Postoperative Nausea and Vomiting

Table 2. Prophylactic doses and timing for the istration of antiemetics Drug

Timing

Dose 30

Adverse effects 31

At end of surgery

Headache, lightheadedness, elevated liver enzymes

Ondansetron

4–8 mg IV

Dolasetron

12.5 mg IV32

At end of surgery32

Headache, lightheadedness, elevated liver enzymes

Granisetron

0.35–1mg IV33–35

At end of surgery33,35

Headache, lightheadedness, elevated liver enzymes

Tropisetron

5 mg IV36,37

At end of surgery36,37

Headache, lightheadedness, elevated liver enzymes

Dexamethasone

5–10 mg IV38–40

Before induction41

Vaginal itching or anal irritation with IV bolus

Droperidol

0.625–1.25 mg IV36,37

At end of surgery42

Sedation, dizziness, anxiety, hypotension, EPS

Dimenhydrinate

1–2mg/kg IV43

Prochlorperazine

5–10mg IV44

Promethazine

12.5–25mg IV

Sedation, dry mouth, blurred vision, dizziness, urinary retention

44 45,46

Scopolamine

Transdermal patch

Metoclopramide

25 or 50 mg IV for prophylaxis47

Diclectin

10 mg doxylamine succinate and 10 mg pyridoxine hydrochloride

At end of surgery44

Sedation, hypotension, EPS

At end of surgery44

Sedation, hypotension, EPS

Prior evening or 4 hours before end of surgery46

Sedation, dry mouth, visual disturbances; CNS effects in elderly patients, renal or hepatic impairment Sedation, hypotension, EPS

Before induction Prior evening, 2 tablets Before induction, morning of surgery, 1 tablet After surgery, 1 tablet

Aprepitant

40 mg PO

1–3 hours prior to induction of anaesthesia

presumably due to the high concentration of histamine and muscarinic cholinergic receptors within the vestibular system.50 Promethazine and prochlorperazine belong to a group of drugs known as phenothiazines, which act primarily via a central antidopaminergic mechanism in the CTZ. The use of these drugs has decreased because of their significant side effects: sedation, dizziness, and extrapyramidal symptoms. Scopolamine is an anticholinergic that blocks emetic muscarinic receptors in the cerebral cortex.51 It is very effective, with a NNT of 3.8 for prevention of PONV.52 Its use is limited because of its two- to four-hour onset of effect and side effect profile as listed above. A recent publication has shown Diclectin to be as effective as ondansetron for the prevention of late postoperative vomiting in women undergoing laparoscopic tubal ligation, with an average NNT of 5.9.53 Diclectin is an antiemetic medication that contains 10 mg doxylamine succinate (a common antihistamine with

Headache, fatigue, dizziness elevated liver enzymes

antiemetic properties found in over-the-counter sleeping medication) and 10 mg pyridoxine hydrochloride (vitamin B6), in a delayed release formulation. Pyridoxine may have intrinsic antiemetic properties and also may be synergistic with the antinauseant property of antihistamines.54–56 Diclectin has been used since the 1950s and is considered to be a safe treatment for nausea and vomiting associated with pregnancy.57 The International Cochrane Collaboration has systematically reviewed randomized trials of Diclectin and concluded that it safely provides considerable relief for nausea and vomiting in pregnancy.58 Aprepitant was the first neurokinin-1 (NK-1) receptor antagonist approved for the treatment of PONV. This drug blocks NK1 receptors in the central and peripheral nervous systems thus preventing emesis. In one study, patients given oral aprepitant alone or in combination with intravenous ondansetron had significantly fewer emetic episodes than those given ondansetron alone.59 In a report of combined data from 2 large trials, oral aprepitant 40 mg was superior to intravenous ondansetron 4 mg for the prevention of PONV.60 Complete response (no nausea, vomiting, or need JULY JOGC JUILLET 2008 l

603

SOGC CLINICAL PRACTICE GUIDELINE

for rescue therapy) was achieved in 37.9% of the aprepitant group compared with 31.2% of the ondansetron group. Its acquisition cost is relatively high, making it less appealing as a first line agent. None of the available agents is entirely effective for preventing PONV, particularly for high-risk patients. As there are four major receptor systems involved in the etiology of PONV, a combination of agents that act on different receptors results in better prophylaxis.61,62 The most commonly studied combinations have included 5-HT3 receptor antagonists with droperidol or dexamethasone, and both are equally efficacious.63,64 The Figure illustrates a proposed algorithm for the management of PONV Recommendations 4. Prophylactic antiemetics should be istered to patients with moderate or high risk of developing PONV. (II-1 A) 5. In patients with a high risk of developing PONV, combination antiemetic therapy should be considered. (III-B) 604

l JULY JOGC JUILLET 2008

Non-pharmacologic Prophylaxis

Acupuncture has been shown to be effective in the management of PONV. Coloma et al.65 compared acustimulation with ondansetron for the treatment of established PONV in outpatient laparoscopic surgery patients. They concluded that acustimulation may be a satisfactory alternative to ondansetron for established PONV, and that ondansetron seems to enhance the efficacy of acustimulation for treatment of established PONV. Ginger root is a commonly used non-medical therapy but is not effective for PONV prophylaxis.66 Similarly, cannabinoids have not been confirmed to be effective in the management of PONV. Recommendation 6. Acupoint electrical stimulation may be used as an alternative or adjuvant therapy for prevention of PONV. (II-1 A)

Guideline for the Management of Postoperative Nausea and Vomiting

Rescue Treatment for PONV

In the presence of persistent nausea and vomiting, possible contributing factors, such as patient-controlled morphine analgesia, presence of blood in the pharynx, or an abdominal obstruction, should be excluded before rescue therapy may be initiated. When prophylaxis with one drug has failed, a repeat dose of this drug should not be initiated as a rescue therapy. Instead a drug from a different class of antiemetics should be istered.67 However, if the PONV occurs more than 6 hours after surgery, repeat dosing of the initial prophylactic drug may be considered. Repeat doses of dexamethasone and transdermal scopolamine should not be istered regardless of the time interval.10 If a patient has received no prophylaxis, treatment with a 5-HT3 receptor antagonist may be considered.68 Rescue treatment doses for 5-HT3 receptor antagonists are approximately 25% the dose of those used for prophylaxis (e.g., 1 mg ondansetron). Recommendations 7. For patients with PONV who did not receive prophylaxis or in whom prophylaxis failed, antiemetic treatment should be istered as soon as feasible. (III-A) 8. When prophylaxis with one drug has failed, a repeat dose of this drug should not be initiated as a rescue therapy; instead, a drug from a different class of antiemetic drugs should be istered. (III-A) Post-discharge Nausea and Vomiting

PDNV is nausea and/or vomiting that occur after discharge from the health care facility, but within the 24-hour period immediately following surgery. Post-discharge nausea and vomiting that occurs after the initial 24-hour postoperative period is considered delayed PDNV.69 Post-discharge nausea and vomiting is becoming more common as more patients are being operated on in an ambulatory setting, and it has been reported in 35% to 50% of patients.70,71 In a recent meta-analysis, the NNT to prevent post discharge nausea following ambulatory surgery was 12.9, 12.2, and 5.2 following the prophylactic istration of ondansetron 4 mg, dexamethasone, and a combination of two antiemetics, respectively. For post-discharge vomiting, the NNT was 13.8 for ondansetron 4 mg and 5 for combination treatment. These results suggest that ondansetron alone should not be used routinely in ambulatory patients at low risk and that patients at high risk are best managed with a combination strategy.72 Optimal management of PDNV is uned by scientific evidence, and the choice of medication for PDNV is left to the clinician.

In a study by Gan et al.73 4 mg IV ondansetron for PONV prophylaxis was istered. Patients were then randomized to receive either ondansetron oral disintegrating tablet (ODT) 8 mg or placebo immediately before discharge from the ambulatory surgery centre and again 12 hours later. Patients who received ondansetron ODT had less severe nausea and fewer vomiting episodes (3% vs. 23%) after discharge. Al-Sadi et al.74 assessed the efficacy of acupuncture as a prophylactic antiemetic. They found a significant difference between groups before and after discharge, with the placebo group four times more likely to have post-discharge nausea and vomiting than the acupuncture group. Recommendations 9. As patients who undergo surgery in surgical daycare units may have PONV after they are discharged, they should be given instructions for its management. (III-B) 10. Patients at high risk of developing PDNV should be provided with rescue treatment. (III-B) REFERENCES 1. Kovac AL. Prevention and treatment of postoperative nausea and vomiting. Drugs 2000;59;213–43. 2. Watcha MF, White PF. Postoperative nausea and vomiting: its aetiology, treatment and prevention. Anesthesiology 1992; 77;162–84 3. Leman J. Surgical and patient factors involved in postoperative nausea and vomiting. Br J Anaesth 1992; 69(Suppl 1):S24–32. 4. Cohen MM, Duncan PG, DeBoer DP, Tweed WA. The postoperative interview; assessing risk factors for nausea and vomiting. Anesth Analg 1994;78:7–16. 5. Camu F, Lauwers MH, Verbessem D. Incidence and aetiology of postoperative nausea and vomiting. Eur J Anaesthesiol 1992; 9(Suppl 6);25–31. 6. Palazzo MG, Strunin L. Anaesthesia and emesis: 1. Etiology, Can Anaesth Soc J 1984;31:178–87. 7. Chung F, Mezei F. Factors contributing to a prolonged stay after ambulatory surgery. Anesth Analg 1999;89:1352–9. 8. Macario A, Weinger M, Carney S, Kim A. Which clinical anesthesia outcomes are important to avoid? Anesth Analg 1999;89:652–8. 9. Gan T, Sloan F, Dear Gde L, El-Moalem HE, Lubarsky DA. How much are patients willing to pay to avoid postoperative nausea and vomiting? Anesth Analg 2001;92;393–400. 10. Gan TJ, Meyer T, Apfel CC, Chung F, Davis PJ, Eubanks S, et al. Consensus guidelines for managing postoperative nausea and vomiting. Anesth Analg 2003;97;62–71. 11. TramPr MR. A rational approach to the control of postoperative nausea and vomiting: evidence from systemic reviews. I. Efficacy and harm of antiemetic interventions, and methodological issues. Acta Anaesthesiol Scand 2001; 45:4–13. 12. Tramèr MR. A rational approach to the control of postoperative nausea and vomiting: evidence from systemic reviews. II. Recommendations for prevention and treatment and research agenda. Acta Anaesthesiol Scand 2001;45:14–9. 13. Apfel CC, Läärä E, Koivuranta M, Greim CA, Roewer N. A simplified risk score for predicting postoperative nausea and vomiting. Anesthesiology 1999;91:693–700.

JULY JOGC JUILLET 2008 l

605

SOGC CLINICAL PRACTICE GUIDELINE

14. Koivuranta M, Laara E, Snare L, Alahuhta S. A survey of postoperative nausea and vomiting. Anaesthesia 1997;52:443–9. 15. Sinclair DR, Chung F, Mezei G. Can postoperative nausea and vomiting be predicted? Anesthesiology 1999;91:109–18. 16. Apfel CC, Kranke P, Katz MH, Goepfert C, Papenfuss T, Rauch S, et al. Volatile anaesthetics may be the main cause of early but not delayed postoperative vomiting: a randomized controlled trial of factorial design. Br J Anaesth 2002;88:659–68. 17. TramPr M, Moore A, McQuay H. Omitting nitrous oxide in general anaesthesia: meta-analysis of intraoperative awareness and postoperative emesis in randomized controlled trials. Br J Anaesth 1996;76:186–93. 18. Apfel CC, Kranke P, Eberhart LH, Roos A, Roewer N. Comparison of predictive models for postoperative nausea and vomiting. Br J Anaesth 2002;88:234–40. 19. Sukhani R, Vazquez J, Pappas AL, Frey K, Aasen M, Slogoff S. Recovery after propofol with and without intraoperative fentanyl in patients undergoing ambulatory gynecologic laparoscopy. Anesth Analg 1996;83:975–81. 20. Mriniche S, Rrmsing J, Dahl JB, TramPr MR. Nonsteroidal anti-inflammatory drugs and the risk of operative site bleeding after tonsillectomy: a quantitative systematic review. Anesth Analg 2003;96:68–77. 21. Polati E, Verlato G, Finco G, Mosaner W, Grosso S, Gottin L, et al. Ondansetron versus metoclopramide in the treatment of postoperative nausea and vomiting. Anesth Analg 1997;85:395–9. 22. Sinclair DR, Chung F, Mezei G. Can postoperative nausea and vomiting be predicted? Anesthesiology 1999;91:109–18. 23. Visser K, Hassink EA, Bonsel GJ, Moen J, Kalkman CJ. Randomized controlled trial of total intravenous anesthesia with propofol versus inhalation anesthesia with isoflurane-nitrous oxide: postoperative nausea with vomiting and economic analysis. Anesthesiology 2001;95:616–26. 24. Greif R, Laciny S, Rapf B, Hickle RS, Sessler DI. Supplemental oxygen reduces the incidence of postoperative nausea and vomiting. Anesthesiology 1999;91:1246–52.

32. Graczyk SG, McKenzie R, Kallar S, Hickok CB, Melson T, Morrill B, et al. Intravenous dolasetron for the prevention of postoperative nausea and vomiting after outpatient laparoscopic gynecologic surgery. Anesth Analg 1997;84:325–30. 33. Wilson AJ, Diemunsch P, Lindeque BG, Scheinin H, Helbo-Hansen HS, Kroeks MV, et al. Single-dose IV granisetron in the prevention of postoperative nausea and vomiting. Br J Anaesth 1996;76:515–8. 34. Cieslak GD, Watcha MF, Phillips MB, Pennant JH. The dose response relation and cost-effectiveness of granisetron for the prophylaxis of pediatric postoperative emesis. Anesthesiology 1996;85:1076–85. 35. Mikawa K, Takao Y, Nishina K, Shiga M, Maekawa N, Obara H. Optimal dose of granisetron for prophylaxis against postoperative emesis after gynaecological surgery. Anesth Analg 1997;85:652–6. 36. Domino KB, Anderson EA, Polissar NL, Posner KL. Comparative efficacy and safety of ondansetron, droperidol, and metoclopramide for preventing postoperative nausea and vomiting: a meta-analysis. Anesth Analg 1999;88:1370–9. 37. Fortney JT, Gan TJ, Graczyk S, Wetchler B, Melson T, Khalil S, et al. A comparison of the efficacy, safety, and patient satisfaction of ondansetron versus droperidol as antiemetics for elective outpatient surgical procedures: S3A-409 and S3A-410 Study Groups. Anesth Analg 1998;86:731–8. 38. Henzi I, Walder B, TramPr MR. Dexamethasone for the prevention of postoperative nausea and vomiting: a quantitative systematic review. Anesth Analg 2000;90:186–94. 39. Liu K, Hsu CC, Chia YY. The effective dose of dexamethasone for antiemesis after major gynecological surgery. Anesth Analg 1999;89:1316–8. 40. Wang JJ, Ho ST, Lee SC, Liu YC, Ho CM. The use of dexamethasone for preventing postoperative nausea and vomiting in females undergoing thyroidectomy: a dose-ranging study. Anesth Analg 2000;91:1404–7. 41. Wang JJ, Ho ST, Tzeng JI, Tang CS. The effect of timing of dexamethasone istration on its efficacy as a prophylactic antiemetic for postoperative nausea and vomiting. Anesth Analg 2000;91:136–9. 42. Henzi I, Sonderegger J, Tramèr MR. Efficacy, dose response, and adverse effects of droperidol for prevention of postoperative nausea and vomiting. Can J Anesth 2000;47:537–51.

25. Goll V, Akça O, Greif R, Freitag H, Arkiliç CF, Scheck T, et al. Ondansetron is no more effective than supplemental intraoperative oxygen for prevention of postoperative nausea and vomiting. Anesth Analg 2001;92:112–7.

43. Kranke P, Morin AM, Roewer N, Eberhart LH. Dimenhydrinate for prophylaxis of postoperative nausea and vomiting: a metaanalysis of randomized controlled trials. Acta Anaesthesiol Scand 2002;46:238–44.

26. Turan A, Apfel CC, Kumpch M, Danzeisen O, Eberhart LH, Forst H, et al. Does the efficacy of supplemental oxygen for the prevention of postoperative nausea and vomiting depend on the measured outcome, observational period or site of surgery? Anaesthesia 2006;61:628–33.

44. Khalil S, Philbrook L, Rabb M, Wells L, Aves T, Villanueva G, et al. Ondansetron / promethazine combination or promethazine alone reduces nausea and vomiting after middle ear surgery. J Clin Anesth 1999;11:596–600.

27. Holte K, Klarskov B, Christensen DS, Lund C, Nielsen KG, Bie P, et al. Liberal versus restrictive fluid istration to improve recovery after laparoscopic cholecystectomy. Ann Surg 2004;240:892–9.

45. Kranke P, Morin AM, Roewer N, Wells L, Aves T, Villanueva G, et al. The efficacy and safety of transdermal scopolamine for the prevention of postoperative nausea and vomiting: a quantitative systematic review. Anesth Analg 2002;95:133–43.

28. Magner JJ, McCaul C, Carton E, Gardiner J, Buggy D. Effect of intravenous crystalloid infusion on postoperative nausea and vomiting after gynaecological laparoscopy: comparison of 30 and 10 ml kg. Br J Anaesth 2004;93:381–5.

46. Bailey PL, Streisand JB, Pace NL, Bubbers SJ, East KA, Mulder S, et al. Transdermal scopolamine reduces nausea and vomiting after outpatient laparoscopy. Anesthesiology 1990;72:977–80.

29. Tramèr MR, Fuchs-Buder T. Omitting reversal of neuromuscular blockade: effect on postoperative nausea and vomiting and risk of residual paralysis: a systemic review. Br J Anaesth 1999;82:379–86.

47. Wallenborn J, Gelbrich G, Bulst D, Behrends K, Wallenborn H, Rohrbach A, et al. Prevention of postoperative nausea and vomiting by metoclopramide combined with dexamethasone: randomized double blind multicentre trial. BMJ 2006;333:324.

30. Tramèr MR, Reynolds DJM, Moore RA, McQuay HJ. Efficacy, dose-response, and safety of ondansetron in prevention of postoperative nausea and vomiting: a qualitative systematic review of randomized placebo-controlled trials. Anesthesiology 1997;87:1277–89. 31. Sun R, Klein KW, White PF. The effect of timing of ondansetron istration in outpatients undergoing otolaryngologic surgery. Anesth Analg 1997;84:331–6.

606

l JULY JOGC JUILLET 2008

48. Habib AS, Gan TJ. Evidence-based management of postoperative nausea and vomiting: a review. Can J Anesth 2004;51:326–41. 49. Rowbotham DJ. Current management of postoperative nausea and vomiting. Br J Anaesth 1992;69:46S–59S. 50. Wilhelm SM, Dehoorne-Smith ML, Kale-Pradhan PB. Prevention of postoperative nausea and vomiting. Ann Pharmacother 2007;41:68–78.

Guideline for the Management of Postoperative Nausea and Vomiting

51. Lerman J. Surgical and patient factors involved in postoperative nausea and vomiting. Br J Anaesth 1992;69:24S–32S. 52. Kranke P, Morin AM, Roewer N, Wulf H, Eberhart LH. The efficacy and safety of transdermal scopolamine for the prevention of postoperative nausea and vomiting: a quantitative systematic review. Anesth Analg 2002;95:133–43.

64. Habib AS, El-Moalem HE, Gan TJ. The efficacy of the 5-HT3 receptor antagonists combined with droperidol for PONV prophylaxis is similar to their combination with dexamethasone. A meta-analysis of randomized controlled trials. Can J Anesth 2004;51:311–19.

53. Reeve B. Prophylactic Diclectin reduces the incidence of postoperative vomiting. Can J Anesth 2005;52:55–61.

65. Coloma M, White PF, Ogunnaike BO, Markowitz SD, Brown PM, Lee AQ, et al. Comparison of acustimulation and ondansetron for the treatment of established postoperative nausea and vomiting. Anesthesiology 2002;97:1387–92.

54. Ornstein M, Einarson A, Koren G. Bendectin/diclectin for morning sickness: a Canadian follow-up of an American tragedy (Editorial). Reprod Toxicol 1995;9:1–6.

66. Ernst E, Pittler MH. Efficacy of ginger for nausea and vomiting: a systematic review of randomized clinical trials. Br J Anaesth 2000;84:367–71.

55. Sahakian V, Rouse D, Sipes S, Rose N, Niebyl J. Vitamin B6 is effective therapy for nausea and vomiting of pregnancy: a randomized, double-blind placebo-controlled study. Obstet Gynecol 1991;78:33–6.

67. Hill RP, Soppitt AJ, Gan TJ. The effectiveness of rescue antiemetics in patients who received a prophylactic antiemetic. Anesth Analg 2000;90:S8 (abstract).

56. Vutyavanich T, Wongtra-ngan S, Ruangsri RA. Pyridoxine for nausea and vomiting of pregnancy: a randomized, double-blind, placebo-controlled trial. Am J Obstet Gynecol 1995;173:881–4.

68. Tramèr M, Moore RA, Reynolds DJM, McQuay HJ. A quantitative systemic review of ondansetron in treatment of established postoperative nausea and vomiting. BMJ 1997;314:1088–92.

57. Brent R. The Bendectin Saga: another American tragedy (Brent ’80); (Editorial). Teratology 1983;27:283–6.

69. American Society of PeriAnesthesia Nurses PONV/PDNV Strategic Work Team. ASPAN’S evidence-based clinical practice guideline for the prevention and/or management of PONV/PDNV. J Perianesth Nurs 2006;21:230–50.

58. Jewell MD, Debendox (Bendectin) for nausea in pregnancy. In: Enkin MW, Keirse MJ, Renfrew MJ, Neilson JP, eds. Pregnancy and Childbirth Module. Disk issue 1. Cochrane Database of Systematic Reviews: Review No 03351, 30 April 1993. Oxford: Cochrane Updates on Disk 1994. 59. Gesztesi Z, Scuderi PE, White PF, Wright W, Wender RH, D’Angelo R, et al. Substance P (Neurokinin 1) antagonist prevents postoperative vomiting after abdominal hysterectomy procedures. Anesthesiology 2000;93:931–7. 60. Diemuncsh PA, Apfel C, Phillip B, Gan TJ, Reiss TR. NK1 antagonist aprepitant vs. ondansetron for prevention of PONV: combined data from 2 large trials (abstract A125). Presented at: American Society of Anesthesiologists 2006 Annual Meeting, Chicago, IL, October 14–18, 2006.

70. Carroll NV, Miederhoff P, Cox FM, Hirsch JD. Postoperative nausea and vomiting after discharge from outpatient surgery centers. Anesth Analg 1995;80:903–9. 71. Gan TJ. Postoperative nausea and vomiting: Can it be eliminated? JAMA 2002; 13:1233–6. 72. Polati E, Verlato G, Finco G, Mosaner W, Grosso S, Gottin L, et al. Ondansetron versus metoclopramide in the treatment of postoperative nausea and vomiting. Anesth Analg 1997;85:395–9.

61. Habib AS, Gan TJ. Combination therapy for postoperative nausea and vomiting—a more effective prophylaxis? Ambul Surg 2001;9:59–71.

73. Gan TJ, Franiak R, Reeves J. Ondansetron orally disintegrating tablet versus placebo for the prevention of postdischarge nausea and vomiting after ambulatory surgery. Anesth Analg 2002;94:1199-200.

62. Habib AS, Gan TJ. Combination antiemetic. What is the evidence? Int Anesthesiol Clin Fall 2003;41:119–44.

74. al-Sadi M, Newman B, Julious SA. Acupuncture in the prevention of postoperative nausea and vomiting. Anaesthesia 1997;52:658-61.

63. Sanchez-Ledesma MJ, Lopez-Olaondo L, Pueyo FJ, Carrascosa F, Ortega A. A comparison of three antiemetic combinations for the prevention of postoperative nausea and vomiting. Anesth Analg 2002;95:1590–5.

75. Woolf SH, Battista RN, Anderson GM, Logan AG, Eel W. Canadian Task force on Preventive Health Care. New grades for recommendations from the Canadian Task force on Preventive Health Care. CMAJ 2003;169:207–8.

JULY JOGC JUILLET 2008 l

607

SOGC CLINICAL PRACTICE GUIDELINE No. 296, September 2013 (Reviewed March 2015)

Induction of Labour: Review This clinical practice guideline review has been prepared by Clinical Practice Obstetrics Committee and approved by the Executive and Board of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Dean Leduc, MD, Ottawa ON Anne Biringer, MD, Toronto ON Lily Lee, RN, MSN, Vancouver BC Jessica Dy, MD, Ottawa ON CLINICAL PRACTICE OBSTETRICS COMMITTEE Hussam Azzam (Chair), MD, Thompson MB Jon Barrett, MD, Toronto ON Anne Biringer, MD, Toronto ON Kim Campbell, RM, Vancouver BC Louise Duperron, MD, Montreal QC Jessica Dy, MD, Ottawa ON Ellen Giesbrecht, MD, Vancouver BC Lisa Graves, MD, Hamilton ON Michael Helewa, MD, Winnipeg MB Ian Lange, MD, Calgary AB Lily Lee, RN, MSN, Vancouver BC Suzanne Muise, MD, Camana Bay, Grand Cayman Barbara Parish, MD, Halifax NS Disclosure statements have been received from all contributors.

J Obstet Gynaecol Can 2015;37(4):380–381

T

he issue of induction of labour and risk of Caesarean section has been a topic of recent discussion, catalyzed by the publication of a new review paper in the Canadian Medical Association Journal.1 In response to an influx of queries regarding the CMAJ paper and its potential effect on SOG guidelines, the Clinical Practice Obstetrics Committee has reviewed the SOGC Induction of Labour guidelines published in 20132 and concluded that no update or revision to the SOGC is required at this time. The committee emphasized that the CMAJ meta-analysis included no new information or studies that were not used in the 2013 SOGC guideline. It is also important to note that results from the CMAJ review paper report on an induction group encoming all indications for induction of labour, with term labour defined as 37 to 42 weeks’ gestation and measured outcomes limited to Caesarean section. The SOGC guideline recommends requiring an obstetrical or medical indication (e.g. premature rupture of membranes, hypertension, intrauterine growth restriction) for induction of labour before 41 weeks. This is consistent with guidelines published by the Royal College of Obstetricians and Gynaecologists and the American Congress of Obstetricians and Gynecologists. The data does confirm that induction of labour for specific indications is not associated with higher risk of Caesarean section and in some indications, such as post-term induction, it lowers the risk of Caesarean section. It is important to note that these study findings should not be generalized to any and all inductions of labour, especially when no indications exist; SOGC stands by its recommendation that induction of labour should be carried out only after careful discussion with women who have specific indications. The SOGC is aware of two clinical trials underway that are examining induction of labour versus expectant management.3,4 The outcomes of these studies will be

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

380 l APRIL JOGC AVRIL 2015

Induction of Labour: Review

monitored by the Clinical Practice Obstetrics Committee for potential change of practice implications. It is to be noted that, to ensure the best quality of care, the SOGC is currently developing a standard of practice under which evidence will be reviewed on a regular basis to decide whether all or part of a guideline should be updated based on new robust (Canadian Task Force on Preventive Health Care5 level I) evidence.

2. Leduc D, Biringer A, Lee L, Dy J; Clinical Practice Obstetrics Committee, Society of Obsetricians and Gynaecologists of Canada. Induction of labour. SOGC Clinical Practice Guideline No. 296, September 2013. J Obstet Gynaecol Can 2013;36:248–52. 3. Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). A Randomized Trial of Induction Versus Expectant Management (ARRIVE). Bethesda, MD: US National Institute of Health; 2014. Available at: http://clinicaltrials.gov/ct2/show/ NCT01990612?term=ARRIVE&rank=2. Accessed on December 10, 2014.

REFERENCES

4. Nottingham Clinical Trials Unit. Induction of labour versus expectant management for women over 35 years of age. Nothingham, GB: NCTU; 2013. Available at: http://www.35-39trial.org. Accessed on December 10, 2014.

1. Mishanina E, Rogozinska E, Thatthi T, Uddin-Khan R, Khan KS, et al. Use of labour induction and risk of cesarean delivery: a systematic review and meta-analysis. CMAJ 2014;186:665–73.

5. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W; Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

APRIL JOGC AVRIL 2015 l 381

SOGC Clinical Practice Guideline No. 296, September 2013 (Replaces No. 107, August 2001)

Induction of Labour This clinical practice guideline has been prepared by the Clinical Practice Obstetrics Committee, reviewed by the Maternal Fetal Medicine and Family Practice Advisory Committees, and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Dean Leduc, MD, Ottawa ON Anne Biringer, MD, Toronto ON Lily Lee, MSN, Vancouver BC Jessica Dy, MD, Ottawa ON CLINICAL PRACTICE OBSTETRICS COMMITTEE Thomas Corbett, MD (Co-chair), Edmonton AB Dean Leduc, MD (Co-chair), Ottawa ON Anne Biringer, MD, Toronto ON Louise Duperron, MD, Kirkland QC Jessica Dy, MD, Ottawa ON Ian Lange, MD, Calgary AB Lily Lee, MSN, Vancouver BC Suzanne Muise, MD, St. Thomas ON

Abstract Objective: To review the most current literature in order to provide evidence-based recommendations to obstetrical care providers on induction of labour. Options: Intervention in a pregnancy with induction of labour. Outcomes: Appropriate timing and method of induction, appropriate mode of delivery, and optimal maternal and perinatal outcomes. Evidence: Published literature was retrieved through searches of PubMed, CINAHL, and The Cochrane Library in 2010 using appropriate controlled vocabulary (e.g., labour, induced, labour induction, cervical ripening) and key words (e.g., induce, induction, augmentation). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to the end of 2010. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Values: The evidence in this document was rated using criteria described in the Report of the Canadian Task Force on Preventative Health Care (Table 1).

Barbara Parish, MD, Halifax NS

Summary Statements

Lexy Regush, MD, Saskatoon SK

01. Prostaglandins E2 (cervical and vaginal) are effective agents of cervical ripening and induction of labour for an unfavourable cervix. (I)

Kathi Wilson, RM, Ilderton ON Grace Yeung, MD, London ON SPECIAL CONTRIBUTORS

02. Intravaginal prostaglandins E2 are preferred to intracervical prostaglandins E2 because they results in more timely vaginal deliveries. (I)

Joan Crane, MD, St. John’s NL Robert Gagnon, MD, Montreal QC Diane Sawchuck, RN, PhD, Vancouver BC Vyta Senikas, MD, Ottawa ON Disclosure statements have been received from all contributors. The literature searches and bibliographic for this guideline were undertaken by Becky Skidmore, Medical Research Analyst, Society of Obstetricians and Gynaecologists of Canada.

J Obstet Gynaecol Can 2013;35(9)

Key Words: Induction, labour, cervical ripening, post-dates

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

SEPTEMBER JOGC SEPTEMBRE 2013 l S1

SOGC Clinical Practice Guideline

Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.111 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care.111

Recommendations 01. The indication for induction must be documented, and discussion should include reason for induction, method of induction, and risks, including failure to achieve labour and possible increased risk of Caesarean section. (III-B) 02. If induction of labour is unsuccessful, the indication and method of induction should be re-evaluated. (III-B) 03. Inductions should not be performed solely for suspected fetal macrosomia. (III-D) 04. Inductions should not be performed solely because of patient or care provider preference. (III-D) 05. Health care providers should assess the cervix (using the Bishop score) to determine the likelihood of success and to select the appropriate method of induction. (II-2A) 06. The Bishop score should be documented. (III-B)

ABBREVIATIONS ARM

artificial rupture of membranes

ART

artificial reproductive technologies

CFAS

Canadian Fertility and Andrology Society

FHR

fetal heart rate

GBS

group B streptococcus

NNT

number needed to treat

NST

non-stress test

PG

prostaglandins

PGE1

prostaglandins E1

PGE2

prostaglandins E2

PROM pre-labour rupture of membranes

S2 l SEPTEMBER JOGC SEPTEMBRE 2013

07. Care providers need to consider that induction of women with an unfavourable cervix is associated with a higher failure rate in nulliparous patients and a higher Caesarean section rate in nulliparous and parous patients. (II-2A) 08. Every woman should ideally have an ultrasound, preferably in the first trimester, to confirm gestational age. (I-A) 09. Institutions should have quality assurance programs and induction policies, including safety tools such as checklists, to ensure that inductions are performed only for acceptable indications. (II-2B) 10. Women should be offered induction of labour between 41+0 and 42+0 weeks as this intervention may reduce perinatal mortality and meconium aspiration syndrome without increasing the Caesarean section rate. (I-A) 11. Women who chose to delay induction > 41+0 weeks should undergo twice-weekly assessment for fetal well-being. (I-A) 12. Intracervical Foley catheters are acceptable agents (II-2B) that are safe both in the setting of a vaginal birth after Caesarean section (I-B) and in the outpatient setting. (II-2B) 13. Double lumen catheters may be considered a second-line alternative. (II-2B) 14. Prostaglandins E2 (cervical and vaginal) should not be used in the setting of vaginal birth after Caesarean section due to the increased risk of uterine rupture. (II-2D) 15. Vaginal prostaglandins E2 may be considered with ruptured membranes at term and can be used in this setting. (I-A) 16. Misoprostol can be considered a safe and effective agent for labour induction with intact membranes and on an inpatient basis. (I-A) 17. Misoprostol should not be used in the setting of vaginal birth after Caesarean section due to the increased risk of uterine rupture. (II-3D)

Induction of Labour

18. Oxytocin should be started no earlier than 4 hours after the last dose of misoprostol. (III-B)

DEFINITIONS

19. Amniotomy should be reserved for women with a favourable cervix. Particular care should be given in the case of unengaged presentation because there is a risk of cord prolapse. (III-B)

Induction of labour is the initiation of contractions in a pregnant woman who is not in labour to help her achieve a vaginal birth within 24 to 48 hours.

20. After amniotomy, oxytocin should be commenced early in order to establish labour. (III-B)

Successful induction is defined as a vaginal delivery within 24 to 48 hours of induction of labour.

21. In the setting of ruptured membranes at term, oxytocin should be considered before expectant management. (I-A) 22. Women positive for group B streptococcus should be started on oxytocin as early as possible after ruptured membranes in order to establish labour within 24 hours. (III-B) 23. Both high- and low-dose oxytocin may be considered within a hospital protocol. (III-B) 24. Because of the various concentrations, oxytocin infusion rates should always be recorded in mU/min rather than mL/hr. (III-L) 25. Oxytocin induction maybe considered in the hospital setting of vaginal birth after Caesarean section. (II-3B)

Epub ahead of print. This document will be published in: J Obstet Gynaecol Can 2013;35(9)

INTRODUCTION

I

nduction of labour is the artificial initiation of labour before its spontaneous onset to deliver the feto-placental unit. The frequency of induction varies by location and institution. The rate of induction in Canada has increased steadily from 12.9% in 1991–1992 to 19.7% in 1999–2000.1 The rate reached a high of 23.7% in 2001–2002, decreased slightly to 21.8% in 2004–2005, and has since remained steady.2 The 2010 BC Perinatal Health Registry reveals a similar trend and rate, with post-term pregnancies (> 41+0 weeks) representing 34%, the largest group, of the total inductions in BC.3 When undertaken for appropriate reasons, and by appropriate methods, induction is useful and benefits both mothers and newborns. The goal of induction is to achieve a successful vaginal delivery that is as natural as possible. The objectives of this guideline are to summarize the indications for induction, review current methods of cervical ripening and labour induction, and evaluate the safety and effectiveness of agents and methods used in cervical ripening and labour induction. Treatment and care should take into women’s individual needs and preferences. Women who are having or being offered induction of labour should have the opportunity to make informed choices about their care and treatment in partnership with their health care providers.

Elective induction is the induction of labour in the absence of acceptable fetal or maternal indications. Cervical ripening is the use of pharmacological or other means to soften, efface, or dilate the cervix to increase the likelihood of a vaginal delivery. Tachysystole refers to > 5 contractions per 10-minute period averaged over 30 minutes. This is further subdivided into two categories, one with and one without fetal heart rate changes.4 Hypertonus refers to excessive uterine contractions lasting > 120 seconds without FHR changes. This term should be abandoned and has been replaced in this guideline by tachystole without FHR changes.4 Hyperstimulation refers to excessive uterine contractions (tachysystole or hypertonus) with abnormal FHR changes. This term has been used in multiple induction studies. It should be abandoned and has been replaced in this guideline by tachystole with FHR changes.4 INDICATIONS

Induction is indicated when the risk of continuing the pregnancy, for the mother or the fetus, exceeds the risk associated with induced labour and delivery. The indication must be convincing, compelling, consented to, and documented. The reason for and method of induction should be discussed between the care provider and the woman in order to obtain clear consent. These conditions are not met when induction is proposed solely for the convenience of the care provider or patient. Induction should be prioritized by the health care team according to the urgency of the clinical situation and the availability of resources. The following list of indications for induction of labour is not meant to be exhaustive or absolute: High Priority

•• Preeclampsia ≥ 37 weeks •• Significant maternal disease not responding to treatment •• Significant but stable antepartum hemorrhage SEPTEMBER JOGC SEPTEMBRE 2013 l S3

SOGC Clinical Practice Guideline

•• Chorioamnionitis

•• invasive cervical carcinoma

•• Suspected fetal compromise

•• previous uterine rupture

•• Term pre-labour rupture of membranes with maternal GBS colonization

Whenever possible, for patients with prior uterine incision or surgery, the operative report or the opinion of the surgeon should be obtained and reviewed.

Other Indications

•• Postdates (> 41+0 weeks) or post-term (> 42+0 weeks) pregnancy

Induction of labour using various methods may be associated with an increased risk of:

•• Uncomplicated twin pregnancy ≥ 38 weeks

•• failure to achieve labour

•• Diabetes mellitus (glucose control may dictate urgency)

•• Caesarean section

•• Alloimmune disease at or near term

•• tachysystole with or without FHR changes

•• Intrauterine growth restriction

•• chorioamnionitis

•• Oligohydramnios

•• cord prolapse with ARM

•• Gestational hypertension ≥ 38 weeks •• Intrauterine fetal death

•• inadvertent delivery of preterm infant in the case of inadequate dating

•• PROM at or near term, GBS negative

•• Uterine rupture in scarred and unscarred uteri

•• Logistical problems (history of rapid labour, distance to hospital) •• Intrauterine death in a prior pregnancy (Induction may be performed to alleviate parental anxiety, but there is no known medical or outcome advantage for mother or baby.) Unacceptable Indications

•• Care provider or patient convenience •• Suspected fetal macrosomia (estimated fetal weight > 4000 gm) in a non-diabetic women is an unacceptable indication because there is no reduction in the incidence of shoulder dystocia but twice the risk of CS.5–7 CONTRAINDICATIONS

Induction should be avoided if there are any contraindications to labour or vaginal delivery. They include, but are not limited to the following: •• placenta or vasa previa or cord presentation •• abnormal fetal lie or presentation (e.g. transverse lie or footling breech) •• prior classical or inverted T uterine incision •• significant prior uterine surgery (e.g. full thickness myomectomy) •• active genital herpes •• pelvic structural deformities S4 l SEPTEMBER JOGC SEPTEMBRE 2013

•• operative vaginal delivery

Recommendations

1. The indication for induction must be documented, and discussion should include reason for induction, method of induction, and risks, including failure to achieve labour and possible increased risk of Caesarean section. (III-B) 2. If induction of labour is unsuccessful, the indication and method of induction should be re-evaluated. (III-B) 3. Inductions should not be performed solely for suspected fetal macrosomia. (III-D) 4. Inductions should not be performed solely because of patient or care provider preference. (III-D) PRE-INDUCTION ASSESSMENT

The goal of labour induction is to achieve a successful vaginal delivery, although induction exposes women to a higher risk of a CS than spontaneous labour. Before induction, there are several clinical elements that need to be considered to estimate the success of induction and minimize the risk of CS. Factors that have been shown to influence success rates of induction include the Bishop score, parity (prior vaginal delivery), BMI, maternal age, estimated fetal weight, and diabetes. The Bishop score was developed in 1964 as a predictor of success for an elective induction. The initial scoring system used 5 determinants (dilatation, effacement, station, position, and consistency) that attributed a value of 0 to 2 or 3 points each (for a maximum score of 13). Bishop

Induction of Labour

Several studies have shown an increased rate of failed induction and CS when women are induced with an unfavourable cervix.12–16 Xenakis’s prospective study of 597 pregnancies stratified by low (4 to 6) and very low (0 to 3) Bishop scores found the highest risk of CS in both nulliparous and parous women with scores of 0 to 3 versus those with a Bishop score > 3. Even women with a score of 4 to 6 had a significantly higher risk of CS than those with spontaneous labour (Figure). The rate of failed induction was higher for women with a very low Bishop score (0 to 3) in both nulliparous and parous women.17 The clinician may consider other non-modifiable factors in the pre-induction counselling period with the woman. Elevated BMI (> 40 kg/m2),13–15 maternal age > 35 years,14,15,18 estimated fetal weight > 4 kg,13,18 and diabetes mellitus13,18 have been shown to increase the CS rate when labour is induced. The presence of these negative predictive factors for a successful induction may play a role in the mutual decision to delay intervention and to allow for the opportunity of a spontaneous labour. These factors should not be used as a deterrent to vaginal delivery. In studies of women with a favourable cervix, the CS rate of induced pregnancies was equivalent to those managed expectantly.19–21 Several studies have compared the ability of the Bishop score to predict successful labour induction with ultrasound assessment of the cervix with conflicting results. Peregrine et al. reported cervical length > 1 cm to be a predictor for CS with induction of labour.22 In contrast, Hatfield et al. found that cervical length was not predictive of successful labour induction,23 and Rozenberg et al. reported that the Bishop score was a better predictor of time interval from induction to delivery.24 Using ultrasound to assess cervical

Score Factor

0

1

2

Dilatation, cm

0

1–2

3–4

Effacement, %

0–30

40–50

60–70

Length, cm

>3

1–3

<1

Consistency

Firm

Medium

Soft

Position

Posterior

Mid

Anterior

Station

Sp −3 or above

Sp −2

Sp −1 or 0

Rates of failed induction (A) and Caesarean delivery (B) in women undergoing induction and stratified by parity and Bishop score at entry.17

A 16 14

% Failed induction

Assessment of cervical status is fundamental for the clinician to estimate the likelihood of a successful vaginal delivery. Of the Bishop score criteria for predicting successful induction, the most important is cervical dilatation, followed by effacement, station, and position, with the least important being consistency.10,11

Table 2. Modified Bishop Scoring System9

Bishop 0–3

13.5

>3

12

9.4

10 8

6.1

6 4 0

0.8

0.7

2

Primipara

0.7 Overall

Multipara

B 40

% Cesaream delivery

showed that women with a score of > 9 were equally likely to deliver vaginally whether induced or allowed to labour spontaneously.8 In 1966, Burnett modified the scoring scheme (still in use and still known as the Bishop score) so that each variable was assigned a maximum value of 2 points (for a maximum score of 10).9 A favourable preinduction Bishop score of > 6 is predictive of a successful vaginal delivery. Initial studies were limited to parous women, but the score was later found also to be applicable to nulliparous women (Table 2).

35

Bishop 0–3

34

25 20

>3

29

30

Spont

23 20

15

12

15

13

10

8

6

5 0

Primipara

Multipara

Overall

Reprinted with permission from Wolters Kluwer Health: Xenakis EM, Piper JM, Conway DL, Langer O. Induction of labor in the nineties: conquering the unfavorable cervix. Obstet Gynecol 1997;90(2):235–9.

SEPTEMBER JOGC SEPTEMBRE 2013 l S5

SOGC Clinical Practice Guideline

ripeness, Bartha et al. found that fewer women were induced with PG with no difference in outcomes.25 Fetal fibronectin and transvaginal ultrasound have been shown to predict successful induction, but neither have been shown to be superior to the Bishop score.10 Recommendations

5. Health care providers should assess the cervix (using the Bishop score) to determine the likelihood of success and to select the appropriate method of induction. (II-2A) 6. The Bishop score should be documented. (III-B) 7. Care providers need to consider that induction of women with an unfavourable cervix is associated with a higher failure rate in nulliparous patients and a higher Caesarean section rate in nulliparous and parous patients. (II-2A) PREVENTION OF INDUCTION

Routine antenatal ultrasound for confirmation of expected date of delivery has been shown to reduce induction rates for postdates (> 41+0 weeks) pregnancies after correction of dates (OR 0.68, 95% CI 0.57 to 0.82).26–28 There is evidence that routine sweeping (stripping) of membranes promotes the onset of labour and that this simple technique decreases induction rates. It is believed that the technique results in an increase of local production of prostaglandins.29 Membrane sweeping involves the insertion of a digit past the internal cervical os followed by three circumferential es of the digit causing separation of the membranes from the lower segment. In clinical studies when the cervix was closed, a massage of the cervical surface with the forefinger and middle finger for 15 to 30 seconds was performed. The woman should be informed of the discomfort and pain and the possibility of bleeding postprocedure before consent is obtained. A 2005 Cochrane review including 32 trials found that routine sweeping performed weekly after 38 weeks resulted in a reduced duration of pregnancy beyond 41 and 42 weeks. The number needed to treat to prevent 1 induction at 41 weeks was 8.30 This procedure has been associated with maternal discomfort during vaginal examination and other minor adverse effects (e.g. bleeding, irregular contractions). Since the publication of the Cochrane review by Boulvain et al.,30 several studies have been published evaluating the sweeping of membranes. Yildirim et al. found that women (> 38 weeks’ gestation) who underwent sweeping in the case S6 l SEPTEMBER JOGC SEPTEMBRE 2013

of an open cervix or cervical massage rather than a pelvic exam had more spontaneous labour within 7 days (73.7% vs. 45.5%, OR 0.2 95%, CI 0.18 to 0.46, P < 0.0001) and a greater number of women went into spontaneous labour before 41 weeks (90.5% vs. 70.7%, OR 2.46, 95% CI 1.22 to 4.95).31 An RCT by de Miranda et al. involving 742 low-risk women showed that sweeping every 2 days starting at 41+0 weeks reduced the number of pregnancies reaching 42 weeks. (NNT = 6).32 In the case of a planned VBAC, Hamdam studied 108 women who underwent serial sweeping at term and found there was no significant effect on the onset of labour, duration of pregnancy, induction of labour, or repeat CS.33 The effect of coitus on promoting labour is unclear. A 2006 prospective study of 200 women by Tan et al. used patient reported data of sexual intercourse after 36 weeks to estimate effect on gestational age and mode of delivery.34 Coitus at term was independently associated with earlier onset of labour (reduction of postdates pregnancy and less requirement for induction at 41 weeks). However, a second prospective study of 210 women by the same researcher compared a coitus-advised group to a no-advice group scheduled to have labour induction. The coitus-advised group reported more sexual activity before delivery than the non-advised group, but there was no significant difference in spontaneous labour.35 Care provider use of appropriate or inappropriate indications for induction has an impact on resources for performing induction and on the overall CS rate. Lydon-Rochelle et al. reviewed the records of 4541 induced pregnancies and found that 15% of inductions were either not clinically indicated or not documented.36 Le Ray et al. measured an increase in CS rate (OR 4.1, 95% CI 1.3 to 12.9) when care providers violated guidelines for inductions by inducing labour before 38 weeks or with a Bishop score < 5 without an indication.37 Quality improvement programs have been shown to reduce the number of elective inductions and unplanned CS. Several studies have shown a significant reduction in the number of elective inductions after the implementation of an induction committee. The role of the committee was to review each request and enforce the use of proper indications for induction.38–40 Institutional factors may play a role in the CS rate of induced labours. Brennan et al. compared CS rates in 10 different groups defined by the Robson criteria. In the group of low-risk women induced at term, the low induction centres had a lower overall CS rate than the higher induction centres (17.7% vs. 27.8%, P < 0.008).41

Induction of Labour

Recommendations

8. Every woman should ideally have an ultrasound, preferably in the first trimester, to confirm gestational age. (I-A) 9. Institutions should have quality assurance programs and induction policies, including safety tools such as checklists, to ensure that inductions are performed only for acceptable indications. (II-2B) POST-DATES INDUCTION

Postdates induction is the leading indication for induction and deserves special consideration. The goal is the prevention of post-term (> 42+0 weeks) pregnancy with its associated increased perinatal morbidity, mortality, and operative delivery rates.42,43 The multi-centre study by Hannah et al. published in 1992 compared elective induction to serial monitoring (daily kick counts; non-stress test 3 times per week; amniotic fluid volume 2 to 3 times per week) after 41 weeks in 3407 women with cephalic singleton pregnancies.44 The induction group had a lower rate of CS for abnormal fetal heart tracing (5.7% vs. 8.3%, P = 0.003) with no difference in perinatal mortality and morbidity. Women with a cervix dilated ≥ 3 cm were excluded. The method of induction differed between groups: the induction group was induced with intracervical PG gel, the serial monitoring group was induced with amniotomy or oxytocin, or had CS regardless of cervical status. After publication of this study, the SOGC recommended that induction was preferred for pregnancies completing 41+0 weeks.45 A 2006 Cochrane meta-analysis that included 19 trials (7984 women) found that labour induction after 41+0 weeks was associated with fewer perinatal deaths but no difference in CS rate.28 Individual analysis for inductions done at 41+0 weeks (10 trials; RR 0.25, 95% CI 0.05 to 1.18, NNT = 369) and 42+0 weeks (2 trials; RR 0.41, 95% CI 0.06 to 2.73) revealed a trend towards reduction of perinatal deathineachgroupbutwasnotstatisticallysignificant.Whenthe 41-week and 42-week trials were analyzed together, the relative risk reached significance at RR 0.30 (95% CI 0.09 to 0.99, NNT = 339). In trials where induction occurred after 41 weeks, there was a reduced risk of meconium aspiration syndrome (RR 0.29; 95% CI 0.12 to 0.68, 4 trials, 1325 women) but there was no difference in the risk of CS (10 trials at 41 weeks, N = 5755, RR 0.92, 95% CI 0.76 to 1.12; and 5 trials at 42 weeks, N = 810, RR 0.97, 95% CI 0.72 to 1.31), assisted vaginal delivery, or Apgar scores of < 7 at 5 minutes. For women who decide to delay induction, fetal wellbeing should be evaluated. Delaney et al. published

a review of the management of this group and recommended measurement of amniotic fluid and conducting an NST.26 Biophysical profile is another acceptable option. Recommendations

10. Women should be offered induction of labour between 41+0 and 42+0 weeks as this intervention may reduce perinatal mortality and meconium aspiration syndrome without increasing the Caesarean section rate. (I-A) 11. Women who chose to delay induction > 41+0 weeks should undergo twice-weekly assessment for fetal well-being. (I-A) OPTIONS FOR CERVICAL RIPENING/INDUCTION: UNFAVOURABLE CERVIX

To increase the success of a vaginal delivery with an unfavourable cervix, several effective cervical ripening methods can be applied that include mechanical and pharmacologic options. Neither amniotomy nor oxytocin are effective cervical ripening agents and should not be used as such. Mechanical Options

Mechanical options of cervical ripening include balloon devices (Foley catheter with and without extra-amniotic saline infusion) that apply pressure on the internal os of the cervix to stretch the lower uterine segment and increase the release of local PG. Simplicity of use, potential for reversibility, reduction in certain side effects such as excessive uterine activity, and low cost are advantages of these methods. Balloon Devices: Foley Catheter

For a single balloon catheter, a no. 18 Foley is introduced under sterile technique into the intracervical canal past the internal os. The bulb is then inflated with 30 to 60 cc of water. The catheter is left in place until either it falls out spontaneously or 24 hours have elapsed. Some practitioners apply a small degree of traction on the catheter by taping it to the inside of the leg.46 Low-lying placenta is an absolute contraindication to the use of a Foley catheter. Relative contraindications to its use include antepartum hemorrhage, rupture of membranes, and evidence of lower tract genital infection. A 2001 Cochrane review reported mechanical methods resulted in less tachysystole with fetal heart changes than PG and misoprostol but no difference in CS rates. Compared with oxytocin alone in women with an unfavourable cervix, the CS rate was reduced with mechanical methods.47 SEPTEMBER JOGC SEPTEMBRE 2013 l S7

SOGC Clinical Practice Guideline

A 2009 RCT of 330 term (pregnancies > 36 weeks) nulliparous women with an unfavourable cervix (Bishop 0 to 4) compared single (16F Foley) and double balloon catheters and vaginal PGE2.48 The overall CS rate was high but not significantly different between groups (43% double balloon, 36% single balloon, and 37% in the PGE2 group P = 0.567). The single balloon catheter had the shortest induction to delivery interval (single balloon = 25.8 h, PGE2 = 25.8 h, double balloon = 30.6 h). Uterine tachysystole occurred in 14% (9% with normal fetal heart tracing; 4% with atypical fetal heart tracing; and 1% with abnormal fetal heart tracing requiring delivery) of the PGE2 group compared to none in the mechanical cervical ripening group. Cervical ripening with the single balloon catheter was associated with significantly less pain than the double balloon or vaginal PGE2.48 Heinemann et al. systematic review of 30 RCTs showed an increased risk of both maternal infection (defined as pyrexia of 38°C, chorioamnionitis, peripartum infection, or chorioamnionitis and/or endomyometritis), and neonatal infection when all (Foley catheters, hydroscopic dilators, laminaria) mechanical methods were analyzed. Studies limited to Foley catheters compared with pharmacological agents for cervical ripening had similar rates for maternal infection and there was no increased risk of neonatal infection.49 The indications and methods of induction should not be altered in the case of women known to be colonized with GBS.50 A prospective, randomized trial compared in-patient versus outpatient use of a Foley catheter for 111 term pregnancies with an indication for induction of labour. Indications included elective (n = 48), post-dates (n = 44), macrosomia (n = 14), gestational diabetes (n = 3), and chronic hypertension (n = 2). The mean Bishop score was 3 for each group. There was no significant difference in the two groups for change in Bishop score, maximum dose of oxytocin, time of oxytocin, epidural rate, induction time, 1-minute and 5-minute Apgar scores, and cord pH. The outpatient group spent an average of 9.6 hours less in hospital.51 The use of a trans-cervical Foley catheter for induction of labour in women who had a previous CS is not associated with an increased risk of uterine rupture.52 Foley catheters have shown to be efficacious with a shorter inductionto-delivery time than PG for induction of labour with an unfavourable cervix.53,54 Both agents have similar CS rates, but Foley catheters result in increased need for oxytocin stimulation and there is more tachysystole with PG.55 S8 l SEPTEMBER JOGC SEPTEMBRE 2013

Recommendations

12. Intracervical Foley catheters are acceptable agents (II-2B) that are safe both in the setting of a vaginal birth after Caesarean section (I-B) and in the outpatient setting. (II-2B) 13. Double lumen catheters may be considered a second-line alternative. (II-2B) Practice Points

•• There is an increased need for oxytocin when Foley catheters are used. •• In comparison with prostaglandins, Foley catheters cause much less uterine tachysystole. •• Foley catheters are not associated with increased rates of maternal infection (chorioamnionitis and endometritis) or neonatal infection. •• Use of Foley catheters does not reduce the rate of CS from that of PG. PHARMACOLOGICAL OPTIONS Prostaglandins

Prostaglandin E2 acts on the cervix by dissolving the collagen structural network of the cervix. Prostaglandin E2, dinoprostone, is available in 3 different preparations as a cervical ripening agent: controlled-release gel 10 mg (Cervidil), intravaginal 1 mg and 2 mg gel (Prostin), and intracervical 0.5 mg gel (Prepidil). Vaginal preparations (Prostin, Cervidil) are easier to istrate than intracervical (Prepidil) preparations. The controlled-release gel preparation (Cervidil) allows easier removal in case of uterine tachysystole with FHR changes and requires only a 30-minute delay before the initiation of oxytocin upon its removal compared with an interval of 6 hours for the gel. Advantages of PGE2 include patient acceptance, a lower operative rate than oxytocin, and less need for oxytocin augmentation when used with an unfavourable cervix (Bishop < 7). Cost savings may be realized by a reduction in operative deliveries and/or lengths of stay. PGE2 is a bronchodilator and is not contraindicated in women who suffer from asthma. In a prospective study of 2513 women with known asthma and who received PG, none had evidence of an exacerbation of their condition.56 A 2009 Cochrane review including 63 studies (10 441 women) reported that compared with placebo vaginal PGE2 reduced both the likelihood of not achieving a vaginal delivery within 24 hours (18% vs. 99%, RR 0.19, 95% CI 0.14 to 0.25) and the use of oxytocin stimulation (21.6% vs. 40.3%).57 There was no difference in CS, but there was an increase with vaginal PGE2 in uterine tachysystole

Induction of Labour

with FHR changes (4.6% versus 0.51%, RR 4.14, 95% CI 1.93 to 8.90). The tablet, pessary, and gel were equivalent, although the sustained released PGE2 insert was associated with a decrease in instrumental deliveries. A 2008 Cochrane review of intracervical gel versus placebo included 28 trials with 3764 women undergoing cervical ripening or induction regardless of membrane status.58 There were fewer women in the PG group who did not achieve vaginal delivery within 24 hours (RR 0.61 95% CI 0.47 to 0.79). There was a non-significant reduction in the overall risk of CS for all women (RR 0.88, CI 0.77 to 1.00), but there was a statistically significant reduction of CS (RR 0.82, 95% CI 0.68 to 0.98) in women with an unfavourable cervix and intact membranes, suggesting that oxytocin alone can and should be used for induction after term PROM. There was an increased risk of uterine tachysystole without changes in FHR (RR 1.59 95% CI 1.09 to 2.33) but no increase tachysystole with FHR changes.58 The same review compared intracervical and intravaginal interventions in 3881 women in 29 trials. The risk of not achieving vaginal delivery at 24 hours was greater in the intracervical group (RR 1.26, 95% CI 1.12 to 1.41) but there were no differences in the risk of CS and tachysystole with or without fetal heart changes.58 PGs have been used to induce labour with PROM at term. A 2006 Cochrane review included 12 trials (6814 women, PROM > 37 weeks) and compared planned management with either oxytocin or vaginal prostaglandin with expectant management. Overall, there was no difference for mode of birth; results were similar for CS and vaginal delivery. For women who underwent planned delivery, there was less chorioamnionitis or endometritis and fewer issions to NICU, but no difference in neonatal infection rates. One trial found that women in the planned group were more likely to perceive the experience as being more positive.59 The timing of insertion may have an influence on interventions. One study of 620 women (nulliparous and parous) compared ission in the morning versus the evening and found that morning inductions were less likely to need oxytocin infusion (45% vs. 54%, RR 0.83, 95% CI 0.70 to 0.97). Nulliparous women itted in the morning had fewer operative vaginal births (16.1% vs. 34.2%, RR 0.47, 95% CI 0.25 to 0.90).60 Adverse effects with the use of prostaglandin E2 include uterine tachysystole and maternal effects (i.e. fever, chills, vomiting, diarrhea). Care must be taken to avoid application of the higher dose vaginal preparations into the cervical canal. Rare, idiopathic adverse cardiovascular events may occur, but they almost always occur immediately after the istration of the agent.

In the event of tachysystole, attempts should be made to remove the prostaglandin from the vagina. Intrauterine rescue may be required and use of a tocolytic agent may be considered (intravenous Nitroglycerin 50 mcg given over 2 to 3 minutes and repeated every 3 to 5 minutes to a maximum of 200 mcg). To date, the evidence for safety and efficacy remains inconclusive. Another option is the use of nitroglycerin spray (0.4 mg, 1 to 2 puffs sublingual), which has the advantage of a simple and rapid istration and uptake, although there have been no clinical trials assessing dosing.61 Outpatient PG is an attractive option for reducing the use of health care resources. Large studies are lacking to determine their overall safety, in particular for rare but serious adverse effects. A 2003 RCT of 300 women evaluated outpatient versus in-patient induction with Cervidil. Three hundred eligible patients with uncomplicated, low-risk pregnancies and a Bishop score ≤ 6, parity ≤ 5, gestation > 37 weeks, a reactive NST, and singleton cephalic pregnancy with intact membranes. Cervidil was inserted and the patient monitored for 1 hour before being allowed to go home. Use of oxytocin, epidural rate, operative delivery rate, CS rate, and median time to labour and delivery within 24 hours were the same for each group. The outpatient group spent a median of 8 hours at home and reported a higher satisfaction during the initial 12 hours (56% vs. 39%).62 Current recommendations for outpatient induction in low-risk pregnancies suggest continuous electronic fetal monitoring for 1 to 2 hours after istration of PG and the use of intermittent auscultation when labour is active.63 A 2010 Cochrane review including 28 RCTs with 2616 women who were induced with mechanical and pharmacological methods concluded that the outpatient setting was feasible, but that there was insufficient evidence to recommend which method was most effective and safe.64 Sweeping of the membranes during induction of labour increases success rates. Two randomized trials recruited women with term, cephalic, nulliparous and parous pregnancies and intact membranes scheduled for induction with PG vaginal gel if the cervix was unfavourable (Bishop ≤ 4) or with amniotomy if the cervix was favourable (Bishop > 4 or cervix > 3 cm). Both groups were treated according to institutional protocols for active management of labour. Both studies showed that membrane sweeping at the time of induction resulted in shorter induction to delivery time, lower use of oxytocin, and a higher rate of spontaneous vaginal deliveries. Tan et al.35 benefit applied to both nulliparous and parous women, while SEPTEMBER JOGC SEPTEMBRE 2013 l S9

SOGC Clinical Practice Guideline

Foong et al.65 found that the benefit of sweeping was limited to nulliparous women with an unfavourable cervix. Tan et al. also found both higher maternal satisfaction in the birth process and higher post-sweeping pain.35 Summary Statements

Benefits of misoprostol include its stability at room temperature, rapid onset of action, multiple potential routes of istration (oral, buccal, sublingual, vaginal, rectal), and low cost. These potential benefits make it an attractive alternative to PGE2.

1. Prostaglandins E2 (cervical and vaginal) are effective agents of cervical ripening and induction of labour for an unfavourable cervix. (I) 2. Intravaginal prostaglandins E2 are preferred to intracervical prostaglandins E2 because they results in more timely vaginal deliveries. (I)

Dosing of misoprotol:

Recommendations

•• Oxytocin can only be used 4 hours after the last dose.

14. Prostaglandins E2 (cervical and vaginal) should not be used in the setting of vaginal birth after Caesarean section due to the increased risk of uterine rupture. (II-2D) 15. Vaginal prostaglandins E2 may be considered with ruptured membranes at term and can be used in this setting. (I-A) Practice Points

•• PGE2 reduce CS rates of women with an unfavourable cervix and result in greater maternal satisfaction. •• Oxytocin can be started 30 minutes after removal of a dinpoprostone insert (Cervidil) and 6 hours hours after gel (Prostin, Prepidil). •• PGE2 in the setting of ruptured membranes had more maternal but no more neonatal infections. •• Care must be taken to avoid the insertion of the higher dose of vaginal PGE2 (2 mg) into the cervical canal. •• Uterine tachysystole without FHR changes is more common with PGE2 but does not lead to a higher CS rate. •• Nitroglycerin can be used to treat uterine tachysystole but requires more study. Misoprostol is a synthetic PGE1 analog that has been approved and marketed for the prevention and treatment of gastric ulcers associated with the use of non-steroidal anti-inflammatory drugs.66 Misoprostol has also been found to be an effective agent for cervical ripening and labour induction, and those off-label uses have been widely adopted. The first study to describe the successful induction of labour in the case of intrauterine fetal demise was published in 1987.67 Since then, there have been over 100 randomized trials studying the efficacy and safety of induction in viable term inductions. S10 l SEPTEMBER JOGC SEPTEMBRE 2013

•• Give 50 mcg orally with a drink of water (ensure that it is swallowed quickly to avoid sublingual absorption) or give 25 mcg vaginally. •• Repeat every 4 hours as long as contractions are absent or non-painful. Serious adverse events with the use of misoprostol are similar to those of other PG and include uterine tachysystole with its potential fetal and maternal effects and meconium staining of liquor. It is generally agreed that it is a potent uterotonic and should not be used in women with a previous CS because it will increase the risk of uterine rupture.68,69 In general, large studies are required to assess the rare, but life-threatening, uterine rupture that has been reported anecdotally in women with and without a previous CS.70 A 2010 Cochrane review of vaginal misoprostol for cervical ripening and induction of labour included 121 trials that compared misoprostol to placebo/ no treatment or to other methods (vaginal PG, cervical PG, and oxytocin) of induction. Vaginal misoprostol was superior to placebo with a reduced failure to achieve vaginal delivery within 24 hours (RR 0.51, 95% CI 0.37 to 0.71) but increased tachysystole without fetal heart changes (RR 3.53, 95% CI 1.78 to 6.99).71 Several studies have compared 25 mcg and 50 mcg doses. Most have found that lower doses of misoprostol resulted in more need for oxytocin augmentation and less uterine tachysystole, with and without FHR changes, compared to higher doses.7,71 The induction to delivery time was shorter with the higher 50 mcg dose.66,72 An RCT of 124 women using several different doses (25, 50, 100, 200 mcg) resulted in more vaginal deliveries at 12 and 24 hours, more tachysystole, and less need for oxytocin with each incremental dose.73 A double-blind RCT of 374 women (> 36 weeks, Bishop ≤ 4) istered either 100 mcg or 200 mcg misoprostol vaginal insert had similar findings with the higher dose resulting in significantly more women achieving vaginal delivery within 24 hours (24% vs. 36%), shorter induction to delivery time (1181 vs. 1744 minutes), and less use of oxytocin (49% vs. 71%), but an increased rate of tachysystole (41% vs. 19.5%). There was a non-significant reduction of CS in the higher 200 mcg dose group (22.9% vs. 32.4%).74

Induction of Labour

A 2006 Cochrane review including 4 trials (474 women) comparing oral misoprostol with placebo found the misoprostol group was less likely to have long labour (RR 0.16, 95% CI 0.05 to 0.49), had less need for oxytocin (RR 0.32, 95% CI 0.24 to 0.43), and had a lower CS rate (RR 0.62, 95% CI 0.40 to 0.96). The author recommended that the oral misoprostol dose should not exceed 50 mcg.75 The same Cochrane review included 16 trials (3645 women) and found that women who were given oral misoprostol had a lower incidence of uterine tachysystole without FHR changes (RR 0.37, 95% CI 0.23 to 0.59) and more need for oxytocin (RR 1.28, 95% CI 1.11 to 1.48), but more meconium stained liquor (RR 1.27, 95% CI 1.01 to 1.60) than women given vaginal misoprostol.75 A prospective RCT of 204 women comparing 25 mcg oral versus 50 mcg vaginal given every 4 hours up to 4 doses found that the lower oral dose had lower incidence of tachysystole with FHR changes (2.2% vs. 5.4%) and a lower CS rate (19.4% vs. 32.4%), but no difference in induction to delivery time or side effects (nausea, vomiting, shivering, or diarrhea) than the higher vaginal dose.76 An RCT of 120 women that compared 12.5 mcg oral misoprostol with 25 mcg vaginal found no difference in outcomes in of mode of delivery, induction to delivery time, need for oxytocin, or complications.77 A 2008 RCT of 205 women comparing oral (20 mcg every hour for up to 4 doses until 3 contractions in 10 minutes) and vaginal (25 mcg every 4 hours until Bishop > 7) misoprostol found that the oral group had a higher rate of vaginal deliveries at 12 hours (74.4% vs. 25.5%) and a lower rate of tachysystole (0% vs. 11.3%), but more nausea (11% vs. 0%). This study was limited because the staff was not blinded and the average total dose of misoprostol was higher in the oral group (180 mcg vs. 50 mcg).78 A 2009 systemic review included 9 studies (2937 women) comparing low-dose oral misoprostol (20 to 25 mcg) to dinoprostone (PGE2), vaginal misoprostol, and oxytocin. Two of the trials compared oral and low-dose vaginal misoprostol and found that the oral route resulted in less uterine tachysystole with FHR changes.79 Misoprostol (PGE1) versus Dinoprostone (PGE2)

A 2006 Cochrane review included 9 trials (2627 women) that compared oral misoprostol to vaginal dinoprostone and found that women who received oral misoprostol were less likely to have a CS.75 However, this only reached significance in women with intact membranes (RR 0.78, 95% CI 0.66 to 0.94). There was more uterine tachysystole in the oral group, but this was not associated with adverse fetal outcomes.

A 2009 systemic review that compared oral misoprostol to vaginal dinoprostone included 5 studies (2281 women), only 1 of which was blinded, and found that women who had oral misoprostol had fewer CS (2% vs. 26%) but their need for oxytocin stimulation, incidence of tachysystole without FHR changes, and maternal adverse effects were similar to those who had vaginal dinoprostone.79 A similar review found that the CS rate was the same, but that the misoprostol group had a higher rate of vaginal deliveries within 24 hours, a lower rate of oxytocin use, and a trend towards higher meconium staining.80 A 2010 Cochrane review concluded that vaginal misoprostol was also superior to other induction agents (vaginal prostaglandin, intracervical prostaglandin, and oxytocin), with less epidural use and fewer failures to achieve vaginal delivery within 24 hours, but more tachysystole with FHR changes.71 Several studies have reported on efficacy of sublingual misoprostol to be comparable to the oral route. An RCT of 212 women compared 50 mcg to 100 mcg sublingual doses and reported the higher dose to be more effective but to result in more tachysystole.81 A double blind RCT of 140 women found that 50 mcg of sublingual misoprostol had a similar efficacy to 25 mcg vaginal misoprostol.82 A systemic review that included 5 studies (740 women) found no difference between sublingual (25 to 50 mcg every 4 hours) and vaginal misoprostol (25 to 50 mcg every 4 hours) in the rates of vaginal deliveries at 24 hours, uterine tachysystole, or CS.83 Two studies reported that patient satisfaction was higher using the sublingual route than the vaginal route.84,85 A prospective randomized study of 96 patients with an unfavourable cervix underwent cervical ripening with either vaginal misoprostol (50 mcg dose) or Foley catheter. The misoprostol group achieved a favourable cervix (Bishop ≥ 6) faster than the Foley group (98% vs. 69%, P < 0.001), although the induction to delivery interval was equivalent. There was lower use of oxytocin in the misoprostol group, part of which could be attributed to the 6-hour wait required before starting oxytocin after the last dose.86 Another study of 100 women comparing a higher single dose of misoprostol (100 mcg vaginal) to Foley catheter for cervical ripening found that misoprostol had a shorter induction to delivery time (11.8 h vs. 20.0 h, P < 0.05). There were two uterine ruptures, both in the misoprostol group. One occurred in a 39-year-old parous woman with 3 previous deliveries induced at term because of an impaired glucose tolerance that developed persistent fetal tachycardia SEPTEMBER JOGC SEPTEMBRE 2013 l S11

SOGC Clinical Practice Guideline

7 hours post-insertion without uterine tachysystole. The second woman with uterine rupture was a nulliparous 32-year-old induced because of prolonged pregnancy complicated by second stage dystocia due to cephalopelvic disproportion who developed uterine tachysystole with abnormal FHR changes 11 hours post-insertion. Both infants were delivered with Apgar ≥ 7 at 5 minutes.87 Few studies have used misoprostol in the case of PROM. An open RCT of 150 women with PROM at term compared vaginal misoprostol (25 mcg every 6 hours × 4 doses) to expectant management followed by oxytocin induction if labour did not begin. The misoprostol group had a shorter latency time to achieve labour (9.4 vs. 15.8 hours), shorter recruitment to delivery time (18.9 vs. 27.5 hours), a trend towards lower oxytocin use, and lower CS.88 An RCT of 758 women compared low dose (25 mcg) oral (Bishop > 6) or vaginal (Bishop ≤ 6) misoprostol to vaginal dinoprostone with rupture of membranes > 34 weeks’ gestation. There was no difference in CS and vaginal delivery rates but there was a trend towards the misoprostol group requiring less oxytocin, less epidural use, and less CS for failure to progress. Misoprostol also seemed to be more effective than dinoprostone in the setting of an unfavourable cervix, whereas oxytocin seemed to be more effective than misoprostol in a favourable cervix. Unfortunately, the predetermined sufficient sample size of 1890 women to provide meaningful results could not be reached due to lack of funding. Larger studies with sufficient numbers are required to complete the analysis.89 Recommendations

16. Misoprostol can be considered a safe and effective agent for labour induction with intact membranes and on an inpatient basis. (I-A) 17. Misoprostol should not be used in the setting of vaginal birth after Caesarean section due to the increased risk of uterine rupture. (II-3D) 18. Oxytocin should be started no earlier than 4 hours after the last dose of misoprostol. (III-B) Practice Points

•• Misoprostol is more effective than PGE2 to achieve vaginal delivery and results in less epidural use but more uterine tachysystole. •• PGE1 and PGE2 both reduce CS rates in an unfavourable cervix. •• The oral and vaginal routes have a similar reduction of CS rates. The oral route needs more oxytocin stimulation but the vaginal route will have more tachysystole. S12 l SEPTEMBER JOGC SEPTEMBRE 2013

•• The lower vaginal dose (25 mcg) tends to need more oxytocin stimulation and the higher vaginal dose (≥ 50 mcg) tends to have more uterine tachysystole. •• All doses of misoprostol can cause uterine tachysystole. •• Fetal well-being is required before istration of misoprostol. Electronic fetal monitoring should be performed for 30 minutes after istration of misoprostol and for 60 minutes after any tachysystole. OPTIONS FOR INDUCTION WITH A FAVOURABLE CERVIX Amniotomy

Amniotomy can be a simple and effective component of labour induction when the membranes are accessible and the cervix is favourable. This intervention creates a commitment to delivery and must be done for convincing and compelling reasons. However, the time interval from amniotomy to established labour may not be acceptable to clinicians or to women, and in a number of cases, after amniotomy alone, labour will not commence. Contraindications include placenta previa, vasa previa, and active genital infection except for women colonized with GBS. Cord prolapse is a risk of amniotomy, especially in a high presentation or unstable lie. After the membranes are ruptured, the care provider should continue to palpate the presenting part until it rests against the cervix to ensure there has been no cord prolapse. The amount, colour, and consistency of the fluid as well as fetal well-being should be assessed. There are no studies comparing amniotomy alone to placebo. Amniotomy can be used for induction when the cervix is favourable, but the onset of labour is unpredictable and often requires oxytocin. A 2007 Cochrane meta-analysis of 17 trials with 2566 women measured the safety of amniotomy and intravenous oxytocin for induction of labour. Amniotomy alone resulted in fewer vaginal deliveries in 24 hours then amniotomy plus oxytocin (RR 0.03, 95% CI 0.01 to 0.49). Amniotomy and oxytocin resulted in fewer instrumental deliveries than placebo (RR 0.18, 95% CI 0.05 to 0.58). However, there was more postpartum hemorrhage (RR 5.5, 95% CI 1.26 to 24.07) and maternal dissatisfaction (RR 53, 95% CI 3.32 to 846.51) with amniotomy and oxytocin than with vaginal PG.90 A more recent small RCT of amniotomy and immediate oxytocin infusion versus amniotomy and delayed oxytocin infusion for induction of labour in 123 women at term

Induction of Labour

found that women in the immediate group were more likely to be in established labour 4 hours post amniotomy, have a shorter amniotomy to delivery interval (P < 0.001), and achieve vaginal delivery within 12 hours (RR 1.5; 95% CI 1.2 to 12.6).91 There was no difference between the groups with regard to mode of delivery or incidence of uterine tachysystole with abnormal FHR recording. Although the study was underpowered to provide an adequate statistical analysis, women in the immediate group were more likely to be satisfied with the induction process (RR 4.1, 95% CI 1.1 to 16.1) and the duration of labour (RR 1.8, 95% CI 1.0 to 3.3). Recommendations

19. Amniotomy should be reserved for women with a favourable cervix. Particular care should be given in the case of unengaged presentation because there is a risk of cord prolapse. (III-B) 20. After amniotomy, oxytocin should be commenced early in order to establish labour. (III-B) Practice Point

•• Amniotomy creates a commitment to delivery and should be performed when the indication for induction is convincing and the reasons compelling and documented. Oxytocin

Intravenous oxytocin, available since the 1950s, has been the most commonly used method of induction for women with a viable pregnancy and favourable cervix. Oxytocin is a peptide produced naturally in the posterior hypothalamus that binds to uterine receptors to produce uterine contractions, but it has no direct effect on the cervix. It has a half-life of 5 to 12 minutes,92 a time to steady plasma concentration of 40 minutes,93 and a steady-state uterine response of 30 minutes or longer.94 The uterus is increasingly responsive to oxytocin as pregnancy progresses.95 Other areas of the body that respond to oxytocin include the breast, vascular smooth muscle, and kidney. At dosages typically used for the induction of labour, there is not a demonstrable effect on renal function or vascular smooth muscle tone. However, IV boluses of as little as 0.5 U can transiently decrease peripheral vascular tone, leading to hypotension.96 Due to its antidiuretic activity, water intoxication is possible with high doses (> 40 mU/min). The physiological dose of oxytocin to produce regular uterine contraction is 8 to 12 mU/min. The ideal dosing regimen of oxytocin is not known and there are both lowdose and high-dose protocols. The low-dose regimen begins with 1 to 2 mU/min, increased incrementally by 1 to 2 mU at 30-minute intervals. The high-dose regimen commences

with a dose of 4 to 6 mU/min, with dose increments of 4 to 6 mU/min every 15 to 30 minutes. The benefits of the low-dose regimen include less risk of tachysystole and the use of a smaller overall dose. However, the high-dose oxytocin regimen has been shown to reduce the length of labour with no appreciable increase in neonatal morbidity97. High-dose oxytocin has been associated with an increase in uterine tachysystole with associated FHR changes.61 Continuous fetal monitoring is recommended with the use of oxytocin.98 Because mixing methods vary, the rate of infusion should always be documented in mU/min rather than ml/hour. Example of low-dose protocol: Initial dose of oxytocin..................................1 to 2 mU/min Increase interval......................................................30 minutes Dosage increment....................................................1 to 2 mU Usual dose for good labour.........................8 to 12 mU/min Maximum dose before reassessment.................30 mU/min Example of high-dose protocol: Initial dose of oxytocin..................................4 to 6 mU/min Increase interval............................................15 to 30 minutes Dosage increment...........................................4 to 6 mU/min Usual dose for good labour.........................8 to 12 mU/min Maximum dose before reassessment.................30 mU/min A 2009 Cochrane review included 61 studies (12 819 women) of the methods of cervical ripening and labour induction.99 Oxytocin alone versus vaginal prostaglandins was associated with an increase in unsuccessful vaginal delivery within 24 hours (70% vs. 21%). Oxytocin versus intracervical prostaglandins also had fewer vaginal deliveries (51% vs. 35%) and increase in CS rates (19.1% vs. 13.7%). For all women with an unfavourable cervix regardless of membrane status, the CS rates were increased (19.0% vs. 13.1%, RR 1.42, 95% CI 1.11 to 1.82) when labour was induced.99 In the case of a favourable cervix, the CS rate was no different whether the pregnancy was induced or managed expectantly.8,17,21 Osmundson et al. measured a significantly higher rate of oxytocin use in the elective induction group than in the group managed expectantly (99.3 % vs. 30.6 %, P < 0.001).21 Term PROM

A 2006 Cochrane analysis reviewed the advantages of early intervention with either oxytocin or prostaglandin versus expectant management in the setting of term PROM.59 SEPTEMBER JOGC SEPTEMBRE 2013 l S13

SOGC Clinical Practice Guideline

Planned delivery resulted in less chorioamnionitis and endometritis and fewer issions to neonatal ICU, with no difference in neonatal infection rates or mode of delivery. PROM with GBS

The 2009 Cochrane review included women with ruptured membranes. In this setting, there was some evidence of less chorioamnionitis (RR 0.66, CI 0.47 to 0.92) and use of antibiotics in the neonatal period with the use oxytocin alone than with vaginal PGE2.99 The authors stated the data should be viewed with caution because the infection had not been not pre-specified. In the setting of term PROM and GBS, the Term PROM trial showed that GBS colonization was predictive of neonatal infection for induction with vaginal PG (OR 5.13, 95% CI 2.54 to 10.37) and in expectant groups (OR 4.12, 95% CI 2.00 to 8.52) but not in the group induced with oxytocin.100 VBAC

Oxytocin can be used in women with a previous CS, but caution, care, and diligence should be used as it has been shown to increase the risk of rupture.69,101 Recommendations

21. In the setting of ruptured membranes at term, oxytocin should be considered before expectant management. (I-A) 22. Women positive for group B streptococcus should be started on oxytocin as early as possible after ruptured membranes in order to establish labour within 24 hours. (III-B) 23. Both high- and low-dose oxytocin may be considered within a hospital protocol. (III-B) 24. Because of the various concentrations, oxytocin infusion rates should always be recorded in mU/min rather than mL/hr. (III-L) 25. Oxytocin induction maybe considered in the hospital setting of vaginal birth after Caesarean section. (II-3B) Practice Points

•• With PROM, oxytocin stimulation is more effective than expectant management to reduce maternal infection and increase vaginal deliveries within 24 hours, but it may increase CS rate. •• In the setting of PROM, women preferred oxytocin induction over expectant management. The care provider should maintain a higher level of vigilance for uterine dehiscence and rupture when using oxytocin in an attempted VBAC. S14 l SEPTEMBER JOGC SEPTEMBRE 2013

UTERINE RUPTURE

Uterine rupture is a rare but potentially devastating complication for both mother and fetus. Uterine rupture is possible during induced labour in the absence of a scarred uterus, and is usually associated with aggressive use of uterotonic agents in the presence of obstructed labour (e.g. brow or posterior presentation). A population-based study in the Netherlands comparing induced and spontaneous labour found 210 cases of uterine rupture with an incidence of 5.9 per 10 000 pregnancies. Ruptures occurred in both scarred and unscarred uteri. The overall relative risk of uterine rupture with induction of labour was 3.6 (95% CI 2.7 to 4.8) with an absolute risk of 1 in 629. For women with a previous CS, PG conferred the greatest risk for rupture of all uterotonic agents.69 Lydon-Rochelle et al. also reported the greatest risk of rupture in women with a previous CS when PG were used, with an incidence of 24.5 per 1000 (RR 15.6, 95% CI 8.1 to 30.0).36 Oxytocin is considered a safe uterotonic agent for use in the presence of a scarred uterus, but it should be used with due care and diligence.102 INDUCTION OF LABOUR AND ADVANCED MATERNAL AGE

Advanced maternal age (35 years or older) now s for 17% of all pregnancies and 17.44% all live births in Canada.103 It has been well documented that these women are at risk of several adverse outcomes in pregnancy including stillbirth. Rates have been stated to be 1/116 in women 40 and older from 37 weeks’ gestation and greater. Population-based studies showed higher perinatal mortality rates among women aged 35 to 39 and those 40 years or older than in women aged 20 to 24.104–106 Given the increased risk of stillbirth in women with advanced maternal age some experts suggest that women ≥ 40 years of age be considered biologically post-term at 39 weeks’ gestation and that delivery be considered at this gestation.107 A single study was found comparing induction of labour with misoprostol to oxytocin in women of advanced maternal age (≥ 35) with an unfavourable cervix (Bishop < 6). The results were consistent with other studies showing the benefit of PG over oxytocin in an unripe cervix.108 INDUCTION OF LABOUR AND ARTIFICIAL REPRODUCTIVE TECHNOLOGIES

ART has been shown to be associated with adverse outcomes in pregnancy including gestational hypertension, gestational diabetes, placenta previa and placental abruption, stillbirth, neonatal death, preterm delivery, low

Induction of Labour

and very low birth weight, small for gestational age, and NICU ission as illustrated in a recent SOGC-CFAS guideline.109 A prospective database review by the FASTER Research Consortium showed an adjusted OR (95% CI) of 2.1 (1.3 to 3.6) for fetal loss or demise (> 24 weeks).110 Many women undergoing ART are older, which increases their risk of the adverse perinatal outcomes listed above. Until there is more evidence available, induction should be considered on an individual basis. SUMMARY

The rate of labour induction has increased significantly since the early 1990s and continues to involve a significant percentage of pregnancies, removing women from the advantageous natural process of labour. While there are indications to recommend induction, postdates pregnancies remain a large contributor to the induction rates. Practitioners need to apply clinical judgement and evidence-based medicine to justify that induction is superior to continuation of pregnancy. The benefit of induction over the continuation of a pregnancy is not always clear, but the clinician has some tools to evaluate the likelihood of a successful vaginal delivery. The clinician should consider all of the tools available to optimize a safe process towards achieving a successful vaginal delivery. REFERENCES 1. Health Canada. Canadian Perinatal Health Report, 2003. Ottawa: Government of Canada; 2003. Available at: http://publications.gc.ca/site/eng/252200/publication.html. Accessed on March 28, 2013. 2. Health Canada. Canadian Perinatal Health Report, 2008. Ottawa: Government of Canada; 2008. Available at: http://www.phac-aspc.gc.ca/publicat/2008/hr-rspc/pdf/ hr-rspc08-eng. Accessed on March 28, 2013. 3. BC perinatal database registry [electronic resource]. Version 2. Vancouver: British Columbia Perinatal Health Program; 2010. Available at: http://bcr.xplorex.com/ Perinatal%20Database%20Registry.htm. Accessed on May 8, 2013. 4. Macones GA, Hankins GD, Spong CY, Hauth J, Moore T. The 2008 National Institute of Child Health and Human Development workshop report on electronic fetal monitoring: update on definitions, interpretation, and research guidelines. Obstet Gynecol 2008;112:661–6. 5. Rayburn WF, Zhang J. Rising rates of labor induction: present concerns and future strategies. Obstet Gynecol 2002;100:164–7. 6. Combs CA, Singh NB, Khoury JC. Elective induction versus spontaneous labor after sonographic diagnosis of fetal macrosomia. Obstet Gynecol 1993;81:492–6. 7. Sanchez-Ramos L, Bernstein S, Kaunitz AM. Expectant management versus labor induction for suspected fetal macrosomia: a systematic review. Obstet Gynecol 2002;100(5 Pt 1):997–1002. 8. Bishop EH. Pelvic scoring for elective induction. Obstet Gynecol 1964;24;266–8.

9. Burnett JE Jr. Preinduction scoring: an objective approach to induction of labor. Obstet Gynecol 1966;28:479–83. 10. Crane JM. Factors predicting labor induction success: a critical analysis. Clin Obstet Gynecol 2006;49:573–84. 11. Laughon SK, Zhang J, Troendle J, Sun L, Reddy UM. Using a simplified Bishop score to predict vaginal delivery. Obstet Gynecol 2011;117:805–11. 12. Vrouenraets FP, Roumen FJ, Dehing CJ, van der Akker ES, Aarts MJ, Scheve EJ. Bishop score and risk of cesarean delivery after induction of labor in nulliparous women. Obstet Gynecol 2005;105:690–7. 13. Ennen CS, Bofill JA, Magann EF, Bass JD, Chauhan SP, Morrison JC. Risk factors for cesarean delivery in preterm, term, and post-term patients undergoing induction of labour with an unfavourable cervix. Gynecol Obstet Invest 2009;67;113–7. 14. Pevnzer L, Rayburn WF, Rumney P, Wing DA. Factors predicting successful labor induction with dinoprostine and misoprostol vaginal inserts. Obstet Gynecol 2009;114(2 Pt 1):261–7. 15. Ehrenthal DB, Jiang X, Strobino DM. Labour induction and the risk of cesarean delivery among nulliparous women at term. Obstet Gynecol 2010;116;35–42. 16. Glantz JC. Term labour induction compared with expectant management. Obstet Gynecol 2010;115;70–6. 17. Xenakis EM, Piper JM, Conway DL, Langer O. Induction of labor in the nineties: conquering the unfavorable cervix. Obstet Gynecol 1997;90:235–9. 18. Coonrod DV, Drachman D, Hobson P, Manriquez M. Nulliparous term singleton vertex cesarean delivery rates: institutional and individual predictors. Am J Obstet Gynecol 2008;198;694.e1–694.e11. 19. Nielsen PE, Howard BC, Crabtree T, Batig AL, Pates JA. Comparison of elective induction of labour with favourable Bishop scores versus expectant management: a randomized clinical trial. J Matern Fetal Neonatal Med 2005;18:59–64. 20. Durudola A, Kuti O, Orji EO, Ogunniyi SO. Rate of increase in oxytocin dose on the outcome of labor induction. Int J Gynaecol Obstet 2005;90;107–11. 21. Osmundson SS, Ou-Yang RJ, Grobman WA. Elective induction compared with expectant management in nulliparous women with a favorable cervix. Obstet Gynecol 2010;116:601–5. 22. Peregrine E, O’Brien P, Omar R, Jauniaux E. Clinical and ultrasound parameters to predict the risk of cesarean delivery after induction of labor. Obstet Gynecol 2006;107;227–33. 23. Hatfield AS, Sanchez-Ramos L, Kaunitz AM. Sonographic cervical assessment to predict the success of labour induction: a systematic review with metaanalysis. Am J Obstet Gynecol 2007;197:186–192. 24. Rozenberg P, Chevret S, Chastang C, Ville Y. Comparison of digital and ultrasonographic examination of the cervix in predicting the interval from induction to delivery in women with low Bishop score. BJOG 2005;112:192–6. 25. Bartha JL, Romero-Carmona R, Martínez-Del-Fresno P, Comino-Delgado R. Bishop score and transvaginal ultrasound for preinduction cervical assessment: a randomized trial. Ultrasound Obstet Gynecol 2005;25;155–9. 26. Delaney M, Roggensack A, Leduc DC, Ballermann C, Biringer A, Dontigny L; Clinical Practice Obstetrics Committee; Maternal Fetal Medicine Committee. Guidelines for the management of pregnancy at 41+0 to 42+0 weeks. SOGC Clinical Practice Guidelines, No. 214, September 2008. J Obstet Gynaecol Can 2008;30:800–10. 27. Neilson JP. Ultrasound for fetal assessment in early pregnancy. Cochrane Database Syst Rev 1998;(4):CD000182. DOI: 10.1002/14651858. CD000182.

SEPTEMBER JOGC SEPTEMBRE 2013 l S15

SOGC Clinical Practice Guideline

28. Gülmezoglu AM, Crowther CA, Middleton P. Induction of labour for improving birth outcomes for women at or beyond term. Cochrane Database Syst Rev 2006;(4):CD004945. DOI: 10.1002/14651858. CD004945.pub2.

46. Public Health Agency of Canada. BC Reproductive Care Program (BCR). Ottawa: Public Health Agency of Canada; 2005. Available at: http://www.phac-aspc.gc.ca/ccasn-rcsac/dss/bc2-eng.php. Accessed on March 18, 2013.

29. Takahashi T, Marcus B, Scheerer RG, Katz M. A new model for objective assessment of cervical ripening: the effect of prostaglandin E2 and prelabor contractility. Am J Obstet Gynecol 1991;164:1115–8.

47. Boulvain M, Kelly A, Lohse C, Stan C, Irion O. Mechanical methods for induction of labour. Cochrane Database Syst Rev2001;(4):CD001233. DOI: 10.1002/14651858.CD001233.

30. Boulvain M, Stan C, Irion O. Membrane sweeping for induction of labour. Cochrane Database Syst Rev 2005;(1):CD000451. DOI: 10.1002/14651858.CD000451.pub2.

48. Pennell C, Henderson J, O’Neill M, McCleery S, Doherty D, Dickinson J. Induction of labour in nulliparous women with an unfavourable cervix: a randomised controlled trial comparing double and single balloon catheters and PGE2 gel. BJOG 2009;116:1443–52.

31. Yildirim G, Güngördük K, Karadağ OI, Aslan H, Turhan E, Ceylan Y. Membrane sweeping to induce labor in low-risk patients at term pregnancy: a randomised controlled trial. J Matern Fetal Neonat Med 2009;23:681–7. 32. de Miranda E, van der Bom J, Bonsel G, Bleker O, Rosendaal F. Membrane sweeping and prevention of post-term pregnancy in low-risk pregnancies: a randomised controlled trial. BJOG 2006;113:402–8. 33. Hamdam M, Sidhu K, Sabir N, Omar SZ, Tan PC. Serial membrane sweeping at term in planned vaginal birth after cesarean: a randomized controlled trial. Obstet Gynecol 2009;114:745–51. 34. Tan PC, Jacob R, Omar SZ. Membrane sweeping at initiation of formal labor induction: a randomized controlled trial. Obstet Gynecol 2006;107:569–77. 35. Tan PC, Andi A, Azmi N, Noraihan MN. Effect of coitus at term on length of gestation, induction of labour, and mode of delivery. Obstet Gynecol 2006;108:134–40. 36. Lydon-Rochelle MT, Cárdenas V, Nelson JC, Holt VL, Gardella C, Easterling TR. Induction of labor in the absence of standard medical indications. Med Care 45;6:505–12.

49. Heinemann J, Gillen G, Sanchez-Ramos L, Kaunitz AM. Do mechanical methods of cervical ripening increase infectious morbidity? A systematic review. Am J Obstet Gynecol 2008;177–87. 50. Centers for Disease Control and Prevention. Prevention of perinatal group B streptococcal disease: revised guidelines from CDC, 2010. Available at: http://www.cdc.gov/groupbstrep/guidelines/ guidelines.html. Accessed on March 14, 2013. 51. Sciscione AC, Muench M, Pollock M, Jenkins TM, Tildon-Burton J, Colmorgen GH. Transcervical Foley catheter for preinduction cervical ripening in an outpatient versus inpatient setting. Obstet Gynecol 2001;98(5 Pt 1):751–6. 52. Bujold E, Blackwell SC, Gauthier RJ. Cervical ripening with transcervical Foley catheter and the risk of uterine rupture. Obstet Gynecol 2004;103:18–23. 53. Dalui R, Suri V, Ray P, Gupta I. Comparisonof extraamniotic Foley catheter and intracervical prostaglandin E2 gel for preinduction cervical ripening. Acta Obstet Gynecol Scand 2005;84:362–7.

37. Le Ray C, Carayol M, Bréart G, Goffinet F; PREMODA Study Group. Elective induction of labor: failure to follow guidelines and risk of cesarean delivery Acta Obstet Gynecol Scand 2007;86:657–65.

54. Prager M, Eneroth-Grimfors E, Edlund M, Marions L. A randomised controlled trial of intravaginal dinoprostone, intravaginal misoprostol and transcervical balloon catheter for labour induction. BJOG 2008;115:1443–50.

38. Oshiro BT, Henry E, Wilson J, Branch DW, Varner MW; Women and Newborn Clinical Integration Program. Decreasing elective deliveries before 39 weeks of gestation in an integrated health care system. Obstet Gynecol 2009;113:804–11.

55. Vaknin Z, Kurzweil Y, Sherman D. Foley catheter balloon vs locally applied prostaglandins for cervical ripening and labor induction: a systematic review and metaanalysis. Am J Obstet Gynecol 2010;203:418–29.

39. Fisch JM, English D, Pedaline S, Brooks K, Simhan HN. Labor induction process improvement: a patient quality-of-care initiative. Obstet Gynecol 2009;113:797–803.

56. Towers CV, Briggs GG, Rojas JA. The use of prostaglandin E2 in pregnant patients with asthma. Am J Obstet Gynecol 2004;190:1777.

40. Reisner DP, Wallin TK, Zingheim RW, Luthy DA. Reduction of elective inductions in a large community hospital. Am J Obstet Gynecol 2009;200:674.e1–674.e7. 41. Brennan DJ, Robson MS, Murphy M, O’Herlihy C. Comparative analysis of international cesarean delivery rates using 10-group classification identifies significant variation in spontaneous labor. Am J Obstet Gynecol 2009;201:308.e1–e8. 42. Sanchez-Ramos L, Olivier F, Delke I, Kaunitz AM. Labor induction versus expectant management for postterm pregnancies: a systematic review with meta-analysis. Obstet Gynecol 2003;101:1312–8. 43. Hermus MA, Verhoeven CJ, Mol BW, de Wolf GS, Fiedeldeij CA. Comparison of induction of labour and expectant management in postterm pregnancy: a matched cohort study. J Midwifery Womens Health 2009;54:351–6. 44. Hannah ME, Hannah WJ, Hellmann J, Hewson S, Milner R, Willan A. Induction of labor as compared with serial antenatal monitoring in post-term pregnancy—a randomized controlled trial. N Engl J Med 1992;326:1587–92. 45. Hannah M; Maternal-Fetal Medicine Committee, Society of Obstetricians and Gynaecologists of Canada. Management of post-term pregnancy. SOGC Committee Opinion No. 5, J Soc Obstet Gynaecol Can 1994;16(4):1581–6.

S16 l SEPTEMBER JOGC SEPTEMBRE 2013

57. Kelly AJ, Malik S, Smith L, Kavanagh J, Thomas J. Vaginal prostaglandin (PGE2 and PFA2a) for induction of labour at term. Cochrane Database Syst Rev 2009;(4):CD003101. doi: 10.1002/14651858.CD003101.pub2. 58. Boulvain M, Kelly AJ, Irion O. Intracervical prostaglandins for induction of labour. Cochrane Database Syst Rev 2008;(1):CD006971. DOI: 10.1002/14651858.CD006971. 59. Dare R, Middleton P, Crowther CA, Flenady VJ, Varatharaju B. Planned early birth versus expectant management for prelabour rupture of membranes at term. Cochrane Database Syst Rev 2006;(1):CD005302. 60. Dodd JJ, van der Goes BY, Pel M, Mol BW, van der Post JA. Morning compared with evening induction of labour. Obstet Gynecol 2006;108;350–60. 61. ACOG Committee on Practice Bulletins—Obstetrics. ACOG practice bulletin: induction of labor, ACOG No. 107, Aug 2009. Obstet Gynecol 2009;114(2 Pt 1):386–97. doi: 10.1097/AOG.0b013e3181b48ef5. 62. Biem SR, Turnell RW, Olatunbosun O, Tauh M, Biem HJ. A randomized controlled trial of outpatient versus inpatient labour induction with vaginal controlled-release prostaglandin E2: effectiveness and satisfaction. J Obstet Gynaecol Can 2003:25;23–31. 63. Liston R, Sawchuck D, Young D. Fetal health surveillance: antepartum and intrapartum consensus guideline 2007. SOGC Clinical Practice Guidelines, No. 197, September 2007. J Obstet Gynaecol Can 2007;29:S3–S36.

Induction of Labour

64. Dowswell T, Kelly AJ, Livio S, Norman JE, Alfirevic Z. Different methods for the induction of labour in outpatient settings. Cochrane Database Syst Rev 2010;(8):CD007701. DOI: 10.1002/14651858. CD007701.pub2. 65. Foong LC, Vanaja K, Tan G, Chua S. Membrane sweeping in conjunction with labor induction. Obstet Gynecol 2000;96:539–42. 66. Eroglu D, Oktem M, Yanik F, Kuscu E. Labor induction at term: a comparison of the effects of 50 microg and 25 microg vaginal misoprostol. Clin Exp Obstet Gynecol 2007;34:102–5. 67. Mariani Neto C, Leao EJ, Baretto EM, Kenj G, De Aquino MM. Use of misoprostol for labour induction in stillbirths. Rev Paul Med 1987;105:325–8. 68. Wing DA, Lovett K, Paul RH. Disruption of prior uterine incision following misoprostol for labor induction in women with previous cesarean delivery. Obstet Gynecol 1998;91(5 Pt 2):828–30. 69. Zwart J, Richters JM, Ory F, de Vries JI, Bloemenkamp KW, van Roosmalen J. Uterine rupture in the Netherlands: a nationwide population-based cohort study. BJOG 2009;116:1069–80. 70. Bennet BB. Uterine rupture during induction of labor at term with intravaginal misoprostol Obstet Gynecol 1997;89(5 Pt 2):832–3. 71. Hofmeyr GJ, Gülmezoglu AM, Pileggi C. Vaginal misoprostol for cervical ripening and induction of labour. Cochrane Database Syst Rev2010;(10): CD000941. DOI: 10.1002/14651858.CD000941.pub2. 72. Sanchez-Ramos L, Kaunitz AM, Delke I. Labor induction with 25 mcg versus 50 mcg intravaginal misoprostol: a systematic review. Obstet Gynecol 2002;99:145–51. 73. Ewert K, Powers B, Robertson S, Alfirevic Z. Controlled-release misoprostol vaginal insert in parous women for labor induction: a randomized controlled trial. Obstet Gynecol 2006;108:1130–7. 74. Wing DA, Miller H, Parker L, Powers BL, Rayburn WF; Misoprostol Vaginal Insert Miso-Obs-204 Investigators. Misoprostol vaginal insert for successful labor induction: a randomized controlled trial. Obstet Gynecol 2011;117:533–41. 75. Alfirevic Z, Weeks A. Oral misoprostol for induction of labour. Cochrane Database Syst Rev2006;( 2): CD001338. DOI: 10.1002/14651858. CD001338.pub2. 76. Colón I, Clawson K, Hunter K, Druzin ML, Taslimi MM. Prospective randomized clinical trial of inpatient cervical ripening with stepwise oral misoprostol vs vaginal misoprostol. AJOG 2005;192:747–52. 77. Cecatti G, Tedesco RP, Pires HM, Calderon IM, Faúndes A. Effectiveness and safety of a new vaginal misoprostol product specifically labeled for cervical ripening and labor induction. Acta Obstet Gynecol Scand 2006;85:706–11. 78. Cheng SY, Ming H, Lee JC. Titrated oral compared with vaginal misoprostol for labor induction a randomized controlled trial. Obstet Gynecol 2008;111:119–25. 79. Kundodyiva TW, Alfirevic Z, Weeks AD. Low-dose oral misoprostol for induction of labor a systematic review. Obstet Gynecol 2009;113:374–83. 80. Crane J, Butler B, Young D, Hannah M. Misoprostol compared with prostaglandin E2 for labour induction in women at term with intact membranes and unfavourable cervix: a systematic review. BJOG 2006;113:1366–76. 81. Wolf SB, Sanchez-Ramos L, Kaunitz AM. Sublingual misoprostol for labor induction: a randomized clinical trial. Obstet Gynecol 2005;105:365–71. 82. Bartusevicius A, Barcaite E, Krikstolaitis R, Gintautas V, Nadisauskiene R. Sublingual compared with vaginal misoprostol for labour induction at term: a randomised controlled trial. BJOG 2006;113:1431–7.

83. Souza A, Amorim M, Feitosa F. Comparison of sublingual versus vaginal misoprostol for the induction of labour: a systematic review. BJOG 2008;115:1340–9. 84. Nassar A, Awwad J, Khalil A, Abu-Musa A, Mehio G, Usta I. A randomised comparison of patient satisfaction with vaginal and sublingual misoprostol for induction of labour at term. BJOG 2007;114:1215–21. 85. Zahran KM, Shahin AY, Abdellah MS, Elsayh KI. Sublingual versus vaginal misoprostol for induction of labor at term: a randomized prospective placebo-controlled study. J Obstet Gynaecol Res 2009;35:1054–60. 86. Adeniji OA, Oladokun A, Olayemi O, Adeniji OI, Odukogbe AA, Ogunbode O, et al. Pre-induction cervical ripening: transcervical foley catheter versus intravaginal misoprostol. J Obstet Gynaecol 2005;25:134–9. 87. Afolabi BB, Oyeneyin OL, Ogedengbe OK. Intravaginal misoprostol versus Foley catheter for cervical ripening and induction of labor. Int J Gynaecol Obstet 2005;89:263–7. 88. da Graça Krupa F, Cecatti JG, de Castro Surita FG, Milanez HM, Parpinelli MA. Misoprostol versus expectant management in premature rupture of membranes at term. BJOG 2005;112:1284–90. 89. Bricker L, Peden H, Tomlinson A, Al-Hussaini T, Idama T, Candelier C, et al. Titrated low-dose vaginal and/or oral misoprostol to induce labour for prelabour membrane rupture: a randomised trial. BJOG 2008;115:1503–11. 90. Howarth GR, Botha DJ. Amniotomy plus intravenous oxytocin for induction of labour. Cochrane Database Syst Rev 2001;(3):CD003250. 91. Selo-Ojeme DO, Pisal P, Lawal O, Rogers C, Shah A, Sinha S. A randomized controlled trial of amniotomy and immediate oxytocin infusion versus amniotomy and delayed oxytocin infusion for induction of labour at term. Arch Gynecol Obstet 2009;279(6):813–20. 92. Leake RD, Weitzman RE, Fisher DA. Pharmacokinetics of oxcytocin in the human subject. ObstetGynecol 1980;56:701–4. 93. Seitchik J, Amico J, Robinson AG, Castillo M. Oxytocin augmentation of dysfunctional labor. IV. Oxytocin pharmacokinetics. Am J Obstet Gyneol 1984;150:225–8. 94. Seitchik J, Castillo M. Oxytocin augmentation of dysfunctional labor. II Uterine activity data. Am J Obstet Gynecol 1983;145:526–9. 95. Caldeyro-Barcia R, Sereno JA. The response of the human uterus to oxytocin throughout pregnancy. In: Caldeyro-Barcia R, Heller H, editors. Oxytocin. New York; Pergamon Press; 1961 p. 177–200. 96. Hendricks CH, Brenner WF. Cardiovascular effects of oxytocic drugs used post partum. Am J Obstet Gyneol 1970;108:751–60. 97. Smith JG, Merrill DC. Oxytocin for induction of labor. Clin Obstet Gynecol 2006;49:594–608. 98. Liston R, Sawchuck D, Young D, Fetal Health Surveillance Consensus Committee. Fetal health surveillance: antepartum and intrapartum consensus guideline. Chapter 2: intrapartum fetal surveillance [SOGC clinical practice guideline no 107]. J Obstet Gynaecol Can 2007;29(9 Suppl 4):S26–S44 99. Alfirevic Z, Kelly AJ, Dowswell T. Intravenous oxytocin alone for cervical ripening and induction of labour. Cochrane Database Syst Rev 2009;(4):CD003246. 100. Hannah ME, Hodnett ED, Willan A, Foster GA, Di Cecco R, Helewa M. Prelabor rupture of the membranes at term: expectant management at home or in hospital? The Term PROM Study Group. Obstet Gynecol 2000;96:533–8.

SEPTEMBER JOGC SEPTEMBRE 2013 l S17

SOGC Clinical Practice Guideline

101. Martel M-J, McKinnon CJ: Clinical Practice Obstetrics Committee. Guidelines for vaginal birth after previous Caesarean birth. SOGC Clinical Practice Guidelines, No. 155, February 2005. J Obstet Gynaecol Can 2005;27:164–74. 102. Martel M-J, McKinnon CJ: Clinical Practice Obstetrics Committee. Guidelines for vaginal birth after previous Caesarean birth. SOGC Clinical Practice Guidelines, No. 155, February 2005. J Obstet Gynaecol Can 2005;27:164–74. 103. Statistics Canada. Pregnancy outcomes by age group, 2005. Ottawa: Statistics Canada, 2008. Available at: http://www.statcan.gc.ca/tablestableaux/sum-som/l01/cst01/hlth65a-eng.htm. Accessed on June 17, 2013. 104. Fretts RC, Schmittdiel J, McLean FH, Usher RH, Goldman MB. Increased maternal age and the risk of fetal death. N Engl J Med 1995;333:953–7. 105. Joseph KS, Allen AC, Dodds L, Turner LA, Scott H, Liston R. The perinatal effects of delayed childbearing. Obstet Gynecol 2005;105:1410–8. 106. Haavaldsen C, Sarfraz AA, Samuelsen SO, Eskild A. The impact of maternal age on fetal death: does length of gestation matter? Am J Obstet Gynecol 2010;203:554.e1–554e8.

S18 l SEPTEMBER JOGC SEPTEMBRE 2013

107. Johnson J-A, Tough S. Delayed child-bearing SOGC Committee Opinion No. 271, January 2012. J Obstet Gynaecol Can 2012;34:80–93. 108. Zeteroglu S, Sahin GH, Sahin HA. Induction of labor with misoprostol in pregnancies with advanced maternal age. Eur J Obstet Gynecol Reprod Biol 2006;129:140–4. 109. Allen VM, Wilson RD, Cheung A; Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada (SOGC); Reproductive Endocrinology Infertility Committee of the Society of Obstetricians and Gynaecologists of Canada (SOGC) Pregnancy outcomes after assisted reproductive technology. SOGC-CFAS guideline, No. 173, March 2006. J Obstet Gynaecol Can 2006;28:220–50. 110. Shevell T, Malone FD, Vidaver J, Porter TF, Luthy DA, Comstock CH, et al. Assisted reproductive technology and pregnancy outcome. Obstet Gynecol 2005;106(5 Pt 1):1039–45. 111. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

SOGC CLINICAL PRACTICE GUIDELINE No. 295, August 2013

Intrauterine Growth Restriction: Screening, Diagnosis, and Management This clinical practice guideline has been prepared by the Maternal Fetal Medicine Committee and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Andrea Lausman, MD, Toronto ON John Kingdom, MD, Toronto ON MATERNAL FETAL MEDICINE COMMITTEE Robert Gagnon, MD (Chair), Verdun QC Melanie Basso, RN, Vancouver BC Hayley Bos, MD, London ON Joan Crane, MD, St. John’s NL Gregory Davies, MD, Kingston ON Marie- Delisle, MD, Vancouver BC Lynda Hudon, MD, Montreal QC Savas Menticoglou, MD, Winnipeg MB William Mundle, MD, Windsor ON Annie Ouellet, MD, Sherbrooke QC Tracy Pressey, MD, Vancouver BC Christy Pylypjuk, MD, Saskatoon SK Anne Roggensack, MD, Calgary AB Frank Sanderson, MD, Saint John NB Disclosure statements have been received from all of the committee.

Key Words: intrauterine growth restriction (IUGR), screening, diagnosis, management, ultrasound, Doppler, placenta.

Abstract Background: Intrauterine growth restriction (IUGR) is an obstetrical complication, which by definition would screen in 10% of fetuses in the general population. The challenge is to identify the subset of pregnancies affected with pathological growth restriction in order to allow intervention that would decrease morbidity and mortality. Objective: The purpose of this guideline is to provide summary statements and recommendations and to establish a framework for screening, diagnosis, and management of pregnancies affected with IUGR. Methods: Affected pregnancies are compared with pregnancies in which the fetus is at an appropriate weight for its gestational age. History, physical examination, and laboratory investigations including biochemical markers and ultrasound characteristics of IUGR are reviewed, and a management strategy is suggested. Evidence: Published literature in English was retrieved through searches of PubMed or MEDLINE, CINAHL, and The Cochrane Library in January 2013 using appropriate controlled vocabulary via MeSH (fetal growth restriction and small for gestational age) and key words (fetal growth, restriction, growth retardation, IUGR, low birth weight, small for gestational age). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technologyrelated agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Values: The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table). Benefits, harms, and costs: Implementation of the recommendations in this guideline should increase clinician recognition of IUGR and guide intervention where appropriate. Optimal long-term follow-up of neonates diagnosed as IUGR may improve their long-term health.

J Obstet Gynaecol Can 2013;35(8):741–748

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

AUGUST JOGC AOÛT 2013 l 741

SOGC Clinical Practice Guideline

Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care. †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

Summary Statements 01. The definition of small-for-gestational age for a fetus in utero is an estimated fetal weight that measures < 10th percentile on ultrasound. This diagnosis does not necessarily imply pathologic growth abnormalities, and may simply describe a fetus at the lower end of the normal range. (III) 02. Intrauterine growth restriction refers to a fetus with an estimated fetal weight < 10th percentile on ultrasound that, because of a pathologic process, has not attained its biologically determined growth potential. (III) A clinical estimation of fetal weight or symphysis-fundal height has poor sensitivity and specificity and should not be relied upon to diagnose intrauterine growth restriction. Intrauterine growth restriction should be considered in the differential diagnosis when the fetus is found to be small for gestational age. (II-1)

menstrual history, relevant assisted reproductive technology information, and either a first trimester or early second trimester dating ultrasound. (I) 04. Symphysis-fundal height determination is of limited value in routine obstetrical care, but continues to be the only physical examination screening test available. (I) 05. Fetal weight determination in fetuses between the 10th and 90th percentiles by ultrasound biometry alone has at least a 10% error rate across gestation, but is effective equally when measuring with abdominal circumference alone or in combination with head size (biparietal diameter or head circumference) and/or femur length to establish an estimated fetal weight. (II-2)

03. Effective screening for intrauterine growth restriction requires accurate dating and includes a review of the mother’s

06. Determining whether intrauterine growth restriction is symmetric or asymmetric is of less clinical importance than careful re-evaluation of fetal anatomy and uterine and umbilical artery Doppler studies. (I)

ABBREVIATIONS

07. In women with risk factors for intrauterine growth restriction, uterine artery Doppler screening at 19 to 23 weeks may identify pregnancies at risk of antepartum stillbirth and preterm delivery due to intrauterine growth restriction and placental disease. (II-2)

AC

abdominal circumference

AFV

amniotic fluid volume

BPP

biophysical profile

DV

ductus venosus

DVP

deepest vertical pocket

EFW

estimated fetal weight

IUGR

intrauterine growth restriction

MCA

middle cerebral artery

NST

non-stress test

SFH

symphysis fundal height

742 l AUGUST JOGC AOÛT 2013

08. In pregnancies in which intrauterine growth restriction due to uteroplacental vascular insufficiency is diagnosed, maternal surveillance for the development of severe preeclampsia with adverse features is warranted. (II-1) 09. Once surveillance of a fetus with intrauterine growth restriction is instituted, umbilical artery Doppler studies and biophysical profile scoring can be used as short-term predictors of fetal well-being. (I) 10. In the presence of abnormal umbilical artery Doppler studies, further investigation of the fetal circulatory system by Doppler

Intrauterine Growth Restriction: Screening, Diagnosis, and Management

examination of the middle cerebral artery, ductus venosus, and umbilical vein can be considered. (II-2) 11. For a fetus with intrauterine growth restriction, the decision for obstetrical intervention, including Caesarean section, in cases of abnormal fetal heart rate or malpresentation is largely based on fetal viability, as assessed by ultrasound. (II-2) 12. Maternal surveillance for the development of preeclampsia is warranted. (II-2) Recommendations 01. Women should be screened for clinical risk factors for intrauterine growth restriction by means of a complete history. (II-2B) 02. Women should be counselled on smoking cessation at any time during pregnancy. (II-2A) 03. First and second trimester screening tests for aneuploidy maybe useful tests of placental function. If two screening test results are abnormal, health care providers should be aware that the fetus is at increased risk of preterm intrauterine growth restriction and associated stillbirth. (II-1A) 04. If intrauterine growth restriction is suspected, further assessment can assist in making the diagnosis. If available, detailed ultrasound examination of the placenta (looking for evidence of a small, thickened placenta, or abnormal morphology) and uterine artery Dopplers should be considered at 19 to 23 weeks. In the absence of available diagnostic testing, closer surveillance should be offered. A maternal– fetal medicine consultation can be considered if the placenta appears abnormal on ultrasound, especially in the context of a growth-restricted fetus and abnormal uterine artery Doppler. In a rural setting, the caregiver needs to decide whether the patient should be delivered immediately, or whether transfer to a tertiary centre is appropriate. A telephone consultation and telemedicine may help. (II-2A) 05. In women without risk factors for intrauterine growth restriction, comprehensive third trimester ultrasound examination including biophysical profile, fetal biometry, amniotic fluid volume, and umbilical artery Doppler studies is not recommended. (II-2D) 06. Low-dose aspirin should be recommended to women with a previous history of placental insufficiency syndromes including intrauterine growth restriction and preeclampsia. It should be initiated between 12 and 16 weeks’ gestation and continued until 36 weeks. (I-A) 07. Low-dose aspirin should also be recommended to women with two or more current risk factors in pregnancy including, but not limited to, pre-gestational hypertension, obesity, maternal age > 40 years, history of use of artificial reproductive technology, pre-gestational diabetes mellitus (type I or II), multiple gestation, previous history of placental abruption, and previous history of placental infarction. It should be initiated between 12 and 16 weeks’ gestation and continued until 36 weeks. (I-A) 08. Umbilical artery Doppler studies are not recommended as a routine screening test in uncomplicated pregnancies. (I-E) 09. An ultrasound examination for estimated fetal weight and amniotic fluid volume should be considered after 26 weeks if the symphysis-fundal height measurement in centimetres deviates by 3 or more from the gestational age in weeks or there is a plateau in symphysis-fundal height. (II-2B)

10. In cases in which the fetus measures < 10th percentile by estimated fetal weight or abdominal circumference measurement, the underlying cause of intrauterine growth restriction may be established by an enhanced ultrasound examination to include a detailed review of fetal anatomy, placental morphology, and Doppler studies of the uterine and umbilical arteries. (II-2A) 11. In cases of intrauterine growth restriction, determination of amniotic fluid volume should be performed to aid in the differential diagnosis of intrauterine growth restriction and increase the accuracy of the diagnosis of placental insufficiency. (II-2B) 12. Umbilical artery Doppler should be performed in all fetuses with an estimated fetal weight or an abdominal circumference < 10th percentile. (I-A) 13. In pregnancies affected by intrauterine growth restriction, umbilical artery Doppler studies after 24 weeks may prompt intervention that reduces perinatal mortality and severe perinatal morbidity due to intrauterine growth restriction. (I-A) 14. In pregnancies in which intrauterine growth restriction has been identified, invasive testing to rule out aneuploidy may be offered where fetal abnormalities are suspected, soft markers are seen, or no ive evidence of underlying placental insufficiency is evident. (II-2A) 15. In patients presenting with intrauterine growth restriction, maternal screening for infectious etiology may be considered. (II-2A) 16. When intrauterine growth restriction is diagnosed, surveillance should be initiated. Serial ultrasound estimation of fetal weight (every 2 weeks), along with umbilical artery Doppler studies should be initiated. If available, a placental assessment and other Doppler studies such as middle cerebral artery, umbilical vein, and ductus venosis can be performed. Increased frequency of surveillance may be required. (II-2A) 17. If fetal growth starts to plateau, amniotic fluid index starts to decline, or fetal tone or gross movements are diminished or absent, then more intensive surveillance (e.g., 2 to 3 times per week) or ission to hospital and delivery planning is required. (II-2A) 18. Abnormal umbilical cord Doppler (e.g., absent or reversed end-diastolic flow) in the presence of intrauterine growth restriction is an ominous finding that requires intervention and possible delivery. (I-A) 19. Cardiotocography (non-stress testing) performed antenatally as a test of fetal well-being should not be used in isolation to monitor fetuses with intrauterine growth restriction. (II-2E) 20. Maternal istration of corticosteroids is indicated if there is a significant possibility of delivery at < 34 weeks’ gestation, as istration may positively affect umbilical Doppler studies. (I-A) 21. If delivery was not indicated prior to 37 weeks in a patient diagnosed with intrauterine growth restriction, expectant management with close fetal and maternal surveillance versus delivery should be discussed after 37 weeks. (I-A) 22. Site of planned delivery should take into consideration facilities and expertise available at each institution including obstetricians, pediatricians or neonatologists as appropriate, anaesthesiologists, and access to Caesarean section. (III-A)

AUGUST JOGC AOÛT 2013 l 743

SOGC Clinical Practice Guideline

INTRODUCTION

I

ntrauterine growth restriction is a problem faced by obstetrical care providers on a daily basis. Neonatal mortality in both term and pre-term neonates is significantly increased in those diagnosed antenatally with IUGR. Despite the importance of the topic, there is a paucity of level I evidence. The purpose of this guideline is to provide summary statements and recommendations and to establish a framework for screening, diagnosis, and management of pregnancies affected with IUGR. A previously published review (Lausman et al., 2012) provides further background. Summary Statements

1. The definition of small-for-gestational age for a fetus in utero is an estimated fetal weight that measures < 10th percentile on ultrasound. This diagnosis does not necessarily imply pathologic growth abnormalities, and may simply describe a fetus at the lower end of the normal range. (III) 2. Intrauterine growth restriction refers to a fetus with an estimated fetal weight < 10th percentile on ultrasound that, because of a pathologic process, has not attained its biologically determined growth potential. (III) A clinical estimation of fetal weight or symphysis-fundal height has poor sensitivity and specificity and should not be relied upon to diagnose intrauterine growth restriction. Intrauterine growth restriction should be considered in the differential diagnosis when the fetus is found to be small for gestational age. (II-1) 3. Effective screening for intrauterine growth restriction requires accurate dating and includes a review of the mother’s menstrual history, relevant assisted reproductive technology information, and either a first trimester or early second trimester dating ultrasound. (I) 4. Symphysis-fundal height determination is of limited value in routine obstetrical care, but continues to be the only physical examination screening test available. (I) 5. Fetal weight determination in fetuses between the 10th and 90th percentiles by ultrasound biometry alone has at least a 10% error rate across gestation, but is effective equally when measuring with abdominal circumference alone or in combination with head size (biparietal diameter or head circumference) and/or femur length to establish an estimated fetal weight. (II-2) 6. Determining whether intrauterine growth restriction is symmetric or asymmetric is of less clinical importance than careful re-evaluation of

744 l AUGUST JOGC AOÛT 2013

fetal anatomy and uterine and umbilical artery Doppler studies. (I) 7. In women with risk factors for intrauterine growth restriction, uterine artery Doppler screening at 19 to 23 weeks may identify pregnancies at risk of antepartum stillbirth and preterm delivery due to intrauterine growth restriction and placental disease. (II-2) 8. In pregnancies in which intrauterine growth restriction due to uteroplacental vascular insufficiency is diagnosed, maternal surveillance for the development of severe preeclampsia with adverse features is warranted. (II-1) 9. Once surveillance of a fetus with intrauterine growth restriction is instituted, umbilical artery Doppler studies and biophysical profile scoring can be used as short-term predictors of fetal well-being. (I) 10. In the presence of abnormal umbilical artery Doppler studies, further investigation of the fetal circulatory system by Doppler examination of the middle cerebral artery, ductus venosus, and umbilical vein can be considered. (II-2) 11. For a fetus with intrauterine growth restriction, the decision for obstetrical intervention, including Caesarean section, in cases of abnormal fetal heart rate or malpresentation is largely based on fetal viability, as assessed by ultrasound. (II-2) 12. Maternal surveillance for the development of preeclampsia is warranted. (II-2) Recommendations

1. Women should be screened for clinical risk factors for intrauterine growth restriction by means of a complete history. (II-2B) 2. Women should be counselled on smoking cessation at any time during pregnancy. (II-2A) 3. First and second trimester screening tests for aneuploidy maybe useful tests of placental function. If two screening test results are abnormal, the fetus is at increased risk of preterm intrauterine growth restriction and associated stillbirth. (II-1A) 4. If intrauterine growth restriction is suspected, further assessment can assist in making the diagnosis. If available, detailed ultrasound examination of the placenta (looking for evidence of a small, thickened placenta, or abnormal morphology) and uterine artery Dopplers should be considered at 19 to 23 weeks. In the absence of available diagnostic testing, closer surveillance should be offered. A maternal–fetal medicine

Intrauterine Growth Restriction: Screening, Diagnosis, and Management



consultation can be considered if the placenta appears abnormal on ultrasound, especially in the context of a growth-restricted fetus and abnormal uterine artery Doppler. In a rural setting, the caregiver needs to decide whether the patient should be delivered immediately, or whether transfer to a tertiary centre is appropriate. A telephone consultation and telemedicine may help. (II-2A) 5. In women without risk factors for intrauterine growth restriction, comprehensive third trimester ultrasound examination including biophysical profile, fetal biometry, amniotic fluid volume, and umbilical artery Doppler studies is not recommended. (II-2D) 6. Low-dose aspirin should be recommended to women with a previous history of placental insufficiency syndromes including intrauterine growth restriction and preeclampsia. It should be initiated between 12 and 16 weeks’ gestation and continued until 36 weeks. (I-A) 7. Low-dose aspirin should also be recommended to women with two or more current risk factors in pregnancy including, but not limited to, pregestational hypertension, obesity, maternal age > 40 years, history of use of artificial reproductive technology, pre-gestational diabetes mellitus (type I or II), multiple gestation, previous history of placental abruption, and previous history of placental infarction. It should be initiated between 12 and 16 weeks’ gestation and continued until 36 weeks. (I-A) 8. Umbilical artery Doppler studies are not recommended as a routine screening test in uncomplicated pregnancies. (I-E) 9. An ultrasound examination for estimated fetal weight and amniotic fluid volume should be considered after 26 weeks if the symphysis-fundal height measurement in centimetres deviates by 3 or more from the gestational age in weeks or there is a plateau in symphysis-fundal height. (II-2B) 10. In cases in which the fetus measures < 10th percentile by estimated fetal weight or abdominal circumference measurement, the underlying cause of intrauterine growth restriction may be established by an enhanced ultrasound examination to include a detailed review of fetal anatomy, placental morphology, and Doppler studies of the uterine and umbilical arteries. (II-2A) 11. In cases of intrauterine growth restriction, determination of amniotic fluid volume should be performed to aid in the differential diagnosis of



intrauterine growth restriction and increase the accuracy of the diagnosis of placental insufficiency. (II-2B) 12. Umbilical artery Doppler should be performed in all fetuses with an estimated fetal weight or an abdominal circumference < 10th percentile. (I-A) 13. In pregnancies affected by intrauterine growth restriction, umbilical artery Doppler studies after 24 weeks may prompt intervention that reduces perinatal mortality and severe perinatal morbidity due to intrauterine growth restriction. (I-A) 14. In pregnancies in which intrauterine growth restriction has been identified, invasive testing to rule out aneuploidy may be offered where fetal abnormalities are suspected, soft markers are seen, or no ive evidence of underlying placental insufficiency is evident. (II-2A) 15. In patients presenting with intrauterine growth restriction, maternal screening for infectious etiology may be considered. (II-2A) 16. When intrauterine growth restriction is diagnosed, surveillance should be initiated. Serial ultrasound estimation of fetal weight (every 2 weeks), along with umbilical artery Doppler studies should be initiated. If available, a placental assessment and other Doppler studies such as middle cerebral artery, umbilical vein, and ductus venosis can be performed. Increased frequency of surveillance may be required. (II-2A) 17. If fetal growth starts to plateau, amniotic fluid index starts to decline, or fetal tone or gross movements are diminished or absent, then more intensive surveillance (e.g., 2 to 3 times per week) or ission to hospital and delivery planning is required. (II-2A) 18. Abnormal umbilical cord Doppler (e.g., absent or reversed end-diastolic flow) in the presence of intrauterine growth restriction is an ominous finding that requires intervention and possible delivery. (I-A) 19. Cardiotocography (non-stress testing) performed antenatally as a test of fetal well-being should not be used in isolation to monitor fetuses with intrauterine growth restriction. (II-2E) 20. Maternal istration of corticosteroids is indicated if there is a significant possibility of delivery at < 34 weeks’ gestation, as istration may positively affect umbilical Doppler studies. (I-A) 21. If delivery was not indicated prior to 37 weeks in a patient diagnosed with intrauterine growth restriction, expectant management with close fetal and maternal surveillance versus delivery should be discussed after 37 weeks. (I-A)

AUGUST JOGC AOÛT 2013 l 745

SOGC Clinical Practice Guideline

22. Site of planned delivery should take into consideration facilities and expertise available at each institution including obstetricians, pediatricians or neonatologists as appropriate, anaesthesiologists, and access to Caesarean section. (III-A) FRAMEWORK FOR APPROACHING INTRAUTERINE GROWTH RESTRICTION IN CLINICAL PRACTICE

Doppler; add growth every 2 weeks; consider delivery near term (38 to 40 weeks) if no other issues. •• If growth plateaus or stops < 34 weeks: –– ister corticosteroids; increase surveillance to 2 to 3 times per week; consider hospitalization; consider maternal–fetal medicine consultation; consider pediatric consultation.

Screening for intrauterine growth restriction

–– If abnormal umbilical artery Doppler studies: add MCA and DV studies.

Physical: SFH measurement

–– If abnormal umbilical artery, MCA, and DV Doppler studies and abnormal NST: deliver. NST can be used selectively if the BPP is abnormal.

History: maternal, fetal, and placental risk factors; establish dates by first trimester ultrasound and last menstrual period Investigations to consider: •• biochemical screening tests for Trisomy 21 as a test of placental insufficiency; •• first trimester ultrasound for dating and nuchal translucency; •• uterine artery Doppler at 19 to 23 weeks if biochemical markers are abnormal; •• if SFH (in centimetres) is less than gestational age (in weeks) by > 3, arrange ultrasound for EFW, AFV or DVP, biophysical profile, and/or umbilical Doppler studies. Diagnosis of intrauterine growth restriction

EFW or AC < 10th percentile

Management of intrauterine growth restriction

Investigations: •• Offer amniocentesis if there is high risk of aneuploidy; •• Consider TORCH screen. Maternal management: •• Conduct ongoing monitoring for preeclampsia; •• Encourage patient to quit smoking; •• Consider adding low-dose aspirin early in the pregnancy if patient fulfills the criteria for its use. Fetal management: •• If pre-viable (< 500 g ± < 24 weeks): offer counselling by multi-disciplinary health care team regarding fetal monitoring and obstetrical intervention until viability. •• If viable (> 500 g and > 24 weeks): conduct initial ultrasound assessment: EFW, AFV, umbilical Doppler; in third trimester (~ 26 weeks) consider weekly BPP and growth every 2 weeks. •• If growth continues along growth curve: conduct weekly biophysical profile and umbilical artery 746 l AUGUST JOGC AOÛT 2013

–– If abnormal Doppler studies (e.g., absent or reversed end-diastolic flow) and normal BPP and NST: continue intensive monitoring with BPP and umbilical Dopplers 2 to 3 times per week; deliver if BPP or umbilical Dopplers worsen or if MCA/DV are abnormal. •• If > 34 weeks: –– If normal AFV and DVP, BPP, and Doppler studies: conduct weekly surveillance and discuss delivery or ongoing monitoring after 37 weeks. –– If abnormal fluid (AFV < 5 cm or DVP < 2 cm), BPP, and/or Doppler studies: consider delivery. DISCUSSION

IUGR is a problem associated with significant perinatal morbidity and mortality. Level 1 evidence to direct clinicians in practice does exist, but is limited to a few high quality trials. Several demographic factors, including advanced maternal age, assisted conception technologies, and pregnancy with maternal comorbidities, interact to steadily increase the risk of IUGR and stillbirth in the third trimester. More effective use of current evidence may reduce this risk, but further studies, especially to evaluate the role of systematic screening of placental function in the second trimester, are needed to improve the perinatal prognosis of IUGR due to placental insufficiency. Since IUGR has many additional causes, when it is suspected, a detailed fetal anatomical ultrasound examination should be performed including further testing when fetal abnormalities are suspected, soft markers are seen, or there is no apparent ive evidence of underlying placental insufficiency. In uncomplicated IUGR attributed to placental insufficiency, no pharmacological interventions are of proven benefit, although the accumulated data from several trials and meta-analyses of low-dose aspirin demonstrate

Intrauterine Growth Restriction: Screening, Diagnosis, and Management

some preventive benefit. By contrast, no evidence currently exists to the preventive use of the parenteral anticoagulant drug heparin for either the prevention or treatment of IUGR. After 36 weeks of gestation, IUGR due to suspected placental insufficiency can be managed equally effectively by early delivery or delayed delivery with increased fetal surveillance. Further research is needed to define optimum management of early-onset IUGR. Following delivery, pathological examination of the placenta may provide key insights into the underlying cause and form the basis of an effective postpartum counselling visit to discuss that cause. Since the events leading up to and following delivery of an infant with severe IUGR may trigger significant emotional stress, a review of mental health status and family circumstances at this visit is prudent. BIBLIOGRAPHY Abdel-Fattah SA, Bhat A, Illanes S, Bartha JL, Carrington D. TORCH test for fetal medicine indications: only CMV is necessary in the United Kingdom. Prenat Diagn 2005;25:1028–31. Alfirevic Z, Neilson JP. Doppler ultrasonography in high-risk pregnancies: systematic review with meta-analysis. Am J Obstet Gynecol 1995;172:1379‑87. Alley MH, Hadjiev A, Mazneikova V, Dimitrov A. Four-quadrant assessment of gestational age-specific values of amniotic fluid volume in uncomplicated pregnancies. Acta Obstet Gynecol Scand 1998;77:290‑4. American College of Obstetricians and Gynecologists. Intrauterine Growth Restriction. ACOG Practice Bulletin No. 12. Washington DC: ACOG; 2000. Ayala DE, Ucieda R, Hermida RC. Chronotherapy with low-dose aspirin for prevention of complications in pregnancy. Chronobiol Int 2013;30:260‑79. doi: 10.3109/07420528.2012.717455. Bamberg C, Kalache KD. Prenatal diagnosis of fetal growth restriction. Semin Fetal Neonatal Med 2004;9:387–94. Baschat AA, Cosmi E, Bilardo CM, Wolf H, Berg C, Rigano S, et al. Predictors of neonatal outcome in early-onset placental dysfunction. Obstet Gynecol 2007;109(2 Pt 1):253–61. Becker R, Keller T, Kiesewetter H, Fangerau H, Bittner U. Individual risk assessment of adverse pregnancy outcome by multivariate regression analysis may serve as basis for drug intervention studies: retrospective analysis of 426 high-risk patients including ethical aspects. Arch Gynecol Obstet 2013; 288:41–8. doi: 10.1007/s00404-013-2723-1. Boers KE, van Wyk L, van der Post JA, Kwee A, van Pampus MG, Spaanderdam ME, et al.; DIGITAT Study Group. Neonatal morbidity after induction vs expectant monitoring in intrauterine growth restriction at term: a subanalysis of the DIGITAT RCT. Am J Obstet Gynecol. 2012;206:344.e1–e7. doi: 10.1016/j.ajog.2012.01.015. Boers KE, Vijgen SM, Bijlenga D, van der Post JA, Bekedam DJ, Kwee A, et al. Induction versus expectant monitoring for intrauterine growth restriction at term: randomised equivalence trial (DIGITAT). BMJ 2010;341:c7087. Brenner WE, Edelman DA, Hendricks CH. A standard of fetal growth for the United States of America. Am J Obstet Gynecol 1976;126:555–64. Bricker L, Neilson JP. Routine Doppler ultrasound in pregnancy. Cochrane Database Syst Rev 2000;2:CD001450.

Bricker L, Neilson JP, Dowswell T. Routine ultrasound in late pregnancy (after 24 weeks’ gestation). Cochrane Database Syst Rev 2008;4:CD001451. Bujold E, Roberge S, Lacasse Y, Bureau M, Audibert F, Marcoux S, et al. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis. Obstet Gynecol 2010;116(2 Pt 1):402‑14. doi: 10.1097/AOG.0b013e3181e9322a. Carberry AE, Gordon A, Bond DM, Hyett J, Raynes-Greenow CH, Jeffery HE. Customised versus population-based growth charts as a screening tool for detecting small for gestational age infants in low-risk pregnant women. Cochrane Database Syst Rev 2011 Dec 7;12:CD008549. doi: 10.1002/14651858.CD008549.pub2. Chauhan SP, Magann EF. Screening for fetal growth restriction. Clin Obstet Gynecol 2006;49:284–94. Dayal AK, Manning FA, Berck DJ, Mussalli GM, Avila C, Harman CR, et al. Fetal death after normal biophysical profile score: an eighteen-year experience. Am J Obstet Gynecol 1999;181(5 Pt 1):1231–6. Dudley NJ. A systematic review of the ultrasound estimation of fetal weight. Ultrasound Obstet Gynecol 2005;25:80–9. Dugoff L. First- and second-trimester maternal serum markers for aneuploidy and adverse obstetric outcomes. Obstet Gynecol 2010;115:1052 61. Dugoff L, Hobbins JC, Malone FD, Vidaver J, Sullivan L, Canick JA, et al. Quad screen as a predictor of adverse pregnancy outcome. Obstet Gynecol 2005;106;2:260–7. Figueras F, Gardosi J. Intrauterine growth restriction: new concepts in antenatal surveillance, diagnosis, and management. Am J Obstet Gynecol 2011;204:288–300. doi: 10.1016/j.ajog.2010.08.055. Gardosi J. Customised assessment of fetal growth potential: implications for perinatal care. Arch Dis Child Fetal Neonatal Ed 2012;97:F314-7. doi: 10.1136/fetalneonatal-2012-301708. Gardosi J, Chang A, Kalyan B, Sahota D, Symonds EM. Customised antenatal growth charts. Lancet 1992;339:283–7. Grivell RM, Alfirevic Z, Gyte GM, Devane D. Antenatal cardiotocography for fetal assessment. Cochrane Database Syst Rev 2010;1:CD007863. Grivell RM, Wong L, Bhatia V. Regimens of fetal surveillance for impaired fetal growth. Cochrane Database Syst Rev 2012 Jun 13;6:CD007113. doi: 10.1002/14651858.CD007113.pub3. Haram K, Softeland E, Bukowski R. Intrauterine growth restriction. Int J Gynaecol Obstet 2006;93:5–12. Konchak PS, Bernstein IM, Capeless EL. Uterine artery Doppler velocimetry in the detection of adverse obstetric outcomes in women with unexplained elevated maternal serum alpha-fetoprotein levels. Am J Obstet Gynecol 1995;173:1115–9. Lackman F, Capewell V, Richardson B, daSilva O, Gagnon R. The risks of spontaneous preterm delivery and perinatal mortality in relation to size at birth according to fetal versus neonatal growth standards. Am J Obstet Gynecol 2001;184(5):946−53. Lausman A, McCarthy FP, Walker M, Kingdom J. Screening, diagnosis, and management of intrauterine growth restriction. J Obstet Gynaecol Can 2012;34:17–28. Lindhard A, Nielsen PV, Mouritsen LA, Zachariassen A, Sorensen HU, Roseno H. The implications of introducing the symphyseal-fundal heightmeasurement. A prospective randomized controlled trial. Br J Obstet Gynaecol 1990;97:675–80. Mari G, Hanif F, Kruger M, Cosmi E, Santolaya-Forgas J, Treadwell MC. Middle cerebral artery peak systolic velocity: a new Doppler parameter in the assessment of growth-restricted fetuses. Ultrasound Obstet Gynecol 2007;293:310–6.

AUGUST JOGC AOÛT 2013 l 747

SOGC Clinical Practice Guideline

Maulik D. Fetal growth compromise: definitions, standards, and classification. Clin Obstet Gynecol 2006;49:214–8. McCowan LM, Dekker GA, Chan E, Stewart A, Chappell LC, Hunter M, et al. Spontaneous preterm birth and small for gestational age infants in women who stop smoking early in pregnancy: prospective cohort study. BMJ 2009;338:b1081.

Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Sys Rev 2006 Jul 19;3:CD004454. Royal College of Obstetricians and Gynecologists (RCOG). The investigation and management of the small-for-gestational age fetus. Guideline No. 31. London: RCOG; 2002.

Mitani M, Matsuda Y, Makino Y, Akizawa Y, Ohta H. Clinical features of fetal growth restriction complicated later by preeclampsia. J Obstet Gynaecol Res 2009;35:882–7.

Siddiqui N, Hladunewich M. Understanding the link between the placenta and future cardiovascular disease. Trends Cardiovasc Med 2011;21:188-93. doi: 10.1016/j.tcm.2012.05.008.

Neilson JP. Symphysis-fundal height measurement in pregnancy. Cochrane Database Syst Rev 2000;2:CD000944.

Simchen MJ, Alkazaleh F, Adamson SL, Windrim R, Telford J, Beyene J, et al. The fetal cardiovascular response to antenatal steroids in severe early-onset intrauterine growth restriction. Am J Obstet Gynecol 2004;190:296304.

Neilson JP, Alfirevic Z. Doppler ultrasound for fetal assessment in high risk pregnancies. Cochrane Database Syst Rev 2000;2:CD000073. Nyberg DA, Abuhamad A, Ville Y. Ultrasound assessment of abnormal fetal growth. Semin Perinatol 2004;28:3–22. Pinar H, Carpenter M. Placenta and umbilical cord abnormalities seen with stillbirth. Clin Obstet Gynecol 2010;53:656–72. Proctor LK, Whittle WL, Keating S, Viero S, Kingdom JC. Pathologic basis of echogenic cystic lesions in the human placenta: role of ultrasound-guided wire localization. Placenta 2010;31:1111–5. Reeves S, Bernstein I. Effects of maternal tobacco-smoke exposure on fetal growth and neonatal size. Expert Rev Obstet Gynecol 2008;3:719–30. Roberge S, Giguère Y, Villa P, Nicolaides K, Vainio M, Forest JC, et al. Early istration of low-dose aspirin for the prevention of severe and mild preeclampsia: a systematic review and meta-analysis. Am J Perinatol 2012;29:551‑6. doi: 10.1055/s-0032-1310527. Roberge S, Nicolaides K, Demers S, Villa P, Bujold E. Prevention of perinatal death and adverse perinatal outcome using low-dose aspirin: a meta-analysis. Ultrasound Obstet Gynecol 2013;41:491‑9. doi: 10.1002/uog.12421. Roberge S, Villa P, Nicolaides K, Giguère Y, Vainio M, Bakthi A, et al. Early istration of low-dose aspirin for the prevention of preterm and term preeclampsia: a systematic review and meta-analysis. Fetal Diagn Ther 2012;31:141‑6. doi: 10.1159/000336662. Robert Peter J, Ho JJ, Valliapan J, Sivasangari S. Symphysial fundal height (SFH) measurement in pregnancy for detecting abnormal fetal growth. Cochrane Database Syst Rev 2012 Jul 11;7:CD008136. doi: 10.1002/14651858. CD008136.pub2.

748 l AUGUST JOGC AOÛT 2013

Smith GC, Smith MF, McNay MB, Fleming JE. The relation between fetal abdominal circumference and birthweight: findings in 3512 pregnancies. Br J Obstet Gynaecol 1997;104:186–90. Smith GC, Yu CK, Papageorghiou AT, Cacho AM, Nicolaides KH. Maternal uterine artery Doppler flow velocimetry and the risk of stillbirth. Obstet Gynecol 2007;109:144–51. Snijders RJ, Sherrod C, Gosden CM, Nicolaides KH. Fetal growth retardation: associated malformations and chromosomal abnormalities. Am J Obstet Gynecol 1993;168:547–55. Toal M, Chaddha V, Windrim R, Kingdom J. Ultrasound detection of placental insufficiency in women with elevated second trimester serum alpha-fetoprotein or human chorionic gonadotropin. J Obstet Gynaecol Can 2008;30:198–206. van Wyk L, Boers KE, van der Post JA, van Pampus MG, van Wassenaer AG, van Baar AL, et al.; DIGITAT Study Group. Effects on (neuro)developmental and behavioral outcome at 2 years of age of induced labor compared with expectant management in intrauterine growth-restricted infants: long-term outcomes of the DIGITAT trial. Am J Obstet Gynecol 2012;206:406.e1–e7. doi: 10.1016/j.ajog.2012.02.003. von Beckerath AK, Kollmann M, Rotky-Fast C, Karpf E, Lang U, Klaritsch P. Perinatal complications and long-term neurodevelopmental outcome of infants with intrauterine growth restriction. Am J Obstet Gynecol 2013;208:130.e1–e6. doi: 10.1016/j.ajog.2012.11.014. Zhang J, Troendle J, Meikle S, Klebanoff MA, Rayburn WF. Isolated oligohydramnios is not associated with adverse perinatal outcomes. BJOG 2004;111:220–5.

Ultrasound Obstet Gynecol 2013; 41: 102–113 Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.12342

isuog

.org

GUIDELINES

ISUOG Practice Guidelines: performance of first-trimester fetal ultrasound scan Clinical Standards Committee The International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) is a scientific organization that encourages safe clinical practice and high-quality teaching and research related to diagnostic imaging in women’s healthcare. The ISUOG Clinical Standards Committee (CSC) has a remit to develop Practice Guidelines and Consensus Statements that provide healthcare practitioners with a consensus-based approach for diagnostic imaging. They are intended to reflect what is considered by ISUOG to be the best practice at the time at which they are issued. Although ISUOG has made every effort to ensure that Guidelines are accurate when issued, neither the Society nor any of its employees or accept any liability for the consequences of any inaccurate or misleading data, opinions or statements issued by the CSC. The ISUOG CSC documents are not intended to establish a legal standard of care because interpretation of the evidence that underpins the Guidelines may be influenced by individual circumstances, local protocol and available resources. Approved Guidelines can be distributed freely with the permission of ISUOG ([email protected]).

INTRODUCTION Routine ultrasound examination is an established part of antenatal care if resources are available and access possible. It is commonly performed in the second trimester1 , although routine scanning is offered increasingly during the first trimester, particularly in high-resource settings. Ongoing technological advancements, including high-frequency transvaginal scanning, have allowed the resolution of ultrasound imaging in the first trimester to evolve to a level at which early fetal development can be assessed and monitored in detail. The aim of this document is to provide guidance for healthcare practitioners performing, or planning to perform, routine or indicated first-trimester fetal ultrasound scans. ‘First trimester’ here refers to a stage of pregnancy starting from the time at which viability can be confirmed (i.e. presence of a gestational sac in the uterine cavity with an embryo demonstrating cardiac activity) up to 13 + 6 weeks of gestation. Ultrasound scans performed after this

Copyright  2013 ISUOG. Published by John Wiley & Sons, Ltd.

gestational age are not considered in these Guidelines. Throughout these Guidelines we use the term ‘embryo’ for before 10 weeks and ‘fetus’ thereafter, to reflect the fact that after 10 weeks of gestation organogenesis is essentially complete and further development involves predominantly fetal growth and organ maturation2,3 .

GENERAL CONSIDERATIONS What is the purpose of a first-trimester fetal ultrasound scan? In general, the main goal of a fetal ultrasound scan is to provide accurate information which will facilitate the delivery of optimized antenatal care with the best possible outcomes for mother and fetus. In early pregnancy, it is important to confirm viability, establish gestational age accurately, determine the number of fetuses and, in the presence of a multiple pregnancy, assess chorionicity and amnionicity. Towards the end of the first trimester, the scan also offers an opportunity to detect gross fetal abnormalities and, in health systems that offer first-trimester aneuploidy screening, measure the nuchal translucency thickness (NT). It is acknowledged, however, that many gross malformations may develop later in pregnancy or may not be detected even with appropriate equipment and in the most experienced of hands.

When should a first-trimester fetal ultrasound scan be performed? There is no reason to offer routine ultrasound simply to confirm an ongoing early pregnancy in the absence of any clinical concerns, pathological symptoms or specific indications. It is advisable to offer the first ultrasound scan when gestational age is thought to be between 11 and 13 + 6 weeks’ gestation, as this provides an opportunity to achieve the aims outlined above, i.e. confirm viability, establish gestational age accurately, determine the number of viable fetuses and, if requested, evaluate fetal gross anatomy and risk of aneuploidy4 – 20 . Before starting the examination, a healthcare provider should counsel the woman/couple regarding the potential benefits and limitations of the first-trimester ultrasound scan. (GOOD PRACTICE POINT)

ISUOG GUIDELINES

ISUOG Guidelines

103

Who should perform the first-trimester fetal ultrasound scan?

What if the examination cannot be performed in accordance with these Guidelines?

Individuals who perform obstetric scans routinely should have specialized training that is appropriate to the practice of diagnostic ultrasound for pregnant women. (GOOD PRACTICE POINT) To achieve optimal results from routine ultrasound examinations it is suggested that scans should be performed by individuals who fulfill the following criteria:

These Guidelines represent an international benchmark for the first-trimester fetal ultrasound scan, but consideration must be given to local circumstances and medical practices. If the examination cannot be completed in accordance with these Guidelines, it is advisable to document the reasons for this. In most circumstances, it will be appropriate to repeat the scan, or to refer to another healthcare practitioner. This should be done as soon as possible, to minimize unnecessary patient anxiety and any associated delay in achieving the desired goals of the initial examination. (GOOD PRACTICE POINT)

1. have completed training in the use of diagnostic ultrasonography and related safety issues; 2. participate in continuing medical education activities; 3. have established appropriate care pathways for suspicious or abnormal findings; 4. participate in established quality assurance programs21 .

What ultrasonographic equipment should be used? It is recommended to use equipment with at least the following capabilities: – real-time, gray-scale, two-dimensional (2D) ultrasound; – transabdominal and transvaginal ultrasound transducers; – adjustable acoustic power output controls with output display standards; – freeze frame and zoom capabilities; – electronic calipers; – capacity to print/store images; – regular maintenance and servicing.

How should the scan be documented? An examination report should be produced as an electronic and/or paper document (see Appendix for an example). Such a document should be stored locally and, in accordance with local protocol, made available to the woman and referring healthcare provider. (GOOD PRACTICE POINT)

What should be done in case of multiple pregnancies? Determination of chorionicity and amnionicity is important for care, testing and management of multifetal pregnancies. Chorionicity should be determined in early pregnancy, when characterization is most reliable26 – 28 . Once this is accomplished, further antenatal care, including the timing and frequency of ultrasound examinations, should be planned according to the available health resources and local guidelines. (GOOD PRACTICE POINT)

GUIDELINES FOR EXAMINATION 1. Assessment of viability/early pregnancy In this Guideline, ‘age’ is expressed as menstrual or gestational age, which is 14 days more than conceptional age. Embryonic development visualized by ultrasound closely agrees with the ‘developmental time schedule’ of human embryos described in the Carnegie staging system3 . The embryo is typically around 1–2 mm long when first detectable by ultrasound and increases in length by approximately 1 mm per day. The cephalic and caudal ends are indistinguishable until 53 days (around 12 mm), when the diamond-shaped rhombencephal cavity (future fourth ventricle) becomes visible18 .

Is prenatal ultrasonography safe during the first trimester?

Defining viability

Fetal exposure times should be minimized, using the shortest scan times and lowest possible power output needed to obtain diagnostic information using the ALARA (As Low As Reasonably Achievable) principle. (GOOD PRACTICE POINT) Many international professional bodies, including ISUOG, have reached a consensus that the use of Bmode and M-mode prenatal ultrasonography, due to its limited acoustic output, appears to be safe for all stages of pregnancy22,23 . Doppler ultrasound is, however, associated with greater energy output and therefore more potential bioeffects, especially when applied to a small region of interest24,25 . Doppler examinations should only be used in the first trimester, therefore, if clinically indicated. More details are available in the ISUOG Safety Statement22 .

The term ‘viability’ implies the ability to live independently outside the uterus and, strictly speaking, cannot be applied to embryonic and early fetal life. However, this term has been accepted in ultrasound jargon to mean that the embryonic or fetal heart is seen to be active and this is taken to mean the conceptus is ‘alive’. Fetal viability, from an ultrasound perspective, is therefore the term used to confirm the presence of an embryo with cardiac activity at the time of examination. Embryonic cardiac activity has been documented in normal pregnancies at as early as 37 days of gestation29 , which is when the embryonic heart tube starts to beat30 . Cardiac activity is often evident when the embryo measures 2 mm or more31 , but is not evident in around 5–10% of viable embryos measuring between 2 and 4 mm32,33 .

Copyright  2013 ISUOG. Published by John Wiley & Sons, Ltd.

Ultrasound Obstet Gynecol 2013; 41: 102–113.

ISUOG Guidelines

104

Defining an intrauterine pregnancy The presence of an intrauterine gestational sac clearly signifies that the pregnancy is intrauterine, but the criteria for the definition of a gestational sac are unclear. The use of such as an ‘apparently empty’ sac, the ‘double-decidual ring’ or even ‘pseudosac’ do not accurately confirm or refute the presence of an intrauterine pregnancy. Ultimately, the decision is a subjective one and is, therefore, influenced by the experience of the person performing the ultrasound examination. In an asymptomatic patient, it is advisable to wait until the embryo becomes visible within the intrauterine sac as this confirms that the ‘sac’ is indeed a gestational sac. (GOOD PRACTICE POINT)

2. Early pregnancy measurements The mean gestational sac diameter (MSD) has been described in the first trimester from 35 days from the last menstrual period onwards. The MSD is the average of the three orthogonal measurements of the fluid-filled space within the gestational sac34 . Nomograms for both crown–rump length (CRL) and MSD are available, but, in the presence of the embryo, the CRL provides a more accurate estimation of gestational age because MSD values show greater variability of age prediction35,36 .

Figure 1 Crown–rump length (CRL) measurement technique in a fetus with CRL 60 mm (12 + 3 weeks). Note neutral position of neck.

3. First-trimester fetal measurements

plexuses should be visible. Towards 13 weeks, the thalamus and third ventricle provide good landmarks. Correct axial orientation is confirmed by including in the image both anterior horns and low occipital lobes of the cerebral ventricles, whilst keeping the plane above the cerebellum1,38 – 41 . For BPD measurement, caliper placement should follow the technique used to produce the selected nomogram. Both outer-to-inner (leading edge) and outer-to-outer measurements are in use1,39,42,43 (Figure 2).

Which measurements should be performed in the first trimester?

Other measurements

CRL measurements can be carried out transabdominally or transvaginally. A midline sagittal section of the whole embryo or fetus should be obtained, ideally with the embryo or fetus oriented horizontally on the screen. An image should be magnified sufficiently to fill most of the width of the ultrasound screen, so that the measurement line between crown and rump is at about 90◦ to the ultrasound beam37,38 . Electronic linear calipers should be used to measure the fetus in a neutral position (i.e. neither flexed nor hyperextended). The end points of crown and rump should be defined clearly. Care must be taken to avoid inclusion of structures such as the yolk sac. In order to ensure that the fetus is not flexed, amniotic fluid should be visible between the fetal chin and chest (Figure 1). However, this may be difficult to achieve at earlier gestations (around 6–9 weeks) when the embryo is typically hyperflexed. In this situation, the actual measurement represents the neck–rump length, but it is still termed the CRL. In very early gestations it is not usually possible to distinguish between the cephalic and caudal ends and a greatest length measurement is taken instead. The biparietal diameter (BPD) and head circumference (HC) are measured on the largest true symmetrical axial view of the fetal head, which should not be distorted by adjacent structures or transducer pressure. At about 10 weeks’ gestation, structures such as the midline third ventricle, interhemispheric fissure and choroid

Copyright  2013 ISUOG. Published by John Wiley & Sons, Ltd.

Nomograms are available for abdominal circumference (AC), femur length and most fetal organs, but there is no reason to measure these structures as part of the routine first-trimester scan.

4. Assessment of gestational age Pregnant women should be offered an early ultrasound scan between 10 + 0 and 13 + 6 weeks to establish accurate gestational age. (Grade A recommendation) Ultrasound assessment of embryonic/fetal age (dating) uses the following assumptions: – gestational (menstrual age) represents post-conception age + 14 days; – embryonic and fetal size correspond to post-conception (post fertilization) age; – structures measured are normal; – measurement technique conforms to the reference nomogram; – measurements are reliable (both within and between observers); – the ultrasound equipment is calibrated correctly. Accurate dating is essential for appropriate follow-up of pregnancies and has been the primary indication for routine ultrasound in the first trimester. It provides valuable information for the optimal assessment of fetal

Ultrasound Obstet Gynecol 2013; 41: 102–113.

ISUOG Guidelines

105

day of conception, to within 5 days either way in 95% of cases48 – 52 . At very early gestations, when the fetus is relatively small, measurement errors will have a more significant effect on gestational age assessment; the optimal time for assessment appears, therefore, to be somewhere between 8 and 13 + 6 weeks48 . (GOOD PRACTICE POINT) At 11 to 13 + 6 weeks, the CRL and BPD are the two most commonly measured parameters for pregnancy dating. Many authors have published nomograms for these variables. Measurements can be made transabdominally or transvaginally. Singleton nomograms remain valid and can be applied in the case of multiple pregnancy27,53 . Details of a few published nomograms are provided in Table 1. It is recommended that CRL measurement should be used to determine gestational age unless it is above 84 mm; after this stage, HC can be used, as it becomes slightly more precise than is BPD41 . (GOOD PRACTICE POINT)

5. Assessment of fetal anatomy

Figure 2 Fetal head. (a) Biparietal diameter (BPD) measurement (calipers). Note true axial view through head and central position of third ventricle and midline structures (T indicates third ventricle and thalamus). Head circumference would also be measured in this plane. (b) Normal choroid plexuses (C) and midline falx and interhemispheric fissure (arrows). Note that choroid plexuses extend from the medial to the lateral border of the posterior horn. Lateral walls of anterior horns are indicated by arrowheads.

growth later in pregnancy, appropriate obstetric care in general and management of preterm or post-term pregnancies in particular44,45 . Except in pregnancies arising following assisted reproductive technology, the exact day of conception cannot be determined reliably and, therefore, dating a pregnancy by ultrasound appears to be the most reliable method with which to establish true gestational age39,46 . It has been recommended, therefore, that all pregnant women be offered an early ultrasound scan between 10 and 13 completed weeks (10 + 0 to 13 + 6 weeks) to determine gestational age and to detect multiple pregnancies47 . In the first trimester, many parameters are related closely to gestational age, but CRL appears to be the most precise, allowing accurate determination of the

Copyright  2013 ISUOG. Published by John Wiley & Sons, Ltd.

The second-trimester ‘18–22-week’ scan remains the standard of care for fetal anatomical evaluation in both low-risk and high-risk pregnancies54 – 57 . First-trimester evaluation of fetal anatomy and detection of anomalies was introduced in the late 1980s and early 1990s with the advent of effective transvaginal probes58,59 . The introduction of NT aneuploidy screening in the 11 to 13 + 6-week window has rekindled an interest in early anatomy scanning (Table 2). Reported advantages include early detection and exclusion of many major anomalies, early reassurance to at-risk mothers, earlier genetic diagnosis and easier pregnancy termination if appropriate. Limitations include need for trained and experienced personnel, uncertain cost/benefit ratio and late development of some anatomical structures and pathologies (e.g. corpus callosum, hypoplastic left heart), which make early detection impossible and can lead to difficulties in counseling due to the uncertain clinical significance of some findings54 – 56,60 – 62 . Head Cranial bone ossification should be visible by 11 completed weeks (Figure 2a). It is helpful to look specifically for bone ossification in the axial and coronal planes. No bony defects (distortion or disruption) of the skull should be present. The cerebral region at 11 to 13 + 6 weeks is dominated by lateral ventricles that appear large and are filled with the echogenic choroid plexuses in their posterior two thirds (Figure 2b). The hemispheres should appear symmetrical and separated by a clearly visible interhemispheric fissure and falx. The brain mantle is very thin and best appreciated anteriorly, lining the large fluid-filled ventricles, an appearance which should not be mistaken for hydrocephalus. At this early age, some cerebral structures (e.g. corpus

Ultrasound Obstet Gynecol 2013; 41: 102–113.

ISUOG Guidelines

106 Table 1 Biometry nomograms for consideration in first trimester to around 13 + 6 weeks Reference

Structure measured

Age range (weeks)

Robinson & Fleming52 (1975); quoted by Loughna et al.41 (2009) Hadlock et al.83 (1992) Daya84 (1993) Verburg et al.43 (2008)

CRL

9 to 13 + 6

CRL CRL CRL

5.0 to 18.0 6.1 to 13.3 6 + 2 to 15 + 0

McLennan & Schluter85 (2008) Hadlock et al.86 (1982)

CRL BPD

5 to 14 12 to 40

Altman & Chitty39 (1997); quoted by Loughna et al.41 (2009) Verburg et al.43 (2008)

BPD

12 + 6 to 35 + 4

BPD

10 to 43

Notes Selected for use by British Medical Ultrasound Society41

Includes BPD, HC, AC, femur, cerebellum Includes BPD to 14 weeks In early pregnancy 1982 chart more accurate than 1984 chart Selected for use by British Medical Ultrasound Society41 Includes CRL, HC, AC, femur, cerebellum

Measurements should be performed according to techniques described in these articles and tested on the local population before being adopted into practice. BPD, biparietal diameter; CRL, crown–rump length.

Table 2 Suggested anatomical assessment at time of 11 to 13 + 6-week scan Organ/anatomical area Head

Neck

Face

Spine Chest Heart Abdomen

Abdominal wall Extremities Placenta Cord

However, in absence of obvious anomaly, failure to examine the fetal face at this time should not prompt further examination earlier than the mid-trimester scan.

Present and/or normal ? Present Cranial bones Midline falx Choroid-plexus-filled ventricles Normal appearance Nuchal translucency thickness (if accepted after informed consent and trained/certified operator available)* Eyes with lens* Nasal bone* Normal profile/mandible* Intact lips* Vertebrae (longitudinal and axial)* Intact overlying skin* Symmetrical lung fields No effusions or masses Cardiac regular activity Four symmetrical chambers* Stomach present in left upper quadrant Bladder* Kidneys* Normal cord insertion No umbilical defects Four limbs each with three segments Hands and feet with normal orientation* Size and texture Three-vessel cord*

*Optional structures. Modified from Fong et al.28 , McAuliffe et al.87 , Taipale et al.60 and von Kaisenberg et al.88 .

callosum, cerebellum) are not sufficiently developed to allow accurate assessment. It has been proposed that the posterior fossa intracranial translucency can be evaluated between 11 and 13 + 6 weeks as a screening test for open neural tube defect, but this is not a standard63 . At 11 to 13 + 6 weeks, an attempt can be made to visualize the eyes with their lenses, interorbital distances, the profile including the nose, the nasal bone and mandible as well as the integrity of the mouth and lips28,64,65 (Figure 3).

Copyright  2013 ISUOG. Published by John Wiley & Sons, Ltd.

Neck Sonographic assessment of NT is part of the screening for chromosomal anomalies and is discussed below. Attention should be paid to proper alignment of the neck with the trunk and identification of other fluid collections such as hygromas and jugular lymph sacs28,65 . Spine Longitudinal and axial views should be obtained to show normal vertebral alignment and integrity, and an attempt should be made to show intact overlying skin (Figure 4). However, in the absence of obvious anomaly, failure to examine the spine at this time should not prompt further examination earlier than the mid-trimester scan. Particular attention should be paid to the normal appearance of the spine when BPD < 5th centile66 . Thorax The chest normally contains lungs of homogeneous echogenicity on ultrasound, without evidence of pleural effusions or cystic or solid masses. Diaphragmatic continuity should be evaluated, noting normal intra-abdominal position of stomach and liver. Heart The normal position of the heart on the left side of the chest (levocardia) should be documented (Figure 5). More detailed sonographic assessment of cardiac anatomy has been demonstrated to be feasible at 11 to 13 + 6 weeks67,68 , but this is not part of routine assessment. For safety reasons, use of Doppler is not indicated during routine scanning.

Ultrasound Obstet Gynecol 2013; 41: 102–113.

ISUOG Guidelines

107

Figure 4 Fetal spine. Intact skin (short thick arrow) is visible posterior to the vertebrae from neck to sacrum in a true median view. Note vertebral bodies show ossification, but neural arches, which are still cartilaginous, are isoechoic or hypoechoic. In cervical region (long arrow) the vertebral bodies have not yet ossified and the cartilaginous anlage is hypoechoic; this is normal.

Figure 5 Axial section of the fetal thorax at the level of the four-chamber view of the heart, with the cardiac apex pointing to the left (L). Note atria and ventricles are symmetrical on either side of the septum (arrow). Lung fields are of homogeneous echogenicity and symmetrical. Aorta is just to left side of spine (S).

Abdominal content

Figure 3 Fetal face. (a) Normal profile showing nasal bones (NB). Note normal length of maxilla and mandible. (b) Normal eyes with globes and lenses (arrows) visible. (c) Fetal lips at 13 weeks. Note intact upper lip and line between the lips (arrow). Nasal detail (N) is limited.

Copyright  2013 ISUOG. Published by John Wiley & Sons, Ltd.

At 11 to 13 + 6 weeks, the stomach and bladder are the only hypoechoic fluid structures in the abdomen (Figure 6a and 6b). The position of the stomach on the left side of the abdomen together with levocardia helps confirm normal situs visceralis. The fetal kidneys should be noted in their expected paraspinal location as bean-shaped slightly echogenic structures with typical hypoechoic central renal pelvis (Figure 6b). By 12 weeks of gestation, the fetal bladder should be visible as a median hypoechoic round structure in the lower abdomen.

Ultrasound Obstet Gynecol 2013; 41: 102–113.

ISUOG Guidelines

108

Figure 7 Fetal limbs. (a) Normal arm showing normal alignment of hand and wrist. (b) Normal leg showing normal orientation of foot with respect to lower leg. Also visible are kidney (K) and stomach (S).

and should be differentiated from omphalocele and gastroschisis28,65,69 . Limbs The presence of each bony segment of the upper and lower limbs and presence and normal orientation of the two hands and feet should be noted at the 11 to 13 + 6-week ultrasound scan. The terminal phalanges of the hands may be visible at 11 weeks, especially with transvaginal scanning (Figure 7a). Figure 6 Fetal abdomen. (a) Axial view of abdomen at level at which abdominal circumference is measured (dashed line), showing stomach (S) and umbilical vein (UV). (b) Coronal view of abdomen showing kidneys with central hypoechoic renal pelvis (K, arrows), stomach (S) and diaphragm (Diaph, lines). (c) Umbilical cord insertion (arrow). Note that the two umbilical arteries are visible.

Genitalia The evaluation of genitalia and gender is based upon the orientation of the genital tubercle in the mid-sagittal plane, but is not sufficiently accurate to be used for clinical purposes.

Abdominal wall

Umbilical cord

The normal insertion of the umbilical cord should be documented after 12 weeks (Figure 6c). The physiological umbilical hernia is present up to 11 weeks

The number of cord vessels, cord insertion at the umbilicus and presence of cord cysts should be noted. Brief evaluation of the paravesical region with color or

Copyright  2013 ISUOG. Published by John Wiley & Sons, Ltd.

Ultrasound Obstet Gynecol 2013; 41: 102–113.

ISUOG Guidelines

109

power Doppler can be helpful in confirming the presence of two umbilical arteries, but this is not part of the routine assessment. Role of three-dimensional (3D) and 4D ultrasound Three-dimensional (3D) and 4D ultrasound are not currently used for routine first-trimester fetal anatomical evaluation, as their resolution is not yet as good as that of 2D ultrasound. In expert hands, these methods may be helpful in evaluation of abnormalities, especially those of surface anatomy70 .

6. Chromosomal anomaly assessment Ultrasound-based screening for chromosomal anomalies in the first trimester may be offered, depending on public health policies, trained personnel and availability of healthcare resources. The first-trimester screening should include NT measurement71,72 . Screening performance is further improved by the addition of other markers, including biochemical measurement of free beta or total human chorionic gonadotropin (hCG) and pregnancy-associated plasma protein-A (PAPP-A)73 . In appropriate circumstances, additional aneuploidy markers, including nasal bone, tricuspid regurgitation, ductal regurgitation and others, may be sought by personnel with appropriate training and certification74 – 76 . Most experts recommend that NT should be measured between 11 and 13 + 6 weeks, corresponding to a CRL measurement of between 45 and 84 mm. This gestational age window is chosen because NT as a screening test performs optimally and fetal size allows diagnosis of major fetal abnormalities, thus providing women who are carrying an affected fetus with the option of an early termination of pregnancy77 . NT implementation requires several elements to be in place, including suitable equipment, counseling and management as well as operators with specialized training and continuing certification. Further details can be obtained from relevant national bodies and charities such as The Fetal Medicine Foundation (www.fetalmedicine.com). However, even in the absence of NT-based screening programs, qualitative evaluation of the nuchal region of any fetus is recommended and, if it appears thickened, expert referral should be considered. How to measure NT NT measurements used for screening should only be done by trained and certified operators. NT can be measured by a transabdominal or transvaginal route. The fetus should be in a neutral position, a sagittal section should be obtained and the image should be magnified in order to include only the fetal head and upper thorax. Furthermore, the amniotic membrane should be identified separately from the fetus. The median view of the fetal face is defined by the presence of the echogenic tip of

Copyright  2013 ISUOG. Published by John Wiley & Sons, Ltd.

Figure 8 Sonographic measurement of nuchal translucency thickness.

the nose and rectangular shape of the palate anteriorly, the translucent diencephalon in the center and the nuchal membrane posteriorly. If the section is not exactly median, the tip of the nose will not be visualized and the orthogonal osseous extension at the frontal end of the maxilla will appear. The ultrasound machine should allow measurement precision of 0.1 mm. Calipers should be placed correctly (on-on) to measure NT as the maximum distance between the nuchal membrane and the edge of the soft tissue overlying the cervical spine (Figure 8). If more than one measurement meeting all the criteria is obtained, the maximum one should be recorded and used for risk assessment. Multiple pregnancy requires special considerations, taking into chorionicity. How to train and control for the quality of NT measurement A reliable and reproducible measurement of NT requires appropriate training. A rigorous audit of operator performance and constructive from assessors has been established in many countries and should be considered essential for all practitioners who participate in NT-based screening programs. (GOOD PRACTICE POINT)

7. Other intra- and extrauterine structures The echostructure of the placenta should be evaluated. Clearly abnormal findings, such as masses, single or multiple cystic spaces or large subchorionic fluid collection (> 5 cm), should be noted and followed up. Position of the placenta in relation to the cervix is of less importance at this stage of pregnancy since most ‘migrate’ away from the internal cervical os78 . Placenta previa should not be reported at this stage. Special attention should be given to patients with a prior Cesarean section, who may be predisposed to scar pregnancy or placenta accreta, with significant complications. In these patients, the area between the bladder and

Ultrasound Obstet Gynecol 2013; 41: 102–113.

ISUOG Guidelines

110

the uterine isthmus at the site of the Cesarean section scar should be scrutinized. In suspected cases, consideration should be given to prompt specialist referral for further evaluation and management79,80 . Although the issue of routine scans in women with a history of Cesarean section may be raised in the future81,82 , there is currently insufficient evidence to inclusion of such a policy in routine practice. Gynecological pathology, both benign and malignant, may be detected during any first-trimester scan. Abnormalities of uterine shape, such as uterine septa and bicornuate uteri, should be described. The adnexa should be surveyed for abnormalities and masses. The relevance and management of such findings are beyond the scope of these Guidelines.

GUIDELINE AUTHORS L. J. Salomon*, Department of Obstetrics and Fetal Medicine and SFAPE (Soci´et´e Franc¸aise d’Am´elioration des Pratiques Echographique), Paris Descartes University, Assistance Publique-Hopitaux de Paris, Hopital Necker Enfants, Paris, Z. Alfirevic*, Department for Women’s and Children’s Health, University of Liverpool, Liverpool, UK C. M. Bilardo, Fetal Medicine Unit, Department of Obstetrics and Gynaecology, University Medical Centre Groningen, Groningen, The Netherlands G. E. Chalouhi, Department of Obstetrics and Fetal Medicine and SFAPE (Soci´et´e Franc¸aise d’Am´elioration des Pratiques Echographique), Paris Descartes University, Assistance Publique-Hopitaux de Paris, Hopital Necker Enfants, Paris, T. Ghi, Department of Obstetrics and Gynaecology, Policlinico S.Orsola-Malpighi, University of Bologna, Bologna, Italy K. O. Kagan, Department of Obstetrics and Gynecology, University of Tuebingen, Tuebingen, T. K. Lau, Fetal Medicine Centre, Paramount Clinic, Central, Hong Kong A. T. Papageorghiou, Fetal Medicine Unit, St George’s, University of London, London, UK N. J. Raine-Fenning, Division of Obstetrics & Gynaecology, School of Clinical Sciences, University of Nottingham, Nottingham, UK J. Stirnemann, Obstetrics and Fetal Medicine, GHU Necker-Enfants Malades, University Paris Descartes, Paris, S. Suresh, Mediscan Systems & Fetal Care Research Foundation, Mylapore, Chennai, India A. Tabor, Fetal Medicine Unit, Department of Obstetrics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark I. E. Timor-Tritsch, Department of Obstetrics and Gynecology, New York University School of Medicine, New York, NY, USA A. Toi, Medical Imaging and Obstetrics and Gynaecology, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada

Copyright  2013 ISUOG. Published by John Wiley & Sons, Ltd.

G. Yeo, Department of Maternal Fetal Medicine, Obstetric Ultrasound and Prenatal Diagnostic Unit, KK Women’s and Children’s Hospital, Singapore *L. J. S. and Z. A. contributed equally to this article.

CITATION These Guidelines should be cited as: ‘Salomon LJ, Alfirevic Z, Bilardo CM, Chalouhi GE, Ghi T, Kagan KO, Lau TK, Papageorghiou AT, Raine-Fenning NJ, Stirnemann J, Suresh S, Tabor A, Timor-Tritsch IE, Toi A, Yeo G. ISUOG Practice Guidelines: performance of first-trimester fetal ultrasound scan. Ultrasound Obstet Gynecol 2013; 41: 102–113.’

REFERENCES 1. Salomon LJ, Alfirevic Z, Berghella V, Bilardo C, HernandezAndrade E, Johnsen SL, Kalache K, Leung KY, Malinger G, Munoz H, Prefumo F, Toi A, Lee W; ISUOG Clinical Standards Committee. Practice guidelines for performance of the routine mid-trimester fetal ultrasound scan. Ultrasound Obstet Gynecol 2011; 37: 116–126. 2. Deter RL, Buster JE, Casson PR, Carson SA. Individual growth patterns in the first trimester: evidence for difference in embryonic and fetal growth rates. Ultrasound Obstet Gynecol 1999; 13: 90–98. 3. Blaas HG. The examination of the embryo and early fetus: how and by whom? Ultrasound Obstet Gynecol 1999; 14: 153–158. 4. Whitworth M, Bricker L, Neilson JP, Dowswell T. Ultrasound for fetal assessment in early pregnancy. Cochrane Database Syst Rev 2010; 4: CD007058. 5. Bennett KA, Crane JMG, O’Shea P, Lacelle J, Hutchens D, Copel JA. First trimester ultrasound screening is effective in reducing postterm labor induction rates: a randomized controlled trial. Am J Obstet Gynecol 2004; 190: 1077–1081. 6. Hoffman CS, Messer LC, Mendola P, Savitz DA, Herring AH, Hartmann KE. Comparison of gestational age at birth based on last menstrual period and ultrasound during the first trimester. Paediatr Perinat Epidemiol 2008; 22: 587–596. 7. Taipale P, Hiilesmaa V. Predicting delivery date by ultrasound and last menstrual period in early gestation. Obstet Gynecol 2001; 97: 189–194. 8. Skalkidou A, Kieler H, Stephansson O, Roos N, Cnattingius S, Haglund B. Ultrasound pregnancy dating leads to biased perinatal morbidity and neonatal mortality among post-term-born girls. Epidemiology 2010; 21: 791–796. 9. Harrington DJ, MacKenzie IZ, Thompson K, Fleminger M, Greenwood C. Does a first trimester dating scan using crown rump length measurement reduce the rate of induction of labour for prolonged pregnancy? An uncompleted randomised controlled trial of 463 women. BJOG 2006; 113: 171–176. 10. Ott WJ. Accurate gestational dating: revisited. Am J Perinatol 1994; 11: 404–408. 11. Wisser J, Dirschedl P, Krone S. Estimation of gestational age by transvaginal sonographic measurement of greatest embryonic length in dated human embryos. Ultrasound Obstet Gynecol 1994; 4: 457–462. ´ K, Eik-Nes SH, Grøttum P, Von During ¨ 12. Tunon V, Kahn JA. Gestational age in pregnancies conceived after in vitro fertilization: a comparison between age assessed from oocyte retrieval, crown–rump length and biparietal diameter. Ultrasound Obstet Gynecol 2000; 15: 41–46. 13. Grange G, Pannier E, Goffinet F, Cabrol D, Zorn JR. Dating biometry during the first trimester: accuracy of an every-day practice. Eur J Obstet Gynecol Reprod Biol 2000; 88: 61–64.

Ultrasound Obstet Gynecol 2013; 41: 102–113.

ISUOG Guidelines 14. Chalouhi GE, Bernard JP, Benoist G, Nasr B, Ville Y, Salomon LJ. A comparison of first trimester measurements for prediction of delivery date. J Matern Fetal Neonatal Med 2011; 24: 51–57. 15. Salomon LJ, Pizzi C, Gasparrini A, Bernard J-P, Ville Y. Prediction of the date of delivery based on first trimester ultrasound measurements: an independent method from estimated date of conception. J Matern Fetal Neonatal Med 2010; 23: 1–9. 16. Caughey AB, Nicholson JM, Washington AE. First- vs secondtrimester ultrasound: the effect on pregnancy dating and perinatal outcomes. Am J Obstet Gynecol 2008; 198: 703.e1–6. ¨ H, Andolf E. Expected day of 17. Thorsell M, Kaijser M, Almstrom delivery from ultrasound dating versus last menstrual period-obstetric outcome when dates mismatch. BJOG 2008; 115: 585–589. 18. Bottomley C, Bourne T. Dating and growth in the first trimester. Best Pract Res Clin Obstet Gynaecol 2009; 4: 439–452. 19. Sonek J. First trimester ultrasonography in screening and detection of fetal anomalies. Am J Med Genet C Semin Med Genet 2007; 145: 45–61. 20. Snijders RJ, Johnson S, Sebire NJ, Noble PL, Nicolaides KH. First-trimester ultrasound screening for chromosomal defects. Ultrasound Obstet Gynecol 1996; 7: 216–226. 21. Ville Y. ‘Ceci n’est pas une e´ chographie’: a plea for quality assessment in prenatal ultrasound. Ultrasound Obstet Gynecol 2008; 31: 1–5. 22. Abramowicz JS, Kossoff G, Marsal K, Ter Haar G. Safety Statement, 2000 (reconfirmed 2003). International Society of Ultrasound in Obstetrics and Gynecology (ISUOG). Ultrasound Obstet Gynecol 2003; 21: 100. ´ AP, Allen 23. Torloni MR, Vedmedovska N, Merialdi M, Betran ´ T, Gonzalez R, Platt LD; ISUOG-WHO Fetal Growth Study Group. Safety of ultrasonography in pregnancy: WHO systematic review of the literature and meta-analysis. Ultrasound Obstet Gynecol 2009; 33: 599–608. 24. Hershkovitz R, Sheiner E, Mazor M. Ultrasound in obstetrics: a review of safety. Eur J Obstet Gynecol Reprod Biol 2002; 101: 15–18. 25. Salvesen K, Lees C, Abramowicz J, Brezinka C, Ter Haar G, ´ K. ISUOG statement on the safe use of Doppler in the Marˇsal 11 to 13 + 6-week fetal ultrasound examination. Ultrasound Obstet Gynecol 2011; 37: 628. 26. Lewi L, Jani J, Blickstein I, Huber A, Gucciardo L, Van Mieghem ´ E, Lewi P, Deprest T, Don´e E, Boes AS, Hecher K, Gratacos J. The outcome of monochorionic diamniotic twin gestations in the era of invasive fetal therapy: a prospective cohort study. Am J Obstet Gynecol 2008; 199: 493.e1–7. 27. Dias T, Arcangeli T, Bhide A, Napolitano R, Mahsud-Dornan S, Thilaganathan B. First-trimester ultrasound determination of chorionicity in twin pregnancy. Ultrasound Obstet Gynecol 2011; 38: 530–532. 28. Fong KW, Toi A, Salem S, Hornberger LK, Chitayat D, Keating SJ, McAuliffe F, Johnson JA. Detection of fetal structural abnormalities with US during early pregnancy. Radiographics 2004; 24: 157–174. 29. Jurkovic D, Gruboeck K, Campbell S. Ultrasound features of normal early pregnancy development. Curr Opin Obstet Gynecol 1995; 7: 493–504. 30. Tezuka N, Sato S, Kanasugi H, Hiroi M. Embryonic heart rates: development in early first trimester and clinical evaluation. Gynecol Obstet Invest 1991; 32: 210–212. 31. Levi CS, Lyons EA, Zheng XH, Lindsay DJ, Holt SC. Endovaginal US: demonstration of cardiac activity in embryos of less than 5.0 mm in crown-rump length. Radiology 1990; 176: 71–74. 32. Goldstein SR. Significance of cardiac activity on endovaginal ultrasound in very early embryos. Obstet Gynecol 1992; 80: 670–672. 33. Brown DL, Emerson DS, Felker RE, Cartier MS, Smith WC. Diagnosis of early embryonic demise by endovaginal sonography. J Ultrasound Med 1990; 9: 631–636.

Copyright  2013 ISUOG. Published by John Wiley & Sons, Ltd.

111 34. Oh JS, Wright G, Coulam CB. Gestational sac diameter in very early pregnancy as a predictor of fetal outcome. Ultrasound Obstet Gynecol 2002; 20: 267–269. 35. Robinson HP, Sweet EM, Adam AH. The accuracy of radiological estimates of gestational age using early fetal crown-rump length measurements by ultrasound as a basis for comparison. Br J Obstet Gynaecol 1979; 86: 525–528. 36. Robinson HP. ‘‘Gestation sac’’ volumes as determined by sonar in the first trimester of pregnancy. Br J Obstet Gynaecol 1975; 82: 100–107. 37. Salomon LJ, Bernard M, Amarsy R, Bernard JP, Ville Y. The impact of crown–rump length measurement error on combined Down syndrome screening: a simulation study. Ultrasound Obstet Gynecol 2009; 33: 506–511. ¨ 38. Sladkevicius P, Saltvedt S, Almstrom H, Kublickas M, Grunewald C, Valentin L. Ultrasound dating at 12–14 weeks of gestation. A prospective cross-validation of established dating formulae in in-vitro fertilized pregnancies. Ultrasound Obstet Gynecol 2005; 26: 504–511. 39. Altman DG, Chitty LS. New charts for ultrasound dating of pregnancy. Ultrasound Obstet Gynecol 1997; 10: 174–191. 40. Salomon LJ, Bernard JP, Duyme M, Dorion A, Ville Y. Revisiting first-trimester fetal biometry. Ultrasound Obstet Gynecol 2003; 22: 63–66. 41. Loughna P, Chitty L, Evans T, Chudleigh T. Fetal size and dating: charts recommended for clinical obstetric practice. Ultrasound 2009; 17: 161–167. 42. Hadlock FP, Deter RL, Carpenter RJ, Park SK. Estimating fetal age: effect of head shape on BPD. AJR Am J Roentgenol 1981; 137: 83–85. 43. Verburg BO, Steegers EAP, De Ridder M, Snijders RJM, Smith E, Hofman A, Moll HA, Jaddoe VW, Witteman JC. New charts for ultrasound dating of pregnancy and assessment of fetal growth: longitudinal data from a population-based cohort study. Ultrasound Obstet Gynecol 2008; 31: 388–396. 44. Crowley P. Interventions for preventing or improving the outcome of delivery at or beyond term. Cochrane Database Syst Rev 2000; (2): CD000170. 45. Mongelli M, Wong YC, Venkat A, Chua TM. Induction policy and missed post-term pregnancies: a mathematical model. Aust N Z J Obstet Gynaecol 2001; 41: 38–40. 46. Hoffman CS, Messer LC, Mendola P, Savitz DA, Herring AH, Hartmann KE. Comparison of gestational age at birth based on last menstrual period and ultrasound during the first trimester. Paediatr Perinat Epidemiol 2008; 22: 587–596. 47. NICE. Antenatal care: Routine care for the healthy pregnant woman. National Institute for Health and Clinical Excellence: London, 2010. 48. Savitz DA, Terry JW, Dole N, Thorp JM, Siega-Riz AM, Herring AH. Comparison of pregnancy dating by last menstrual period, ultrasound scanning, and their combination. Am J Obstet Gynecol 2002; 187: 1660–1666. 49. Bagratee JS, Regan L, Khullar V, Connolly C, Moodley J. Reference intervals of gestational sac, yolk sac and embryo volumes using three-dimensional ultrasound. Ultrasound Obstet Gynecol 2009; 34: 503–509. 50. Grisolia G, Milano K, Pilu G, Banzi C, David C, Gabrielli S, Rizzo N, Morandi R, Bovicelli L. Biometry of early pregnancy with transvaginal sonography. Ultrasound Obstet Gynecol 1993; 3: 403–411. 51. Robinson HP. Sonar measurement of fetal crown-rump length as means of assessing maturity in first trimester of pregnancy. Br Med J 1973; 4: 28–31. 52. Robinson HP, Fleming JE. A critical evaluation of sonar ‘‘crown-rump length’’ measurements. Br J Obstet Gynaecol 1975; 82: 702–710. 53. Dias T, Mahsud-Dornan S, Thilaganathan B, Papageorghiou A, Bhide A. First-trimester ultrasound dating of twin pregnancy: are singleton charts reliable? BJOG 2010; 117: 979–984. 54. Saltvedt S, Almstrom H, Kublickas M, Valentin L, Grunewald C. Detection of malformations in chromosomally normal fetuses

Ultrasound Obstet Gynecol 2013; 41: 102–113.

ISUOG Guidelines

112

55.

56.

57.

58.

59.

60.

61.

62. 63.

64.

65.

66.

67. 68.

69.

70.

71.

72.

by routine ultrasound at 12 or 18 weeks of gestation-a randomised controlled trial in 39,572 pregnancies. BJOG 2006; 113: 664–674. Chen M, Lee , Lam YH, Tang RYK, Chan B, Wong SF, Tse LH, Tang MH. Comparison of nuchal and detailed morphology ultrasound examinations in early pregnancy for fetal structural abnormality screening: a randomized controlled trial. Ultrasound Obstet Gynecol 2008; 31: 136–146; discussion 146. Timor-Tritsch IE, Fuchs KM, Monteagudo A, D’Alton ME. Performing a fetal anatomy scan at the time of first-trimester screening. Obstet Gynecol 2009; 113: 402–407. Abu-Rustum RS, Daou L, Abu-Rustum SE. Role of firsttrimester sonography in the diagnosis of aneuploidy and structural fetal anomalies. J Ultrasound Med 2010; 29: 1445–1452. Timor-Tritsch IE, Bashiri A, Monteagudo A, Arslan AA. Qualified and trained sonographers in the US can perform early fetal anatomy scans between 11 and 14 weeks. Am J Obstet Gynecol 2004; 191: 1247–1252. Bronshtein M, Zimmer EZ. Transvaginal ultrasound diagnosis of fetal clubfeet at 13 weeks, menstrual age. J Clin Ultrasound. 1989; 17: 518–520. ¨ a¨ M, Salonen R, Hiilesmaa V. Learning Taipale P, Ammal curve in ultrasonographic screening for selected fetal structural anomalies in early pregnancy. Obstet Gynecol 2003; 101: 273–278. Cedergren M, Selbing A. Detection of fetal structural abnormalities by an 11–14-week ultrasound dating scan in an unselected Swedish population. Acta Obstet Gynecol Scand 2006; 85: 912–915. Fisher J. First-trimester screening: dealing with the fall-out. Prenat Diagn 2011; 31: 46–49. Chaoui R, Nicolaides KH. From nuchal translucency to intracranial translucency: towards the early detection of spina bifida. Ultrasound Obstet Gynecol 2010; 35: 133–138. Sepulveda W, Wong AE, Martinez-Ten P, Perez-Pedregosa J. Retronasal triangle: a sonographic landmark for the screening of cleft palate in the first trimester. Ultrasound Obstet Gynecol 2010; 35: 7–13. Syngelaki A, Chelemen T, Dagklis T, Allan L, Nicolaides KH. Challenges in the diagnosis of fetal non-chromosomal abnormalities at 11–13 weeks. Prenat Diagn 2011; 31: 90–102. Bernard J-P, Cuckle HS, Stirnemann JJ, Salomon LJ, Ville Y. Screening for fetal spina bifida by ultrasound examination in the first trimester of pregnancy using fetal biparietal diameter. Am J Obstet Gynecol 2012; 207: 306.e1–5. DeVore GR. First-trimester fetal echocardiography: is the future now? Ultrasound Obstet Gynecol 2002; 20: 6–8. Yagel S, Cohen SM, Messing B. First and early second trimester fetal heart screening. Curr Opin Obstet Gynecol 2007; 19: 183–190. van Zalen-Sprock RM, Vugt JM, van Geijn HP. First-trimester sonography of physiological midgut herniation and early diagnosis of omphalocele. Prenat Diagn 1997; 17: 511–518. Bhaduri M, Fong K, Toi A, Tomlinson G, Okun N. Fetal anatomic survey using three-dimensional ultrasound in conjunction with first-trimester nuchal translucency screening. Prenat Diagn 2010; 30: 267–273. Nicolaides KH, Azar G, Byrne D, Mansur C, Marks K. Fetal nuchal translucency: ultrasound screening for chromosomal defects in first trimester of pregnancy. BMJ; 1992; 304: 867–869. Nicolaides KH, Snijders RJ, Gosden CM, Berry C, Campbell S. Ultrasonographically detectable markers of fetal chromosomal abnormalities. Lancet 1992; 340: 704–707.

73. Kagan KO, Wright D, Baker A, Sahota D, Nicolaides KH. Screening for trisomy 21 by maternal age, fetal nuchal translucency thickness, free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A. Ultrasound Obstet Gynecol 2008; 31: 618–624. 74. Kagan KO, Cicero S, Staboulidou I, Wright D, Nicolaides KH. Fetal nasal bone in screening for trisomies 21, 18 and 13 and Turner syndrome at 11–13 weeks of gestation. Ultrasound Obstet Gynecol 2009; 33: 259–264. 75. Kagan KO, Valencia C, Livanos P, Wright D, Nicolaides KH. Tricuspid regurgitation in screening for trisomies 21, 18 and 13 and Turner syndrome at 11 + 0 to 13 + 6 weeks of gestation. Ultrasound Obstet Gynecol 2009; 33: 18–22. 76. Maiz N, Valencia C, Kagan KO, Wright D, Nicolaides KH. Ductus venosus Doppler in screening for trisomies 21, 18 and 13 and Turner syndrome at 11–13 weeks of gestation. Ultrasound Obstet Gynecol 2009; 33: 512–517. 77. Nicolaides KH. Screening for fetal aneuploidies at 11 to 13 weeks. Prenat Diagn 2011; 31: 7–15. 78. Mustafa´ SA, Brizot ML, Carvalho MHB, Watanabe L, Kahhale S, Zugaib M. Transvaginal ultrasonography in predicting placenta previa at delivery: a longitudinal study. Ultrasound Obstet Gynecol 2002; 20: 356–359. 79. Timor-Tritsch IE, Monteagudo A, Santos R, Tsymbal T, Pineda G, Arslan AA. The diagnosis, treatment, and follow-up of cesarean scar pregnancy. Am J Obstet Gynecol 2012; 207: 44.e1–13. 80. Timor-Tritsch IE, Monteagudo A. Unforeseen consequences of the increasing rate of cesarean deliveries: early placenta accreta and cesarean scar pregnancy. A review. Am J Obstet Gynecol 2012; 207: 14–29. 81. Stirnemann JJ, Chalouhi GE, Forner S, Saidji Y, Salomon LJ, Bernard J-P, Ville Y. First-trimester uterine scar assessment by transvaginal ultrasound. Am J Obstet Gynecol 2011; 205: 551.e1–6. 82. Stirnemann JJ, Mousty E, Chalouhi G, Salomon LJ, Bernard J-P, Ville Y. Screening for placenta accreta at 11–14 weeks of gestation. Am J Obstet Gynecol 2011; 205: 547. e1–6. 83. Hadlock FP, Shah YP, Kanon DJ, Lindsey JV. Fetal crownrump length: reevaluation of relation to menstrual age (5–18 weeks) with high-resolution real-time US. Radiology 1992; 182: 501–505. 84. Daya S. Accuracy of gestational age estimation by means of fetal crown-rump length measurement. Am J Obstet Gynecol 1993; 168: 903–908. 85. McLennan AC, Schluter PJ. Construction of modern Australian first trimester ultrasound dating and growth charts. J Med Imaging Radiat Oncol 2008; 52: 471–479. 86. Hadlock FP, Deter RL, Harrist RB, Park SK. Fetal biparietal diameter: a critical re-evaluation of the relation to menstrual age by means of real-time ultrasound. J Ultrasound Med 1982; 1: 97–104. 87. McAuliffe FM, Fong KW, Toi A, Chitayat D, Keating S, Johnson J-A. Ultrasound detection of fetal anomalies in conjunction with first-trimester nuchal translucency screening: a feasibility study. Am J Obstet Gynecol 2005; 193: 1260–1265. 88. von Kaisenberg CS, Kuhling-von Kaisenberg H, Fritzer E, Schemm S, Meinhold-Heerlein I, Jonat W. Fetal transabdominal anatomy scanning using standard views at 11 to 14 weeks’ gestation. Am J Obstet Gynecol 2005; 192: 535–542.

(Guideline review date: June 2015) The authorship of this article was incomplete as initially published. This version of the article correctly acknowledges all authors who contributed to the development of the Guidelines. Copyright  2013 ISUOG. Published by John Wiley & Sons, Ltd.

Ultrasound Obstet Gynecol 2013; 41: 102–113.

ISUOG Guidelines

113

APPENDIX: ROUTINE ULTRASOUND WORKSHEET (EXAMPLE)

Patient:

ID number:

Date of birth (DD/MM/YYYY): Referring physician: Date of exam (DD/MM/YYYY): Sonographer / Supervisor: Indication for scan and relevant clinical information: LMP Technical conditions: Good / Limited by: Singleton / Multiple (use 1 sheet/fetus) => Chorionicity: ADNEXA: Appearance Anomaly:

Normal

Abnormal*

MEASUREMENTS mm Centile (Reference range) Crown–rump length Nuchal translucency (optional) Biparietal diameter Head circumference Abdominal circumference Femoral diaphysis length *Abnormal findings (please detail): Ultrasound-based estimate of GA: ………..weeks + ………..days

CONCLUSION: Normal and complete examination. Normal but incomplete examination. Abnormal examination* Plans: No further ultrasound scans required Follow up planned in ….. weeks. Referred to …………… Other:

SONOGRAPHIC APPEARANCE OF FETAL ANATOMY:

N

Ab*

NV

(N = Normal; Ab = Abnormal*; NV = Not visualized) Gray = optional

Head Shape Cranial ossification Midline falx Choroid plexus Face Orbits Profile Neck Thorax Pulm. area Diaphragm Heart Heart activity Size Cardiac axis Four-chamber view Abdomen Stomach Bowel Kidneys Urinary bladder Cord insertion / abdominal wall Cord vessels Spine Limbs Right arm (incl. hand) Right leg (incl. foot) Left arm (incl. hand) Left leg (incl. foot) Gender (optional): M F Other:

Produced

Printed

Stored

No. of images

Copyright  2013 ISUOG. Published by John Wiley & Sons, Ltd.

Ultrasound Obstet Gynecol 2013; 41: 102–113.

SOGC CLINICAL PRACTICE GUIDELINE No. 297, October 2013

Investigation and Management of Non-immune Fetal Hydrops This clinical practice guideline has been prepared by the Genetics Committee, reviewed by Maternal Fetal Medicine Committee, and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Valérie Désilets, MD, Montreal QC François Audibert, MD, Montreal QC GENETICS COMMITTEE R. Wilson, MD (Chair), Calgary AB Francois Audibert, MD, Montreal QC Jo-Ann Brock, MD, Halifax NS June Carroll, MD, Toronto ON Lola Cartier, MSc, Montreal QC Alain Gagnon, MD, Vancouver BC Jo-Ann Johnson, MD, Calgary AB Sylvie Langlois, MD, Vancouver BC William MacDonald, MD, Halifax NS Lynn Murphy-Kaulbeck, MD, Moncton NB Nanette Okun, MD, Toronto ON Melanie Pastuck, RN, Cochrane AB Vyta Senikas, MD, Ottawa ON Disclosure statements have been received from all contributors.

Key Words: Non-immune hydrops fetalis, fetal hydrops, fetal therapy, fetal metabolism

J Obstet Gynaecol Can 2013;35(10):923–936

Abstract Objective: To describe the current investigation and management of non-immune fetal hydrops, with a focus on treatable or recurring etiologies. Outcomes: To provide better counselling and management in cases of prenatally diagnosed non-immune hydrops. Evidence: Published literature was retrieved through searches of PubMed or MEDLINE, CINAHL, and The Cochrane Library in 2011 using key words (non-immune hydrops fetalis, fetal hydrops, fetal therapy, fetal metabolism). Results were restricted to systematic reviews, randomized controlled trials/controlled clinical trials, observational studies, and significant case reports. Additional publications were identified from the bibliographies of these articles. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to May 2012. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Benefits, harms, and costs: These guidelines educate readers about the causes of non-immune fetal hydrops and its prenatal counselling and management. It also provides a standardized approach to non-immune fetal hydrops, emphasizing the search for prenatally treatable conditions and recurrent genetic etiologies. Values: The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). Recommendations 1. All patients with fetal hydrops should be referred promptly to a tertiary care centre for evaluation. Some conditions amenable to prenatal treatment represent a therapeutic emergency after 18 weeks. (II-2A) 2. Fetal chromosome analysis and genetic microarray molecular testing should be offered where available in all cases of non-immune fetal hydrops. (II-2A) 3. Imaging studies should include comprehensive obstetrical ultrasound (including arterial and venous fetal Doppler) and fetal echocardiography. (II-2A)

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

OCTOBER JOGC OCTOBRE 2013 l 923

SOGC Clinical Practice Guideline

Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.78 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care.78

4. Investigation for maternal–fetal infections, and alpha-thalassemia in women at risk because of their ethnicity, should be performed in all cases of unexplained fetal hydrops. (II-2A) 5. To evaluate the risk of fetal anemia, Doppler measurement of the middle cerebral artery peak systolic velocity should be performed in all hydropic fetuses after 16 weeks of gestation. In case of suspected fetal anemia, fetal blood sampling and intrauterine transfusion should be offered rapidly. (II-2A) 6. All cases of unexplained fetal hydrops should be referred to a medical genetics service where available. Detailed postnatal evaluation by a medical geneticist should be performed on all

ABBREVIATIONS AF

amniotic fluid

CBC

complete blood count

CMV

cytomegalovirus

FISH

fluorescent in situ hybridization

Hb

hemoglobin

HbH

hemoglobin H

MCA

middle cerebral artery

MPS

mucopolysaccharidosis

NICHD National Institute of Child Health and Human Development NIHF

non-immune hydrops fetalis

QF-PCR quantitative fluorescent polymerase chain reaction RT-PCR real-time polymerase chain reaction TORCH toxoplasmosis, rubella, cytomegalovirus, herpes simplex UA

umbilical artery

VZV

Varicella-zoster virus

924 l OCTOBER JOGC OCTOBRE 2013

cases of newborns with unexplained non-immune hydrops. (II-2A) 7. Autopsy should be recommended in all cases of fetal or neonatal death or pregnancy termination. (II-2A) Amniotic fluid and/or fetal cells should be stored for future genetic testing. (II-2B)

INTRODUCTION

H

ydrops fetalis is defined as the accumulation of abnormal fluid in at least two different fetal compartments. It implies an excess of total body water, which is usually evident as extracellular accumulation of fluid in tissues and serous cavities.1,2 It generally presents as subcutaneous edema, accompanied by effusions in two or more serous cavities including pericardial or pleural effusions, and ascites. Polyhydramnios or placental thickening (> 6 cm) are often associated. When the fluid accumulation is limited to one cavity, for example isolated ascitis or pleural effusion, the situation should be described in of the involved site, since this may be helpful in narrowing the differential diagnosis. The three primary mechanisms associated with hydrops are intrauterine anemia, intrauterine heart failure, and hypoproteinemia. In addition to these three basic mechanisms, fetal hydrops has a causal relationship with a variety of structural abnormalities that interfere with the fetoplacental circulation. Chromosomal anomalies (aneuploidy, deletion, duplication, genetic mutation) and skeletal dysplasia may also be associated with hydrops through a variety of mechanisms.1,2 Fetal hydrops carries a poor prognosis; however, several etiologies can be treated in utero with potential good

Investigation and Management of Non-immune Fetal Hydrops

results. The growing number of recognized etiologies requires a comprehensive and systematic search for causes, in particular for treatable or recurrent conditions. Recommendation

1. All patients with fetal hydrops should be referred promptly to a tertiary care centre for evaluation. Some conditions amenable to prenatal treatment represent a therapeutic emergency after 18 weeks. (II-2A) DEFINITIONS Immune versus Non-Immune Fetal Hydrops

Immune hydrops Maternal red cell alloimmunization occurs when a pregnant woman has an immunological response to a paternally-derived antigen that is foreign to the mother and inherited by the fetus.3 The maternal antibodies may cross the placenta, bind to antigens present on the fetal erythrocytes, and cause hemolysis, hydrops fetalis, and fetal death. The prognosis of this condition has been considerably improved over the last decades, due to interventions including antenatal and postpartum Rhesus immune globulin, non-invasive prenatal surveillance with cerebral Doppler, and intrauterine transfusion. The complete description and management of this condition is beyond the scope of this guideline.3,4 Non-immune hydrops Non-immune hydrops fetalis refers to hydrops in the absence of maternal circulating red-cell antibodies.5 With the introduction of widespread immunoprophylaxis for red cell alloimmunization and the use of in utero transfusions for immune hydrops therapy, non-immune causes have become responsible for at least 85% of all cases of fetal hydrops.6 The reported incidence is around 3 per 10 000 births; however, the incidence is much higher at the first- and second-trimester ultrasounds because of higher fetal death rates.7 Hydrops in the First Trimester and Cystic Hygroma

Signs of hydrops can be found as early as in the first trimester. This is usually seen in association with increased nuchal translucency and/or cystic hygroma,8,9 a septated cystic structure in the occipitocervical region and sometimes the axillary region. The evaluation of increased nuchal translucency and cystic hygromas with or without fetal hydrops differs from that of non-immune fetal hydrops and is beyond the scope of this guideline. Pertinent SOGC guidelines can be found elsewhere.10–12 Twin Gestation as a Different Situation

Non-immune fetal hydrops in one or both twins may imply a different etiology, especially in monochorionic twins, given

the possibility of twin-to-twin transfusion syndrome. Review articles discussing the assessment and management of twinto-twin transfusion syndrome and other complications specific to twin pregnancies are available elsewhere.13–17 ETIOLOGIES

Despite extensive investigations, the etiology of nonimmune fetal hydrops may remain unknown in 15% to 25% of patients.1,6,18–20 The goal of this guideline is to propose a standardized approach to the investigation and management of non-immune fetal hydrops with a focus on the rare treatable or potentially recurring causes. A growing number of conditions can result in NIHF. A systematic review has recently analyzed a total of 225 relevant articles describing 5437 individual cases of NIHF.21 All cases were sub-classified into one of the following diagnostic categories: cardiovascular (21.7%), hematologic (10.4%), chromosomal (13.4%), syndromic (4.4%), lymphatic dysplasia (5.7%), inborn errors of metabolism (1.1%), infections (6.7%), thoracic (6.0%), urinary tract malformations (2.3%), extra-thoracic tumours (0.7%), twin-to-twin transfusion or placental (5.6%), gastrointestinal (0.5%), miscellaneous (3.7%), and idiopathic (17.8%). See Table 2 for details. Chromosomal Abnormalities

Chromosomal abnormalities are the cause of NIHF in 25% to 70% of cases.22 The risk of fetal aneuploidy is higher when identified earlier in gestation or when fetal structural anomalies are seen.5,23 Standard fetal chromosome analysis is indicated in all cases of hydrops. Additional genetic microarray molecular testing should be considered in all NIHF cases as the NICHD Microarray Study has shown additional genetic chromosomal anomalies (smaller than can be seen by standard cytogenetic studies) in 7% of fetuses with congenital anomalies and standard normal karyotype.24 Recommendation

2. Fetal chromosome analysis and genetic microarray molecular testing should be offered where available in all cases of non-immune fetal hydrops where available. (II-2A) Cardiac Etiologies

Cardiac etiologies for 10% to 20% of cases of NIHF.2,25 These include not only structural abnormalities, but also cardiac arrhythmias, tumours, physiological dysfunction due to infection, inflammation, infarction, and arterial calcification. Cardiac and intrathoracic lesions that result in right atrial pressure or volume OCTOBER JOGC OCTOBRE 2013 l 925

overload seem to be most commonly associated with hydrops fetalis. Fetal cardiac tumours, cardiomyopathy, and other myocardial conditions probably result in hydrops fetalis by a similar mechanism. Fetal tachyarrhythmia has been shown to result in elevation of atrial pressure and is the most treatable of cardiac causes of hydrops fetalis.26 Fetal bradyarrhythmias are less easily treatable and a rare causative mechanism of hydrops fetalis, except when the fetal heart rate is persistently below 50 per minute.

17.8

No

5.7

No

8.4

966 310

455

Idiopathic Lymphatic dysplasia

Various*

SOGC Clinical Practice Guideline

Placental (TTTS)

304

5.6

Yes (Placental laser therapy)

Syndromic

237

4.4

No

Infectious Diseases

Intrauterine infections are a common cause of fetal hydrops (4 to 15%), with parvovirus B19 infection and secondary anemia the most frequent.27 Fetal toxoplasmosis, syphilis, cytomegalovirus, and varicella can also present as fetal hydrops, with commonly associated findings such as hepatomegaly, splenomegaly, or ascites.2,28 (Tables 2 and 3) Strategies for the prenatal screening and diagnosis of maternal–fetal infections are detailed below.

926 l OCTOBER JOGC OCTOBRE 2013

Hematological disorders can be identified in 7% of cases of NIHF. Ethnicity at increased risk of fetal thalassemia may affect this frequency. For example, homozygous alpha-thalassemia ed for 55.1% of NIHF diagnosed after 20 weeks in Southern China.29 Structural Congenital Anomalies

Structural congenital anomalies should be evaluated as they represent a large group of disorders that can be identified through detailed fetal imaging and may be treatable. A list of congenital anomalies associated with fetal hydrops is presented in Table 2. Primary chylothorax,2,30 congenital cystic adenomatoid malformation,31 various fetal tumours,32 and metabolic diseases have been also described as causal factors of hydrops.33,34 Single Gene Disorders

†For fetal tachyarrythmias only

*including: inborn storage diseases, urinary tract malformations, extra-thoracic tumours, gastro-intestinal, miscellaneous

IUT: intrauterine transfusion; TTTS: twin-to-twin transfusion syndrome

Adapted from Bellini et al.18,26

Based on a total number of 5437 cases of NIHF

6.0

Yes (Thoracoamniotic shunting)

6.7

No

Yes (IUT for parvovirus)

13.4

Yes (IUT)

21.7

Yes† (anti-arrythmic drugs) Potential fetal therapy

%

10.4

327 366 727 1181 Cases, n

564

Thoracic Infection Chromosomal Hematologic Cardiovascular

Table 2. Conditions associated with non-immune fetal hydrops

Hematological Disorders

Known single-gene disorders affecting metabolic pathways, hematological conditions, skeletal dysplasia, neurologic disorders, cardiomyopathies, congenital nephrosis, congenital lymphedema, and mitochondrial mutations have been reported as causes of potentially recurring fetal hydrops.26 However, many families have had more than one child with fetal or neonatal hydrops in whom the underlying genetic defect has not been discovered. Some genes may be expressed specifically during fetal development, while others may represent an early-onset form of a known pediatric disorder (e.g., Gaucher, fetal akinesia, glycogen storage disorder type IV).35,36 The identification of a single gene disorder not

Investigation and Management of Non-immune Fetal Hydrops

Table 3. Ultrasound findings in fetal infections causing fetal hydrops Infection Toxoplasmosis

CNS

Cardiac

Abdominal

Placental/AF

IUGR

+

+

Rare

+

+

Rare

+

Syphilis Rubella

+

Parvovirus CMV

+

Varicella

+

+

+

+

+

+

+

+

+

+

+

+

+

+

Adapted from Klein et al.52 CNS: central nervous system; IUGR: intrauterine growth restriction

only helps in predicting the outcome of the current pregnancy, but also has an impact on the management or screening of future pregnancies in the family.26 Recent data suggest that metabolic disorders may be responsible for some idiopathic NIHF. Lysosomal storage disorders are the group of disorders most commonly involved in NIHF. Hydrops fetalis is a relatively common presentation in mucopolysaccharidosis type VII,37 infantile galactosialidosis,38 type 2 Gaucher disease, and infantile free sialic acid storage disease. At least 15 other inborn errors of metabolism may cause NIHF34,39: GM1 gangliosidosis, NiemannPick type A, Niemann-Pick type C, MPS I, MPS IVA, mucolipidosis II, sialidosis, multiple sulfatase deficiency, Farber disease, Wolman disease, I cell disease, glycogen storage disease IV,36 transaldolase deficiency,40 Pearson syndrome (mitochondrial disorder), and congenital disorders of glycosylation. Specific enzyme assays are available to test for these disorders on cultured amniocytes or specific metabolite measurement in amniotic fluid supernatant.41,42 Diagnosing or ruling out a metabolic disorder as the causal factor for NIHF is important because these single gene disorders carry a 25% risk of recurrence, and their identification may allow for prenatal diagnosis at an earlier stage in future pregnancies. Prenatal diagnosis of such conditions also facilitates postnatal management. Despite thorough investigations, earlier reports conclude that at least 28% of cases of NIHF remain unexplained2; a recent systematic review of the literature found that 17.8% were considered idiopathic.21 PRENATAL MANAGEMENT

Fetal hydrops mandates urgent referral to a maternal– fetal medicine specialist for rapid evaluation because some situations must be considered true prenatal medical emergencies, particularly after 16 to 18 weeks.

Triage depends on gestational age, etiology, and severity. Ultrasound examination including umbilical artery and middle cerebral artery Doppler studies may guide lifesaving treatments such as in utero transfusions, fetal cardioversion, or placement of diversion shunts. Table 4 outlines the baseline investigations for all fetal hydrops. One should not wait for complete results before initiating referral, invasive diagnostic procedures, or treatments. Clinical Evaluation

A detailed history should be taken focusing on the mother’s past medical and reproductive history, including previous fetal, neonatal, or infantile deaths. A clear determination of gestational age and history of viral exposure/illness, travelling, bleeding, or use of medication during the pregnancy should be obtained. Parental past medical history, ethnic background, and consanguinity should be documented. A 3-generation pedigree, including specific questions on fetal loss, death in infancy, developmental delay, congenital malformation, genetic syndrome, skeletal dysplasia, chronic infantile illness, inherited cardiomyopathies, and neurodegenerative disorders should be completed. Maternal history, physical examination, and laboratory tests should be used to rule out developing preeclampsia (mirror syndrome) and underlying chronic illness associated with fetal hydrops (e.g., Sjogren, lupus, uncontrolled diabetes, Graves disease). Non-invasive Testing

Timely referral to a maternal–fetal medicine specialist allows for detailed and comprehensive ultrasound examination and the early identification of any treatable causes. A careful search for structural fetal anomalies or genetic syndromes, signs of fetal infection, and evidence of umbilical cord or placental anomalies may rapidly indicate the cause of hydrops. Multiple mechanisms of hydrops may coexist and the primary cause is often not obvious. Determination of prognosis is important and may be achieved by a semiOCTOBER JOGC OCTOBRE 2013 l 927

SOGC Clinical Practice Guideline

Table 4. Step-wise investigation of non-immune fetal hydrops STEP 1: Urgent Fetal imaging •  Detailed morphology obstetrical ultrasound in a tertiary care centre and the assessment of the fetal venous and arterial circulation •  Doppler (MCA, venous, arterial) •  Fetal echocardiogram Maternal blood • CBC • Kleihauer-Betke •  ABO blood type and antigen status •  Indirect Coombs (antibody screen) •  Venereal disease research laboratory test for syphilis •  Acute phase titres (parvovirus, toxoplasmosis, cytomegalovirus, rubella) •  Liver function tests, uric acid, coagulation tests (suspected mirror syndrome) •  SS-A, SS-B antibodies (fetal bradyarrhythmia) •  Depending on ethnic origin: hemoglobin electrophoresis, G6PD deficiency screen STEP 2: Invasive / referral / treatment Amniotic fluid •  FISH or QF-PCR on uncultured amniocytes, followed by karyotype or microarray analysis •  PCR for CMV •  PCR for parvovirus-B19/toxoplasmosis (selected cases) •  CMV and bacterial cultures in selected cases •  Inform the laboratory to keep the amniotic cells and supernatant for future studies •  DNA extraction if alpha-thalassemia suspected •  Fetal lung maturity testing (depending on gestational age) Fetal blood sampling (maternal fetal medicine specialist) •  CBC, white blood cell count differential, platelets •  Direct Coombs’ test •  Blood group and type •  Karyotype (standard) with genetic microarray consideration •  TORCH/viral serologies •  Protein/albumin/liver function tests (not on all cases) •  Hemoglobin electrophoresis (depending on ethnicity) Cavity aspiration (may be done at the time of amniocentesis) •  Lymphocyte count • Protein/albumin •  Creatinin/ionogram (ascites) •  PCR for CMV and viral and bacterial cultures Consider consultation with neonatalogy (depending on gestational age) STEP 3: Post-delivery Examination of the placenta Neonatal survival •  Detailed physical examination •  Cardiac monitoring •  Cranial ultrasound •  Abdominal ultrasound •  Cardiac monitoring • Echocardiography •  CBC, liver function tests, creatinine kinase, albumin, protein •  TORCH, viral culture •  Specialized testing guided by results of prenatal work-up Neonatal / fetal demise •  Clinical pictures •  Fetal cells culture (skin, others) •  Freeze fetal tissues and AF supernatant •  Bank fetal DNA •  Skeletal survey •  Placental pathology • Autopsy10

928 l OCTOBER JOGC OCTOBRE 2013

Investigation and Management of Non-immune Fetal Hydrops

quantitative measure of heart failure. Specific questions may be addressed through arterial and venous Doppler ultrasound in conjunction with fetal echocardiogram.43

finding should not be considered a final diagnosis in and of itself. A careful search for underlying maternal illness or single-gene disorder is indicated.

Doppler Ultrasound

Enlargement of the cardiac chambers is a common sign of heart failure.50 The right atrium is the final pathway for venous return and frequently shows enlargement in situations of relative foramen obstruction, volume overload, tricuspid valve regurgitation, and increased afterload. Normally, the ratio of the cardiac circumference over the thoracic circumference at the level of the 4-chamber view should be less than 0.5.51

The measurement of MCA peak systolic velocity to assess fetal anemia is essential to the management of fetuses with NIHF. After 16 weeks of gestation, there is a significant association between delta-MCA peak flow and delta hemoglobin concentration, especially when the fetal Hb concentration is very low.44 A peak systolic above 1.5 multiples of the median has a 100% (95% CI 86 to 100%) sensitivity for detecting fetal anemia from various causes.4,45 An abnormal ductus venosus waveform helps both to identify a fetus at risk for cardiac anomalies and to predict prognosis.46 In a group of fetuses with congenital heart defects and hydrops, abnormal hepatic vein and ductus venosus blood velocities, along with umbilical venous pulsations were strongly associated with mortality.47 The most useful predictor of perinatal death in fetal hydrops is the presence of umbilical venous pulsations, because the most common pathway of perinatal demise is fetal congestive heart failure.43 Arterial Doppler is an indicator of the redistribution of fetal cardiac output affecting the blood flow in the descending aorta and in the UA. Absent or reversed end diastolic flow in the umbilical artery reflects elevated placental resistance. Absent end diastolic flow is common in non-survivors, and often associated with increased cardiac afterload.47 Changes in UA Doppler appear later than venous Doppler and cardiac function alterations. Fetal Echocardiogram

Fetal echocardiogram is used to assess cardiac anatomy and function. Congenital cardiac malformations are common with an underlying genetic syndrome or a chromosome anomaly. Depending on the type of the cardiac malformation, a syndromic differential diagnosis should be considered and investigated.48 Cardiac arrhythmia may be primary or may occur secondary to a systemic etiology such as hyperthyroidism or in mothers with autoimmune conditions associated with high titres of circulating anti–SS-A or anti–SS-B antibodies.49,50 The two most common important fetal arrhythmias are supra­ ventricular tachyarrythmias and severe bradyarrhythmias associated with complete heart block.50 Finally, congestive heart failure may be secondary to other systemic causes that need to be evaluated. In fact, when identifying a cardiac component in the context of NIHF, this important

Recommendation

3. Imaging studies should include comprehensive obstetrical ultrasound (including arterial and venous fetal Doppler) and fetal echocardiography. (II-2A) Search for Fetal Infections

This section describes the different laboratory tests for infectious disorders that may present as fetal hydrops, mainly to review the limitations of these tests. Tests need to be prioritized as shown in the algorithm presented in Table 4. Fetal ultrasound may reveal a pattern of findings typical of a particular infectious agent. Laboratory methods for the assessment of viral infections are in two categories: serology and virus or parasite detection.52 Serology is very sensitive but often cannot conclusively determine the time of infection, which may be critical for risk assessment. Traditional serological tests, which measure antibody levels including immunoglobulin M and immunoglobulin G, usually require two samples separated by a significant time period for determination of seroconversion or a substantial rise in titre.52 IgM identification is more indicative than IgG of a recent infection; however, IgM may persist several months or even years in some cases. IgM can also be negative at the time of fetal hydrops if the seroconversion occurred several weeks earlier. Various tests may distinguish between IgG and IgM and may allow diagnosis in one serum sample, but biological and technical difficulties are common and may cause false-positive and false-negative results.53 Maternal toxoplasmosis, rubella, cytomegalovirus, herpes simplex, and parvovirus B19 serologies are commonly searched for suspicion of fetal infection. A study of 476 patients in the United Kingdom found that, among TORCH agents, only CMV was commonly found as a cause of fetal ultrasound findings.54 The archived serum from routine first-trimester baseline tests is very useful, OCTOBER JOGC OCTOBRE 2013 l 929

SOGC Clinical Practice Guideline

when available, to establish prior immune status and to document seroconversion. Testing for rare infectious diseases (syphilis, enterovirus) may be considered in particular clinical situations (ultrasound findings, HIV positive mother, clinical symptoms). Parvovirus B19

Infection during pregnancy may affect the fetus, resulting in hydrops or fetal demise.55 The predominant ultrasound feature in fetuses infected by Parvovirus B19 is ascites,44 sometimes associated with poorly contractile echogenic myocardium. Early diagnosis of maternal infection will allow fetal assessment and treatment by intrauterine blood transfusion. Unfortunately, mothers are often unaware of their infection until fetal signs are observed. Confirmation of B19 infection requires laboratory assessment, which is complicated by the nature of the viral infection and immune response. Serology, using enzyme-linked immunosorbent assays, relies on recombinant antigens, and concordance is low among all commercial assays available. In the absence of a “gold standard” assay, false positive and false negative results prevail. Furthermore, maternal IgM may have dropped below the detection limit by the time fetal hydrops is identified.56 Viral culture is difficult and virus detection is based on various molecular assays. In spite of several studies there is no consensus regarding the most appropriate clinical specimen and method for detection of viral DNA. Currently, on practical grounds, it is recommended to use ELISA IgM and IgG assays based on recombinant conformational epitopes of polyomavirus capsid proteins 1 and 2 or polyomavirus capsid protein 2 alone, and to use amniotic fluid or fetal serum for detection of fetal infection by the most sensitive molecular methods available (nested PCR or RT-PCR).56 Recommendations for evaluation and treatment of parvovirus infection during pregnancy have been published by the SOGC Maternal–Fetal Medicine and Infectious Diseases Committees.57 Rubella

If the patient is not immune to rubella, serial IgG and IgM titres should be done. If congenital rubella is strongly suspected, amniotic fluid culture or fetal blood sampling for IgM determination is indicated as infection leads to severe fetal morbidity. Postnatal determination is achieved through evaluation of IgG and IgM levels, along with viral isolation. Cytomegalovirus

CMV is excreted in the urine of the infected fetus, so detection of the virus in AF has proven to be a highly sensitive and reliable method.58 Numerous studies have 930 l OCTOBER JOGC OCTOBRE 2013

focused on the most appropriate timing for performing amniocentesis to yield the best sensitivity for detection of fetal infection. These studies clearly indicated that AF should be collected after 21 gestational weeks and after at least 6 weeks maternal infection. Most studies state that the timing of amniocentesis is more critical for sensitivity in detecting the virus in AF than the laboratory methods used. If invasive testing is performed, PCR is the preferred method for detection of CMV in amniotic fluid. Problems with molecular contamination (false positive results) and the need to address prognostic issues led to the development of quantitative PCR assays; the highly advanced real-time PCR is the most up-to-date method.58,59 Laboratory testing to determinate intrauterine CMV infection involves several steps that should be done simultaneously in fetal hydrops. Maternal primary or recurrent infection is assessed by serology using IgM, IgG, and IgG-avidity assays. A second blood sample should be sought to demonstrate antibody kinetics typical of the current infection and not of a remote infection or a non-specific reaction. If maternal primary infection has been established and the pregnancy continues, prenatal diagnosis follows at 21 to 23 weeks gestation or at 6 to 9 weeks after seroconversion (if known). Detection of CMV in AF is achieved by virus culturing and/or PCR. Quantitative PCR in the amniotic fluid can determine the viral load and could be useful for the assessment of fetal impact and prognosis, although the clinical value of this test is still under investigation.60 Further information on CMV infection in pregnancy is available in a previously published SOGC guideline.58 Varicella-zoster virus

VZV is rarely found as a cause of fetal hydrops.61 The primary tool for assessing maternal infection is isolation of the virus from maternal lesions. Type-specific IgG assays must be applied to determine recurrent maternal infections. Antigen detection or DNA detection by PCR in skin lesion samples are additional tools for the rapid and sensitive diagnosis of symptomatic current infection. Prenatal diagnosis can be performed by PCR detection of the virus in AF, but false negative results are common and positive results do not necessarily correlate with fetal damage.62 Neonatal infection is diagnosed by virus culture or PCR in skin lesions or other clinical specimens in case of a disseminated form. Other viral infections

A few studies report fetuses with NIHF caused by various subtypes of Coxsackie virus and adenovirus identified through targeted PCR amplification in affected fetal tissues.19,63

Investigation and Management of Non-immune Fetal Hydrops

Testing for Alpha-thalassemia

The most severe form of alpha-thalassemia is called Bart’s disease.64 The absence of normal copies of alphahemoglobin genes in a fetus causes severe anemia leading to hydrops during fetal life.64 This autosomal recessive condition occurs at a higher frequency in some ethnic groups such as Mediterranean, African, and South-East Asian populations.64 From a practical point of view in Canada, one can take the approach that any patient who is not Japanese, Korean, Caucasian of Northern European ancestry, First Nations, or Inuit should be screened.64 Carriers are suspected on the basis of the presence of low red blood cell volume (microcytosis) with normal ferritin. HbH bodies identified on blood smear examination are characteristic of alpha-thalassemia carrier status. Even in the absence of HbH bodies, when microcytosis is present, molecular testing should be performed in both parents to look for the frequent deletion and rarer point mutations. In cases suspected of alpha-thalassemia, MCA Doppler should be done to confirm anemia. When anemia is suspected, it should be confirmed by fetal blood sampling for rapid initiation of treatment (intrauterine transfusion). The diagnosis should be further confirmed by fetal DNA testing through amniocentesis or placental biopsy.64 If fetal blood is taken by cordocentesis, Hb Bart’s can be identified. When confirmed, parents should be informed of the poor prognosis and counselled about the 25% recurrence risk and the availability of invasive prenatal diagnosis for future pregnancies. Intrauterine transfusion in affected fetuses has been reported with various results.65 Invasive Investigation

Fetal karyotyping and genetic microarray molecular testing should be conducted in all cases of unexplained NIHF. Cytogenetic laboratories can provide a preliminary result of the fetal karyotype within 24 to 48 hours using QF-PCR or FISH techniques (amniotic fluid), direct analysis (placental biopsy), or conventional karyotyping (fetal blood). Amniotic fluid should also be obtained for viral and bacterial cultures, viral/parasitic-specific PCR studies, and karyotyping. In selected cases, the supernatant can be used for biochemical studies.34,66 Amniotic cells should be kept in culture for future studies and DNA extraction or frozen for later analysis. Fetal blood sampling to determine fetal hemoglobin levels may be performed under the following circumstances: MCA Doppler results suggestive of fetal anemia, documented parvovirus B19 seroconversion,

parental microcytic anemia from at risk-ethnicity, and documented fetal bleeding. Baseline studies to consider on fetal blood sampling include CBC, platelets, direct Coombs’ test, blood group, karyotype, TORCH/ parvovirus B19 (IgM), and albumin. If fetal anemia is strongly suspected, O-negative CMV-negative maternally cross-matched blood should be ready for transfusion. In specific situations (positive family history, recurring hydrops), targeted metabolic investigations may also be performed. For example, fetal blood sample was used to diagnose a congenital disorder of glycosylation type Ia in a 27-week fetus with NIHF.67 The fetal loss rate after cordocentesis was 11.32% in a group of hydropic fetuses, probably due in part to the high loss rate associated with hydrops itself.68 Specific enzyme assays are available to test for lysosomal storage disorders on cultured amniocytes (N-acetylglalactosamine-6S-sulfatase, beta-glucoronidase, beta-galactosidase, beta-glucosidase, alpha-iduronidase, a-D-neuraminidase, sphigomyelinase) or specific metabolite measurement in amniotic fluid supernatant (total hexosaminidase, betaglucoronidase, alpha-mannosidase, chitotriosidase).41,42 These assays must be performed by a specialized biochemical genetics laboratory. The recommended metabolic investigation for unexplained fetal hydrops is shown in Table 5. The laboratory should be informed of the need to keep frozen supernatant and amniotic cells for future studies. Diagnosing a metabolic disorder as the causal factor for NIHF is important because these single-gene disorders carry a 25% recurrence risk. Their identification may allow for prenatal diagnosis at an earlier stage in future pregnancies.26,41 Prenatal diagnosis of such conditions also facilitates postnatal management. Fetal cavity aspiration may be used as a diagnostic and therapeutic measure. A lymphocyte count (pleural effusion, cystic hygroma), biochemical studies, protein/albumin determination, histology, and viral and bacterial cultures are indicated.26,41 Recommendations

4. Investigation for maternal–fetal infections, and alpha-thalassemia in women at risk because of their ethnicity, should be performed in all cases of unexplained fetal hydrops. (II-2A) 5. To evaluate the risk of fetal anemia, Doppler measurement of the middle cerebral artery peak systolic velocity should be performed in all hydropic fetuses after 16 weeks of gestation. In case of suspected fetal anemia, fetal blood sampling and intrauterine transfusion should be offered rapidly. (II-2A)

OCTOBER JOGC OCTOBRE 2013 l 931

SOGC Clinical Practice Guideline

Table 5. Lysosomal enzymatic assays used for NIHF a.

Beta-galactosidase (GM1)

b.

Beta-glucuronidase (MPS VII)

c.

Beta-glucosidase (Gaucher)

d.

Neuraminidase (sialidose)

e.

Beta-galactosidase and neuraminidase (galactosialidose)

f.

Sphyngomyelinase (Niemann-Pick A and B)

g.

Mucolipidosis type II

PROGNOSIS

NIHF from all causes has a high mortality rate. Fetal chromosomal anomaly, gestational age < 24 weeks and fetal structural anomalies other than chylothorax are indicators of a poor prognosis. However, fetal treatment has significantly improved survival in selected cases. When a pregnancy is continued with known fetal hydrops, the occurrence of maternal “mirror” syndrome should be carefully monitored. Mirror syndrome, also referred to as Ballantyne’s syndrome, is defined as the development of maternal edema secondary to fetal hydrops.21,69 Severe preeclampsia is usually associated with the syndrome. Because the maternal prognosis can be poor, the option of continuing a pregnancy with fetal hydrops should be carefully discussed. Excluding chromosomal abnormalities, the survival rate of NIHF is about 31% to 48%.7 Most of the causes, a large proportion of which are lethal disorders, respond poorly to therapy. Without treatment the prognosis is generally poor, except in the rare case of spontaneous resolution of parvovirus B19 infection.70 In a series of 38 cases of NIHF, Negishi et al. reported a 23% survival rate in the treatment group.30 The presence of a chromosomal anomaly, along with an earlier age at detection of NIHF, was associated with a poorer outcome. In a series of 30 cases of NIHF diagnosed between 10 and 14 weeks of gestation, all cases resulted in spontaneous abortion, intrauterine fetal death, or pregnancy termination.23 In another series of 45 cases diagnosed between 11 and 17 weeks, only 2 resulted in a normal outcome.71 McCoy et al. reported a survival rate of < 5% for infants with hydrops diagnosed before 24 weeks of gestation and 20% survival for infants diagnosed after 24 weeks of gestation.19 In a report on 23 women with NIHF, termination of pregnancy was performed for 10 chromosomal and 5 structural abnormalities, and there was one intrauterine 932 l OCTOBER JOGC OCTOBRE 2013

fetal death.72 One baby with diaphragmatic hernia died in the neonatal period from pulmonary hypoplasia despite reversal of hydrops by in utero shunting, and one baby with treated polyhydramnios was born at 30 weeks and died on day 5. The remaining 5 cases, in which structural and chromosomal abnormalities were excluded, had fetal therapy between 22 and 32 weeks’ gestation (4 shunt insertions, 1 blood transfusion) and in all the hydrops reversed and the pregnancy continued to at least 35 weeks’ gestation. All 5 neonates were discharged from hospital alive and well. Fetal therapy in cases of NIHF with normal structure and karyotype was associated with a very good outcome.72 Two recent studies address the issues of postnatal survival in live-born neonates with hydrops. Data from a large national database73 reveals that mortality rates were highest among neonates with congenital anomalies (57.7%) and lowest among neonates with congenital chylothorax (5.9%). Factors associated with death were younger gestational age, low 5-minute Apgar score, and need for high levels of during the first 24 hours of life (high oxygen needs and high-frequency ventilation). Of the 597 neonates included in the study, 115 were transferred from another hospital, 215 died before discharge, and 267 were discharged from the hospital.73 Huang et al. reported a 50% survival rate in a group of 28 live-born neonates with NIHF.74 The survival rate was 83% in infants with lymphatic malformations. Preterm birth at less than 34 weeks and low serum albumin concentration were two poor prognostic factors for survival.74 Few studies have examined the long-term outcome of NIHF identified prenatally. Breur et al. reported normal neurodevelopmental outcomes in 5 children who presented with fetal heart block and hydrops fetalis. In his series of 10 fetuses, 3 died in utero, 2 died from dilated cardiomyopathy at age 9 months and 4 years, and 5 survived.75 These results demonstrate that the prognosis of NIHF differs markedly between different etiological groups. It is essential to attempt to identify the etiology to better predict prognosis, offer prenatal treatment when available, and deliver in a tertiary perinatal care centre to improve postnatal outcome. Recommendation

6. All cases of unexplained fetal hydrops should be referred to a medical genetics service where available. Detailed postnatal evaluation by a medical geneticist should be performed on all cases of newborns with unexplained non-immune hydrops. (II-2A)

Investigation and Management of Non-immune Fetal Hydrops

Table 6. Fetal therapies for non-immune hydrops 1.

Intrauterine transfusion for anemia –  Maternal acquired pure red cell aplasia –  Maternal fetal hemorrhage –  Fetal hemolysis (G6PD) –  Fetal parvovirus infection

2.

Repeated centesis or shunt insertion –  Pleural effusion – Ascitis –  Thoracic cystic lesions –  Congenital cystic adenomatoid malformation –  Pulmonary sequestration –  Pulmonary lymphangiectasia

3.

Intravascular or maternal treatment with anti-arrhythmic drugs –  Fetal tachyarrythmia –  Atrioventricular block (anti–SS-A/SS-B)

4.

Fetal procedures: open fetal surgery or laser vessel ablation/radio frequency ablation –  Congenital cystic adenomatoid malformation – Sequestration –  Sacrococcygeal teratoma –  Twin-to-twin transfusion syndrome (stage IV)

5.

Others –  Antithyroid drugs (fetal thyrotoxicosis)

PERINATAL MANAGEMENT Fetal Treatment

Fetal hydrops is a medical emergency that mandates urgent referral to a maternal–fetal medicine specialist and a medical geneticist for rapid evaluation. The hydropic fetus is usually in a precarious state and even minimal delays may prevent access to life-saving procedures. Fetal treatment options for NIHF depend on the etiology and the gestational age at diagnosis. A maternal–fetal specialist should undertake this evaluation. Options available consist of: 1. intrauterine transfusion for anemia, 2. repeated centesis or shunt insertion for pleural effusion, ascites, or thoracic cystic lesions, 3. intravascular or maternal treatment with antiarrhythmic drugs to treat fetal tachyarrythmia, in close collaboration with cardiologists, 4. laser surgery for severe and early twin-to-twin transfusion syndrome with hydrops (stage IV), and 5. open fetal surgery where available, or laser or radiofrequency ablation for major structural anomalies associated with NIHF (Table 6).

Fetuses diagnosed with a treatable cause of NIHF should be delivered in a tertiary care centre with prenatal consultation with appropriate subspecialties including maternal– fetal medicine specialists, geneticists, neonatologists, and pediatric surgeons. Antenatal consultation allows for parental counselling, adequate preparation of the resuscitation team, and planning of specialized equipment required in the delivery room. Pre-delivery cavity aspiration (pleural effusions, severe ascitis, severe polyhydramnios) by the perinatologist may facilitate neonatal management and reduce maternal complications. Postnatal therapy begins with vigorous resuscitation including thoracocentesis and/ or paracentesis to establish adequate lung expansion; this is followed by efforts to determine the cause and correct the condition responsible for the hydrops. Once the neonate is stabilized, a detailed physical examination, cardiac monitoring, chest radiograph, and ultrasound examinations (head, cardiac, and abdominal) are performed. Additional testing is guided by the investigation initiated antenatally.5 Postmortem Evaluation (Fetus and Placenta)

It is mandatory to continue the investigation after the death of the fetus or newborn with NIHF. Referral to a genetic service should be made to plan for additional investigation. Clinical photography and fetal X-rays should be obtained OCTOBER JOGC OCTOBRE 2013 l 933

SOGC Clinical Practice Guideline

to evaluate possible dysmorphic syndrome or skeletal dysplasia. Autopsy should be strongly recommended, at least for non-chromosomal cases.10,76 Storage of fetal blood, tissue, DNA, and amniotic fluid supernatant should be collected in the appropriate tube and setting (i.e. frozen at –70˚C). The preservation of a potentially dividing fetal cell line (amniocytes, skin biopsy) is indicated for future biochemical or molecular genetic testing. Extensive sampling from various sources is necessary to test for tissue-specific enzymatic activity or gene expression. Placental examination (microscopy, histopathology) focusing on tumours, fetal anemia, infection, and metabolic disorder is indicated.77 Recommendation

7. Autopsy should be recommended in all cases of fetal or neonatal death or pregnancy termination. (II-2A) Amniotic fluid and/or fetal cells should be stored for future genetic testing. (II-2B) CONCLUSION

The prognosis of NIHF differs markedly between different etiological groups. Recent progress in prenatal genetics and maternal–fetal medicine provides us with newer tools to identify the underlying etiology. Prompt access to maternal–fetal medicine units for fetal evaluation and treatment has improved outcomes. It is essential to attempt to identify the etiology to better predict prognosis, offer treatment when appropriate, and assess recurrence risk to plan for the management of future pregnancies. REFERENCES 1. Machin GA. Hydrops revisited: literature review of 1,414 cases published in the 1980s. Am J Med Gen A 1989;34:366–90. 2. Machin GA. Hydrops, cystic hygroma, hydrothorax, pericardial effusion and fetal ascites. In: Gilbert-Barness E, ed. Potter’s pathology of the fetus and infant. St-Louis: Mosby; 1997. 3. Fung Kee Fung K, Eason E, Crane J, Armson A, De La Ronde S, Farine D, et al; SOGC Maternal-Fetal Medicine Committee; SOGC Genetics Committee. Prevention of Rh alloimmunization. SOGC Clinical Practice Guidelines, No. 133, September 2003. J Obstet Gynaecol Can 2003;25:765–73. 4. Mari G, Deter RL, Carpenter RL, Rahman F, Zimmerman R, Moise KJ Jr, et al. Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell alloimmunization. Collaborative Group for Doppler Assessment of the Blood Velocity in Anemic Fetuses. N Engl J Med 2000;342:9–14. 5. Hansen T. Non immune hydrops fetalis. In: Rudolph A, Kamei R, Overby K, eds. Rudolph’s pediatrics. 21st ed. New York: McGraw-Hill; 2003. 6. Ismail KM, Martin WL, Ghosh S, Whittle MJ, Kilby MD. Etiology and outcome of hydrops fetalis. J Matern Fetal Med 2001;10:175–81. 7. Milunsky A. Genetic disorders of the fetus: diagnosis, prevention and treatment. 5th ed. Baltimore: John Hopkins University Press; 2004.

934 l OCTOBER JOGC OCTOBRE 2013

8. Kharrat R, Yamamoto M, Roume J, Couderc S, Vialard F, Hillion Y, et al. Karyotype and outcome of fetuses diagnosed with cystic hygroma in the first trimester in relation to nuchal translucency thickness. Prenat Diagn 2006;26:369–72. 9. Molina FS, Avgidou K, Kagan KO, Poggi S, Nicolaides KH. Cystic hygromas, nuchal edema, and nuchal translucency at 11-14 weeks of gestation. Obstet Gynecol 2006;107:678–83. 10. Desilets V, Oligny LL; Genetics Committee of the Society of Obstetricians and Gynaecology Canada; Family Physicians Advisory Committee; Medico–Legal Committee of the SOGC. Fetal and perinatal autopsy in prenatally diagnosed fetal abnormalities with normal karyotype. SOGC Clinical Practice Guidelines, No. 267, October 2011. J Obstet Gynaecol Can 2011;33:1047–57. 11. Gagnon A, Wilson RD, Allen VM, Audibert F, Blight C, Brock JA, et al.; Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada. Evaluation of prenatally diagnosed structural congenital anomalies. SOGC Clinical Practice Guidelines, No. 234, September 2009. J Obstet Gynaecol Can 2009;31:875–81. 12. Chitayat D, Langlois S, Wilson RD; Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada; Prenatal Diagnosis Committee of the Canadian College of Medical Geneticists. Prenatal screening for fetal aneuploidy in singleton pregnancies. SOGC Clinical Practice Guidelines, No. 261, July 2011. J Obstet Gynaecol Can 2011;33:736–50. 13. Morin L, Lim K; SOGC Diagnostic Imaging Committee. Ultrasound in twin pregnancies. SOGC Clinical Practice Guidelines, No. 260, June 2011. J Obstet Gynaecol Can 2011;33:643–56. 14. Senat MV, Deprest J, Boulvain M, Paupe A, Winer N, Ville Y. Endoscopic laser surgery versus serial amnioreduction for severe twin-to-twin transfusion syndrome. N Engl J Med 2004;351:136–44. 15. Yamamoto M, Ville Y. Twin-to-twin transfusion syndrome: management options and outcomes. Clin Obstet Gynecol 2005;48:973–80. 16. Chalouhi GE, Stirnemann JJ, Salomon LJ, Essaoui M, Quibel T, Ville Y. Specific complications of monochorionic twin pregnancies: twin-twin transfusion syndrome and twin reversed arterial perfusion sequence. Semin Fetal Neonatal Med 2010;15:349–56. 17. Audibert F, Gagnon A; SOGC Genetics Committee; Prenatal Diagnosis Committee of the Canadian College of Medical Geneticists. Prenatal screening for and diagnosis of aneuploidy in twin pregnancies. SOGC Clinical Practice Guidelines, No. 262, July 2011. J Obstet Gynaecol Can 2011;33:754–67. 18. Bellini C, Hennekam RC, Bonioli E. A diagnostic flow chart for non-immune hydrops fetalis. Am J Med Genet A 2009;149A:852–3. 19. McCoy MC, Katz VL, Gould N, Kuller JA. Non-immune hydrops after 20 weeks’ gestation: review of 10 years’ experience with suggestions for management. Obstet Gynecol 1995;85:578–82. 20. Santo S, Mansour S, Thilaganathan B, Homfray T, Papageorghiou A, Calvert S, et al. Prenatal diagnosis of non-immune hydrops fetalis: what do we tell the parents? Prenat Diagn 2011;31:186–95. 21. Braun T, Brauer M, Fuchs I, Czernik C, Dudenhausen JW, Henrich W, et al. Mirror syndrome: a systematic review of fetal associated conditions, maternal presentation and perinatal outcome. Fetal Diagn Therapy 2010;27:191–203. 22. Jauniaux E, Van Maldergem L, De Munter C, Moscoso G, Gillerot Y. Nonimmune hydrops fetalis associated with genetic abnormalities. Obstet Gynecol 1990;75:568–72. 23. Has R. Non-immune hydrops fetalis in the first trimester: a review of 30 cases. Clin Exp Obstet Gynecol 2001;28:187–90. 24. Wapner RJ, Driscoll DA, Simpson JL. Integration of microarray technology into prenatal diagnosis: counselling issues generated during the NICHD clinical trial. Prenat Diagn 2012;32:396–400.

Investigation and Management of Non-immune Fetal Hydrops

25. Knilans TK. Cardiac abnormalities associated with hydrops fetalis. Semin Perinatol 1995;19:483–92. 26. Bellini C, Hennekam RC. Non-immune hydrops fetalis: a short review of etiology and pathophysiology. Am J Med Genet A 2012;158A:597–605. 27. de Jong EP, Walther FJ, Kroes AC, Oepkes D. Parvovirus B19 infection in pregnancy: new insights and management. Prenat Diagn 2011;31:419–25. 28. Crino JP. Ultrasound and fetal diagnosis of perinatal infection. Clin Obstet Gynecol 1999;42:71–80; quiz 174–5. 29. Liao C, Xie XM, Li DZ. Two cases of homozygous alpha0-thalassemia diagnosed prenatally in pregnancies at risk for beta-thalassemia in China. Ultrasound Obstet Gynecol 2007;29:474–5. 30. Negishi H, Yamada H, Okuyama K, Sagawa T, Makinoda S, Fujimoto S. Outcome of non-immune hydrops fetalis and a fetus with hydrothorax and/or ascites: with some trials of intrauterine treatment. J Perinat Med 1997;25:71–7. 31. Yong PJ, von Dadelszen P, Carpara D, Lim K, Kent N, Tessier F, et al. Prediction of pediatric outcome after prenatal diagnosis and expectant antenatal management of congenital cystic adenomatoid malformation. Fetal Diagn Ther 2012;31:94–102. 32. Isaacs H Jr. Fetal hydrops associated with tumors. Am J Perinatol 2008;25:43–68. 33. Norton ME. Nonimmune hydrops fetalis. Semin Perinatol 1994;18:321–32. 34. Kooper AJ, Janssens PM, de Groot AN, Liebrand-van Sambeek ML, van den Berg CJ, Tan-Sindhunata GB, et al. Lysosomal storage diseases in non-immune hydrops fetalis pregnancies. Clin Chim Acta 2006;371:176–82. 35. Gort L, Granell MR, Fernandez G, Carreto P, Sanchez A, Coll MJ. Fast protocol for the diagnosis of lysosomal diseases in nonimmune hydrops fetalis. Prenat Diagn 2012;32:1139–42. 36. L’Hermine-Coulomb A, Beuzen F, Bouvier R, Rolland MO, Froissart R, Menez F, et al. Fetal type IV glycogen storage disease: clinical, enzymatic, and genetic data of a pure muscular form with variable and early antenatal manifestations in the same family. Am J Med Genet A 2005;139A:118–22. 37. Venkat-Raman N, Sebire NJ, Murphy KW. Recurrent fetal hydrops due to mucopolysaccharidoses type VII. Fetal Diagn Ther 2006;21:250–4. 38. Carvalho S, Martins M, Fortuna A, Ramos U, Ramos C, Rodrigues MC. Galactosialidosis presenting as nonimmune fetal hydrops: a case report. Prenat Diagn 2009;29:895–6. 39. Saudubray J, Van der Berghe G, Walter J. Inborn metabolic diseases: diagnosis and treatment. Berlin: Springer-Verlag; 2007. 40. Valayannopoulos V, Verhoeven NM, Mention K, Salomons GS, Sommelet D, Gonzales M, et al. Transaldolase deficiency: a new cause of hydrops fetalis and neonatal multi-organ disease. J Pediatr 2006;149:713–7. 41. Burin MG, Scholz AP, Gus R, Sanseverino MT, Fritsh A, Magalhães JA, et al. Investigation of lysosomal storage diseases in nonimmune hydrops fetalis. Prenat Diagn 2004;24:653–7. 42. Stone DL, Sidransky E. Hydrops fetalis: lysosomal storage disorders in extremis. Adv Pediatr 1999;46:409–40. 43. Huhta JC. Guidelines for the evaluation of heart failure in the fetus with or without hydrops. Pediatr Cardiol 2004;25:274–86. 44. Hernandez-Andrade E, Scheier M, Dezerega V, Carmo A, Nicolaides KH. Fetal middle cerebral artery peak systolic velocity in the investigation of non-immune hydrops. Ultrasound Obstet Gynecol 2004;23:442–5. 45. Mari G. Middle cerebral artery peak systolic velocity for the diagnosis of fetal anemia: the untold story. Ultrasound Obstet Gynecol 2005;25:323–30.

46. Cosmi E, Dessole S, Uras L, Capobianco G, D’Antona D, Andrisani A, et al. Middle cerebral artery peak systolic and ductus venosus velocity waveforms in the hydropic fetus. J Ultrasound Med 2005;24:209–13. 47. Hofstaetter C, Hansmann M, Eik-Nes SH, Huhta JC, Luther SL. A cardiovascular profile score in the surveillance of fetal hydrops. J Matern Fetal Neonatal Med 2006;19:407–13. 48. Pajkrt E, Weisz B, Firth HV, Chitty LS. Fetal cardiac anomalies and genetic syndromes. Prenat Diagn 2004;24:1104–15. 49. Eliasson H, Sonesson SE, Sharland G, Granath F, Simpson JM, Carvalho JS, et al.; Fetal Working Group of the European Association of Pediatric Cardiology. Isolated atrioventricular block in the fetus: a retrospective, multinational, multicenter study of 175 patients. Circulation 2011;124:1919–26. 50. Fouron JC. Fetal arrhythmias: the Saint-Justine hospital experience. Prenat Diagn 2004;24:1068–80. 51. Berg C, Geipel A, Kohl T, Breuer J, Germer U, Krapp M, et al. Atrioventricular block detected in fetal life: associated anomalies and potential prognostic markers. Ultrasound Obstet Gynecol 2005;26:4–15. 52. Klein JO, Baker CJ, Remington JS, Wilson CB. Current concepts of infections of the fetus and newborn infant. In: Remington JS, Klein JO, Wilson CB, Baker CJ, eds. Infectious diseases of the fetus and newborn infant. Philadelphia: Elsevier Saunders; 2006: pp. 3–25. 53. Mendelson E, Aboudy Y, Smetana Z, Tepperberg M, Grossman Z. Laboratory assessment and diagnosis of congenital viral infections: rubella, cytomegalovirus (CMV), varicella-zoster virus (VZV), herpes simplex virus (HSV), parvovirus B19 and human immunodeficiency virus (HIV). Reprod Toxicol 2006;21:350–82. 54. Abdel-Fattah SA, Bhat A, Illanes S, Bartha JL, Carrington D. TORCH test for fetal medicine indications: only CMV is necessary in the United Kingdom. Prenat Diagnosis 2005;25:1028–31. 55. Enders M, Weidner A, Zoellner I, Searle K, Enders G. Fetal morbidity and mortality after acute human parvovirus B19 infection in pregnancy: prospective evaluation of 1018 cases. Prenat Diagn 2004;24:513–8. 56. Enders M, Schalasta G, Baisch C, Weidner A, Pukkila L, Kaikkonen L, et al. Human parvovirus B19 infection during pregnancy--value of modern molecular and serological diagnostics. J Clin Virol 2006;35:400–6. 57. Crane J.; SOGC Fetal Medicine Committee. Parvovirus B19 infection in pregnancy. SOGC Clinical Practice Guidelines, No. 119, September 2002. J Obstet Gynaecol Can 2002;24:727–43; quiz 44–6. 58. Yinon Y, Farine D, Yudin MH, Gagnon R, Hudon L, Basso M, et al. SOGC Fetal Medicine Committee. Cytomegalovirus infection in pregnancy. SOGC Clinical Practice Guidelines, No. 240, April 2010. J Obstet Gynaecol Can 2010;32:348–54. 59. Yinon Y, Farine D, Yudin MH. Screening, diagnosis, and management of cytomegalovirus infection in pregnancy. Obstet Gynecol Surv 2010;65:736–43. 60. Lazzarotto T, Gabrielli L, Foschini MP, Lanari M, Guerra B, Eusebi V, et al. Congenital cytomegalovirus infection in twin pregnancies: viral load in the amniotic fluid and pregnancy outcome. Pediatrics 2003;112:e153–e157. 61. Harger JH, Ernest JM, Thurnau GR, Moawad A, Thom E, Landon MB, et al.; National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. Frequency of congenital varicella syndrome in a prospective cohort of 347 pregnant women. Obstet Gynecol 2002;100:260–5. 62. Mouly F, Mirlesse V, Meritet JF, Rozenberg F, Poissonier MH, Lebon P, et al. Prenatal diagnosis of fetal varicella-zoster virus infection with polymerase chain reaction of amniotic fluid in 107 cases. Am J Obstet Gynecol 1997;177:894–8.

OCTOBER JOGC OCTOBRE 2013 l 935

SOGC Clinical Practice Guideline

63. Bachmaier N, Fusch C, Stenger RD, Grabow D, Mentel R, Warzok R. Nonimmune hydrops fetalis due to enterovirus infection. Eur Jour Obstet Gynecol Reprod Biol 2009;142:83–4.

70. Kelly T, Mathers A. Early presentation and spontaneous resolution of hydrops fetalis, secondary to parvovirus B19 infection. J Obstet Gynaecol 1998;18:190–1.

64. Langlois S, Ford JC, Chitayat D, Désilets VA, Farrell SA, Geraghty M, et al.; CCMG Prenatal Diagnosis Committee; SOGC Genetics Committee. Carrier screening for thalassemia and hemoglobinopathies in Canada. J Obstet Gynaecol Can 2008;30:950–71.

71. Iskaros J, Jauniaux E, Rodeck C. Outcome of nonimmune hydrops fetalis diagnosed during the first half of pregnancy. Obstet Gynecol 1997;90:321–5.

65. Dwinnell SJ, Coad S, Butler B, Albersheim S, Wadsworth LD, Wu JK, et al. In Utero diagnosis and management of a fetus with homozygous α-Thalassemia in the second trimester: a case report and literature review. J Pediatr Hematol Oncol 2011;33:e358–e360. 66. Ramsay SL, Maire I, Bindloss C, Fuller M, Whitfield PD, Piraud M, et al. Determination of oligosaccharides and glycolipids in amniotic fluid by electrospray ionisation tandem mass spectrometry: in utero indicators of lysosomal storage diseases. Mol Genet Metab 2004;83:231–8. 67. Edwards M, McKenzie F, O’Callaghan S, Somerset D, Woodford P, Spilsbury J, et al. Prenatal diagnosis of congenital disorder of glycosylation type Ia (CDG-Ia) by cordocentesis and transferrin isoelectric focussing of serum of a 27-week fetus with non-immune hydrops. Prenat Diagn 2006;26:985–8. 68. Acar A, Balci O, Gezginc K, Onder C, Capar M, Zamani A, et al. Evaluation of the results of cordocentesis. Taiwan J Obstet Gynecol 2007;46:405–9. 69. Gedikbasi A, Oztarhan K, Gunenc Z, Yildirim G, Arslan O, Yildirim D, et al. Preeclampsia due to fetal non-immune hydrops: mirror syndrome and review of literature. Hypertens Pregnancy 2011;30:322–30.

936 l OCTOBER JOGC OCTOBRE 2013

72. Ayida GA, Soothill PW, Rodeck CH. Survival in non-immune hydrops fetalis without malformation or chromosomal abnormalities after invasive treatment. Fetal Diagn Ther 1995;10:101–5. 73. Abrams ME, Meredith KS, Kinnard P, Clark RH. Hydrops fetalis: a retrospective review of cases reported to a large national database and identification of risk factors associated with death. Pediatrics 2007;120:84–9. 74. Huang HR, Tsay PK, Chiang MC, Lien R, Chou YH. Prognostic factors and clinical features in liveborn neonates with hydrops fetalis. Am J Perinatol 2007;24:33–8. 75. Breur JM, Gooskens RH, Kapusta L, Stoutenbeek P, Visser GH, van den Berg P, et al. Neurological outcome in isolated congenital heart block and hydrops fetalis. Fetal Diagn Ther 2007;22:457–61. 76. Rodriguez MM, Bruce JH, Jiménez XF, Romaguera RL, Bancalari E, García OL, et al. Nonimmune hydrops fetalis in the liveborn: series of 32 autopsies. Pediatric and developmental pathology 2005;8:369–78. 77. Knisely AS. The pathologist and the hydropic placenta, fetus, or infant. Semin Perinatol 1995;19:525–31. 78. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

SOGC CLINICAL PRACTICE GUIDELINE No. 313, October 2014

Menstrual Suppression in Special Circumstances This clinical practice guideline has been prepared by the Canadian Paediatric and Adolescent Gynaecology and Obstetricians (CANPAGO) Committee, reviewed by the Family Practice Advisory Committee, and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Yolanda A. Kirkham, MD, Toronto ON Melanie P. Ornstein, MD, Toronto ON Anjali Aggarwal, MD, Toronto ON Sarah McQuillan, MD, Calgary AB CANPAGO COMMITTEE Lisa Allen, MD (Co-chair), Toronto ON Debra Millar, MD (Co-chair), Vancouver BC Nancy Dalziel, RN, Ottawa ON Suzy Gascon, MD, Montreal QC Julie Hakim, MD, Ottawa ON Julie Ryckman, MD, Ottawa ON Rachel Spitzer, MD, Toronto ON Nancy Van Eyk, MD, Halifax NS Disclosure statements have been received from all contributors.

Options: This document reviews the options available for menstrual suppression, its specific indications, contraindications, and side effects, both immediate and long-term, and the investigations and monitoring necessary throughout suppression. Outcomes: Clinicians will be better informed about the options and indications for menstrual suppression in patients with cognitive and/or physical disabilities and patients undergoing chemotherapy, radiation, or other treatments for cancer. Evidence: Published literature was retrieved through searches of Medline, EMBASE, OVID, and the Cochrane Library using appropriate controlled vocabulary and key words (heavy menstrual bleeding, menstrual suppression, chemotherapy/radiation, cognitive disability, physical disability, learning disability). Results were restricted to systematic reviews, randomized controlled trials, observation studies, and pilot studies. There were no language or date restrictions. Searches were updated on a regular basis and new material was incorporated into the guideline until September 2013. Grey (unpublished) literature was identified through searching websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Values: The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). Benefits, harms, and costs: There is a need for specific guidelines on menstrual suppression in at-risk populations for health care providers. Recommendations

Abstract Objective: To provide a Canadian consensus document for health care providers with recommendations for menstrual suppression in patients with physical and/or cognitive challenges or those who are undergoing cancer treatment in whom menstruation may have a deleterious effect on their health.

Key Words: menstruation, menstrual suppression, amenorrhea, chemotherapy, radiation, disability, contraception

J Obstet Gynaecol Can 2014;36(10):915–924

1. Menstrual suppression and therapeutic amenorrhea should be considered safe and viable options for women who need or want to have fewer or no menses. (II-2A) 2. Menstrual suppression should not be initiated in young women with developmental disabilities until after the onset of menses. (II-2B) 3. Combined hormonal or progesterone-only products can be used in an extended or continuous manner to obtain menstrual suppression. (I-A) 4. Gynaecologic consultation should be considered prior to the initiation of treatment in all premenopausal women at risk for abnormal uterine bleeding from chemotherapy. (II-1A) 5. Leuprolide acetate or combined hormonal contraception should be considered highly effective in preventing abnormal uterine bleeding when initiated prior to cancer treatment in premenopausal women at risk for thrombocytopenia. (II-2A)

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

OCTOBER JOGC OCTOBRE 2014 l 915

SOGC Clinical Practice Guideline

Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.62 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care.62

INTRODUCTION

M

enstrual suppression involves the use of various hormonal regimes prescribed in an extended or continuous fashion to achieve therapeutic amenorrhea. This can involve decreasing the blood loss and the number of menstrual cycles per year or eliminating menses altogether. The goal may also include management of associated menstrual side effects, such as bloating, nausea and vomiting, headaches, mood and behavioural changes, and cyclic exacerbation of seizures or migraines. The ultimate goals of menstrual suppression are to reduce morbidity and improve quality of life for women and/ or their caregivers.1,2 Menstrual suppression is often ABBREVIATIONS AUB

abnormal uterine bleeding

BMD

bone mineral density

CHC

combined hormonal contraception

DEXA

dual X-ray absorptiometry

DMPA

depot medroxyprogesterone acetate

GnRH

gonadotropin releasing hormone

IM

intramuscular

IUD

intrauterine device

IV

intravenous

LA

leuprolide acetate

LNG-IUS levonorgestrel intrauterine system O

oral contraceptive pill

POP

progestin-only pill

916 l OCTOBER JOGC OCTOBRE 2014

medically indicated. The Canadian Consensus Guideline on Continuous and Extended Hormonal Contraception describes many indications for suppression.2 These include social choice, severe dysmenorrhea associated with endometriosis, abnormal uterine bleeding, hemorrhagic diatheses, hormone withdrawal symptoms, and premenstrual dysphoric disorders. This guideline focuses on the needs of women with developmental disabilities and women undergoing cancer treatment and at risk for iatrogenic thrombocytopenia. Both of these conditions present commonly in adolescence. For management of women with inherited bleeding disorders, please refer to SOGC Clinical Practice Guideline No. 163.3 The following guideline will address each indication for menstrual suppression (disabilities and cancer treatment) separately. CONSIDERATIONS AND OPTIONS FOR MENSTRUAL SUPPRESSION IN WOMEN WITH DISABILITIES

Women with developmental challenges and disabilities are a varied group. Patients may have cognitive and/or physical impairments, various levels of communication and independence in activities of daily living, numerous comorbidities, polypharmacy, and differences in their abilities to participate in informed consent. Families of adolescents with disabilities often present for counselling before or after menarche, which usually occurs at the same age as in the general population.4,5 There is some indication that women with cerebral palsy undergo puberty earlier, but reach menarche slightly later, than the general

Menstrual Suppression in Special Circumstances

population,5,6 people with neurologic impairment have a higher risk of precocious puberty,7 and neuroleptic drugs can lead to hyperprolactinemia and amenorrhea.5,7 While menstrual irregularities are common in the first 2 to 3 years post menarche because of anovulatory cycles, AUB and dysmenorrhea in women with disabilities require the same investigations as those undertaken in the general population. In a retrospective study of 300 adolescents with developmental disabilities, 30% experienced heavy, painful, or irregular menstrual bleeding, and rates of behavioural or mood symptoms approached 22%.8 In 2 retrospective studies, 32% to 43% of caregivers approached physicians for information on menstrual suppression prior to the young woman’s menarche because of their anxiety and concerns about coping with hygiene and possible behavioural changes.4,8 Behavioural concerns can include mood changes, aggression, and self-mutilation,6 which may also reflect pain.9 Defining the reasons for intervention can assist in the formation of treatment goals.1 Table 2 outlines the pertinent points to elicit from history prior to initiation of therapy when considering menstrual suppression. There is a general consensus that menstrual suppression therapy should not commence until menarche.4 Often, education and of the normal progression through puberty and menarche are all that is required.4,8,9 Awaiting menarche also confirms normal hormonal function and the absence of an obstructive anomaly. Once a decision is made to pursue treatment, medical interventions that are the least intrusive, are reversible, and have the lowest side effect profile are desirable. Surgical or permanent interventions are rarely required and are fraught with ethical and legal issues if the individual is unable to participate fully in consent.1,5,7,9,10 All of the available options for reversible contraception are acceptable for menstrual suppression (Table 3) and satisfaction can be achieved in most disabled adolescents and their families with 1 or 2 hormonal methods.8 Recommendations

1. Menstrual suppression and therapeutic amenorrhea should be considered safe and viable options for women who need or want to have fewer or no menses. (II-2A) 2. Menstrual suppression should not be initiated in young women with developmental disabilities until after the onset of menses. (II-2B) Combined Hormonal Options

Decreased number of periods or complete menstrual suppression, with control of menstrual-related side effects, can be achieved with extended or continuous use of CHC. There have been several studies in the general

population that examine the different routes for delivering extended or continuous CHC, and no single regimen has been recognized as superior to the others.11–13 Unscheduled bleeding generally decreases over time.1,2 For patients without contraindications to estrogen, the O, contraceptive patch, or vaginal ring can be used to prevent cyclical or abnormal menstrual bleeding. The safety, efficacy, and acceptability of extended or continuous use have been studied in randomized controlled studies14,15 and are similar to rates for contraceptives used cyclically. The extended use of hormones for menstrual suppression for dysmenorrhea, endometriosis, heavy menstrual bleeding, and menstrual-related symptoms is also well established. For specific details, please refer to SOGC Clinical Practice Guideline no. 195.2 There are no data on the long-term safety of CHC in patients with cognitive or physical impairments. The prescription of extended use of CHC has been shown to be acceptable in adolescents16 and patients with disabilities.4,8 CHC also suppresses ovulation, which improves menstrual-related mood symptoms or behaviours. These are common presenting complaints in adolescents with Down syndrome, autism, and cerebral palsy.6 Adjustment to a higher dose estrogen-containing formulation or to an alternate antiepileptic may be required because enzyme-inducing anti-epileptic drugs can interfere with the cytochrome p450 system and metabolism of CHC.17 The need for frequent courses of antibiotics may affect the efficacy of hormonal therapy. Malnutrition or gastric feeding tubes can affect the route of drug istration and absorption.5 Immobile and wheelchair-bound individuals may be at increased risk of venous thromboembolism.6,18 In a recent cohort study of adolescents with disabilities, none of the permanent wheelchair s who used an O or the patch developed thromboembolisms during the study period.8 The choice of a monophasic or triphasic combined contraception pill is often at the discretion of the prescriber. Similarly, the dose of the pill should depend on the side effects experienced or the comorbidities and polypharmacy of the patient. There is some concern regarding a decrease in the expected gain in BMD in adolescents who use 20 mcg ethinyl estradiol formulations.19 For adolescents with heavy or irregular menstrual bleeding, it may be appropriate to consider starting with cyclic use prior to extended or continuous use to minimize breakthrough spotting and discontinuation.16 In a recent retrospective study, O was the most commonly selected initial and second-choice method for menstrual suppression in adolescents with disabilities.8 OCTOBER JOGC OCTOBRE 2014 l 917

SOGC Clinical Practice Guideline

Table 2. Considerations for menstrual suppression in girls and women with developmental disabilities Menarchal status Premenarchal: counselling and education Postmenarchal: menstrual suppression options Quality of life Hygiene Degree of anxiety Activity restrictions Caregiver concerns Treatment goals Degree of suppression or amenorrhea desired Contraceptive needs Type of disability or risk Cognitive Physical Communicative Abuse Degree of required Ambulatory vs. wheelchair required with activities of daily living Access to (home, school, and respite care) Menstrual symptoms Menstrual bleeding patterns Dysmenorrhea Behavioural, mood, and/or premenstrual symptoms Medical history and comorbidities Cerebrovascular disease Complicated valvular heart disease Diabetes with end-organ disease Decreased BMD Liver disease Malnutrition or feeding tube Migraines with neurological symptoms Obesity Seizure disorder Thromboembolic risk or history Thyroid dysfunction Uncontrolled hypertension Medications Antiepileptics Antibiotics Neuroleptics Steroids

918 l OCTOBER JOGC OCTOBRE 2014

The contraceptive patch delivers 35 mcg of ethinyl estradiol and 150  mcg of norelgestromin daily and requires weekly replacement. The patch may be considered in patients with gastrointestinal issues (difficulty swallowing or malabsorption) or in those with poor compliance using daily oral contraceptives.1 In a randomized controlled trial evaluating continuous use of the patch in the general population, menstrual bleeding was delayed to 54 days and amenorrhea rates of 28% and 12% were achieved through extended use to 8 and 12 weeks, respectively.11 The side effect profile is similar to that of O,20,21 with spotting as a common initial side effect. Based on data analyzed for pregnancy outcome, the efficacy of the patch appears to be reduced in patients who weigh 90 kg or more.22 In a cohort study of adolescents with disabilities, 20% of patients and their families elected to use the patch as their first choice for menstrual suppression.8 Disadvantages of the transdermal patch included skin irritation, behavioural or mood concerns, breast tenderness, and attempted removal of the patch by the disabled adolescent. The transvaginal ring is a preparation with daily delivery of 15 mcg ethinyl estradiol and 120 mcg etonogestrel.22 One randomized controlled trial in the general population evaluated continuous use of the ring versus extended use with a 4-day ring-free interval, with the latter resolving breakthrough bleeding or spotting.23 Continuous or extended use had high continuation rates and reduced menstrual flow and pelvic pain. An advantage of the ring is that it can be used for one month before requiring replacement. Although the use of the transvaginal ring has not been studied in the developmentally delayed population, this option can be presented to patients with minor cognitive delay and familiarity with tampon use or no physical impairment to ring insertion. Progestin-only Options

Progestin-only options for menstrual suppression offer alternatives to estrogen-containing contraceptives and can be istered by intramuscular, oral, or intrauterine routes. The progestin implant is not available in Canada. Oral progestins (0.35  mg norethindrone tablets) are prescribed daily without a pill-free interval. The POP does not confer the same degree of amenorrhea (10% of patients),24 but it is effective contraception with a failure rate of only 0.5% with perfect use.22 Side effects are much less common with POP than with O, but may include breakthrough bleeding, emotional disturbances, acne, and breast tenderness. POP treatment has not been studied exclusively in patients with disabilities.

Not studied in disabled population

Breakthrough bleeding Weight gain

Amenorrhea within 1 year in 50% of patients

Safe for patients with contraindications to estrogen

Breakthrough bleeding

Safe for patients with contraindications to estrogen

Minimal uterine length of 5–6 cm Post-operative ultrasound for placement in patients with disabilities

Progressive reduction in menstrual flow and pain

Amenorrhea within 1 year in 50% of patients

Effective for prevention of heavy menstrual bleeding with iatrogenic thrombocytopenia

Amenorrhea rates of 73–96%

*Various add-back therapy regimens (estrogen and/or progestin) are available.

Long-term use requires add-back therapy* to prevent hypoestrogenic symptoms of endometriosis

Ideal istration 3–4 weeks prior to chemotherapy in luteal phase

Intramuscular injection

Cost

Initial irregular bleeding

Minimal systemic effects

istration every 4 (3.75 mg im) or 12 weeks (11.25 mg im)

Insertion may require general anaesthesia

5-year effectiveness

Weight gain

Compliance with daily istration

Oral or feeding tube istration

Requires dietary calcium and vitamin D supplementation

Injection

istration every 10–12 weeks

Same as O

Insertion by woman or caregiver

Reduced efficacy in patients > 90kg

Same as O

Avoids first metabolism

Removal (inadvertant or deliberate)

Avoids first metabolism

istration every 3 weeks

Skin irritation

Weekly transdermal application

Reduction in ovarian, endometrial, colorectal cancer

None of these methods protect against sexually transmitted infections.

GnRH analogue leuprolide

LNG-IUS

Oral progesterone

DMPA injection

Vaginal ring

Contraceptive patch

Breakthrough bleeding

Extended or continuous regimen

Reduced menstrual flow and dysmenorrhea

Compliance with daily istration

Oral or feeding tube istration

O

Difficulties

Benefits

Type of contraception

Table 3. Reversible therapeutic hormonal options for menstrual suppression

Reduced BMD during treatment; add-back therapy or adequate dietary calcium and vitamin D supplementation are recommended

Infection (first 21 days)

Expulsion

Perforation

Minimal

Reduced BMD during treatment (reversible)

Same as O

Same as O

Contraindicated in patients with hepatic disease or hormone-dependent cancers on chemotherapy

Gallbladder disease

Venous thromboembolism

Risks

Menstrual Suppression in Special Circumstances

OCTOBER JOGC OCTOBRE 2014 l 919

SOGC Clinical Practice Guideline

DMPA is an injectable progesterone of 150  mg istered intramuscularly every 12 weeks. Despite American and Canadian advisories in 2004 and 2005, respectively, regarding concerns over loss of BMD, the advantages of DMPA have led to its continued use. Prior to evidence of the association between DMPA and bone loss, DMPA was the most commonly prescribed method of menstrual suppression (59%) in adolescents with developmental delay.4 Recent Canadian data have shown a shift in prescribing methods to the extended combined oral contraceptive, although DMPA remains a popular initial choice in 12% of adolescent patients with disabilities.8 The dosing schedule of DMPA, istered every 12 weeks or sometimes every 10 weeks in patients on anti-epileptic medications,25,26 confers a possible advantage in patients with disabilities. DMPA also minimizes concerns over compliance and is acceptable in patients who are unable to swallow pills or tolerate a vaginal ring or transdermal patch. DMPA may also be considered for the quick initial induction of amenorrhea, to be followed by the use of alternative longer-term methods of menstrual suppression. Rates of amenorrhea at 12 to 24 months reach 55% to 70% in the general population,25,27 with irregular bleeding as a common initial side effect that diminishes over time. It is an extremely effective contraceptive with a failure rate of 0.3%.24 Additional advantages include a relative lack of drug interactions and reductions in seizures28 and sickle cell crises.29 The reduction in estrogen levels from the use of DMPA during adolescence is associated with bone loss of 3.1% at the lumbar spine and 6.1% at the hip.19,30 Fortunately, studies suggest that loss of BMD is transient and its recovery has been demonstrated in adult and adolescent patients with cessation of the injection.30–33 Modifiable factors such as dietary calcium intake, even at levels lower than the daily recommended intake of 1300 mg per day, contribute to BMD gain in the femoral neck and lumbar regions in adolescents.34 The DEXA scan can be used to quantify bone mass during DMPA treatment. Age appropriate norms should be used. However, whether this surrogate marker for bone strength translates into a measure of fracture risk has yet to be elucidated. Considerations of bone density are particularly important in wheelchair-bound and immobile patients or those on systemic steroids, who are already at risk for lower BMD. Regular appointments to readdress the need for continued DMPA, to consider alternatives, and to encourage adequate dietary calcium with vitamin D supplementation and weight-bearing exercise are strongly encouraged.35 Weight gain of 1 to 2 kg per year of use is also a possible side effect of DMPA through appetite stimulation.36 Obese young women are more susceptible to increased weight 920 l OCTOBER JOGC OCTOBRE 2014

gain on DMPA,36 and weight gain may be an important issue in individuals who require assistance with transfers.6 Levonorgestrel Intrauterine System

The LNG-IUS is indicated for control of heavy menstrual bleeding and long-acting reversible contraception. Through daily delivery of 20 mcg of levonorgestrel, the local effects of the device lead to inhibition of endometrial proliferation, thickening of cervical mucus, and impaired sperm mobility.37 In the general population, menstrual blood loss is reduced by 85% in 3 months,38 and rates of amenorrhea reach nearly 50% in 6 months39 and continue to increase over time, while irregular spotting, particularly in the months following insertion, diminishes. In a randomized controlled trial, LNG-IUS was shown to be more effective in reducing menstrual bleeding than a 10day regimen of 10 mg oral medroxyprogesterone acetate per month.40 In adolescents, the most common indication for use of the LNG-IUS was heavy menstrual bleeding, which occurred in 17% of patients.41 A significant benefit of the LNG-IUS is its length of treatment (5 years), after which it can be removed and alternatives can be re-evaluated or a new IUS can be reinserted. Side effects are few and complications such as perforation, expulsion, and infection are rare in adult and adolescent populations,18,40–42 with high rates of continuation in adolescents of 75% to 85%.41,43 In one study of 14 young women with disabilities,44 50% achieved amenorrhea with LNG-IUS and there was 1 expulsion, which is in keeping with the low rates of expulsion (7 to 8%) of IUDs in young women with or without disabilities.41,43 In another study of adolescents with cognitive and physical challenges,8 the LNG-IUS was a popular second-line option for menstrual suppression in 19% of patients who switched from alternate methods. Ovulation is not suppressed by the LNG-IUS, and thus hormonal cycling and associated mood symptoms or behaviours may not be ameliorated. Insertion in virginal or young women with disabilities may require general anaesthesia or conscious sedation. Preinsertion considerations include vaginal and cervical swabs in patients at risk for infection, screening for pregnancy, ultrasound for vertical length of the uterine cavity (5 to 6 cm is recommended), and istration of oral or vaginal misoprostol.44,45 Long-term menstrual suppression with LNG-IUS offers effective reduction in menstrual blood loss, high rates of amenorrhea, and low rates of complications.8,41,44 Recommendation

3. Combined hormonal or progesterone-only products can be used in an extended or continuous manner to obtain menstrual suppression. (I-A)

Menstrual Suppression in Special Circumstances

MENSTRUAL SUPPRESSION FOR ONCOLOGY PATIENTS

Each year in Canada there are approximately 600 new cancer cases and 80 deaths from cancer in girls and women aged 0 to 19 years and 12 450 new cases and 4800 deaths in women aged 20 to 49 years.46 This constitutes a substantial number of women of reproductive age who will develop cancer and require treatment, such as chemotherapy, radiation, or hematopoietic stem cell or bone marrow transplantation. Ablative therapy may induce pancytopenia with thrombocytopenia and result in moderate to severe uterine bleeding in nearly 40% of oncology patients.47 AUB in premenopausal women with malignancy is caused by thrombocytopenia from the cancer itself and can be further exacerbated by cancer treatment. The resulting bleeding worsens thrombocytopenia through increased platelet consumption. Heavy bleeding may result in the need for transfusion and delay or interrupt their treatment regime.47,48 These immunosuppressed women are also at increased risk of infection from both neutropenia and prolonged bleeding. Iatrogenic thrombocytopenia necessitates prevention of heavy menstrual bleeding through menstrual suppression. Recommendation

4. Gynaecologic consultation should be considered prior to the initiation of treatment in all premenopausal women at risk for abnormal uterine bleeding from chemotherapy. (II-1A) GnRH Analogues

Most of the data on menstrual suppression in women with malignancies focus on the use of the GnRH agonist LA. Heavy menstrual bleeding can be mitigated through induced hypo-estrogenism and gonadal suppression. The first reported study by Ghalie et al. (1993) compared LA istered 1 mg IV daily or 7.5 mg IM monthly prior to bone marrow transplant at different times during the menstrual cycle in 34 patients.48 No adverse effects were observed and menstruation was prevented in 73% of patients. When LA was started at least 2 weeks prior to the onset of thrombocytopenia, the failure rate was 6%; when it was initiated at a later time, the failure rate was 33%.48 Prospective studies with different doses or routes of istration of LA, such as 3.75 mg IM prior to chemotherapy,49–51 showed similar relations between the success of therapeutic amenorrhea and the timing of the treatment. The efficacy of GnRH analogues in preventing bleeding has been shown in 85% to 100% of patients when initiated at least 1 month prior to chemotherapy.49,50 Duration of therapy is usually directed by the risk or presence of thrombocytopenia or is dependent on the duration of myelosuppressive therapy.

Recommendation

5. Leuprolide acetate or combined hormonal contraception should be considered highly effective in preventing abnormal uterine bleeding when initiated prior to cancer treatment in premenopausal women at risk for thrombocytopenia. (II-2A) In 2007, Quaas and Ginsburg published a systematic review on the prevention and treatment of uterine bleeding in premenopausal patients with malignancies. They concluded that GnRH agonists are very effective for the prevention of uterine bleeding in these patients. The prevention of bleeding was recommended over the acute treatment of bleeding and a consultation with a gynaecologist prior to starting any treatments was encouraged.52 Prophylactic management with LA was recommended in a 2011 review.53 Tranexamic acid, medroxyprogesterone or O, or IV estrogen followed by danazol or recombinant factor V11a with desmopressin were recommended as escalated treatment for heavy menstrual bleeding. In a worldwide survey, mainly of oncologists of pediatric bone marrow transplant patients, GnRH agonists were preferentially chosen by 41% of respondents over CHC (29%), progesterone-only oral medication (21%), DMPA (6%), and ethinyl estradiol/norelgestromin patch (3%) for the induction of amenorrhea.54 There are no studies comparing GnRH agonists directly to Os to demonstrate superior effectiveness. Neither GnRH agonists nor Os have been shown conclusively to confer protection against ovarian insufficiency.55,56 Oral Contraceptive Pills

Although the O is often referred to as a standard method for menstrual suppression in women with malignancies, there is little published in this area.53 Only one small retrospective series of oral contraceptives for prevention of heavy menstrual bleeding in women undergoing stem cell transplantation has been published.57 Gynaecologic consultation occurred at a median of 12 days after transplantation. Prior to consultation, 21 (64%) of 33 patients had been on O; most of the other patients had no hormonal treatments and a small minority were on medroxyprogesterone alone or combined with conjugated estrogens. Heavy menstrual bleeding resolved in 97% of patients, but 21% required more than one form of hormonal therapy and 12% required progressive treatment with higher dose O and/or IV conjugated estrogen.57 O is an important option for patients who cannot tolerate IM injections or who show evidence of osteoporosis. However, oral contraceptives may increase both liver toxicity following stem cell transplant and the frequency of venous thromboembolic events, which are OCTOBER JOGC OCTOBRE 2014 l 921

SOGC Clinical Practice Guideline

already increased in patients with malignancy. O may also be poorly tolerated or absorbed due to mucositis, vomiting, or diarrhea secondary to radiation enterocolitis or chemotherapy.57 In a prospective cohort trial by Sica et al.,58 16 premenopausal women with acute leukemia were istered O alone (n = 8) or O with LA (n = 8) for the prevention of vaginal bleeding during chemotherapy. There were no statistical differences in red blood cell or platelet transfusions or duration of vaginal bleeding, nor were there any flares in either group. Liver toxicity was noted in both groups. However, once the O was discontinued, liver damage resolved and menses also resumed in 6 of the 8 patients on O versus none in the combined group for whom the Os were istered to prevent flares. The authors attributed these findings to the more profound induction of amenorrhea by LA than by O alone. Depot Medroxyprogesterone Acetate

SUMMARY

Menstrual suppression is often medically indicated. The Canadian Consensus Guideline on Continuous and Extended Hormonal Contraception2 describes many indications for suppression, including social choice, severe dysmenorrhea associated with endometriosis, abnormal uterine bleeding, hemorrhagic diatheses, hormone withdrawal symptoms, and premenstrual dysphoric disorders. This guideline focuses on 2 groups who often benefit significantly from reduced menstrual bleeding or amenorrhea: women with cognitive and/or physical impairments and women undergoing cancer therapy. While there is a paucity of data from large trials to dictate clinical practice, several options are available to induce therapeutic amenorrhea in women with disabilities or prophylactic menstrual suppression in women with malignancies prone to thrombocytopenia. REFERENCES

In 2006, Meirow et al. compared D-tryptophan-6-luteinizing hormone-releasing hormone (a GnRH agonist) to DMPA or no treatment in patients prior to myelosuppresive chemotherapy retrospectively in 101 patients.47 Significantly fewer urgent gynaecologic consultations were required in the patients who were istered GnRHa. In the DMPA group 20% experienced moderate or severe menstrual bleeding. Urgent treatment with conjugated estrogens was required in untreated patients and in patients on DMPA, but not in any of the patients who received GnRH agonists. The authors of this and other studies52 emphasize the importance of gynaecologic evaluation prior to the initiation of treatment and conclude that GnRH agonist treatment is more effective than DMPA for menstrual suppression and the reduction of heavy menstrual bleeding.

1. American College of Obstetricians and Gynecologists Committee on Adolescent Health Care. ACOG Committee Opinion No. 448: Menstrual manipulation for adolescents with disabilities. Obstet Gynecol 2009;114:1428–31.

Levonorgestrel Intrauterine System

5. Zacharin M, Savasi I, Grover S. The impact of menstruation in adolescents with disabilities related to cerebal palsy. Arch Dis Child 2009;95:526–30.

No studies have been published regarding menstrual management by LNG-IUS in patients undergoing cancer treatment. However, according to the World Health Organization’s medical eligibility criteria for contraceptive use, the IUS is acceptable in immunosuppressed patients (such as those with lupus undergoing immunosuppressive treatment and patients with HIV) and patients at risk for venous thromboembolism.59 Surgical Options

There are no case reports or trials assessing prophylactic surgical techniques such as uterine artery embolization, endometrial ablation, or hysterectomy to prevent menstrual bleeding in hematologic malignancy. Case reports describe the use of uterine artery embolization to control chemotherapyinduced heavy menstrual bleeding unresponsive to medical management.60,61 922 l OCTOBER JOGC OCTOBRE 2014

2. Guilbert E, Boroditsky R, Black A, Kives S, Leboeuf M, Mirosh M, et al.; Society of Obstetricians and Gynaecologists of Canada. Canadian consensus guideline on continuous and extended hormonal contraception. SOGC Clinical Practice Guidelines, No. 195, July 2007. J Obstet Gynaecol Can 2007; 29(7 Suppl 2):S1–S32. 3. Demers C, Derzko C, David M, Douglas J; Society of Obstetricians and Gynecologists of Canada. Gynaecological and obstetric management of women with inherited bleeding disorders. SOGC Clinical Practice Guidelines, No. 163, July 2005. J Obstet Gynaecol Can 2005;27:707–32. 4. Dizon C, Allen L, Ornstein M. Menstrual and contraceptive issues among young women with developmental delay: a retrospective review of cases at the Hospital for Sick Children, Toronto. J Pediatr Adolesc Gynecol 2005;18:157–62.

6. Burke L, Kalpakjian C, Smith Y, Quint H. Gynecologic issues of adolescents with Down syndrome, autism, and cerebral palsy. J Pediatr Adolesc Gynecol 2010;23:11–5. 7. Albanese A, Hopper NW. Suppression of menstruation in adolescents with severe learning disabilities. Arch Dis Child 2007;92:629–32. 8. Kirkham YA, Allen L, Kives S, Caccia N, Spitzer RF, Ornstein MP. Trends in menstrual concerns and suppression in adolescents with developmental disabilities. J Adolesc Health 2013;53:407–12. 9. Grover S. Menstrual and contraceptive management in women with an intellectual disability. Med J Aust 2002;176:108–10. 10. Paransky OI, Zurawin RK. Management of menstrual problems and contraception in adolescents with mental retardation: a medical, legal, and ethical review with new suggested guidelines. J Pediatr Adolesc Gynecol 2003;16:223–35. 11. Stewart FH, Kaunitz AM, La Guardia KD, Karvois DI, Fisher AC, Friedman AJ. Extended use of transdermal norelgestromin/EE: a randomized trial. Obstet Gynecol 2005;105:1389–96.

Menstrual Suppression in Special Circumstances

12. Miller L, Verhoeven CH, Hout J. Extended regimens of the contraceptive vaginal ring: a randomized trial. Obstet Gynecol 2005;106:473–82. 13. Hamerlynck JV, Vollebregt JA, Doornebos CM, Muntendam P. Postponement of withdrawal bleeding in women using low-dose combined oral contraceptives. Contraception 1987;35:199–205. 14. Edelman A, Gallo MF, Nichols MD, Jensen JT, Schulz KF, Grimes DA. Continuous versus cyclic use of combined oral contraceptives for contraception: systematic Cochrane review of randomized controlled trials. Hum Reprod 2006;21:573–8. 15. Teichmann A, Apter D, Emerich J, Greven K, Klasa-Mazurkiewicz D, Melis GB, et al. Continuous, daily levonorgestrel/ethinyl estradiol vs. 21-day, cyclic levonorgestrel/ethinyl estradiol: efficacy, safety and bleeding in a randomized, open-label trial. Contraception 2009;80:504–11. 16. Gold MA, Duffy K. Extended cycling or continuous use of hormonal contraceptives for female adolescents. Curr Opin Obstet Gynecol 2009;21:407–11. 17. Gaffield ME, Culwell KR, Lee CR. The use of hormonal contraception among women taking anticonvulsant therapy. Contraception 2011;83:16–29. 18. Savasi I, Spitzer RF, Allen LM, Ornstein MP. Menstrual suppression for adolescents with developmental disabilities. J Pediatr Adolesc Gynecol 2009; 22:143–9. 19. Cromer BA, Stager M, Bonny A, Lazebnik R, Rome E, Ziegler J, et al. Depot medroxyprogesterone acetate, oral contraceptives and bone mineral density in a cohort of adolescent girls. J Adolesc Health 2004;35:434–41. 20. Rubinstein ML, Halpern-Felsher BL, Irwin CE Jr. An evaluation of the use of the transdermal contraceptive patch in adolescents. J Adolesc Health 2004;34:395–401. 21. Harel Z, Riggs S, Vaz R, Flanagan P, Dunn K, Harel D. Adolescents’ experience with the combined estrogen and progestin transdermal contraceptive method Ortho Evra. J Pediatr Adolesc Gynecol 2005;18:85–90. 22. Zieman M, Guillebaud J, Weisberg E, Shangold GA, Fisher AC, Creasy GW. Contraceptive efficacy and cycle control with the Ortho Evra/Evra transdermal system: the analysis of pooled data. Fertil Steril 2002;77(2 Suppl 2):S13–S18. 23. Sulak PJ, Smith V, Coffee A, Witt I, Kuehl AL, Kuehl TJ. Frequency and management of breakthrough bleeding with continuous use of the transvaginal contraceptive ring: a randomized controlled trial. Obstet Gynecol 2008;112:563–71. 24. Black A, Francoeur D, Rowe T. Canadian contraception consensus. SOGC Clinical Practice Guidelines, No. 143: Part 2 of 3. J Obstet Gynaecol Can 2004;26:219–54. 25. Quint EH. Menstrual issues in adolescents with physical and developmental disabilities. Ann N Y Acad Sci 2008;1135:230–6. 26. Crawford P. Interactions between antiepileptic drugs and hormonal contraception. CNS Drugs 2002;16:263–272. 27. Black A; Ad Hoc DMPA Committee of the Society of Obstetricians and Gynaecologists of Canada. Canadian Contraception Consensus— Update on Depot Medroxyprogesterone Acetate (DMPA). SOGC Clinical Practice Guidelines, No. 174, April 2006. J Obstet Gynaecol Can 2006;28:305–13. 28. Zupanc ML. Antiepileptic drugs and hormonal contraceptives in adolescent women with epilepsy. Neurol 2006;66(6 Suppl 3):S37–S45. 29. de Abood M, de Castillo Z, Guerrero F, Espino M, Austin KL. Effect of Depo-Provera or Microgynon on the painful crises of sickle cell anemia patients. Contraception 1997;56:313–6.

30. Scholes D, LaCroix AZ, Ichikawa LE, Barlow WE, Ott SM. Change in bone mineral density among adolescent women using and discontinuing depot medroxyprogesterone acetate contraception. Arch Pediatr Adolesc Med 2005;159:139–44. 31. Kaunitz AM, Arias R, McClung M. Bone density recovery after depot medroxyprogesterone acetate injectable contraception. Contraception 2007;77:67–76. 32. Harel Z, Johnson CC, Gold MA, Cromer B, Peterson E, Burkman R, et al. Recovery of bone mineral density in adolescents following the use of depot medroxyprogesterone acetate contraceptive injections. Contraception 2010;81:281–91. 33. Isley MM, Kaunitz AM. Update on hormonal contraception and bone density. Rev Endocr Metab Disord 2011;12:93–106. doi: 10.1007/s11154-011-9180-6. 34. de Oliveria MRM, da Silva CC, Kurokawa CS, Fortes CMT, Capela RC, Teixeira AS, et al. Bone mineral density in healthy female adolescents according to age, bone age and pubertal breast stage. Open Orthop J 2011;5:324–30. 35. Pitts SA, Feldman HA, Dorale A, Gordon CM. Bone mineral density, fracture, and vitamin D in adolescents and young women using depot medroxyprogesterone acetate. J Pediatr Adolesc Gynecol 2012;25:23–6. Epub 2011 Nov 12. 36. Bonny AE, Britto MT, Huang B, Succop P, Slap GB. Weight gain, adiposity, and eating behaviors among adolescent females on depot medroxyprogesterone acetate (DMPA). J Pediatr Adolesc Gynecol 2004;17:109–15. 37. Jensen JT. Contraceptive and therapeutic effects of the levonorgestrel intrauterine system: an overview. Obstet Gynecol Surv 2005;60:604–12. 38. Andersson JK, Rybo G. Levonorgestrel-releasing intrauterine device in the treatment of menorrhagia. Br J Obstet Gynaecol 1990;97:690–4. 39. Hidalgo M, Bahamondes L, Perrotti M, Diaz J, Dantas-Monteiro C, Petta C. Bleeding patterns and clinical performance of the levonorgestrelreleasing intrauterine system (Mirena) up to two years. Contraception 2002;65:129–32. 40. Kaunitz, AM, Bissonnette F, Monteiro I, Lukkari-Lax E, Muysers C, Jensen JT. Levonorgestrel-releasing intrauterine system or medroxyprogesterone for heavy menstrual bleeding: a randomized controlled trial. Obstet Gynecol 2010;116:625–32. 41. Paterson H, Ashton J, Harrison-Woolrych M. A nationwide cohort study of the use of the levonorgestrel intrauterine device in New Zealand adolescents. Contraception 2009;79:433–8. 42. Savasi I, Moore P, Jayasinghe Y, Grover S. The use of Mirena IUS in adolescents: a review of the RCH experience. J Pediatr Adolesc Gynecol 2010;23(2):e83. 43. Toma A, Jamieson MA. Revisiting the intrauterine contraceptive device in adolescents. J Pediatr Adolesc Gynecol 2006;19:291–6. 44. Pillai M, O’Brien K, Hill E. The levonorgestrel IUS (Mirena) for the treatment of menstrual problems in adolescents with medical disorders or physical or learning disabilities. BJOG 2010;117:216–21. 45. Hillard PJ. Menstrual suppression with the levonorgestrel intrauterine system in girls with developmental delay. J Pediatr Adolesc Gynecol 2012;25:308–13. 46. Canadian Cancer Society’s Steering Committee on Cancer Statistics. Canadian Cancer Statistics 2011. Toronto ON: Canadian Cancer Society; 2011. 47. Meirow D, Rabinovici J, Katz D, Or R, Shufaro Y, Ben-Yehuda D. Prevention of severe menorrhagia in oncology patients with treatmentinduced thrombocytopenia by luteinizing hormone-releasing hormone agonist and depo-medroxyprogesterone acetate. Cancer 2006;107:1634–41.

OCTOBER JOGC OCTOBRE 2014 l 923

SOGC Clinical Practice Guideline

48. Ghalie R, Porter C, Radwanska E, Fitzsimmons W, Richman C, Kaizer H. Prevention of hypermenorrhea with leuprolide in premenopausal women undergoing bone marrow transplantation. Am J Hematol 1993;42:350–3. 49. Chiusolo P, Salutari P, Sica S, Scirpa P, Laurenti L, Piccirillo N, et al. Luteinizing hormone-releasing hormone analogue: leuprorelin acetate for the prevention of menstrual bleeding in premenopausal women undergoing stem cell transplantation. Bone Marrow Transplant 1998;21:821–3. 50. Lhomme C, Brault PH, Bourhis J, Pautier P, Dohollou N, Dietrich PY, et al. Prevention of menstruation with leuprorelin (GnRH agonist) in women undergoing myelosuppressive chemotherapy or radiochemotherapy for hematological malignancies: a pilot study. Leuk Lymphoma 2001;42:1033–41. 51. Laufer MR, Townsend NL, Parsons KE, Brody KA, Diller LR, Emans SJ, et al. Inducing amenorrhea during bone marrow transplantation. A pilot study of leuprolide acetate. J Reprod Med 1997;42:537–41. 52. Quaas AM, Ginsburg ES. Prevention and treatment of uterine bleeding in hematologic malignancy. Eur J Obstet Gynecol Reprod Biol 2007;134:3–8.

56. Behringer K, Wildt L, Mueller H, Mattle V, Ganitis P, van den Hoonaard B, et al.; German Hodgkin Study Group. No protection of the ovarian follicle pool with the use of GnRH-analogues or oral contraceptives in young women treated with escalated BEACOPP for advanced-stage Hodgkin lymphoma. Final results of a phase II trial from the German Hodgkin Study Group. Ann Oncol 2010;21:2052–60. 57. Amsterdam A, Jakubowski A, Castro-Malaspina H, Baxi E, Kauff N, Krychman M, et al. Treatment of menorrhagia in women undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant 2004;34:363–6. 58. Sica S, Salutari P, Di Mario A, Chiusolo P, Rutella S, Ortu La Barbera E, et al. Treatment and prophylaxis of hypermenorrhea with leuprorelin in premenopausal women affected by acute leukemia at diagnosis. Am J Hematol 1996;51:248–9. 59. World Health Organization. Medical eligibility criteria for contraceptive use. 4th ed. Geneva: World Health Organization; 2009.

53. Bates JS, Buie LW, Woodis CB. Management of menorrhagia associated with chemotherapy-induced thrombocytopenia in women with hematologic malignancy. Pharmacotherapy 2011;31:1092–110.

60. Katagiri S, Tsubakio T, Minami G, Higashimoto Y, Yonezawa T, Tarui S, et al. Successful embolization for uterine hemorrhage in a patient with acute promyelocytic leukemia. Acta Haematol 1983;70:199–21.

54. Adegite EA, Goyal RK, Murray PJ, Marshal M, Sucato GS. The management of menstrual suppression and uterine bleeding: a survey of current practices in the Pediatric Blood and Marrow Transplant Consortium. Pediatr Blood Cancer 2012;59:553–7. doi: 10.1002/pbc.23360. Epub 2012 Feb 13.

61. Phelan J, Broder J, Kouides P. Near-fatal uterine hemorrhage during induction chemotherapy for acute myeloid leukemia: a case report of bilateral uterine artery embolization. Am J Hematol 2004;77:151–5.

55. Elgindy EA, El-Haieg DO, Khorshid OM, Ismail EI, Abdelgawad M, Sallam HN, et al. Gonadatrophin suppression to prevent chemotherapyinduced ovarian damage: a randomized controlled trial. Obstet Gynecol 2013;121:78–86.

62. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

924 l OCTOBER JOGC OCTOBRE 2014

SOGC COMMITTEE OPINION No. 287, February 2013

Current Status in Non-Invasive Prenatal Detection of Down Syndrome, Trisomy 18, and Trisomy 13 Using Cell-Free DNA in Maternal Plasma This committee opinion has been prepared by the Genetics Committee and approved by the Executive of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Sylvie Langlois, MD, Vancouver BC Jo-Ann Brock, MD, Halifax NS GENETICS COMMITTEE R. Douglas Wilson, MD (Chair), Calgary AB François Audibert, MD, Montreal QC Jo-Ann Brock, MD, Halifax NS

fetal DNA, aneuploidy screening). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. Searches were updated on a regular basis and incorporated in the guideline to October 31, 2012. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Values: The studies reviewed were classified according to criteria described by the Canadian Task Force on Preventive Health Care, and the recommendations for practice were ranked according to this classification (Table 1).

June Carroll, MD, Toronto ON

Recommendations

Lola Cartier, MSc, CCGC, Montreal QC

1. Non-invasive prenatal testing using massive parallel sequencing of cell-free fetal DNA to test for trisomies 21, 18, and 13 should be an option available to women at increased risk in lieu of amniocentesis. Pretest counselling of these women should include a discussion of the limitations of non-invasive prenatal testing. (II-2A)

Alain Gagnon, MD, Vancouver BC Jo-Ann Johnson, MD, Calgary AB Sylvie Langlois, MD, Vancouver BC William MacDonald, MD, Halifax NS Lynn Murphy-Kaulbeck, MD, Moncton NB Nanette Okun, MD, Toronto ON Melanie Pastuck, RN, Cochrane AB Vyta Senikas, MD, Ottawa ON Disclosure statements have been received from all of the committee.

2. No irrevocable obstetrical decision should be made in pregnancies with a positive non-invasive prenatal testing result without confirmatory invasive diagnostic testing. (II-2A) 3. Although testing of cell-free fetal DNA in maternal plasma appears very promising as a screening test for Down syndrome and other trisomies, studies in average-risk pregnancies and a significant reduction in the cost of the technology are needed before this can replace the current maternal screening approach using biochemical serum markers with or without fetal nuchal translucency ultrasound. (III-A)

Abstract Objective: To provide a review of published studies on the use of cell-free fetal DNA in maternal plasma for the non-invasive diagnosis of Down syndrome, trisomy 18, and trisomy 13. Evidence: PubMed was searched for articles published between 2006 and October 2012, using appropriate key words (e.g., non-invasive prenatal diagnosis, Down syndrome, cell-free

J Obstet Gynaecol Can 2013;35(2):177–181 Key Words: Non-invasive prenatal diagnosis, prenatal screening, Down syndrome, trisomy 18, trisomy 13, cell-free fetal DNA

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

FEBRUARY JOGC FÉVRIER 2013 l 177

SOGC COMMITTEE OPINION

Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.21 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care.21

INTRODUCTION

U

ntil recently, prenatal genetic diagnosis, either for increased risk of chromosome aneuploidy or for specific gene testing, has required a sample of fetal tissue obtained through invasive diagnostic procedures (CVS, amniocentesis, or umbilical blood sampling) that have associated fetal and maternal procedural risks including pregnancy loss. The finding of intact fetal cells and cffDNA in maternal blood has allowed the development of non-invasive prenatal diagnosis of certain fetal conditions. Several studies have validated the use of cffDNA in maternal plasma fetal sex determination1 and fetal Rh typing.2,3 Molecular testing of cffDNA has also been carried out for the detection of paternally inherited mutations in single genes.4 The presence of cffDNA in maternal plasma in all pregnancies, along with the development of new molecular technologies, has prompted research into the use of maternal plasma testing to detect fetal Down syndrome. As fetal DNA represents only 10% to 20% of the total DNA found in maternal plasma, the primary challenge of developing an accurate assay has been discriminating between a DNA sample with a fetal complement that

ABBREVIATIONS cffDNA cell free fetal DNA CVS

chorionic villus sampling

NIPT

non-invasive prenatal testing

178 l FEBRUARY JOGC FÉVRIER 2013

contributes 3 and one that contributes 2 copies of chromosome 21 to the total amount of plasma cellfree DNA of the mother. A recently developed massive parallel shotgun sequencing technology, in conjunction with sophisticated sequencing data analyses, has been used successfully to detect fetal Down syndrome in women with pregnancies at high risk for chromosomal abnormalities. In essence, millions of small fragments of cffDNA (either random or specific to chromosomes of interest) from maternal plasma (containing both fetal and maternal cell-free DNA) are amplified and sequenced. After the fragments are mapped to the human genome and analyzed for frequency/density along each chromosome, fetal Down syndrome is detected with a high degree of accuracy by observing an over-representation of chromosome 21. The same approach can be taken for the detection of other chromosomal abnormalities. REVIEW OF REPORTED NIPT STUDIES USING MASSIVELY PARALLEL SEQUENCING TO DETECT DOWN SYNDROME, TRISOMY 18, AND TRISOMY 13

Studies comparing the detection rate of Down syndrome by cffDNA testing with the detection rate by cytogenetic analysis of chorionic villus samples or amniocytes have been limited to high-risk pregnancies to enrich the cohort with cases that would indeed have Down syndrome and therefore allow validation of the technology being developed. Although the initial work was done in small cohorts of patients as proof of feasibility of this new technology,5–7 more recent studies validated its use in larger

Current Status in Non-Invasive Prenatal Detection of Down Syndrome, Trisomy 18, and Trisomy 13 Using Cell-Free DNA in Maternal Plasma

Table 2. Results of validation studies for non-invasive detection of fetal trisomy 21 Number samples tested

Failure rate*

Sequencing approach

Detection rate

Falsepositive rate

764

1.4%

8-plex, shotgun

79.1% (68/86)

1.1%

232

N/A

2-plex shotgun

100% (86/86)

2.1%

Palomaki et al. 20119

1696

0.8%

4-plex shotgun

98.6% (209/212) 95% CI 95.9 to 99.7

0.2% 95% CI < 0.1 to 0.6

Ehrich et al. 201110

467

3.9%

4-plex shotgun

100% (39/39) 95% CI 89 to 100

0.2% 95% CI 0.1 to 1.5

Lau et al. 201111

108

0

12-plex shotgun

100% (11/11)

0

Sehnert et al. 201112

47

0

1-plex shotgun

100% (13/13)

0

Sparks et al. 201213

167

0†

96-plex selective

100% (36/36)

0.8%

Ashoor et al. 201214

400

0.75%

96-plex selective

100% (50/50)

0

Bianchi et al. 201215

532

3%

6-plex

100% (89/89) 95% CI 95.9 to 100

0

Norton et al. 201216

3228

4.5%

96-plex selective

100% (81/81) 95% CI 95.5 to 100

0.03% 95% CI 0.002 to 0.2

Study Chiu et al. 20118

*Percentage of samples that did not meet quality control requirements for the sequencing so that no results could be obtained. †5% failure in their training set. N/A: not applicable—only samples that ed original sequencing quality control were retested with the 2-plex.

cohorts of pregnant women who had undergone an invasive procedure (CVS or amniocentesis).8–16 The indications for invasive diagnostic testing included advanced maternal age, abnormal aneuploidy screening results, and/or sonographically diagnosed fetal abnormalities. Results of these clinical trials are summarized in Table 2. Only trials that collected maternal blood samples before invasive procedures are included. While all studies used massive parallel sequencing, there were differences in methodology and sequencing data analysis between studies that prevent summing of the results. However, the detection rate for Down syndrome in all studies was, or approached, 100% with a false-positive rate less than 1%. The focus of studies so far has been the detection of Down syndrome; however, this technology has also been used to detect trisomy 18 and trisomy 13, although initially with less success because of a larger coefficient of variation and therefore lower precision in estimating the proportion of chromosomes 18 or 1311,17 to the total chromosomes. However, recent publications suggest that this can be overcome by using a targeted sequencing approach13,14,16 and/or a different sequencing data analysis approach.15,18 This is leading to the utilization of this technology for the detection of trisomy 18 and trisomy 13 in addition to Down syndrome. Results of those studies are presented in Table 3. ISSUES FOR CONSIDERATION

The development of new screening methods to detect Down syndrome through testing of cffDNA in maternal plasma offers promising opportunities to improve prenatal

screening. Before these methods can replace current prenatal screening options, validation studies using them in averagerisk pregnancies need to be done. Only one cohort study of 2049 women has so far been done in women at average risk.19 As the cost of the technology is high compared with current screening methods, cost-effectiveness studies are also needed. Given the demonstrated value of NIPT in high risk pregnancies, this testing should be an option available to pregnant women found to be at increased risk of fetal Down syndrome, trisomy 18, and trisomy 13 on the basis of currently available screening tests or ultrasound findings. It is important for these women to receive detailed pretest counselling that explains the benefits and limitations of the test.20 Counselling should include the following points: •• Non-invasive cffDNA testing should not be considered equivalent to conventional cytogenetic analysis of CVS or amniocytes. •• Cytogenetic testing of CVS or amniocytes detects 100% of cases of Down syndrome, trisomy 18, and trisomy 13 (thus is diagnostic), whereas the test done on cffDNA does miss some cases (see Table 2 and Table 3, detection rate). •• The currently available tests screen only for Down syndrome, trisomy 18, and trisomy 13. Other trisomies, triploidy, and structural chromosomal abnormalities would not be detected by the commercially available ccfDNA test. FEBRUARY JOGC FÉVRIER 2013 l 179

SOGC COMMITTEE OPINION

Table 3. Results of validation studies for non-invasive detection of fetal trisomy 18 and trisomy 13 Sequencing approach

Trisomy 18 detection rate

Trisomy 18 false-positive rate

Trisomy 13 detection rate

Trisomy 13 false-positive rate

12-plex shotgun

90% (9/10)

0

100% (2/2)

0

Sehnert et al. 2011

1-plex shotgun

100% (8/8)

0

No data

No data

Sparks et al. 201213

96-plex selective

100% (8/8)

0.8%

No data

No data

Ashoor et al. 201214

96-plex selective

98% (49/50)

0

No data

No data

Study Lau et al. 201111 12

Bianchi et al. 2012

15

Norton et al. 201216 Palomaki et al. 201218

6-plex

97.2% (35/36)

0

78.6% (11/14)

0

96-plex selective

97.4% (37/38)

0.07%

No data

No data

4-plex shotgun

100% (59/59)

0.28%

91.7% (11/12)

0.97%

•• cffDNA testing has a higher rate of false-positive results than current diagnostic tests based on cytogenetic analysis of amniocytes or chorionic villi. (Tables 2 and 3, false positive rate). •• Some women will have a cffDNA positive result and not carry a fetus with Down syndrome, trisomy 18, or trisomy 13 (false positive). No irrevocable obstetrical decision should be made in pregnancies with a positive cffDNA test for Down syndrome without confirmatory invasive diagnostic testing. •• cffDNA testing fails to provide a result in a small percentage of women. CONCLUSION

NIPT using massive parallel sequencing for the detection of Down syndrome, trisomy 18, and trisomy 13 has shown promising results in clinical trials of women identified by screening as having a high-risk pregnancy. NIPT should be an option as a second-level contingent screening test (after a positive result from currently used serum and ultrasound screening techniques) for women wishing to avoid invasive testing. Further studies are needed to determine if this approach can be reliably used as a first-tier screening test in average-risk pregnancies. Finally, cost-effectiveness studies are needed before this cffDNA approach can replace current screening options. Recommendations

1. Non-invasive prenatal testing using massive parallel sequencing of cell-free fetal DNA to test for trisomies 21, 18, and 13 should be an option available to women at increased risk in lieu of amniocentesis. Pretest counselling of these women should include a discussion of the limitations of non-invasive prenatal testing. (II-2A) 180 l FEBRUARY JOGC FÉVRIER 2013

2. No irrevocable obstetrical decision should be made in pregnancies with a positive non-invasive prenatal testing result without confirmatory invasive diagnostic testing. (II-2A) 3. Although testing of cell-free fetal DNA in maternal plasma appears very promising as a screening test for Down syndrome and other trisomies, studies in average-risk pregnancies and a significant reduction in the cost of the technology are needed before this can replace the current maternal screening approach using biochemical serum markers with or without fetal nuchal translucency ultrasound. (III-A) REFERENCES 1. Avent ND, Chitty LS. Non-invasive diagnosis of fetal sex; utilisation of free fetal DNA in maternal plasma and ultrasound. Prenat Diagn 2006;26:598–603. 2. Minon JM, Gerard C, Senterre JM, Schaaps JP, Foidart JM. Routine fetal RHD genotyping with maternal plasma: a four-year experience in Belgium. Transfusion 2008; 48:373–81. 3. Finning K, Martin P, Summers J, Massey E, Poole G, Daniels G. Effect of high throughput RHD typing of fetal DNA in maternal plasma on use of anti-RhD immunoglobulin in RhD negative pregnant women; prospective feasibility study. Br Med J 2008;336:816–8. 4. Wright CF, Burton H. The use of cell-free fetal nucleic acids in maternal blood for non-invasive prenatal diagnosis. Hum Reprod Update 2009;15:139–51. 5. Fan HC, Blumenfeld YJ, Chitkara U, Hudgins L, Quake SR. Noninvasive diagnosis of fetal aneuploidy by shotgun sequencing DNA from maternal blood. PNAS 2008;105:16266–71. 6. Chiu RWK, Chan KCA, Gao Y, Lau VYM, Zheng W, Leung TY, et al. Noninvasive prenatal diagnosis of fetal chromosomal aneuploidy by massively parallel genomic sequencing of DNA in maternal plasma. PNAS 2008;105:20458–63. 7. Chiu RWK, Sun H, Akolekar R, Clo C, Lee C, McKernan K, et al. Maternal plasma DNA analysis with massively parallel sequencing by ligation for noninvasive prenatal diagnosis of trisomy 21. Clin Chem 2010;56:459–63. 8. Chiu RWK, Akolekar R, Zheng YWL, Leung TY, Sun H, Chan KCA, et al. Non-invasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DNA sequencing: large scale validity study. BMJ 2011;342:c7401.

Current Status in Non-Invasive Prenatal Detection of Down Syndrome, Trisomy 18, and Trisomy 13 Using Cell-Free DNA in Maternal Plasma

9. Palomaki GE, Kloza EM, Lambert-Messerlian GM, Haddow JE, Neveux LM, Ehrich M, et al. DNA sequencing of maternal plasma to detect Down syndrome: an international clinical validation study. Genet Med 2011;13:913–20. 10. Ehrich M, Deciu C, Zwiefelhofer T, Tynan JA, Cagasan L, Tim R, et al. Noninvasive detection of fetal trisomy 21 by sequencing of DNA in maternal blood: a study in a clinical setting. Am J Obstet Gynecol 2011;204(3):205e1–11. 11. Lau TK, Chan F, Pan X, Pooh RK, Jiang F, Li Y, et al. Noninvasive prenatal diagnosis of common fetal chromosomal aneuploidies by maternal plasma DNA sequencing. J Matern Fetal Neonatal Med 2012;25(8):1370–4. 12. Sehnert AJ, Rhees B, Comstock D, de Feo E, Heilek G, Burke J, et al. Optimal detection of fetal chromosomal abnormalities by massively parallel DNA sequencing of cell-free fetal DNA from maternal blood. Clin Chem 2011:57:1042–9. 13. Sparks AB, Struble ET, Wang ET, Song K, Oliphant A. Non-invasive prenatal detection and selective analysis of cell-free DNA obtained from maternal blood: evaluation for trisomy 21 and trisomy 18. Am J Obstet Gynecol 2012;206:319.e1–9. 14. Ashoor G, Syngelaki A, Wagner M, Birdir C, Nicolaides KH. Chromosome-selective sequencing of maternal plasma cell-free DNA for first-trimester detection of trisomy 21 and trisomy 18. Am J Obstet Gynecol 2012; 206:322.e1–5. 15. Bianchi DW, Platt LD, Goldberg JD, Abuhamad AZ, Sehnert A, Rava RP. Genome-wide fetal aneuploidy detection by maternal plasma. Obstet Gynecol 2012;119(5);890–901.

16. Norton ME, Brar H, Weiss J, Karimi A, Laurent LC, Caughey AB, et al. Non-invasive chromosomal evaluation (NICE) study: results of a multicenter prospective cohort study for detection of fetal trisomy 21 and trisomy 18. Am J Obstet Gynecol 2012; 207:e1–8. 17. Chen EZ, Chiu RW, Sun H, Akolekar R, Chan KC, Leung TY, et al. Noninvasive prenatal diagnosis of fetal trisomy 18 and trisomy 13 by maternal plasma DNA sequencing. PLoS ONE 2011;6:e21791. 18. Palomaki GE, Deciu C, Kloza EM, Lambert-Messerlian GM, Haddow JE, Neveux LM, et al. DNA sequencing of maternal plasma reliably identifies trisomy 18 and trisomy 13 as well as Down syndrome: an international collaborative study. Genet Med 2012;14(3):295–305. 19. Nicolaides KH, Syngelaki A, Ashoor G, Birdir C, Touzet G. Noninvasive prenatal testing for fetal trisomies in a routinely screened first-trimester population. Am J Obstet Gynecol 2012;207(5):374.e1–6 20. Benn P, Borrell A, Cuckle H, Dugoff L, Gross S, Johnson J, et al. Prenatal detection of Down syndrome using massively parallel sequencing (MPS): a rapid response statement from a committee on behalf of the Board of the International Society for Prenatal Diagnosis, 24 October 2011. Prenat Diagn 2012;32:1–2. 21. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

FEBRUARY JOGC FÉVRIER 2013 l 181

SOGC CLINICAL PRACTICE GUIDELINE No. 298, October 2013 (Replaces No. 149, September 2004)

The Prevention of Early-Onset Neonatal Group B Streptococcal Disease This Clinical Practice Guideline has been prepared by the Infectious Disease Committee, reviewed by the Infectious Diseases and Immunization and the Fetus and Newborn Committees of the Canadian Paediatric Society, and the SOGC Family Practice Advisory Committee, and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Deborah Money, MD, Vancouver BC Victoria M. Allen, MD, Halifax NS INFECTIOUS DISEASES COMMITTEE Mark H. Yudin, MD (Chair), Toronto ON Victoria M. Allen, MD, Halifax NS Celine Bouchard, MD, Quebec QC Marc Boucher, MD, Montreal QC Sheila Caddy, MD, Edmonton AB Eliana Castillo, MD, Calgary AB Deborah Money, MD, Vancouver BC Kellie E. Murphy, MD, Toronto ON Gina Ogilvie, MD, Vancouver BC Caroline Paquet, RM, Trois-Rivieres QC Vyta Senikas, MD, Ottawa ON Julie van Schalkwyk, MD, Vancouver BC Disclosure statements have been received from all of the committees

Key Words: Group B streptococcus, antibiotic therapy, infection, prevention

Abstract Objective: To review the evidence in the literature and to provide recommendations on the management of pregnant women in labour for the prevention of early-onset neonatal group B streptococcal disease. The key revisions in this updated guideline include changed recommendations for regimens for antibiotic prophylaxis, susceptibility testing, and management of women with pre-labour rupture of membranes. Outcomes: Maternal outcomes evaluated included exposure to antibiotics in pregnancy and labour and complications related to antibiotic use. Neonatal outcomes of rates of early-onset group B streptococcal infections are evaluated. Evidence: Published literature was retrieved through searches of MEDLINE, CINAHL, and The Cochrane Library from January 1980 to July 2012 using appropriate controlled vocabulary and key words (group B streptococcus, antibiotic therapy, infection, prevention). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to May 2013. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Values: The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). Benefits, Harms, and Costs: The recommendations in this guideline are designed to help clinicians identify and manage pregnancies at risk for neonatal group B streptococcal disease to optimize maternal and perinatal outcomes. No cost-benefit analysis is provided.

J Obstet Gynaecol Can 2013;35(10):939–948

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

OCTOBER JOGC OCTOBRE 2013 l 939

SOGC Clinical Practice Guideline

Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.73 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care.73

Summary Statement There is good evidence based on randomized control trial data that in women with pre-labour rupture of membranes at term who are colonized with group B streptococcus, rates of neonatal infection are reduced with induction of labour. (I) There is no evidence to safe neonatal outcomes with expectant management in this clinical situation. Recommendations 1. Offer all women screening for colonization with group B streptococcus at 35 to 37 weeks’ gestation with culture taken from one swab first to the vagina and then to the rectum (through the anal sphincter). (II-1A) This includes women with planned Caesarean delivery because of their risk of labour or ruptured membranes earlier than the scheduled Caesarean delivery. (II-2B) 2. Because of the association of heavy colonization with early onset neonatal disease, provide intravenous antibiotic prophylaxis for group B streptococcus at the onset of labour or rupture of the membranes to: • any woman positive for group B streptococcus by vaginal/rectal swab culture screening done at 35 to 37 weeks’ gestation (II-2B); • any woman with an infant previously infected with group B streptococcus (II-3B);

ABBREVIATIONS CDC

Centers for Disease Control and Prevention

GBS

group B streptococcus

IV intravenous PCR

polymerase chain reaction

PPROM preterm pre-labour rupture of membranes PROM pre-labour rupture of membranes

940 l OCTOBER JOGC OCTOBRE 2013

• any woman with documented group B streptococcus bacteriuria (regardless of level of colony-forming units) in the current pregnancy. (II-2A) 3. Manage all women who are < 37 weeks’ gestation and in labour or with rupture of membranes with intravenous group B streptococcus antibiotic prophylaxis for a minimum of 48 hours, unless there has been a negative vaginal/rectal swab culture or rapid nucleic acid-based test within the previous 5 weeks. (II-3A) 4. Treat all women with intrapartum fever and signs of chorioamnionitis with broad spectrum intravenous antibiotics targeting chorioamnionitis and including coverage for group B streptococcus, regardless of group B streptococcus status and gestational age. (II-2A) 5. Request antibiotic susceptibility testing on group B streptococcus-positive urine and vaginal/rectal swab cultures in women who are thought to have a significant risk of anaphylaxis from penicillin. (II-1A) 6. If a woman with pre-labour rupture of membranes at ≥ 37 weeks’ gestation is positive for group B streptococcus by vaginal/rectal swab culture screening, has had group B streptococcus bacteriuria in the current pregnancy, or has had an infant previously affected by group B streptococcus disease, ister intravenous group B streptococcus antibiotic prophylaxis. Immediate obstetrical delivery (such as induction of labour) is indicated, as described in the Induction of Labour guideline published by the Society of Obstetricians and Gynaecologist in September 2013. (II-2B) 7. At ≥ 37 weeks’ gestation, if group B streptococcus colonization status is unknown and the 35- to 37-week culture was not performed or the result is unavailable and the membranes have been ruptured for greater than 18 hours, ister intravenous group B streptococcus antibiotic prophylaxis. (II-2B) 8. If a woman with pre-labour rupture of membranes at < 37 weeks’ gestation has an unknown or positive group B streptococcus culture status, ister intravenous group B streptococcus prophylaxis for 48 hours, as well as other antibiotics if indicated, while awaiting spontaneous or obstetrically indicated labour. (II-3B)

The Prevention of Early-Onset Neonatal Group B Streptococcal Disease

INTRODUCTION

T

he purpose of this guideline is to review the literature and evidence for management of pregnant women in Canada in order to minimize the risk of early-onset neonatal disease due to group B streptococcus. Since publication of the 2004 SOGC guideline “The Prevention of Early-onset Neonatal Group B streptococcal Disease,”1 there has been ongoing evaluation of screening, intrapartum antibiotic management, and neonatal outcomes. BACKGROUND

Group B streptococci (streptococcus agalactiae) are grampositive, aerobic diplococci that typically produce a narrow zone of beta hemolysis on 5% sheep blood agar. These organisms are divided into 10 types on the basis of capsular polysaccharides (Ia, Ib, II, and III through IX). Types Ia, Ib, II, III, and V for approximately 95% of cases in infants in the United States. Type III is the predominant cause of early-onset meningitis and the majority of late-onset infections in infants. Pilus-like structures are important virulence factors and potential vaccine candidates.2 Neonatal GBS disease can be classified as early- or lateonset. Early-onset disease occurs less than 7 days after birth and is associated with a mortality rate of 5% to 20%.3 Davies et al. reviewed the distribution of early-onset disease in neonates in Canada and found 71% developed bacteremia, 11% meningitis, and 19% pneumonia.4 The introduction of universal GBS screening in 2002 was associated with a reduction in rates of early-onset GBS disease to approach rates of late-onset disease.5,6 Infection with GBS remains a significant cause of neonatal morbidity and mortality in North America.2,6 Associated with the introduction of systematic intrapartum chemoprophylaxis, the incidence of neonatal disease in Canada and the United States has decreased from 1 to 3 per 1000 in the early 1990s to 0.35 to 0.5 per 1000 since the adoption of universal screening.6–8 A Centers for Disease Control and Prevention surveillance study estimated that the use of intrapartum chemoprophylaxis has prevented 4500 cases per year of GBS sepsis and 225 deaths per year in the United States.9 A Canadian population-based study demonstrated an overall incidence of neonatal GBS infections of 0.64 per 1000 live births, 57% of which were early-onset disease. This study demonstrated a case fatality rate from early-onset GBS infection of 9%, with 11% of all cases of GBS disease ending in stillbirth.4 Case fatality rates of 20% to 30% are seen in infants with GBS disease born preterm, compared with 2% to 3% among term infants.9

Group B streptococcus is part of the normal vaginal microbiome, and in North America 10% to 30% of women are colonized.10 A Canadian study published in 1998 showed an overall colonization rate of 11%,11 while a study in a different Canadian population showed a colonization rate of 30% at time of delivery.12 An estimated 1% to 2% of infants born to colonized women develop early-onset GBS disease.13 The overall case fatality rate is currently 5% to 9% compared with 70% three decades ago.3,11,14 The prevalence of GBS colonization appears to differ among different populations. In the United Kingdom, the incidence of early-onset GBS disease, in the absence of systematic screening or widespread intrapartum antibiotic prophylaxis, is lower than in Canada, with a rate of 0.5 per 1000 births.15 In addition, there was a comparable incidence of 0.4 per 1000 live births in Sweden,16 ing subsequent European clinical practice guidelines recommending a risk factorbased approach to prevention of GBS disease. Lower urogenital tract colonization with GBS may be chronic, transient, or intermittent. The presence of GBS in clean-catch urine cultures reflects heavy genital tract maternal colonization, which is associated with neonatal disease.17,18 Vaginal colonization in early pregnancy does not predict colonization at delivery,19 but vaginal colonization has generally been associated with young maternal age,20 sexual activity, tampon use, infrequent handwashing,21 high temperatures, and humidity.22 Most of these data are from small studies and require confirmation. Risk factors for neonatal infection include <  37 completed weeks of gestation at birth, prolonged rupture of membranes (> 18 hours), intra-amniotic infection, low socioeconomic status, and low maternal levels of anticapsular antigen.14,23–27 A UK study found the main risk factors to be prematurity, rupture of membranes for longer than 18 hours, and maternal fever in labour.28 Of note, diabetes in pregnancy is associated with higher rates of GBS colonization.29,30 One study using Canadian data has implicated intrauterine fetal monitoring (fetal scalp electrode) as an independent risk factor for neonatal GBS disease.27 When birth weight is ed for, maternal carriage of GBS has been shown to be independently associated with early-onset GBS disease (OR 6.9; 95% CI 2.8 to 17.1).31 Recent information demonstrates that known antepartum or intrapartum predisposing risk factors for GBS disease are lacking in 30% to 50% of women with infants with GBS disease.27,32–34 The diagnosis of GBS sepsis in infants with risks for or signs of sepsis, therefore, should not be ruled out because OCTOBER JOGC OCTOBRE 2013 l 941

SOGC Clinical Practice Guideline

of negative maternal GBS screening. This emerging information from European and Canadian populations was not available at the time of the Canadian Task Force on Preventative Health Care’s 2001 report on the prevention of early-onset group B streptococcal infection in the newborn, which recommended that universal screening with selective intrapartum chemoprophylaxis be given to colonized women with risk factors.35 Heavy colonization with GBS has been associated with adverse pregnancy outcomes including preterm labour and preterm pre-labour rupture of membranes.36,37 GBS bacteriuria occurs in 2% to 4% of pregnancies and is associated with both maternal urinary tract disease and an increased risk of neonatal disease.17 Maternal colonization with GBS has been associated with endometritis and wound infection.38,39 There is no convincing evidence that GBS bacteriuria with low colony counts (< 108 CFU/L or < 105 CFU/mL) is associated with increased risks for pyelonephritis, chorioamnionitis, or preterm birth, and antepartum treatment (prior to the onset of labour or rupture of membranes) for low colony counts is therefore not recommended. Intrapartum IV antibiotic prophylaxis is still recommended for GBS bacteriuria in the current pregnancy, regardless of colony count.40 Laboratory reporting of any colony count of GBS in the urine in pregnancy is variable among centres in Canada. STRATEGIES TO PREVENT NEONATAL GBS

Chemoprophylaxis before the onset of labour or rupture of membranes has been shown to be ineffective;41 antepartum antibiotic prophylaxis of colonized women results in a 67% recurrence of GBS colonization later in pregnancy.42 Intrapartum therapy has been found to be effective in preventing neonatal GBS disease.39,43 Immunization strategies have been proposed as a preferred prevention approach but vaccine development has been challenging, however, a multivalent capsular antigen based vaccine is in clinical trials at present.44 The pivotal randomized controlled trial of Boyer and Gotoff in 1985 showed that use of intrapartum antibiotics decreased the risk of early-onset disease in neonates and decreased perinatal febrile morbidity in colonized women.45 An early meta-analysis of 7 studies (5 controlled trials and 2 cohort studies) demonstrated a 30-fold reduction in early-onset GBS disease with the use of intrapartum penicillin prophylaxis for GBS-colonized women.46 This culminated in screening and prophylaxis recommendations from the CDC in 1996.8 These 942 l OCTOBER JOGC OCTOBRE 2013

recommendations advised one of two approaches: a universal screening or a risk-factor approach. The screening approach involved performing a rectovaginal swab at 35 to 37 weeks and culturing in selective broth. All women colonized with GBS were to receive intrapartum antibiotics, and women with negative cultures were to receive antibiotics only if they developed signs of chorioamnionitis. A risk-factor approach (onset of labour at < 37 weeks’ gestation, membrane rupture > 18 hours, intrapartum temperature > 38.0°C) was considered an acceptable alternative. If women had GBS bacteriuria in the current pregnancy or a previous infant who had invasive GBS disease, they were to receive intrapartum chemoprophylaxis regardless of current colonization status, and would not require a vaginal/anal swab for GBS culture at 35 to 37 weeks’ gestation. In June 1997, the Society of Obstetricians and Gynaecologists of Canada presented guidelines which were congruent to those recommended by the CDC.47 The Canadian guideline stated that two methods were acceptable, either universal screening at 35 to 37 weeks by combined vaginal/rectal swab and intrapartum chemoprophylaxis of all colonized women, or intrapartum chemoprophylaxis of women with risk factors. It was acknowledged that additional research was required to evaluate the prevention of neonatal GBS disease. The influence of the 1996 CDC and 1997 SOGC guidelines can be evaluated by the epidemiologic changes which occurred following their implementation. There has been a decline in perinatal GBS disease, with a 70% decrease in early-onset disease to 0.5 per 1000 live births.25,26 Maternal infection also declined by 21% from 0.29 to 0.23 per 1000 deliveries from 1993 to 1998.26 While multiple studies have provided data demonstrating a general reduction of neonatal GBS rates with concomitant maternal benefits, health-care providers’ difficulties in complying with the complex protocol was often commented upon in the studies.4,9,48–52 Improved management of preterm deliveries and improved collection, processing, and reporting of culture results were recently identified as potential areas for improved prevention of early-onset GBS disease.53 Despite a comment on the lack of quality of the studies reviewed, a Cochrane Review performed in 2000 concluded that the use of intrapartum antibiotic prophylaxis of women colonized with GBS reduces neonatal infection.43 A more recent Cochrane Review suggested that intrapartum antibiotic prophylaxis showed no statistically significant reduction in the risk for neonatal all-cause mortality, or mortality from

The Prevention of Early-Onset Neonatal Group B Streptococcal Disease

GBS and non-GBS organisms (primary outcome analyses).54 However, analysis of secondary outcomes suggested a statistically significant reduction (80%) in the incidence of both confirmed early-onset GBS disease (RR 0.17, 95% CI 0.04 to 0.74, number needed to benefit 25) and probable early-onset GBS disease (RR 0.17, 95% CI 0.03 to 0.91, number needed to benefit 20) in neonates following intrapartum antibiotics compared to no prophylaxis. There was no reduction in the incidence of late-onset GBS neonatal disease. The trials included in this meta-analysis were of poor quality and had significant methodological biases.54 RISK-BASED VERSUS SCREENING APPROACH

No randomized trials have evaluated intrapartum antibiotic prophylaxis based on risk factors versus universal screening approaches, although a number of non-randomized studies have attempted to evaluate the merits of screening versus a risk-based approach.55,56 In most studies, the screening approach included intrapartum prophylaxis for all women who were colonized at the time of labour or rupture of membranes. A large CDC multistate study of a stratified random sample of 626 912 live births in 1998 and 1999 demonstrated that of 5144 births, the risk of early-onset disease was significantly lower among the infants of screened women compared to those born to mothers managed with the risk-based approach (adjusted RR 0.46; 95% CI 0.36 to 0.60).56 This information prompted the development of revised guidelines by the CDC in 2002.57 The most significant recommendation in the CDC guideline at that time included a change from a dual approach to universal prenatal culture-based screening for vaginal and rectal GBS colonization of all pregnant women at 35 to 37 weeks’ gestation. Updated prophylaxis regimens for women with a penicillin allergy were provided, including cefazolin if not at high risk for anaphylaxis, clindamycin or erythromycin if high risk for anaphylaxis and GBS susceptible, or vancomycin if GBS resistant or susceptibility unknown. Clindamycin can only be utilized for erythromycin-resistant isolates if inducible clindamycin resistance has been excluded. Intrapartum antibiotic GBS prophylaxis for GBS-colonized women undergoing planned Caesarean delivery before the onset of labour with intact membranes was not recommended.57 A further update by the CDC in 2010 has included a change in the recommended dose for penicillin G for prophylaxis (acceptable dose range of 2.5 to 3.0 million units for doses subsequent to the initial dose), changes to prophylaxis regimens for women with penicillin allergy (removal of erythromycin as an acceptable alternative

due to an increase in resistance in GBS seen recently), and updated and separate algorithms for women with preterm labour (discontinue GBS prophylaxis if not in labour) and PPROM (provide GBS prophylaxis intravenously for 48 hours [or less if the swab for GBS culture is subsequently negative], as well as antibiotics for latency if other antibiotic regimens are usually used).13 Economic analyses of risk-based and universal culturebased approaches have been conducted and showed that universal culture-based is equivalent in cost to risk-based approach if one considers the cost savings involved with reduction of morbidity and mortality. It has also been shown that a risk-based versus screening approach is essentially equivalent in cost and in the number of women receiving antibiotics prophylaxis.58 Recommendations

1. Offer all women screening for colonization with group B streptococcus at 35 to 37 weeks’ gestation with culture taken from one swab first to the vagina and then to the rectum (through the anal sphincter). (II-1A) This includes women with planned Caesarean delivery because of their risk of labour or ruptured membranes earlier than the scheduled Caesarean delivery. (II-2B) 2. Because of the association of heavy colonization with early onset neonatal disease, provide intravenous antibiotic prophylaxis for group B streptococcus at the onset of labour or rupture of the membranes to: • any woman positive for group B streptococcus by vaginal/rectal swab culture screening done at 35 to 37 weeks’ gestation (II-2B); • any woman with an infant previously infected with group B streptococcus (II-3B); • any woman with documented group B streptococcus bacteriuria (regardless of level of colony-forming units) in the current pregnancy. (II-2A) 3. Manage all women who are < 37 weeks’ gestation and in labour or with rupture of membranes with intravenous group B streptococcus antibiotic prophylaxis for a minimum of 48 hours, unless there has been a negative vaginal/rectal swab culture or rapid nucleic acid-based test within the previous 5 weeks. (II-3A) 4. Treat all women with intrapartum fever and signs of chorioamnionitis with broad spectrum intravenous antibiotics targeting chorioamnionitis and including coverage for group B streptococcus, regardless of group B streptococcus status and gestational age. (II-2A)

OCTOBER JOGC OCTOBRE 2013 l 943

SOGC Clinical Practice Guideline

Table 2. Recommended antibiotic regimens for intrapartum prophylaxis 1.

Penicillin G 5 million units IV, then 2.5 to 3.0 million every 4 hours until delivery or

2.

If the woman is allergic to penicillin but has a low risk of anaphylaxis: cefazolin 2 g IV then 1 g every 8 hours until delivery or

3.

If the woman is allergic to penicillin and at risk of anaphylaxis: clindamycin 900 mg IV every 8 hours until delivery (if isolate is susceptible to clindamycin with no inducible resistance) or vancomycin 1 g IV every 12 hours until delivery

PRACTICAL ASPECTS OF THE SCREENING METHODS

A vaginal/rectal (not vaginal/perianal) swab is taken at 35 to 37 weeks’ gestation to screen women and detect GBS colonization of the genital tract. This is done by using a single swab first in the vagina then in the rectum and transporting it at room temperature to the laboratory in a non-nutritive transport medium; Amies or Stuart’s medium is recommended.59 These specimens should be labelled clearly to inform the laboratory of the need to perform specific GBS culturing. In addition, if the woman is allergic to penicillin and is at a high risk for anaphylaxis, this should be stated and a request made to perform susceptibility testing (see Table 2).60,61 The laboratory can then culture the organism in selective broth media to maximize the isolation of GBS. Self-sampling for GBS at 35 to 37 weeks’ gestation, with appropriate instruction in the clinical examination room or washroom, has been shown to be accurate and acceptable when compared with physician sampling in a Canadian population.62 Recommendation

5. Request antibiotic susceptibility testing on group B streptococcus-positive urine and vaginal/rectal swab cultures in women who are thought to have a significant risk of anaphylaxis from penicillin. (II-1A) Antenatal GBS cultures at 35 to 37 weeks’ gestation have been shown in a recent systematic review to have acceptable positive and negative predictive values for colonization at delivery (mean positive predictive value 69%, mean negative predictive value 94%).63 A preferable method may be a rapid accurate test to detect the presence of GBS at the actual time of delivery. The use of a polymerase chain reaction has been shown to have a sensitivity of 97% and a negative predictive value of 98.8%.64 The one negative PCR in the 33 women evaluated was in a woman with ruptured membranes prior to testing. In a Canadian single-centre study evaluating the use of rapid PCR (IDIStrep B assay) in the labour and delivery suite, 85% of the 944 l OCTOBER JOGC OCTOBRE 2013

190 women enrolled had results of the standard screen at 35 to 37 weeks available for comparison.12 The sensitivity and specificity of the standard 35- to 37-week screen were 84.3% (95% CI 71.4% to 93.0%) and 93.2% (95% CI 86.5% to 97.2%), respectively, whereas the sensitivity and specificity of the rapid PCR were 90.7% (95% CI 79.7% to 96.9%) and 97.6% (95% CI 93.1% to 99.5%), respectively. The median reporting time for the rapid PCR test was 99 minutes (range 50 to 255). Results were available more than 4 hours before delivery in 81% of cases.12 The advantage of PCR screening is the rapid, real-time result; the disadvantages are the lack of antibiotic susceptibility data, potentially false-negative results related to rupture of membranes, and the fact that there is insufficient time for use of selective enrichment broth for at least 4 hours prior to PCR in the intrapartum setting. The 2010 CDC guideline suggests that a useful intrapartum screening test should be simple, have a turn-around time of < 30 minutes, and have a sensitivity and specificity of ≥ 90%.13 This technique would be reserved for hospitals that had diagnostic laboratory capabilities of realtime PCR testing, validated PCR performance, and appropriate quality controls. A study comparing the estimated direct costs (including screening test costs and hospital costs) and consequences of intrapartum PCR screening for early-onset GBS disease (Xpert GBS test) with antenatal lower vagina culture screening demonstrated a higher detection rate of GBS colonization with PCR (16.7% versus 11.7%). The average total cost per delivery was US$1759 ± 1209 for antenatal screening in 2009 and US$1754 ± 842 for intrapartum screening in 2010 (P = 0.9).65 With improved techniques, therefore, in some institutions GBS screening may be replaced by intrapartum PCR assessment. ANTIBIOTIC CHOICES

Since GBS appears to be uniformly susceptible to the penicillins, it is recommended that IV penicillin G be used instead of IV ampicillin because of penicillin G’s narrow spectrum of action, which diminishes the risk of selective pressure on other organisms and decreases the

The Prevention of Early-Onset Neonatal Group B Streptococcal Disease

risk of ampicillin resistance.66,67 The efficacy of alternatives to penicillin to prevent early-onset GBS disease (such as cephalosporins, clindamycin, or vancomycin) has not been evaluated in controlled trials.13 Intravenous cefazolin is recommended as the alternative for penicillin-allergic women who are at low risk for anaphylaxis (do not have a history of anaphylaxis, angioedema, respiratory distress, or significant urticaria). It has a relatively narrow spectrum, with similar pharmacokinetics to penicillin, and achieves high intra-amniotic concentrations.13 The risk of allergic or anaphylactic reaction to penicillins is between 4 per 10 000 and 4 per 100 000.56 For first-generation cephalosporins, the risk of cross-reaction with penicillins is 0.5%; the risk with second- and third-generation cephalosporins appears to be even lower.68 Erythromycin and clindamycin were previously proposed as alternative antibiotics for women at high risk for anaphylaxis; however, the prevalence of resistance among invasive GBS isolates has increased over the last 20 years and ranges from 25% to 32% for erythromycin and from 13% to 20% for clindamycin.13,60,69 Although efficacy data is limited, the 2010 CDC guidelines recommend intravenous vancomycin and clindamycin for women (if susceptible) at high risk for anaphylaxis from penicillin; clindamycin susceptibilities including a search for inducible clindamycin resistance should be performed if possible on prenatal GBS isolates from penicillinallergic women.13 If susceptibilities are not available for these women, intravenous vancomycin is the preferred intrapartum prophylaxis. Oral antibiotic preparations are not adequate for GBS prophylaxis, as they do not show satisfactory rates of clearance of GBS from the genital tract in the time frame of labour. Table 2 summarizes the recommended regimens for intravenous intrapartum antibiotic prophylaxis for the prevention of early-onset GBS disease. The implementation of a screening protocol will result in approximately 10% to 25% of women in labour receiving antibiotics for the prevention of GBS neonatal disease. Concern that the use of antibiotics for GBS prophylaxis may result in the selection of other organisms such as E. coli is certainly an issue in theory; however, a study of trends in neonatal sepsis has been reassuring, with no increase in the rate of neonatal sepsis overall in the postGBS prophylaxis era, but some increase in E. coli sepsis in preterm or low-birth-weight infants only.70 It would be prudent to continue to be vigilant in tracking trends in sepsis and antibiotic resistance as new prophylactic antibiotic regimens are implemented.

PRE-LABOUR RUPTURE OF MEMBRANES

In the term PROM study, Hannah et al. reviewed their outcomes in GBS-colonized women versus GBS-negative women.71 In that study, 4834 women were randomized to induction versus expectant management. Researchers found that 10.7% of women were GBS positive by vaginal/ rectal swab culture and 127 infants had neonatal infections, of which 10 were due to GBS, all in the expectant arm; there was one death due to GBS in the expectant group. The analysis revealed that for GBS-positive women, induction of labour at term decreased the risk of neonatal infection (OR 0.29; 95% CI 0.08 to 1.05, P = 0.06). In the expectant management group, GBS-positive women had a significantly greater risk of neonatal infection (OR 4.12; 95% CI 2.00 to 8.52, P < 0.001). The conclusion of the study was that for GBS-colonized women with PROM at term, immediate induction with oxytocin results in a lower risk of infection than expectant management or induction with prostaglandin E2 (if there are no contraindications to vaginal delivery). Summary Statement

There is good evidence based on randomized control trial data that in women with pre-labour rupture of membranes at term who are colonized with group B streptococcus, rates of neonatal infection are reduced with induction of labour. (I) There is no evidence to safe neonatal outcomes with expectant management in this clinical situation. Recommendations

6. If a woman with pre-labour rupture of membranes at ≥ 37 weeks’ gestation is positive for group B streptococcus by vaginal/rectal swab culture screening, has had group B streptococcus bacteriuria in the current pregnancy, or has had an infant previously affected by group B streptococcus disease, ister intravenous group B streptococcus antibiotic prophylaxis. Immediate obstetrical delivery (such as induction of labour) is indicated, as described in the Induction of Labour guideline published by the Society of Obstetricians and Gynaecologist in September 2013. (II-2B) 7. At ≥ 37 weeks’ gestation, if group B streptococcus colonization status is unknown and the 35- to 37week culture was not performed or the result is unavailable and the membranes have been ruptured for greater than 18 hours, ister intravenous group B streptococcus antibiotic prophylaxis. (II-2B) OCTOBER JOGC OCTOBRE 2013 l 945

SOGC Clinical Practice Guideline

The 2010 CDC guideline provides an updated and separate algorithm for women with PPROM. It recommends providing GBS prophylaxis intravenously for 48 hours (or less if the swab for GBS culture proves negative) and additional antibiotics to prolong the latency period when the standard of care would suggest that increased latency and expectant management might show improved maternal and fetal/neonatal outcomes over indicated obstetrical delivery (such as induction of labour).13 Recommendation

8. If a woman with pre-labour rupture of membranes at < 37 weeks’ gestation has an unknown or positive group B streptococcus culture status, ister intravenous group B streptococcus prophylaxis for 48 hours, as well as other antibiotics if indicated, while awaiting spontaneous or obstetrically indicated labour. (II-3B) NEONATAL MANAGEMENT

Information related to the current management of the infant at increased risk of sepsis, including risk of GBS disease, may be found on the website of the Canadian Paediatric Society (Fetus and Newborn Committee).72 REFERENCES 1. Dobson S, Money D. The prevention of early-onset neonatal group B streptococcal disease. Society of Obstetricians and Gynaecologists of Canada Clinical Practice Guideline, No. 149, September 2004. J Soc Obstet Gynaecol Can 2004;26:826–32. 2. American Academy of Pediatrics. Pickering LK, ed. Red book: 2012 report of the Committee on Infectious Diseases. 29th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2012. 3. Franciosi RA, Knostman JD, Zimmerman RA. Group B streptococcal neonatal and infant infections. J Pediatr 1973;82:707–18. 4. Davies HD, Raj S, Adair C, Robinson J, McGeer A. Population-based active surveillance for neonatal group B streptococcal infections in Alberta, Canada: implications for vaccine formulation. Pediatr Infect Dis J 2001;20:879–84. 5. Centers for Disease Control and Prevention. Perinatal group B streptococcal disease after universal screening recommendations– United States 2003-2005. Morb Mortal Wkly Rep 2007;56:701–5. 6. Centers for Disease Control and Prevention. Trends in perinatal group B streptococcal disease–United States 2000-2006. Morb Mortal Wkly Rep 2009;58:109–12.

10. Schuchat A, Wenger JD. Epidemiology of group B streptococcal disease: risk factors, prevention strategies, and vaccine development. Epidemiol Rev 1994;16:374–402. 11. Seaward PG, Hannah ME, Myhr TL, Farine D, Ohlsson A, Wang EE, et al. International multicenter term PROM study: evaluation of predictors of neonatal infection in infants born to patients with premature rupture of membranes at term. Am J Obstet Gynecol 1998;179(3 Pt 1):635–9. 12. Money D, Dobson S, Cole L, Karacabeyli E, Blondel-Hill E, Milner R, et al. An evaluation of a rapid real time polymerase chain reaction assay for detection of group B streptococcus as part of a neonatal group B streptococcus prevention strategy. J Obstet Gynaecol Can 2008;30:770–5. 13. Centers for Disease Control and Prevention. Prevention of perinatal group B streptococcal disease. Mor Mortal Wkly Rep 2010;59(RR-10):1–32. 14. Schuchat A, Deaver-Robinson K, Plikaytis BD, Zangwill KM, Mohle-Boetani JC, Wenger JD. Multistate case-control study of maternal risk factors for neonatal group B streptococcal disease. Pediatr Infect Dis J 1994;13:623–9. 15. Royal College of Obstetricians and Gynaecologists. The prevention of early-onset neonatal group B streptococcal disease. Green-top Guideline No. 36, 2nd ed. London: RCOG; 2012. 16. Håkansson S, Källén K. Impact and risk factors for early-onset group B streptococcal morbidity: analysis of a national, population-based cohort in Sweden 1997-2001. BJOG 2006;113;1452–8. 17. Wood EG, Dillon HC Jr. A prospective study of group B streptococcal bacteremia in pregnancy. Am J Obstet Gynecol 1981;140:515–20. 18. Persson K, Bjerre B, Elfstrom L, Polberger S, Forsgren A. Group B streptococci at delivery: high count in urine increases risk for neonatal colonization. Scand J Infect Dis 1986;18:525–31. 19. Yancey MK, Schuchat A, Brown LK, Ventura VL, Arkenson GR. The accuracy of late antenatal screening cultures in predicting genital group B streptococcal colonization at delivery. Obstet Gynecol 1996;88:811–5. 20. Regan JA, Klebanoff MA, Nugent RP, for the Vaginal Infections and Prematurity Study Group. The epidemiology of group B streptococcal colonization in pregnancy. Obstet Gynecol 1991;77:604–10. 21. Bliss SJ, Manning SD, Tallman P, Baker CJ, Pearlman MD, Marrs CF, et al. Group B streptococcus colonization in male and nonpregnant female university students: a cross-sectional prevalence study. Clin Infect Dis 2002;34:184–90. 22. Dadvand P, Basagana X, Figueras F, Sunyer J, Nieuwenhuijsen MJ. Climate and group B streptococci colonization during pregnancy: present implications and future concerns. BJOG 2011;118:1396–400. 23. Schuchat A, Oxtoby M, Cochi S, Sikes RK, Hightower A, Plikaytis B, et al. Population-based risk factors for neonatal group B streptococcal disease: results of a cohort study in metropolitan Atlanta. J Infect Dis 1990;162:672–7. 24. Davies HD, Adair C, McGeer A, Ma D, Robertson S, Mucenski M, et al. Antibodies to capsular polysaccharides of group B streptococcus in pregnant Canadian women: relationship to colonization status and infection in the neonate. J Infect Dis 2001;184:285–91.

7. Davies HD, Adair C, Schuchat A, Low DE, Suave RS. Physicians’ prevention practices and incidence of neonatal group B streptococcal disease in 2 Canadian regions. CMAJ 2001;164:479–85.

25. Schuchat A, Zywicki SS, Dinsmoore MJ, Mercer B, Romaguera J, O’Sullivan MJ, et al. Risk factors and opportunities for prevention of early-onset neonatal sepsis: a multicenter case-control study. Pediatrics 2000;105:21–6.

8. Centers for Disease Control and Prevention. Prevention of group B streptococcal disease: a public health perspective. Mor Mortal Wkly Rep 1996;45(RR-7):1–24.

26. Zaleznik DF, Rench MA, Hillier SL, Krohn MA, Platt R, Lee ML, et al. Invasive diseases due to group B streptococcus in pregnant women and neonates from diverse population groups. Clin Infect Dis 2000;30:276–81.

9. Schrag SJ, Zywicki S, Farley MM, Reingold AL, Harrison LH, Lefkowitz LB, et al. Group B streptococcal disease in the era of intrapartum antibiotic prophylaxis. N Engl J Med 2000;342:15–20.

27. Adair C, Kowalsky L, Quon H, Ma D, Stoffman J, McGeer A, et al. Risk factors for early-onset group B streptococcal disease in neonates: a population-based case-control study. CMAJ 2003;169:198–203.

946 l OCTOBER JOGC OCTOBRE 2013

The Prevention of Early-Onset Neonatal Group B Streptococcal Disease

28. Oddie S, Embleton ND. Risk factors for early-onset neonatal group B streptococcal sepsis: case-control study. BMJ 2002;325:308. 29. Ramos E, Gaudier FL, Hearing LR, Del Valle GO, Jenkins S, Briones D. Group B streptococcus colonization in pregnant diabetic women. Obstet Gynecol 1997;89:257–60. 30. Alvarez JR, Fechner AJ, Williams SF, Ganesh VL, Apuzzio JJ. Asymptomatic bacteriuria in pregestational diabetic pregnancies and the role of group B streptococcus. Am J Perinatol 2012;27:231–4. 31. Heath PT, Balfour GF, Tighe H, Verlander NQ, Lamagni TL, Efstratiou A. Group B streptococcal disease in infants: a case control study. Arch Dis Child 2009;94:674–80. 32. Hamada S, Vearncombe M, McGreer A, Shah PS. Neonatal group B streptococcal disease: incidence, presentation and mortality. J Matern Fetal Neonatal Med 2008;21:53–7. 33. Rosenstein NE, Schuchat A. Opportunities for prevention of perinatal group B streptococcal disease: a multistate surveillance analysis. The Neonatal Group B Streptococcal Disease Study Group. Obstet Gynecol 1997;90:901–6. 34. Puopolo KM, Madoff LC, Eichenwald EC. Early-onset group B streptococcal disease in the era of maternal screening. Pediatr 2005;115:1240–6. 35. Shah V, Ohlsson A; Canadian Task Force on Preventive Health Care. Prevention of early-onset group B Streptococcal (GBS) infection in the newborn: systematic review and recommendations. CTFPHC Technical Report 01-6. London, ON: Canadian Task Force; 2001. 36. Regan JA, Klebanoff MA, Nugent RP, Eschenbach DA, Blackwelder WC, Lou Y, et al. Colonization with group B streptococci in pregnancy and adverse outcome. VIP Study Group. Am J Obstet Gynecol 1996;174:1354–60. 37. Feikin DR, Thorsen P, Zywicki S, Arpi M, Westergaard JG, Schuchat A. Association between colonization with group B streptococci during pregnancy and preterm delivery among Danish women. Am J Obstet Gynecol 2001;184:427–33. 38. Krohn MA, Hillier SL, Baker CJ. Maternal peripartum complications associated with vaginal group B streptococcal colonization. J Infect Dis 1999;179:1410–5. 39. Rouse DJ, Goldenberg RL, Cliver SP, Cutter GR, Mennemeyer ST, Fargason CA. Strategies for the prevention of early-onset neonatal group B streptococcal sepsis: a decision analysis. Obstet Gynecol 1994;83:483–94. 40. Allen VM, Yudin M; Society of Obstetricians and Gynaecologists of Canada Infectious Diseases Committee. Management of group B streptococcal bacteriuria in pregnancy. SOGC Clinical Practice Guideline, No. 276, May 2012. J Obstet Gynaecol Can 2012;34:482–6. 41. Baker CJ, Edwards MS. Group B streptococcal infections: perinatal impact and prevention methods. Ann N Y Acad Sci 1988;549:193–202. 42. Gardner SE, Yow MD, Leeds LJ, Thompson PK, Mason EO, Clark DJ. Failure of penicillin to eradicate group B streptococcal colonization in pregnant women: a couple study. Am J Obstet Gynecol 1979;135:1062–5. 43. Smaill F. Intrapartum antibiotics for group B streptococcal colonisation. Cochrane Database Syst Rev 2000;(2):CD000115. 44. US National Institutes of Health. Group B streptococcal vaccines. Available at: http://clinicaltrials.gov/ct2/home. Accessed on July 16, 2012. 45. Boyer KM, Gotoff SP. Strategies for chemoprophylaxis of GBS early onset infections. Antibiot Chemother 1985;35:267–80. 46. Allen UD, Navas L, King SM. Effectiveness of intrapartum penicillin prophylaxis in preventing early-onset group B streptococcal infection: results of a meta-analysis. CMAJ 1993;149:1659–65.

47. Society of Obstetricians and Gynaecologists of Canada. Statement on the prevention of early-onset group B streptococcal infections in the newborn. J Soc Obstet Gynaecol Can 1997;19:751–8. 48. Brozanski BS, Jones JG, Krohn MA, Sweet RL. Effect of a screening based prevention policy on prevalence of early-onset group B streptococcal sepsis. Obstet Gynecol 2000;95:496–501. 49. Cheon-Lee E, Amstey MS. Compliance with the Centers for Disease Control and Prevention antenatal culture protocol for preventing group B streptococcal neonatal sepsis. Am J Obstet Gynecol 1998;179:77–9. 50. Gibbs RS, McDuffie RS, McNabb F, Fryer GE, Miyoshi T, Merenstein G. Neonatal group B streptococcal sepsis during 2 years of a universal screening program. Obstet Gynecol 1994;84:496–500. 51. Wendel GD, Leveno KJ, Sanchez PJ, Jackson GL, McIntire DD, Siegel JD. Prevention of neonatal group B streptococcal disease: a combined intrapartum and neonatal protocol. Am J Obstet Gynecol 2002;186:618–26. 52. Factor SH, Whitney CG, Zywicki S, Schuchat A. Effects of hospital policies based on 1996 group B streptococcal disease consensus guidelines. The Active Bacterial Core Surveillance Team. Obstet Gynecol 2000;95:377–82. 53. Van Dyke MK, Phares CR, Lynfield R, Thomas AR, Arnold KE, Craig AS, et al. Evaluation of universal antenatal screening for group B streptococcus. New Engl J Med 2009;360:2626–36. 54. Ohlsson A, Shah VS. Intrapartum antibiotics for known maternal Group B streptococcal colonization. Cochrane Database Syst Rev 2009;(3):CD007467. DOI: 10.1002/14651858.CD007467.pub2. 55. Heath PT. An update on vaccination against group B streptococcus. Expert Rev Vaccines 2011;10:685–94. 56. Schrag SJ, Zell ER, Lynfield R, Roome A, Arnold KE, Craig AS, et al. A population-based comparison of strategies to prevent early-onset group B streptococcal disease in neonates. N Engl J Med 2002;347:233–9. 57. Centers for Disease Control and Prevention. Prevention of perinatal group B streptococcal disease. Mor Mortal Wkly Rep 2002;51(RR-11):1–22. 58. Yancey MK, Duff P. An analysis of the cost-effectiveness of selected protocols for the prevention of neonatal group B streptococcal infection. Obstet Gynecol 2003;83:367–71. 59. Fenton LJ, Harper MH. Evaluation of colistin and nalidixic acid in Todd-Hewitt broth for selective isolation of group B streptococci. J Clin Microbiol 1979;9:167–9. 60. Bland ML, Vermillion ST, Soper DE. Antibiotic resistance patterns for group B streptococci in late third-trimester rectovaginal cultures. Am J Obstet Gynecol 2001;184:1125–6. 61. Silverman NS, Morgan M, Nichols WS. Antibiotic resistance patterns of group B streptococcus in antenatal genital cultures. J Reprod Med 2000;45:979–82. 62. Price D, Shaw E, Howard M, Zazulak J, Waters H, Kaczorowski J. Self-sampling for group B streptococcus in women 35 to 37 weeks pregnant is accurate and acceptable: a randomized cross-over trial. J Obstet Gynaecol Can 2006;28:1083–8. 63. Valkenburg-van den burg AW, Houtman-Roelofsen RL, Oostvogel PM, Dekker FW, Dörr PJ, Sprij AJ. Timing of group B streptococcus screening in pregnancy: a systematic review. Gynecol Obstet Invest 2010;69:174–83. 64. Bergeron MG, Ke D, Menard C, Picard FJ, Gagnon M, Bernier M, et al. Rapid detection of group B streptococci in pregnant women at delivery. N Engl J Med 2000;343:175–9. 65. El Helali N, Giovangrandi Y, Guyot K, Chevet K, Gutmann L, Durand-Zaleski I. Cost and effectiveness of intrapartum group B streptococcus polymerase chain reaction screening for term deliveries. Obstet Gynecol 2012;119:822–9.

OCTOBER JOGC OCTOBRE 2013 l 947

SOGC Clinical Practice Guideline

66. Amstey MS, Gibbs RS. Is penicillin G a better choice than ampicillin for prophylaxis of neonatal group B streptococcal infections? Obstet Gynecol 1994;84:1058–9. 67. Johnson JR, Columbo DF, Gardner D, Cho E, Fan-Havard P, Shellhaas CS. Optimal dosing of penicillin G in the third trimester for the prophylaxis against group B streptococcus. Am J Obstet Gynecol 2001;185:850–3. 68. Pichichero ME. A review of evidence ing the American Academy of Pediatrics recommendation for prescribing cephalosporin antibiotics for penicillin-allergic patients. Pediatrics 2005:115:1048–57. 69. Mitchell TF, Pearlman MD, Chapman RL, Bhatt-Mehta V, Faiz RG. Maternal and transplacental pharmacokinetics of cefazolin. Obstet Gynecol 2001;98:1075–9. 70. Stoll BJ, Hansen N, Fanaroff AA, Wright LL, Carlo WA, Ehrenkranz RA, et al. Changes in pathogens causing early-onset sepsis in very-low-birth-weight infants. N Engl J Med 2002;347:240–7.

948 l OCTOBER JOGC OCTOBRE 2013

71. Hannah ME, Ohlsson A, Wang EE, Matlow A, Foster GA, Willan AR, et al. Maternal colonization with group B streptococcus and prelabor rupture of membranes at term: the role of induction of labor. Term PROM Study Group. Am J Obstet Gynecol 1997;177:780–5. 72. KJ Barrington; Canadian Paediatric Society, Fetus and Newborn Committee. Position statement: management of the infant at increased risk for sepsis. Paediatr Child Health 2007;12:893–8. Available at: http://www.s.ca/en/documents/position/management-infant-sepsis. Accessed on June 6, 2013. 73. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

T SOGC-GOC-SCC CLINICAL PRACTICE GUIDELINE No. 290, April 2013

The Role of Adjuvant Therapy in Endometrial Cancer This clinical practice guideline has been prepared by the SOGC-GOC-SCC Policy and Practice Guidelines Committee and approved by the Executive and Council of the Society of Gynecologic Oncology of Canada and the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Rachel Kupets, MD, Toronto ON Tien Le, MD, Ottawa ON SOGC-GOC-SCC POLICY AND PRACTICE GUIDELINES COMMITTEE Tien Le, MD (Chair), Ottawa ON James Bentley, MB ChB, Halifax NS Scott Farrell, MD, Halifax NS Michel P. Fortier, MD, Quebec QC Christopher Giede, MD, Saskatoon SK Rachel Kupets, MD, Toronto ON Marie Plante, MD, Quebec QC Patti Power, MD, St. John’s NL Marie-Claude Renaud, MD, Quebec QC Alexandra Schepansky, MD, Edmonton AB Vyta Senikas, MD, Ottawa ON SPECIAL CONTRIBUTORS Janice Kwon, MD, Vancouver BC Michel Préfontaine, MD, London ON Isabelle Germain, MD, Quebec QC Robert Pearcey, MD, Edmonton AB

Abstract Objective: To review the evidence relating to the use of adjuvant therapy after surgical treatment for endometrial cancer. Options: Women with endometrial cancer can be given the option of receiving adjuvant radiotherapy and/or chemotherapy according to pathologic findings at time of surgery. Outcomes: The outcomes measured are postoperative progressionfree and overall survival in endometrial cancer patients. Evidence: Published literature was retrieved through searches of PubMed, CINAHL, and The Cochrane Library, using appropriate controlled vocabulary (e.g., endometrial neoplasms) and key words (e.g., endometrium cancer, endometrial carcinoma). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to December 31, 2011. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, national and international medical specialty societies, and recent conference abstracts. Values: The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table). Benefits, harms, and costs: This guideline is intended to help standardize postoperative treatment of endometrial cancer and minimize undertreatment and overtreatment. Validation: The guideline was reviewed for accuracy by content experts in pathology, radiation oncology, and medical oncology. Guideline content was also compared with relevant documents from the American Congress of Obstetricians and Gynecologists.

David D’Souza, MD, London ON Mary Senterman, MD, Ottawa ON Paul Hoskins, MD, Vancouver BC Disclosure statements have been received from all contributors. The literature searches and bibliographic for this guideline were undertaken by Becky Skidmore, Medical Research Analyst, Society of Obstetricians and Gynaecologists of Canada.

J Obstet Gynaecol Can 2013;35(4):375–376

Key Words: Endometrial cancer, radiation therapy, chemotherapy

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

APRIL JOGC AVRIL 2013 l 375



Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care. †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

SUMMARY STATEMENTS Stage I Intermediate-Risk Endometrial Cancers External beam pelvic radiotherapy 1. Pelvic radiation has been shown to reduce local recurrence in lowto intermediate-risk endometrial carcinoma. (II-1) 2. Pelvic radiation has been shown to reduce local pelvic and vaginal recurrences in intermediate- to high-risk endometrial carcinoma. (II-1) Vaginal brachytherapy 3. Vaginal brachytherapy alone in the treatment of women with intermediate- to high-risk endometrial cancer has been shown to have outcomes in local control and overall survival that are similar to those of pelvic radiotherapy in a well-defined intermediate- to high-risk group. (I) 4. Vaginal brachytherapy has the same outcome as external beam radiotherapy with respect to overall survival in the defined intermediate- to high-risk group. (I) Chemotherapy 5. Chemotherapy has not been well studied in stage I intermediateto high-risk endometrial cancers. There is no strong evidence for or against chemotherapy in this population at present. The benefits of chemotherapy in addition to adjuvant radiotherapy specifically in surgically stage I patients with high-risk features are not clearly defined. (III) Expectant Management 6. Patients in the intermediate-risk category who are managed expectantly have a higher recurrence rate than those who are treated, although there has not been a lack of survival

376 l APRIL JOGC AVRIL 2013

benefit demonstrated. Patients who are managed expectantly report higher scores in quality of life studies because of less gastrointestinal toxicity. (II-3) Advanced Stage (II to IV) Endometrial Cancer 7. Chemotherapy with cisplatin and doxorubicin or carboplatin and paclitaxel has demonstrated efficacy in advanced uterine cancer in published phase III studies. (II-2) RECOMMENDATIONS Stage I Low-Risk Endometrial Cancers 1. As risk for recurrent disease is low in this patient group, no further treatment should be given after definitive surgery. Regular followup should be performed to monitor for signs and symptoms of recurrences. (II-1B) Advanced Stage (II to IV) Endometrial Cancer 2. Treatment of these patients should be tailored according to disease distribution and local treatment practices. (II-2C)

The full version of this document is available online at http://www.sogc.org and http://www.jogc.com.

SOGC CLINICAL PRACTICE GUIDELINE No. 286, January 2013

Surgical Safety Checklist in Obstetrics and Gynaecology This clinical practice guideline has been reviewed by the Clinical Practice Gynaecology Committee and reviewed and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Sukhbir S. Singh, MD, Ottawa ON

Values: The quality of evidence was rated with use of the criteria described by the Canadian Task Force on Preventive Health Care. Recommendations for practice were ranked according to the method described by the Task Force (Table). Benefits, harms, and costs: Implementation of the guideline recommendations will improve the health and well-being of women undergoing obstetrical or gynaecologic surgery.

Neeraj Mehra, MD, Ottawa ON Laura Hopkins, MD, Ottawa ON

SUMMARY STATEMENTS AND RECOMMENDATIONS

CLINICAL PRACTICE GYNAECOLOGY COMMITTEE

Summary Statements

Nicholas Leyland, MD (Co-Chair), Ancaster ON Wendy Wolfman, MD (Co-Chair), Toronto ON Catherine Allaire, MD, Vancouver BC Alaa Awadalla, MD, Winnipeg MB Sheila Dunn, MD, Toronto ON Mark Heywood, MD, Vancouver BC Madeleine Lemyre, MD, Quebec QC Violaine Marcoux, MD, Ville Mont-Royal QC Chantal Menard, RN, Ottawa ON Frank Potestio, MD, Thunder Bay ON David Rittenberg, MD, Halifax NS Sukhbir S. Singh, MD, Ottawa ON

1. Surgery may for up to 40% of all hospital adverse events. (II-2) 2. Good communication is essential for safer surgical care, as communication failure is common in the operating room. (III) 3. The concept of a surgical safety checklist has been studied globally, and there have been decreases in complications and mortality when the checklist has been implemented. (II-1) 4. Emergency cases such as a “crash” Caesarean section will require a modified approach that is centre- and situationdependent. (III) 5. The SOGC endorses the adoption of the surgical safety checklist in obstetrics and gynaecology. (III)

Vyta Senikas, MD, Ottawa ON

Recommendations

Disclosure statements have been received from all of the committee.

1. The surgical safety checklist should be adopted by all surgical care providers and their respective institutions to improve patient safety. (II-1A)

Abstract

2. Surgeons should be familiar with, advocate for the use of, and participate in all 3 parts of the surgical safety checklist. (II-1A)

Objective: To provide guidance on the implementation of a surgical safety checklist in the practice of obstetrics and gynaecology.

3. The surgical safety checklist may be modified and adapted for use in surgical obstetrics cases. (II-2A)

Outcomes: Outcomes evaluated include the impact of the surgical safety checklist on surgical morbidity and mortality. Evidence: Medline databases were searched for articles on subjects related to “surgical safety checklist” published in English from January 2001 to January 2011. Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. Searches were updated on a regular basis and incorporated in the guideline to January 2012.

J Obstet Gynaecol Can 2013;35(1):82–83

Key Words: Patient safety, surgical safety checklist

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

82 l JANUARY JOGC JANVIER 2013

Surgical Safety Checklist in Obstetrics and Gynaecology

Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care. †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

The full version of this document is available online at http://www.sogc.org and http://www.jogc.com.

JANUARY JOGC JANVIER 2013 l 83

T SOGC-GOC-SCC CLINICAL PRACTICE GUIDELINE No. 291, April 2013 (Replaces no. 51, November 1996)

Epidemiology and Investigations for Suspected Endometrial Cancer This clinical practice guideline has been prepared by the SOGC-GOC-SCC Policy and Practice Guidelines Committee, reviewed by the Clinical Practice Gynaecology Committee and approved by the Executive and Council of the Society of Gynecologic Oncology of Canada and the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Marie-Claude Renaud, MD, Quebec QC Tien Le, MD, Ottawa ON SOGC-GOC-SCC POLICY AND PRACTICE GUIDELINES COMMITTEE Tien Le, MD (Chair), Ottawa ON James Bentley, MB ChB, Halifax NS Scott Farrell, MD, Halifax NS Michel P. Fortier, MD, Quebec QC Christopher Giede, MD, Saskatoon SK Rachel Kupets, MD, Toronto ON Marie Plante, MD, Quebec QC Patti Power, MD, St. John’s NL Marie-Claude Renaud, MD, Quebec QC Alexandra Schepansky, MD, Edmonton AB Vyta Senikas, MD, Ottawa ON SPECIAL CONTRIBUTORS Janice Kwon, MD, Vancouver BC Michel Préfontaine, MD, London ON Isabelle Germain, MD, Montreal QC Robert Pearcey, MD, Edmonton AB

Abstract Objective: To review the evidence relating to the epidemiology of endometrial cancer and its diagnostic workups. Options: Women with possible endometrial cancer can undergo an endometrial evaluation by office biopsy, hysteroscopy, or dilatation and curettage. To assist in treatment planning, pelvic ultrasound, CT scan, or MRI may be considered. Outcomes: The identification of optimal diagnostic tests to evaluate patients with possible endometrial cancer. Evidence: Published literature was retrieved through searches of PubMed, CINAHL, and The Cochrane Library, using appropriate controlled vocabulary (e.g., endometrial neoplasms) and key words (e.g., endometrium cancer, endometrial carcinoma). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to December 31, 2011. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, national and international medical specialty societies, and recent conference abstracts. Values: The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table). Benefits, harms, and costs: This document is intended to guide the development of a standardized cost-effective investigation of patients with suspected endometrial cancer. Validation: The guideline was reviewed for accuracy by experts in pathology, radiation oncology, and medical oncology. Guideline content was also compared with relevant documents from the American Congress of Obstetricians and Gynecologists.

David D’Souza, MD, London ON Mary Senterman, MD, Ottawa ON Paul Hoskins, MA, Vancouver BC

J Obstet Gynaecol Can 2013;35(4):380–381

Disclosure statements have been received from all contributors. The literature searches and bibliographic for this guideline were undertaken by Becky Skidmore, Medical Research Analyst, Society of Obstetricians and Gynaecologists of Canada.

Key Words: Endometrial cancer, diagnostic workup, endometrial evaluation, ultrasound, magnetic resonance imaging, MRI, postmenopausal bleeding

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

380 l APRIL JOGC AVRIL 2013

Epidemiology and Investigations for Suspected Endometrial Cancer

Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care. †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

Recommendations 1. A complete focused history should be taken and a physical examination carried out in patients with suspected endometrial cancer. Attention should be paid to predisposing factors for excess estrogen stimulation of the endometrium such as long history of anovulation, obesity, menstrual irregularity, or long-term use of unopposed estrogen or tamoxifen. Patients with a strong family history of endometrial, ovarian, and colorectal cancers might have inherited Lynch syndrome (hereditary non-polyposis colorectal cancer syndrome) that increases their lifetime risk of developing endometrial cancer. Genetic counselling and testing can be used to individualize risk-management interventions including screening strategies and treatment options. (III-B)

4. Histologic evaluation of the endometrium should be done in all patients in whom endometrial cancer is suspected. (II-1A) 5. Hysteroscopic examination should be considered in patients with persistent uterine bleeding with benign endometrial sampling or insufficient endometrial sampling after ultrasound. (II-2B) 6. Formal review of the histopathology should be considered in patients with high grade tumours or rare histologic types such as serous, clear cell, or mucinous types. (III-B) 7. Additional tumour markers, CT scan, and MRI scan should not be used routinely. (III-D)

2. Endometrial cancer should be ruled out in perimenopausal and postmenopausal patients with abnormal vaginal bleeding. (II-1A) 3. Depending on access, histologic endometrial evaluation and transvaginal ultrasound are the preferred initial diagnostic investigations for patients with suspected endometrial cancer. (II-1B)

The full version of this document is available online at http://www.sogc.org and http://www.jogc.com.

APRIL JOGC AVRIL 2013 l 381

SOGC TECHNICAL UPDATE No. 294, July 2013

Technical Update on Pessary Use This technical update has been prepared by the Urogynaecology Committee, reviewed by the Family Practice Advisory Committee, and approved by the Executive of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Magali Robert, MD, Calgary AB Jane A. Schulz, MD, Edmonton AB Marie-Andrée Harvey, MD, Kingston ON UROGYNAECOLOGY COMMITTEE Danny Lovatsis, MD (Co-Chair), Toronto ON Jens-Erik Walter, MD (Co-Chair), Montreal QC Queena Chou, MD, London ON William A. Easton, MD, Scarborough ON Annette Epp, MD, Saskatoon SK Scott A. Farrell, MD, Halifax NS Roxana Geoffrion, MD, Vancouver BC Lise Girouard, RN, Winnipeg MB Chander K. Gupta, MD, Winnipeg MB Marie-Andrée Harvey, MD, Kingston ON Annick Larochelle, MD, St-Lambert QC Kenny D. Maslow, MD, Winnipeg MB Grace Neustaeder, RN, Calgary AB

Abstract Objective: To review the use, care, and fitting of pessaries. Options: Pessaries are an option for women presenting with prolapse and/or urinary incontinence. Outcomes: Pessaries can be successfully fitted in the majority of women with excellent satisfaction rates and minimal complications. Evidence: PubMed and Medline were searched for articles published in English to September 2010, using the key words pessary, prolapse, incontinence, fitting, and complications. Results were restricted to systematic reviews, randomized control trials/ controlled clinical trials, and observational studies. Searches were updated on a regular basis, and articles were incorporated in the guideline to May 2012. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Values: The quality of evidence was rated with use of the criteria described by the Canadian Task Force on Preventive Health Care. Recommendations for practice were ranked according to the method described by the Task Force (Table 1). Benefits, harms, and costs: Women may choose a pessary for management of their prolapse and/or stress incontinence rather than opt for surgery. Major complications have been seen only with neglected pessaries. Minor complications such as vaginal discharge, odour, and erosions can usually be successfully treated.

Dante Pascali, MD, Ottawa ON

SUMMARY STATEMENTS AND RECOMMENDATION

Marianne Pierce, MD, Halifax NS

Summary Statements

Magali Robert, MD, Calgary AB

1. Most women can be successfully fitted with a pessary when they present with prolapse. (II-2)

Sue Ross, PhD, Calgary AB Joyce Schachter, MD, Ottawa ON Jane A. Schulz, MD, Edmonton AB Vyta Senikas, MD, Ottawa ON David H.L. Wilkie, MD, Vancouver BC Disclosure statements have been received from all contributors. Scott Farrell is Vice-President Medical and a major stakeholder of EastMed Inc. (Halifax, NS), the company marketing Uresta. Roxana Geoffrion is a shareholder of EastMed Inc.

J Obstet Gynaecol Can 2013;35(7):664–674

2. Complications of pessary use are usually minor, and vaginal discharge is the most common complaint. (II-3) 3. Vaginal erosions can be treated with removal of the pessary and optional vaginal estrogen supplementation. (II-2) 4. Satisfaction rates with pessary use are very high. (II-2) Recommendation 1. Pessaries should be considered in all women presenting with symptomatic prolapse and/or urinary stress incontinence. (II-1A) Key Words: Pessary, prolapse, incontinence, fitting, complications

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

664 l JULY JOGC JUILLET 2013

Technical Update on Pessary Use

Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.54 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care.54

INTRODUCTION

P

elvic organ prolapse is seen in up to 50% of parous women.1 Although often asymptomatic, it may present with symptoms of bulging, pelvic pressure, and occasionally backache. It is often associated with bladder, bowel, and sexual dysfunction. Treatment options include pelvic floor exercises,2 expectant management, use of mechanical vaginal devices (pessaries), and surgical correction. This technical update guides care providers on the use of pessaries. A pessary is a device placed into the vagina to the prolapsing vaginal walls or to provide urinary continence. Pessaries have the distinct advantage of being minimally invasive, and they provide immediate relief of symptoms. Although in the past, pessaries were reserved for the frail and elderly, they are also an excellent alternative for symptomatic women who have not finished child-bearing and for those who choose a non-surgical intervention or who wish symptomatic relief while awaiting surgery. Pessaries are experiencing a resurgence in popularity and are an option for the treatment of prolapse and incontinence for women in any age group.

Pessaries are made primarily of medical grade silicone; only the largest sizes are made of surgical steel with a covering of silicone. This has the advantage of making them inert and less likely to have an odour or cause an allergic reaction.3 Pessaries used for the treatment of prolapse can be classified as pessaries or space-

occupying pessaries.4 The pessaries sit in the posterior fornix and generally rest above the pubic bone and/or pelvic floor. The commonly used types include ring pessaries (with or without diaphragms, Figure 1) and the Shaatz pessaries (Figure 2). The space-occupying pessaries include the cube (Figure 3), Inflatoball (Figure 4), and donut (Figure 5) pessaries. The cube works by bringing the vaginal walls towards the midline, and the others occupy a larger space than the introitus.4 They are most often used for more severe prolapse. The commonly used Gellhorn pessary (Figure 6) works as a combination of these 2 methods.4 There are many other styles to address specific defects, but their use is not often reported in the literature. Incontinence pessaries are often designed as pessaries with extra anteriorly (Figure 7) to elevate and slightly constrict the urethra.5 The ring incontinence pessary (Figure 8) and the incontinence dish (Figure 9) are specifically designed to treat stress urinary incontinence. If a woman develops stress incontinence after being fitted with a prolapse pessary, switching to an incontinence pessary may be beneficial.3 INDICATIONS

Pessaries can be used for diagnostic or therapeutic purposes. Pessaries are often used to relieve symptoms of prolapse6 and of urinary stress incontinence. They are cost-effective in the treatment of prolapse.7 Women choosing pessary for the treatment of prolapse are as likely to be satisfied and to have improved pelvic floor function as those selecting surgery.8 JULY JOGC JUILLET 2013 l 665

SOGC TECHNICAL UPDATE

Figure 1. Ring pessary with

Figure 3. Cube pessary

Figure 5. Donut pessary

666 l JULY JOGC JUILLET 2013

Figure 2. Shaatz pessary

Figure 4. Inflatoball pessary

Figure 6. Gellhorn pessary

Technical Update on Pessary Use

Figure 7. Ring pessary with and continence knob at 12 o’clock

Figure 9. Incontinence dish

Figure 8. Incontinence ring

Figure 10. Uresta kit

Figures 1 to 9 are reproduced with permission from CooperSurgical Inc., Trumbull CT, and Figure 10 is reproduced with permission from EastMed Inc., Halifax NS

Pessaries can also be used for the preoperative evaluation of women with prolapse by unmasking latent stress incontinence9 and providing information on postoperative voiding dysfunction.10,11 This could be revealed during the use of a pessary, or during the performance of urodynamic testing with and without pessary. Although urodynamic testing has poor sensitivity, its specificity is high (93%), and the absence of occult incontinence has an excellent negative predictive value (91% to 98%) for postoperative continence.12,13 Pessaries can also be used as a temporary treatment of symptoms while patients are waiting for surgery, and they can help to heal vaginal ulcers that result from erosions due to a large prolapse. They may also play a role in preventing progression of prolapse.

Prolapse

Women can be successfully fitted with a pessary 71% to 90% of the time.14–19 Symptoms of bulging and pressure are relieved in 70% to 90% and 29% to 49% of women, respectively.15,16 When pessaries are successful at the 4-week point, most women continue to use them at 5 years.20 Ring pessaries are the most commonly used and widely available, followed by Gellhorn and cube or donut pessaries.15,16,21 In a randomized crossover trial, there was no difference in patient satisfaction or symptom relief between those using the ring and those using the Gellhorn pessary.19 Ring pessaries may be open or covered (also referred to as “with ” or “with diaphragm”). The purpose of the covered ring pessary is to the cervix; perforations JULY JOGC JUILLET 2013 l 667

SOGC TECHNICAL UPDATE

Table 2. Change in symptoms after pessary fitting Improved, %

Worsened, %

Stress urinary incontinence

22 to 45

15,16

Urge urinary incontinence

28 to 46

15,16

6 to 1315,16

Voiding difficulties

39 to 5315,16

4 to 1415,16

17 to 2115,16

Incomplete evacuation of bowel

27

Fecal urgency

2216

916

Fecal incontinence

19

16

916

Frequency of sexual activity

1616

316

Satisfaction of sexual activity

11

516

allow the escape of vaginal secretions. Open and covered ring pessaries are best used in POP-Q (pelvic organ prolapse quantification) stage I and II prolapse (mild to moderate prolapse), although they often work well with a more advanced degree of prolapse if there is an adequate perineal body to ensure the pessary is retained.3 It has the advantage of ease of insertion and removal, and comfort. If the pessary fails to remain in position or there continues to be protrusion, a stiffer pessary such as a Shaatz or a Gellhorn, or a space-occupying pessary such as a cube or a donut may be used. Cube pessaries have been successfully used in severe prolapse. However, they may be more prone to erosion, and they require frequent removal, nightly in some cases. Patients can learn to remove and re-insert a cube pessary. Successful use of a pessary is dependent on both adequate fit and patient satisfaction. The most common reasons women choose to use a pessary are to improve lower urinary tract symptoms secondary to pelvic organ prolapse, such as bulging, and to improve activity and general health.22 Pessary use can also alleviate other symptoms, including difficulty with bladder emptying, urinary urgency symptoms, and defecatory symptoms.15,16 Contrary to common belief, sexual activity is not a predictor for discontinued pessary use15,23; in fact, pessary use may enhance sexual activity and satisfaction.17,24 Table 2 shows the change in symptoms after pessary fitting. Predictors for unsuccessful fitting include a short vagina (< 6 cm),18,25 a wide introitus (> 4-finger breadth),18,25 the presence of a rectocele,26 previous vaginal surgery,14,16,17,25,27,28 and coexisting stress urinary incontinence.27 Predictors of discontinuation include posterior wall pro­lapse,14,16 younger age (<  65 years old),15 urinary 15 28 incontinence, and discomfort. However, in one study, women who had previously undergone pelvic reconstructive surgery were more likely to continue pessary use.27 668 l JULY JOGC JUILLET 2013

16

16

1816

Urinary Incontinence

Some pessaries have been specifically designed to treat urinary stress incontinence. These include the ring pessary with and knob (Figure 7), the incontinence ring (Figure 8), the incontinence dish (Figure 9) and the Uresta device (Figure 10). They appear to stabilize the urethra and increase urethral resistance.5 Initial successful fitting varies between 60% and 92%29,30 with an incontinence ring. Continued use drops to 55% by 6 months.31 By 1 year, the overall continuation may be as low as 16%, but this finding was from a study in which an incontinence ring pessary with diaphragm was used, and most women discontinued use because of lack of efficacy.32 In a retrospective chart review33 of 100 women successfully fitted with pessaries, 59% were continent or mostly continent at 11 months. Reasons for discontinuation included persistent incontinence, pessary falling out, or pain and bleeding. One crossover study showed that the incontinence ring was more effective than no treatment for the management of stress urinary incontinence, significantly decreasing the number of incontinence episodes and improving quality of life.34 Eighty percent of women saw an improvement of their incontinence, and 20% were dry. Using the new Uresta device, continuation rates at 1 year were 50%.35 In that case series (n = 32), continence was obtained by 31% of women, and incontinence was improved in a further 34%.35 There is insufficient evidence to state that pessaries are more effective in treating urinary incontinence than other devices or other treatments,36 including pelvic floor exercises.37 Pregnancy

Women who develop prolapse3,38,39 during pregnancy or who develop urinary retention because of an incarcerated uterus40 can be fitted with a pessary, although not always successfully.41 By 18 weeks, when the uterus lifts out of the pelvis, symptoms often resolve, and pessary use can be discontinued. The use of an incontinence pessary in pregnancy has not yet been described.

Technical Update on Pessary Use

In small cohort studies, pessaries placed around the cervix, such as the Arabin pessary,42 have been shown to have some benefit in preventing preterm birth in women with cervical incompetence.43,44 Multiple randomized clinical trials, some international and multicentre, are ongoing.45 An RCT by Goya et al.,46 published in 2012, found that the use of the Arabin pessary was associated with a significant reduction of premature birth (< 34 weeks) from 27% to 6% in women identified as having a short cervix (< 25 mm) on ultrasound at 22 weeks, as well as with a decrease in premature rupture of membrane (9% to 2%) and a decrease in composite neonatal severe outcomes from 16% to 3%, mostly for sepsis and respiratory distress syndrome. However, until the results of this trial are reproduced, the use of pessary for prevention of premature birth cannot be recommended, as its safety for this indication remains to be established.47  GUIDELINES FOR FITTING

Successful fitting and continued use is dependent on adequate patient education (Appendix). It is imperative that the woman and/or her caregiver commit to proper care of the pessary.48 As part of the history, health care providers should inquire about symptoms of prolapse, bladder and bowel dysfunction, and sexual activity. This is followed by a comprehensive examination: assessing vaginal mucosal health; assessing the degree and compartment of prolapse, including genital hiatus and vaginal length; and measuring pelvic floor strength. It is common but not essential49 to begin vaginal estrogen therapy in postmenopausal women to improve the health of the vaginal epithelium.3,4 The approximate size of pessary required is determined by assessing the width of the vaginal canal by separating the 2 examining fingers at the vault in a sagittal plane and estimating their separation distance. A ring pessary is usually fitted initially, as it is easy to use and tends to be more comfortable. The pessary is folded, and the leading edge is lubricated. It is inserted by directing it towards the sacrum, and it is unfolded above the pelvic floor, with the anterior edge just behind the symphysis. There should be a finger’s breadth between the pessary (edge) and the symphysis anteriorly and between the side of the pessary and the lateral vaginal wall. The ring pessary should be turned one quarter turn in either direction following placement to ensure the foldable edge is not placed in front of the introitus, thus potentially limiting spontaneous expulsion. Once the pessary has been fitted, the patient should ambulate in the clinic and perform activities such as squatting and Valsalva manoeuvre to ensure it will not

fall out. It is necessary to ensure that patients are able to void and that they are given appropriate education before leaving the clinic with their new pessary (Appendix). A post-void residual can be done to rule out the possibility of obstruction. Dental floss can be attached to aid in removal of difficult pessaries. An incontinence ring is fitted by assessing the distance between the posterior cul-de-sac and the mid urethra. Because the incontinence ring is more flexible, it will adapt to the configuration of the vagina. The health care provider must ensure that the knob is centred underneath the mid-urethra and that the proximal ring is placed in the posterior cul-de-sac and not in front of the cervix in the anterior fornix.50 A ring pessary with incontinence knob is placed like a regular ring, but once it is opened, the knob will be facing the sidewall: it must therefore be rotated one quarter turn to place the knob under the mid-urethra.50 If the vaginal introitus is more than the width of 3 or 4 fingers, a space-occupying pessary is the most likely to be successful. A Shaatz pessary is fitted similarly, with the convex portion placed anteriorly. A Gellhorn pessary is fitted by folding of the disc as above when possible with the stem folded down for ease of insertion. The stem will be directed caudally (pointing out), and it should be possible to a finger between the disc and the vaginal side wall. Because of its shape, a cube pessary need not be as large as the width of the vagina (as measured with the examining fingers spread apart), but approximately one half that width. Insertion simply involves compressing the edge that is introduced into the vaginal opening, and pushing it up and back. Donut pessaries also require compression for insertion. Follow-up Pessary Care

Following a successful fitting, the woman is seen again within 2 to 4 weeks to see if she is satisfied or whether another size or style is required. If possible, instruction on removal and care should be given.3 Although there are no clear guidelines for pessary care, women who are able to perform self-care are advised to remove the pessary once a week and to wash it with water or mild soapy water. Women who are not able to perform self-care should be followed at 3-month intervals. Maintenance of pessary care by a health care professional rather than the patient is often required with Gellhorn, cube, or donut pessaries. Some pessaries may be difficult to remove. The Gellhorn pessary is easier to remove when the health care professional uses a ring or packing self-closing forceps on the base of the stem to apply outwards traction, and then uses one JULY JOGC JUILLET 2013 l 669

SOGC TECHNICAL UPDATE

finger to break the suction and fold the round disc along the stem. A cube pessary requires removal and cleaning more often than every 3 months, because a greater amount of discharge is usually trapped within the suction cups (although the cube is available with drainage holes). The frequency of cleaning required for a cube pessary will vary among patients, from as often as every few days to every few weeks. Once removed, the pessary should be washed using plain soap and water. The perforations of the Gellhorn and Shaatz pessaries are best cleansed using a cytobrush or a small cotton swab. The vaginal epithelium should be inspected for erosions or ulcerations, and special attention should be paid to the posterior and lateral fornices of the vagina. This is best accomplished using a large cotton swab to displace the cervix to the contralateral direction. If no complications arise and the patient is able to perform self-care, the interval between visits can be increased to 6 months or 1 year.30 Women can be sexually active with the ring or Shaatz pessary in place. A cube, donut, or Gellhorn pessary must generally be removed before intercourse. COMPLICATIONS

Published complication rates vary, which likely reflects a difference in reporting. In a study by Hanson et al. 88.5% of 1216 women did not develop complications.17 Common complications included erosions (8.9%) and vaginal infections (2.5%).17 This is in contrast to the study by Bai et al., in which 73% of women had complications, including bleeding, erosions, or foul odour.51 Despite this relatively high rate, over 70% reported being satisfied with the pessary and wanted to continue its use,51 suggesting that these complications are minor. Local pressure from the pessary can lead to focal devascularisation and cause erosions. Reported rates range from 2% to 9%.8,10 Erosions may present as vaginal bleeding, odour, or increased discharge, which is typically brown. A strong odour is usually present upon removal of the pessary. When such strong odour is detected during routine pessary care, careful examination of the vagina should be performed, often facilitated by the use of large swabs to push the cervix and sidewalls apart. If neglected, erosions can progress to ulcers or a fistula. Other causes of vaginal bleeding cannot be excluded in pessary s, and endometrial or ulcer biopsy may be indicated if they persist. Therapy consists of pessary removal for a period of 2 to 4 weeks and local estrogen use (tablet or cream). Resolution of erosions may also 670 l JULY JOGC JUILLET 2013

occur without local estrogen.17 For ongoing problems, more frequent visits and a change in pessary type or size may be required. Vaginal cancer is a rare association with neglected pessary use but should be considered with nonhealing ulcers.Vaginal discharge is a common complaint of pessary s. It can be caused by a physiologic response to friction of the pessary on the vaginal mucosa, bacterial vaginosis, or yeast. Bacterial vaginosis can cause malodorous vaginal discharge, which can be problematic but is not related to the appearance of an ulcer.17 Alnaif and Drutz showed that in matched women, pessary s had a 32% rate of diagnosed bacterial vaginosis compared with 10% in non-s.52 The use of estrogen cream did not appear to have a protective effect. More frequent pessary removal can often alleviate this problem. The use of Trimo-San cream (Cooper Surgical) or Replens may decrease the odour and discharge.3 Antibiotic treatment with oral or vaginal metronizadole is also effective. Often simple reassurance that the problem is physiologic may be sufficient. Yeast can be treated in conventional ways. Often it is recommended to keep the pessary removed during treatment, although there is no evidence that this makes a difference. If a pessary is repeatedly dislodged, women often discontinue use. This is best averted by preventing constipation and avoiding straining in general. Major complications are uncommon with pessary use. In case reports documenting complications including vesicovaginal fistulae, bowel fistulae, incarcerated pessaries etc.,53 91% were related to neglected pessaries. This stresses the importance of continued and diligent follow-up. CONCLUSION

Pessaries have a high success rate and minimal complication rate for the treatment of both incontinence and prolapse. When successfully fitted, they are associated with high patient satisfaction. They should therefore be considered as first-line treatment for all women presenting with pelvic prolapse and/or stress urinary incontinence. Summary Statements

1. Most women can be successfully fitted with a pessary when they present with prolapse. (II-2) 2. Complications of pessary use are usually minor, and vaginal discharge is the most common complaint. (II-3) 3. Vaginal erosions can be treated with removal of the pessary and optional vaginal estrogen supplementation. (II-2) 4. Satisfaction rates with pessary use are very high. (II-2)

Technical Update on Pessary Use

Recommendation

1. Pessaries should be considered in all women presenting with symptomatic prolapse and/or urinary stress incontinence. (II-1A) REFERENCES 1. Swift SE. The distribution of pelvic organ in a population of female subjects seen for routine gynecologic health care. Am J Obstet Gynecol 2000;183(2):277–85. 2. Braekken IH, Majida M, Engh ME, Bø K. Can pelvic floor muscle training reverse pelvic organ prolapse and reduce prolapse symptoms? An assessor-blinded, randomized, controlled trial. Am J Obstet Gynecol 2010;203(2):170–7. 3. Schulz JA, Kwon E. Pelvic organ prolapse: pessary treatment. In: Baessler K, Schussler B, Burgio KL, Moore KH, Norton PA, Stanton SL, eds. Pelvic floor reeducation: principles and practice. London UK: Springer-Verlag London Limited; 2009:271–7. 4. Trowbridge ER, Fenner DE. Practicalities and pitfalls of pessaries in older women. Clin Obstet Gynecol 2007;50(3):709–19. 5. Komesu YM, Ketai LH, Rogers RG, Eberhardt SC, Pohl J. Restoration of continence by pessaries: magnetic resonance imaging assessment of mechanism of action. Am J Obstet Gynecol 2008;198(5):563–6. 6. Patel M, Mellen C, O’Sullivan DM, LaSala CA. Impact of pessary use on prolapse symptoms, quality of life, and body image. Am J Obstet Gynecol 2010;202(5):499e1–499e4. 7. Hullfish KL, Trowbridge ER, Stukenborg GJ. Treatment strategies for pelvic organ prolapse: a cost-effectiveness analysis. Int Urogynecol J Pelvic Floor Dysfunct 2011;22(5):507–15. 8. Abdool Z, Thakar R, Sultan AH, Oliver RS. Prospective evaluation of outcome of vaginal pessaries versus surgery in women with symptomatic pelvic organ prolapse. Int Urogynecol J Pelvic Floor Dysfunct 2011;22(3):273–8. 9. Liapis A, Bakas P, Georgantopoulou C, Creatsas G. The use of the pessary test in preoperative assessment of women with severe genital prolapse. Eur J Obstet Gynecol Reprod Biol 2011;155(1):110–3.

16. Fernando RJ, Thakar R, Sultan AH, Shah SM, Jones PW. Effect of vaginal pessaries on symptoms associated with pelvic organ prolapse. Obstet Gynecol 2006;108(1):93–9. 17. Hanson LA, Schulz JA, Flood CG, Cooley B, Tam F. Vaginal pessaries in managing women with pelvic organ prolapse and urinary incontinence: patient characteristics and factors contributing to success. Int Urogynecol J Pelvic Floor Dysfunct 2006;17(2):155–9. 18. Manchana T. Ring pessary for all pelvic organ prolapse. Arch Gynecol Obstet 2011;284(2):391–5. 19. Cundiff GW, Amundsen CL, Bent AE, Coates KW, Schaffer JI, Strohbehn K, et al. The PESSRI study: symptom relief outcomes of a randomized crossover trial of the ring and Gellhorn pessaries. Am J Obstet Gynecol 2007;196(4):405–8. 20. Lone F, Thakar R, Sultan AH, Karamalis G. A 5-year prospective study of vaginal pessary use for pelvic organ prolapse. Int J Gynaecol Obstet 2011;114(1):56–9. 21. Cundiff GW, Weidner AC, Visco AG, Bump RC, Addison WA. A survey of pessary use by of the American urogynecologic society. Obstet Gynecol 2000;95(6 Pt 1):931–5. 22. Komesu YM, Rogers RG, Rode MA, Craig EC, Schrader RM, Gallegos KA, et al. Patient-selected goal attainment for pessary wearers: what is the clinical relevance? Am J Obstet Gynecol 2008;198(5):577–5. 23. Brincat C, Kenton K, Pat FM, Brubaker L. Sexual activity predicts continued pessary use. Am J Obstet Gynecol 2004;191(1):198–200. 24. Kuhn A, Bapst D, Stadlmayr W, Vits K, Mueller MD. Sexual and organ function in patients with symptomatic prolapse: are pessaries helpful? Fertil Steril 2009;91(5):1914–8. 25. Clemons JL, Aguilar VC, Tillinghast TA, Jackson ND, Myers DL. Risk factors associated with an unsuccessful pessary fitting trial in women with pelvic organ prolapse. Am J Obstet Gynecol 2004;190(2):345–50. 26. Yamada T, Matsubara S. Rectocoele, but not cystocoele, may predict unsuccessful pessary fitting. J Obstet Gynaecol 2011;31(5):441–2. 27. Nguyen JN, Jones CR. Pessary treatment of pelvic relaxation: factors affecting successful fitting and continued use. J Wound Ostomy Continence Nurs 2005;32(4):255–61. 28. Mutone MF, Terry C, Hale DS, Benson JT. Factors which influence the short-term success of pessary management of pelvic organ prolapse. Am J Obstet Gynecol 2005;193(1):89–94.

10. Lazarou G, Scotti RJ, Mikhail MS, Zhou HS, Powers K. Pessary reduction and postoperative cure of retention in women with anterior vaginal wall prolapse. Int Urogynecol J Pelvic Floor Dysfunct 2004;15(3):175–8.

29. Noblett KL, McKinney A, Lane FL. Effects of the incontinence dish pessary on urethral and urodynamic parameters. Am J Obstet Gynecol 2008;198(5):592–5.

11. Liang CC, Chang YL, Chang SD, Lo TS, Soong YK. Pessary test to predict postoperative urinary incontinence in women undergoing hysterectomy for prolapse. Obstet Gynecol 2004;104(4):795–800.

30. Nager CW, Richter HE, Nygaard I, Paraiso MF, Wu JM, Kenton K, et al. Incontinence pessaries: size, POPQ measures, and successful fitting. Int Urogynecol J Pelvic Floor Dysfunct 2009;20(9):1023–8.

12. Srikrishna S, Robinson D, Cardozo L. Ringing the changes in evaluation of urogenital prolapse. [Erratum appears in Int Urogynecol J Pelvic Floor Dysfunct 2011 Jul;22(7):901]. Int Urogynecol J Pelvic Floor Dysfunct 2011;22(2):171–5.

31. Donnelly MJ, Powell-Morgan S, Olsen AL, Nygaard IE. Vaginal pessaries for the management of stress and mixed urinary incontinence. Int Urogynecol J Pelvic Floor Dysfunct 2004;15(5):302–7.

13. Ellstrom Engh AM, Ekeryd A, Magnusson A, Olsson I, Otterlind L, Tobiasson G. Can de novo stress incontinence after anterior wall repair be predicted? Acta Obstet Gynecol Scand 2011;90(5):488–93. 14. Maito JM, Quam ZA, Craig E, Danner KA, Rogers RG. Predictors of successful pessary fitting and continued use in a nurse-midwifery pessary clinic. J Midwifery Womens Health 2006;51(2):78–84. 15. Clemons JL, Aguilar VC, Tillinghast TA, Jackson ND, Myers DL. Patient satisfaction and changes in prolapse and urinary symptoms in women who were fitted successfully with a pessary for pelvic organ prolapse. Am J Obstet Gynecol 2004;190(4):1025–9.

32. Robert M, Mainprize TC. Long-term assessment of the incontinence ring pessary for the treatment of stress incontinence. Int Urogynecol J Pelvic Floor Dysfunct 2002;13(5):326–9. 33. Farrell SA, Singh B, Aldakhil L. Continence pessaries in the management of urinary incontinence in women. J Obstet Gynaecol Can 2004;26(2):113–7. 34. Harvey MA. The treatment of stress urinary incontinence using an incontinence ring: a randomized, cross-over trial treatment of stress urinary. Neurourol Urodyn 2009;28: 817–8. 35. Farrell SA, Baydock S, Amir B, Fanning C. Effectiveness of a new self-positioning pessary for the management of urinary incontinence in women. Am J Obstet Gynecol 2007;196(5):474–8.

JULY JOGC JUILLET 2013 l 671

SOGC TECHNICAL UPDATE

36. Lipp A, Shaw C, Glavind K. Mechanical devices for urinary incontinence in women. [Update of Cochrane Database Syst Rev. 2006;3:CD001756; PMID: 16855977]. Cochrane Database Syst Rev 2011;7(CD001756). 37. Richter HE, Burgio KL, Brubaker L, Nygaard IE, Ye W, Weidner A, et al. Continence pessary compared with behavioral therapy or combined therapy for stress incontinence: a randomized controlled trial. Obstet Gynecol 2010;115(3):609–17. 38. Ng YW, Paramasivan A, Ahmed AKS. Uterine prolapse in pregnancy: a case report and review of literature. Internet Journal of Gynecology and Obstetrics 2010; 13(2). 39. De Vita D, Giordano S. Two successful natural pregnancies in a patient with severe uterine prolapse: a case report. J Med Case Rep 2011;5:459. 40. Yohannes P, Schaefer J. Urinary retention during the second trimester of pregnancy: a rare cause. Urology 2002;59(6):946i–946iii. 41. Brown HL. Cervical prolapse complicating pregnancy. J Natl Med Assoc 1997;89(5):346–8. 42. Quaas L, Hillemanns HG, Du BA, Schillinger H. The Arabin-cerclage pessary—alternative to surgery [article in German]. Geburtshilfe Frauenheilkd 1990;50(5):429–433. 43. Dharan VB, Ludmir J. Alternative treatment for a short cervix: the cervical pessary. Semin Perinatol 2009;33(5):338–42. 44. Abdel-Aleem H, Shaaban OM, Abdel-Aleem MA. Cervical pessary for preventing preterm birth. Cochrane Database Syst Rev 2010;(9):CD007873. 45. Hegeman MA, Bekedam DJ, Bloemenkamp KW, Kwee A, Papatsonis DN, van der Post JA, et al. Pessaries in multiple pregnancy as a prevention of preterm birth: the ProTwin Trial. BMC Pregnancy Childbirth 2009;9:44.

672 l JULY JOGC JUILLET 2013

46. Goya M, Pratcorona L, Merced C, Rodo C, Valle L, Romero A, et al. Pesario Cervical para Evitar Prematuridad (PECEP) Trial Group. Cervical pessary in pregnant women with a short cervix (PECEP): an open-label randomised controlled trial. Lancet 2012;279(9828):1800–6. 47. Jorde A, Kastli K, Hamann B, Pockrandt H. Changes in the vaginal flora caused by ing pessary treatment in pregnancy [article in German]. Zentralbl Gynakol 1983;105(13):855–62. 48. Wu V, Farrell SA, Baskett TF, Flowerdew G. A simplified protocol for pessary management. Obstet Gynecol 1997;90(6):990–4. 49. Ramsay S, Bouchard F, Tu LM. Long term outcomes of pessary use in women with pelvic organ prolapse. Neurourol Urodyn 2011;30(6):1105–6. 50. Farrell SA. Pessaries for the management of stress urinary incontinence. J Obstet Gynaecol Can 2001;23(12):1184–9. 51. Bai SW, Yoon BS, Kwon JY, Shin JS, Kim SK, Park KH, et al. Survey of the characteristics and satisfaction degree of the patients using a pessary. Int Urogynecol J Pelvic Floor Dysfunct 2005;16(3):182–6. 52. Alnaif B, Drutz HP. Bacterial vaginosis increases in pessary s. Int Urogynecol J Pelvic Floor Dysfunct 2000;11(4):219–22. 53. Arias BE, Ridgeway B, Barber MD. Complications of neglected vaginal pessaries: case presentation and literature review. Int Urogynecol J Pelvic Floor Dysfunct 2008;19(8):1173–8. 54. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

Technical Update on Pessary Use

APPENDIX. SAMPLE PATIENT CARE GUIDELINE AND INFORMATION Courtesy:  Pelvic Floor Clinic, Calgary

Pessary Care Guidelines and Follow-Up                      Date:                           Size:                    Type:                     After your pessary fitting, book a follow-up appointment in weeks. • This visit is to see if the pessary is helping you, and to examine your vagina to make sure it remains healthy looking. • Further follow-up appointments are very important. When you are comfortable with caring for your pessary, the follow-up appointments will be less often. • You may learn to care for your pessary yourself. If you can remove and insert your pessary yourself, then you should remove your pessary overnight at least once a week and clean it with warm water. Book regular follow-up visits to check on the health of your vaginal tissue. Occasional Problems and Suggestions Problem

Suggestions

•  Pessary falls out

Reinsert your pessary if you are able to. Go to your scheduled appointment, and bring your pessary with you.

•  You have pelvic pain

If you feel that your pessary is the cause of the pain, remove it and bring it with you to your next appointment. If you are unable to remove your pessary, the clinic.

•  Vaginal odour and/or discharge

Some odour and discharge is normal. If the odour is very foul, remove the pessary if you can, and go to your scheduled appointment. If you are unable to remove your pessary, the clinic.

•  Vaginal bleeding

This may be a sign that the pessary is irritating your vaginal lining. Remove the pessary if you can, and go to your scheduled appointment. If you are unable to remove your pessary, the clinic.

•  Leaking urine

If you feel that the pessary is making your leakage worse, remove it. Go to your scheduled appointment. If you are unable to remove your pessary, the clinic.

If you are having urgent problems, phone the Pessary Clinic at: This material is designed for information purposes only. It should not be used in place of medical advice, instruction, and/or treatment. If you have specific questions, please consult your doctor or appropriate health care professional. Discharge and Odour Some women find that they have an increased vaginal discharge, with or without an odour, when using a pessary. Usually this is normal. It is the body’s reaction to wearing a foreign body inside of you. This can be controlled with various creams or gels—speak to a doctor or nurse about it. Insertion and Removal Most women are able to insert and remove the pessary on their own. The clinic nurse will teach you some way to do this, but you may find a way that works best for you over time. We suggest that you should try to remove your pessary at least once each week. Leave it out overnight to give your tissues a break. Some women remove it nightly and others leave it out longer. Everyone’s vaginal tissues have a different tolerance level for the pessary, in the same way that everyone’s skin varies in its sensitivity. How often you remove your pessary also depends on whether you are on hormones, and the type of pessary you wear. Some women are unable to remove or insert the pessary due to arthritis or for other reasons. The clinic nurse can help you work out what works best for you, along with helping you find a schedule that works best for you. Insertion of Your Pessary Fold the pessary and insert it through the vaginal opening, aiming down towards your tailbone, and pushing down on the back of the vaginal wall. Using your forefinger, guide the pessary as far back as you can, then push the pessary up and behind the pubic bone.

JULY JOGC JUILLET 2013 l 673

SOGC TECHNICAL UPDATE

APPENDIX. Continued Removing Your Pessary Hook your forefinger under the edge of ring, or in a hole, and pull it down and out of the vagina.

PESSARIES: INFORMATION FOR WOMEN What Are They? A pessary is a device that can be used to help control your leakage problem, or for of sagging or prolapsing pelvic organs such as your bladder, uterus, or rectum. They are made of silicone and are worn inside the vagina. • Pessaries are not a new invention. They have been used for centuries and come in many styles and sizes. They are being used more today as an effective and simple option for pelvic organ prolapse and/or urinary incontinence. • Pessaries can be used for years. • They should fit comfortably. If you have the right style and size, you should not be aware you are using one. • Once fitted, they can be worn once in a while or most of the time. Pessaries are a tool used to help you, and each woman can use them differently. • Pessaries work very well for many women, offer some help for others, and do not seem to be helpful for other women. You can try different styles and sizes to find the one that works best for you. Cleaning Use warm tap water and mild soap (for example, Sunlight dish detergent). Make sure that you rinse the pessary well. Store it in a clean, dry place. Do not boil or disinfect the pessary. that your hands, and the pessary, must be clean before insertion. Sex The pessary may be left in or may be removed before intercourse, depending on your comfort level. This is a trial and error process. Some styles must be removed before intercourse. Bowel movements Most women wearing a pessary have no trouble or interference when having bowel movements. Women who tend to be constipated may have some problems. It is important that you keep your stools soft and regular. Some women may find it necessary to remove their pessary before they have a bowel movement. This material is designed for information purposes only. It should not be used in place of medical advice, instruction, and/or treatment. If you have specific questions, please consult your doctor or appropriate health care professional.

674 l JULY JOGC JUILLET 2013

T SOGC-GOC-SCC CLINICAL PRACTICE GUIDELINE No. 289, April 2013

The Role of Surgery in Endometrial Cancer This clinical practice guideline has been prepared by the SOGC-GOC-SCC Policy and Practice Guidelines Committee, reviewed by the SOGC Clinical Practice Gynaecology Committee and approved by the Executive and Council of the Society of Gynecologic Oncology of Canada and the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Christopher Giede, MD, Saskatoon SK Tien Le, MD, Ottawa ON Patti Power, MD, St. John’s NL SOGC-GOC-SCC POLICY AND PRACTICE GUIDELINES COMMITTEE Tien Le, MD (Chair), Ottawa ON James Bentley, MB ChB, Halifax NS Scott Farrell, MD, Halifax NS Michel P. Fortier, MD, Quebec QC Christopher Giede, MD, Saskatoon SK Rachel Kupets, MD, Toronto ON Marie Plante, MD, Quebec QC Patti Power, MD, St. John’s NL Marie-Claude Renaud, MD, Quebec QC Alexandra Schepansky, MD, Edmonton AB Vyta Senikas, MD, Ottawa ON SPECIAL CONTRIBUTORS Janice Kwon, MD, Vancouver BC Michel Préfontaine, MD, London ON Isabelle Germain, MD, Montreal QC Robert Pearcey, MD, Edmonton AB David D’Souza, MD, London ON Mary Senterman, MD, Ottawa ON

Abstract Objective: To review current practice and make recommendations for the management and treatment of endometrial cancer. Outcomes: This guideline makes recommendations with respect to extended surgical staging, which provides important prognostic information and aids in determining the need for adjuvant treatments. Evidence: Published literature was retrieved through searches of PubMed, CINAHL, and The Cochrane Library, using appropriate controlled vocabulary (e.g., endometrial neoplasms) and key words (e.g., endometrium cancer, endometrial carcinoma). Results were restricted to systematic reviews, randomized control trials/ controlled clinical trials, and observational studies. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to December 31, 2011. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, national and international medical specialty societies, and recent conference abstracts Benefits, harms, and costs: This guideline reviews the benefit of extended surgical staging compared with the potential harm of a limited surgery in grade 2 and 3 disease. Values: The quality of evidence is rated and recommendations are made using the criteria described by the Canadian Task Force on Preventive Health Care (Table). SUMMARY STATEMENTS Low-risk disease (grade 1 adenocarcinoma on biopsy) 1. In low-risk disease, there is no evidence that lymphadenectomy improves survival in grade 1 adenocarcinoma. (I) 2. Endometrial cancer requires a coordinated multidisciplinary team approach for management. (III) 3. The purpose of lymphadenectomy is to guide adjuvant therapy that may affect survival in high-risk populations or prevent treatments that may result in unnecessary toxicity. (III)

Paul Hoskins, MA, Vancouver BC Disclosure statements have been received from all contributors. The literature searches and bibliographic for this guideline were undertaken by Becky Skidmore, Medical Research Analyst, Society of Obstetricians and Gynaecologists of Canada.

J Obstet Gynaecol Can 2013;35(4):370–371

Key Words: Endometrial cancer, lymphadenectomy, surgical staging, sentinel nodes for endometrial cancer

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

370 l APRIL JOGC AVRIL 2013

The Role of Surgery in Endometrial Cancer

Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care. †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

Extent of lymph node evaluation 4. Decisions regarding adjuvant therapy in endometrial cancer are dependent on both histopathologic risk factors for recurrences post-hysterectomy and the status of retroperitoneal lymph nodes when lymphadenectomy is performed. (III) RECOMMENDATIONS Low-risk disease 1. Surgery may be limited to hysterectomy and bilateral salpingooophorectomy as an acceptable alternative to staging patients with grade 1 disease. However, relying on preoperative tumour grading will underestimate high-risk status in a proportion of patients and may subject these women to either second surgery or a more liberal use of external beam adjuvant radiation. (III-B) 2. Additional risk assessment can include preoperative or intraoperative evaluation of depth of myometrial invasion. For final histopathological stage and grade, regional multidisciplinary teams should come to consensus on the use of prognostic factors to guide adjuvant therapy. (III-B) High-risk disease (grade 2 or 3 adenocarcinoma / clear cell / papillary serous on biopsy) 3. Consideration should be given to performing pelvic and/or paraaortic lymphadenectomies in patients with preoperative grade 2 and 3 disease to facilitate accurate planning of adjuvant therapy,

which is often required postoperatively. The survival benefit of lymphadenectomy in this specific group of patients has not been studied. (II-2B) 4. Patients with high-risk histological subtypes of endometrial cancer such as clear cell and papillary serous adenocarcinomas should receive full staging surgery that includes pelvic and/or para-aortic lymphadenectomy and omentectomy. (II-2B) 5. A coordinated multidisciplinary team approach should be used for management of high-risk endometrial cancer. (III-B) 6. Regional multidisciplinary teams should come to local consensus on the use of prognostic factors to guide adjuvant therapy. (III-B) 7. Performing lymphadenectomy on the basis of palpation for “bulky” nodes is inaccurate and should not be done. (II-2E) Advanced disease 8. Patients presenting with advanced disease should be referred to gynaecologic oncologists at a regional cancer centre for treatment planning. (II-2B)

The full version of this document is available online at http://www.sogc.org and http://www.jogc.com.

APRIL JOGC AVRIL 2013 l 371

SOGC CLINICAL PRACTICE GUIDELINE No. 285, January 2013

Toxoplasmosis in Pregnancy: Prevention, Screening, and Treatment This clinical practice guideline has been prepared by the Infectious Disease Committee, reviewed by the Family Practice Advisory Committee and the Maternal Fetal Medicine Committee, and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Caroline Paquet, RM, Trois-Rivières QC Mark H. Yudin, MD, Toronto ON INFECTIOUS DISEASE COMMITTEE Mark H. Yudin, MD (Chair), Toronto ON Victoria M. Allen, MD, Halifax NS Céline Bouchard, MD, Quebec QC Marc Boucher, MD, Montreal QC Sheila Caddy, MD, Edmonton AB Eliana Castillo, MD, Calgary AB Deborah M. Money, MD, Vancouver BC Kellie E. Murphy, MD, Toronto ON Gina Ogilvie, MD, Vancouver BC Caroline Paquet, RM, Trois-Rivières QC Julie van Schalkwyk, MD, Vancouver BC Vyta Senikas, MD, Ottawa ON Disclosure statements have been received from all of the committee.

Abstract Background: One of the major consequences of pregnant women becoming infected by Toxoplasma gondii is vertical transmission to the fetus. Although rare, congenital toxoplasmosis can cause severe neurological or ocular disease (leading to blindness), as well as cardiac and cerebral anomalies. Prenatal care must include education about prevention of toxoplasmosis. The low prevalence of the disease in the Canadian population and limitations in diagnosis and therapy limit the effectiveness of screening strategies. Therefore, routine screening is not currently recommended.

Objective: To review the prevention, diagnosis, and management of toxoplasmosis in pregnancy. Outcomes: Outcomes evaluated include the effect of screening on diagnosis of congenital toxoplasmosis and the efficacy of prophylaxis and treatment. Evidence: The Cochrane Library and Medline were searched for articles published in English from 1990 to the present related to toxoplasmosis and pregnancy. Additional articles were identified through references of these articles. Values: The quality of evidence is rated and recommendations made according to guidelines developed by the Canadian Task Force on Preventive Health Care (Table). Benefits, harms, and costs: Guideline implementation should assist the practitioner in developing an approach to screening for and treatment of toxoplasmosis in pregnancy. Patients will benefit from appropriate management of this condition. Sponsor: The Society of Obstetricians and Gynaecologists of Canada. Recommendations 01. Routine universal screening should not be performed for pregnant women at low risk. Serologic screening should be offered only to pregnant women considered to be at risk for primary Toxoplasma gondii infection. (II-3E) 02. Suspected recent infection in a pregnant woman should be confirmed before intervention by having samples tested at a toxoplasmosis reference laboratory, using tests that are as accurate as possible and correctly interpreted. (II-2B) 03. If acute infection is suspected, repeat testing should be performed within 2 to 3 weeks, and consideration given to starting therapy with spiramycin immediately, without waiting for the repeat test results. (II-2B) 04. Amniocentesis should be offered to identify Toxoplasma gondii in the amniotic fluid by polymerase chain reaction (a) if maternal primary infection is diagnosed, (b) if serologic testing cannot

J Obstet Gynaecol Can 2013;35(1):78–79 Key Words: Toxoplasmosis, pregnancy, congenital, prenatal, disease transmission, mass screening, counselling

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

78 l JANUARY JOGC JANVIER 2013

Toxoplasmosis in Pregnancy: Prevention, Screening, and Treatment

Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care. †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

confirm or exclude acute infection, or (c) in the presence of abnormal ultrasound findings (intracranial calcification, microcephaly, hydrocephalus, ascites, hepatosplenomegaly, or severe intrauterine growth restriction). (II-2B) 05. Amniocentesis should not be offered for the identification of Toxoplasma gondii infection at less than 18 weeks’ gestation and should be offered no less than 4 weeks after suspected acute maternal infection to lower the occurrence of false-negative results. (II-2D) 06. Toxoplasma gondii infection should be suspected and screening should be offered to pregnant women with ultrasound findings consistent with possible TORCH (toxoplasmosis, rubella, cytomegalovirus, herpes, and other) infection, including but not limited to intracranial calcification, microcephaly, hydrocephalus, ascites, hepatosplenomegaly, or severe intrauterine growth restriction. (II-2B) 07. Each case involving a pregnant woman suspected of having an acute Toxoplasma gondii infection acquired during gestation should be discussed with an expert in the management of toxoplasmosis. (III-B) 08. If maternal infection has been confirmed but the fetus is not yet known to be infected, spiramycin should be offered for fetal prophylaxis (to prevent spread of organisms across the placenta from mother to fetus). (I-B)

09. A combination of pyrimethamine, sulfadiazine, and folinic acid should be offered as treatment for women in whom fetal infection has been confirmed or is highly suspected (usually by a positive amniotic fluid polymerase chain reaction). (I-B) 10. Anti-toxoplasma treatment in immunocompetent pregnant women with previous infection with Toxoplasma gondii should not be necessary. (I-E) 11. Women who are immunosuppressed or HIV-positive should be offered screening because of the risk of reactivation and toxoplasmosis encephalitis. (I-A) 12. A non-pregnant woman who has been diagnosed with an acute Toxoplasma gondii infection should be counselled to wait 6 months before attempting to become pregnant. Each case should be considered separately in consultation with an expert. (III-B) 13. Information on prevention of Toxoplasma gondii infection in pregnancy should be made available to all women who are pregnant or planning a pregnancy. (III-C)

The full version of this document is available online at http://www.sogc.org and http://www.jogc.com.

JANUARY JOGC JANVIER 2013 l 79

SOGC Committee Opinion No. 273, March 2012

Genetic Considerations for a Woman’s Annual Gynaecological Examination This committee opinion has been prepared by the Genetics Committee, reviewed by the Family Physicians Advisory Committee and approved by the Executive of the Society of Obstetricians and Gynaecologists of Canada (SOGC). PRINCIPAL AUTHORS R. Douglas Wilson, MD, Calgary AB Sylvie Langlois, MD, Vancouver BC SOGC GENETICS COMMITTEE R. Douglas Wilson, MD (Chair), Calgary AB François Audibert, MD, Montreal QC Jo-Ann Brock, MD, Halifax NS June Carroll, MD, Toronto ON Lola Cartier, MSc, Montreal QC Valérie A. Désilets, MD, Montreal QC Alain Gagnon, MD, Vancouver BC Jo-Ann Johnson, MD, Calgary AB Sylvie Langlois, MD, Vancouver BC Lynn Murphy-Kaulbeck, MD, Moncton NB Nanette Okun, MD, Toronto ON Melanie Pastuck, RN, Calgary AB Vyta Senikas, MD, Ottawa ON Disclosure statements have been received from all of the committee.

Abstract Objective: To provide the physician with an overview of common genetic conditions that should be considered during a women’s annual gynaecological assessment to determine the patient’s risk or to initiate specific testing or referral to another subspecialty service, depending on personal or family history. Options: This genetic information can be used for patient education and possible disease and/or mutation screening or diagnosis. Outcomes: The use of this genetic information may allow improved risk-benefit assessment and management at the annual gynaecological examination. Evidence: Studies published in English up to and including May 2010 were retrieved through searches of PubMed and the Cochrane Library, using appropriate controlled vocabulary (gynaecological diagnosis, genetic inheritance) and key words (genetic risk, genetic mutation, inheritance, family history, uterus, ovary, endometrial, vagina, colon, gastric, renal, breast, cardiac, thrombophilia, diabetes, epilepsy, leiomyomata uteri). Other literature sources were identified through searching the web sites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Values: The levels of evidence are not adequate for evidence-based recommendations to be made. Benefits, harms, and costs: This committee opinion will enhance the use of new genetic knowledge and its application to the annual gynaecological care of women. Risk management and diagnostic opportunities for genetic gynaecological conditions will be improved. A more complete understanding of genetic conditions may increase anxiety and psychological stress for women and their families. Sponsors: Society of Obstetricians and Gynaecologists of Canada. Recommendations

Key Words: Genetic risk, genetic mutation, gynaecology, inheritance, family history, uterus, ovary, endometrial, vagina, colon, gastric, renal, breast, cardiac, thrombophilia, diabetes, epilepsy, uterine leiomyomata uteri, uterine leiomyomas

The levels of evidence are not adequate for evidence-based recommendations to be made.

J Obstet Gynaecol Can 2012;34(3):276–284

This document reflects the emerging clinical and scientific advancement on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

276 l MARCH JOGC MARS 2012

Genetic Considerations for a Woman’s Annual Gynaecological Examination

INTRODUCTION

T

he objective of this committee opinion is to provide physicians with an overview of genetic conditions that should be considered during a woman’s annual gynaecological assessment. This will help to determine whether the patient has any specific genetic risk conditions so that specific testing can be initiated or referral made to another specialty service, depending on the patient’s personal or family history. New genes and other genetic factors are being rapidly identified, and a basic understanding of the common medical and surgical conditions that arise from them will help clinicians when they conduct systematic reviews at a woman’s annual or semi-annual gynaecological visit or when these conditions are discovered incidentally during other gynaecological investigations or surgeries. This committee opinion reviews medical and surgical conditions with a genetic etiology that have gynaecological or obstetrical implications, and cancer and hereditary cancer syndromes that require annual follow-up. MEDICAL OR SURGICAL CONDITIONS WITH A GENETIC ETIOLOGY THAT HAVE GYNAECOLOGICAL OR OBSTETRICAL IMPLICATIONS

Table 1 shows common medical and surgical conditions that have a multifactorial or single gene mode of inheritance that may be part of a woman’s personal or family history. Diabetes Mellitus

The teratogenic risks associated with glucose imbalance in insulin-dependent diabetes were reviewed in a 2007 SOGC clinical practice guideline and in a 2002 review article.1,2 Maternal Cardiac Disease

Genetic cardiac disease can be considered as either congenital heart disease, with multifactorial, chromosomal, or genetic etiology, or coronary artery disease, with genetic and lifestyle risk factors.3 Congenital heart disease is typically identified in childhood, but with improved cardiac ABBREVIATIONS AD

autosomal dominant

AR

autosomal recessive

CRC

colorectal cancer

FAP

familial adenomatous polyposis

HLRCC hereditary leiomyomatosis and renal cell cancer HNPCC hereditary nonpolyposis colon cancer MRKH

Mayer-Rokitansky-Kuster-Ha

MTHFR methylenetetrahydrofolate reductase

care, patients with congenital heart disease now live longer, frequently reaching child-bearing age. Chromosomal deletions (22q DiGeorge syndrome) and single gene disorders associated with congenital heart disease are summarized in Tables 2 and 3. Depending on the age of the patient and when the genetic association with the cardiac anomaly was recognized, testing for the specific gene mutation or chromosomal deletions may not have been completed when a patient presents for prenatal care. Pre-conception counselling issues may be identified at an annual gynaecological visit. Patients should be made aware that if mutation/deletion is present in either parent, there is a risk it may be transmitted to the fetus. The availability of prenatal evaluation by invasive testing (amniocentesis, chorionic villus sampling) as indicated or by non-invasive screening/diagnosis by fetal echocardiography should be discussed with the prospective parents before pregnancy. Parents whose chromosome complement is “normal” according to test results (dependent on the cytogenetic/ molecular level or detail of genetic testing) and who have an isolated congenital heart defect have an empiric increased risk of having a child with a congenital heart defect because of the multifactorial inheritance nature of the cardiac defect. This recurrence risk for isolated non-syndromic heart defects is estimated at 6.5% for an affected mother and 2.2% for an affected father.4 A fetal echocardiogram should be considered when either parent or a previous child was born with a congenital heart defect. Factors related to screening and treatment of atherosclerotic heart disease are beyond the scope of this committee opinion, but if a strong family history is identified, the patient’s primary care physician and cardiology care provider should be notified that this is an area for evaluation and potentially for primary prevention Epilepsy

Women with epilepsy have specific fertility and sexual issues that include a higher incidence of anovulatory cycles and infertility, ovarian cysts, and seizures related to changes in hormones of the hypothalamic pituitary axis (luteinizing hormone, prolactin).5 A woman with epilepsy may be up to 50% less likely to conceive spontaneously than a sibling without a seizure disorder. The exact etiology for this decreased fertility is unclear. Pre-conception counselling should be considered at a woman’s annual visits. For an epileptic woman who becomes pregnant, there are increased risks for birth defects secondary to the antiepileptic drugs she may be using. The teratology of prescription drugs was reviewed in a 2007 SOGC clinical practice guideline.6 Congenital malformations are estimated at 4% to 8% in MARCH JOGC MARS 2012 l 277

SOGC Committee Opinion

Table 1. Common conditions with genetic contribution Medical multifactorial

Atherosclerotic heart disease Diabetes mellitus Hypertension Seizure disorders

Oncology (indirect) multifactorial or single gene

Cancer (breast, ovarian, endometrial, colon)

Genetic (single gene inheritance)

Bleeding disorder Clotting disorder

– hemophilia

XL

– von Willebrand

AD

– antithrombin III

AD

– protein C or S

AD

– factor V Leiden

AD

Cystic fibrosis

AR

Familial hypercholesterolemia

AD

Fragile-X

XL

Glucose-6-phosphate dehydrogenase def

XL

Hemoglobinopathies

– sickle cell

AR

– thalessemia

AR

Huntington disease

AD

Marfan syndrome

AD

Muscular dystrophy

XL

Myotonic dystrophy

AD

Neural tube defect

MF

Neurofibromatosis

AD

Polycystic kidney

AD/AR

XL: X linked inheritance; MF: multifactorial

Table 2. Estimated 22q11 deletion frequency in congenital heart disease Cardiac defect Interrupted aortic arch VSDs

Estimated deletion frequency, % 50 to 89 10

With normal aortic arch*

3

With aortic arch anomaly†

45

Truncus arteriosus

34 to 41

Tetralogy of Fallot

8 to 35

Isolated aortic arch anomalies

24

Double-outlet right ventricle

<5

Transposition of the great arteries

<1

VSD: ventricular septal defect. *Left-sided aortic arch with normal branching pattern. †Includes right aortic arch and/or abnormal branching pattern, cervical location, and/or discontinuous branch pulmonary arteries. Table adapted with permission from Pierpont ME, Basson CT, Benson W, Gelb BD, Giglia TM, Goldmuntz E, et al.3

278 l MARCH JOGC MARS 2012

women with epilepsy and fetal antiepileptic drug exposure. The majority of defects are identified in the central nervous, orofacial, cardiovascular, and urogenital systems. Congenital anomaly screening in pregnancy should include a detailed ultrasound to identify structural defects in the fetus from 18 to 20 weeks, and possibly maternal serum alpha fetoprotein screening for open neural tube defects specifically. t SOGC-Motherisk guidelines indicate that women with epilepsy should supplement their diets with 5 mg of folic acid daily and a multivitamin to minimize the teratogenic component of the antiepileptic drugs.7 Monotherapy for epilepsy should be reviewed with the patient and her other physicians as a treatment option minimizing teratogenic risks. Uterine Leiomyomas

Uterine leiomyomas are the most common benign neoplasia developing within the uterus. It is not known whether a leiomyoma actually transforms into a malignant leiomyosarcoma, but the incidence of leiomyosarcoma is extremely low in premenopausal women when compared with the incidence in older postmenopausal women in whom they for < 1% of uterine malignancies.8,9

Genetic Considerations for a Woman’s Annual Gynaecological Examination

Genetic factors are now being identified. Somatic mutations and, less frequently, molecular alterations in the X chromosome must occur for the initiation and subsequent development of a myoma. The high prevalence of leiomyomas suggests that they result from stable mutations. Very specific genetic risks have been identified for HLRCC,10 which is inherited in an autosomal dominant fashion. Affected individuals demonstrate an increased risk for leiomyomas of the skin and uterus, as well as renal cancers. As leiomyomas have a prevalence of 30% in the female population (although this varies according to ethnicity), it is important for clinicians, gynaecologists, and other caregivers to be aware that HLRCC-associated kidney tumours are often biologically aggressive. Although screening for this mutation or for renal tumour in all women with leiomyomas is not recommended, clinicians should have a high index of suspicion when women present with hematuria suggestive of a renal tumour.

Table 3. Genes associated with congenital heart defects Chromosome location

Condition Congenital heart defects Familial congenital heart disease (ASD, atrioventricular block)

5q

D-TGA, DORV

2q

D-TGA

12q

Tetralogy of Fallot

8q 5q 20p

Atrioventricular septal defect

3p

ASD/VSD

8p Xq

Heterotaxy

2q 3p 1q

Syndromes

Thrombophilias

Thrombophilias can be inherited or acquired.11–14 The most common inherited disorders are mutations of factor V Leiden, prothrombin gene (G20210A mutation), and MTHFR mutation or homozygosity to MTHFR C677T, but the complete list of inherited disorders includes deficiencies in protein S, C, and Z or antithrombin III, homozygosity to 4G/4G mutation in PAI-1 gene, and polymorphisms in thromobomodulin gene. People of Caucasian heritage have a higher rate of genetic thrombophilias than other ethnic groups. have identified the association Several large studies between thrombophilias and adverse pregnancy outcomes. Maternal problems are venous thromboembolism with deep vein thrombosis, pulmonary embolism, and cerebral vein thrombosis; peripheral and cerebral arterial thrombosis; and severe preeclampsia. Fetal and placental issues are thrombosis/infarction, placental abruption, recurrent miscarriage, fetal growth restriction, death, and stroke. In the presence of an inherited thrombophilia, the risk of developing preeclampsia has an estimated frequency of 4% to 27% with factor V Leiden, 0% to 11% with the prothrombin gene mutation, 1% to 25% with protein S deficiency, and 8% to 24% with the MTHFR variant. As some studies show the risk as being similar to baseline and others show a significantly increased risk, it remains unclear whether this association is significant. 11–14

DiGeorge syndrome

22q11

Holt-Oram syndrome

12q24

Alagille syndrome (PPS)

20p12

Char syndrome (PDA)

6p12

Noonan syndrome

12q24 12p1.21 2p21

CHARGE association

8q12

Ellis-van Creveld syndrome

4p16

Marfan syndrome

15q21.1

Marfan-like syndrome

3p22

Cardiofaciocutaneous syndrome

12p12.1 7q34 15q21 7q32

Costello syndrome

11p15.5

William syndrome/supravalvar aortic stenosis

7q11

ASD: atrial septal defect; D-TGA: D-transposition of great arteries; VSD: ventricular septal defect; DORV: double-outlet right ventricle; PPS: peripheral pulmonary stenosis; PDA: patent ductus arteriosus; CHARGE: coloboma, heart anomaly, choanal atresia, retardation, and genital and ear anomalies. Table adapted with permission from Pierpont ME, Basson CT, Benson W, Gelb BD, Giglia TM, Goldmuntz E, et al.3

Screening for inherited thrombophilias should be considered for women with a history of thromboembolism, including deep vein thrombosis. There have been few randomized trials, so definitive treatment and prophylaxis regimens have not been established. Within the genetic MARCH JOGC MARS 2012 l 279

SOGC Committee Opinion

Table 4. Estimated number and lifetime risk of women who would develop or die of various types of cancer in 2007 Lifetime risk of developing, 1 in

Lifetime risk of dying of, 1 in

Breast

008

034

Lung

017

030

Colorectal

018

045

Endometrial

038

196

Skin

077

500

Ovarian

068

095

Cervical

135

385

Type of cancer

Data from Adams Hillard PJ and Berek JS,20 Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ,21 American Cancer Society.22

thrombophilia group, most studies are observational with small, heterogeneous groups. A single RCT15 is available in which 160 women with at least 1 fetal loss after 10 weeks and heterozygosity for a single thrombophilia mutation (factor V Leiden, prothrombin G20210A mutation, protein S) were randomized to enoxparin 40 mg or low-dose ASA 100 mg daily. The enoxparin group had an increased live birth rate (86% vs. 29%), higher birth weight, and lower intrauterine growth restriction rates (10% vs. 30%) than the low-dose ASA group. Other thrombophilia treatment protocols are available.16,17 Referral to a treatment centre with expertise in the topic should be considered before anticoagulant treatment is initiated before or during pregnancy. Pre-conception discussion with a woman with a thrombophilia and a past history of poor pregnancy outcome should include increased fetal surveillance starting at 24 weeks, with serial ultrasound (every 4 weeks) for fetal growth, umbilical artery Doppler, non-stress test and/or biophysical profile used as clinically required, and consideration of delivery by 39 weeks.11 Contraception with estrogen-containing products is contraindicated unless long-term anticoagulation is used. Progestin-only products do not increase thromboembolic risks. Estrogen-containing hormone therapy may increase the risk of stroke and thromboembolic disease. Surgery on a woman with factor V Leiden requires thromboprophylaxis according to published protocols to decrease her thrombotic risk.18 Congenital Mullerian Anomalies

Women with agenesis of the uterus and vagina but normal ovarian function and secondary sexual characteristics have 280 l MARCH JOGC MARS 2012

Mayer-Rokitansky-Kuster-Ha syndrome.19 A 2006 report of a cohort of 106 consecutive women with the MRKH syndrome reviewed other congenital anomalies associated with MRKH syndrome.18 Hypoplastic vagina was present in 61 women. Laterally displaced Mullerian remnants were present in 92 women, and 26% of the remnants had a cavity with endometrial mucosa. Ovaries were extrapelvic in 16%. Urinary tract abnormalities were present in 30%, with unilateral renal agenesis (18%), pelvic kidney (11%), and horseshoe kidney (2%) being the most common anomalies. The recognition of this wide variability of anatomical presentations is important for appropriate surveillance, diagnosis, and treatment of gynaecological problems in women with MRKH syndrome. A renal ultrasound is recommended to assess urinary tract anomalies, particularly before abdominal or pelvic surgery. RISK ASSESSMENT FOR CANCER AND HEREDITARY CANCER SYNDROMES (BACKGROUND, PERSONAL, FAMILY)

Recent estimates of lifetime risk of a woman developing or dying from various types of cancer are shown in Table 4.20–22 Breast cancer occurs most frequently. It has a lifetime presentation risk of 1 in 8 and a death risk of 1 in 34 compared with cervical cancer, which has a presentation risk of 1 in 135 and a death risk of 1 in 385. Despite these risks, a recent publication23 reported that a financially stable and well-educated population of women had very little knowledge or understanding of hereditary cancer risks. Cancers studied in this population included hereditary breast cancer, Lynch syndrome, and p16-related melanoma. Although approximately 11% were identified as being at high-risk for at least 1 of the 3 syndromes (breast cancer 88.5%, Lynch syndrome 6.1%, p16-related melanoma 3.8%), < 3% had ever had genetic counselling or testing. The discovery of genes responsible for hereditary cancer syndrome has led to specific recommendations for genetic testing for mutations in BRCA1 and BRCA2, responsible for hereditary breast and ovarian cancer, and the mismatchrepair genes responsible for the hereditary nonpolyposis colon cancer also known as Lynch syndrome.24 A 2007 commentary25 emphasized the need for more public education. A 2005 US Preventive Services Task Force recommendation26 indicates that women whose family history (first and second degree relatives) is indicative of an increased risk for deleterious mutations in BRCA10r BRCA2 genes should be referred for genetic counselling and evaluation for these mutations. These women would benefit from obtaining information that would allow

Genetic Considerations for a Woman’s Annual Gynaecological Examination

informed choice about testing and further prophylactic treatment and risk-reduction surgery. This counselling should be done within a genetic oncology program by trained health care providers. There is increasing evidence to consider the benefits of chemoprevention or intensive screening in improving health outcomes in women who test positive for deleterious BRCA1 or BRCA2 mutations.27,28 However, there is fair evidence that risk-reduction surgery for these women significantly decreases breast and ovarian cancer incidence. In 2007, the American Cancer Society issued guidelines29 for offering screening breast MRI in women with a lifetime risk of breast cancer of 20% to ≥ 25% (based on models of family history) using an annual breast MRI examination beginning at age 30. A more recent study30 indicates that although family history is a strong predictor of risk, it is not always required, as a cohort of women with apparently sporadic (no first or second degree relatives with breast or ovarian cancer) and early onset breast cancer had a 9.5% incidence BRCA1 or BRCA2 mutation. For women with BRCA1 or BRCA2 mutations, the risk of breast cancer is up to 87% by the age of 70. Clinicians should ensure that women at risk are given tools to help them make the difficult decision about prophylactic salpingo-oophorectomy or bilateral mastectomy and the increased lifetime risks for BRCA-associated gynaecologic (ovarian, fallopian tube, and primary peritoneal) cancers.31 Recent reviews27,28 of ovarian cancer prevention in patients with BRCA1 or BRCA2 germline mutations indicate that although chemoprevention (tamoxifen, raloxifene) and screening (twice yearly vaginal ultrasound and serum CA-125) both have a role, neither is efficacious enough to eliminate the need for risk reducing salpingooophorectomy in women with an inherited predisposition to ovarian cancer; therefore, risk reducing salpingooophorectomy will remain an important component of gynaecologic cancer risk reduction. Although BRCA1 and BRCA2 for the largest proportion of genetic susceptibility to breast cancer, other rare disorders make up approximately 10% to 20% of the genetic susceptibility. These include ataxia-telangiectasia (AR), oculocutaneous telangiectasia, cerebellar ataxia, variable immunodeficiency, lymphoid and epithelial cancers, Li-Fraumeni syndrome (AD), childhood bone or softtissue sarcomas, early onset breast cancer, acute leukemias, brain tumours, carcinoma of the lung or pancreas, melanoma, Cowden disease (AD), mucocutaneous lesions, thyroid, breast, hamartomatous polyps of the GI tract, macrocephaly, uterine leiomyomas), and very rare syndromes such as Gorlin syndrome (AD), Muir-Torre

syndrome (AD), Peutz-Jeghers syndrome (AD), and partial androgen insensitivity syndrome (X-linked recessive). For women with BRCA1 or BRCA2 mutations who have not undergone risk-reduction mastectomy, intensive breast screening with both annual mammogram and annual breast MRI beginning at age 25 years could be considered. American Cancer Society guidelines29 for breast cancer screening with MRI as an adjunct to mammography recommend that an annual MRI could also be used not only for the high-risk BRCA mutation carrier and first degree relative cohort but also for screening other high-risk breast cancer groups, such as women with a history of therapeutic radiation (e.g., for Hodgkin’s disease) to the chest between the ages of 10 and 30 years, women with Li-Fraumeni syndrome and first degree relatives, and women with Cowden or BannayanRiley-Ruvalcaba syndrome and first degree relatives. In 2010, the Public Health Agency of Canada produced a “Decision Aid for Breast Cancer Screening in Canada.” It provides information on mammography to assist women aged ≥ 40 in making decisions about screening. The document recommends that women aged 50 to 69 years who are at average risk should have screening mammograms every 2 years.32 Endometrial cancers can also be a component of an inherited cancer susceptibility syndrome. For example, endometrial cancer is associated with HNPCC/Lynch syndrome. HNPCC is likely the most common hereditary cancer syndrome, causing about 1 in 20 cases of colorectal cancer.33 The mutation confers a lifetime risk of about 80% that a carrier will develop CRC. Men with these mutations appear to have a greater risk of developing CRC than women. The mutation confers a 30% to 60% lifetime risk for endometrial cancer in female carriers. This is an inherited autosomal dominant mutation, and there are 4 known genes: hMLH1, hMSH2, hMSH6, PMS2. Decision models for Lynch/HNPCC34 have compared 3 management strategies: (1) annual gynaecological examination alone; (2) annual examination with screening (ultrasound, endometrial biopsy, CA 125); and (3) hyster­ ectomy with bilateral salpingo-oophorectomy. The third option may be considered for appropriately counselled women with Lynch/HPNCC to prevent gynaecologic cancers and their associated morbidities. The same research group has reported that this surgical approach is cost effective.35 Recommendations for presymptomatic women with documented HPNCC/Lynch mutations include colonoscopic screening starting at age 25 and continuing as MARCH JOGC MARS 2012 l 281

SOGC Committee Opinion

Table 5. Routine cancer screening clinical approach (American Congress of Obstetricians and Gynecologists, The Society of Obstetricians and Gynaecologists of Canada, and The Society of Gynecologic Oncologists of Canada) Topic

Guideline

Breast Cancer

ACOG: Mammography should be performed every 1 to 2 years beginning at age 40 years and yearly beginning at age 50 years. All women should have an annual clinical breast examination as part of the physical examination. Despite a lack of definitive data for or against breast self-examination, it has the potential to detect palpable breast cancer and can be recommended. SOGC/GOC: Age 40 to 49, clinical breast examination by trained professional every 2 years; age 50 to 69, clinical breast examination by trained professional and mammogram every 2 years; > age 70, personal plan discussed with trained professional

Colorectal Cancer

ACOG: Beginning at age 50 years, 1 of 5 screening options should be selected: 1.  Yearly patient-collected FOBT or FIT,* or 2.  Flexible sigmoidoscopy every 5 years, or 3.  Yearly patient-collected FOBT or FIT* plus flexible sigmoidoscopy every 5 years, or 4.  Double-contrast barium enema every 5 years, or 5.  Colonoscopy every 10 years SOGC/GOC: Women at low risk > age 50 fecal occult blood every 2 years; Women at high risk (first degree relative affected with CRC, FAP, HNPCC, history of inflammatory bowel disease, benign polyps in colon or rectum) should discuss surveillance such as colonoscopy with trained gastrointestinal professional

Ovarian Cancer

ACOG and SOGC/GOC: Currently, there are no effective techniques for the routine screening of asymptomatic, women at low risk for ovarian cancer. It appears that the best way to detect early ovarian cancer is for both the patient and her clinician to have a high index of suspicion of the diagnosis in the symptomatic woman, and both should be aware of the symptoms commonly associated with ovarian cancer. Persistent symptoms such as an increase in abdominal size, abdominal bloating, fatigue, abdominal pain, indigestion, inability to eat normally, urinary frequency, pelvic pain, constipation, back pain, urinary incontinence of recent onset, or unexplained weight loss should be evaluated, with ovarian cancer included in the differential diagnosis. Research in progress: combining CA125 and transvaginal ultrasound in a small study detected 34/38 ovarian cancers with 50% in stage I or II.

FIT: fecal immunochemical testing; FOBT: fecal occult blood testing; CA125 blood test for cancer screening. *Both FOBT and FIT require 2 or 3 samples of stool collected by the patient at home and returned for analysis. A single stool sample for FOBT or FIT obtained by digital rectal examination is not adequate for the detection of CRC. Table adapted from Adams Hillard PJ and Berek JS,20 Canadian Cancer Society.46,47

Table 6. Primary and preventive care: periodic assessments in women who have a family history Age range

Periodic assessment (consider family history/risk)

Leading causes of death (genetic disease)

13 to 18 years

genetic testing/counselling

malignant neoplasms

2

congenital conditions

6

19 to 39 years

genetic testing/counselling

malignant neoplasms

1

cardiovascular risk

cardiac

3

diabetes

8

CRC screening

malignant neoplasms

1

lipid/cholesterol profile

cardiac

2

diabetes

diabetes

6

cardiac

1

malignant neoplasms

2

Alzheimer’s disease

5

diabetes

7

40 to 64 years

Rank

breast cancer thyroid (TSH) ≥ 65 years

as above

TSH: thyroid stimulating hormone Table adapted from ACOG Committee Opinion No. 452.48

282 l MARCH JOGC MARS 2012

Genetic Considerations for a Woman’s Annual Gynaecological Examination

frequently as once per year.36 Gynaecological surveillance should start at age 30 (17% of endometrial cancers and 42% of ovarian cancers in these patients cohort are diagnosed by age 40). Women with Lynch syndrome do not have an increased risk for breast cancer, so they may benefit from estrogen-replacement therapy after oophorectomy to prevent or minimize the potential sequelae of surgically induced menopause. Other genetic gastrointestinal cancers, including hamartomatous polyposis syndromes, gastric cancer, and CRC/familial adenomatous polyposis, are described in the Appendix.37–45 Table 5 summarizes general approaches for cancer screening of breast, colon and ovary20,46,47 considering both Canadian and American sources. Table 6 summarizes the primary and preventive care periodic assessments by female age groups.48 REFERENCES 1. Allen VM, Armson BA; SOGC Genetics Committee; SOGC Maternal Fetal Medicine Committee. Teratogenicity associated with pre-existing and gestational diabetes. SOGC Clinical Practice Guideline No. 200, November 2007. J Obstet Gynaecol Can 2007;29:927–34. 2. McLeod L, Ray LJ. Prevention and detection of diabetic embryopathy. Community Genet 2002;5:33–9. 3. Pierpont ME, Basson CT, Benson W, Gelb BD, Giglia TM, Goldmuntz E, et al. Genetic basis for congenital heart defects: current knowledge. A scientific statement from the American Heart Association Congenital Cardiac Defects Committee, Council on Cardiovascular Disease in the Young. Endorsed by the American Academy of Pediatrics. Circulation 2007;115:3015–38. 4. Burn J, Goodship J. Congenital heart disease. In: Emery and Rimoin’s principles and practice of medical genetics. 4th ed. Edinburgh: Churchill Livinstone;2001:1239–326. 5. Shulman LP, Montouris G. Women with epilepsy: clinical guidelines. Female Patient 2006; (Suppl):5–12S. 6. Wilson RD; SOGC Genetics Committee; SOGC Infectious Disease Committee. Principles of human teratology: drug, chemical, and infectious exposure. SOGC Clinical Practice Guideline No. 199, November 2007. J Obstet Gynaecol Can 2007;23:911–7. 7. Wilson RD; SOGC Genetics Committee; Motherisk. Pre-conceptional vitamin/folic acid supplementation 2007: the use of folic acid in combination with a multivitamin supplement for the prevention of neural tube defects and other congenital anomalies. t SOGC-Motherisk Clinical Practice Guideline No. 201, December 2007. J Obstet Gynaecol Can 2007;201:1003–13. 8. Blake RE. Leiomyomata uteri: hormonal and molecular determinants of growth. J Natl Med Assoc 2007;99:1170–84. 9. Stewart EA, Morton CC. The genetics of uterine leiomyomata. What clinicians need to know. Obstet Gynecol 2006;107:917–21. 10. Sudarshan S, Pinto PA, Linehan WM. Mechanisms of disease: hereditary leiomyomatosis and renal cell cancer—a distinct form of hereditary kidney cancer. Nature 2007;4:104–10.

11. Sibai BM, How HY, Stella CL. Thrombophilia in pregnancy: whom to screen, when to treat. OBG Management 2007;19:50–64. 12. James AJ, Brancazio LR. Factor V Leiden thrombophilia. Female Patient 2007; 32:14–6. 13. Gibson CS, MacLennan AH, Janssen NG, Kist WJ, Hague WM, Haan EA, et al.; South Australian Cerebral Palsy Research Group. Associations between fetal inherited thrombophilia and adverse pregnancy outcomes. Am J Obstet Gynecol 2006;194:947–53. 14. Spector EB, Grody WW, Matteson CJ, Palomaki G, Bellissino DB, Wolff DJ, et al. Technical standards and guidelines: venous thromboembolism (Factor V Leiden and prothrombin 20210G>A testing): a disease-specific supplement to the standards and guidelines for clinical genetics laboratories. Genet Med 2005;7:444–53. 15. Gris JC, Mercier E, Quéré I, Lavigne-Lissalde G, Cochery-Nouvellon E, Hoffet M, et al. Low-molecular-weight heparin versus low-dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder. Blood 2004;103:3695–9. 16. Qaseem A, Snow V, Barry P, Hornbake ER, Rodnick JE, Tobolic T, et al. t American Academy of Family Physicians/American College of Physicians on Deep Venous Thrombosis/Pulmonary Embolism. Current diagnosis of venous thromboembolism in primary care: a clinical practice guideline from the American Academy of Family Physicians and the American College of Physicians. Ann Fam Med 2007;5:57–62. 17. De Carolis S, Gerrazzani S, DeStefano V, Garofalo S, Fatigante G, Rossi E, et al. Inherited thrombophilia: treatment during pregnancy. Fetal Diagn Ther 2006;21:281–6. 18. Marik PE, Plante LA. Venous thromboembolic disease and pregnancy. N Engl J Med 2008;359:2025–33. 19. Fedele L, Bianchi S, Frontino G, Ciappina N, Fontana E, Borruto F. Laparoscopic findings and pelvic anatomy in Mayer-Roitansky-KüsterHa syndrome. Obstet Gynecol 2007;109:1111–5. 20. AdamsHillard PJ, Berek JS, eds. Guidelines for women’s healthcare. A resource manual. 3rd ed. Washington DC: American College of Obstetricians and Gynecologists: 2007. 21. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin 2007;57:43–66. 22. American Cancer Society. Lifetime probability of developing or dying from cancer. Dallas (TX); ACS; 206. 23. Manuel M, Kieran S, Lilja J. Cancer risk assessment in a community setting: prevalence of patients with high risk family histories. Gynecol Oncol 2007 Mar;104(3 Suppl 1):S2–35. Abstract 15, presented at the 38th Annual Meeting on Women’s Cancer, Society of Gynecologic Oncologists, March 3–7, 2007, San Diego CA. 24. Karlan BY, Berchuck A, Mutch D. The role of genetic testing for cancer susceptibility in gynecologic practice. Obstet Gynecol 2007;110:155–67. 25. Nisker JA. The need for public education: surveillance and risk reduction strategies for women at risk for carrying BRCA gene mutations. J Obstet Gynaecol Can 2007;29:510–1. 26. US Preventive Services Task Force. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: recommendation statement. Ann Intern Med 2005;143:355–61. 27. Metcalfe KA, Poll A, O’Connor A, Gershman S, Armel S, Finch A, et al. Development and testing of a decision aid for breast cancer prevention for women with BRAC1 or BRAC2 mutation. Clin Genet 2007;72:208–17. 28. Kauff ND, Barakat RR. Risk-reducing salpingo-oophorectomy in patients with germline mutations in BRCA1 and BRCA2. J Clin Oncol 2007;25:2921–7. 29. Saslow D, Boetes C, Burke W, Harms S, Leach MO, Lehman CD, et al. American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin 2007;57:75–89.

MARCH JOGC MARS 2012 l 283

SOGC Committee Opinion

30. Weitzel JN, Lagos VI, Cullinane CA, Gambol PJ, Culver JO, Blazer KR, et al. Limited family structure and BRCA gene mutation status in single cases of breast cancer. JAMA 2007;297:2587–95. 31. Kauff ND, Barakat RR. Surgical risk-reduction in carriers of BRCA mutations: where do we go from here? Gynecol Oncol 2004;93:277–9. 32. Public Health Agency of Canada. Information on mammography for women aged 40 and older: a decision aid for breast cancer screening in Canada. Ottawa: Public Health Agency of Canada;2009. Available at: http://www.phac-aspc.gc.ca/cd-mc/mammography-mammographie-eng.php. Accessed August 10, 2011. 33. Feero G. Inherited cancer syndromes. Guest Editorial. Ob Gyn News 2007;42(17):10. 34. Chen L-M, Yang KY, Little SE, Cheung MK, Caughey AB. Gynecologic cancer prevention in Lynch syndrome/hereditary nonpolyposis colorectal cancer families. Obstet Gynecol 2007;110:18–25. 35. Yang KY, Caughey AB, Little SE, Cheung MK, Chen L-M. A costeffectiveness analysis of prophylactic surgery versus gynecologic surveillance for women from hereditary nonpolyposis colorectal cancer (HNPCC) families. Gynecol Oncol 2007;104(3 Suppl 1): Abstract 68. Presented at the 38th Annual Meeting of the Society of Gynecologic Oncologists, San Diego, CA. March 3–7, 2007. 36. Offit K, Kauff ND. Reducing the risk of gynecologic cancer in the lynch syndrome. N Engl J Med 2006;354:293–5. 37. Zbuk KM, Eng C. Hamartomatous polyposis syndromes. Nat Clin Pract Gastroenterol Hepatol 2007;4:492–502. 38. Kaurah P, MacMillan A, Boyd N, Senz J, DeLuca A, Chun N, et al. Founder and recurrent CDH1 mutations in families withy hereditary diffuse gastric cancer. JAMA 2007;297:2360–72. 39. Lynch HT, Grady W, Suriano G, Huntsman D. Gastric cancer: new genetic developments. J Surg Oncol 2005;90:114–33.

40. t Test and Technology Transfer Committee Working Group. Genetic testing for colon cancer: t statement of the American College of Medical Genetics and American Society of Human Genetics. Genet Med 2000;2:362–6. 41. Ramsoekh D, van Leerdam ME, Tops CMJ, Dooijes D, Steyerberg EW, Kuipers EJ, et al. The use of genetic testing in hereditary colorectal cancer syndromes: genetic testing in HNPCC, (A)FAP and MAP. Clin Genet 2007;72:562–7. 42. Zarychanski R, Chen Y, Bernstein CN, Hébert PC. Frequency of colorectal cancer screening and the impact of family physicians on screening behavior. CMAJ 2007; 177:593–7. 43. Barkun A, Flegel K. Outliving colorectal cancer. CMAJ 2007;177:545. 44. Leddin D, Hunt R, Champion M, Cockeram A, Flook N, Gould M, et al. Canadian Association of Gastroenterology and the Canadian Digestive Health Foundation. Guidelines on colon cancer screening. Can J Gastroenterol 2004;18:93–9. 45. Kahi CJ, Rex DK. Primer: applying the new postpolypectomy surveillance guidelines in clinical practice. Nature 2007;4:571–8. 46. Canadian Cancer Society. Breast cancer screening guideline. Available at: http://www.cancer.ca/Canada-wide/Prevention/Getting%20checked/ Breast%20cancer%20NEW.aspx?sc_lang=en. Accessed August 8, 2011. 47. Canadian Cancer Society. Colorectal cancer recommendations. Available at: http://www.cancer.ca/Canada-wide/Prevention/Getting%20checked/ Colorectal%20cancer%20NEW.aspx?sc_lang=en. Accessed August 8, 2011. 48. American College of Obstetricians and Gynecologists Committee on Gynecologic Practice. Primary and preventative care periodic assessments. ACOG Committee Opinion No. 452, December 2009. Obstet Gynecol 2009;114:1444–51.

Appendix. Additional Gastrointestinal Cancer Information The hamartomatous polyposis syndromes are a heterogeneous group of disorders that share an autosomal-dominant pattern of inheritance and are characterized by hamartomatous polyps of the gastrointestinal tract.37 These syndromes include juvenile polyposis syndrome, Peutz-Jeghers syndrome, and PTEN hamartoma tumour syndrome. The frequency and location of the polyps vary considerably, as does the predisposition for the development of gastrointestinal and other malignancies. In addition, there are non-malignant manifestations, such as bleeding, intussusception, and bowel obstruction. Surveillance guidelines for these rare syndromes were published in 2007.37 Gastric cancer is the second most common cause of cancer death worldwide. A germline mutation in the epithelial cadherin (CDH1) has an increased risk for diffuse gastric cancer and lobular breast cancer. A recent publication indicates the presence of a founder mutation from Newfoundland pedigrees.38 Published guidelines39,40 recommend providing genetic counselling to the family and beginning screening in the late teens or early 20s. The timing of prophylactic gastrectomy is an individual decision. Colorectal cancer is the second leading cause of cancer death in North America. CRC evolves in an adenoma to carcinoma sequence during which a series of somatic alterations accumulate in the DNA of the tumour tissue.40 About 75% of these molecular changes are sporadic events, but the remaining 25% arise in individuals with a family history of colon cancer. HNPCC (etiology for 1 in 20 CRC) has been discussed previously. The other hereditary cancer (much rarer with 100 to thousands of polyps) is FAP, which is an autosomal dominant syndrome with germline mutations. Clinical onset is at a young age (12 to 15 years) with hundreds of adenomatous polyps in the colon and increased risk for gastric polyps, duodenal cancer, thyroid cancer, and desmoids tumours. There is an attenuated variety, AFAP, that has fewer than 100 adenomas with a proximal predominance and a later age of onset (55 years).40 Cancer genetic risk assessment for hereditary colon cancer would include HNPCC and FAP.41 A recent mutation was identified specifically in the Ashkenazi Jewish population. A 2002 statement from American College of Medical Genetics and the American Society of human Genetics presents guidelines for screening and tumour analysis.40 Identification of this colorectal family history should allow discussion with the patient about counselling, possible testing and referral to a hereditary cancer program through medical or provincial cancer agencies.41 Recently published results42,43 from a 2003 survey indicate only 23.5% of Canadians at risk for colon cancer reported receiving screening, but this dropped to 17.6% when only up-to-date screening was considered. Canadian recommendations44 are that screening involves geographic availability and patient discussion with the screening options of fecal occult blood testing every 2 years; flexible sigmoidoscopy every 5 years; double contrast barium enema every 5 years; colonoscopy every 10 years. The use of colonoscopy as a screening test for CRC has indentified increased numbers of patients with polyps requiring follow-up. A recent review45 reports that most patients do not require intensive surveillance, as patients with 1 or 2 small (< 1 cm) adenomas can safely repeat colonoscopy after 5 to 10 years.

284 l MARCH JOGC MARS 2012

SOGC CLINICAL PRACTICE GUIDELINE No. 275, April 2012

Antibiotic Prophylaxis in Gynaecologic Procedures This clinical practice guideline has been prepared by the Infectious Diseases Committee, reviewed by the Family Physician Advisory Committee, and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Nancy Van Eyk, MD, Halifax NS Julie van Schalkwyk, MD, Vancouver BC INFECTIOUS DISEASES COMMITTEE Mark H. Yudin, MD (Chair), Toronto ON Victoria M. Allen, MD, Halifax NS Céline Bouchard, MD, Quebec QC Marc Boucher, MD, Montreal QC Sheila Caddy, MD, Edmonton AB Eliana Castillo, MD, Calgary AB Deborah M. Money, MD, Vancouver BC Kellie E. Murphy, MD, Toronto ON Gina Ogilvie, MD, Vancouver BC Caroline Paquet, RM, Trois-Rivières QC Julie van Schalkwyk, MD, Vancouver BC Vyta Senikas, MD, Ottawa ON Disclosure statements have been received from all of the committee. The literature searches and bibliographic for this guideline were undertaken by Becky Skidmore, Medical Research Analyst, Society of Obstetricians and Gynaecologists of Canada.

J Obstet Gynaecol Can 2012;34(4):382–391

Key Words: Antibiotics, prophylaxis, hysterectomy, hysteroscopy, gynaecologic surgery

Abstract Objective: To review the evidence and provide recommendations on antibiotic prophylaxis for gynaecologic procedures. Outcomes: Outcomes evaluated include need and effectiveness of antibiotics to prevent infections in gynaecologic procedures. Evidence: Medline and The Cochrane Library were searched for articles published between January 1978 and January 2011 on the topic of antibiotic prophylaxis in gynaecologic procedures. Results were restricted to systematic reviews, randomized control trials/ controlled clinical trials, and observational studies. Searches were updated on a regular basis and incorporated in the guideline to June 2011. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Values: The quality of evidence obtained was rated using the criteria described in the Report of the Canadian Task Force on Preventative Health Care (Table 1). Benefits, harms, and costs: Guideline implementation should result in a reduction of cost and related harm of istering antibiotics when not required and a reduction of infection and related morbidities when antibiotics have demonstrated a proven benefit. Recommendations 01. All women undergoing an abdominal or vaginal hysterectomy should receive antibiotic prophylaxis. (I-A) 02. All women undergoing laparoscopic hysterectomy or laparoscopically assisted vaginal hysterectomy should receive prophylactic antibiotics. (III-B) 03. The choice of antibiotic for hysterectomy should be a single dose of a first-generation cephalosporin. If patients are allergic to cephalosporin, then clindamycin, erythromycin, or metronidazole should be used. (I-A) 04. Prophylactic antibiotics should be istered 15 to 60 minutes prior to skin incision. No additional doses are recommended. (I-A) 05. If an open abdominal procedure is lengthy (e.g., > 3 hours), or if the estimated blood loss is > 1500 mL, an additional dose of the prophylactic antibiotic may be given 3 to 4 hours after the initial dose. (III-C)

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

382 l APRIL JOGC AVRIL 2012

Antibiotic Prophylaxis in Gynaecologic Procedures

06. Antibiotic prophylaxis is not recommended for laparoscopic procedures that involve no direct access from the abdominal cavity to the uterine cavity or vagina. (l-E) 07. All women undergoing surgery for pelvic organ prolapse and/or stress urinary incontinence should receive a single dose of firstgeneration cephalosporin. (III-B) 08. Antibiotic prophylaxis is not recommended for hysteroscopic surgery. (II-2D) 09. All women undergoing an induced (therapeutic) surgical abortion should receive prophylactic antibiotics to reduce the risk of postabortal infection. (I-A) 10. Prophylactic antibiotics are not suggested to reduce infectious morbidity following surgery for a missed or incomplete abortion. (I-E) 11. Antibiotic prophylaxis is not recommended for insertion of an intrauterine device. (I-E) However, health care professionals could consider screening for sexually transmitted infections in high-risk populations. (III-C) 12. There is insufficient evidence to the use of antibiotic prophylaxis for an endometrial biopsy. (III-L) 13. The best method to prevent infection after hysterosalpingography is unknown. Women with dilated tubes found at the time of hysterosalpingography are at highest risk, and prophylactic antibiotics (e.g., doxycycline) should be given. (II-3B) 14. Antibiotic prophylaxis is not recommended for urodynamic studies in women at low risk, unless the incidence of urinary tract infection post-urodynamics is > 10%. (1-E) 15. In patients with morbid obesity (BMI > 35 kg/m2), doubling the antibiotic dose may be considered. (III-B) 16. istration of antibiotics solely to prevent endocarditis is not recommended for patients who undergo a genitourinary procedure. (III-E)

INTRODUCTION

I

nfectious complications following gynaecologic surgical procedures are a significant source of morbidity and potential mortality. They include urinary tract infection, endometritis, wound infection, vaginal cuff cellulitis, perineal infection, and sepsis, which lead to prolonged hospital stays and increased health care costs. Much work has been done to study the effect of prophylactic antibiotics in reducing infectious morbidity. A plethora of antibiotic types, dosing schedules, and routes of istration have been investigated. There is evidence to the use of prophylactic antibiotics for a number of procedures in gynaecology. Unfortunately, few comparative trials have been conducted, leaving the clinician with uncertainty as to which regimen is superior.

ABBREVIATIONS BV

bacterial vaginosis

HSG

hysterosalpingography

PID

pelvic inflammatory disease

STI

sexually transmitted infection

UTI

urinary tract infection

The presence of antibiotic resistant organisms is a reality in Canadian health care facilities.1 These organisms include methicillin resistant Staphylococcus aureus, vancomycin resistant Enterococcus, and extended-spectrum betalactamase-producing organisms. Both morbidity and mortality are increased in infections involving these organisms, as they may be more virulent and are more difficult to treat because therapeutic options are limited. Antibiotic resistance development results mainly from the inappropriate use of antibiotics. Incomplete courses of antibiotic therapies and the unnecessary use of broader spectrum regimens play a role.2 Adherence to treatment and prophylaxis guidelines likely assists in reducing infection and antibiotic resistance. Physician adherence to antibiotic prophylaxis guidelines is variable and frequently at odds with published guidelines.3,4 In addition to antibiotic prophylaxis, all factors that affect infectious risk reduction in our specialty must be reviewed. Sterile surgical fields must be ensured, and ongoing quality assessment of sterilization technique, air ventilation, and postoperative wound care are needed. Consistent infection control surveillance and reporting of infectious complications track ability to minimize these morbidities and possibly to identify clusters of infection and the emergence of antibiotic resistant organisms. This will dictate changes to operative routines to respond to evolving microbial diversity that seems inevitable. PRINCIPLES OF ANTIBIOTIC PROPHYLAXIS

The purpose of antibiotic prophylaxis in surgical procedures is not to sterilize tissues but to reduce the colonization pressure of microorganisms introduced at the time of operation to a level that the patient’s immune system is able to overcome.5 Prophylaxis does not prevent infection caused by postoperative contamination. Prophylactic antibiotic use differs from treatment with antibiotics in that the former is intended to prevent infection, whereas the latter is intended to resolve an established infection, typically requiring a longer course of therapy. Prophylaxis is intended for elective procedures in which the incision will be closed in the operating room. Before an agent can be considered for use as a prophylactic, there must be evidence that it reduces postoperative infection. It must also be safe and inexpensive, and it must be effective against organisms likely to be encountered in the surgical procedure. The agent must be istered in a way that ensures that serum and tissue levels are adequate before an incision is made and that therapeutic levels of the agent can be maintained in serum and tissue APRIL JOGC AVRIL 2012 l 383

SOGC CLINICAL PRACTICE GUIDELINE

Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well–designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.56 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care.56

during surgery and for a few hours (at most) after the incision is closed.5

SURGICAL PROCEDURES

Wound infections—surgical site infections—in the form of cellulitis, abscess, or dehiscence can occur following laparotomy. Pelvic infections, such as an abscess or infected hematoma, are a risk with any surgical procedure that enters the abdominal cavity. Cuff cellulitis is a specific risk for hysterectomy. Endometritis can result from Caesarean section or surgical abortion. Urinary tract infections can occur as a result of any procedure that involves catheterization of the bladder.

A hysterectomy is considered a “class II or cleancontaminated” wound (Table 2).5 The method of hysterectomy may modify the inherent risk of postoperative infection. A Cochrane review suggested that vaginal hysterectomy results in fewer unspecified infections or febrile episodes (OR 0.42; 95% CI 0.21 to 0.83) than abdominal hysterectomy.9

A 1999 guideline published by the United States Centers for Disease Control and Prevention lists the specific and stringent criteria that must be met for diagnosis of a surgical site infection.5 Accurate surveillance for surgical site infection monitoring requires follow-up for 30 days postoperatively, and the trend towards early discharge from hospital makes surveillance a challenge. It is estimated that up to 84% of surgical site infections occur following discharge from hospital.5 If prophylactic antibiotics are to be given, they should be istered shortly before or at bacterial inoculation.6,7 This should be done 15 to 60 minutes before skin incision. The majority of studies suggest that a single dose is effective but that for lengthy procedures (> 3 hours) the dose should be repeated at intervals 1 or 2 times the halflife of the drug. It has also been suggested that with large blood loss (> 1500 mL), a second dose should be given.8 384 l APRIL JOGC AVRIL 2012

Vaginal Hysterectomy

There is no meta-analysis or systematic review regarding antibiotic prophylaxis for vaginal hysterectomy. A review by Duff and Park10 included 20 studies, the majority of which were prospective randomized trials (18/20) and many of which were double-blinded (13/20). Without prophylaxis, the incidence of febrile morbidity averaged 40% to 50% but was reduced to 5% to 20% with prophylactic antibiotics.10 The type, dose, and duration of antibiotics used were highly variable, but a first-generation cephalosporin was used in the majority of studies. A randomized trial comparing amoxicillin-clavulanic acid with cefazolin (n = 178) showed no difference in infection rates.11 Another trial comparing use of cefuroxime, metronidazole, or both showed an increased morbidity when metronidazole was added.12 Treating bacterial vaginosis with metronidazole rectally for at least 4 days prior to vaginal hysterectomy appears to reduce the incidence of vaginal cuff infection (n = 59; 0 vs. 27%) but may be impractical given the possibility of surgery

Antibiotic Prophylaxis in Gynaecologic Procedures

Table 2. Centers for Disease Control and Prevention surgical wound classification Class I/Clean: 

An uninfected operative wound in which no inflammation is encountered and the respiratory, alimentary, genital, or uninfected urinary tract is not entered. In addition, clean wounds are primarily closed and, if necessary, drained with closed drainage. Operative incisional wounds that follow nonpenetrating (blunt) trauma should be included in this category if they meet the criteria.

Class II/Clean-Contaminated: 

An operative wound in which the respiratory, alimentary, genital, or urinary tracts are entered under controlled conditions and without unusual contamination. Specifically, operations involving the biliary tract, appendix, vagina, and oropharynx are included in this category, provided no evidence of infection or major break in technique is encountered.

Class III/Contaminated: 

Open, fresh, accidental wounds. In addition, operations with major breaks in sterile technique (e.g., open cardiac massage) or gross spillage from the gastrointestinal tract, and incisions in which acute, nonpurulent inflammation is encountered are included in this category.

Class IV/Dirty-Infected: 

Old traumatic wounds with retained devitalized tissue and those that involve existing clinical infection or perforated viscera. This definition suggests that the organisms causing postoperative infection were present in the operative field before the operation.

Centers for Disease Control and Prevention. Guideline for Prevention of Surgical Site Infection, 1999.5

cancellation.13 It is also difficult to comment on the costbenefit of screening all women for BV prior to surgery. Abdominal Hysterectomy

There are 3 meta-analyses exploring the efficacy of antibiotic prophylaxis for abdominal hysterectomy. The most recent, by Tanos and Rojansky in 1994,14 compared 17 trials (n = 2752) that used single dose or up to 24 hours of intramuscular or intravenous cephalosporins. There was a significant reduction in the incidence of infection in the treatment groups (OR = 0.35; 95% CI 0.3 to 0.4). Febrile morbidity was prevented by first-generation cephalosporins but not by some second- and third-generation choices. The authors concluded that a single dose of a first- or secondgeneration cephalosporin was efficacious and cost-effective. Mittendorf et al.15 (1993) meta-analyzed 25 RCTs (n = 3604) with varying antibiotic choice, duration, and routes of istration. They found that serious infections were less common in the treatment groups (9% vs. 21.1%, P = 0.001). Among those who received cefazolin or metronidazole, 11.4% and 6.3% respectively had serious postoperative infections. Lastly, Wttewaall-Evelaar16 (1990) examined 17 RCTs, the majority of which (14 of 17) used first- or secondgeneration cephalosporins. Infections were significantly reduced in the treatment groups (P < 0.001). A randomized trial with women undergoing a gynaecologic procedure via laparotomy (which included abdominal hysterectomy) comparing amoxicillin-clavulanic acid with cefazolin (n = 511) showed no difference in infection rates.17 A randomized trial (n = 321) comparing placebo, ampicillin, and cefazolin, demonstrated significant superiority of cefazolin to reduce postoperative infection.18 A randomized study comparing a single dose versus 24-hour regimen of cefuroxime plus metronidazole, showed no difference.19

Laparoscopic Hysterectomy

A Cochrane review showed that laparoscopic hysterectomy (laparoscopically assisted vaginal hysterectomy or laparo­ scopic subtotal hysterectomy) results in fewer wound or abdominal wall infections (OR 0.32; 95% CI 0.12 to 0.85) and fewer unspecified infections or febrile episodes (OR 0.65; 95% CI 0.49 to 0.87) than abdominal hysterectomy. There was no difference in any infections between laparoscopic hysterectomy and vaginal hysterectomy.9 There are no trials assessing the use of prophylactic antibiotics for any types of laparoscopic hysterectomy. Given that this is a clean-contaminated procedure with a rate of postoperative infections similar to that of vaginal hysterectomy, it would seem reasonable to treat these patients in a similar fashion. A single dose of cefazolin was determined to be as effective as multiple doses in a study of 310 women who underwent laparoscopically assisted vaginal hysterectomy.20 Laparoscopy not Entering the Uterus and/or Vagina

These procedures are considered clean (Table 2), as the genital tract is not entered. A randomized non-blinded trial of 450 women undergoing laparoscopy for various indications (not hysterectomy), found no difference in infection rates between those who received a single dose of cefazolin and those who did not.21 Recommendations

1. All women undergoing an abdominal or vaginal hysterectomy should receive antibiotic prophylaxis. (I-A) 2. All women undergoing laparoscopic hysterectomy or laparoscopically assisted vaginal hysterectomy should receive prophylactic antibiotics. (III-B) APRIL JOGC AVRIL 2012 l 385

SOGC CLINICAL PRACTICE GUIDELINE

3. The choice of antibiotic for hysterectomy should be a single dose of a first-generation cephalosporin. If patients are allergic to cephalosporin, then clindamycin, erythromycin, or metronidazole should be used. (I-A) 4. Prophylactic antibiotics should be istered 15 to 60 minutes prior to skin incision. No additional doses are recommended. (I-A) 5. If an open abdominal procedure is lengthy (e.g., > 3 hours), or if the estimated blood loss is > 1500 mL, an additional dose of the prophylactic antibiotic may be given 3 to 4 hours after the initial dose. (III-C) 6. Antibiotic prophylaxis is not recommended for laparoscopic procedures that involve no direct access from the abdominal cavity to the uterine cavity or vagina. (I-E) Surgery for Pelvic Organ Prolapse and/or Stress Urinary Incontinence

A randomized double-bind, placebo-controlled trial enrolled 449 patients to receive nitrofurantoin monohydrate monocrystals or placebo preoperatively. Procedures included surgery for pelvic organ prolapse and/or stress incontinence with suprapubic catheterization. Positive urine cultures were significantly reduced (46% vs. 61%), as was symptomatic urinary tract infection (7.2% vs. 19.8%).22 There are no studies assessing prophylactic antibiotics prior to these surgeries without use of a suprapubic catheter. There are also no studies regarding isolated sub-urethral sling procedures (e.g., transvaginal or transobturator tapes), but given the very poor outcomes associated with mesh infection, istration of a single preoperative dose of a first-generation cephalosporin is common practice. Recommendation

7. All women undergoing surgery for pelvic organ prolapse and/or stress urinary incontinence should receive a single dose of first-generation cephalosporin. (III-B) Hysteroscopic Surgery

A Cochrane review of prophylactic antibiotics for transcervical intrauterine procedures did not identify any randomized trials that met their criteria.23 A pseudorandomized study that used centre-specific antibiotic prophylaxis analyzed 631 infertile women who underwent office hysteroscopy. Two hundred sixty-six women received amoxicillin-clavulanate and doxycycline 2 hours pre-procedure. There was no difference in postprocedural infection (1 in the antibiotic group).24 A randomized trial of amoxicillin and clavulanate versus placebo for hysteroscopic ablation (n = 116) found a 386 l APRIL JOGC AVRIL 2012

significant difference in the occurrence of bacteremia (16% vs. 2%); however, the authors comment that the majority of organisms were of dubious clinical significance and that contamination could not be excluded in 7 of 10 cases. No significant difference was found for women treated for presumed infection (11.4% vs. 9%), but no objective measures were used.25 A case series of 568 women suggests that the infection risk is low (< 1%).26 There are no studies addressing prophylactic antibiotics in the setting of hysteroscopic myomectomy. Recommendation

8. Antibiotic prophylaxis is not recommended for hysteroscopic surgery. (II-2D) Induced (Therapeutic) Abortion

A meta-analysis that included 12 randomized clinical trials, demonstrated that prophylactic antibiotics significantly reduced post-abortal infection (at < 16 weeks), compared with placebo.27 The relative risk of upper genital tract infection following surgical abortion was 0.58 (95% CI 0.47 to 0.71) with antibiotics. The benefit was seen in women considered to be at high risk and in those at low risk for infection; thus, the authors conclude that universal prophylaxis should be given and that no more placebocontrolled trials should be performed. The most appropriate antibiotic regimen, however, is yet to be determined, as no comparative or superiority trials have been conducted. The largest trial to date (n = 1074), which had the most statistically significant reduction in postoperative infection rates (RR 0.12; 95% CI 0.08 to 0.38), used doxycycline 100 mg orally before the procedure followed by 200 mg after the procedure.28 Other regimens that have been effective in a randomized trial include metronidazole 400 mg orally 1 hour before the procedure and then repeated 4 and 8 hours after the procedure (RR 0.19; 95% CI 0.10 to 0.83)29 and doxycycline 400 mg orally 10 to 12 hours before the procedure (RR 0.33; 95% CI 0.22 to 0.73)30 A cost-effectiveness study looking at universal screening for sexually transmitted infections versus prophylactic azithromycin (1 g) showed that prophylactic treatment provided a significant cost savings.31 Disadvantages of not screening include the lack of case identification and the inability to complete therapy or conduct tracing. Some authors have questioned whether the presence of BV influences the rate of postoperative infection after induced abortion. In a double-blind placebo-controlled trial, treatment using 2% vaginal clindamycin for at least 3 days preoperatively did not decrease the risk of postoperative infection in patients with or without documented BV. The only statistically significant difference was seen when the authors combined the women who had intermediate

Antibiotic Prophylaxis in Gynaecologic Procedures

flora with those who had BV (RR = 4.2 in untreated group; 95% CI 1.2 to 15.9).32 Another randomized blinded trial found that giving a single 2 g metronidazole suppository preoperatively to women who had confirmed bacterial vaginosis33 did not make a significant difference (RR = 0.53; P = 0.055). Screening and treating for bacterial vaginosis prior to surgery also may be impractical, and the cost-effectiveness is not known. Recommendation

9. All women undergoing an induced (therapeutic) surgical abortion should receive prophylactic antibiotics to reduce the risk of post-abortal infection. (I-A) Missed or Incomplete Abortion

There are two randomized placebo-controlled trials that assess the effectiveness of prophylactic antibiotics to reduce infectious morbidity following uterine evacuation for incomplete abortion. One trial involving 240 women used a preoperative intravenous dose of doxycycline or placebo.34 Chlamydia and gonorrhea rates were low (3% to 6%) in this population. No difference in postoperative infectious morbidity rates occurred up to 2 weeks postprocedure. A second study of 300 women investigated the use of 200 mg oral doxycycline at 30 to 60 minutes pre-procedure. Again, no significant difference between groups was found.35 A 2007 Cochrane Review on this topic concluded there is not enough evidence to recommend routine antibiotic prophylaxis for incomplete abortion at the time of evacuation of the uterus.36 Recommendation

10. Prophylactic antibiotics are not suggested to reduce infectious morbidity following surgery for a missed or incomplete abortion. (I-E) OFFICE PROCEDURES Intrauterine Device Insertion

Various authors have demonstrated that the risk of IUD-related infection is limited to the first few weeks to months after insertion.37,38 It is therefore likely related to contamination of the endometrial cavity at the time of insertion, rather than the IUD or strings themselves.39 A 1999 Cochrane Review that included 4 randomized control trials found no difference in the occurrence of PID after IUD insertion in patients who were given prophylactic doxycycline or azithromycin and in those given placebo (OR 0.89; 95% CI 0.53 to 1.51). Use of these antibiotics also did not affect whether the IUD was removed within 90 days of insertion (OR 1.05; 95% CI 0.68 to 1.63).40 However, if the patient is considered at

high risk for sexually transmitted infections, it would be reasonable to consider screening before IUD placement. Recommendation

11. Antibiotic prophylaxis is not recommended for insertion of an intrauterine device. (I-E) However, health care professionals could consider screening for sexually transmitted infections in high-risk populations. (III-C) Endometrial Biopsy

There are no studies that assess the use of prophylactic antibiotics given before an endometrial biopsy procedure, and this is not considered standard of care. Recommendation

12. There is insufficient evidence to the use of antibiotic prophylaxis for an endometrial biopsy. (III-L) Hysterosalpingography

There are many options for preventing infection that may occur as a result of HSG: 1. Universal screening for STIs could be carried out, and patients treated as necessary. 2. Only patients at high risk (determined by history) could be screened. 3. All patients could receive prophylactic antibiotics. 4. Antibiotics could be given to patients at high risk (determined by history and/or as indicated by the presence of tubal obstruction at the time of HSG). Many of the patients may already have had screening performed as part of an infertility work-up. If infection is found, treatment should follow the Canadian Guidelines for STIs.41 There are no prospective studies that investigate any of these options. A retrospective study found that among 278 women who did not receive antibiotics, the incidence of PID after HSG was 1.4% (4/278), and all 4 patients had dilated tubes; 31 other patients with dilated tubes did not develop infection. A second group of patients (n = 326) received a single dose of oral doxycycline before HSG; no patient (including 56 who had dilated tubes) developed PID. This study suggests that the incidence of PID with normal tubes is very low, regardless of prophylactic antibiotics (0/398) and that the highest-risk group of women with dilated tubes at the time of HSG did benefit from prophylactic doxycycline.42 APRIL JOGC AVRIL 2012 l 387

SOGC CLINICAL PRACTICE GUIDELINE

Table 3. Cardiac conditions associated with the highest risk of adverse outcome from endocarditis Prosthetic cardiac valve or prosthetic material used for cardiac valve repair Previous infective endocarditis Congenital heart disease (CHD) Unrepaired cyanotic CHD (including palliative shunts and conduits) Completely repaired CHD with prosthetic material < 6 months after procedure Repaired CHD with residual defects at/near site of prosthetic material Cardiac transplant recipient with cardiac valvulopathy Adapted from Wilson W, Taubert KA, Gewitz M, Lockhart PB, Baddour LM, Levison M, et al. Prevention of Infective Endocarditis: Guidelines From the American Heart Association: A Guideline From the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 2007;116:1736–54.54 Used with permission of Wolters Kluwer Health.

Recommendation

13. The best method to prevent infection after hysterosalpingography is unknown, Women with dilated tubes found at the time of hysterosalpingography are at highest risk, and prophylactic antibiotics (e.g., doxycycline) should be given. (II-3B) URODYNAMIC STUDIES

A systematic review in 2008 included 8 RCTs, with 995 patients, most of whom were women.43 The prophylactic antibiotics differed in type, dose, and duration and were compared with either placebo or no treatment. The authors noted that most of the trials had poor methodology. They concluded that there was a 40% reduction in the risk of bacteriuria (OR 0.39; 95% CI 0.24 to 0.61), correlating to a number needed to treat of 13. This study assessed only the occurrence of bacteriuria and not that of symptomatic UTI; therefore, the clinical significance is unknown. It has been estimated that only 8% of women develop a symptomatic UTI within 1 week of a diagnosis of asymptomatic bacteriuria.44 On the basis of the results of a decision-analysis that incorporated reasonable estimates of benefits and adverse events from the published literature, the authors concluded that prophylactic antibiotics after urodynamics in women at low risk should be istered only when the background rate of UTIs after urodynamics without prophylaxis is higher than 10%.45 Recommendation

14. Antibiotic prophylaxis is not recommended for urodynamic studies in women at low risk, unless the incidence of urinary tract infection posturodynamics is > 10%. (1-E) 388 l APRIL JOGC AVRIL 2012

DOSAGE OF ANTIBIOTIC PROPHYLAXIS IN OBESE PATIENTS

Increased BMI is associated with higher rates of surgical infectious complications. Expert opinion recommends twice the normal dose of prophylaxis for morbidly obese patients (BMI > 35 km/m2).46 However, controlled trials assessing the required dosage for antibiotic prophylaxis based on patient BMI have not been assessed in our specialty, and future research is needed. Recommendation

15. In patients with morbid obesity (BMI > 35 kg/m2), doubling the antibiotic dose may be considered. (III-B) RECOMMENDATIONS FOR PENICILLIN/ CEPHALOSPORIN ALLERGY

Penicillin allergy is self-reported by up to 10% of patients, yet only 10% of those who report themselves as allergic are allergic when skin testing is performed.47–49 True anaphylactic response to penicillin is rare, occurring in 1 to 4 per 10 000 istrations.50 Allergic reaction to a cephalosporin occurs at rates of 0.17% to 8.4% in those with a penicillin allergy.51–53 Alternative prophylactic antibiotics for those deemed truly penicillin allergic include clindamycin 600 mg IV and erythromycin 500 mg IV. PREVENTION OF INFECTIVE ENDOCARDITIS

The American Heart Assocation guideline published in 200754 found no evidence that genitourinary procedures cause infectious endocarditis or that istration of antibiotics prevents infectious endocarditis following such procedures. The American Heart Assocation therefore does not recommend prophylactic antibiotics for patients undergoing genitourinary procedures; this is a change from

Antibiotic Prophylaxis in Gynaecologic Procedures

Table 4. Prophylactic antibiotics recommendations for gynaecologic procedures Procedure

Antibiotic

Dosage

Level

Vaginal hysterectomy

First- or second-generation cephalosporin

Single dose, IV

I-A

Abdominal hysterectomy

First- or second-generation cephalosporin

Single dose, IV

I-A

Laparoscopic hysterectomy

First- or second-generation cephalosporin

Single dose, IV

III-B

Laparoscopy (uterus and/or vagina not entered)

None recommended

Pelvic organ prolapse and/or stress urinary incontinence surgery

First-generation cephalosporin

Hysteroscopy

None recommended

Therapeutic abortion

doxycycline

Missed/incomplete abortion

None recommended

I-E

IUD insertion

None recommended*

I-E

Endometrial biopsy

None recommended

III-L

Hysterosalpingogram

1. Consider screening for STIs†

1. Rx as per STI guidelines‡

III-B

2. Antibiotics if dilated tubes

2. e.g., doxycycline

II-3B

Urodynamic testing

I-E Single dose, IV

III-B II-2D

100 mg po pre-procedure and 200 mg po post-procedure

None recommended§

I-A

I-E

IV: intravenous *Considering screening for sexually transmitted infections in high risk populations †Evidence for/against screening unknown ‡Canadian guidelines on sexually transmitted infections—2006 edition43 §In patients at low risk with a background risk of UTI < 10% after urodynamics

the 1997 American Heart Assocation guideline. The 2007 guideline identifies 4 conditions that are at highest risk of adverse outcome (Table 3). For patients with the conditions listed in Table 3 who have an established gastrointestinal or genitourinary infection, or for those who receive antibiotic therapy for another reason (e.g., to prevent wound infection), it may be reasonable that the antibiotic used also be active against enterococci (ampicillin, piperacillin, or vancomycin). The guidelines also suggest that it may be reasonable for patients at high risk of infectious endocarditis who have a known enterococcal urinary tract infection or colonization to receive antibiotic treatment prior to any urinary tract manipulation. A review of this recommendation change has recently been published.55 Recommendation

16. istration of antibiotics solely to prevent endocarditis is not recommended for patients who undergo a genitourinary procedure. (III-E) SUMMARY

For a number of procedures in gynaecology, the use of prophylactic antibiotics has been shown to reduce infectious morbidity in a safe and cost-effective manner (Table 4). There remain a number of procedures for which

the utility of prophylactic antibiotics is either unclear or not studied. Appropriate antibiotics used at the correct dose and time and with the appropriate frequency will reduce infectious postoperative complications and minimize the development of antibiotic resistant organisms. REFERENCES 1. Zoutman DE, Ford BD. A comparison of infection control program resources, activities, and antibiotic resistant organism rates in Canadian acute care hospitals in 1999 and 2005: pre and post-severe acute respiratory syndrome. Am J Infect Control 2008;36:711–7. 2. Dancer SJ. How antibiotics can make us sick: the less obvious adverse effects of antimicrobial chemotherapy. Lancet Infect Dis 2004;4:611–9. 3. Huskins WC, Ba-Thike K, Festin MR, Limpongsanurak S, Lumbiganon P, Peedicayil A, et al.; Global Network for Perinatal and Reproductive Health. An international survey of practice variation in the use of antibiotic prophylaxis in cesarean section. Int J Gynaecol Obstet 2001;73:141–5. 4. Bratzler DW, Houck PM, Richards C, Steele L, Dellinger EP, Fry DE, et al. Use of antimicrobial prophylaxis for major surgery: baseline results from the National Surgical Infection Prevention Project. Arch Surg 2005;140:174–82. 5. Mangram AJ, Horan TC, Pearson ML, Silver LC, Jarvis WR. Guideline for prevention of surgical site infection, 1999. Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory Committee. Am J Infect Control 1999;27:97–134. 6. Classen DC, Evans RS, Pestotnik SL, Horn SD, Menlove RL, Burke JP. The timing of prophylactic istration of antibiotics and the risk of surgical-wound infection. N Engl J Med 1992;326:281–6.

APRIL JOGC AVRIL 2012 l 389

SOGC CLINICAL PRACTICE GUIDELINE

7. Bratzler DW, Houck PM; Surgical Infection Prevention Guidelines Writers Workgroup; American Academy of Orthopaedic Surgeons; American Association of Critical Care Nurses; American Association of Nurse Anesthetists; American College of Surgeons; American College of Osteopathic Surgeons; American Geriatrics Society; American Society of Anesthesiologists; American Society of Colon and Rectal Surgeons; American Society of Health-System Pharmacists; American Society of PeriAnesthesia Nurses; Ascension Health; Association of periOperative ed Nurses; Association for Professionals in Infection Control and Epidemiology; Infectious Diseases Society of America; Medical Letter; Premier; Society for Healthcare Epidemiology of America; Society of Thoracic Surgeons; Surgical Infection Society. Antimicrobial prophylaxis for surgery: an advisory statement from the National Surgical Infection Prevention Project. Clin Infect Dis 2004;38:1706–15. 8. Dellinger EP, Gross PA, Barrett TL, Krause PJ, Martone WJ, McGowan JE Jr, et al. Quality standard for antimicrobial prophylaxis in surgical procedures. Infectious Diseases Society of America. Clin Infect Dis 1994;18:422–7. 9. Johnson N, Barlow D, Lethaby A, Tavender E, Curr E, Garry R. Surgical approach to hysterectomy for benign gynaecological disease. Cochrane Database Syst Rev 2006;Issue 2. Art. No.: CD003677. DOI: 10.1002/14651858.CD003677.pub3. 10. Duff P, Park RC. Antibiotic prophylaxis in vaginal hysterectomy: a review. Obstet Gynecol 1980;55(Suppl 5):193–202. 11. Cormio G, Vicino M, Loizzi V, Tangari D, Selvaggi L. Antimicrobial prophylaxis in vaginal gynecologic surgery: a prospective randomized study comparing amoxicillin-clavulanic acid with cefazolin. J Chemother 2007;19:193–7. 12. Kauer FM, Wijma J, Manson WL. Vaginal hysterectomy: cefuroxime, metronidazole or both? Pharm Weekbl Sci 1990;12(6A):284–8. 13. Larsson PG, Carlsson B. Does pre and postoperative metronidazole lower vaginal cuff infection rate after abdominal hysterectomy among women with bacterial vaginosis? Infect Dis Obstet Gynecol 2002:10:133–40. 14. Tanos V, Rojansky N. Prophylactic antibiotics in abdominal hysterectomy. J Am Coll Surg 1994;179:593–600. 15. Mittendorf R, Aronson MP, Berry RE, Williams MA, Kipelnick B, Klickstein A, et al. Avoiding serious infections associated with abdominal hysterectomy: a meta-analysis of antibiotic prophylaxis. Am J Obstet Gynecol 1993;169:1119–24. 16. Wttewaall-Evelaar EW. Meta-analysis of randomized controlled trials of antibiotic prophylaxis in abdominal hysterectomy. Pharm Weekbl Sci 1990;12(6A):296–9. 17. Cormio G, Di Fazio F, Lorusso F, Di Gesù G, Cacciapuoti C, Loverro G, et al. Antimicrobial prophylaxis in laparotomic gynecologic surgery: a prospective randomized study comparing amoxicillin-clavulanic acid with cefazolin. J Chemother 2002;14:618–22. 18. Chongsomchai C, Lumbiganon P, Thinkhamrop J, Ounchai J, Vudhikamraksa N. Placebo-controlled, double-blind, randomized study of prophylactic antibiotics in elective abdominal hysterectomy. J Hosp Infect 2002;52:302–6. 19. Eckenhausen FW, Jonker PL. Antibiotic prophylaxis in abdominal hysterectomy, with special reference to the duration of the prophylaxis. Pharm Weekbl Sci 1990;12(6A):289–91. 20. Chang WC, Lee MC, Yeh LS, Hung YC, Lin CC, Lin LY. Quality-initiated prophylactic antibiotic use in laparoscopic-assisted vaginal hysterectomy. Aust N Z J Obstet Gynaecol 2008;48:592–5.

macrocrystals on the development of urinary tract infections after surgery for pelvic organ prolapse and/or stress incontinence with suprapubic catheterization. Am J Obstet Gynecol 2004;191:182–7. 23. Thinkhamrop J, Laopaiboon M, Lumbiganon P. Prophylactic antibiotics for transcervical intrauterine procedures. Cochrane Database Syst Rev 2007;Art. No.: CD005637. DOI 10.1002/14651858.CD005637.pub2. 24. Kasius J, Broekmans F, Fa B, Devroey P, Fatemi H. Antibiotic prophylaxis for hysteroscopy evaluation of the uterine cavity. Fertil Steril 2011;95:792–4. 25. Bhattacharya S, Parkin DE, Reid TM, Abramovich DR, Mollison J, Kitchener HC. A prospective randomized study of the effects of prophylactic antibiotics on the incidence of bacteremia following hysteroscopic surgery. Eur J Obstet Gynecol Reprod Biol 1995;63:37–40. 26. Baggish MS, Sze EH. Endometrial ablation: a series of 568 patients treated over an 11-year period. Am J Obstet Gynecol 1996;174:908–13. 27. Sawaya GF, Grady D, Kerlikowske K, Grimes DA Antibiotics at the time of induced abortion: the case for universal prophylaxis based on a metaanalysis. Obstet Gynecol 1996;87(5 Pt 2):884–90. 28. Lavellois P, Rioux JE. Prophylactic antibiotics for suction curettage abortion: results of a clinical controlled trial. Am J Obstet Gynecol 1988;158:100–5. 29. Heisterberg L, Peterson K. Metronidazole prophylaxis in elective first trimester abortion. Obstet Gynecol 1985;65:371–4. 30. Darj E, Stralin EB, Nilsson S. The prophylactic effect of doxycycline on postoperative infection rate after first-trimester abortion. Obstet Gynecol 1987;70:755–8. 31. Chen S, Li J, van den Hoek A. Universal screening or prophylactic treatment for Chlamydia trachomatis infection among women seeking induced abortions: which strategy is more cost-effective? Sex Transm Dis 2007;34:230–6. 32. Larsson PG, Platz-Christensen JJ, Dalaker K, Eriksson K, Fåhraeus L, Irminger K, et al. Treatment with 2% clindamycin vaginal cream prior to first trimester surgical abortion to reduce signs of postoperative infection: a prospective, double-blinded, placebo-controlled, multicenter study. Acta Obstet Gynecol Scand 2000;79:390–6. 33. Crowley T, Low N, Turner A, Harvey I, Bidgood K, Horner P. Antibiotic prophylaxis to prevent post-abortal upper genital tract infection in women with bacterial vaginosis: randomised controlled trial. BJOG 2001;108:396–402. 34. Prieto JA, Eriksen NL, Blanco JD. A randomized trial of prophylactic doxycycline for curettage in incomplete abortion. Obstet Gynecol 1995;85(5 Pt 1):692–6. 35. Ramin KD, Ramin SM, Hemsell PG, Nobles BJ, Heard MC, Johnson VB, et al. Prophylactic antibiotics for suction curettage in incomplete abortion. Infect Dis Obstet Gynecol 1995;2:213–7. 36. May W, Gülmezoglu AM, Ba-Thike K. Antibiotics for incomplete abortion. Cochrane Database Syst Rev 2007;Issue 4. Art. No.: CD001779. DOI: 10.1002/14651858.CD001779.pub2. 37. Lee NC, Rubin GL, Ory HW, Nurkman RT. Type of intrauterine device and the risk of pelvic inflammatory disease. Obstet Gynecol 1983:96:119–26. 38. Farley TMM, Rosenberg MJ, Rowe P, Chen J-H, Meirik O. Intraterine devices and pelvic inflammatory disease: an international perspective. Lancet 1992;339:785–8.

21. Kocak I, Ustun C, Emre B, Uzel A. Antibiotic prophylaxis in laparoscopy. Ceska Gynekol 2005;70:269–72.

39. Mishell DR Jr, Bell JH, Good RG, Moyer DL. The intrauterine device: a bacteriologic study of the endometrial cavity. Am J Obstet Gynecol 1966;96:119–26.

22. Rogers RG, Kammerer-Doak D, Olsen A, Thompson PK, Walters MD, Lukacz ES, et al. A randomized, double-blind, placebocontrolled comparison of the effect of nitrofurantoin monohydrate

40. Grimes DA, Lopez LM, Schulz KF. Antibiotic prophylaxis for intrauterine contraceptive device insertion. Cochrane Database Syst Rev 1999; Issue 3. Art. No.: CD001327. DOI: 10.1002/14651858.CD001327.

390 l APRIL JOGC AVRIL 2012

Antibiotic Prophylaxis in Gynaecologic Procedures

41. Public Health Agency of Canada. Canadian Guidelines on Sexually Transmitted Infections; 2006. Available at: http://www.publichealth.gc.ca/sti. Accessed January 30, 2012.

50. International Rheumatic Fever Study Group. Allergic reactions to long-term benzathine penicillin prophylaxis for rheumatic fever. Lancet 1991;337(8753):1308–10.

42. Pittaway DE, Winfield AC, Maxson W, Daniell J, Herbert C, Wentz AC. Prevention of acute inflammatory disease after hysterosalpingography: efficacy of doxycycline prophylaxis. Am J Obstet Gynecol 1983;147:623–6.

51. Dash, CH. Penicillin allergy and the cephalosporins. J Antimicrob Chemother 1975;1:107.

43. Latthe P, Foon R, Toozs-Hobson P. Prophylactic antibiotics in urodynamics: a systematic review of effectiveness and safety. Neurol Urodyn 2008;27:167–73.

52. Daulat, S, Solensky, R, Earl, HS, Casey W, Gruchalla RS. Safety of cephalosporin istration to patients with histories of penicillin allergy. J Allergy Clin Immunol 2004;113:1220.

44. Hooton TM, Scholes D, Stapleton AE, Roberts PL, Winter C, Gupta K, et al. A prospective study of asymptomatic bacteriuria in sexually active young women. N Engl J Med 2000;343:992–7.

53. Fonacier L, Hirschberg R, Gerson S. Adverse drug reactions to cephalosporins in hospitalized patients with a history of penicillin allergy. Allergy Asthma Proc 2005;26:135.

45. Lower J, Burrows L, Howden N, Weber A. Prophylactic antibiotics after urodynamics in women: a decision analysis. Int Urogynecol J 2007;18:159–64.

54. Wilson W, Taubert KA, Gewitz M, Lockhart PB, Baddour LM, Levison M, et al.; American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee; American Heart Association Council on Cardiovascular Disease in the Young; American Heart Association Council on Clinical Cardiology; American Heart Association Council on Cardiovascular Surgery and Anesthesia; Quality of Care and Outcomes Research Interdisciplinary Working Group. Prevention of Infective Endocarditis: Guidelines From the American Heart Association. Circulation 2007;116:1736–54

46. Gordon SM. Antibiotic prophylaxis against postoperative wound infections. Cleve Clin J Med 2006;73(Suppl 1):S42–5. 47. Lee CE, Zembower TR, Fotis MA, Postelnick MJ, Greenberger PA, Peterson LR, et al. The incidence of antimicrobial allergies in hospitalized patients: implications regarding prescribing patterns and emerging bacterial resistance. Arch Intern Med 2000;160:2819–22. 48. del Real GA, Rose ME, Ramirez-Atamoros MT, Hammel J, Gordon SM, Arroliga AC, et al. Penicillin skin testing in patients with a history of betalactam allergy. Ann Allergy Asthma Immunol 2007;98:355–9. 49. Sogn DD, Evans R 3rd, Shepherd GM, Casale TB, Condemi J, Greenberger PA, et al. Results of the National Institute of Allergy and Infectious Diseases collaborative clinical trial to test the predictive value of skin testing with major and minor penicillin derivatives in hospitalized adults. Arch Intern Med 1992;152:1025.

55. Castillo E, Magee LA, von Dadelszen P, Money D, Blonde-Hill E, van Schalkwyk J. Our patients do not need endocarditis prophylaxis for genitourinary tract procedures: insights fro the 2007 American Heart Association Guidelines. J Obstet Gynaecol Can 2008;30:796–9. 56. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

APRIL JOGC AVRIL 2012 l 391

SOGC CLINICAL PRACTICE GUIDELINE No. 278, June 2012

Canadian HIV Pregnancy Planning Guidelines These guidelines have been written and reviewed by the Canadian HIV Pregnancy Planning Guideline Development Team in partnership with the Society of Obstetricians and Gynaecologists of Canada, the Canadian Fertility and Andrology Society and the Canadian HIV/AIDS Trials Network. They were reviewed by the Infectious Diseases Committee and the Reproductive Endocrinology and Infertility Committee of the Society of Obstetricians and Gynaecologists of Canada and by the Canadian HIV Pregnancy Planning Guideline Development Team Core Working Group,* and endorsed by the Executive and Council of the SOGC. PRINCIPAL AUTHORS Mona R. Loutfy, MD, Toronto ON Shari Margolese, Toronto ON Deborah M. Money, MD, Vancouver BC Mathias Gysler, MD, Mississauga ON Scot Hamilton, PhD, Mississauga ON Mark H. Yudin, MD, Toronto ON *See Appendix for a list of working group . Disclosure statements have been received from all authors.

Abstract Objective: Four main clinical issues need to be considered for HIV-positive individuals and couples with respect to pregnancy planning and counselling: (1) pre-conceptional health; (2) transmission from mother to infant, which has been significantly reduced by combined antiretroviral therapy; (3) transmission between partners during conception, which requires different prevention and treatment strategies depending on the status and needs of those involved; and (4) management of infertility issues. The objective of the Canadian HIV Pregnancy Planning Guidelines is to provide clinical information and recommendations for health care providers to assist HIV-positive individuals and couples with their fertility and pregnancy planning decisions. These guidelines are evidence- and community-based and flexible, and they take into diverse and intersecting local/population needs and the social determinants of health.

Outcomes: Intended outcomes are (1) reduction of risk of vertical transmission and horizontal transmission of HIV, (2) improvement of maternal and infant health outcomes in the presence of HIV, (3) reduction of the stigma associated with pregnancy and HIV, and (4) increased access to pregnancy planning and fertility services. Evidence: PubMed and Medline were searched for articles published in English or French to December 20, 2010, using the following : “HIV” and “pregnancy” or “pregnancy planning” or “fertility” or “reproduction” or “infertility” or “parenthood” or “insemination” or “artificial insemination” or “sperm washing” or “IVF” or “ICSI” or “IUI.” Other search included “HIV” and “horizontal transmission” or “sexual transmission” or “serodiscordant.” The following conference databases were also searched: Conference on Retroviruses and Opportunistic Infections, International AIDS Conference, International AIDS Society, Interscience Conference on Antimicrobial Agents and Chemotherapy, the Canadian Association of HIV/AIDS Research, and the Ontario HIV Treatment Network Research Conference. Finally, a hand search of key journals and conferences was performed, and references of retrieved articles were reviewed for additional citations. Subsequently, abstracts were categorized according to their primary topic (based on an outline of the guidelines) into table format with the following headings: author, title, study purpose, participants, results and general comments. Finally, experts in the field were consulted for their opinions as to whether any articles were missed. Values: The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care. Recommendations for practice were ranked according to the method described in that report (Table) and through use of the Appraisal of Guidelines Research and Evaluation instrument for the development of clinical guidelines. Sponsors: The Society of Obstetricians and Gynaecologists of Canada, Women and HIV Research Program, Women’s College Research Institute, Women’s College Hospital, University of Toronto, Abbott Laboratories Canada, the Ontario HIV Treatment Network, the Canadian Institutes of Health Research, and the Canadian HIV Trials Network. Key Points and Recommendations HIV-positive people who are considering pregnancy should be counselled on the following issues so they can make an informed decision.

Key Words: HIV, pregnancy, insemination, fertility, transmission J Obstet Gynaecol Can 2012;34(6):575–590

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

JUNE JOGC JUIN 2012 l 575

SOGC CLINICAL PRACTICE GUIDELINE

Ensuring a Healthy Mother, Child, and Family Recommendations 01. Reproductive health counselling, including contraception and pregnancy planning, should be offered to all reproductive-aged HIV-positive individuals soon after HIV diagnosis and on an ongoing basis. (II-3A) 02. Men and women should be counselled on all relevant aspects of pregnancy planning, such as maintaining a healthy diet and lifestyle, the risk of genetic disease occurrence, and integrated prenatal screening, as outlined in current Canadian practice guidelines irrespective of their known HIV status. (III-A) 03. Women with no risk factors should start taking folic acid (in the form of vitamin supplements) 1 mg a day for 3 months before becoming pregnant and for at least the first 3 months of their pregnancy. (II-3A) 04. Women should be encouraged to give up smoking, drinking alcohol, and using recreational drugs, and should be referred for if required. (III-A) 05. Both prospective parents should be tested for other sexually transmitted infections, even if they have conceived in the past and have no symptoms of infection. (III-A) Psychosocial/Mental Health Issues Related to HIV Pregnancy Planning and Fertility All individuals or couples planning pregnancy are potentially susceptible to psychosocial and mental health problems. An additional burden may be placed on the HIV-positive individual or couple because of stigma associated with the condition and the risks of HIV transmission. Recommendations 06. Counselling should be performed by a knowledgeable health care professional or trained peer counsellor in a ive, nonjudgemental manner that takes into sexual diversity and ethnocultural or religious beliefs and practices. (III-A) 07. Counselling should include a discussion of the potential risk for both horizontal (between partners) and vertical (from mother to child) transmission and how that might affect the mental health of one or both parents. (III-A) 08. HIV-positive people who intend to conceive should be made aware of the potential stigma and discrimination they may face from others who are less informed about how HIV is transmitted, horizontally and vertically. In addition, HIV-positive women who are not breastfeeding should be made aware that they may face disapproval from people who are not aware of their HIV status. (II-3A) 09. Further counselling may be suggested to help couples and individuals cope more effectively with fear, stigma, and other psychosocial issues, such as postpartum depression. (II-3A)

11. HIV-positive women who are considering pregnancy should be counselled on the possibility of legal action if they do not permit antiretroviral therapy to be given to their baby after birth. (III-B) 12. Ethical considerations, including those related to the health status of HIV-positive individuals or couples, should be discussed during pre-conception counselling. (III-B) Antiretroviral and Other Drugs in Pregnancy Planning Recommendations 13. Clinicians should review all medications that HIV-positive men and women may be using, including antidepressants, pain medications, over-the-counter medications, and hepatitis treatment, to ensure that they are safe during conception and pregnancy. (II-3A) 14. All HIV-positive men and women who require combination antiretroviral therapy for their own health during the preconception period should be advised to continue their current regimens, but women should not take any drugs that are potentially teratogenic or considered toxic in pregnancy, substituting other drugs when necessary or possible. The most efficacious regimen that is safe in pregnancy should be selected. (II-3A) 15. HIV-positive women who do not require combination antiretroviral therapy for their own health need to consider starting treatment before becoming pregnant or no later than late in the first trimester of pregnancy. The most efficacious regimen that is safe in pregnancy should be selected. (II-3A) 16. HIV-positive men and women who require treatment should be encouraged to initiate combination antiretroviral therapy during the pre-conception period to reduce HIV plasma viral load, which can reduce the risk of HIV transmission to their HIV-negative partner or reduce the risk of superinfection of their HIV-positive partner. (II-3B) 17. All decisions about the use of combination antiretroviral therapy and other drugs during pregnancy should be made in consultation with experts such as HIV specialists and pharmacists. (III-A) Scenario-Based Recommendations for the Prevention of Horizontal HIV Transmission The recommended option may not always be the most practical or preferred option for the patient, given availability of services, cost, cultural beliefs, or personal risk evaluation. Physicians and other health care providers should provide non-judgemental of the patient’s decision.

Legal and Ethical Issues

HIV-Positive Woman and HIV-Negative Man

Recommendations

Recommendations

10. All HIV-positive individuals should be counselled on the possible legal ramifications of non-disclosure of their HIV status to their sexual partner(s). (III-A)

18. For serodiscordant couples in which the woman is HIV positive, it is preferable to attempt home insemination with the partner’s sperm during ovulation for 3 to 6 months before considering other methods. (III-A)

ABBREVIATIONS cART

combined antiretroviral therapy

ICS

intracytoplasmic sperm injection 

IUI

intrauterine insemination 

576 l JUNE JOGC JUIN 2012

19. If home insemination is unsuccessful, couples should be referred to a gynaecologist for consultation and then to a fertility specialist for a complete fertility work-up and appropriate treatment when necessary, including counselling on all assisted reproductive technologies if pregnancy is not achieved in 6 to 12 months. (III-A)

Canadian HIV Pregnancy Planning Guidelines

Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.80 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care.80

HIV-Positive Single Woman or HIV-Positive Woman in a Same-Sex Relationship Recommendation 20. Single HIV-positive women or HIV-positive women in a samesex relationship should be referred to a fertility specialist and should consider the option of intrauterine insemination with HIV-negative donor sperm. This option is preferred over home insemination with donor sperm because the cost of sperm is high and intrauterine insemination performed in a fertility clinic has a higher success rate than home insemination. If sperm from a known donor is used for intrauterine insemination, regulations applicable to the donation of sperm must be followed. (III-A) HIV-Positive Man and HIV-Negative Woman Recommendations 21. Serodiscordant couples in which the man is HIV positive should be referred to a fertility specialist and should consider the preferred option of sperm washing with intrauterine insemination. (II-2A) 22. If intrauterine insemination is unsuccessful, couples should consider in vitro fertilization or intracytoplasmic sperm injection with either sperm washing or the use of donor sperm. (II-3A) 23. HIV-positive men who do not require combination antiretroviral therapy for their own health should be encouraged to initiate combination antiretroviral therapy during the pre-conception period to reduce HIV plasma viral load, which can reduce the risk of HIV transmission to their HIV-negative partner. (II-3B) HIV-Positive Single Man or Male Same-Sex Couple Recommendation 24. HIV-positive single men or men in same-sex relationships who have an HIV-negative or HIV-positive surrogate should be referred to a fertility specialist. (III-A)

HIV-Positive Man and HIV-Positive Woman It is common for seroconcordant couples to attempt natural conception, especially if both partners have fully suppressed viral loads. Seroconcordant couples may wish to consider intrauterine insemination with sperm washing to reduce the potential risk of super-infection or transmission of drug-resistant strains of HIV between partners. Recommendations 25. Timed natural conception is recommended for seroconcordant couples who are taking combination antiretroviral therapy and who have fully suppressed HIV plasma viral loads. (II-3A) 26. Seroconcordant couples should be counselled on the risks and benefits of timed natural conception (including HIV superinfection and transmission of drug-resistant strains of HIV). (II-3A) 27. If timed natural conception is unsuccessful, couples should be referred to a gynaecologist for consultation and then to a fertility specialist for a complete fertility work-up and appropriate treatment when necessary, including counselling on all assisted reproductive technologies. (III-A) Infertility Investigations and Treatment Historically, fertility clinics in Canada have been reluctant to provide fertility investigation and treatment to HIV-positive people. Fertility experts concur that this has likely been due to a lack of information about HIV and its successful treatment coupled with a concern that serving HIV-positive people could deter HIV-negative individuals from accessing services. In 2010, the American Association of Reproductive Medicine released a statement in which it endorsed the provision of fertility services to all HIV-positive individuals. Recommendations 28. HIV-positive people should be counselled about fertility problems that occur in the general population, including genetic disorders and advancing maternal age. (III-A) 29. Infertility investigations and treatment should be offered to HIVpositive people if required. (III-A)

JUNE JOGC JUIN 2012 l 577

SOGC CLINICAL PRACTICE GUIDELINE

30. All decisions about combination antiretroviral therapy during the pre-conception period and during pregnancy should consider the health of the HIV-positive person and reduction of the risk of horizontal and vertical transmission of HIV. Decisions about combination antiretroviral therapy should be made in consultation with an HIV specialist. (III-A) HIV Infection Control in Fertility Clinics Recommendations 31. Fertility laboratories should follow Canadian Standards Association guidelines for infection control when handling HIVpositive materials. (III-A) 32. Potentially infectious materials should be stored in segregated containers and incubators to reduce the risk of HIV contamination. (III-A) 33. Bio-containment straws for specimen storage should be used to further reduce the risk of cross-contamination of samples. (III-A)

INTRODUCTION Demand for HIV Pregnancy Planning and Fertility Services in Canada

T

he natural history of human immunodeficiency virus infection has changed significantly in the last decade with advances made in medical treatment, most specifically with the introduction of highly successful combination antiretroviral therapy.1 As a result, individuals living with HIV are now experiencing an improved quality of life and a prolonged life expectancy.1–3 In countries with greater resources, the mortality caused by HIV has significantly decreased and approaches general population norms. A recent study indicated that HIV-positive individuals within 7 years of their diagnosis have the same life expectancy as the general population.2 While the overall current life expectancy of someone infected with HIV is difficult to predict (as successful treatment has been widely prescribed only since 1996), present projections estimate that an individual living with HIV today will live at least 30 to 40 years from the time of infection.3 Another significant change in the field of HIV in the past 2 decades is that the rate of HIV infection in women has been steadily on the rise. By the end of 2007, it was estimated that approximately 65 000 Canadians were living with HIV and that 10 114 were women.4 This represents a 23% increase from 2002. Similarly, women now for more than one quarter of new positive HIV test reports.4 The use of cART, possible Caesarean section (as indicated by current guidelines on pregnancy and HIV), and abstaining from breastfeeding have reduced the chance of vertical transmission of HIV to < 1%. These factors have likely led to the increasing number of pregnancies in HIV-positive women over the past decade.5 In Canada, all pregnancies to HIV-positive mothers are reported 578 l JUNE JOGC JUIN 2012

through a registry created by the Canadian Perinatal HIV Surveillance Program of the Public Health Agency of Canada. Their 2009 annual report indicates that 180 children were born to HIV-positive women in Canada that year. In the 4 preceding years, the number of children born to HIV-positive women was as follows: 238 (2008), 208 (2007), 194 (2006), and 189 (2005).5 Furthermore, pregnancy planning has been identified as a key area of importance to people with HIV in Canada.6 Nevertheless, the reproductive health concerns and services available and provided to people living with HIV have received minimal attention. A gap exists between the desires and intentions of people living with HIV to have children and their need for in doing so and the resources, relevant research, and networks necessary for them to do so successfully and in a medically safe manner. Issues to consider in pregnancy planning when at least one partner has HIV are not just the prevention of vertical transmission but also the prevention of horizontal transmission and the management of potential infertility issues. In 2006, Ogilvie et al.7 conducted a research study to examine the fertility intentions of women living with HIV in British Columbia. Of the 182 women analyzed in the study, 25.8% expressed intentions to have children regardless of their clinical HIV status.7 Most recently, Loutfy et al.8 completed a cross-sectional study designed to assess fertility desires, intentions, and actions. This study surveyed 490 HIVpositive women of reproductive age (18 to 52) living in Ontario. Sixty-one percent were born outside Canada, 52% lived in Toronto, 47% were of African ethnicity, 74% were currently on cART, and the median age was 38. Sixty-nine percent wanted to give birth, and 57% intended to give birth in the future. This study found that the significant predictors of fertility intentions were younger age (age < 40), African ethnicity, living in Toronto, and a lower number of lifetime births (P = 0.02).8 In 2005, Oladapo et al. conducted a study determining the fertility desires and intentions of people living with HIV who were receiving care at a suburban specialist clinic in Sagamu, Nigeria.9 Of the 147 participants, 63.3% expressed a desire for child-bearing, even though 50.4% of them already had 2 or more children. Of those who wanted to have children, 71.5% of men and 93.8% of women intended to have 2 or more children in the near future.9 In 2009, Nattabi et al. conducted a systematic review of 29 studies of factors influencing fertility desires and intentions among people living with HIV and found that fertility desires were influenced by a variety of demographic, health, stigmaassociated, cultural, and psychosocial factors.10

Canadian HIV Pregnancy Planning Guidelines

In all of the aforementioned studies, it was concluded that the desire and intention of HIV-positive individuals to have children were high and that clinical HIV status did not seem to be a predictor of fertility intentions. Specialized counselling, services, and will be required to meet the needs of this group. Access to HIV Pregnancy Planning and Fertility Services in Canada

Despite the fact that many HIV-positive individuals and couples wish to have children, there is a scarcity of HIV or fertility clinics in North America offering advice to HIVpositive individuals and couples on the management of HIV during pregnancy planning, timing of ovulation to allow fertilization, sperm washing (a procedure designed to remove viral particles from the sperm, reducing the chance of horizontal transmission), management of individuals or couples affected by infertility issues, and fertility treatments including intrauterine insemination and in vitro fertilization. In Europe, HIV-positive couples have had access to reproductive assistance since the 1980s, and at least 5 European countries have national programs to assist people living with HIV in their pregnancy planning.11 As of 2003, less than 5% of fertility clinics in the United States offered reproductive care to HIV-serodiscordant couples.12 In Canada, services and treatment protocols differ depending on the clinic or centre, and therefore so do the costs. It is important to note that in most jurisdictions in Canada sperm washing, IUI, IVF, and ICSI are not covered by provincial medical services plans, so costs are charged directly to the patient. A 2010 study by Yudin et al. showed that while over 70% of clinics surveyed were willing to see people living with HIV in consultation, substantially fewer had actually seen any people living with HIV within the previous 12 months.13 Services offered also varied by region, with clinics located in only 5 provinces offering fertility treatments to people living with HIV. Some important procedures were also less commonly available to people living with HIV. In particular, sperm washing was available in only 26% of clinics in 4 provinces, a service gap noted in the Newmeyer et al. study that described the barriers to services experienced by people living with HIV.14 In addition to a deficiency in assisted reproductive services, there remains a scarcity of pregnancy planning, prenatal and postnatal care, and counselling programs for HIVpositive individuals and couples in Canada. Unintended Pregnancy

As is the case in the general population, many pregnancies in people with HIV are unintended. An Ontario study of

HIV-positive women of reproductive age found that 56% of their most recent pregnancies were unintended.15 One of the goals of these guidelines is to encourage health care providers to discuss pregnancy planning, including contraception, with their patients as early as possible after diagnosis to reduce the incidence of unintended pregnancy and to reduce the risk of both vertical and horizontal transmission of HIV. HIV/AIDS AND HUMAN RIGHTS

The World Health Organization states that “all couples and individuals have the right to decide freely and responsibly the number and spacing of their children and to have access to the information, education and means to do so.”16 This includes people living with HIV or AIDS. The human rights of those infected with and affected by HIV are frequently violated, and this can affect their intentions and desires with respect to having children. There is a need to integrate these guiding principles into all aspects of HIV pregnancy planning, fertility care, treatment and for people living with HIV in Canada. Recommendations for care must be evidencebased, and their implementation must be flexible and ethnoculturally sensitive, and must also take into diverse and intersecting local/population needs and the social determinants of health.17 SCOPE OF DOCUMENT

This guideline does not address the management of HIV during pregnancy or HIV testing during pregnancy, because this information is available elsewhere.18 Similarly, as there are guidelines dealing with fertility and infertility issues in the general population, these issues are not addressed in this document.19 The postpartum period and infant feeding options for people with HIV are outside of the scope of this document. ENSURING A HEALTHY MOTHER, CHILD, AND FAMILY

Although management of HIV in pregnancy planning entails many special considerations, it is important to that most general recommendations for pregnancy planning also apply to HIV-positive individuals and couples. The Public Health Agency of Canada is an important source of information to ensure a healthy mother, child, and family. Eating Well with Canada’s Food Guide provides women with the information they need to eat well during pregnancy and includes specific advice for all women JUNE JOGC JUIN 2012 l 579

SOGC CLINICAL PRACTICE GUIDELINE

of child-bearing age. Detailed recommendations for pregnancy and breastfeeding are available for health professionals. The Public Health Agency of Canada has described alcohol use in pregnancy as “an important public health and social issue for Canadians,” recognizing the increasing societal awareness of the significant personal and social costs associated with fetal alcohol spectrum disorder.20 In addition to specific guidelines for alcohol use and nutrition during pregnancy, the agency has produced The Sensible Guide to a Healthy Pregnancy, which includes guidance on general nutrition, folic acid, alcohol, physical activity, smoking and oral health.21 In addition, SOGC has published numerous guidelines addressing most of these topics.22 Recommendations

1. Reproductive health counselling, including contraception and pregnancy planning, should be offered to all reproductive-aged HIV-positive individuals soon after HIV diagnosis and on an ongoing basis. (II-3A) 2. Men and women should be counselled on all relevant aspects of pregnancy planning, such as maintaining a healthy diet and lifestyle, the risk of genetic disease occurrence, and integrated prenatal screening, as outlined in current Canadian practice guidelines irrespective of their known HIV status. (III-A) 3. Women with no risk factors should start taking folic acid (in the form of vitamin supplements) 1 mg a day for 3 months before becoming pregnant and for at least the first 3 months of their pregnancy. (II-3A) 4. Women should be encouraged to give up smoking, drinking alcohol, and using recreational drugs, and should be referred for if required. (III-A) 5. Both prospective parents should be tested for other sexually transmitted infections, even if they have conceived in the past and have no symptoms of infection. (III-A) PSYCHOSOCIAL/MENTAL HEALTH ISSUES RELATED TO HIV PREGNANCY PLANNING AND FERTILITY

All individuals or couples planning pregnancy must consider the implications of psychosocial and mental health issues. An additional burden is placed on the HIV-positive individual or couple because of the stigma and discrimination associated with the condition and the risks of transmission. People living with HIV considering pregnancy may be concerned that they will experience stigma and discrimination simply 580 l JUNE JOGC JUIN 2012

for choosing to become parents and may worry that they will feel guilty about conceiving or breastfeeding, or that family , friends, or community may disapprove and withdraw . As with legal and ethical issues, little information is available on this subject, and recommendations for psychosocial counselling have been based on expert consensus. The transition to parenthood is often a time of great joy, but it is also life-altering and can result in considerable stress and anxiety.23–25 When one or both prospective parents have HIV, the stress can be greatly increased. Even in 2009, the stigma and marginalization associated with HIV continued to place a significant psychological burden on those who were affected.26,27 A 2007 study showed that health care professionals play a large role in the systemic discrimination against people living with HIV who wish to have children.28 Thus the environment in which HIV-positive parents live is one that can easily cause psychological distress. Although the mental health needs of pregnant women have been studied,29–31 less is known about the specific mental health needs of HIV-positive pregnant women. A large 2004 American study examined minority women who were pregnant and HIV- positive in 4 regions of the United States.32 They found that depressive symptoms were severe and that social isolation, perceived stress, and ineffective coping strategies were among the factors associated with depression. On the other hand, the presence of a ive partner was associated with fewer depressive symptoms. This type of research might enable the development of appropriate interventions that will decrease the risk of psychological morbidity for HIV-positive women during the pregnancy planning and antenatal periods. An earlier, longitudinal study by Larrabee et al.,33 in Texas followed 21 HIV-positive and 21 HIV-negative women from the antenatal period until 6 months postpartum using the Medical Outcome Survey–Short Form to assess overall quality of life. Overall, HIV-positive women reported increased health distress and a more difficult transition during the antenatal period than did HIV-negative control subjects. A similar difference was found at 6 months postpartum, but not during the perinatal period. Once again, seropositivity appears to be associated with poorer mental health during pregnancy. There are few published studies about the mental health concerns of fathers, and even fewer about the mental health of HIV-positive fathers.34,35 However, it is known that a father’s behaviour during the early postnatal weeks can significantly affect the mental health status of new mothers,35 particularly with respect to postpartum depression, which has a prevalence rate of about 10%.36,37 As more and more people with HIV are living longer, healthier lives when they have access to medication, this will become an increasingly important area of research.

Canadian HIV Pregnancy Planning Guidelines

Recommendations

6. Counselling should be performed by a knowledgeable health care professional or trained peer counsellor in a ive, non-judgemental manner that takes into sexual diversity and ethnocultural or religious beliefs and practices. (III-A) 7. Counselling should include a discussion of the potential risk for both horizontal (between partners) and vertical (from mother to child) transmission and how that might affect the mental health of one or both parents. (III-A) 8. HIV-positive people who intend to conceive should be made aware of the potential stigma and discrimination they may face from others who are less informed about how HIV is transmitted, horizontally and vertically. In addition, HIV-positive women who are not breastfeeding should be made aware that they may face disapproval from people who are not aware of their HIV status. (II-3A) 9. Further counselling may be suggested to help couples and individuals cope more effectively with fear, stigma, and other psychosocial issues, such as postpartum depression. (II-3A) LEGAL AND ETHICAL ISSUES

Legal, ethical, and policy issues related to pregnancy and HIV remain challenging, and guidelines are still evolving because of the absence of policies and the inconsistencies in case law pertaining to the criminalization of HIV nondisclosure in cases of otherwise consensual sex. This section of the guidelines is therefore based on expert consensus and on the premise that people living with HIV are entitled to reproductive freedom without discrimination. HIV-positive people who are planning pregnancy must access health services to assist them in dealing with medical and psychosocial issues, but this typically requires them to disclose their HIV status to partners and others. A 2004 report by the World Health Organization summarizing barriers to HIV serostatus disclosure by women in resource-poor countries indicates that the most common reasons for failure to disclose to partners included fear of accusations of infidelity, abandonment, discrimination, and violence.38 Fear of disclosing HIV status can also create difficulties in resource-rich countries. A recent case report suggested that cultural and family pressure contributed to the mother’s inability to adhere to antiretroviral therapy during pregnancy and breastfeeding with consequent

vertical transmission.17 Canadian laws with respect to the criminal non-disclosure of HIV-positive status related to sexual activity continue to evolve on the basis of case law. In 1998 (R. v. Cuerrier,39) the Supreme Court of Canada ruled that people living with HIV could be found guilty of serious charges, such as aggravated assault, if they failed to disclose their HIV status to sexual partners when there was a significant risk of HIV transmission. According to the Canadian HIV/AIDS Legal Network, charges in these cases are becoming more serious: aggravated sexual assault, (which carries a maximum penalty of life imprisonment), and even murder.40 The Swiss have taken a different approach to criminalization of HIV transmission. In a public statement published in the Bulletin des Médecins Suisses41 Dr Pietro Vernazza and colleagues argued that HIV-positive individuals on effective antiretroviral treatment cannot transmit HIV through sexual as long as the following criteria are met: the HIVpositive person is adhering to cART under the supervision of a medical doctor, his or her viral load has remained undetectable in the previous 6 months, and the person does not have another sexually transmitted infection. The report concludes that unprotected sex between an HIVpositive and an HIV-negative person does not constitute criminal negligence if the above-mentioned criteria have been met. This is in keeping with a UNAIDS policy brief42 stating that criminal charges against HIV-positive individuals who transmit the virus through sexual cannot be justified if the accused individual “took reasonable measures to reduce risk of transmission.” In this case, reasonable measures would include adherence to cART. There is little information available on the effects of HIV criminalization laws on pregnancy planning, but legal cases do exist. In 2006, an HIV-positive woman in Hamilton, Ontario, was convicted of failing to provide the necessities of life for hiding her HIV-positive status from doctors, preventing them from istering antiretroviral therapy to her baby immediately after birth, which would have significantly reduced the child’s risk of becoming infected. The child tested HIV positive at 2 months of age, and the mother was sentenced to a conditional 6-month sentence to be served in the community.43 The imposition of criminal penalties for not disclosing HIV-positive status before having otherwise consensual sex will no doubt discourage HIV-positive people who are thinking about starting a family. Although it is not illegal in Canada for an HIV-positive man or woman to have children, criminalization of non-disclosure might deter disclosure of HIV status to health care providers and partners, and this could result in unplanned pregnancies and limit access to JUNE JOGC JUIN 2012 l 581

SOGC CLINICAL PRACTICE GUIDELINE

prenatal care and conception counselling. Ideally, doctors and other health care providers should be involved from pre-conception when women are HIV-positive, so routine prevention measures can be planned in addition to cART to decrease transmission rates. A 1996 paper published by Williams et al. reviewed the modest data available on reproductive decision-making in HIV-positive women and found that awareness of their HIV infection was not associated with pregnancy termination or subsequent pregnancy prevention.44 This confirms the fact that HIV-positive women are having and will continue to have children, so health professionals must be prepared to guide them in this process. There are ethical concerns associated with all pregnancies and with conception and assisted reproductive interventions, and these are addressed in SOGC guidelines.22 Ethical considerations common in HIV infection, such as the health of the prospective parents and their financial ability to care for a child, are reasonable and should be discussed with HIV-positive individuals and couples. Many health care providers cite “ethical” considerations when refusing to provide care. These are often “perceived” ethical considerations, such as concern that a child or partner will be infected with HIV, or they are based on stereotypes associated with a history of drug use. These perceptions generally arise from lack of information or failure to review and/or accept current scientific evidence on HIV transmission risk reduction. Refusal to provide HIV transmission risk-reduction services for people planning pregnancy is itself unethical and contrary to the human right to non-discrimination and the right to choose the number and spacing of children.45 Recommendations

10. All HIV-positive individuals should be counselled on the possible legal ramifications of nondisclosure of their HIV status to their sexual partner(s). (III-A) 11. HIV-positive women who are considering pregnancy should be counselled on the possibility of legal action if they do not permit antiretroviral therapy to be given to their baby after birth. (III-B) 12. Ethical considerations, including those related to the health status of HIV-positive individuals or couples, should be discussed during pre-conception counselling. (III-B) COMBINATION ANTIRETROVIRAL AND OTHER DRUGS IN PREGNANCY PLANNING

A substantial body of evidence has shown that potent cART not only prolongs the lives of people living with HIV but also significantly reduces the risk of both horizontal 582 l JUNE JOGC JUIN 2012

and vertical HIV transmission, thus leading to a greater number of people living with HIV having or planning to have children.1–5,7–10 These breakthroughs affect both men and women by reducing viral load to decrease the risk of horizontal HIV transmission and, for women, the risk of vertical transmission. It is well accepted that cART during pregnancy should take into consideration the health of both mother and child and that, with some exceptions, cART is generally safe in pregnancy. The selection of cART in pregnancy should consider drugs that are effective in and tolerable to the mother and that are of least toxicity to the fetus and newborn. Specifically, the mother should be treated not only to prevent vertical HIV transmission but also to ensure optimal therapy for herself. Both the Canadian consensus guidelines for the care of HIV-positive pregnant women, Putting Recommendations into Practice, and the United States Department of Health and Human Services guidelines recommend that women who are not already on cART for their own health before becoming pregnant can delay the initiation of therapy until after the first trimester. Delaying treatment until the second trimester is intended to reduce any theoretic teratogenic effects of cART, which may be greater in the first trimester. Fertility clinics generally require an HIV-positive woman to be on a successful cART regimen before she seeks fertility services, regardless of whether or not she requires cART for her own health. This is ed by recently presented conference abstract findings of the French cohort, which show that initiation of cART before conception or early in the first trimester led to the lowest vertical transmission rate of 0% to 0.6 %.46 There is seldom discussion about the benefit of starting cART during the pre-conception period for men and women who do not require cART for their own health. Treatment before conception is a horizontal risk-reduction issue—as reduction in viral plasma load often correlates to reduction of viral load in semen and vaginal fluid—and should be discussed with the patient in all scenarios to reduce risk to his or her HIV-negative partner or reduce the risk of superinfection to his or her HIV-positive partner.47–49 There are currently several ongoing studies looking at the efficacy of HIV pre-exposure prophylaxis in preventing HIV transmission to a non-infected partner in a serodiscordant couple during conception. The United States Centers for Disease Control and Prevention published an interim guidance document for the use of pre-exposure prophylaxis in men who have sex with men.50 This document is primarily based on the results of the investigators for the Pre-Exposure Prophylaxis Initiative

Canadian HIV Pregnancy Planning Guidelines

study,51 which has shown pre-exposure prophylaxis to be efficacious in this population. Currently, the Centers for Disease Control and Prevention cautions against the use of pre-exposure prophylaxis by women for HIV prevention, as the FEM-PrEP Project (a study of pre-exposure prophylaxis for HIV prevention among heterosexual women)52 was stopped early because it was highly unlikely to be able to demonstrate the effectiveness of Truvada (emtricitabine and tenofovir disoproxil fumarate) in preventing HIV infection in women. There are many non-cART medications that people living with HIV may be using to treat concurrent conditions, including but not limited to hepatitis C and depression, and adverse events from cART. Clinicians should review all prescribed, over-the-counter, and complementary therapies, as well as street drugs used by HIV-positive individuals before conception. Most notably, treatment for hepatitis C is considered to be teratogenic when used by either male or female partners. Hepatitis C treatment should be stopped at least 6 months before couples attempt to conceive. Recommendations

13. Clinicians should review all medications that HIV-positive men and women may be using, including antidepressants, pain medications, overthe-counter medications, and hepatitis treatment, to ensure that they are safe during conception and pregnancy. (II-3A) 14. All HIV-positive men and women who require combination antiretroviral therapy for their own health during the pre-conception period should be advised to continue their current regimens, but women should not take any drugs that are potentially teratogenic or considered toxic in pregnancy, substituting other drugs when necessary or possible. The most efficacious regimen that is safe in pregnancy should be selected. (II-3A) 15. HIV-positive women who do not require combina­ tion antiretroviral therapy for their own health need to consider starting treatment before becoming pregnant or no later than late in the first trimester of pregnancy. The most efficacious regimen that is safe in pregnancy should be selected. (II-3A) 16. HIV-positive men and women who require treatment should be encouraged to initiate combination antiretroviral therapy during the preconception period to reduce HIV plasma viral load, which can reduce the risk of HIV transmission to their HIV-negative partner or reduce the risk of superinfection of their HIV-positive partner. (II-3B)

17. All decisions about the use of combination anti­ retroviral therapy and other drugs during pregnancy should be made in consultation with experts such as HIV specialists and pharmacists. (III-A) OPTIONS FOR REDUCING RISK OF HORIZONTAL HIV TRANSMISSION DURING CONCEPTION

HIV-positive couples and individuals who wish to conceive a child need to consider the risk of horizontal HIV transmission during conception. That risk depends on a number of variables, including the HIV serostatus of each partner (i.e., HIV-positive woman and HIV-negative man or HIV-positive man and HIV-negative woman) and the plasma viral load and level of drug-resistant virus of each prospective parent. Couples and individuals should be counselled thoroughly about all horizontal HIV transmission risk-reduction methods before conception so they can make an informed choice about which conception method is most appropriate to their particular situation. Furthermore, prospective parents should be informed about the rate of success, availability, and cost of each conception option. Timed Natural Conception

Natural conception has only recently been seen as an option for people living with HIV. Although not for everyone, natural conception is suitable in some circumstances, and the nature of each individual case must be evaluated. Prospective parents must have a frank discussion about the risks of horizontal HIV transmission to make an informed decision about this option. The relative risk of horizontal HIV transmission involved in natural conception is dependent on the plasma viral load of the HIV-positive partner, the frequency of intercourse, the presence of concurrent sexually transmitted infections, and which partner is infected.41,52,53 People living with HIV who do not have access to or who cannot afford assisted conception services may be more likely to attempt natural conception. Additionally, people living with HIV who fear stigma will be associated with the use of assisted conception services may be more likely to consider natural conception. More research is needed to determine the factors considered when couples decide to conceive naturally. In the case of an HIV-positive man who is not taking cART, the risk of HIV transmission to his uninfected female partner is quoted as 0.1% to 0.3% per act of intercourse.54 This assumes that the couple is in a stable relationship and that they are not participating in any other form of high-risk activity.54 Without the intervention of cART, the risk of transmission from an HIV-positive woman to her uninfected male partner is reported to be 0.03% to 0.09%.54 In general, plasma viral load may be concordant with the viral load of genital secretions. JUNE JOGC JUIN 2012 l 583

SOGC CLINICAL PRACTICE GUIDELINE

However, people living with HIV and their uninfected partners should be counselled that this is not always the case. cART further reduces the risk when long-term viral suppression is achieved. Normally, the viral load in semen is lower than that in blood; however, this is greatly influenced by the use of cART, known to have optimal penetration of the genital tract, as well as the absence of coexisting sexually transmitted infections and the absence of drug resistance.55–57 It is possible to achieve an undetectable viral load in genital secretions with the long-term use of cART; however, assays to detect genital fluid viral load are not readily available.58 In early 2008, the Swiss Federal Commission for HIV/AIDS issued a controversial statement authored by Vernazza et al.,41 known as the Swiss Statement, claiming that an HIVinfected person on antiretroviral therapy with completely suppressed viremia (effective ART) is not sexually infectious and cannot transmit HIV through sexual provided that “the HIV-positive individual takes anti-retroviral therapy consistently and as prescribed and is regularly followed by his/ her doctor; viral load is undetectable (i.e., < 40 copies/mL) and has been so for at least 6 months; and the HIV-positive individual does not have any sexually transmitted infections.” Thus, although there remains a slight risk of transmisson,59,60 some serodiscordant couples opt to proceed with timed unprotected intercourse—only during ovulation—to reduce the number of exposures to HIV by the uninfected partner and to increase the probability of conception. Women should be directed to health care providers and the websites of relevant health care agencies for information about timing ovulation. Ovulation timing kits are available over the counter at most pharmacies. Home Insemination

Home insemination is a particularly popular option for conception for HIV-positive women with HIV-negative partners and for same-sex female couples and single HIV-positive women with access to donor sperm. The procedure involves collecting sperm from a partner or donor in a sterile container or a condom. The sperm is drawn into a needle-less syringe and then inserted into the vagina as close to the cervix as possible. Optimal results are achieved when insemination is done during ovulation. This is a particularly attractive method, as it is very low cost and does not require the assistance of a fertility specialist. If home insemination is unsuccessful after 3 to 6 months, HIV-positive women should be advised to seek the assistance of a fertility specialist. Sperm Washing

Sperm washing is a well-established, effective, and safe risk-reduction fertility option for serodiscordant couples in which the man is HIV-positive and the woman is 584 l JUNE JOGC JUIN 2012

HIV-negative and for seroconcordant couples when superinfection is a concern. Semen is centrifuged to separate live sperm (which do not carry HIV) from seminal plasma and non-germinal cells (which may carry HIV) and then inseminated into the female partner at the time of ovulation. This practice is well ed by the literature, which is extensive.12,61–75 In technical , sperm washing involves centrifuging ejaculated semen in a 40% to 80% colloidal silica density gradient to separate progressively motile HIV-free sperm from non-sperm components and seminal plasma, which remain in the supernatant. The sperm pellet at the bottom is re-suspended in a fresh medium and centrifuged twice before the preparation of a final swim-up. There is no consensus among researchers about the need to test washed sperm for detectable HIV RNA before the sample is used. A nucleic-acid-based sequence amplification (NASBA; Biomerieux, Basingstoke, UK) or similar commercial assay can be used; however, these assays are not commercially available in Canada. The risk of the sample having detectable HIV is 3% to 6%. This is because centrifugation fails to remove all of the seminal plasma and leukocytes in a small proportion of cases. The number of washes is limited because repeated centrifuging leads to loss of sperm quality and quantity. A double-tube technique has been proposed to increase yield and reduce the need for post-wash HIV testing. Unfortunately, this technique has not been adopted by the majority of centres offering sperm washing, because it is not currently available commercially. According to studies published to date, there have been no reported cases of infection of the female partner when sperm washing is carried out following the reported published protocols in more than 3000 cycles of sperm washing combined with intrauterine insemination, in vitro fertilization and intracytoplasmic sperm injection.12 The results of a multicentre retrospective analysis of 1036 serodiscordant couples from 8 European centres offering sperm washing reported 2840 IUI cycles, 107 IVF cycles, 394 ICSI cycles, and 49 frozen embryo transfers. At least 6 months post-treatment there was careful HIV followup of the HIV-negative women. All tests recorded on the women were negative (7.1% lost to follow-up), giving a calculated probability of contamination equal to zero (95% CI 0 to 0.09). Clinical pregnancy rates recorded with all forms of treatment were comparable to those found in cycles carried out in HIV-negative couples.76 IUI, IVF, and ICSI

IUI, IVF, and ICSI are fertility techniques that can reduce the risk of HIV transmission to the uninfected partner. IUI is most commonly used and is combined with sperm washing if the male partner is HIV positive. This process involves placing prepared sperm directly into the uterus

Canadian HIV Pregnancy Planning Guidelines

during ovulation. For couples who wish to further reduce the risk of horizontal HIV transmission or for those who have infertility issues, sperm washing can be combined with ovulation induction, IVF, or ICSI. IVF refers to the procedure whereby oocytes are exposed to spermatozoa outside the uterus, and a fertilized embryo is returned to the uterus for the gestation period. Some studies have shown that because ICSI involves fertilization with only one sperm, the risk of possible HIV transmission in serodiscordant couples should be lower than with traditional assisted reproductive technology methods. This is because in traditional IUI women receive millions of spermatozoa, and in classic IVF the oocytes are exposed to thousands of spermatozoa.77 Both IVF and ICSI are very expensive, costing up to $15 000 per cycle, making these procedures inaccessible to many people living with HIV. A 2003 meta-analysis assessing the efficacy of assisted reproductive technologies in serodiscordant couples found they were less successful in the group in which the female partner was infected, with an overall pregnancy rate per assisted reproductive technology attempt of 6.7%. No pregnancies resulted from the IUI attempts, while 2 pregnancies resulted from the IVF and ICSI attempts.66 A 2007 study examining the safety and effectiveness of assisted reproduction (IUI, IVF, and ICSI) using sperm washing for HIV-1 serodiscordant couples in which the male partner was infected showed pregnancy resulting in 580 of 3315 cycles. Throughout the period of treatment, all couples were required to use condoms during intercourse. IUI was the most frequently used procedure, representing 84% of procedure use. Out of the 580 pregnancies, there were 112 miscarriages, 8 extra-uterine pregnancies, 2 pregnancy terminations and 1 intrauterine death. Overall, no transmission of HIV to the female partner was observed with complete follow-up information in 967 out of 1036 cases.67 Sperm Donation, Egg Donation, and Surrogacy

Sperm donation, egg donation, and surrogacy are discussed in depth in a t policy statement on ethical issues in assisted reproduction prepared by the Society of Obstetricians and Gynaecologists of Canada and the Canadian Fertility and Andrology Society.19 However, these policies do not directly address the issues of people living with HIV.78 Sperm donation is available to the uninfected partners of HIV-positive men and to HIV-positive women. Surrogacy is not currently an option in Canada for HIVpositive single men or HIV-positive men in a same-sex

couple. Sperm donation by HIV-positive men is restricted by Canadian law; however, it may be possible through the Donor Semen Special Access Program when the recipient is known to the donor. Further information is available from Assisted Human Reproduction Canada and fertility specialists. HIV-positive individuals and couples who require sperm donation, egg donation, or a surrogate are likely to require legal advice and contracts. Adoption

Adoption is a legal and social process. It involves the transferring of rights over a child from birth parents to adoptive parents. In Canada, adoption is regulated provincially, so requirements vary depending upon geographical location. They may also differ depending upon whether the adoption is undertaken privately or through the public system, or is international.79 No current data are available on the success rate of adoption in Canada if one or both prospective parents are HIV positive. In the United States, Lambda Legal has successfully assisted same-sex couples and people living with HIV to adopt children. SCENARIO-BASED RECOMMENDATIONS FOR THE PREVENTION OF HORIZONTAL HIV TRANSMISSION

The scenario-based recommendations are intended to guide health care providers during the pre-conception counselling process. All options, including risks and benefits, should be presented to prospective parents to facilitate informed decision making. Although the recommendations are based on expert opinion of the safest and most practical option for most individuals and couples, they may not always be the most practical or preferred option for some patients, depending on availability of services, cost, cultural beliefs, and personal preference. In these cases, physicians and other health care providers should provide non-judgemental of the decision of the patient(s) involved. HIV-Positive Woman and HIV-Negative Man

HIV serodiscordant couples in which the woman is HIV positive and the man is HIV negative should be counselled on the risks and benefits of timed natural conception, home insemination, IUI, IVF, ICSI, the option of a gestational carrier or true surrogate, and adoption. Recommendations

18. For serodiscordant couples in which the woman is HIV positive, it is preferable to attempt home insemination with the partner’s sperm during ovulation for 3 to 6 months before considering other methods. (III-A) JUNE JOGC JUIN 2012 l 585

SOGC CLINICAL PRACTICE GUIDELINE

19. If home insemination is unsuccessful, couples should be referred to a gynaecologist for consultation and then to a fertility specialist for a complete fertility work-up and appropriate treatment when necessary, including counselling on all assisted reproductive technologies if pregnancy is not achieved in 6 to 12 months. (III-A) HIV-Positive Single Woman or HIV-Positive Woman in a Same-Sex Relationship

HIV-positive single women or HIV-positive women in a same-sex relationship should be counselled on the risks and benefits of home insemination with donor sperm (known donor or purchased sperm), IUI with donor sperm, IVF with donor sperm, ICSI with donor sperm, and the option of a gestational carrier or true surrogate with donor sperm, and adoption. Recommendation

20. Single HIV-positive women or HIV-positive women in a same-sex relationship should be referred to a fertility specialist and should consider the option of intrauterine insemination with HIV-negative donor sperm. This option is preferred over home insemination with donor sperm because the cost of sperm is high and intrauterine insemination performed in a fertility clinic has a higher success rate than home insemination. If sperm from a known donor is used for intrauterine insemination, regulations applicable to the donation of sperm must be followed. (III-A) HIV-Positive Man and HIV-Negative Woman

HIV serodiscordant couples in which the male partner is HIV positive should be counselled on the risks and benefits of timed natural conception, home insemination, IUI with sperm washing or donor sperm, IVF with sperm washing or donor sperm, ICSI with sperm washing or donor sperm, and adoption. Recommendations

21. Serodiscordant couples in which the man is HIV positive should be referred to a fertility specialist and should consider the preferred option of sperm washing with intrauterine insemination. (II-2A) 22. If intrauterine insemination is unsuccessful, couples should consider in vitro fertilization or intracytoplasmic sperm injection with either sperm washing or the use of donor sperm. (II-3A)

586 l JUNE JOGC JUIN 2012

23. HIV-positive men who do not require combination antiretroviral therapy for their own health should be encouraged to initiate combination antiretroviral therapy during the pre-conception period to reduce HIV plasma viral load, which can reduce the risk of HIV transmission to their HIV-negative partner. (II-3B) HIV-Positive Single Man or Male Same-Sex Couple Recommendation

24. HIV-positive single men or men in same-sex relationships who have an HIV-negative or HIV-positive surrogate should be referred to a fertility specialist. (III-A) HIV-Positive Man and HIV-Positive Woman

Heterosexual couples in which both partners are HIV positive should be counselled on the risks and benefits of timed natural conception, IUI with sperm washing, IVF with sperm washing, ICSI with sperm washing, and adoption. Recommendations

25. Timed natural conception is recommended for seroconcordant couples who are taking combination antiretroviral therapy and who have fully suppressed HIV plasma viral loads. (II-3A) 26. Seroconcordant couples should be counselled on the risks and benefits of timed natural conception (including HIV superinfection and transmission of drug-resistant strains of HIV). (II-3A) 27. If timed natural conception is unsuccessful, couples should be referred to a gynaecologist for consultation and then to a fertility specialist for a complete fertility work-up and appropriate treatment when necessary, including counselling on all assisted reproductive technologies. (III-A) FERTILITY ISSUES IN THE CONTEXT OF HIV AND HIV INFECTION CONTROL IN FERTILITY CLINICS Infertility Investigations and Treatment

Historically, fertility clinics in Canada have been reluctant to provide fertility investigation and treatment to people living with HIV. Fertility experts concur that this has likely been due to lack of information about HIV and concern that serving people living with HIV could deter HIVnegative individuals from accessing services. However, it is common practice in many fertility clinics across Canada to offer investigation, treatment, and storage of potentially infected specimens to people with other infectious diseases

Canadian HIV Pregnancy Planning Guidelines

such as hepatitis B and C, and similar practices can be applied to the handling of HIV-infected materials. As all fertility clinics should be operating using Canadian Standards Association procedures for universal precautions and infection control, there are no scientific grounds on which to refuse services to people living with HIV. Recommendations

28. HIV-positive people should be counselled about fertility problems that occur in the general population, including genetic disorders and advancing maternal age. (III-A) 29. Infertility investigations and treatment should be offered to HIV- positive people if required. (III-A) 30. All decisions about combination antiretroviral therapy during the pre-conception period and during pregnancy should consider the health of the HIV-positive person and reduction of the risk of horizontal and vertical transmission of HIV. Decisions about combination antiretroviral therapy should be made in consultation with an HIV specialist. (III-A) HIV Infection Control in Fertility Clinics

Fertility laboratories routinely treat all samples as potentially infectious, in accordance with the Canadian Standards Association guidelines, for the protection of both health care workers and patients. Storage of potentially infectious materials in segregated containers and incubators may slightly decrease the risk of HIV contamination. Recommendations

31. Fertility laboratories should follow Canadian Standards Association guidelines for infection control when handling HIV-positive materials. (III-A) 32. Potentially infectious materials should be stored in segregated containers and incubators to reduce the risk of HIV contamination. (III-A) 33. Bio-containment straws for specimen storage should be used to further reduce the risk of crosscontamination of samples. (III-A) APPLICABILITY

There are potential barriers to applying the recommendations outlined in these guidelines. Fertility services are not available to HIV-positive individuals and couples in all provinces.13 Additionally, many of the fertility services recommended in these guidelines are expensive and not covered by most provincial or private health insurance coverage and are therefore inaccessible to many people living with HIV.

SUMMARY

The implementation of these guidelines will assist HIVpositive individuals and couples with their fertility and pregnancy planning needs through the provision of clinical information and recommendations. It will also reduce the risk of transmission of HIV between partners and transmission from mother to child and will increase the rate of pregnancy planning in the HIV-positive population by providing safer options for conception, reducing the stigma associated with pregnancy and HIV, and improving access to pregnancy planning and fertility services. REFERENCES 1. Palella FJ Jr, Baker RK, Moorman AC, Chmiel JS, Wood KC, Brooks JT, et al. HIV Outpatient Study Investigators. Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study. J Acquir Immune Defic Syndr 2006;43:27–34. 2. Mocroft A, Ledergerber B, Katlama C, Kirk O, Reiss P, d’Arminio Monforte A, et al.; EuroSIDA study group. Decline in the AIDS and death rates in the EuroSIDA study: an observational study. Lancet 2003;362(9377):22–9. 3. The Antiretroviral Therapy Cohort Collaboration. Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies. Lancet 2008;372(9635):293–9. 4. Public Health Agency of Canada. HIV and AIDS in Canada. Surveillance report to December 31, 2007. Ottawa: Surveillance and Risk Assessment Division, Centre for Communicable Diseases and Infection Control, Public Health Agency of Canada 2008. Available at: http://www.phac-aspc.gc.ca/aids-sida/publication/survreport/2007/ surveillance_2007_10-eng.php. Accessed April 25, 2011. 5. Public Health Agency of Canada. HIV and AIDS in Canada. Surveillance Report to December 31, 2008. Surveillance and Risk Assessment Division, Centre for Communicable Diseases and Infection Control, Public Health Agency of Canada; 2009. Available at: http://www.phac-aspc.gc.ca/ aids-sida/publication/survreport/2008/dec/pdf/survrepdec08.pdf. Accessed April 25 2011. 6. Tharao W, Logie C, James L, Loutfy M. “These are some of the things we need”: women living with HIV discuss issues in their daily lives as research priorities. Oral abstract presented at Canadian Association for AIDS Researchers Conference Toronto 2011. 7. Ogilvie GS, Palepu A, Remple VP, Maan E, Heath K, MacDonald G, et al. Fertility intentions of women of reproductive age living with HIV in British Columbia, Canada. AIDS 2007;21(Suppl 1):583–8. 8. Loutfy MR, Hart TA, Mohammed SS, Su D, Ralph ED, Walmsley SL, et al.; Ontario HIV Fertility Research Team. Fertility desires and intentions of HIV-positive women of reproductive age in Ontario, Canada: a crosssectional study. PLoS ONE 2009;4(12):e7925. 9. Oladapo OT, Daniel OJ, Odusoga OL, Ayoola-Sotubo O. Fertility desires and intentions of HIV-positive patients at a suburban specialist center. J Natl Med Assoc 2005;97:1672–81. 10. Nattabi B, Li J, Thompson SC, Orach CG, Earnest J. A systematic review of factors influencing fertility desires and intentions among people living with HIV/AIDS: implications for policy and service delivery. AIDS Behav 2009;13(5):949–68. 11. Semprini AE, Levi-Setti P, Bozzo M, Ravizza M, Taglioretti A, Sulpizoo P, et al. Insemination of HIV-negative women with processed semen of HIV-positive partners. Lancet 1992;340:1317–9.

JUNE JOGC JUIN 2012 l 587

SOGC CLINICAL PRACTICE GUIDELINE

12. Sauer MV, Wang JG, Douglas NC, Nakhuda GS, Vardhana P, Jovanovic V, et al. Providing fertility care to men seropositive for human immunodeficiency virus: reviewing 10 years of experience and 420 consecutive cycles of in vitro fertilization and intracytoplasmic sperm injection. Fertil Steril 2009;91(6):2455–60. 13. Yudin MH, Shapiro HM, Loutfy MR. Access to infertility services in Canada for HIV-positive individuals and couples: a cross-sectional study. Reprod Health 2010;7:7. doi:10.1186/1742–4755–7–7. 14. Newmeyer T, Tecimer SN, Jaworsky D, Chihrin S, Gough K, Rachlis A, et al.  Case series of fertility treatment in HIV-discordant couples (male positive, female negative): the Ontario experience.  PLoS ONE  2011;6(9):e24853. 15. Loutfy M, Rouboud J, Wong J, Yudin M, Diong C, Blitz S, et al.; Ontario HIV Fertility Research Team.  High prevalence of unintended pregnancies in HIV-positive women of reproductive age in Ontario, Canada: a retrospective study.  HIV Med 2012;13(2):107-17. 16. Wilcher R, Cates W. Reproductive choices for women with HIV. Bull World Health Organ 2009;87(11):833–9. 17. O’Bryan T, Jadavji T, Kim J, Gill MJ. An avoidable transmission of HIV from mother to child CMAJ 2011;183:690–2. 18. Burdge DR, Money DM, Forbes JC, Walmsley SL, Smaill FM, Boucher M, et al.; Canadian HIV Trials Network Working Group on Vertical HIV Transmission. Canadian consensus guidelines for the management of pregnant HIV-positive women: putting recommendations into practice. CMAJ 2003;168(13):1683–8. Revised: June 24, 2003. 19. Canadian Fertility and Andrology Society [website]. Available at: http://www.cfas.ca. Accessed June 10, 2011. 20. Public Health Agency of Canada. What is fetal alcohol spectrum disorder (FASD)? Available at: http://www.phac-aspc.gc.ca/hp-ps/dca-dea/ prog-ini/fasd-etcaf/publications/fs-fi_01-eng.php. Accessed April 16, 2012. 21. Public Health Agency of Canada. The sensible guide to a healthy pregnancy. Available at: http://www.phac-aspc.gc.ca/hp-gs/guide-eng.php. Accessed April 19, 2011.

32. Blaney N. Psychosocial and behavioral correlates of depression among HIV-infected pregnant women. AIDS Patient Care STDS 2004;18(7):405. 33. Larrabee K, Monga M, Eriksen N, Helfgott A. Quality of life assessment in pregnant women with the human immunodeficiency virus. Obstet Gynecol 1996;88(6):1016–20. 34. Clinton JF, Kelber ST. Stress and coping in fathers of newborns: comparisons of planned versus unplanned pregnancy. Int J Nurs Stud 1993;30(5):437–43. 35. Greening L. And–how was it for you, dad? Community Pract 2006;79(6):184–7. 36. Matthey S, Barnett B, Ungerer J, Waters B. Paternal and maternal depressed mood during the transition to parenthood. J Affect Disord 2000;60:75–85. 37. Ramchandani P, Stein A, Evans J, O’Connor TG. Paternal depression in the postnatal period and child development: a prospective population study. Lancet 2005;365:2201–5. 38. Medley A, Garcia-Moreno C, McGill S, Maman S. Rates, barriers and outcomes of HIV serostatus disclosure among women in developing countries: implications for prevention of mother-to-child transmission programmes. Bull World Health Organ 2004;82:299–307. 39. R. v. Cuerrier, [1998] 2 S.C.R. 371. Available at: http://www.canlii.org/ en/ca/scc/doc/1998/1998canlii796/1998canlii796.html. Accessed April 16, 2012. 40. Symington A. Criminalization confusion and concerns: the decade s ince the Cuerrier decision. HIV/AIDS Policy and Review, Canadian HIV/AIDS Legal Network 2009;14(1):1–10. 41. Vernazza P, Hirschel B, Bernasconi E, Flepp M. Les Personnes séropositives ne souffrant d’aucune autre MST et suivant un traitement antirétroviral efficace ne transmettent pas le VIH par voie sexuelle. Bulletin des Médecins Suisses 2008;89(5):165–9. 42. United Nations AIDS. Criminalization of HIV transmission. (2008). UNAIDS Policy Brief. 43. Priest, L. Mother avoiding AZT. The Globe and Mail; April, 2006.

22. The Society of Obstetricians and Gynaecologists of Canada. Clinical Practice Guidelines. Available at: http://www.sogc.org/guidelines/ index_e.asp. Accessed October 6, 2011.

44. Williams H, Watkins C, Risby J. Reproductive decision-making and determinants of contraceptive use in HIV-infected women. Clin Obstet Gynecol 1996;39(2):333–43.

23. Britton JR. Pre-discharge anxiety among mothers of well newborns: prevalence and correlates. Acta Paediatrica 2005;94:1771–6.

45. United Nations Entity for Gender Equality and the Empowerment of Women. Convention on the elimination of all forms of discrimination against women. Article 16.1;1979.

24. Britton JR. Maternal anxiety: course and antecedents during the early postpartum period. Depress Anxiety 2008;25:793–800. 25. Clinton JF, Kelber ST. Stress and coping in fathers of newborns: comparisons of planned versus unplanned pregnancy. Int J Nurs Stud 1993;30(5):437–43. 26. Bell E, Mthembu P, O’Sullivan S. Sexual and reproductive health services and HIV testing: perspectives and experiences of women and men living with HIV and AIDS. Reprod Health Matters 2007;15(29 Suppl):113–35. 27. Nduna M, Farlane L. Women living with HIV in South Africa and their concerns about fertility. AIDS Behav 2009;13(Suppl 1):62–5. 28. Bharat S Mahendra V. Meeting the sexual and reproductive heath needs of people living with HIV: challenges for health providers. Reprod Health Matters 2007;15(29 Suppl):93–112. 29. Bartell S. On becoming a mother: the psychological journey. Int J Childbirth Educ 2005;20(1):28–30. 30. Clement S, Sikorski J, Wilson J, Das S. Planning antenatal services to meet women’s psychological needs. British Journal of Midwifery 1997;5(5):298–302. 31. Deave T, Johnson D, Ingram J. Transition to parenthood: the needs of parents in pregnancy and early parenthood. BMC Pregnancy Childbirth 2008;8(30):1–11.

588 l JUNE JOGC JUIN 2012

46. Tubiana, R. Extremely low risk of MTCT of HIV in women starting HAART before pregnancy: French Perinatal Cohort, ANRS EPF C01/11. Abstract presented at the 18th Conference on Retroviruses and Opportunistic Infections, Boston, Massachusetts, February 27 to March 2, 2011. Available at: http://www.retroconference.org/2011/Abstracts/ 41451.htm. Accessed June 14, 2011. 47. Angel JB, Hu YW, Kravcik S, Tsui R, Lee KH, Barbour J, et al. Virological evaluation of the ‘Ottawa case’ indicates no evidence for HIV-1 superinfection. AIDS 2004;18(2):331–4. 48. Angel JB, Kravcik S, Balaskas E, Yen P, Badley AD, Cameron DW, et al. Documentation of HIV-1 superinfection and acceleration of disease progression. Abstract presented at 7th Conference on Retroviruses and Opportunistic Infections; February 2, 2000; San Francisco CA. 49. Blackard JT, Cohen DE, Mayer KH. Human immunodeficiency virus superinfection and recombination: current state of knowledge and potential clinical consequences. Clin Infect Dis 2002;34(8):1108–14. 50. The United States Centers for Disease Control and Prevention. Interim guidance: preexposure prophylaxis for the prevention of HIV infection in men who have sex with men. MMWR Morb Mortal Wkly Rep 2011;60(03):60–8. Available at: http://www.cdc.gov/mmwr/preview/ mmwrhtml/mm6003a1.htm. Accessed April 14, 2011.

Canadian HIV Pregnancy Planning Guidelines

51. Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med 2010;363:2587–99. 52. The United States Centers for Disease Control and Prevention. Results of FEM-PrEP clinical trial examining pre-exposure prophylaxis (PrEP) for HIV prevention among heterosexual women. Available at: http://www.cdc.gov/hiv/prep/femprep.htm. Accessed April 14, 2011. 53. Barreiro P, Castilla JA, Labarga P, Soriano V. Is natural conception a valid option for HIV-serodiscordant couples? Hum Reprod 2007;22(9):2353–8. 54. Barreiro P, del Romero J, Leal M, Hernando V, Asencio R, de Mendoza C, et al.; Spanish HIV-Discordant Study Group. Natural pregnancies in HIV-serodiscordant couples receiving successful antiretroviral therapy. J Acquir Immune Defic Syndr 2006;43(3):324–6. 55. Melo MG, Santos BR, De Cassia Lira R, Varella IS, Turella ML, Rocha TM, et al. Sexual transmission of HIV-1 among serodiscordant couples in Porto Alegre, southern Brazil. Sex Transm Dis 2008;35(11):912–5. 56. Hart CE, Lennox JL, Pratt-Palmore M, Wright TC, Schinazi RF, Evans-Strickfaden T, Correlation of human immunodeficiency virus type 1 RNA levels in blood and the female genital tract. J Infect Dis 1999;179(4):871–82. 57. Public Health Agency of Canada. HIV/AIDS Epi Updates, December 2007. Available at: http://www.phac-aspc.gc.ca/aids-sida/publication/ index-eng.php. Accessed March 21, 2012. 58. Quinn TC, Wawer MJ, Sewankambo N, Serwadda D, Li C, Wabwire-Mangen F, et al. Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group. N Engl J Med 2000;342(13):921–9. 59. Fiore JR, Suligoia B, Saracinob A, Stefanob MD, Bugarinia R, Leperac A, et al. Correlates of HIV-1 shedding in cervicovaginal secretions and effects of antiretroviral therapies. AIDS 2003;17(15):2169–76. 60. Anglemyer A, Rutherford GW, Baggaley RC, Egger M, Siegfried N. Antiretroviral therapy for prevention of HIV transmission in HIV-discordant couples.  Cochrane Database Syst Rev 2011;8:CD009153. 61. Liuzzi G, Chirianni A, Clementi M, Bagnarelli P, Valenza A, Cataldo PT, et al. Analysis of HIV-1 load in blood, semen and saliva: evidence for different viral compartments in a cross-sectional and longitudinal study. AIDS 1996;10:51–6. 62. Coombs RW, Speck CE, Hughes JP, Lee W, Sampoleo R, Ross SO, et al. Association between culturable human immunodeficiency virus type 1 (HIV-1) in semen and HIV-1 RNA levels in semen and blood: evidence for compartmentalization of HIV-1 between semen and blood. J Infect Dis 1998;177:320–30. 63. Vitorino RL, Grinsztejn BG, de Andrade CA, Hökerberg YH,  de Souza CT, Friedman RK, et al. Systematic review of the effectiveness and safety of assisted reproduction techniques in couples serodiscordant for human immunodeficiency virus where the man is positive. Fertil Steril 2011;95:1684–90. 64. Al-Khan A, Colon J, Palta V, Bardeguez A. Assisted reproductive technology for men and women infected with human immunodeficiency virus type 1. Clin Infect Dis 2003;36(2):195–200. 65. Bagasra O, Farzadegan H, Seshamma T, Oakes JW, Saah A, Pomerantz RJ. Detection of HIV-1 proviral DNA in sperm from HIV-1-infected men. AIDS 1994;8(12):1669–74.

66. Baker HW, Mijch A, Garland S, Crowe S, Dunne M, Edgar D, et al. Use of assisted reproductive technology to reduce the risk of transmission of HIV in discordant couples wishing to have their own children where the male partner is seropositive with an undetectable viral load. J Med Ethics 2003;29(6):315–20. 67. Bujan L, Hollander L, Coudert M, Gilling-Smith C, Vucetich A, Guibert J, et al.; CREAThE network. Safety and efficacy of sperm washing in HIV-1-serodiscordant couples where the male is infected: results from the European CREAThE network. AIDS 2007;21(14):1909–14. 68. Bujan L, Pasquier C, Labeyrie E, Lanusse-Crousse P, Morucci M, Daudin M. Insemination with isolated and virologically tested spermatozoa is a safe way for human immunodeficiency type 1 virusserodiscordant couples with an infected male partner to have a child. Fertil Steril 2004;82(4):857–62. 69. Bujan L, Sergerie M, Kiffer N, Moinard N, Seguela G, Mercadier B, et al. Good efficiency of intrauterine insemination programme for serodiscordant couples with HIV-1 infected male partner: a retrospective comparative study. Eur J Obstet Gynecol Reprod Biol 2007;135(1):76–82. 70. Barreiro P, Duerr A, Beckerman K, Soriano V. Reproductive options for HIV serodiscordant couples. AIDS Rev 2006;8(3):158–70. 71. Garrido N, Gil-Salom M, Martínez-Jabaloyas JM, Meseguer M. First report of the absence of viral load in testicular sperm samples obtained from men with hepatitis C and HIV after washing and their subsequent use. Fertil Steril 2009;92(3):1012–5. 72. Garrido N, Meseguer M, Bellver J, Remohí J, Simón C, Pellicer A. Report of the results of a 2 year programme of sperm wash and ICSI treatment for human immunodeficiency virus and hepatitis C virus serodiscordant couples. Hum Reprod 2004;19(11):2581–6. 73. Savasi V, Ferrazzi E, Lanzani C, Oneta M, Parrilla B, Persico T. Safety of sperm washing and ART outcome in 741 HIV-1-serodiscordant couples. Hum Reprod 2007;22(3):772–7. 74. Kim LU, Johnson MR, Barton S, Nelson MR, Sontag G, Smith JR, et al. Evaluation of sperm washing as a potential method of reducing HIV transmission in HIV-discordant couples wishing to have children. AIDS 1999;13(6):645–51. 75. Lasheeb AS, King J, Ball JK, Curran R, Barratt CL, Afnan M, et al. Semen characteristics in HIV-1 positive men and the effect of semen washing. Genitourin Med 1997;73(4):303–5. 76. Hanabusa H, Kuji N, Kato S, Tagami H, Kaneko S, Tanaka H, et al. An evaluation of semen processing methods for eliminating HIV-1. AIDS 2000;14(11):1611–6. 77. Kashima K, Takakuwa K, Suzuki M, Makino M, Kaneko S, Kato S, et al. Studies of assisted reproduction techniques (ART) for HIV-1-discordant couples using washed sperm and the nested PCR method: a comparison of the pregnancy rates in HIV-1-discordant couples and control couples. Jpn J Infect Dis 2009;62(3):173–6. 78. Loutradis D, Drakakis P, Kallianidis K, Patsoula E, Bletsa R, Michalas S. Birth of two infants who were seronegative for human immunodeficiency virus type 1 (HIV-1) after intracytoplasmic injection of sperm from HIV-1-seropositive men. Fertil Steril 2001;75(1):210–2. 79. Adoption Council of Canada. Adoption in Canada. Available at: http://www.adoption.ca/adoption-in-canada. Accessed April 12, 2012. 80. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

JUNE JOGC JUIN 2012 l 589

SOGC CLINICAL PRACTICE GUIDELINE

Appendix. Canadian HIV Pregnancy Planning Guideline Development Team Core Working Group William Cameron, MD, Ottawa ON

Mona R. Loutfy, MD, Toronto ON

Adriana Carvalhal, MD, Hamilton ON

Julie Maggi, MD, Toronto ON

Sandra Ka Hon Chu, LLM, Toronto ON

Shari Margolese, Toronto ON

Anthony Cheung, MD, Vancouver BC

John Maxwell, BA, Toronto ON

Michael Dahan, MD, Montreal QC

Jay MacGillivray, RM, Toronto ON

Alexandra de Pokomandy, MD, Montreal QC

David McLay, PhD, Toronto ON

Believe Dhliwayo, Toronto ON

Shauna McQuarrie, MD, Winnipeg MB

Mathias Gysler, MD, Mississauga ON

Deborah M. Money, MD, Vancouver BC

David Haase, MBBS, Halifax NS

Marvelous Muchenje, Toronto ON

Scot Hamilton, PhD, Mississauga ON

Tamer Said, MD, Toronto ON

Precious Hove, Toronto ON

Robyn Salter, MSW, Toronto ON

Denise Jaworsky, MD, Toronto ON

Vyta Senikas, MD, Ottawa ON

Marina Klein, MD, Montreal QC

Heather Shapiro, MD, Toronto ON

Julie LaPrise, Mississauga ON

Sharon Walmsley, MD, Toronto ON

Marc LaPrise, Mississauga ON

Joanna Wong, Toronto ON

Kecia Larkin, Vancouver BC

Mark H. Yudin, MD, Toronto ON

Clifford Librach, MD, Toronto ON

590 l JUNE JOGC JUIN 2012

SOGC COMMITTEE OPINION No. 281, October 2012

Classification of Caesarean Sections in Canada: The Modified Robson Criteria This committee opinion has been prepared by the Maternal Fetal Medicine Committee, reviewed by the Clinical Practice Obstetrics Committee, and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Dan Farine, MD, Toronto ON Debra Shepherd, MD, Regina SK SPECIAL CONTRIBUTOR Michael Robson, MD, Dublin, Ireland MATERNAL FETAL MEDICINE COMMITTEE Robert Gagnon, MD (Chair), Montreal QC Lynda Hudon, MD (Co-Chair), Montreal QC Melanie Basso, RN, Vancouver BC Hayley Bos, MD, London ON Gregory Davies, MD, Kingston ON Marie- Delisle, MD, Vancouver BC Dan Farine, MD, Toronto ON Savas Menticoglou, MD, Winnipeg MB William Mundle, MD, Windsor ON

Abstract Objective: To advocate for the use of a common classification system for Caesarean section across Canada. Options: A variety of clinical parameters for classification were considered. Outcomes: Consideration of a common system for classifying Caesarean section. Evidence: Studies published in English from 1976 to December 2011 were retrieved through searches of Medline and PubMed, using appropriate controlled vocabulary and key words (Caesarean section, vaginal birth after Caesarean, classification). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. Grey (unpublished) literature was identified through searching the web sites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and the web sites of national and international medical specialty societies. Values: The studies reviewed were classified according to criteria described by the Canadian Task Force on Preventive Health Care, and the recommendation for practice ranked according to this classification (Table 1). Sponsors: The Society of Obstetricians and Gynaecologists of Canada.

Lynn Murphy-Kaulbeck, MD, Allison NB Annie Ouellet, MD, Sherbrooke QC

Recommendation

Tracy Pressey, MD, Vancouver BC

Modified Robson criteria should be used to enable comparison of Caesarean section rates and indications. (III-B)

Anne Roggensack, MD, Calgary AB Frank Sanderson, MD, Saint John NB Vyta Senikas, MD, Ottawa ON Disclosure statements have been received from all authors and of the committee.

Key Words: Caesarean section, vaginal birth after Caesarean, VBAC, classification

J Obstet Gynaecol Can 2012;34(10):976–979

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

976 l OCTOBER JOGC OCTOBRE 2012

Classification of Caesarean Sections in Canada: The Modified Robson Criteria

Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.14 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care.14

TRENDS IN CAESAREAN SECTION RATES

3. Be easily derived from current obstetric databases.

T

4. Have mutually exclusive criteria so each Caesarean section falls into a single class.

he Caesarean section rate has been increasing during the last 50 years.1 The rate was 5% in the 1940s and 1950s and remained unchanged for 10 to 15 years. In the late 1970s, the rate rose to 15% and remained unchanged for the next 10 years. In the last decade there has been a dramatic increase in the Caesarean section rate worldwide, which now exceeds 30% in some regions.1 The latest Statistics Canada Caesarean section rate published in 2009 is 26.8%, with provincial rates ranging from 20.2% in Manitoba to 31.5% in Newfoundland and Labrador.2

Although several guidelines, including those issued by the World Health Organization3 and the United States Healthy People 2000 initiative,4 suggest that the optimal Caesarean section rate is 15%, there seems to be little effect on the current Caesarean section rate. THE CURRENT METHODS OF ASSESSING CAESAREAN SECTION RATES

Currently the heterogeneity of Caesarean section classification does not allow valid comparisons. Specifically, there is a lack of clarity regarding operative indications and relevant obstetric history. The classification of Caesarean sections should 1. Be relevant to obstetric care providers. 2. Include all Caesarean sections.

5. Allow detailed analysis without excessive complexity. 6. Be applicable for local, regional, national, and international use. A common classification system allows reflection and research at the local, regional, and national levels to better guide future care. Michael Robson, MD, has developed such a classification system.5,6 This system’s criteria are widely used in the United Kingdom, Ireland, and Scandinavia and in many centres worldwide,7–10 and this classification system has already been used in Canada.11,12 A recent meta-analysis comparing different classifications of Caesarean section concluded that the 10-group Robson classification was optimal.13 A modification to the Robson criteria is proposed for Canadian use (Table 2). This modification includes subclassification of women having Caesarean section after spontaneous onset of labour, after induction of labour, and before labour. Recommendation

Modified Robson criteria should be used to enable comparison of Caesarean section rates and indications. (III-B) OCTOBER JOGC OCTOBRE 2012 l 977

SOGC COMMITTEE OPINION

Table 2. The modified Robson criteria Group

Description

1

Nullipara, singleton cephalic, ≥ 37 weeks, spontaneous labour

2

Nullipara, singleton cephalic, ≥ 37 weeks A: Induced B: Caesarean section before labour

3

Multipara, singleton cephalic, ≥ 37 weeks, spontaneous labour

4

Multipara, singleton cephalic, ≥ 37 weeks A: Induced B: Caesarean section before labour

5

Previous Caesarean section, singleton cephalic, ≥ 37 weeks A: Spontaneous labour B: Induced labour C: Caesarean section before labour

6

All nulliparous breeches A: Spontaneous labour B: Induced labour C: Caesarean section before labour

7

All multiparous breeches (including previous Caesarean section) A: Spontaneous labour B: Induced labour C: Caesarean section before labour

8

All multiple pregnancies (including previous Caesarean section) A: Spontaneous labour B: Induced labour C: Caesarean section before labour

9

All abnormal lies (including previous Caesarean section but excluding breech) A: Spontaneous labour B: Induced labour C: Caesarean Section before labour

10

All singleton cephalic, ≤ 36 weeks (including previous Caesarean section) A: Spontaneous labour B: Induced labour C: Caesarean section before labour

SUMMARY

A common classification of Caesarean section rates and indications allows evaluation and comparison of the contributors to the Caesarean section rate and their impact. It also allows comparison between institutions, regions, and countries that adopt this classification. REFERENCES

3. [No authors listed]. Appropriate technology for birth. Lancet 1985;2:436–7. 4. Department of Health and Human Services; Centers for Disease Control and Prevention; National Center for Health Statistics. Healthy People 2000: national health promotion and disease prevention objectives: Full report, with commentary (DHHS publication no. (PHS) 91–50212). Washington: Government Printing Office; 1990:378. 5. Robson MS. Classification of caesarean sections. Fetal and Maternal Medicine Review 2001;12(1):23–39.

1. National Institutes of Health state-of-the-science conference statement. Cesarean delivery on maternal request. Obstet Gynecol 2006;107:1386–97.

6. Robson MS, Scudamore IW, Walsh SM. Using the medical audit cycle to reduce caesarean section rates. Am J Obstet Gynecol 1996;174(1):199–205.

2. Canadian Institute for Health Information. Health indicators interactive tool: Caesarean section rates; 1997–2009. Ottawa: CIHI. Available at: http://www.cihi.ca/hirpt/?language=en&healthIndicatorSelection=Csec. Accessed August 8, 2012.

7. Brennan DJ, Robson MS. Murphy M, O’Herlihy C. Comparative analysis of international cesarean delivery rates using 10-group classification identifies significant variation in spontaneous labor. Am J Obstet Gynecol 2009;201(3):308.e1–8.

978 l OCTOBER JOGC OCTOBRE 2012

Classification of Caesarean Sections in Canada: The Modified Robson Criteria

8. McCarthy FP, Rigg L, Cady L, Cullinane F. A new way of looking at Caesarean section births. Aust N Z J Obstet Gynaecol 2007;47(4):316–20. 9. Nesheim BI, Eskild A, Gjessing L. Does allocation of low risk parturient women to a separate maternity unit decrease the risk of emergency cesarean section? Acta Obstet Gynecol Scand 2010;89(6):813–6. 10. Betrán AP, Gulmezoglu AM, Robson M, Merialdi M, Souza JP, Wojdyla D, et al. WHO global survey on maternal and perinatal health in Latin America: classifying caesarean sections. Reprod Health 2009;6:18. 11. The Maternal Newborn Services Task Force, Child Health Network for the Greater Toronto Area. The birthing review project. Application of the Robson classification of cesarean sections. In focus: Robson groups 1 & 2. Toronto: Child Health Network for the Greater Toronto Area; April 2010. Available at: http://www.childhealthnetwork.com/documents/ CHN-BirthingReview-Phase1-Apri12010.pdf. Accessed August 8, 2012.

12. Perinatal Services BC. Examining cesarean delivery rates in British Columbia using the Robson ten classification. Part 1: understanding the ten groups. A Perinatal Services BC surveillance special report. Perinatal Services BC: December 2011;1(4). Available at: http://www.perinatalservicesbc.ca/NR/ rdonlyres/3CE464BF-3538–4A78-BA51–451987FDD2EF/0/ SurveillanceSpecialReportRobsonTenClassificationDec2011.pdf. Accessed August 8, 2012. 13. Torloni MR, Betran AP, Souza JP, Widmer M, Allen T, Gulmezoglu M, et al. Classifications for cesarean section: a systematic review. PLoS One. 2011;6(1):e14566. 14. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

Limitations of the Modified Robson Criteria 1. This classification does not allow the analysis of Caesarean section by demand and indicated Caesarean section for specific conditions (e.g., placenta previa). 2. This classification does not for pre-existing medical, surgical or fetal disease; indications for and methods used for induction of labour; and degrees of prematurity, all of which may influence the rate of Caesarean section. 3. Group 5 includes 2 quite different groups: (1) those who planned or needed a repeat Caesarean section, and (2) those who attempted VBAC and required Caesarean section. This classification system should be considered flexible. Interested parties may choose to further sub-classify the major categories to address specific research and clinical issues.

OCTOBER JOGC OCTOBRE 2012 l 979

SOGC Committee Opinion No. 271, January 2012

Delayed Child-Bearing This Committee Opinion has been prepared by the Genetics Committee, reviewed by the Reproductive Endocrinology and Infertility Committee, and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHOR Jo-Ann Johnson, MD, Calgary AB Suzanne Tough, PhD, Calgary AB SOGC GENETICS COMMITTEE R. Douglas Wilson, MD (Chair), Calgary AB François Audibert, MD, Montreal QC Claire Blight, RN, Dartmouth NS Jo-Ann Brock, MD, Halifax NS Lola Cartier, MSc, CCGC, Montreal QC Valérie A. Désilets, MD, Montreal QC Alain Gagnon, MD, Vancouver BC Sylvie Langlois, MD, Vancouver BC Lynn Murphy-Kaulbeck, MD, Moncton NB Nanette Okun, MD, Toronto ON The literature searches and bibliographic for this guideline were undertaken by Becky Skidmore, Medical Research Analyst, Society of Obstetricians and Gynaecologists of Canada. Disclosure statements have been received from all of the committee.

J Obstet Gynaecol Can 2012;34(1):80–93

Key Words: Maternal age, delayed child-bearing, reproductive technology, oocyte donation, late maternal age

Abstract Objective: To provide an overview of delayed child-bearing and to describe the implications for women and health care providers. Options: Delayed child-bearing, which has increased greatly in recent decades, is associated with an increased risk of infertility, pregnancy complications, and adverse pregnancy outcome. This guideline provides information that will optimize the counselling and care of Canadian women with respect to their reproductive choices. Outcomes: Maternal age is the most important determinant of fertility, and obstetric and perinatal risks increase with maternal age. Many women are unaware of the success rates or limitations of assisted reproductive technology and of the increased medical risks of delayed child-bearing, including multiple births, preterm delivery, stillbirth, and Caesarean section. This guideline provides a framework to address these issues. Evidence: Studies published between 2000 and August 2010 were retrieved through searches of PubMed and the Cochrane Library using appropriate key words (delayed child-bearing, deferred pregnancy, maternal age, assisted reproductive technology, infertility, and multiple births) and MeSH (maternal age, reproductive behaviour, fertility). The Internet was also searched using similar key words, and national and international medical specialty societies were searched for clinical practice guidelines and position statements. Data were extracted based on the aims, sample, authors, year, and results. Values: The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). Sponsor: The Society of Obstetricians and Gynaecologists of Canada. Recommendations 1. Women who delay child-bearing are at increased risk of infertility. Prospective parents, especially women, should know that their fecundity and fertility begin to decline significantly after 32 years of age. Prospective parents should know that assisted reproductive technologies cannot guarantee a live birth or completely compensate for age-related decline in fertility. (II-2A) 2. A fertility evaluation should be initiated after 6 months of unprotected intercourse without conception in women 35 to 37 years of age, and earlier in women > 37 years of age. (II-2A) 3. Prospective parents should be informed that semen quality and male fertility deteriorate with advancing age and that the risk of genetic disorders in offspring increases. (II-2A)

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

80 l JANUARY JOGC JANVIER 2012

Delayed Child-Bearing

4. Women ≥ 35 years of age should be offered screening for fetal aneuploidy and undergo a detailed second trimester ultrasound examination to look for significant fetal birth defects (particularly cardiac defects). (II-1A) 5. Delayed child-bearing is associated with increased obstetrical and perinatal complications. Care providers need to be aware of these complications and adjust obstetrical management protocols to ensure optimal maternal and perinatal outcomes. (II-2A) 6. All adults of reproductive age should be aware of the obstetrical and perinatal risks of advanced maternal age so they can make informed decisions about the timing of child-bearing. (II-2A) 7. Strategies to improve informed decision-making by prospective parents should be designed, implemented, and evaluated. These strategies should provide opportunity for adults to understand the potential medical, social, and economic consequences of childbearing throughout the reproductive years. (III-B) 8. Barriers to healthy reproduction, including workplace policies, should be reviewed to optimize the likelihood of healthy pregnancies. (III-C)

INTRODUCTION

T

here is a growing trend in Canada for child-bearing to occur later in women’s lives. Not only are more women aged > 30 years giving birth, but the proportion of first births occurring among women aged > 30 has been increasing steadily over the past 20 years.1 Currently, 11% of first births occur in women aged ≥ 35 years.1 This trend towards delayed child-bearing is also occurring in Western Europe, Australia, New Zealand, and the United States.2

maternal age and the use of reproductive assistance.4,5 These pregnancy complications include ectopic pregnancy, spontaneous abortion, fetal chromosomal abnormalities, certain congenital anomalies, placenta previa, gestational diabetes, preeclampsia, multiple births, PTD, and Caesarean section. These in turn are associated with an increased risk of preterm birth and perinatal and maternal mortality and morbidity.6–10 Infants born preterm, especially multiples, are at increased risk of morbidity, mortality, and long-term disability. If the trend towards delayed child-bearing continues, society can anticipate increased demand for reproductive assistance and associated increases in the need for more sophisticated prenatal, postpartum, and early development care. While a short delay in age at parenting poses little absolute risk for the individual woman, small shifts in population distribution curves affect large numbers of women, which has important implications for the health care system. The SOGC hopes to alert care providers to the implications of this emerging public health issue and s the urgent need for better public information to enable more informed reproductive choices. DEFINITION OF DELAYED CHILD-BEARING

Many of the reasons why women are choosing to postpone child-bearing reflect the availability of safe, effective, and reversible contraception, which has allowed women the reproductive autonomy to decide if and when they will have children. Biologically, the optimum period for childbearing is between 20 and 35 years of age. After 35 years of age, fecundity decreases, and the chance of miscarriage, spontaneous abortion, pregnancy complications, and adverse pregnancy outcomes (including PTD and multiple birth) increases.3 As women age, many opt for fertility treatment to improve their chance of conception. The effectiveness of various reproductive technologies declines steadily after the age of 35, while the risk of pregnancy complications and adverse outcome increases with both

Fertility declines with increasing maternal age, especially after the mid-30s. For this reason, delayed child-bearing is traditionally defined as pregnancy occurring in women aged ≥ 35 years. This population has been referred to as advanced maternal age or late maternal age. In recent years, advances in ART have challenged the traditional age-related boundaries of reproduction, enabling even postmenopausal women to conceive and give birth.11 Before ART, the oldest naturally conceived pregnancy was in a 57-year-old woman.12 With use of ART and donor oocytes, the birth rate in older mothers has risen dramatically, and in one case, a 70-year-old woman has given birth. These women are defined as “very advanced maternal age” (44 years of age or older), “mature” gravida, or “extremely elderly” gravida.

ABBREVIATIONS

INCIDENCE OF DELAYED CHILD-BEARING

ART

assisted reproductive technology

OR

odds ratio

ICSI

intracytoplasmic sperm injection

IUI

intrauterine insemination

LBW

low birth weight

PTD

preterm delivery

SGA

small for gestational age

Currently, the average age of a woman giving birth in Canada is 29 years, which represents a significant increase from previous decades.7 The proportion of first births occurring among women aged ≥ 35 has also increased from 4% in 1987 to 11% in 2005. At the same time, the proportion of first births occurring among women between 30 and 34 years increased from 18.9% in 1982 to 31.4% in 2006, and for the first time, JANUARY JOGC JANVIER 2012 l 81

SOGC Committee Opinion

Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well–designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.101 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care.101

the fertility rate of 30- to 34-year-old women exceeded the rate for women aged 25 to 29 years.13 Over the same time period, the proportion of live births to women between the ages of 35 to 39 and 40 to 44 years also increased, from 4.7% to 14.8%, and from 0.6% to 2.8% respectively.14

relationship factors (e.g., partner’s interest in and suitability for parenting) ranked as the 2 most important factors influencing readiness for child-bearing.16

As women delay child-bearing and age at first birth increases, the total number of births to each woman decreases, and the size, composition, and future growth of the population is affected. The postponement of first births has been associated with smaller family sizes and increased childlessness, all of which contribute to the overall decline in fertility rate as experienced in Canada and other countries, including Spain, Sweden, the United Kingdom, and Australia. In Canada the fertility rate (average number of children per woman) of 1.66 (2007) is well below the replacement level of 2.1 children per woman.15

A false sense of security is associated with advances in ART, and most women are unaware that technology cannot compensate completely for the effects of reproductive aging, except potentially through oocyte donation. A recent survey of 360 Canadian undergraduate women assessing their understanding of reproductive aging found that while most were aware of the drop in fertility with age, they significantly overestimated the likelihood of pregnancy at all ages and were not aware of the steep rate of fertility decline with age. These women also overestimated the chance of pregnancy loss at all ages, but they did not identify a woman’s age as the strongest risk factor for this event.17

CAUSES OF DELAYED CHILD-BEARING

CONSEQUENCES OF DELAYED CHILD-BEARING

A number of factors have been proposed in the demographic and sociological literature to explain the phenomenon of delayed child-bearing, including safe, effective contraception, changes in societal expectations of women in post-secondary education and the workforce, and an increased population of women 35 to 44 years of age.12

Delayed child-bearing is associated with an increased risk of infertility, maternal comorbidity, pregnancy and birth complications, and increased maternal and fetal morbidity and mortality. Women who start their families in their 20s and complete them by age 35 face significantly reduced risks.

Indeed, maternal education has been identified as one of the strongest predictors of use of contraception, timing of child-bearing, and the total number of children a woman will bear. In a study by Tough et al., financial security and 82 l JANUARY JOGC JANVIER 2012

MATERNAL AGE-RELATED SUBFERTILITY

Advancing maternal age is associated with a longer average time to achieve conception.18 Fecundability (i.e., the probability of achieving a pregnancy in one menstrual

Delayed Child-Bearing

35

70

30

60

25

50

20

40

15

30

10

20

5

10

0

22

24

26

28

30

32

34

36

38

40

42

44

46

Percentage Pregnancies that Miscarry

Percentage Pregnancy per Month

Figure 1. Natural conception: schematic demonstrating trends in pregnancy and miscarriage rates according to age

0

Age of Woman

Reproductive Ageing: Guidelines for First Line Physicians for Investigation of Infertility Problems (Canadian Fertility and Andrology Society;2004). Used with permission.

cycle) begins to decline significantly in the early 30s (about age 32), and typically subfecundability becomes more evident by age 37.19 The influence of female age on fertility has been clearly established by a number of observational studies that have consistently demonstrated a decline in pregnancy rates with advancing maternal age (Figure 1).7,20–22 Furthermore, cycles that result in pregnancy are less likely to progress to live births because of higher rates of aneuploidy and spontaneous abortion among older women.19 The progressive decrease in the number and quality of oocytes from fetal life until menopause is the cause of the age-related decline in female fertility. The oocyte pool peaks while the female fetus is in utero, reaching approximately 6 to 7 million at 20 weeks of gestation.23 Subsequently, progressive atresia occurs so that the number of remaining oocytes is approximately 1 to 2 million at birth and 250 000 at the onset of puberty. During the reproductive years, there is continued atresia, which occurs at an accelerated rate after the age of 37 in the average woman.18 The average age of menopause is 51, at which time approximately 1000 oocytes remain. As the number of oocytes declines, so too does the quality, eventually reaching a threshold below which pregnancy is no longer possible. The decrease in quality is primarily due to an increased prevalence of aneuploid oocytes.18 Autosomal trisomy is the most frequent finding and is thought to be associated with age-related changes in the meiotic spindle that predispose to non-disjunction.24 Chromosomally abnormal embryos for the lower chances of pregnancy and the higher rates of spontaneous abortion.

In addition to ovarian factors, older women have an increased probability of underlying medical pathology that adversely affects fertility, such as endometriosis, fibroids, tubal disease, and polyps. These and other pathologies increase the likelihood of a history of ovarian surgery, radiation, or chemotherapy, which are threats to fertility. Older women are more likely to be obese, to have a chronic medical condition, and to have lifestyle issues, including decreased coital frequency, all of which may affect fertility. INCREASED USE OF REPRODUCTIVE TECHNOLOGY

Women who delay child-bearing fall into 3 broad categories: (1) those who conceive without intervention, (2) those who still have fertilizable oocytes and conceive through use of ART, and (3) those who conceive after egg donation. Women who are < 37 years of age should be ed with expectant management for up to 6 months, after which a referral should be offered. For women aged ≥ 37, referral to a specialist is recommended without waiting 6 months for “spontaneous” conception, because ovarian reserve can further deplete during the waiting period. For women in categories 2 and 3, active treatment options may be initiated after appropriate investigations (which are beyond the scope of this guideline); these include controlled ovarian hyperstimulation with IUI, in vitro fertilization, and oocyte donation. While IUI and IVF can accelerate the time to conception, they cannot compensate for the natural decline of fertility due to age. With increasing maternal age, the chance of a woman progressing from the beginning of ART treatment to pregnancy and live birth using her own eggs decreases at every stage of ART JANUARY JOGC JANVIER 2012 l 83

SOGC Committee Opinion

Figure 2. Percentages of transfers that resulted in live births for ART cycles using fresh embryos from own and donor eggs, by ART patient’s age, 2006

Live births per transfer, percent

70 Donor eggs

60 50 40 30

Own eggs

20 10 0 <25

26

28

30

32

34

36

38

40

42

44

46

>47

Reproduced from: Assisted Reproductive Technology Success Rates: National Summary Reproduced from Assisted Reproductive Technology Success Rates: National Summary and Fertility and Fertility Clinic Reports Atlanta: Centers for Disease Control and Prevention 2006. Clinic Reports. Atlanta: Centers for Disease Control and Prevention;2006.

treatment (Figure 2).3 The live birth rate per cycle of IVF for example has been shown to drop from approximately 31% at age 35 to < 5% at age 42.25 The only effective option for older women (> 40) with decreased ovarian reserve is oocyte donation.25 In contrast to IVF with non-donor eggs, the success of IVF with donor eggs does not vary significantly according to the recipient’s age up to age 50, after which declining rates of implantation, clinical pregnancy, and delivery are seen.26,27 In the largest study of delivery outcomes among recipients of donated eggs, (17 339 ART recipient cycles) no effect of recipient age was observed between ages 25 and 45 years; however, older recipient age was associated with statistically reduced rates of implantation, clinical pregnancy, and delivery.27 This effect first appeared when women were in their late 40s and became more pronounced at age 50.27 Pregnancy loss rates among recipients ≥ 45 years versus younger recipients were also slightly higher (3%).27 Agerelated uterine factors are proposed to play a role in these outcomes, with reduced uterine blood flow affecting uterine receptivity to both implantation and pregnancy maintenance.27–30 The risk of multiple births is substantially elevated in ART pregnancies. In Canada, the incidence of twin births increased by 35%, and triplets and higher order multiple births by over 250%, between 1974 and 1990.31 Multiple gestations are at greater risk of pregnancy loss, preterm birth, and maternal complications than singleton 84 l JANUARY JOGC JANVIER 2012

pregnancies. Children of a multiple birth are at increased risk of neonatal mortality, developmental disabilities, and significant and lifelong special needs. Since the majority of multiple births are premature and consequently require additional medical attention before discharge, the effect on obstetric and neonatal intensive care resources and the health care system has been dramatic. Caring for multiples rather than singletons, has been associated with significant physical, economic, and psychological stress for families.7,32–37 Recommendations

1. Women who delay child-bearing are at increased risk of infertility. Prospective parents, especially women, should know that their fecundity and fertility begin to decline significantly after 32 years of age. Prospective parents should know that assisted reproductive technologies cannot guarantee a live birth or completely compensate for agerelated decline in fertility. (II-2A) 2. A fertility evaluation should be initiated after 6 months of unprotected intercourse without conception in women 35 to 37 years of age, and earlier in women > 37 years of age. (II-2A) ADVANCED PATERNAL AGE

While the reproductive consequences of advanced paternal age (≥ 40 years of age at the time of conception)38 are not as well-defined as the risks of advanced maternal age, the

Delayed Child-Bearing

Table 2. Risk of Down syndrome and other chromosome abnormalities in live births by maternal age Risk

Risk

Risk

Maternal age (at term)

Down syndrome

Total chromosome abnormalities

Maternal age (at term)

Down syndrome

Total chromosome abnormalities

Maternal age (at term)

Down syndrome

Total chromosome abnormalities

25

1 in 1250

1 in 476

32

1 in 637

1 in 323

39

1 in 125

1 in 81

26

1 in 1190

1 in 476

33

1 in 535

1 in 286

40

1 in 94

1 in 63

27

1 in 1111

1 in 455

34

1 in 441

1 in 224

41

1 in 70

1 in 49

28

1 in 1031

1 in 435

35

1 in 356

1 in 179

42

1 in 52

1 in 39

29

1 in 935

1 in 417

36

1 in 281

1 in 149

43

1 in 40

1 in 31

30

1 in 840

1 in 385

37

1 in 217

1 in 123

44

1 in 30

1 in 21

31

1 in 741

1 in 385

38

1 in 166

1 in 105

≥ 45

≥ 1 in 24

≥ 1 in 19

Source: Hecht CA, Hook EB.1996 Reproduced from BC Prenatal Genetic Screening Program, Provincial Health Services Authority.

data suggest a decrease in fertility and an increase in genetic disorders in the offspring of older fathers. The decreased fertility associated with advanced paternal age is related to a number of factors. These include decreased coital frequency, reduced sexual function, and poorer semen quality (decreased volume, sperm motility, and percent normal sperm). It is important to note, however, that standard sperm parameters do not necessarily correlate with fertilizing capacity and pregnancy rate.39,40 Advanced paternal age is associated with an increased risk of new gene mutations.41–43 During spermatogenesis, the male germ cells through more mitotic replications than female germ cells, creating greater opportunity for errors, which increase with paternal age. The conditions most strongly associated with advanced paternal age are those caused by single base substitutions resulting in autosomal dominant conditions such as, in decreasing order of frequency, achondroplasia, thanatophoric dysplasia, Apert syndrome, Pfeiffer syndrome, Crouzon syndrome, and multiple endocrine neoplasia 2A and multiple endocrine neoplasia 2B.44 There is also evidence that advanced paternal age is associated with an increased risk of some congenital anomalies, schizophrenia, autism spectrum disorders, and some forms of cancer. For most of these conditions, the relative risk is ≤ 2, and the mechanism is unknown.38 There is no evidence that advanced paternal age is associated with increased risk of chromosomal abnormalities with the possible exception of trisomy 21 and Klinefelter syndrome.38 Presently, there are no specific screening tests to target conditions related to advanced paternal age. When the male partner is aged ≥ 40, the couple should be treated as any other couple and offered prenatal screening and diagnosis according to SOCG guidelines.

Recommendation

3. Prospective parents should be informed that semen quality and male fertility deteriorate with advancing age and that the risk of genetic disorders in offspring increases. (II-2A) Maternal age-related risk of Genetic Conditions and Congenital Anomalies Chromosomal Aneuploidy

The risk of fetal chromosome aneuploidy, primarily trisomies, increases with maternal age (Table 2).6 The biological basis for this observation is that oocytes reach metaphase I during the fetal period (5 months postfertilization), and chromosomes remain aligned on the metaphase plate until the oocyte divides prior to ovulation. Age-related errors, largely due to dysfunction of the meiotic spindle, increase the risk of non-disjunction, which leads to unequal chromosome products at completion of division. This results in higher rates of aneuploid embryos, higher rates of spontaneous abortion, and lower chances of successful pregnancy outcome. It is estimated that after the age of 45, the majority of oocytes may be aneuploid.6 It is standard of care to offer all pregnant women, regardless of age, non-invasive screening for chromosomal aneuploidy using various combinations of ultrasound and maternal serum markers to adjust the mother’s agerelated risk.45 Women whose screening tests suggest a high risk of aneuploidy are offered diagnostic invasive testing (amniocentesis, chorionic villus sampling). With the exception of pregnancies conceived though the use of ICSI, the rate of chromosome abnormalities in couples undergoing ART treatment is similar to the rate in JANUARY JOGC JANVIER 2012 l 85

SOGC Committee Opinion

spontaneously conceived pregnancies. The use of sperm from subfertile men and the ICSI procedure itself are thought to increase the risk of chromosomal abnormalities in children conceived using this method.46,47 Couples undergoing IVF-ICSI for male-factor infertility should receive information and be offered genetic counselling about the increased risk of de novo chromosomal abnormalities (mainly sex chromosomal anomalies) associated with their condition. Prenatal diagnosis by chorionic villus sampling or amniocentesis should be offered to these couples if they conceive.47 Preimplantation genetic diagnosis with transfer of chromosomally normal embryos has been suggested as a way to increase rates of implantation and reduce risks of spontaneous abortion in older women and to avoid chromosomally abnormal births. However, despite the high number of aneuploid embryos that are selected out using this procedure, preimplantation genetic diagnosis for aneuploidy screening selection has not been found to be effective in improving pregnancy outcomes for women 35 to 41 years of age, and it is currently not recommended solely for advanced maternal age.48,49 Gene Abnormalities 

The effect of advanced maternal age on single gene disorders and epigenetic events, other than in the clinical area of assisted reproduction, is not well known. Epidemiologic studies have suggested a correlation between autism and advanced maternal and paternal age, but larger studies are needed to understand this association.50 Congenital Malformations 

The risk of certain non-chromosomal birth defects has been shown to increase with maternal age. In a study of > 1 million singleton infants born after 20 weeks of gestation who did not have a chromosomal abnormality, advanced maternal age (35 to 40 years) was associated with an increased risk for all types of heart defects (OR 1.12; 95% CI 1.03 to 1.22), tricuspid atresia (OR 1.24; 95% CI 1.02 to 1.50), right outflow tract defects (OR 1.28; 95% CI 1.10 to 1.49), hypospadias second degree or higher (OR 1.85; 95% CI 1.33 to 2.58), male genital defects excluding hypospadias (OR 1.25; 95% CI 1.08 to 1.45), and craniosynostosis (OR 1.65; 95% CI 1.18 to 2.30).51 Hollier et al., prospectively catalogued malformations detected at birth or in the newborn nursery over a 6-year period for 102 728 pregnancies, including abortions, stillbirths, and live births.46 After excluding infants with chromosomal abnormalities, the incidence of structurally malformed infants increased progressively with maternal age. The OR for cardiac defects was 3.95 in infants of women 86 l JANUARY JOGC JANVIER 2012

≥ 40 years of age compared with women 20 to 24 years of age.52 The risks of clubfoot and diaphragmatic hernia also increased as maternal age increased. Overall, the additional age-related risk of non-chromosomal malformations was approximately 1% in women ≥ 35 years of age. Recommendation

4. Women ≥ 35 years of age should be offered screening for fetal aneuploidy and undergo a detailed second trimester ultrasound examination to look for significant fetal birth defects (particularly cardiac defects). (II-1A) IMPACT OF MATERNAL AGE ON PREGNANCY OUTCOME

A large body of literature exists describing the impact of advanced maternal age on pregnancy outcome. When compared with younger women, women > 35 years are at increased risk of spontaneous abortion, ectopic pregnancy, placenta previa,8,52,53 pre-gestational diabetes, eclampsia,8,53,54 and pregnancy-induced hypertension,8 as well as Caesarean section8,52,55 and induction of labour. 8,55,56 Perinatal and neonatal death and stillbirth also increase with increasing maternal age.55 Some of these obstetrical complications appear to be related to the aging process alone, while others are related to coexisting factors such as multiple gestation, higher parity, and underlying chronic medical conditions (hypertension, diabetes mellitus and other chronic diseases) that become more prevalent with increasing age.8,52,55,56 In September 2011, the Canadian Institute of Health Information published the results of a 3-year study (2006 to 2009)57 which determined that advanced maternal age was associated with an increased risk of pregnancy complications and other adverse outcomes. The study linked the birth records and mothers’ hospital records of > 1 million hospital live births. Findings included the following: • Women > 40 were at least 3 times more likely to develop gestational diabetes and placenta previa than younger women • More than 50% of first time mothers > 40 years of age were delivered by Caesarean section compared with 25% of women 20 to 24 years • The incidence of chromosome disorders was 4-fold higher, and the rates of preterm birth and SGA were 20% and 7% higher in women ≥ 35 years than in women 20 to 34 years.

Delayed Child-Bearing

These data are consistent with the literature reviewed in these guidelines and provide additional to the recommendations. They also further highlight the importance of increasing public awareness of this potentially preventable cause of maternal and neonatal morbidity. The paper also suggests that the additional cost to the system associated with in-hospital births among older women (≥ 35 years) compared with younger women was $ 61.1 million over the 3 years. The main cost drivers of maternity care are labour and delivery complications and/or interventions, Caesarean section, PTD, and length of hospital stay, all of which were higher in older than in younger women. This costing information has important implications for policy, planning, and provision of care in Canada. Spontaneous Abortion

Older women have a higher rate of spontaneous abortion. These losses are both aneuploid and euploid, and most occur between 6 and 14 weeks’ gestation. In a large study from Denmark, the calculated risk of spontaneous loss in women > 35 years of age was more than double that in women < 30 years of age (25% vs. 12%), and was > 90% in women ≥ 45 years of age.58 The influence of maternal age on the spontaneous abortion rate was independent of parity and history of previous abortion, although these characteristics were also risk factors for pregnancy loss. Chromosomally abnormal embryos (mainly autosomal trisomies) for the majority of spontaneous abortions in older women. In a recent study of over 2000 IVF pregnancies in which fetal cardiac activity was documented by transvaginal ultrasound, the pregnancy loss rate was significantly higher in older women, increasing from 5% in women < 30 years of age to 13% and 22% in women aged 35 to 39, and ≥ 40 years, respectively.59,60 Ectopic Pregnancy

Ectopic pregnancy is a major source of maternal mortality and morbidity in early pregnancy. Maternal age ≥ 35 years is associated with a risk of ectopic pregnancy 4- to 8-fold greater than that of younger women.60 This is due to an accumulation of risk factors over time, such as multiple sexual partners, pelvic infection, and tubal pathology. Coexisting Medical Conditions

The 2 most common medical problems complicating pregnancy are hypertension (pre-existing and gestational) and diabetes mellitus (pre-gestational and gestational), and the risk of both of these complications increases with maternal age. The prevalence of medical and surgical illnesses, such as cancer and cardiovascular, renal, and autoimmune disease, increases with advancing age. As a

result, pregnant women ≥ 35 years of age have 2-to 3-fold higher rates of hospitalization, Caesarean section, and pregnancy-related complications than younger women.61–67 Lifestyle factors, such as smoking and alcohol use during pregnancy have been associated with an increased risk of LBW, perinatal morbidity, and stillbirth in all age groups, and the risks are further elevated in older women.68–70 Hypertension Although the maternal and fetal morbidity and mortality related to hypertensive disorders during pregnancy can be reduced with careful monitoring and timely intervention, these disorders are associated with an increased incidence of preterm birth, SGA infants, and Caesarean section. The incidence of chronic hypertension is 2- to 4-fold greater in women ≥ 35 years of age than in women 30 to 34 years of age.71 Rates of preeclampsia in the general obstetric population are 3% to 4%. They increase to 5% to 10% in women over 40, and up to 35 % percent in women > 50 years of age.72 Diabetes Pre-existing diabetes is associated with increased risks of congenital anomalies and perinatal morbidity and mortality, while the major complication of gestational diabetes is fetal macrosomia and its sequelae.73 The prevalence of diabetes increases with maternal age. The incidence of both preexisting diabetes mellitus and gestational diabetes is 3- to 6-fold higher in women ≥ 40 years of age than in women aged 20 to 29.53,65,73 The incidence of gestational diabetes is also 3- to 4-fold higher in older women (7% to 12 % in women > 40; 20% in women > 50) compared with the 3% incidence in the general obstetric population. Placental Abnormalities

The prevalence of placental problems, such as placental abruption, placenta previa, and placenta accreta, is higher among older women.12,74 Multiparity s for a significant proportion of the excess risk in these disorders. For example, there is no significant correlation between maternal age and abruption when parity and hypertension are taken into . Maternal age is, however, an independent risk factor for placenta previa. Nulliparous women ≥ 40 years of age have a 10-fold increased risk of placenta previa compared with nulliparous women aged 20 to 29 years, although the absolute risk is small (0.25% vs. 0.03%).74 Placenta accreta occurs in approximately 1 of 2500 deliveries, and the incidence is as high as 10% in women with placenta previa. Advanced maternal age and previous Caesarean section are independent risk factors for placenta accreta.74 JANUARY JOGC JANVIER 2012 l 87

SOGC Committee Opinion

Figure 3. Hazard (risk) of stillbirth for singleton births without congenital anomalies by gestational age, 2001–2002 <20 years

2.50

20-24 years 25-29 years

2.25

30-34 years 35-39 years

Hazard of fetal death per 1,000 ongoing pregnancies

2.00

≥40 years

1.75 1.50 1.25 1.00 0.75 0.50 0.25 0.00

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

Gestation (Weeks)

Reprinted from Am J Obstet Gynecol 2006;195(3), Reddy UM, Ko CW, Willinger M., Maternal age and the risk of stillbirth throughout pregnancy in the United States, 764–70, Copyright 2006, with permission from Elsevier.

Perinatal Morbidity 

Preterm and LBW infants are at increased risk of death, morbidity, and long-term disability. These disabilities include developmental disorders (e.g., cerebral palsy and blindness), respiratory problems, learning problems (e.g., lower IQ and lower academic achievement), and behavioural problems (e.g., attention deficit hyperactivity disorder).75–77 Advanced maternal age has been associated with an increased risk of LBW (< 2500 g) and PTD. A large prospective study from Sweden compared birth outcomes in healthy nulliparous women delivering singletons at 35 to 40 years of age with those in women who were 20 to 24 years of age.78 After adjusting for smoking, history of infertility, and other medical conditions, older maternal age was associated with a significantly higher risk of LBW and PTD: very LBW, < 1500 g (OR 1.9); moderate LBW, 1500 to 2499 g) (OR 1.7); very preterm birth ≤ 32 weeks (OR 1.7); moderately preterm birth 33 to 36 weeks (OR 1.2); and SGA infant < 2 SD for GA (OR 1.7). A subsequent prospective population-based study, also from Sweden, evaluated pregnancy outcome in over 32 000 women ≥ 40 years of age and confirmed an increased risk of PTD.51 After adjustment for confounders such as multiple gestation, smoking, parity, and maternal medical 88 l JANUARY JOGC JANVIER 2012

diseases, the rates of PTD < 32 weeks for women 20 to 29, 40 to 44, and ≥ 45 years of age were 1.01, 1.80, and 2.24%, respectively. Tough et al. compared birth weight and PTD rates in women aged ≥ 35 with those < 35 years.72 Among older mothers, the risk of LBW delivery was significantly higher in every weight category (< 2500 g, < 1500 g, < 1250 g, < 1000 g) (OR 1.1 to 1.6), as was the rate of PTD (< 37, < 35, < 32, and < 30 weeks of gestation) (OR 1.1 to 1.3). During the study period, delayed child-bearing ed for 78% of the increase in the rate of LBW and 36% of the increase in the rate of PTD in the population. Maternal age was not related to changes in SGA, suggesting that the age effect was through pregnancy complications that led to PTD and LBW. In 2005, Joseph et al.56 published the results of a large population-based study of all singleton births (n = 157 445) in the province of Nova Scotia during 1988 to 1995. The risk of very preterm (< 32 weeks) and preterm (< 37 weeks) birth and SGA (3rd and 10th percentile) increased with advanced maternal age, showing a statistically significant excess risk for women ≥ 35 compared with 20 to 24 year olds.56

Delayed Child-Bearing

Perinatal Mortality

Most large studies worldwide have reported that women ≥ 35 years of age are at greater risk of perinatal mortality than younger women, with relative risks of 1.2 to 4.5.79 This excess perinatal mortality in older women is present even after controlling for risk factors such as hypertension, diabetes, antepartum bleeding, smoking, and multiple gestation, and is mostly due to unexplained stillbirths.47,79–85 In a study of over 5 million singleton pregnancies in the United States, Reddy et al. reported the risk of stillbirth was 3.73, 6.41, and 8.65 per 1000 ongoing pregnancies in women < age 35, 35 to 39 years, and ≥ 40 years of age respectively, with the risk increasing sharply at 40 weeks of gestation (Figure 3).83 Bahtiyar et al.85 analyzed > 6 million singleton pregnancies in the United States to determine the influence of maternal age on stillbirth risk. After women with congenital anomalies and medical complications were excluded, older women were compared with a group of 25- to 29-year-old women with the lowest stillbirth risk. The odds of stillbirth at term increased significantly with advancing maternal age: 30 to 34 years, OR 1.24, (95% CI 1.13 to 1.36), 35 to 39 years, OR 1.45, (95% CI 1.21 to 1.74), and 40 to 44 years, OR 3.04 (95% CI 1.58 to 5.86).85 Of note, the risk of stillbirth for women 40 to 44 years of age at 39 weeks was comparable to the risk for women 25 to 29 years old at 42 weeks. The authors concluded that advanced maternal age is an independent predictor of stillbirth and that antenatal testing in women ≥ 40 years of age should begin at 38 weeks’ gestation. They also suggested delivery by 39 weeks in women > 40 years of age, since the cumulative risk of stillbirth in women 40 to 44 years of age at 39 weeks is the same as the risk in a 25- to 29-year-old at 42 weeks’ gestation.85 These data suggest that women ≥ 40 years of age should be considered biologically “post-term” at 39 weeks’ gestation, and fetal monitoring (twice-weekly fetal assessment) should be initiated at 38 weeks in this age group. Multiple Pregnancy

Advancing maternal age is associated with an increased prevalence of twin pregnancy, related to both a higher rate of naturally conceived twins and a higher use of ART in older women.86 Data from the Centers for Disease Control and Prevention87 show that between 1980 and 2006, twin birth rates rose 27% for mothers < age 20 years compared with 80% for women aged 30 to 39, and 190% for mothers aged ≥ 40 years. In 2006, 20% of births to women aged 45 to 54 years were twins, compared with about 2% of births to women aged 20 to 24 years. These data mainly reflect the increased use of ART in older women.86 The

overall twin birth rate increased 70% between 1980 and 2004, from 18.9 per 1000 to 32.1 per 1000 births, but it was essentially unchanged between 2004 and 2006, indicating a possible slowing of the upward trend. The rate of triplet and higher order multiple births (quadruplets, quintuplets and other higher order multiples per 100 000 live births), which climbed more than 400% during the 1980s and 1990s, also declined (by 21%) over the same period from the all-time high in 1998 (193.5 per 100 000 total births).87 This is likely due in part to changes in practices in IVF clinics across the country. There is a high risk of an adverse outcome for multiple births, and > 12% of twins and 30% of triplets are born at < 32 weeks, compared with 2% of singletons. The perinatal mortality rate is significantly higher among twins (29.8 per 1000) and triplets (59.6 per 1000) than among singletons (6.0 per 1000).86,87 Caesarean Section

Women ≥ 35 years of age are more likely than younger women to be delivered by Caesarean section.25,50 The Caesarean section rate in women 40 to 45 approximates 50%, and this increases to approximately 80% in women aged 50 to 63 years, although the rate in the general obstetric population is about 25%.55,68,87 The reasons for the high rate of Caesarean section in older women include an increased prevalence of medical complications, fetal malposition, cephalopelvic disproportion, induction of labour, a failed trial of labour, and uterine rupture.88–93 In a study by Smith et al., a linear increase in ORs for Caesarean section with advancing maternal age (≥ 16 years) was demonstrated (adjusted OR for a 5-year increase in age: 1.49; 95% CI 1.48 to 1.50).91 During the study period (1980 to 2005), the proportion of women aged 30 to 34 years increased 3-fold, the proportion of women aged 35 to 40 years increased 7-fold, and the proportion of women aged > 40 years increased more than 10-fold. The authors used these data in a calculation model to determine the contribution of advanced maternal age to the overall Caesarean section rate and concluded that if the maternal age distribution had stayed at the 1980 level, 38% of the additional Caesarean sections would not have been performed. There is also a lower threshold among both women and physicians for performing a Caesarean section in older women, and maternal request for Caesarean section is more common among older women.88 There is a continuous negative relationship between age and uterine function throughout the child-bearing years.90 JANUARY JOGC JANVIER 2012 l 89

SOGC Committee Opinion

Maternal Mortality

Maternal mortality increases with maternal age94–96 however, the risk of dying during childbirth is very low in developed countries (total maternal mortality rate in Canada 6.1 per 100 000 live births).97 As the proportion of women who are delaying child-bearing to later in life continues to increase, age-specific increases in mortality may be observed.98,99 Recommendations

5. Delayed child-bearing is associated with increased obstetrical and perinatal complications. Care providers need to be aware of these complications and adjust obstetrical management protocols to ensure optimal maternal and perinatal outcomes. (II-2A) 6. All adults of reproductive age should be aware of the obstetrical and perinatal risks of advanced maternal age so they can make informed decisions about the timing of child-bearing. (II-2A) Benefits of Delayed Child-Bearing

There are advantages and disadvantages to parenting when older: there is more anxiety during pregnancy, but parents are more mature and likely to be more financially secure and to have higher levels of education. Multiple pregnancies have a slightly more favourable outcome in older women. Overall, if older women can sustain a pregnancy, the pregnancy outcomes can be positive, and parents may be well prepared to cope with the physical and emotional stresses of pregnancy and parenting.57 Older parents can bring experience, knowledge, and economic resources to the task of child raising, which may suggest a social advantage to delayed parenting.100 SUMMARY

The proportion of women who delay child-bearing beyond the age of 35 years has increased greatly in recent decades. Pregnancy after 35 years has been associated with increased likelihood of infertility, miscarriage, spontaneous abortion, stillbirth, medical risks, operative delivery, and pregnancy complications. Advanced maternal age increases the risk for multiple births, PTD and/or LBW, each of which increases the potential need for additional medical care, and poses lifelong threats to development. While most women have some awareness of the “biological clock” and realize that conception difficulties increase with age, many are unaware of the limitations of ART or the increased risk of adverse influences on child development associated with PTD and multiple birth. Given these gaps in reproductive knowledge and awareness, widespread pre-conception counselling and education are needed and 90 l JANUARY JOGC JANVIER 2012

must be implemented so that the 95% of Canadians who anticipate parenting at some point can make informed decisions. Women (and men) need to be informed that age is the single most important determinant of female fertility, either natural or treated, and that ART cannot compensate for age-related decline in fertility. There is an opportunity for SOGC to lead this initiative through the development and distribution of high-quality, respected, educational and public health materials. In addition, communication strategies may be most effective if they align with the needs of government, policy makers, and employers who are vested in the development of a healthy, competent workforce, which may be threatened by delayed child-bearing and its consequences. There is an opportunity to improve public understanding about reproductive health and child-bearing between 25 and 35 years, the limits of ART, and the limitations of science to predict which families will be at risk when child-bearing is delayed. The influences of maternity leave, child care, work environments and relationship security on childbearing decisions require further understanding (beyond the scope of this paper). Recommendations

7. Strategies to improve informed decisionmaking by prospective parents should be designed, implemented, and evaluated. These strategies should provide opportunity for adults to understand the potential medical, social, and economic consequences of child-bearing throughout the reproductive years. (III-B) 8. Barriers to healthy reproduction, including workplace policies, should be reviewed to optimize the likelihood of healthy pregnancies. (III-C) REFERENCES 1. Bushnick T, Garner R. The children of older first-time mothers in Canada: their health and development. Ottawa (ON): Statistics Canada. Sept 2008. Available at: http://www.statcan.gc.ca/pub/89–599-m/ 89–599-m2008005-eng.htm. Accessed October 3, 2011. 2. Royal College of Obstetricians and Gynaecologists. RCOG statement on later maternal age. Available at: http://www.rcog.org.uk/what-we-do/ campaigning-and-opinions. Accessed October 3, 2011. 3. Leridon H. Can assisted reproductive technology compensate for the natural decline in fertility with age? A model assessment. Hum Reprod 2004;19:1548–53. 4. Human Fertilisation and Embryology Authority, facts and figures 2006: fertility problems and treatment, October 2008. London: HEFA; 2010. 5. Leader A. Pregnancy and motherhood: the biological clock. Sex Reprod Menopause 2006;4:3–6. 6. Hassold T, Chiu D. Maternal age-specific rates of numerical chromosome abnormalities with special reference to trisomy. Hum Genet 1985;70:11–7. 7. Nybo Andersen A, Wohlfahrt J, Christens P, Olsen J, Melbye M. Maternal age and fetal loss: population based linkage study. BMJ 2000;320(7251):1708–12.

Delayed Child-Bearing

8. Cleary-Goldman J, Malone FD, Vidaver J, Ball RH, Nyberg DA, Comstock CH, et al. Impact of maternal age on obstetric outcome. Obstet Gynecol 2005;105:983–90.

32. Bissonnette F, Cohen J, Collins J, et al. Incidence and complications of multiple gestation in Canada: Proceedings of an expert meeting. Reprod Biomed Online 2007;14:773–90.

9. Storeide O, Veholmen M, Eide M, Bergsjø P, Sandvei R. The incidence of ectopic pregnancy in Hordaland County, Norway 1976–1993. Acta Obstet Gynecol Scand 1997;76:345–9.

33. Helmerhorst FM, Perquin DAM, Donker D, Keirse MJNC. Perinatal outcome of singletons and twins after assisted conception: a systematic review of controlled studies. BMJ 2004;328:261–8.

10. Luke B, Brown MB. Contemporary risks of maternal morbidity and adverse outcomes with increasing maternal age and plurality. Fertil Steril 2007;88:283–93. 11. Blickstein I. Motherhood at or beyond the edge of reproductive age. In J Fertil Womens Med 2003;48:17–24. 12. Frets RC. Effect of advanced age on fertility and pregnancy in women. 2009. Available at http://www.uptodate.com. Accessed October 28, 2011. 13. Statistics Canada. Births 2005. (Cat. No. 84F0210XIE). 2007. Ottawa, Ministry of Industry, 2007. 14. Fell DB, Joseph KS, Dodds L, Allen AC, Jangaard K, Van den Hof M. Changes in maternal characteristics in Nova Scotia, Canada from 1988 to 2001. Can J Public Health 2005;96:234–8. 15. Statistics Canada. The Daily. September 26, 2002. Available at: http://www.statcan.ca/Daily/English/ 020926/d020926c.htm. Accessed October 3, 2011. 16. Tough S, Tofflemire K, Benzies K, Fraser-Lee N, Newburn-Cook C. Factors influencing childbearing decisions and knowledge of perinatal risks among Canadian men and women. Matern Child Health J 2007;11:189–98. 17. Brehterick KL, Fairbroher N, Avila L, Harbord S, Robinson WP, Karla L. Fertility and aging: do reproductive-aged Canadian women know what they need to know? Fertil Steril 2010;93:2162–8. 18. Committee on Gynecologic Practice of American College of Obstetricians and Gynecologists; Practice Committee of American Society for Reproductive Medicine. Age-related fertility decline: a committee opinion. Fertil Steril 2008;90:486–7. 19. Faddy MJ, Gosden RG, Gougeon A, Richardson SJ, Nelson JF. Accelerated disappearance of ovarian follicles in mid-life: implications for forecasting menopause. Hum Reprod 1992;7:1342–6. 20. Menken J, Trussell J, Larsen U. Age and infertility. Science 1986;233:1389–94. 21. Laufer N, Simon A, Samueloff A, Yaffe H, Milwidsky A, Gielchinsky Y. Successful spontaneous pregnancies in women older than 45 years. Fertil Steril 2004;81:1328–32. 22. Dunson DB, Colombo B, Baird DD. Changes with age in the first level and duration of fertility in the menstrual cycle. Hum Reprod 2002;17:1399–403. 23. Peters H. Intrauterine gonadal development. Fertil Steril 1976;27:493–500. 24. Pellestor F, Andreo B, Arnal F, Humeau C, Demaille J, Maternal aging and chromosomal abnormalities: new data drawn from in vitro unfertilized human oocytes, Hum Genet 2003;112:195–203. 25. Fretts R, Wilkins-Haug L, Barss V. Management of infertility and pregnancy in women of advanced age. UpToDate 2009. Available at: http://www.uptodate.com. Accessed October 3, 2011.

34. Bower C, Hansen M. Assisted reproductive technologies and birth outcomes: overview of recent systematic reviews. Reprod Fertil Dev 2005;17:329–33. 35. Fisher J, Stocky A. Maternal perinatal mental health and multiple births: implications for practice. Twin Res 2003;6:506–13. 36. Cook R, Bradley S, Golombok S. A preliminary study of parental stress and child behaviour in families with twins conceived by in-vitro fertilization. Hum Reprod 1998;13:3244–6. 37. Ellison MA, Hall JE. Social stigma and compounded losses: quality-of-life issues for multiple-birth families. Fertil Steril 2003;80:405–14. 38. Toriello HV, Meck JM; Professional Practice and Guidelines Committee. Statement on guidance for genetic counseling in advanced paternal age. Genet Med 2008;10:457–60. 39. Eskenazi B, Wyrobek AJ, Sloter E, Kidd SA, Moore L, Young S, Moore D. The association of age and semen quality in healthy men. Hum Reprod 2003;18:447–54. 40. Araujo AB, Mohr BA, McKinlay JB. Changes in sexual function in middleaged and older men: longitudinal data from the Massachusetts Male Aging Study. J Am Geriatr Soc 2004;52:1502–9. 41. Risch N, Reigh EW, Wishnick MW, McCarthy JG. Spontaneous mutation and parental age in humans. Am J Hum Genet 1987;41:218–48. 42. Crow JF. The high spontaneous mutation rate: is it a health risk? Proc Natl Acad Sci U S A 1997;94:8380–6. 43. Crow JF. Age and sex effects on human mutation rates: an old problem with new complexities. J Radiat Res 2006;47(Suppl B):B72–B82. 44. Hook EB. Paternal age and effects on chromosomal and specific locus mutations and on other genetic outcomes in offspring. In: Mastroianni L, Paulsen CA, eds. Aging, reproduction, and the climacteric. New York: Plenum Press; 1986:117–45. 45. Summers AM, Langlois S, Wyatt P, Wilson RD; SOGC Genetics Committee; CCMG Committee On Prenatal Diagnosis; SOGC Diagnostic Imaging Committee. Prenatal screening for fetal aneuploidy. SOGC Clinical Practice Guideline No. 187, February 2007. J Obstet Gynaecol Can 2007;29:146–61. 46. Wennerholm UB, Bergh C, Hamberger L, Lundin K, Nilsson L, Wikland M, et al. Incidence of congenital malformations in children born after ICSI. Hum Reprod 2000;15:944–8. 47. Allen VM, Wilson RD, Cheung A; SOGC Genetics Committee; SOGC Reproductive Endocrinology Infertility Committee. Pregnancy outcomes after assisted reproductive technology. SOGC Clinical Practice Guideline N0.173, March 2006. J Obstet Gynaecol Can 2006;28:220–50. 48. Gianaroli L, Magli MC, Munne S, Fiorentino A, Montanaro N, Ferraretti AP. Will preimplantation genetic diagnosis assist patients with a poor prognosis to achieve pregnancy? Hum Reprod 1997;12:1762–7.

26. Balasch J. Ageing and infertility: an overview. Gynecol Endocrinol 2010;26:855–60.

49. Mastenbroek S, Twisk M, van Echten-Arends J, Sikkema-Raddatz B, Korevaar JC, Verhoeve HR, et al. In vitro fertilization with preimplantation genetic screening. N Engl J Med 2007;357:9–17.

27. Toner JP, Grainger DA, Frazier LM. Clinical outcomes among recipients of donated eggs: an analysis of the U.S. national experience, 1996–1998. Fertil Steril 2002;78:1038–45.

50. Kolevzon A, Gross R, Reichenberg A. Prenatal and perinatal risk factors for autism: a review and integration of findings. Arch Pediatr Adolesc Med 2007;161:326–33.

28. Stolwijk AM, Zielhuis GA, Sauer MV, Hamilton CJ, Paulson RJ. The impact of the woman’s age on the success of standard and donor in vitro fertilization. Fertil Steril 1997;67:702–10.

51. Reefhuis J, Honein MA. Maternal age and non-chromosomal birth defects, Atlanta—1968–2000: teenager or thirty-something, who is at risk? Birth Defects Res A Clin Mol Teratol 2004;70:572–9.

29. Sauer MV, Paulson RJ, Lobo RA. Reversing the natural decline in human fertility. An extended clinical trial of oocyte donation to women of advanced reproductive age. JAMA 1992;268:1275–9.

52. Hollier LM, Leveno KJ, Kelly MA, MCIntire DD. Maternal age and malformations in singleton births. Obstet Gynecol 2000;96(5 pt. 1):701–6.

30. Paulson RJ, Hatch IE, Lobo RA, Sauer MV. Cumulative conception and live birth rates after oocyte donation: implications regarding endometrial receptivity. Hum Reprod 1997;12:835–9. 31. Millar WJ, Wadhera S, Nimrod C Multiple Births: Trends and Patterns in Canada 1974–1990 Health Reports.

53. Jacobsson B. Advanced maternal age and adverse perinatal outcome. Obstet Gynecol 2004;104:727–33. 54. Jolly M, Sebire N, Harris J, Robinson S, Regan L. The risks associated with pregnancy in women aged 35 years or older. Hum Reprod 2000;15:2433–7. 55. Ozalp S, Tanir HM, Sener T, Yazan S, Keskin AE. Health risks for early (< or =19) and late (> or = 35) childbearing. Arch Gynecol Obstet 2003;268:172–4.

JANUARY JOGC JANVIER 2012 l 91

SOGC Committee Opinion

56. Joseph KS, Allen AC, Dodds L, Turner LA, Scott H, Liston R. The perinatal effects of delayed childbearing. Obstet Gynecol 2005;105:1410–8.

80. Huang L, Sauve R, Birkett N, Fergusson D, van Walraven C. Maternal age and risk of stillbirth: a systematic review. CMAJ 2008;178:165–72.

57. Canadian Institute of Health Information. In due time: why maternal age matters. Sept 2011. Ottawa: Canadian Institute of Health Information. Available at: http://secure.cihi.ca/cihiweb/ products/AIB_InDueTime_WhyMaternalAgeMatters_E.pdf. Accessed October 6, 2011.

81. Fretts RC, Usher RH. Fetal death in women in the older reproductive age group. Contemp Rev Obstet Gynecol 1997;9:173–7.

58. Smith KE, Buyalos RP. The profound impact of patient age on pregnancy outcome after early detection of fetal cardiac activity. Fertil Steril 1996;65:35–40.

83. Reddy, UM, Ko, CW, Willinger, M. Maternal age and the risk of stillbirth throughout pregnancy in the United States. Am J Obstet Gynecol 2006;195:764–70.

59. Spandorfer SD, Davis OK, Barmat LI, Chung PH, Rosenwaks Z. Relationship between maternal age and aneuploidy in in vitro fertilization pregnancy loss. Fertil Steril 2004;81:1265–9. 60. Hook EB. Rates of chromosome abnormalities at different maternal ages. Obstet Gynecol 1981;58:282. 61. Bell JS, Campbell DM, Graham WJ, Penney GC, Ryan M, Hall MH. Can obstetric complications explain the high levels of obstetric interventions and maternity service use among older women? A retrospective analysis of routinely collected data. BJOG 2001;108:910–8. 62. Newcomb WW, Rodriguez M, Johnson JW. Reproduction in the older gravida. A literature review. J Reprod Med 1991;36:839–45. 63. Hollander D, Breen JL. Pregnancy in the older gravida: how old is old? Obstet Gynecol Surv 1990;45:106–12. 64. Seoud MA, Nassar AH, Usta IM, Melhem Z, Kazma A, Khalil AM. Impact of advanced maternal age on pregnancy outcome. Am J Perinatol 2002;19:1–8. 65. Edge V, Laros RK Jr. Pregnancy outcome in nulliparous women aged 35 or older. Am J Obstet Gynecol 1993;168(6 pt 1):1881–4. 66. Gilbert WM, Nesbitt TS, Danielsen B. Childbearing beyond age 40: pregnancy outcome in 24,032 cases. Obstet Gynecol 1999;93:9–14.

82. Bateman BT, Simpson LL. Higher rate of stillbirth at the extremes of reproductive age: a large nationwide sample of deliveries in the United States. Am J Obstet Gynecol 2006;194:840–5.

84. Canterino JC, Ananth CV, Smulian J, Harrigan JT, Vintzileos AM. Maternal age and risk of fetal death in singleton gestations: USA, 1995–2000. J Matern Fetal Neonatal Med 2004;15:193–7. 85. Bahtiyar MO, Funai EF, Rosenberg V, Norwitz E, Lipkind H, Buhimschi C, Copel JA. Stillbirth at term in women of advanced maternal age in the United States: when could the antenatal testing be initiated? Am J Perinatol 2008;25:301–4. 86. Delbaere I, Verstraelen H, Goetgeluk S, Martens G, Derom C, De Bacquer D, et al. Perinatal outcome of twin pregnancies in women of advanced age. Hum Reprod 2008;23:2145–50. 87. Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Menacker F, Kirmeyer S, et al. Division of Vital Statistics Births: final data for 2006. National vital statistics reports Hyattsville, MD: National Center for Health Statistics. 2009;57(7). 88. Callaway LK, Lust K, McIntyre HD. Pregnancy outcomes in women of very advanced maternal age. Aust N Z J Obstet Gynaecol 2005;45:12–6. 89. Lin HC, Xirasagar S. Maternal age and the likelihood of a maternal request for cesarean delivery: a 5-year population-based study. Am J Obstet Gynecol 2005;192:848–55.

67. Bianco A, Stone J, Lynch L, Lapinski R, Berkowitz G, Berkowitz RL. Pregnancy outcome at age 40 and older. Obstet Gynecol 1996;87:917–22.

90. Main DM, Main EK, Moore DH, 2nd. The relationship between maternal age and uterine dysfunction: a continuous effect throughout reproductive life. Am J Obstet Gynecol 2000;182:1312–20.

68. Salihu HM, Shumpert MN, Aliyu MH, Kirby RS, Alexander GR. Smokingassociated fetal morbidity among older gravidas: a population study. Acta Obstet Gynecol Scand 2005; 84:329–34.

91. Smith GC, Cordeaux Y, White IR, Pasupathy D, Missfelder-Lobos H, Pell JP, et al. The effect of delaying childbearing on primary Cesarean section rates. PLoS Med 2008;5(7):E144.

69. Salihu HM, Shumpert MN, Aliyu MH, Alexander MR, Kirby RS, Alexander GR. Stillbirths and infant deaths associated with maternal smoking among mothers aged > or = 40 years: a population study. Am J Perinatol 2004;21:121–9.

92. Greenberg MB, Cheng YW, Sullivan M, Norton ME, Hopkins LM, Caughey AB. Does length of labor vary by maternal age? Am J Obstet Gynecol 2007;197:428.e1–7.

70. Aliyu MH, Salihu HM, Wilson RE, Alio AP, Kirby RS. The risk of intrapartum stillbirth among smokers of advanced maternal age. Arch Gynecol Obstet 2008;278:39–45. 71. Luke B, Brown MB. Elevated risks of pregnancy complications and adverse outcomes with increasing maternal age. Hum Reprod 2007;22:1264–72. 72. Paulson RJ, Boostanfar R, Saadat P, Mor E, Tourgeman DE, Slater CC, et al. Pregnancy in the sixth decade of life. Obstetric outcomes in women of advanced reproductive age. JAMA 2002;288:2320–3. 73. Casey, BM, Lucas, MJ, Mcintire, DD, Leveno, KJ. Pregnancy outcomes in women with gestational diabetes compared with the general obstetric population. Obstet Gynecol 1997;90:869–73. 74. Miller DA, Chollet JA, Goodwin TM. Clinical risk factors for placenta previa– placenta accreta. Am J Obstet Gynecol 1997;177:210–4. 75. Hack M, Flannery DJ, Schluchter M, Cartar L, Borawski E, Klein N. Outcomes in young adulthood for very-low-birth-weight infants. N Engl J Med 2002;346:149–57. 76. McCormick MC, Richardson DK. Premature infants grow up. N Engl J Med 2002;346:197–8. 77. Hack M, Fanaroff AA. Outcomes of children of extremely low birthweight and gestational age in the 1990s. Early Hum Dev 1999;53:193–218.

93. Bujold E, Hammoud AO, Hendler I, Berman S, Blackwell SC, Duperron L, et al. Trial of labor in patients with a previous cesarean section: Does maternal age influence the outcome? Am J Obstet Gynecol 2004;190:1113–8. 94. Shipp TD, Zelop C, Repke JT, Cohen A, Caughey AB, Lieberman E. The association of maternal age and symptomatic uterine rupture during a trial of labor after prior cesarean delivery. Obstet Gynecol 2002;99:585–8. 95. Public Health Agency of Canada. Special report on maternal mortality and severe morbidity in Canada enhanced surveillance: the path to prevention. Available at: http://www.phac-aspc.gc.ca/rhs-ssg/srmm-rsmm/ page3-eng.php. Accessed October 3, 2011. 96. Chang J, Elam-Evans LD, Berg CJ, Herndon J, Flowers L, Seed KA, Syverson CJ. Pregnancy-related mortality surveillance—United States, 1991–1999. MMWR Surveill Summ 2003;52:1–8. 97. Department of Health, Welsh Office, Scottish Office Department of Health, Department of Health and Social Services, Northern Ireland. Why Mothers Die. Report on Confidential Enquiries into Maternal Deaths in the United Kingdom, 1997–1999. London: The Stationary Office, 2001. 98. Australia Institute of Health and Welfare. Report on Maternal Deaths in Australia, 1994–96. AIHW Cat. No. PER 13. Canberra: Australia Institute of Health and Welfare, 2000. 99. Health Canada. Canadian Perinatal Health Report, 2003. Ottawa: Minister of Public Works and Government Services, 2003.

78. Cnattingius S, Forman MR, Berendes HW, Isotalo L. Delayed childbearing and risk of adverse perinatal outcome. A population-based study. JAMA 1992;268:886–90.

100. Stein Z, Susser M. The risks of having children later in life: Social Advantage may make up for biologic disadvantage. BMJ 2000;320;1681–2.

79. Tough SC, Newburn-Cook C, Johnston DW, Svenson LW. Delayed childbearing and its impact on population rate changes in lower birth weight, multiple birth, and preterm delivery. Pediatrics 2002;109:399–403.

101. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

92 l JANUARY JOGC JANVIER 2012

Delayed Child-Bearing

Appendix. Delayed Child-Bearing Facts Advanced maternal age (≥ 35 years) is associated with • • • • •

Decreased fertility and fecundity Increased risk of miscarriage Increased risk of ectopic pregnancy Increased risk of chromosomal aberrations and birth defects Increased risk of multiple pregnancy

Advanced paternal age (≥ 40 years) is associated with • Decreased fertility and semen quality • Increased risk of certain genetic disorders

Practice Points • Pre-conceptional counselling is recommended for all couples when one or both partners are of advanced reproductive age. • Pre-conceptional counselling and education at a government and public health level are required in order to inform younger women and men about the possible consequences of delaying child-bearing before they make the decision whether or not to do so. • When women ≥ 35 years become pregnant, an early ultrasound to document location, number, and viability of the pregnancy should be undertaken. • Prenatal screening for chromosome abnormalities and a second trimester ultrasound should be offered as is standard of care for all women.

Pregnancy in women of ≥ 35 years is associated with • • • • • • •

Increased risk of coexisting medical disorders Hypertensive disorders of pregnancy and preeclampsia Preexisting diabetes and gestational diabetes Increased risk of placenta previa Increased risk of LBW and PTD Increased risk of stillbirth Increased rate of Caesarean section

Practice Points Women ≥ 35 years should • Have a thorough history and physical examination. • Have prenatal bloodwork that includes baseline liver and kidney function, as well as mammogram (> 40 years) and cardiology consultation > 45 years. • Be monitored closely for hypertensive disorders of pregnancy and preeclampsia, and all should undergo screening for gestational diabetes. • Have careful placental localization with ultrasound at the time of the second trimester scan, to be followed up at 28 weeks’ gestation if low lying or previa. A third trimester scan to document fetal growth and placental location should be considered. The cumulative risk of stillbirth in women of 40 to 44 years of age at 39 weeks’ gestation is nearly identical to the risk in those of 25 to 29 years of age at 42 weeks’ gestation. Therefore, a strategy of antenatal testing beginning at 38 gestational weeks with delivery by the completion of the 39th week for women > 40 years of age should be considered.

JANUARY JOGC JANVIER 2012 l 93

SOGC COMMITTEE OPINION No. 277, May 2012

Counselling Considerations for Prenatal Genetic Screening This committee opinion has been prepared by the Genetics Committee and approved by the Executive of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Lola Cartier, MSc, CCGC, Montreal QC Lynn Murphy-Kaulbeck, MD, Moncton NB GENETics COMMITTEE R. Douglas Wilson, MD (Chair), Calgary AB François Audibert, MD, Montreal QC Jo-Ann Brock, MD, Halifax NS June Carroll, MD, Toronto ON Lola Cartier, MSc, CCGC, Montreal QC Alain Gagnon, MD, Vancouver BC Jo-Ann Johnson, MD, Calgary AB Sylvie Langlois, MD, Vancouver BC Lynn Murphy-Kaulbeck, MD, Moncton NB Nanette Okun, MD, Toronto ON Melanie Pastuck, RN, Cochrane AB Disclosure statements have been received from all of the committee.

Abstract This document has been developed to aid clinicians in counselling patients about prenatal screening and to provide assistance in counselling about both positive and negative screening results.

J Obstet Gynaecol Can 2012;34(5):489–493

Key Words: Aneuploidy, prenatal screening, chromosomal anomalies, trisomy

INTRODUCTION

T

risomies 21, 18, and 13 are the most frequently occurring fetal aneuploidies, although all have been observed at term. Eighty percent of fetuses with trisomy 18 or 13 and 30% with trisomy 21 die in utero between 12 and 40 weeks of gestation. Trisomy 21, or Down syndrome, is the most common viable chromosomal anomaly, with an incidence of 1/770 live births. Individuals with trisomy 21 may have physical abnormalities such as a cardiac defect, early onset Alzheimer disease, and/or increased rates of leukemia, and all will have some degree of developmental delay. The 18to 20-week ultrasound examination will show no abnormal findings in 50% of fetuses with trisomy 21. The risk of having an affected fetus increases with maternal age. However, as most pregnancies occur in young women, most fetuses with trisomy 21 occur in younger mothers. SCREENING

Prenatal screening for fetal aneuploidy is a rapidly changing field, and there are variations in screening protocols both provincially and regionally. Clinicians should be aware of the availability of and protocols for screening in their geographical area. Biochemical and ultrasound screening tests are now available during pregnancy to assess the risk of having a fetus with trisomy 21. If the risk of trisomy 21 is higher than a specified risk cut-off as determined by the screening program, a diagnostic test (e.g., amniocentesis) is offered to confirm or exclude the presence of trisomy 21 (and some other chromosome abnormalities).

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

MAY JOGC MAI 2012 l 489

SOGC COMMITTEE OPINION

It is important to ensure that these screening tests are offered within the context of an organized program, ensuring laboratory tests and ultrasound operators have appropriate validation to meet quality assurance standards. Screening is intended to identify women in the general pregnancy population who are at increased risk of having a child with an anomaly. Health care professionals should discuss the screening tests with all pregnant women. Information pamphlets can also be helpful in explaining the purpose and limitations of screening tests, but health care providers should be aware that some women may not have sufficient English or French to understand them. Health care providers must be satisfied that patients understand the screening available and that screening is entirely voluntary, and that they are making an informed decision about whether to have testing. The decision should be documented. Screening Methods

Screening can be divided into two broad categories: 1. Maternal serum sampling: measure of maternal biochemical markers in the first and/or second trimester of pregnancy. This can be done with or without ultrasound screening. 2. Ultrasound screening: measure of first trimester nuchal translucency and other ultrasound markers in the first and/or second trimester of pregnancy. Their performance, in of sensitivity and specificity, varies according to the approach, but the results are improved by using a combination of these methods. For example, an ultrasound examination is performed in the first trimester, and blood tests in the first and second trimester to provide a single assessment of risk. It is not appropriate to use one method to assess risk and then use another method to give a separate risk assessment. When multiple screening options are available, factors to consider include the detection rate and false-positive rate of the screening test, and the gestational age at the time testing is considered. Screen Positive Rate

•• This is the proportion of the screened population who test positive. It includes both true positives and false positives. Women who screen positive are eligible for and are offered counselling and invasive testing. Most women who screen positive will not have a fetus with trisomy 21; that is, they will have a false-positive result. Sensitivity (Detection Rate)

•• Sensitivity refers to the test’s ability to detect all individuals who have the condition. 490 l MAY JOGC MAI 2012

•• The higher the sensitivity of the screening test, the more likely it is to identify individuals with the condition. •• Sensitivity is the probability that an individual who has the condition will test positive; it is not the risk for trisomy 21 after a positive screening test result. Specificity

•• Specificity refers to the probability that an individual who does not have the condition will test negative. •• The higher the specificity of the screening test, the more likely it is to correctly identify individuals who do not have the condition. •• Specificity measures the test’s ability to identify only individuals who have the condition. Positive Predictive Value

•• Positive predictive value is the probability that an individual has the condition given a positive screening result. •• Positive predictive value is determined/assessed on the basis of test sensitivity and specificity, and the prevalence of the condition. Negative Predictive Value

•• Negative predictive value is the probability that an individual does not have the condition given a negative screening result. TIPS FOR PRE-SCREENING COUNSELLING

•• Counsel your patient that all pregnant women have some risk of having a fetus affected by trisomy 21, 18, or 13. •• Tell your patient that prenatal screening will use specific maternal and pregnancy factors (e.g., age, ethnicity) to assess her individual risk of having an affected fetus. •• Discuss the following points with your patient. –– Maternal age is one factor used in the assessment of risk, and the screening result is more likely to be positive with increasing age. –– A positive screening result may provide an older woman with a risk assessment/adjustment lower than the risk associated with her age alone. –– The screening may assess a younger woman’s risk as greater than that indicated by her age alone, but it may not be high enough to result in a positive screening test result.

Counselling Considerations for Prenatal Genetic Screening

Current available screening options and their screening performance* Screening option

Markers

Trimester

Term risk cut-off

DR, %

FPR, %

OAPR

Options that meet the minimum standard FTS1,2

NT, free β-hCG, PAPP-A, MA

First

1 in 325

83

5.0

1:27

Quad screening3

AFP, uE3, free β-hCG, inhibin A, MA

Second

1 in 385

77

5.2

1:50

IPS

NT, PAPP-A, AFP, uE3, free β-hCG/ total hCG, inhibin A, MA

First and second

1 in 200

87

1.9

1:10

IPS without inhibin A1

NT, PAPP-A, AFP, uE3, total hCG, MA

First and second

1 in 200

88

3.0

1:20

Serum IPS

PAPP-A, AFP, uE3, free β-hCG/ total hCG, inhibin A

First and second

1 in 200

85

4.4

1:26

MA

First and second

1 in 385

44

16

1:218

AFP, uE3, total hCG, MA

Second

1 in 385

71

7.2

1:59

1,2

1,2

Options that do not meet the minimum standard Maternal age4 Triple screening

4

*Some centres in Canada may offer variation on IPS (sequential screening or contingent screening) with cut-offs set that achieve at least the minimum standard. DR: detection rate; FPR: false positive rate; OAPR: odds of an affected pregnancy result; FTS: first trimester combined screening; NT: nuchal translucency; hCG: human chorionic gonadotropin; PAPP-A: pregnancy associated plasma protein A; MA: maternal age; IPS: integrated prenatal screening; AFP: alpha fetaprotein; uE3: unconjugated estriol. 1

Wald NJ, Rodeck C, Hackshaw AK, Walters J, Chitty L, Mackinson AM. First and second trimester antenatal screening for Down’s syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURUSS). J Med Screen 2003;10:56–104.

2

Malone FD, Canick JA, Ball RH, Nyberg DA, Comstock CH, Bukowski R, et al. First- and Second-Trimester Evaluation of Risk (FASTER) Research Consortium. First-trimester or second-trimester screening, or both, for Down’s syndrome. N Engl J Med 2005;353:2001–11.

3

Wald NJ, Kennard A, Hackshaw A, McGuire A. Antenatal screening for Down’s syndrome. J Med Screen 1997;4:181–246.

4

Summers AM, Farrell SA, Huang T, Meier C, Wyatt PR. Maternal serum screening in Ontario using the triple marker test. J Med Screen 2003;10:107–11.

•• Counsel your patient that a positive screen will mean that her risk is above a pre-determined cutoff (set by regional programs), not that her fetus is necessarily affected. Some patients may have difficulty understanding the difference between a screening test and a diagnostic test. •• Counsel your patient that her risk is specific and personalized. For example, a risk of 1:100 means that for one woman carrying an affected fetus, there are 99 women carrying a fetus that is not affected. Prenatal aneuploidy screening using age and nuchal translucency measurement in the first trimester is appropriate for screening in multiple gestations. For multiple gestations, it is important to check with the screening centre close to you, as availability of maternal serum screening varies from centre to centre. •• When screening is offered, discuss options and the invasive prenatal testing that may need to be considered after screening. •• Tell your patient that if screening is negative, no further testing is indicated other than routine second trimester ultrasound. Remind her that there is a risk to invasive procedures. Inform the patient that negative screening does not guarantee the birth of a healthy

baby and that her child could still be born with an aneuploidy or another genetic or developmental condition not detected through screening. Inform your patient that if the screening test is positive she is eligible for diagnostic testing. –– This testing would be done by amniocentesis, which carries a procedural risk of 1/100 to 1/175 for loss of the pregnancy or by chorionic villus sampling, which carries a procedural risk of 1/100 for loss of the pregnancy.2,3 –– Ensure your patient is aware that diagnostic testing is entirely voluntary. –– Ensure your patient knows that she has the option of continuing or terminating the pregnancy if the test shows that her fetus has an aneuploidy or another significant chromosomal anomaly. It is a common misconception that screening is offered only to patients who would terminate a pregnancy if an anomaly were found. It is important to tell patients who may choose to continue the pregnancy that their fetus will be given the best care possible. In the case of chromosomal anomalies that have an extremely poor prognosis, this may include referring the patient to a neonatologist to discuss palliative MAY JOGC MAI 2012 l 491

SOGC COMMITTEE OPINION

care. For the care of a fetus with Down syndrome this should include ○

Ensuring that the fetus receives necessary testing and monitoring, such as fetal echocardiogram and increased surveillance.

○

Informing the patient of the available for parents choosing to raise a child with Down syndrome, including the Canadian Down Syndrome Society.

–– Be aware that undecided patients may pursue or decline screening and testing at any point in the screening process. POST-SCREENING COUNSELLING

A screening program should include a reliable laboratory that can provide a report of results within a working week. Screening results should be reported to the patient as soon as possible after results have been reported to the practitioner. Ideally, screening results should be discussed in person. Negative Screen

For women with a negative screen, as defined by a predetermined cut-off, counselling should include the risk for trisomy 21 determined by screening rather than by prescreening risk determined by age. As part of counselling, the patient should be informed that a negative screen does not guarantee that her fetus does not have one of the conditions screened for; however, the risk is low enough that invasive testing will not offered. Routine second trimester ultrasound will still be carried out. In younger women, the assessment may indicate that their risk is greater than the risk that would have been determined by age alone but may result in a negative screen. Counselling may be needed to help some women understand that although the risk is increased, the result is still negative, and invasive diagnostic testing is not required. As regions differ with respect to the use of ultrasound markers, regional protocols will guide any further adjustment of risk. If one or more ultrasound markers are present at the time of the anatomical survey, the risk for trisomy 21, as determined by screening, will be adjusted by the likelihood ratio assigned to the specific marker(s). The risk for other genetic conditions is not assessed through screening. 492 l MAY JOGC MAI 2012

Positive Screen

A positive screen for trisomy 21 is anxiety provoking and needs to be discussed with the patient in an environment that allows proper explanation and discussion of options. Allow sufficient time for the woman and her partner to ask questions. The first point of counselling should be that there are a number of reasons why a screen may be positive. A positive screen is not a diagnosis of a chromosome anomaly: it is a positive screen as established by a predetermined cut-off, and further investigation and possibly invasive testing will be required. It may be necessary to discuss with the patient the false-positive rate of the tests used. Counselling should include a discussion of risk. Patients often find it easier to understand risks when they are explained as percentages. For example, a risk of 1/100 is a 1% risk of the fetus having the condition whereas a risk of 1/200 is a risk of 0.5%. Stated another way, a risk of 1/200 means that there is a 99.5% chance that the fetus does not have trisomy 21 or that if 200 women have this same result, 1 of them will have a fetus with trisomy 21 and 199 will not. An explanation of a negative screen and the percentage of risk may also be helpful. For women of advanced maternal age (≥ 35 years of age), screening may result in a woman’s risk for aneuploidy being lowered but still result in a positive screen. This lowered risk may be acceptable to some women, but counselling is required to help women understand their risk and that they are eligible for invasive testing. Counselling for a positive screen should review the patient’s options and should include a discussion about invasive testing, what the test will diagnose, the risk of the procedure, and why she may or may not wish to have the test(s). In the vast majority of cases, amniocentesis will provide a definitive answer as to whether or not the fetus has a chromosomal anomaly. Chorionic villus sampling is available in some centres in Canada and may be available for women who screen positive after first trimester biochemistry and/or nuchal translucency measurement. In some centres in Canada, women with positive screens are referred for further ultrasound assessment, and the risk determined by serum screening is adjusted depending on the presence or absence of fetal soft markers. If a soft marker or markers are present, the risk is increased as determined by the likelihood ratio for the marker or markers present. The absence of any markers or anomalies may result in a lowering of the risk. Regardless of the risk adjustment from the ultrasound, women may still choose to have amniocentesis for a definitive diagnosis.

Counselling Considerations for Prenatal Genetic Screening

Counselling should include the information that if invasive testing does reveal a fetus has trisomy 21 or any other chromosomal anomaly, pregnancy termination may be one option. It should be made clear to the patient that the offer of invasive testing is not contingent upon her terminating the pregnancy if her baby has a chromosomal anomaly. It is important for women to understand that if a diagnosis of Down syndrome or other anomaly is made, further consultation and will be available to help her decide whether to continue or terminate the pregnancy. Women and families may require more information about what trisomy 21 is and about the possible health implications and long-term outcomes for people with this condition. A request for consultation at a genetics service can be helpful. Also, diagnosing trisomy 21 or other non-lethal chromosomal anomaly prenatally ensures that the fetus receives the most appropriate prenatal and neonatal care, including testing and monitoring that may be necessary, such as fetal echocardiogram and increased antenatal and intrapartum surveillance. Women should be made aware that although invasive testing is being offered, it is not mandatory following a positive screen. They should be reassured that they will still receive the best possible care they if they choose not to have diagnostic testing. TIPS FOR COUNSELLING PATIENTS WITH A POSITIVE SCREENING RESULT

Tell your patient that •• A positive screen does not mean her baby is affected. •• Her risk for having an affected fetus has been adjusted from her age-only related risk and that her risk is higher than the pre-determined cut-off, which results in a positive screen. •• False positives do occur. •• She is eligible for diagnostic invasive testing, but this is her choice, and she can decline the procedure.

•• A positive screen does not warrant further genetic testing other than amniocentesis or chorionic villus sampling unless there are other indications for more indepth testing on the basis of previous pregnancy history or family history. •• Chromosome analysis is specific; no other genetic testing is done unless indicated. •• The pregnancy loss risk associated with amniocentesis is 1:175 to 1:100. •• If she has a fetus diagnosed with a chromosomal anomaly, she has the option of continuing or terminating the pregnancy. •• If she chooses to continue her pregnancy, special tests, such as a fetal echocardiogram, will be performed as necessary, and routine obstetrical care will be adjusted because there is an increased risk for adverse outcome with a trisomy 21 affected pregnancy. •• This is a difficult and very personal decision and she will be ed whatever she chooses to do. Acknowledge that a positive screen is anxiety provoking and the woman in her decision making. BIBLIOGRAPHY Chitayat D, Langlois S, Wilson RD; SOGC Genetics Committee; CCMG Prenatal Diagnosis Committee. Prenatal screening for fetal aneuploidy in singleton pregnancies. SOGC Clinical Practice Guideline no. 261, July 2011. J Obstet Gynaecol Can 2011;33:736–50. Audibert F, Gagnon A. SOGC Genetics Committee; CCMG Prenatal Diagnosis Committee. Prenatal screening for fetal aneuploidy in twin pregnancies. SOGC Clinical Practice Guideline no. 262, July 2011. J Obstet Gynaecol Can 2011;33:754–67. Chodirker BN, Cadrin C, Davies GAL, Summers AM, Wilson RD, Winsor EJT, et al.; SOGC Genetics Committee; CCMG Prenatal Diagnosis Committee. Canadian guidelines for prenatal diagnosis: techniques of prenatal diagnosis. SOGC Clinical Practice Guideline, no. 105, July 2001. J Obstet Gynaecol Can 2001;23:616–24. Summers AM, Langlois S, Wyatt P, Wilson RD; SOGC Genetics Committee; CCMG Committee on Prenatal Diagnosis; SOGC Diagnostic Imaging Committee. Prenatal screening for fetal aneuploidy. t SOGC-CCMG Clinical Practice Guideline no. 187, February 2007. J Obstet Gynaecol Can 2007;29:146–61.

•• If she has diagnostic testing following a positive screening result, it will diagnose Down syndrome and that other chromosome anomalies may be diagnosed.

Van den Hof MC, Wilson DR; SOGC Diagnostic Imaging Committee; SOGC Genetics Committee. Fetal soft markers in obstetric ultrasound. SOGC Clinical Practice Guideline no. 162, June 2005. J Obstet Gynaecol Can 2005;27:592–612.

•• The identification of a chromosomal anomaly may require further investigation of the parents’ chromosomes before a firm diagnosis can be made.

Wilson RD, Langlois S, Johnson J; SOGC Genetics Committee; CCMG Prenatal Diagnosis Committee. Mid-trimester amniocentesis fetal loss rate. SOGC Committee Opinion, No. 194, July 2007. J Obstet Gynaecol Can 2007;29:586–90.

MAY JOGC MAI 2012 l 493

SOGC CLINICAL PRACTICE GUIDELINE No. 283, November 2012

Treatments for Overactive Bladder: Focus on Pharmacotherapy This clinical practice guideline has been prepared by the Urogynaecology Committee, reviewed by Family Practice Advisory Committee, and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHOR Roxana Geoffrion, MD, Vancouver BC UROGYNAECOLOGY COMMITTEE Danny Lovatsis, MD (Co-Chair), Toronto ON Jens-Erik Walter, MD (Co-Chair), Montreal QC Queena Chou, MD, London ON William Easton, MD, Scarborough ON Annette Epp, MD, Saskatoon SK Roxana Geoffrion, MD, Vancouver BC Marie-Andrée Harvey, MD, Kingston ON Annick Larochelle, MD, St-Lambert QC Kenny Maslow, MD, Winnipeg MB Grace Neustaedter, RN, Calgary AB

Outcomes: To provide understanding of current available evidence concerning safety and clinical efficacy of pharmacotherapy for OAB; to guide selection of anticholinergic therapy based on individual patient characteristics. Evidence: The Cochrane Library and Medline were searched for articles published from 1950 to the present related to individual anticholinergic drugs. Review articles on management of refractory OAB were also examined. Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to 2010. Values: The quality of evidence is rated and recommendations are made using the criteria described by the Canadian Task Force on Preventive Health Care (Table 1). Benefits, harms, and costs: Anticholinergics are the mainstay of pharmacotherapy for OAB. Evidence for their efficacy is mostly derived from short-term phase III randomized drug trials. Placebo response is strong, and long-term follow-up and patient subjective outcome data are lacking. Care providers need to be well acquainted with the side effects of anticholinergics and select therapy based on individual patient parameters.

Dante Pascali, MD, Ottawa ON Marianne Pierce, MD, Halifax NS

Recommendations

Jane A. Schulz, MD, Edmonton AB

01. Behavioural management protocols and functional electrical stimulation should be offered in the spectrum of effective primary treatments for overactive bladder syndrome. (I-A)

Vyta Senikas, MD, Ottawa ON David Wilkie, MD, Vancouver BC

Objective: To provide guidelines for pharmacotherapy to treat overactive bladder syndrome (OAB).

02. Oral oxybutynin, immediate and extended release, as well as transdermal oxybutynin, may be offered as treatment for overactive bladder syndrome, as they are associated with significant objective clinical improvement at 12 weeks. (I-A) Oxybutynin immediate release has superior cost-effectiveness but more side effects than other anticholinergics. (I-A) Adverse events associated with transdermal oxybutynin are fewer than with oral oxybutynin. (I-A)

Options: Pharmacotherapy for OAB includes anticholinergic (antimuscarinic) drugs and vaginal estrogen. Both oral and transdermal anticholinergic preparations are available.

03. Tolterodine, immediate and extended release, may be offered as treatment for overactive bladder syndrome, as it is associated with significant objective clinical improvement at 12 weeks. (I-A)

Disclosure statements have been received from all of the committee.

Abstract

Key Words: Anticholinergic, overactive bladder, urinary incontinence

J Obstet Gynaecol Can 2012;34(11):1092–1101

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

1092 l NOVEMBER JOGC NOVEMBRE 2012

Treatments for Overactive Bladder: Focus on Pharmacotherapy

Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.82 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care.82

04. Trospium, immediate and extended release, may be offered as treatment for overactive bladder syndrome as it is associated with significant clinical improvement at 12 weeks. (I-A) Trospium is an adequate anticholinergic choice for overactive bladder syndrome patients with pre-existing cognitive impairment (II-B) and for overactive bladder syndrome patients taking concurrent CYP450 inhibitors. (III-B) 05. Solifenacin may be offered as treatment for overactive bladder syndrome, as it is associated with significant objective clinical improvement at 12 weeks. (I-A) Solifenacin may be an adequate anticholinergic choice for elderly overactive bladder syndrome patients or patients with pre-existing cognitive dysfunction. (I-B) 06. Darifenacin may be offered as treatment for overactive bladder syndrome, as it is associated with significant objective clinical improvement at 12 weeks. (I-A) Darifenacin is an adequate anticholinergic choice for overactive bladder syndrome patients with pre-existing cardiac concerns or cognitive dysfunction. (I-B) 07. Overactive bladder syndrome patients should be offered a choice between bladder training, functional electric stimulation, and anticholinergic therapy, as there is no difference in cure rates. Combination therapy does not have a clear advantage over one therapy alone. (I-A) 08. The choice of anticholinergic therapy should be guided by individual patient comorbidities, as objective efficacy of anticholinergic drugs is similar. (I-A) Dose escalation does not improve objective parameters and causes more anticholinergic

ABBREVIATIONS CNS

central nervous system

CYP450 cytochrome p450 ER

extended release

IR

immediate release

OAB

overactive bladder syndrome

XR

extended release

adverse effects. It is, however, associated with improved subjective outcomes. (I-A) To decrease side effects, switching to a lower dose or using an extended release formulation or a transdermal delivery mechanism should be considered. (I-A) 09. Education on treatment efficacy, realistic expectations, and length of treatment should be offered to patients upon initiation of anticholinergic therapy, as continuation rates for anticholinergic therapy are low. (III-B) 10. Oral or transdermal estrogen supplementation should not be recommended for treatment of overactive bladder syndrome as its effects are comparable to placebo. (I-E) Vaginal estrogen can be suggested for subjective improvements in overactive bladder syndrome symptoms. (III-B) 11. Intravesical botulinum toxin injection and sacral nerve and posterior tibial nerve stimulation are clinically effective options for patients with overactive bladder syndrome unresponsive to conservative options, anticholinergics, or vaginal estrogen. (I-A)

INTRODUCTION

O

veractive bladder syndrome comprises symptoms related to abnormal urinary bladder storage. It is defined as urinary urgency, usually accompanied by frequency and nocturia, with or without urgency urinary incontinence, in the absence of urinary tract infection or other obvious pathology.1 It can be associated with detrusor overactivity on urodynamic studies.1 The prevalence of OAB is reported at 11.8% to 17% in women and significantly increases with age.2–5 Most women with OAB (96%) report leakage of urine with an overall prevalence of urgency incontinence of 12%.2 OAB has a greater impact on quality of life than stress urinary incontinence6,7 and is responsible for several medical comorbidities. Up to 67% of women with OAB report a NOVEMBER JOGC NOVEMBRE 2012 l 1093

SOGC CLINICAL PRACTICE GUIDELINE

Table 2. Anticholinergic drugs and properties Drug

Route

Oxybutynin

Oral

Dose

Receptor selectivity

IR

5 mg bid-tid

Non-selective

5 or 10 mg qd

Hepatic; patch and gel avoid first

High

ER

Non-selective

Hepatic

High

Non-selective

Renal

Low

Transdermal, patch

3.9 mg/day; apply twice weekly

Main metabolism

CNS penetration

Transdermal, gel 10%

1 g (1 sachet) qd

Tolterodine

Oral

IR

2 mg bid

ER (LA)

4 mg qd

Trospium

Oral

IR

20 mg bid Age > 75:20 mg qd

ER (XR)

60 mg qd

Solifenacin

Oral

5 to 10 mg qd

M3 M1 selective

Hepatic

High

Darifenacin

Oral

7.5 to 15 mg qd

M3 selective

Hepatic

Low

Fesoterodine

Oral

4 mg

Non-selective

Hepatic

High

ER

8 mg LA: long acting. Tolterodine, solifenacin, darifenacin—use ½ dose in hepatic insufficiency; avoid use in severe hepatic insufficiency Tolterodine, trospium, solifenacin—use ½ dose when creatinine clearance < 30 mL/min All anticholinergics should be prescribed with caution if CYP inhibitors are used concurrently (typical examples are antifungals, antiretrovirals and macrolide antibiotics)

negative effect on daily living.4 Significant comorbidities associated with OAB include depression,8 falls and fractures,9 and increased issions to hospitals and nursing homes.10

(Detrol or Detrol LA), trospium chloride (Trosec IR and XR), solifenacin (VESIcare), darifenacin (Enablex), and fesoterodine (Toviaz).

Conservative, pharmacotherapeutic, and surgical interventions are available. This consensus guideline reviews these interventions, focusing mainly on pharmacotherapy.

Mechanism of Action and Drug Properties

CONSERVATIVE INTERVENTIONS

Conservative management of urinary incontinence has been reviewed in a previous consensus guideline.11 Many inter­ ventions have been described. They include Kegel exercises, functional electrical stimulation, continence pessaries, behavioural management, and bladder training programs. Recommendation

1. Behavioural management protocols and functional electrical stimulation should be offered in the spectrum of effective primary treatments for overactive bladder syndrome. (I-A) PHARMACOTHERAPEUTIC INTERVENTIONS: ANTICHOLINERGICS

There are currently six approved medications for OAB (Table 2). These are oxybutynin (Ditropan, Ditropan XL, Oxytrol patch, Gelnique gel 10%), tolterodine tartrate 1094 l NOVEMBER JOGC NOVEMBRE 2012

Normal human bladder contractions are initiated via muscarinic (cholinergic) receptors in the detrusor muscle.12 These receptors are of the M2 and M3 subtypes in the bladder.12 Normal voiding occurs via parasympathetic activation of the M2 or M3 receptors, while the M2 receptors also inhibit sympathetically mediated bladder relaxation.12,13 Anticholinergic drugs competitively block acetylcholine and increase bladder storage capacity.14,15 Furthermore, the urothelium also expresses muscarinic receptors and consequently may be the site of action of anti-muscarinics.16 The release of other substances, such as adenosine triphosphate, may be affected by anticholinergic drugs blocking these urothelial receptors.17 Muscarinic receptors are widely distributed throughout the body, and therefore anticholinergic drugs often have undesirable systemic side effects.14 Anticholinergics have certain characteristics ing for slight differences in efficacy and side-effect profiles (Table 3).18 Most United States Food and Drug istrationapproved agents are tertiary amines with the exception of trospium, a quaternary amine with greater polarity and

Treatments for Overactive Bladder: Focus on Pharmacotherapy

Table 3. Published short-term safety of anticholinergics in different populations at time of manuscript preparation Elderly and/ or cognitively impaired

Concomitant use of cholinesterase inhibitors

Cardiac

Concomitant use of CYP450 inhibitors

Oxybutynin

–

–

–

–

Tolterodine

 IA

Trospium

 IIB

Solifenacin

 IB

Darifenacin

 IB

 IA  IIB

 IIIB

 IB

NOTE: A checkmark indicates “safe to use.” The corresponding level of evidence is indicated. A dash means the drug is not necessarily unsafe but indicates that safety studies specific to each concern are lacking.

hydrophilic properties.18 Smaller molecules, neutral in charge and lipophilic, are more likely to cross the blood–brain barrier and cause central nervous system side effects. These can be immediate (confusion, delirium, headache, blurred vision, dizziness and hallucinations) or delayed (memory loss).19,20 Specific patient factors such as increased permeability of the blood–brain barrier in older adults, and comorbid diseases predisposing to adverse CNS effects, as well as the intake of other drugs with anticholinergic effects may render individual patients particularly susceptible to antimuscarinic adverse CNS events.20 Non-selective molecules with some M2 receptor affinity may lead to an increase in heart rate.19 Some molecules acting on potassium channels within the heart may cause small increases in the QT interval.19 Tolterodine and solifenacin have led to small increases in the QT interval; on the other hand, darifenacin, fesoterodine, and trospium have not.19 These small recordable changes in heart function do not seem to cause clinically adverse outcomes.19 Most anticholinergics are metabolized by the CYP450 system in the liver with the exception of trospium, which undergoes minimal hepatic metabolism. Therefore, other medications or dietary components affecting the CYP450 mechanism may interact with anticholinergic drugs.19 Clinical Efficacy: Anticholinergics Compared With Placebo

A Cochrane Review of 5 of 6 anticholinergic drugs currently on the market concluded that anticholinergics lead to statistically significant improvements in OAB symptoms.20 The number needed to treat for clinical improvement or cure was 7. On average, patients on anticholinergics had 4 fewer leakage episodes and 5 fewer voids per week when compared with patients on placebo. As anticholinergics are not curative in most instances, clinical success depends on ongoing use; thus a recommendation was made for future trials to include long-term, patient-centred outcomes.

Oxybutynin (Ditropan, Ditropan XL) Oxybutynin oral preparations have established clinical efficacy when compared with placebo.20 Oxybutynin IR is also more cost-effective.21 However, it is associated with significant anticholinergic adverse events in up to 80% of patients22 and with discontinuation rates of up to 33%.23 Shortly after treatment initiation, oxybutynin may cause cognitive impairment, and long-term trials of cognitive function while on this anticholinergic are lacking.24–26 Two transdermal preparations, a patch (Oxytrol) and a gel (Gelnique 10%), have been developed to improve on the sideeffect profile of oral oxybutynin.27–29 Both preparations have superior clinical efficacy to placebo, with fewer side effects than oral oxybutynin.27–30 Application site reactions (pruritus and erythema) are more common with the transdermal preparations (14% for the patch and 5% for the gel).27–29 Recommendation

2. Oral oxybutynin, immediate and extended release, as well as transdermal oxybutynin, may be offered as treatment for overactive bladder syndrome, as they are associated with significant objective clinical improvement at 12 weeks. (I-A) Oxybutynin immediate release has superior costeffectiveness but more side effects than other anticholinergics. (I-A) Adverse events associated with transdermal oxybutynin are fewer than with oral oxybutynin. (I-A) Tolterodine (Detrol, Detrol LA,) Both IR and ER tolterodine are associated with improvements in health-related quality of life and objective OAB parameters in the results of several randomized placebo controlled trials with 12-week duration of followup.30–32 Greater effects are noted in patients with moderate NOVEMBER JOGC NOVEMBRE 2012 l 1095

SOGC CLINICAL PRACTICE GUIDELINE

to severe OAB symptoms at baseline.33 Dry mouth is a common side effect that occurs in one third of patients on tolterodine,34 but it does not increase the number of treatment discontinuations.35 Tolterodine does not seem to cause any cardiovascular or CNS adverse effects.35 Recommendation

3. Tolterodine, immediate and extended release, may be offered as treatment for overactive bladder syndrome, as it is associated with significant objective clinical improvement at 12 weeks. (I-A) Trospium (Trosec IR and XR) Trospium, both IR and XR, was associated with improved OAB symptoms in reports from several randomized placebo controlled trials with 12-week duration of followup.20,36,37 Adverse effects are more common than with placebo but do not affect discontinuation rates. The XR formulation significantly improves OAB symptoms and condition-specific quality of life.38,39 Trospium has low penetration into the CNS and thus fewer CNS side effects.36,37,40 In addition, it offers benefits for the bladder and does not affect cognitive function even when used concurrently with a cholinesterase inhibitor for the treatment of Alzheimer’s disease.41 Trospium undergoes minimal hepatic metabolism. Therefore patients who receive concurrent medications that inhibit the CYP450 hepatic metabolism are good candidates for therapy with trospium.40 Trospium is primarily excreted intact in the urine; however, medications competing for renal elimination, such as digoxin, have not shown significant interactions.42 Recommendation

4. Trospium, immediate and extended release, may be offered as treatment for overactive bladder syndrome as it is associated with significant clinical improvement at 12 weeks. (I-A) Trospium is an adequate anticholinergic choice for overactive bladder syndrome patients with pre-existing cognitive impairment (II-B) and for overactive bladder syndrome patients taking concurrent CYP450 inhibitors. (III-B) Solifenacin (VESIcare) Several double-blind placebo-controlled randomized controlled trials with 12-week follow-up the safety and clinical efficacy of solifenacin compared with placebo.43–46 Solifenacin also significantly improves the quality of life in patients with OAB symptoms up to 1 year.46–48 At 1 year, discontinuation rates are low.46 The incidence of dry mouth in patients on solifenacin is significantly lower than in patients on oxybutynin (35 vs. 83%, P < 0. 001).49 1096 l NOVEMBER JOGC NOVEMBRE 2012

The incidence of constipation is 7% to 8%.43 Solifenacin does not appear to affect cognitive function, as shown in a pilot randomized trial of healthy elderly volunteers.50 Recommendation

5. Solifenacin may be offered as treatment for overactive bladder syndrome, as it is associated with significant objective clinical improvement at 12 weeks. (I-A) Solifenacin may be an adequate anticholinergic choice for elderly overactive bladder syndrome patients or patients with pre-existing cognitive dysfunction. (I-B) Darifenacin (Enablex) The safety and clinical efficacy of darifenacin compared with placebo is shown by three randomized double-blind placebocontrolled multicentre phase III trials with 12-week duration of follow-up.51–53 The most common side effects are dry mouth and constipation, but discontinuations are rare (0.6% to 2.1% vs. 0.3% in the placebo group).54 Specifically, women over 65 have a significant improvement in condition-specific quality of life compared with those on placebo.55 Because of its M3 receptor selectivity, darifenacin does not affect heart rate.56 Moreover, darifenacin does not affect memory or other cognitive functions.57 Recommendation

6. Darifenacin may be offered as treatment for overactive bladder syndrome, as it is associated with significant objective clinical improvement at 12 weeks. (I-A) Darifenacin is an adequate anticholinergic choice for overactive bladder syndrome patients with pre-existing cardiac concerns or cognitive dysfunction. (I-B) Clinical Efficacy: Anticholinergics Compared With Non-Drug Therapies

A Cochrane Review compared the effects of various anticholinergic drugs with those of non-pharmacologic therapies, consisting mainly of bladder training, pelvic floor muscle exercises, and electrostimulation.58 Thirteen trials, with a total of 1770 participants, were analyzed. Follow-up was up to 24 weeks after initiation of treatment. Tolterodine and oxybutynin had similar cure rates and subjective improvement for OAB when compared with bladder training alone. Objective improvement was better in the anticholinergic group than in the bladder training group. When oxybutynin was compared with a more comprehensive behavioural intervention consisting of pelvic floor muscle exercises, bio, and bladder training, the overall effect subjectively and objectively favoured the behavioural intervention (RR 2.42; 95% CI 1.00 to 5.85).

Treatments for Overactive Bladder: Focus on Pharmacotherapy

Oxybutynin or trospium compared with functional electrostimulation yielded no statistically significant difference in cure rates or subjective or objective measures of improvement.58,59 Oxybutynin or tolterodine and bladder training compared with bladder training alone showed a subjective advantage of the combination treatment. Tolterodine and bladder training or pelvic floor muscle exercises compared with tolterodine alone did not show any statistically significant difference in subjective improvement.58 Since the most recent Cochrane update of this review, an additional randomized controlled trial was published comparing darifenacin with darifenacin and a behavioural modification program consisting of patient education given in a primary physician’s office (timed voiding, dietary modifications, Kegel exercises).60 There were no significant differences between treatment groups in efficacy or healthrelated quality of life variables.60 Recommendation

7. Overactive bladder syndrome patients should be offered a choice between bladder training, functional electric stimulation, and anticholinergic therapy, as there is no difference in cure rates. Combination therapy does not have a clear advantage over one therapy alone. (I-A) Choice of Anticholinergic Drug and Dose

A Cochrane Review analyzed 49 parallel trials comparing different anticholinergics and commonly used doses.61 Follow-up was mostly 2 weeks to 3 months, except for 2 trials with treatment periods of 1 year or more. Comparing oxybutynin with tolterodine, there were no differences in subjective or objective cure. There were fewer withdrawals among those taking tolterodine (7% vs. 12%, RR 0.57; 95% CI 0.43 to 0.75), mainly because there were fewer side effects.61 There were no statistically significant differences in outcomes when oxybutynin and trospium were compared. When several doses of tolterodine were studied, ranging from 0.5 mg twice daily to 4 mg twice daily, there were no statistically significant differences in objective improvement or withdrawals because of side effects. Subjective cure was more likely with the higher doses, but these higher doses were more commonly associated with high post-void residuals and dry mouth. Subjective cure was also more likely with higher doses of extended release oxybutynin (10 mg vs. 5 mg daily). Oxybutynin, 2.5 mg 3 times daily and 2.5 mg used as needed were equally effective in of objective measures of improvement. Trospium 40 mg daily and twice daily dosing had similar

effects in of objective measures of improvement. Extended release preparations of both oxybutynin and tolterodine, including the extended release oxybutynin patch, were associated with less dry mouth than immediate release preparations.61 Several other comparative randomized controlled trials comparing anticholinergics have been published since the most recent Cochrane Review update. One trial compared solifenacin 5 mg and 10 mg daily with tolterodine extended release 4 mg daily.62 Subjective cure was significantly more common in the solifenacin group (59% vs. 49%, P = 0.006). Objective measures of improvement and withdrawals because of side effects were not significantly different between the groups. Another trial comparing darifenacin 15 mg and 30 mg daily with oxybutynin 5 mg 3 times daily showed comparable efficacy and improved tolerability of darifenacin.63 The other trials compared fesoterodine 4 mg and 8 mg daily with tolterodine extended release 4 mg daily.64,65 Fesoterodine was superior to tolterodine on several objective measures of improvement such as urge incontinence episodes, severe urgency with incontinence, mean voided volume, and number of continent days per week. Diary dry rates were significantly better in the fesoterodine group than in the tolterodine group (64% vs. 57%; P = 0.015).64,65 Recommendation

8. The choice of anticholinergic therapy should be guided by individual patient comorbidities, as objective efficacy of anticholinergic drugs is similar. (I-A) Dose escalation does not improve objective parameters and causes more anticholinergic adverse effects. It is, however, associated with improved subjective outcomes. (I-A) To decrease side effects, switching to a lower dose or using an extended release formulation or a transdermal delivery mechanism should be considered. (I-A) Contraindications

Absolute contraindications to anticholinergic use include urinary retention, gastric retention, uncontrolled narrowangle glaucoma, and known hypersensitivity to the individual drugs or any of their ingredients. Relative contraindications that warrant cautious use include partial bladder outlet obstruction (borderline or high post-void residuals), controlled narrow-angle glaucoma, impaired cognitive function, reduced renal or hepatic function, concomitant excessive alcohol use (added sedating effects), decreased gastrointestinal motility, constipation, and myasthenia gravis. Elderly patients in particular should NOVEMBER JOGC NOVEMBRE 2012 l 1097

SOGC CLINICAL PRACTICE GUIDELINE

be monitored for drug interactions or polypharmacy of drugs with anticholinergic effect (e.g., antidepressants, antipsychotics, anxiolytics), as the overall anticholinergic load is associated with confusion, falls, and fractures.66 Anticholinergics are category C drugs in pregnancy, to be used only if the benefits clearly outweigh the risk. Adherence and Continuation Rates

Patient adherence to a prescribed anticholinergic treatment plan has been shown to be low. In a study of oxybutynin and tolterodine ER and IR prescriptions in 1117 adult patients, only 13.2% persisted with treatment for at least 1 year, with a median time to discontinuation of 31 days.67 Adherence was significantly better but still suboptimal for the extended release formulations.67 In another trial of patients on immediate release oxybutynin, at 2-year followup, 67% of respondents had stopped drug therapy, most within 2 months of initiation.68 Reasons for discontinuation were adverse effects (24%) and symptomatic improvement or cure (53%).68 White ethnicity, previous hospitalization length, starting with tolterodine or oxybutynin extendedrelease, and previous use of topical drugs or antipsychotics were associated with increased adherence to anticholinergics during a 6-month period.69 Previous depression or urinary tract infection diagnosis and polypharmacy significantly increased the odds of early discontinuation.69 Patient counselling about efficacy of treatment, realistic expectations, and length of treatment was recommended to improve long-term adherence to anticholinergic therapy.70 Recommendation

9. Education on treatment efficacy, realistic expectations, and length of treatment should be offered to patients upon initiation of anticholinergic therapy, as continuation rates for anticholinergic therapy are low. (III-B) PHARMACOTHERAPEUTIC INTERVENTIONS: ESTROGENS

The lower urinary tract (urethra and trigone) derives from the cloaca, which shares an embryological origin with the lower vaginal canal. Therefore, the trigonal squamous epithelium differs from the transitional epithelium and undergoes squamous metaplasia. The urethral mucosa is continuous with the squamous epithelium of the vestibule. Both areas are hormonally sensitive.71 A Cochrane Review examined the effect of estrogen supplementation on urinary incontinence in postmenopausal women.72 Heterogeneous evidence derived from trials investigating other conditions such as stress urinary incontinence and using greater than low dose vaginal estrogen of different types, showed that there were 1 to 2 fewer voids in 24 hours and nocturnal 1098 l NOVEMBER JOGC NOVEMBRE 2012

voids amongst women treated with local estrogen.72 A small trial showed modest benefit from vaginal estriol ovules in prevention of symptoms of urgency and frequency after tension-free vaginal tape placement.72 Oral estriol or a subcutaneous estradiol implant were not significantly better than placebo for OAB symptoms.73,74 Recommendation

10. Oral or transdermal estrogen supplementation should not be recommended for treatment of overactive bladder syndrome as its effects are comparable to placebo. (I-E) Vaginal estrogen can be suggested for subjective improvements in overactive bladder syndrome symptoms. (III-B) PHARMACOTHERAPEUTIC INTERVENTIONS: OTHER DRUG OPTIONS

There is a long list of medications with anticholinergic effects, few of which have been studied as treatment specifically for overactive bladder. Tricyclic antidepressants such as imipramine and amitryptyline have been used for overactive bladder. With a dual activity as an anticholinergic (to relax the detrusor) and an alpha agonist (to contract the urethral sphincter), they have adequate biologic plausibility for the treatment of urinary urge incontinence. Unfortunately, their anticholinergic activity is weaker than that of modern bladder anticholinergics.75 There is minimal evidence to the use of imipramine for urinary incontinence in the elderly.75 There are no randomized controlled trials to compare tricyclics with modern anticholinergics used to treat overactive bladder.75 REFRACTORY OAB

Options for OAB symptoms resistant to anticholinergic therapy are limited and costly. These options include but are not limited to local bladder therapies such as botulinum toxin type A detrusor injections, central neurostimulation, and peripheral neurostimulation (e.g., tibial nerve). Botulinum toxin for OAB (100 to 300 units injected into the detrusor muscle) has been shown, in several randomized controlled trials, to reduce number of voids and urgency and incontinence episodes per day and to improve maximum cystometric capacity and condition-specific quality of life.76 Generally, around 80% of patients treated with botulinum toxin experienced improvement, with some patients requiring reinjection for recurrence of OAB symptoms.76 Overall patient satisfaction with botulinum toxin was high.76 The most common complication related to intravesical botulinum toxin was transient urinary

Treatments for Overactive Bladder: Focus on Pharmacotherapy

retention. Up to 43% of patients needed clean intermittent self-catheterization, and the incidence of retention was reported to be dose-dependent.76

2. Lawrence JM, Lukacz ES, Nager CW, Hsu J-W, Luber KM. Prevalence and co-occurrence of pelvic floor disorders in community-dwelling women. Obstet Gynecol 2008;111(3):678–85.

There are also data from randomized controlled trials to the use of sacral nerve stimulation. Good clinical response, with improvement on several objective measures of OAB severity, was reported in 64% 88% of patients, and clinical success seems to persist in the long term. Subjective outcomes are also favourable.76 However, lead migration, pain, and infection result in a 33% reoperation rate to treat these complications.77

4. Milsom I, Abrams P, Cardozo L, Roberts RG, Thuroff J, Wein AJ. How widespread are the symptoms of overactive bladder and how are they managed? A population-based prevalence study. Br J Urol Int 2001;87(9):760–6.

Another form of neurostimulation, tibial nerve stimulation, is gaining acceptance. Two double-blind randomized sham-controlled trials showed significant objective and subjective improvements in OAB when compared with placebo.78,79 Treatment benefit was sustained at 12 months.80 A randomized controlled trial of tibial nerve stimulation versus tolterodine showed similar objective improvement and superior subjective improvement or cure at 12 weeks.81 Recommendation

11. Intravesical botulinum toxin injection and sacral nerve and posterior tibial nerve stimulation are clinically effective options for patients with overactive bladder syndrome unresponsive to conservative options, anticholinergics, or vaginal estrogen. (I-A) CONCLUSION

Overactive bladder syndrome is a common bothersome condition. Options for therapy include behavioural, pharmacologic, and surgical interventions. Pharmacotherapy for OAB includes anticholinergics and local vaginal estrogen. Anticholinergics have been shown to offer some symptomatic improvement over placebo, with a strong placebo therapeutic effect noted. Anticholinergics are similar to behavioural therapy and electrical stimulation in clinical efficacy. They have significant side effects that need to be carefully considered along with individual patient comorbidities. Newer formulations, particularly those istered transdermally, have been shown to have a better side-effect profile. Long-term effects of anticholinergics and patientcentred outcomes should be the focus of future studies. REFERENCES 1. Haylen BT, de Ridder D, Freeman RM, Swift SE, Berghmans B, Lee J, et al. An International Urogynecological Association (IUGA)/ International Continence Society (ICS) t report on the terminology for female pelvic floor dysfunction. Int Urogynecol J 2010;21:5–26.

3. Irwin DE, Milsom I, Hunskaar S, Reilly K, Kopp Z, Herschorn S, et al. Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study. Eur Urol 2006;50(6):1306–15.

5. Stewart WF, Van Rooyen JB, Cundiff GW, Abrams P, Herzog AR, Corey R, et al. Prevalence and burden of overactive bladder in the United States. World J Urol 2003; 20(6):327–36. 6. Bartoli S, Aguzzi G, Tarricone R. Impact on quality of life of urinary incontinence and overactive bladder: a systematic literature review. Urology 2010;75(3):491–500. 7. Kelleher CJ, Cardozo LD, Khullar V, Salvatore S. A new questionnaire to assess the quality of life of urinary incontinent women. Br J Obstet Gynaecol 1997;104(12):1374–9. 8. Zorn BH, Montgomery H, Pieper K, Gray M, Steers WD. Urinary incontinence and depression. J Urol 1999;162:82–4. 9. Brown JS, Vittinghoff E, Wyman JF, Stone KL, Nevitt MC, Ensrud KE, et al. Urinary incontinence: does it increase risk for falls and fractures? Study of Osteoporotic Fractures Research Group: Collaboration. J Am Ger Soc 2000;48(7):721–5. 10. Thom DH, Haan MN, Van Den Eeden SK. Medically recognized urinary incontinence and risks of hospitalization, nursing home ission and mortality. Age Ageing 1997;26(5)367–74. 11. Robert M, Ross S; SOGC Urogynaecology Committee. Conservative management of urinary incontinence. J Obstet Gynaecol Can 2006;28(12):1113–8. 12. Andersson KE, Chapple C, Wein A. The basis for drug treatment of the overactive bladder. World J Urol 2001;19:294–8. 13. Braverman AS, Ruggieri MR, Pontari MA. The M2 muscarinic receptor subtype mediates cholinergic bladder contractions in patients with neurogenic bladder dysfunction. J Urol 2001;165(Suppl):36. 14. Andersson KE. Antimuscarinics for treatment of overactive bladder. Lancet Neurol 2004;3:46–53. 15. Jensen D. Uninhibited neurogenic bladder treated with prazosin. Scand J Urol Nephrol 1981;15:229–33. 16. Tyagi S, Tyagi P, Van-le S, Yoshimura N, Chancellor MB, de Miguel F. Qualitative and quantitative expression profile of muscarinic receptors in human urothelium and detrusor. J Urol 2006;176(4 Pt 1):1673–8. 17. Giglio D, Tobin G. Muscarinic receptor subtypes in the lower urinary tract. Pharmacology 2009;83(5):259–69. 18. Robinson D, Cardozo L. New drug treatments for urinary incontinence. Maturitas 2010;65:340–7. 19. Ellsworth P, Kirshenbaum E. Update on the pharmacologic management of overactive bladder: the present and the future. Urol Nursing 2010;30(1):29–53. 20. Nabi G, Cody JD, Ellis G, Hay-Smith J, Herbison GP. Anticholinergic drugs versus placebo for overactive bladder syndrome in adults. Cochrane Database Syst Rev 2009;(1):CD003781. 21. Cardozo L, Thorpe A, Warner J, Sidhu M. The cost-effectiveness of solifenacin vs fesoterodine, oxybutynin immediate-release, propiverine, tolterodine extended-release and tolterodine immediate-release in the treatment of patients with overactive bladder in the UK National Health Service. BJU Int 2010;106(4):506–14.

NOVEMBER JOGC NOVEMBRE 2012 l 1099

SOGC CLINICAL PRACTICE GUIDELINE

22. Cardozo LD, Cooper D, Versi E. Oxybutynin chloride in the management of idiopathic detrusor instability. Neurourol Urodyn 1987;6:256–7. 23. Tapp AJ, Cardozo LD, Versi E, Cooper D. The treatment of detrusor instability in post-menopausal women with oxybutynin chloride: a doubleblind placebo controlled study. Br J Obstet Gynecol 1990;97(6):521–6. 24. Kay G, Crook T, Rekeda L, Lima R. Differential effects of the antimuscarinic agents darifenacin and extended-release oxybutynin on recent memory in older subjects. Eur Urol Suppl 2006;5(2):117. 25. Katz IR, Sands LP, Bilker W, DiFilippo S, Boyce A, D’Angelo K. Identification of medications that cause cognitive impairment in older people: the case of oxybutynin chloride. J Am Ger Soc 1998;46(1):8–13.

39. Dmochowski RR, Rosenberg MT, Zinner NR, Staskin DR, Sand PK. Extended-release trospium chloride improves quality of life in overactive bladder. Value Health 2010;13(2)251–7. 40. Biastre K, Burnakis T. Trospium chloride treatment of overactive bladder. Ann Pharmacother 2009;43(2):283–95. 41. Isik AT, Celik T, Bozoglu E, Doruk H. Trospium and cognition in patients with late onset Alzheimer disease. J Nutr Health Aging 2009;13(8)672–6. 42. Sandage B, Sabounjian L, Shipley J, Profy A, Lasseter K, Fox L, et al. Predictive power of an in vitro system to assess drug interactions of an antimuscarinic medication: a comparison of in vitro and in vivo drugdrug interaction studies of trospium chloride with digoxin. J Clin Pharm 2006;46(7)776–84.

26. Wesnes KA, Edgar C, Tretter RM, Bolodeoku J. Exploratory pilot study assessing the risk of cognitive impairment or sedation in the elderly following singe doses of solifenacin 10 mg. Expert Opin Drug Saf 2009;8(6)615–26.

43. Chapple CR, Rechberger T, Al-Shukri S, Meffan P, Everaert K, Huang M, et al. Randomized, double-blind placebo- and tolterodine-controlled trial of the once-daily antimuscarinic agent solifenacin in patients with symptomatic overactive bladder. BJU Int 2004;93(3):303–10.

27. Dmochowski RR, Sand PK, Zinner NR, Gittelman MC, Davila GW, Sanders SW; Transdermal Oxybutynin Study Group. Comparative efficacy and safety of transdermal oxybutynin and oral tolterodine versus placebo in previously treated patients with urge and mixed urinary incontinence. Urology 2003;62:237–42.

44. Cardozo L, Lisec M, Millard R, van Vierssen Trip O, Kuzmin I, Drogendijk TE, et al. Randomized, double-blind placebo controlled trial of the once daily muscarinic agent solifenacin succinate in patients with overactive bladder. J Urol 2004;172: 1919–24.

28. Staskin DR, Robinson D. Oxybutynin chloride topical gel: a new formulation of an established antimuscarinic therapy for overactive bladder. Expert Opin Pharmacother 2009;10(18):3103–11. 29. Staskin DR, Dmochowski RR, Sand PK, Macdiarmid SA, Caramelli KE, Thomas H, et al. Efficacy and safety of oxybutynin chloride topical gel for overactive bladder: a randomized, double-blind, placebo-controlled, multicenter study. J Urol 2009;181:1764–72. 30. Sand P, Zinner N, Newman D, Lucente V, Dmochowski R, Kelleher C. Oxybutynin transdermal system improves the quality of life in adults with overactive bladder: a multicentre, community-based, randomized study. BJU Int 2007;99(4):836–44. 31. Kelleher CJ, Reese PR, Pleil AM, Okano GJ. Health-related quality of life of patients receiving extended-release tolterodine for overactive bladder. Am J Managed Care 2002;8(19 Suppl):S608–15. 32. Kelleher CJ, Kreder KJ, Pleil AM, Burgess SM, Reese PR. Long-term health-related quality of life of patients receiving extended-release tolterodine for overactive bladder. Am J Managed Care 2002;8(19 Suppl):S616–30. 33. Sussman D, Garely A. Treatment of overactive bladder with once-daily extended-release tolterodine or oxybutynin: the antimuscarinic clinical effectiveness trial (ACET). Curr Med Res Opin 2002;18:177–84. 34. Appell RA, Sand P, Dmochowski R, Anderson R, Zinner N, Lama D, et al.; Overactive Bladder: Judging Effective Control and Treatment Study Group. Prospective randomized controlled trial of extended-release oxybutynin chloride and tolterodine tartrate in the treatment of overactive bladder: results of the OBJECT study. Mayo Clin Proc 2001;76:358–63. 35. Van Kerrebroeck P, Kreder K, Jonas U, Zinner N, Wein A. Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urol 2001;57(3)414–21. 36. Zinner N, Gittelman M, Harris R, Susset J, Kanelos A, Auerbach S; Trospium Study Group. Trospium chloride improves overactive bladder symptoms: a multi- center phase III trial. J Urol 2004;171:2311–5.

45. Chapple CR, Arano P, Bosch JL, De Ridder D, Kramer AE, Ridder AM. Solifenacin appears effective and well tolerated in patients with symptomatic idiopathic detrusor overactivity in a placebo- and tolterodine-controlled phase 2 dose-finding study. BJU Int 2004;93(1):71–7. 46. Haab F, Cardozo L, Chapple C, Ridder AM; Solifenacin Study Group. Long-term open-label solifenacin treatment associated with persistence with therapy in patients with overactive bladder syndrome. Eur Urol 2005;47:376–84. 47. Kelleher CJ, Cardozo L, Chapple CR, Haab F, Ridder AM. Improved quality of life in patients with overactive bladder symptoms treated with solifenacin. BJU Int 2005; 95:81–5. 48. Toglia MR, Serels SR, Laramée C, Karram MM, Nandy IM, Andoh M, et al. Solifenacin for overactive bladder: patient-reported outcomes from a large placebo-controlled trial. Postgrad Med 2009;121(5):151–8. 49. Herschorn S, Stothers L, Carlson K, Egerdie B, Gajewski JB, Pommerville P, et al. Tolerability of 5 mg solifenacin once daily versus 5 mg oxybutynin immediate release 3 times daily: results of the VECTOR trial. J Urol 2010;183(5):1892–8. 50. Wesnes KA, Edgar C, Tretter RN, Bolodeoku J. Exploratory pilot study assessing the risk of cognitive impairment or sedation in the elderly following single doses of solifenacin 10 mg. Expert Opin Drug Saf 2009;8(6):615–26. 51. Haab F, Stewart L, Dwyer P. Darifenacin, an M3 selective receptor antagonist, is an effective and well-tolerated once-daily treatment for overactive bladder. Eur Urol 2004; 45(4):420–9. 52. Steers W, Corcos J, Foote J Karlidis G. An investigation of dose titration with darifenacin, an M3-selective receptor antagonist. BJU Int 2005;95:580–6. 53. Hill S, Khullar V, Wyndaele JJ, Lheritier K; Darifenacin Study Group. Dose response with darifenacin, a novel once-daily M3 selective receptor antagonist for the treatment of overactive bladder: results of a fixed dose study. Int Urogynecol J Pelvic Floor Dysfunct 2006;17(3):239–47.

37. Rudy D, Cline K, Harris R, Goldberg K, Dmochowski R. Multicenter phase III trial studying trospium chloride in patients with overactive bladder. Urology 2006; 67:275–80.

54. Chapple CR, Steers W, Norton P, Millard R, Kralidis G, Glavind K, et al. A pooled analysis of three phase III studies to investigate the efficacy, tolerability and safety of darifenacin, a muscarinic M3 selective receptor antagonist, in the treatment of overactive bladder. BJU Int 2005;95(7):993–1001.

38. Sand PK, Dmochowski RR, Zinner NR, Staskin DR, Appell RA. Trospium chloride extended release is effective and well tolerated in women with overactive bladder syndrome. Int Urogynecol J 2009;20(12):1431–8.

55. Chapple C, DuBeau C, Ebinger U, Rekeda L, Viegas A. Darifenacin treatment of patients > or = 65 years with overactive bladder: results of a randomized, controlled, 12-week trial. Curr Med Res Opin 2007;23(10):2347–58.

1100 l NOVEMBER JOGC NOVEMBRE 2012

Treatments for Overactive Bladder: Focus on Pharmacotherapy

56. Olshansky B, Ebinger U, Brum J, Egermark M, Viegas A, Rekeda L. Differential pharmacological effects of antimuscarinic drugs on heart rate: a randomized, placebo-controlled, double-blind, crossover study with tolterodine and darifenacin in healthy participants > or = 50 years. J Cardiovasc Pharmacol Ther 2008;13(4):241–51. 57. Kay GG. Ebinger U. Preserving cognitive function for patients with overactive bladder: evidence for a differential effect with darifenacin. Int J Clin Pract 2008;62(11):1792–800. 58. Alhasso AA, McKinlay J, Patrick K, Stewart L. Anticholinergic drugs versus non-drug active therapies for overactive bladder syndrome in adults. Cochrane Database Syst Rev 2006;(2):CD003193. 59. Ozdedeli S, Karapolat H, Akkoc Y. Comparison of intravaginal electrical stimulation and trospium hydrochloride in women with overactive bladder syndrome: a randomized controlled study. Clin Rehabil 2010;24(4):342–51. 60. Chancellor MB, Kianifard F, Beamer E, Mongay L, Ebinger U, Hicks G, et al. A comparison of the efficacy of darifenacin alone vs. darifenacin plus a behavioural modification programme upon the symptoms of overactive bladder. Int J Clin Pract 2008;62(4):606–13.

69. Yu YF, Nichol MB, Yu AP, Ahn J. Persistence and adherence of medications for chronic overactive bladder/urinary incontinence in the Californian Medicaid program. Value Health 2005;8:495–505. 70. Basra RK, Wagg A, Chapple C, Cardozo L, Castro-Diaz D, Pons ME, et al. A review of adherence to drug therapy in patients with overactive bladder. BJU Int 2008; 102(7):774–9. 71. DeLancey JO. Anatomy. In: Cardozo L, Staskin D, eds. Textbook of female urology and urogynecology. 3rd ed. London: Informa Healthcare; 2010. 72. Cody JD, Richardson K, Moehrer B, Hextall A, Glazener CMA. Oestrogen therapy for urinary incontinence in post-menopausal women Cochrane Database Syst Rev 2010;(1):CD001405. 73. Cardozo L, Rekers H, Tapp A, Barnick C, Shepherd A, Schussler B, et al. Oestriol in the treatment of postmenopausal urgency: a multicentre study. Maturitas 1993;18:47–53. 74. Rufford J, Hextall A, Cardozo L, Khullar V. A double-blind placebocontrolled trial on the effects of 25 mg estradiol implants on the urge syndrome in postmenopausal women. Int Urogynecol J 2003;14(2):78–83.

61. Hay-Smith J, Ellis G, Herbison GP. Which anticholinergic drug for overactive bladder symptoms in adults. Cochrane Database Syst Rev 2009;(1):CD005429.

75. Roxburgh C, Cook J, Dublin N. Anticholinergic drugs versus other medications for overactive bladder syndrome in adults. Cochrane Database Syst Rev 2007;(3):CD003190.

62. Chapple CR, Martinez-Garcia, Selvaggi L, Toozs-Hobson P, Warnack W, Drogendijk T, et al. A comparison of the efficacy and tolerability of solifenacin succinate and extended release tolterodine at treating overactive bladder syndrome; results of the STAR trial. Eur Urol 2005;48(3):464–70.

76. Leong RK, De Wachter SG, van Kerrebroeck PE. Current information on sacral neuromodulation and botulinum toxin treatment for refractory idiopathic overactive bladder syndrome: a review. Urol Int 2010;84(3):245–53.

63. Zinner N, Tuttle J, Marks L. Efficacy and tolerability of darifenacin, a muscarinic M3 selective receptor antagonist (M3 SRA), compared with oxybutynin in the treatment of patients with overactive bladder. World J Urol 2005;23:248–52. 64. Chapple CR, Van Kerrebroeck PE, Junemann KP, Wang JT, Brodsky M. Comparison of fesoterodine and tolterodine in patients with overactive bladder. BJU Int 2008;102:1128–32. 65. Herschorn S, Swift S, Guan Z, Carlsson M, Morrow JD, Brodsky M, et al. Comparison of fesoterodine and tolterodine extended release for the treatment of overactive bladder: a head-to-head placebo-controlled trial. BJU Int 2010;105(1):58–66.

77. Brazzelli M, Murray A, Fraser C. Efficacy and safety of sacral nerve stimulation for urinary urge incontinence: a systematic review. J Urol 2006;175(3 Pt 1):835–41. 78. Peters KM, Carrico DJ, Perez-Marrero RA, Khan AU, Woolridge LS, Davis GL, et al. Randomized trial of percutaneous tibial nerve stimulation versus sham efficacy in the treatment of overactive bladder syndrome: results from the SUmiT trial. J Urol 2010;183:1438–43. 79. Finazzi-Agro E, Petta F, Sciobica F, Pasqualetti P, Musco S, Bove P. Percutaneous tibial nerve stimulation effects on detrusor overactivity incontinence are not due to a placebo effect: a randomized, double-blind, placebo controlled trial. J Urol 2010;184(5): 2001–6.

66. Wilson NM, Hilmer SN, March LM, Cameron ID, Lord SR, Seibel MJ, et al. Associations between drug burden index and falls in older people in residential aged care. J Am Geriatr Soc 2011;59(5):875–80.

80. MacDiarmid SA, Peters KM, Shobeiri SA, Wooldridge LS, Rovner ES, Leong FC, et al. Long-term durability of percutaneous tibial nerve stimulation for the treatment of overactive bladder. J Urol 2010;183(1) 234–40.

67. D’Souza AO, Smith MJ, Miller LA, Doyle J, Ariely R. Persistence, adherence, and switch rates among extended-release and immediaterelease overactive bladder medications in a regional managed care plan. J Manage Care Pharm 2008;14(3):291–301.

81. Peters KM, Macdiarmid SA, Wooldridge LS, Leong FC, Shobeiri SA, Rovner ES, et al. Randomized trial of percutaneous tibial nerve stimulation versus extended-release tolterodine: results from the overactive bladder innovative therapy trial. J Urol 2009;182(3):1055–61.

68. Salvatore S, Khullar V, Cardozo L, Milani R, Athanasiou S, Kelleher C. Long-term prospective randomized study comparing two different regimens of oxybutynin as a treatment for detrusor overactivity. Eur J Obstet Gynecol Reprod Biol 2005;119:237–41.

82. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

NOVEMBER JOGC NOVEMBRE 2012 l 1101

SOGC clinical practice guideline No. 274, March 2012

Management of Varicella Infection (Chickenpox) in Pregnancy This Clinical Practice Guideline has been prepared by the Maternal Fetal Medicine Committee, reviewed by the Infectious Diseases Committee and the Family Physician Advisory Committee, and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Alon Shrim, MD, Montreal QC Gideon Koren, MD, Toronto ON Mark H. Yudin, MD, Toronto ON Dan Farine, MD, Toronto ON MATERNAL FETAL MEDICINE COMMITTEE Robert Gagnon, MD (Co-Chair), Verdun QC Lynda Hudon, MD (Co-Chair), Montreal QC Melanie Basso, RN, Vancouver BC Hayley Bos, MD, London ON Joan Crane, MD, St. John’s NL Gregory Davies, MD, Kingston ON Marie- Delisle, MD, Vancouver BC Savas Menticoglou, MD, Winnipeg MB William Mundle, MD, Windsor ON Annie Ouellet, MD, Sherbrooke QC Tracy Pressey, MD, Vancouver BC Christy Pylypjuk, MD, Saskatoon SK Anne Roggensack, MD, Calgary AB Frank Sanderson, MD, Saint John NB Vyta Senikas, MD, Ottawa ON Disclosure statements have been received from all of the committee.

J Obstet Gynaecol Can 2012;34(3):287–292

Key Words: Chickenpox, varicella, diagnosis, pregnancy

Abstract Objective: To review the existing data regarding varicella zoster virus infection (chickenpox) in pregnancy, interventions to reduce maternal complications and fetal infection, and antepartum and peripartum management. Methods: The maternal and fetal outcomes in varicella zoster infection were reviewed, as well as the benefit of the different treatment modalities in altering maternal and fetal sequelae. Evidence: Medline was searched for articles and clinical guidelines published in English between January 1970 and November 2010. Values: The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care. Recommendations for practice were ranked according to the method described in that report (Table). Recommendations 1. Varicella immunization is recommended for all non-immune women as part of pre-pregnancy and postpartum care. (II-3B) 2. Varicella vaccination should not be istered in pregnancy. However, termination of pregnancy should not be advised because of inadvertent vaccination during pregnancy. (II-3D) 3. The antenatal varicella immunity status of all pregnant women should be documented by history of previous infection, varicella vaccination, or varicella zoster immunoglobulin G serology. (III-C) 4. All non-immune pregnant women should be informed of the risk of varicella infection to themselves and their fetuses. They should be instructed to seek medical help following any with a person who may have been contagious. (II-3B) 5. In the case of a possible exposure to varicella in a pregnant woman with unknown immune status, serum testing should be performed. If the serum results are negative or unavailable within 96 hours from exposure, varicella zoster immunoglobulin should be istered. (III-C) 6. Women who develop varicella infection in pregnancy need to be made aware of the potential adverse maternal and fetal sequelae, the risk of transmission to the fetus, and the options available for prenatal diagnosis. (II-3C) 7. Detailed ultrasound and appropriate follow-up is recommended for all women who develop varicella in pregnancy to screen for fetal consequences of infection. (III-B)

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

MARCH JOGC MARS 2012 l 287

SOGC clinical practice guideline

8. Women with significant (e.g., pneumonitis) varicella infection in pregnancy should be treated with oral antiviral agents (e.g., acyclovir 800 mg 5 times daily). In cases of progression to varicella pneumonitis, maternal ission to hospital should be seriously considered. Intravenous acyclovir can be considered for severe complications in pregnancy (oral forms have poor bioavailability). The dose is usually 10 to 15 mg/kg of BW or 500 mg/m2 IV every 8 h for 5 to 10 days for varicella pneumonitis, and it should be started within 24 to 72 h of the onset of rash. (III-C) 9. Neonatal health care providers should be informed of peripartum varicella exposure in order to optimize early neonatal care with varicella zoster immunoglobulin and immunization. (III-C) Varicella zoster immunoglobulin should be istered to neonates whenever the onset of maternal disease is between 5 days before and 2 days after delivery. (III-C)

INTRODUCTION

V

aricella zoster virus is a highly contagious DNA virus of the herpes family. It is transmitted by respiratory droplets and by direct personal with vesicular fluid. The primary infection is characterized by fever, malaise, and a pruritic rash that develops into crops of maculopapules, which become vesicular and crust over before healing. The incubation period lasts 10 to 21 days, and the disease is infectious 48 hours before the rash appears and continues to be infectious until the vesicles crust over.1 Chickenpox (or primary VZV infection) is a common childhood disease. In this population it usually causes mild infection, and mortality rates in the United States are as low as 0.4 per 1 million population.2 It is estimated that > 90% of the antenatal population are seropositive for VZV IgG antibody3 and therefore almost invariably immune to infection. Because of this high frequency of immunity, with chickenpox among pregnant women rarely results in primary maternal VZV infection, which is estimated to complicate up to 2 to 3 of every 1000 pregnancies.4 Therefore in Canada, with about 350 000 pregnancies per year,5 700 to 1050 cases of chickenpox in pregnant women are expected to occur annually. Following the primary infection, the virus may remain dormant in sensory nerve root ganglia but can be reactivated to cause a vesicular erythematous skin rash in a dermatomal distribution known as herpes zoster or shingles. As shingles in pregnancy is not associated with viremia and does not appear to cause fetal sequelae, it is not discussed in these guidelines.

ABBREVIATIONS IgG

immunoglobulin G

VZIG

varicella zoster immunoglobulin

VZV

varicella zoster virus

288 l MARCH JOGC MARS 2012

POSSIBLE SEQUELAE OF VARICELLA INFECTION IN PREGNANCY: MATERNAL

The mortality rate for chickenpox increases with age. Thus in early adulthood it is associated with mortality rate that is 15 times higher than the childhood mortality rate.6 According to the Centers for Disease Control and Prevention, the case fatality rate increases from 2.7 per 100 000 persons aged 15 to 19 years, to 25.2 per 100 000 persons aged 30 to 39.7 Mortality rates are higher in pregnant women than in nonpregnant adults, and death usually results from respiratory disease. It is estimated that 5% to 10% of pregnant women with varicella infection develop pneumonitis.8 Risk factors for the development of varicella pneumonitis in pregnancy include cigarette smoking and > 100 skin lesions.9 Most of the complications of adult chickenpox, such as pneumonitis occur on day 4 or later.10 In one prospective study,11 12 out 21 pregnant patients who were diagnosed with varicella pneumonitis and treated with acyclovir in the second or third trimester of pregnancy required intubation and mechanical ventilation. The strongest correlate with maternal death was onset of disease in the third trimester, with no deaths among the second-trimester subjects. POSSIBLE SEQUELAE OF VARICELLA INFECTION IN PREGNANCY: FETAL

Fetal effects of varicella can manifest as either congenital varicella syndrome (embryopathy) or neonatal varicella (no embryopathy, but chickenpox infection within the first 10 days of life). Since the first described cases in 1947, the overall number of neonates that have been reported to have congenital varicella syndrome is as low as 41 per year in the United States, 4 per year in Canada, and 7 per year in the United Kingdom and .12,13 Maternal varicella during the first half of pregnancy may cause congenital malformations or deformations by transplacental infection. Some of these manifestations include chorioretinitis, cerebral cortical atrophy, hydronephrosis, and cutaneous and bony leg defects, often presenting as a partial limb reduction.14 Rates of infection are approximately 0.4% before 13 weeks and 2% between 13 and 20 weeks.4,15 In a systematic review by the Motherisk program (Canadian data), with all available cohort studies, the risk was 0.7% in the first trimester, 2% in the second, and 0% in the third trimester.16 In most of the cohorts, there was no clinical evidence of congenital varicella embryopathy after 20 weeks’ gestation.17 Yet, Tan and Koren reviewed the literature and identified 9 case reports of fetal varicella syndrome occurring in weeks 21 to 28 of gestation.12 In 8 out of these 9 cases there were serious adverse effects in the central nervous system, an incidence as high as the rates of central nervous system involvement in earlier trimesters.13

Management of Varicella Infection (Chickenpox) in Pregnancy

Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well–designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.36 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care.36

Findings that can be seen on ultrasound include musculoskeletal abnormalities seen as asymmetric limb shortening or malformations, chest wall malformations, intestinal and hepatic echogenic foci, intrauterine growth restriction, polyhydramnios, fetal hydrops, or fetal demise. Cerebral anomalies documented with ultrasound include ventriculomegaly, hydrocephalus, microcephaly with polymicrogyria, and porencephaly. Congenital cataract and microphthalmos are the most common ocular lesions but are not readily visible on ultrasound.18 In most of the relevant studies, ultrasound findings suggestive of congenital varicella syndrome were detected in the majority of the affected fetuses.19,20 PERIPARTUM EXPOSURE

Exposure of the baby to the virus just before or during delivery poses a serious threat to the neonate, which may develop a fulminant neonatal infection (neonatal varicella). Rarely, these neonates can develop disseminated visceral and central nervous system disease, which is commonly fatal. Neonatal infection occurs primarily when symptoms of maternal infection occur less than 5 days before delivery to 2 days after.21 This period correlates with the development of maternal IgG and is therefore too short to provide transplacental ive immunization to the fetus and neonate. When varicella zoster immune globulin is istered to the mother, 30% to 40% of newborns still develop infection; however, the number of complications is reduced.22

PREVENTION OF MATERNAL COMPLICATIONS

The efficacy of antiviral therapy in treating varicella pneumonia in adults has not been uniformly established through randomized clinical trials, and its efficacy has been debated.23 However, in one study, oral acyclovir was shown to be more effective than placebo in reducing the duration of fever and symptoms of varicella infection in immunocompromised children and immunocompetent adults if commenced within 24 hours of development of the rash.24,25 As a result it is generally recommended that children at high risk and adults with a substantive varicella infection (> 100 lesions) and/or respiratory co-factors should be treated with oral antivirals. Pregnant women with varicella pneumonitis should definitely be treated with oral antivirals and, if level of illness warrants, with IV antivirals. PREVENTION OF INTRAUTERINE INFECTION Definition of Significant Exposure

Direct exposure is defined as direct that lasts an hour or longer with an infectious person while indoors. Substantial exposure for hospital s consists of sharing the same hospital room with an infectious patient or prolonged, direct, faceto-face with an infectious person (e.g., health care workers). Brief s with an infectious person (e.g., with X-ray technicians or housekeeping personnel) are less likely than more prolonged s to result in VZV transmission. MARCH JOGC MARS 2012 l 289

SOGC clinical practice guideline

Persons with continuous exposure to household who have varicella are at greatest risk for infection.7 Vaccine

An attenuated live-virus vaccine (Varivax) was approved for use in 1995.26 Two doses, given 4 to 8 weeks apart, are recommended for adolescents ≥ 13 years of age and for adults with no history of varicella. This results in 97% seroconversion.27 The vaccine, however, is not recommended for pregnant women or for those within a month of pregnancy. Nevertheless, a pregnancy registry listing 362 vaccine-exposed pregnancies has reported no case of congenital varicella syndrome or other congenital malformation.28 Therefore, termination of pregnancy should not be recommended because of inadvertent vaccination during pregnancy. Varicella Zoster Immunoglobulin

As prevention is the most effective strategy for the reduction of maternal complications associated with varicella infections, immunoglobulin prophylaxis is an important objective for susceptible, exposed pregnant women.23 VZIG has been shown to lower varicella infection rates if istered within 72 to 96 hours after exposure.4 The effectiveness of VZIG when given beyond the 96 hours after initial exposure has not been evaluated. Protection is estimated to extend through 3 weeks, which corresponds with the half-life of the immunoglobulin. The principal indication for the use of VZIG in pregnant women is reduction of the maternal risks of varicella infection-related complications associated with adult disease.4 If the mother does not acquire varicella infection, this eliminates risk for the neonate, but this has not been studied as an end point because of the low frequency of cases. The dose is 125 units per 10 kg given intramuscularly, with a maximum dose of 625 units. VZIG is recommended7 for all susceptible pregnant women.29 To determine if an exposed pregnant woman is susceptible, a history of varicella infection should be taken, and, if this is positive, the woman can be assumed to be immune. If the history is negative and no varicella antibody testing was done in early pregnancy, antibody testing with enzymelinked immunosorbent assay or fluorescent antibody to membrane antigen should, if possible, precede use of VZIG. However, in settings where pregnant women might be tested too late and/or results may not be available quickly, using VZIG before antibody testing results are available might be practical. 290 l MARCH JOGC MARS 2012

The value of VZIG in averting fetal varicella is primarily in its ability to prevent maternal infection, but it may have some effect in decreasing the risk of fetal infection even in those women who go on to develop varicella. In a study of 1373 women who had varicella during pregnancy, 9 cases of congenital varicella syndrome were identified, all occurring after maternal varicella during the first 20 weeks of gestation. However, no cases of congenital varicella syndrome were reported in any of the 97 women in whom varicella occurred after post-exposure prophylaxis with anti-VZIG.4,30,31 The most frequent adverse reaction following VZIG istration is local discomfort at the injection site, with pain, redness, and swelling occurring in approximately 1% of people.32 Less frequent adverse events include gastrointestinal symptoms, malaise, headache, rash, and respiratory symptoms, which occur in approximately 0.2% of recipients. Severe events, such as angioneurotic edema and anaphylactic shock, are rare (occurring in < 0.1% of recipients). Obstetrical care providers need to be aware of the availability of testing and therapy in their local environment. As both testing and therapy are time sensitive, it is important to know the turnover time for the test in local laboratories, and how to arrange VZIG istration. As VZIG is a blood product, patient consent is required. TREATMENT Acyclovir

Acyclovir is a synthetic nucleoside analogue that inhibits replication of human herpes viruses, including VZV. Acyclovir crosses the placenta readily and can be found in fetal tissues, cord blood as well as in the amniotic fluid. It may inhibit viral replication during maternal viremia, limiting transplacental age of the virus.33,34 Safety Data published since acyclovir became available do not indicate increased adverse effects related to its use in pregnancy.35 Efficacy When compared with placebo, oral acyclovir reduces the duration of fever and symptoms of varicella infection in immunocompromised children and immunocompetent adults if commenced within 24 hours of development of the rash.24,25 In instances of serious, viral-mediated complications (e.g., pneumonitis), the American Academy of Pediatrics states that intravenous acyclovir should be considered.7 It is not given as prophylaxis to exposed women during pregnancy.

Management of Varicella Infection (Chickenpox) in Pregnancy

Recommendations

1. Varicella immunization is recommended for all non-immune women as part of pre-pregnancy and postpartum care. (II-3B) 2. Varicella vaccination should not be istered in pregnancy. However, termination of pregnancy should not be advised because of inadvertent vaccination during pregnancy. (II-3D) 3. The antenatal varicella immunity status of all pregnant women should be documented by history of previous infection, varicella vaccination, or varicella zoster immunoglobulin G serology. (III-C) 4. All non-immune pregnant women should be informed of the risk of varicella infection to themselves and their fetuses. They should be instructed to seek medical help following any with a person who may have been contagious. (II-3B) 5. In the case of a possible exposure to varicella in a pregnant woman with unknown immune status, serum testing should be performed. If the serum results are negative or unavailable within 96 hours from exposure, varicella zoster immunoglobulin should be istered. (III-C) 6. Women who develop varicella infection in pregnancy need to be made aware of the potential adverse maternal and fetal sequelae, the risk of transmission to the fetus, and the options available for prenatal diagnosis. (II-3C) 7. Detailed ultrasound and appropriate follow-up is recommended to all women who develop varicella in pregnancy to screen for fetal consequences for infection. (III-B) 8. Women with significant (e.g., pneumonitis) varicella infection in pregnancy should be treated with oral antiviral agents (e.g., acyclovir 800 mg 5 times daily). In cases of progression to varicella pneumonitis, maternal ission to hospital should be seriously considered. Intravenous acyclovir can be considered for severe complications in pregnancy (oral forms have poor bioavailability). The dose is usually 10 to 15 mg/kg of BW or 500 mg/m2 IV every 8 h for 5 to 10 days for varicella pneumonitis, and it should be started within 24 to 72 h of the onset of rash. (III-C) 9. Neonatal health care providers should be informed of peripartum varicella exposure in order to optimize early neonatal care with varicella zoster immunoglobulin and immunization. (III-C) Varicella zoster immunoglobulin should be istered to neonates whenever the onset of maternal disease is between 5 days before and 2 days after delivery. (III-C)

REFERENCES 1. Tyring SK. Natural history of varicella zoster virus. Semin Dermatol 1992;11:211–7. 2. Nguyen HQ, Jumaan AO, Seward JF. Decline in mortality due to varicella after implementation of varicella vaccination in the United States. N Engl J Med 2005; 352:450–8. 3. Glantz JC, Mushlin AI. Cost-effectiveness of routine antenatal varicella screening. Obstet Gynecol 1998;91:519–28. 4. Enders G, Miller E, Cradock-Watson J, Bolley I, Ridehalgh M. Consequences of varicella and herpes zoster in pregnancy: prospective study of 1739 cases. Lancet 1994; 343(8912):1548–51. 5. Statistics Canada. Births and birth rate, by province and territory. Available at: http://www40.statcan.gc.ca/101/cst01/dem004a-eng.htm. Accessed December 28, 2011. 6. Rouse DJ, Gardner M, Allen SJ, Goldenberg RL. Management of the presumed susceptible varicella (chickenpox)-exposed gravida: a costeffectiveness/cost-benefit analysis. Obstet Gynecol 1996;87:932–6. 7. Centers for Disease Control and Prevention. Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 1996;45(RR-11):1–36. 8. Paryani SG, Arvin AM. Intrauterine infection with varicella-zoster virus after maternal varicella. N Engl J Med 1986;314(24):1542–6. 9. Harger JH, Ernest JM, Thurnau GR, Moawad A, Momirova V, Landon MB, et al. Risk factors and outcome of varicella-zoster virus pneumonia in pregnant women. J Infect Dis 2002;185:422–7. 10. Grose C. Varicella infection during pregnancy. Herpes 1999;6:33–7. 11. Smego RA Jr, Asperilla MO. Use of acyclovir for varicella pneumonia during pregnancy. Obstet Gynecol 1991;78:1112–6. 12. Tan MP, Koren G. Chickenpox in pregnancy: revisited. Reprod Toxicol 2006;21:410–20. 13. Koren G. Congenital varicella syndrome in the third trimester. Lancet 2005;366(9497):1591–2. 14. Andrews JI. Diagnosis of fetal infections. Curr Opin Obstet Gynecol 2004;16:163–6. 15. Pastuszak AL, Levy M, Schick B, Zuber C, Feldkamp M, Gladstone J, et al. Outcome after maternal varicella infection in the first 20 weeks of pregnancy. N Engl J Med 1994;330(13):901–5. 16. Koren G. Risk of varicella infection during late pregnancy. Can Fam Physician 2003;49:1445–6. 17. Chiang , Chiu CH, Huang YC, Lin TY. Two cases of disseminated cutaneous herpes zoster in infants after intrauterine exposure to varicellazoster virus. Pediatr Infect Dis J 1995;14:395–7. 18. Degani S. Sonographic findings in fetal viral infections: a systematic review. Obstet Gynecol Surv 2006;61:329–36. 19. Skibsted L. Abnormal fetal ultrasound findings after maternal chickenpox infection [article in Danish]. Ugeskr Laeger 2000;162(18):2546–9. 20. Pretorius DH, Hayward I, Jones KL, Stamm E. Sonographic evaluation of pregnancies with maternal varicella infection. J Ultrasound Med 1992;11:459–63. 21. Meyers JD. Congenital varicella in term infants: risk reconsidered. J Infect Dis 1974;129:215–7. 22. Royal College of Obstetricians and Gynecologists. Chickenpox in pregnancy. RCOG Green-top Guideline no. 13, September 2007. Available at: http://www.rcog.org.uk/womens-health/guidelines. Accessed December 26, 2011.

MARCH JOGC MARS 2012 l 291

SOGC clinical practice guideline

23. Maupin RT. Obstetric infectious disease emergencies. Clin Obstet Gynecol 2002;45(2):393–404. 24. Wallace MR, Bowler WA, Murray NB, Brodine SK, Oldfield EC III. Treatment of adult varicella with oral acyclovir. A randomized, placebocontrolled trial. Ann Intern Med 1992;117:358–63. 25. Nyerges G, Meszner Z, Gyarmati E, Kerpel-Fronius S. Acyclovir prevents dissemination of varicella in immunocompromised children. J Infect Dis 1988;157:309–13. 26. ACOG practice bulletin. Perinatal viral and parasitic infections. Number 20, September 2000. (Replaces educational bulletin number 177, February 1993). American College of Obstetrics and Gynecologists. Int J Gynaecol Obstet 2002;76:95–107. 27. ACOG Committee Opinion. Immunization during pregnancy. Obstet Gynecol 2003;101:207–12. 28. Shields KE, Galil K, Seward J, Sharrar RG, Cordero JF, Slater E. Varicella vaccine exposure during pregnancy: data from the first 5 years of the pregnancy registry. Obstet Gynecol 2001;98:14–9. 29. Gruslin A, Steben M, Halperin S, Money DM, Yudin MH; SOGC Infectious Diseases Committee. Immunization in pregnancy. SOGC Clinical Practice Guideline no. 236, November 2009. J Obstet Gynaecol Can 2009;31:1085–101. 30. Mouly F, Mirlesse V, Meritet JF, Rozenberg F, Poissonier MH, Lebon P, et al. Prenatal diagnosis of fetal varicella-zoster virus infection

292 l MARCH JOGC MARS 2012

with polymerase chain reaction of amniotic fluid in 107 cases. Am J Obstet Gynecol 1997;177:894–8. 31. Enders G Miller E. Varicella and herpes zoster in pregnancy and the newborn. In: Arvin AM, Gershon AA, eds. Varicella-zoster virus: virology and clinical management. Cambridge: Cambridge University Press;2000:317–47. 32. Koren G, Money D, Boucher M, Aoki F, Petric M, Innocencion G, et al. Serum concentrations, efficacy, and safety of a new, intravenously istered varicella zoster immune globulin in pregnant women. J Clin Pharmacol 2002;42:267–74. 33. Henderson GI, Hu ZQ, Johnson RF, Perez AB, Yang Y, Schenker S. Acyclovir transport by the human placenta. J Lab Clin Med 1992;120:885–92. 34. Landsberger EJ, Hager WD, Grossman JH III. Successful management of varicella pneumonia complicating pregnancy. A report of three cases. J Reprod Med 1986;31:311–4. 35. Spangler JG, Kirk JK, Knudson MP. Uses and safety of acyclovir in pregnancy. J Fam Pract 1994;38:186–91 36. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

SOGC Clinical Practice Guideline No. 269, November 2011

Advanced Reproductive Age and Fertility This clinical practice guideline has been prepared by the Reproductive Endocrinology and Infertility Committee, reviewed by the Family Physicians Advisory Committee and the Maternal-Fetal Medicine Committee, and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Kimberly Liu, MD, Toronto ON Allison Case, MD, Saskatoon SK Reproductive Endocrinology and Infertility COMMITTEE Anthony P. Cheung, MD (Co-Chair), Vancouver BC Sony Sierra, MD (Co-Chair), Toronto ON Saleh AlAsiri, MD, Vancouver BC Belina Carranza-Mamane, MD, Sherbrooke QC Allison Case, MD, Saskatoon SK Cathie Dwyer, RN, Toronto ON James Graham, MD, Calgary AB Jon Havelock, MD, Burnaby BC Robert Hemmings, MD, Montreal QC Francis Lee, MD, Winnipeg MB Kimberly Liu, MD, Toronto ON Ward Murdock, MD, Fredericton NB Vyta Senikas, MD, Ottawa ON Tannys D.R. Vause, MD, Ottawa ON Benjamin Chee-Man Wong, MD, Calgary AB Disclosure statements have been received from all of the committee.

Key Words: Ovarian aging, advanced reproductive age, assisted reproductive technology

Abstract Objective: To improve awareness of the natural age-related decline in female and male fertility with respect to natural fertility and assisted reproductive technologies (ART) and provide recommendations for their management, and to review investigations in the assessment of ovarian aging. Options: This guideline reviews options for the assessment of ovarian reserve and fertility treatments using ART with women of advanced reproductive age presenting with infertility. Outcomes: The outcomes measured are the predictive value of ovarian reserve testing and pregnancy rates with natural and assisted fertility. Evidence: Published literature was retrieved through searches of PubMed or Medline, CINAHL, and The Cochrane Library in June 2010, using appropriate key words (ovarian aging, ovarian reserve, advanced maternal age, advanced paternal age, ART). Results were restricted to systematic reviews, randomized controlled trials/controlled clinical trials, and observational studies. There were no date or language restrictions. Searches were updated on a regular basis and incorporated into the guideline to December 2010. Values: The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care. Recommendations for practice were ranked according to the method described in that report (Table). Benefits, harms, and costs: Primary and specialist health care providers and women will be better informed about ovarian aging and the age-related decline in natural fertility and about options for assisted reproductive technology. Recommendations 1. Women in their 20s and 30s should be counselled about the agerelated risk of infertility when other reproductive health issues, such as sexual health or contraception, are addressed as part of their primary well-woman care. Reproductive-age women should be aware that natural fertility and assisted reproductive technology success (except with egg donation) is significantly lower for women in their late 30s and 40s. (II-2A) 2. Because of the decline in fertility and the increased time to conception that occurs after the age of 35, women > 35 years of age should be referred for infertility work-up after 6 months of trying to conceive. (III-B)

This document reflects emerging clinical and scientific advances on the date issued, and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

NOVEMBER JOGC NOVEMBRE 2011 l 1165

SOGC Clinical Practice Guideline

3. Ovarian reserve testing may be considered for women ≥ 35 years of age or for women < 35 years of age with risk factors for decreased ovarian reserve, such as a single ovary, previous ovarian surgery, poor response to follicle-stimulating hormone, previous exposure to chemotherapy or radiation, or unexplained infertility. (III-B) 4. Ovarian reserve testing prior to assisted reproductive technology treatment may be used for counselling but has a poor predictive value for non-pregnancy and should be used to exclude women from treatment only if levels are significantly abnormal. (II-2A) 5. Pregnancy rates for controlled ovarian hyperstimulation are low for women > 40 years of age. Women > 40 years should consider IVF if they do not conceive within 1 to 2 cycles of controlled ovarian hyperstimulation. (II-2B) 6. The only effective treatment for ovarian aging is oocyte donation. A woman with decreased ovarian reserve should be offered oocyte donation as an option, as pregnancy rates associated with this treatment are significantly higher than those associated with controlled ovarian hyperstimulation or in vitro fertilization with a woman’s own eggs. (II-2B) 7. Women should be informed that the risk of spontaneous pregnancy loss and chromosomal abnormalities increases with age. Women should be counselled about and offered appropriate prenatal screening once pregnancy is established. (II-2A) 8. Pre-conception counselling regarding the risks of pregnancy with advanced maternal age, promotion of optimal health and weight, and screening for concurrent medical conditions such as hypertension and diabetes should be considered for women > age 40. (III-B) 9. Advanced paternal age appears to be associated with an increased risk of spontaneous abortion and increased frequency of some autosomal dominant conditions, autism spectrum disorders, and schizophrenia. Men > age 40 and their partners should be counselled about these potential risks when they are seeking pregnancy, although the risks remain small. (II-2C)

J Obstet Gynaecol Can 2011;33(11):1165–1175

INTRODUCTION

S

ocial trends in Canada and around the world have led to women delaying child-bearing into their 30s and, in some cases, their 40s. The average age of women giving birth has increased from 27 to 29.3 over the last 20 years.1 In 2006, the fertility rate for women aged 30 to 34 was the highest of any age group, suring that of the previous highest group, women aged 25 to 29.2 The percentage of

ABBREVIATIONS AFC

antral follicle count

AMH

antimüllerian hormone

ART

assisted reproductive technology

COH

controlled ovarian hyperstimulation

FSH

follicle-stimulating hormone

IUI

intrauterine insemination

1166 l NOVEMBER JOGC NOVEMBRE 2011

first-time mothers who are > 30 years of age increased steadily from 11% in 1987 to 26% in 2005.1 During the same period, there was a significant rise in first-time mothers > 35 years of age, from 4% in 1987 to 11% in 2005, and a corresponding decrease in the group who are < 25 years.1 Similar trends have been seen in other parts of the world.3 Ovarian function declines as women approach their later reproductive years until menopause, and increasing age is associated with lowered fecundity and infertility. Women experience a decline in natural fertility that begins in the mid-30s, and they will often reach sterility many years before the complete cessation of menses.4 Although ART may aid some couples who present with fertility issues, it will not compensate for the decline in natural fertility that occurs with delayed child-bearing.5 ART is also invasive, expensive, and not covered by most provincial health plans for this indication. In addition, complications of pregnancy increase for both the mother and the offspring with advanced maternal age.6 Women and their health care providers should be aware of the effects of age on reproductive potential. OVARIAN AGING

The loss of oocytes from the ovaries is a continual process that begins in utero. The ovaries in the female fetus contain 6 to 7 million oocytes at approximately 20 weeks’ gestation. At birth, 1 to 2 million oocytes remain, and only 300 000 to 500 000 are present at the onset of puberty.7 This process continues until menopause, when only a few hundred oocytes remain.8 During the reproductive years, 400 to 500 oocytes will be ovulated; the majority of oocytes are lost through apoptosis, or programmed cell death. Earlier research suggested that a more accelerated process of decline occurs in the last 10 to 15 years before menopause, beginning around the age of 38 years.9 However, more recent data suggest that oocyte loss occurs at the same rate through the reproductive lifetime, with the slope of decline remaining fairly consistent until menopause.10 As the ovarian follicular pool decreases, women will experience infertility, sterility, cycle shortening, menstrual irregularity, and finally menopause (Figure 1).10 In Western countries, the mean age of menopause is 51, and 1% will experience premature ovarian failure before age 40.11 There appears to be a fixed interval through these stages of ovarian function. Women who experience an earlier menopause will have an earlier loss of fertility12; therefore, approximately 10% of women will have decreased ovarian function in their early to mid-30s.13

Advanced Reproductive Age and Fertility

Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well–designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.95 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care.95

Child-bearing usually ends 10 years before menopause, and this time period is consistent regardless of the age of menopause.14,15 Cycle irregularity will usually occur 6 to 7 years before menopause,14 regardless of the age of menopause, coinciding with approximately 10 000 follicles remaining.8 As the total number of remaining follicles decreases, there is a corresponding decrease in the available follicular cohort. As a consequence of a smaller follicular cohort, there is a decline in inhibin-B, which is produced by the granulosa cells in the early follicular phase.16 There is an inverse correlation between FSH and inhibin-B, which is likely due to a loss in negative ; the rise in FSH during the early follicular phase is one of the earliest signs of ovarian aging.17 This initial stage may not be clinically apparent, or present only as infertility, because ovarian hormone production remains constant, and women continue to ovulate and have regular cycles. The first clinical signs of ovarian aging may be shortening of menstrual cycles, which is due to a shorter follicular phase. More rapid follicular development leads to earlier recruitment of a dominant follicle.18 As this transition continues, women will notice that their cycles lengthen and become more irregular as they enter the menopause transition and ovulation is less consistent.8 Once women start to notice clinical signs of ovarian aging such as cycle shortening or irregularity, their fertility may already be greatly diminished. One review article found that women who were sterile after age 35 had already demonstrated lower fecundity before the age of

30.12 Markers of ovarian reserve may be useful to predict an earlier menopause or menopause transition for women who do not yet have clinical signs or symptoms of ovarian aging but who may already have decreased fertility. When menopause occurs, there are often a few hundred follicles remaining. There is still ovarian activity and estrogen production during the first year after menopause.14 Although the mean age of menopause in Western countries is 51, there is a significant range, from 40 to 60 years of age. Sibling and twin studies have shown a significant genetic component to the age of menopause.19 Smoking has been associated with a decreased follicular pool and earlier menopause.14 Oocyte quality also appears to be affected by age. Studies on IVF oocytes have shown that the rate of oocyte aneuploidy increases with age.20 The rate is low in women < age 35 (10%), but increases to 30% at the age of 40, to 40% at the age of 43, and to 100% in women > age 45.20 These were gonadotropin stimulated oocytes, and therefore may not reflect the rate of aneuploidy in oocytes from a dominant follicle recruited during a non-stimulated or natural cycle; however, this correlates with the increase in chromosomally abnormal pregnancies and spontaneous abortions with age. The decline in oocyte quality may be in the formation and function of the spindles, which appear to be more diffuse.21 This may result in chromosomes being less tightly arranged and may therefore lead to meiotic errors. Data also suggest that the selection process may deteriorate with age, allowing NOVEMBER JOGC NOVEMBRE 2011 l 1167

SOGC Clinical Practice Guideline

Figure 1. Schematic representation of the number of primordial follicles present in the ovaries and the chromosomal quality of oocytes in relation to female age and corresponding reproductive events.

Proportion of poor quality oocytes

Number of follicles

10T 10

Optimal fertility

6

Declining fertility

105

End of fertility

Menopause

Irregular cycles

100

104

75 50

103 10

25

2

0

10

20

30

40

50

60

Proportion of poor quality oocytes (%)

Number of follicles

Age (years) Graph was drawn after Hansen et al. and de Bruin et al. Broekmans FJ, Soules MR, Fa BC. Ovarian aging: mechanisms and clinical consequences. Endocr Rev 2009;30:465–93.12 Copyright 2009, The Endocrine Society. Reproduced with permission.

poorer quality oocytes the opportunity to develop into the dominant follicle, or to be selected during an IVF cycle. The selection of the available follicular cohort may be less discriminating, allowing follicles to mature which should have undergone atresia.22 Other proposed mechanisms include cumulative damage to the oocyte with age and decreasing quality of granulosa cells.23

Figure 2. Natural fertility by age 600

Rate per 1000 wives

500 400 300

FEMALE ADVANCED REPRODUCTIVE AGE AND INFERTILITY

200 100 0 20

25

30

35 40 Age of wife

45

50

The ten populations (in descending order at age 20 to 24) are Hutterites, marriages 1921–30 ( ); Geneva bourgeoisie, husbands born 1600–49 ( ); Canada, marriages 1700–30 ( ); Normandy, marriages 1760–90 ( ); Hutterites, marriages before 1921 ( ); Tunis, marriages of Europeans 1840-59 ( ); Normandy, marriages 1674–1742 ( ); Norway, marriages 1874–76 ( ); Iran, village marriages, 1940–50 ( ); Geneva bourgeoisie, husbands born before 1600 ( ). Menken J, Trussell J, Larsen U. Age and infertility. Science 1986; 233(4771):1389–1394.4 Reprinted with permission from AAAS.

1168 l NOVEMBER JOGC NOVEMBRE 2011

Population studies have consistently noted that the decline in birth rates begins when women reach the age of 35 (Figure 2).4 On average, women will deliver their last child at age 41, with a range of 23 to 51.24 Natural population studies may not take into non-reproductive factors, such as desire to prevent pregnancy, coital frequency, aging partners, and other medical conditions that may affect live birth rates. In addition, conditions such as fibroids and endometriosis are more frequent in later reproductive years. These studies therefore may not offer a full reflection of a woman’s maximum fertility potential. Natural fertility studies of patients who had recently discontinued contraception have shown that younger women have a higher fecundity rate, and therefore conceive sooner than older women.25

Advanced Reproductive Age and Fertility

The incidence of infertility and sterility increases as the age of the female partner increases. Although the true incidence of sterility is difficult to determine because of non-reproductive factors such as voluntary childlessness, population studies can provide some insight. In one study of 7 populations in which contraception use is rare and in which there is a low incidence of premarital conceptions, the percentage of women who remained childless was higher in those who married later.4 Only 6% of women who married in their early 20s remained childless, while 64% of women who were not married until their 40s remained childless. Studies in the Hutterite population confirm an increase in infertility with age, escalating from 11% after age 34 to 33% by age 40 and to 87% by age 45.26 Although social changes have led to women delaying their reproduction, concomitant advances in reproductive sciences have led to increased options for fertility treatment and ART. Unfortunately, this may give women false optimism that they can delay pregnancy while pursing their education and careers with the expectation that ART will help them to conceive if they have difficulty conceiving later. However, success rates for ART treatment for women using their own eggs are directly linked to the age of the women,27 and many women may not realize that older women are successful using ART to achieve pregnancy later in life only with donor eggs. Computer models have demonstrated that the current ART success rates cannot compensate for the loss in natural fertility that occurs in a women who has delayed childbearing from 30 to 35 years of age.5 Studies on donor insemination confirm an age-related decline in pregnancy rates. Most of the earlier donor insemination studies were performed in couples with severe male factor infertility. These studies are thought to be a good reflection of female fertility because non-reproductive factors such as coital frequency are removed. A negative effect on pregnancy rates is seen in women > age 30, and is even more pronounced for women > age 35.28–31 One study of almost 3000 cycles showed cumulative pregnancy rates of 62% for women < 30 years of age, and 44% for women aged ≥ 30 years after 12 cycles. Younger women often conceive quickly, and more cycles of treatment were often needed for women aged ≥ 35 years.29,31 Pregnancy rates collected from ART treatment cycles show the significant impact of female age on success. The 2007 Canadian live birth rate after IVF was 37.4% for women < 35 years of age, 26.5% for women aged 35 to 39 years, and 11.4% for women aged ≥ 40 years.32 ART reports from the United States show similar age-related success rates.33 Age is the most significant prognostic factor for IVF success.

Age-associated infertility appears to be primarily related to ovarian aging and the diminishing ovarian follicle count. The uterine endometrium has the capacity to maintain a pregnancy throughout a woman’s reproductive years and, with newer technologies such as egg donation, even beyond the natural reproductive years. Age does not affect the endometrium’s response to hormonal stimulation.34 Pregnancy rates from donor egg cycles also confirm that the age of the recipient does not affect pregnancy rates.33 Recommendations

1. Women in their 20s and 30s should be counselled about the age-related risk of infertility when other reproductive health issues, such as sexual health or contraception, are addressed as part of their primary well-woman care. Reproductive-age women should be aware that natural fertility and assisted reproductive technology success (except with egg donation) is significantly lower for women in their late 30s and 40s. (II-2A) 2. Because of the decline in fertility and the increased time to conception that occurs after the age of 35, women > 35 years of age should be referred for infertility work-up after 6 months of trying to conceive. (III-B) ASSESSMENT OF OVARIAN AGING

Ovarian aging will have begun before women notice any clinical changes to their menstrual cycles; therefore, they are often unaware that they may be at greater risk of infertility. Ovarian reserve testing has been explored as a means to determine a woman’s fertility potential and provide an assessment of ovarian aging. Although chronological age alone serves as a good marker of ovarian reserve, some women will experience a decline in their natural fertility sooner than average, while some older women may maintain above average ovarian function. Identification of these two groups, in which ovarian reserve is inconsistent with chronological age, may be useful for counselling and planning treatment.35 Many tests of ovarian reserve have been tried. However, testing has mainly been performed on infertile populations, with little data on the distribution in the normal fertile population. Ovarian reserve testing cannot be used to predict infertility or time to infertility; therefore, its application to the general population as a screening tool is untested. Most studies have used these tests to try to predict a woman’s ovarian response and prognosis with fertility treatment and IVF. Overall, markers of ovarian NOVEMBER JOGC NOVEMBRE 2011 l 1169

SOGC Clinical Practice Guideline

reserve have been shown to correlate with egg quantity and response to ovarian stimulation, but not with egg quality. The most commonly used test of ovarian reserve is the cycle day 3 or basal FSH level. An elevated basal FSH level (> 14 IU/L) is the first sign of ovarian aging that can be detected in women, and usually occurs in women aged 35 to 40.36 Physiologically, the follicular pool is reduced to approximately 10% of the levels present at puberty.9 The rise in basal FSH is due to a loss in ovarian (inhibin-A and B) as the available follicular cohort diminishes. Basal FSH levels are easy to obtain, and no special skills are required to perform the test or interpret the results; therefore, it is easily accessible. However, basal FSH levels have been shown to be predictive for poor response to ovarian stimulation and for non-pregnancy only when the levels are extremely elevated.35 Although a high threshold may improve the usefulness of the test in predicting a poorer prognosis, only a small number of women will have abnormal tests at this threshold. In addition, it has been associated with a false positive rate of 5%.35 Elevated basal FSH levels are also less predictive of pregnancy for women < age 35.37,38 An ovarian antral follicle count can be performed early in the menstrual cycle. Antral follicles between 2 mm and 10 mm can be identified by transvaginal ultrasound performed by an experienced sonographer using a vaginal transducer with a minimum frequency of 7 MHz.39 Antral follicles are sensitive to FSH and are considered to be representative of the available follicle pool. The number of antral follicles seems to correlate with the number of primordial follicles in the ovary, with a decline in primordial follicles being reflected in a lower number of antral follicles.24 In later reproductive years, the proportion of antral follicles to total follicles may increase as the ovary allows a higher proportion of follicles to be selected. This may reflect a loosening of the selection process.14 The decline in AFC may not be as steep as the decline in fertility. Although decline in AFC is correlated with both the menopause transition and ovarian response to stimulation, it is not a good predictor of pregnancy.35 Antimüllerian hormone is produced by the granulosa cells of pre-antral and small antral follicles but not dominant follicles.12 AMH levels decrease with decreasing AFC, which in turn is a marker of the primordial follicle count. Levels remain consistent throughout the menstrual cycle40 and become undetectable in women after menopause.41 Although AMH provides moderate value in prediction of ovarian response in IVF, it is a poor predictor of pregnancy.35 Currently, AMH testing is not widely available across Canada. 1170 l NOVEMBER JOGC NOVEMBRE 2011

The clomiphene challenge test is performed by istering 100 mg of clomiphene daily from day 5 to day 9 of the cycle. FSH is measured on day 3 and on day 10. If an adequate response to clomiphene is generated, the rise in FSH will be suppressed by the release of estradiol and inhibin-B by developing follicles. Systematic reviews have not shown a benefit to the clomiphene challenge test over basal FSH or AFC.35 Inhibin-B and basal estradiol have not been shown to be more useful predictors of poor response or pregnancy than basal FSH.35 However, basal estradiol levels are often screened in conjunction with FSH and can confirm correct timing in the menstrual cycle. An elevated estradiol level may also falsely suppress FSH levels. Ovarian reserve tests performed before ART treatment is begun may be useful for counselling, but they have a poor predictive power for pregnancy.12 AFC and AMH have been shown to be useful for prediction of poor ovarian response with IVF.12 Although significantly abnormal results are associated with lower pregnancy rates (< 5%), only about 3% of women will have results in this category.35 In general, ovarian reserve testing is useful for predicting egg quantity and ovarian response to stimulation but has little value for the prediction of egg quality. Therefore, although these tests may be useful for counselling before ART treatment, testing should not be used to exclude women from ART treatment, and abnormal tests do not preclude the possibility of pregnancy. These test results can be used to obtain individual prognostic information to help to guide the choice of treatment and best use of resources. Ovarian reserve testing may be considered in women > age 35 to screen for age-related infertility, although its results may be useful only for counselling and to aid women in their decision-making process. Testing in women < 35 years may be considered if they have risk factors for decreased ovarian reserve, such as a single ovary, previous ovarian surgery, poor response to FSH, previous exposure to chemotherapy or radiation, or unexplained infertility.42 Although markers of ovarian reserve are not good predictors of pregnancy rate with ART for women < 35,38 identification of these women may prompt shorter delay to infertility investigations and treatment. Recommendations

3. Ovarian reserve testing may be considered for women ≥ 35 years of age or for women < 35 years of age with risk factors for decreased ovarian reserve, such as a single ovary, previous ovarian surgery, poor response to follicle-stimulating hormone, previous exposure to chemotherapy or radiation, or unexplained infertility. (III-B)

Advanced Reproductive Age and Fertility

4. Ovarian reserve testing prior to assisted reproductive technology treatment may be used for counselling but has a poor predictive value for nonpregnancy and should be used to exclude women from treatment only if levels are significantly abnormal. (II-2A) TREATMENT OF AGE-RELATED INFERTILITY

Fertility treatment for age-related infertility is aimed at increasing monthly fecundity and decreasing the time to conception. Women may be offered controlled ovarian hyperstimulation with clomiphene citrate or gonadotropins, or IVF to improve their chances of pregnancy and decrease time to pregnancy. Both treatments are intended to increase the number of mature oocytes each month to balance decreasing oocyte quality, but they do not address the underlying issue of oocyte quantity or quality. The only effective treatment for age-related infertility and declining oocyte quality is oocyte donation. In reality, pregnancy and live birth rates with COH in older women are low. In one retrospective review of more than 4000 treatment cycles using clomiphene citrate and intrauterine insemination, pregnancy rates were 7% for women aged 38 to 40, 4% for women 41 to 42, and 1% for women > 42.43 A small study of 130 cycles of COH with gonadotropins and IUI found a live birth rate of 6% for women aged 38 to 39, and 2% for women > 40.44 All live births happened within the first or second cycles. Older women may consider 1 to 2 cycles of COH if they do not want to try IVF as a first-line treatment, but they should move on to IVF quickly if they are unsuccessful within the first couple of cycles.45 Although chance of success diminishes with age, IVF still offers higher pregnancy and live birth rates than COH, although significantly lower rates than oocyte donation. In 2007, live birth rates were 11.4% per cycle for women aged > 40 in Canada.32 One study of women aged > 40 undergoing IVF, showed that for women aged ≥ 42, live birth rates drop to below 5%.46 In this study, no live births were reported in 54 cycles for women aged ≥ 45. A separate study found a significant drop in IVF live birth rates in women aged ≥ 43 and over. Live birth rates were 7.4% for women 40 to 42 years of age, and only 1.1% for women ≥ 43 years. Miscarriage rates were 43.1% in the younger age group and 65.2% in the older age group.47 Oocyte donation offers women with an intact uterus the opportunity to carry a pregnancy despite declining ovarian function or menopause. In Canada, the 2004

Assisted Human Reproduction Act regulates all reproductive technologies, including the use of donor gametes. Specifically, the Act prohibits the sale of eggs, sperm, or surrogacy services.48 Compensation to donors for receiptable expenses such as medications and parking are allowed,49 although the specific regulations are not yet available. Many countries, including the United States, rely on paid, often anonymous, egg donors to ensure an adequate supply to meet the significant demand for this treatment option. However, as this practice is prohibited in Canada, Canadian women must rely on altruistic egg donors, usually family , close friends, or colleagues. Unfortunately, many women will not know an appropriate donor, so egg donation may not be an option for them. Other women turn to reproductive tourism and seek treatment in the United States or Europe. Pregnancy rates with oocyte donation are based on the age of the donor, not the recipient.33,50 Pregnancies and live births have been reported in women into their 60s51; however, the use of donor eggs for women after the age of 50 is controversial. There are increased rates of obstetrical and maternal complications with increasing maternal age, including maternal death, hypertension, prematurity, fetal and neonatal death, and operative delivery.52–55 At least one death immediately after delivery has been reported in a 50-year-old woman who conceived with oocyte donation.56 However, many of these studies show these risks are already increased in women > age 40, and treatment is offered to women between the ages of 40 and 50 without significant debate. Many clinicians feel the natural age of menopause is an appropriate maximum age for offering oocyte donation, although others argue this is an arbitrary cut-off point.57 In Canada, there are no regulations that set an age limit for oocyte donation, although many clinics have set the age of menopause as the maximum age for this treatment. Recommendations

5. Pregnancy rates for controlled ovarian hyperstimulation are low for women > 40 years of age. Women > 40 should consider IVF if they do not conceive within 1 to 2 cycles of controlled ovarian hyperstimulation. (II-2B) 6. The only effective treatment for ovarian aging is oocyte donation. A woman with decreased ovarian reserve should be offered oocyte donation as an option, as pregnancy rates associated with this treatment are significantly higher than those associated with controlled ovarian hyperstimulation or in vitro fertilization with a woman’s own eggs. (II-2B)

NOVEMBER JOGC NOVEMBRE 2011 l 1171

SOGC Clinical Practice Guideline

EARLY PREGNANCY AND MATERNAL COMPLICATIONS

Advanced reproductive age is associated with early and later pregnancy complications in addition to infertility. Age is a recognized risk factor for spontaneous abortion. Although the risk of clinical pregnancy loss is low in women < 30 years of age (7% to 15%), it begins to rise for women aged 30 to 34 (8% to 21%) and women aged 35 to 39 (17% to 28%), and it increases dramatically for women aged ≥ 40 (34% to 52%).15 Data from the Canadian ART clinics also show an increase in spontaneous pregnancy loss after ART treatment. Pregnancy loss rates after clinical intrauterine pregnancy ranged from 10.4% for women aged < 35 to 16.4% for women aged 35 to 39, and increased to 33% for women aged ≥ 40.27 An increased risk of chromosomal abnormalities also occurs with age. Much of the increased risk of early pregnancy loss may be due to the increased rate of chromosomally abnormal conceptions. The previously discussed underlying mechanisms for ovarian aging and declining egg quality leading to increased oocyte aneuploidy may lead to an increased rate of chromosomal abnormalities in resultant embryos and pregnancies. The age-related risks for Down syndrome increase from 1 in 1477 for women at age 20 to 1 in 939 at age 30, 1 in 353 at age 35, 1 in 85 at age 40, and 1 in 39 at age 44. The age-related risk for all chromosomal abnormalities rises from 1 in 526 for women at age 20 to 1 in 384 at age 30, 1 in 204 at age 35, 1 in 65 at age 40, and 1 in 2 at age 45.58 Pregnancy in women > 40 years of age is also associated with a higher risk of obstetrical complications, including operative delivery, gestational diabetes, preeclampsia, IUGR, and low birth weight.6 Pre-conception screening for significant medical conditions such as hypertension or diabetes should be considered for women at high risk before fertility treatment is begun. Recommendations

7. Women should be informed that the risk of spontaneous pregnancy loss and chromosomal abnormalities increases with age. Women should be counselled about and offered appropriate prenatal screening once pregnancy is established. (II-2A) 8. Pre-conception counselling regarding the risks of pregnancy with advanced maternal age, promotion of optimal health and weight, and screening for concurrent medical conditions such as hypertension and diabetes should be considered for women > age 40. (III-B)

1172 l NOVEMBER JOGC NOVEMBRE 2011

ADVANCED PATERNAL AGE

Although significant focus has been placed on female reproductive aging, there is also an age-related decline in sperm function and male fertility. Although “andropause” is not a clearly defined event for men as menopause is for women, there is a decline in testicular function, which includes declining testosterone levels each year.59 Sperm parameters including semen volume, motility, and morphology decrease with age, although a decline in sperm concentration has not been shown.60 Studies trying to delineate the effects of male age on natural fertility often have not ed for female age. One study has suggested that the odds of conception decrease 3% per year, while other studies have shown that the effect of male age alone on natural monthly conception is small.61,62 Similarly, studies in ART treatment have often not controlled adequately for maternal age.63,64 One study suggested that male age > 35 years may have an effect on IUI, but most studies suggest that male age does not affect IVF/ intracytoplasmic sperm injection pregnancy rates despite lower motility and fertilization rates.65,66 There was also no difference seen in egg donation cycles.67,68 In couples undergoing ART treatment, it appears that the effect of paternal age on the number of cleavage-stage embryos is small.69 However, a significant decrease in the rate of blastocyst embryo formation on day 5 and in the number of cryopreservable embryos has been noted.70,71 Paternal age > 40 years does appear to be associated with risk of spontaneous abortion, even when maternal age is controlled for.72,73 For chromosomal abnormalities, the effect of maternal age is such a significant factor, the paternal age effect is small in comparison and is not found at all in many studies after maternal age is controlled for.74–77 However, recent studies suggest that, either alone or in combination with a maternal effect, paternal effect may increase the risk of Down syndrome.78 Although there has been conflicting evidence for an association with pre-term birth and low birth weight, a study conducted in the United States and a population study undertaken in Alberta did not find this association after multiple and logistic regression analysis.79–81 Advanced paternal age has been associated with autosomal dominant disorders such as Alport syndrome, achondroplasia, and neurofibromatosis.82–87 The estimated risk for autosomal dominant disorders in offspring of fathers ≥ 40 years of age is thought to be < 0.5%.78 Autism spectrum disorders and schizophrenia have been associated with advanced paternal age through larger cohort and population database studies. A large Danish prospective study on autism with one million children

Advanced Reproductive Age and Fertility

found a relative risk 1.6 for fathers > 40 to 44 years of age, and an Israeli cohort study found an OR 5.75 for fathers aged 40 to 49.88,89 A large US study found an association between autism and both maternal and paternal age, with a relative risk of 1.3 for every 10-year increase in paternal age.90 The link between paternal age and schizophrenia was initially felt to be constitutional: people with this condition tend to marry and reproduce later in life. A cohort of almost 90 000 children in Jerusalem was linked to the Israeli Psychiatric Registry. The relative risk for offspring with schizophrenia was 2.0 for fathers aged 45 to 49, and 3.0 for fathers > age 50.91 This finding has been seen across other studies in other ethnic populations, including populations in Denmark, Sweden, and Japan.92–94 The American College of Medical Genetics does not recommend additional prenatal testing solely on the basis of advanced paternal age (defined as ≥ 40), although prenatal counselling about the potential risks of advanced paternal age should be undertaken.78 Recommendation

9. Advanced paternal age appears to be associated with an increased risk of spontaneous abortion and increased frequency of some autosomal dominant conditions, autism spectrum disorders, and schizophrenia. Men > age 40 and their partners should be counselled about these potential risks when they are seeking pregnancy, although the risks remain small. (II-2C) CONCLUSIONS

Female reproductive aging is a common cause of infertility in women in their late 30s and 40s. Health care providers should counsel women about the realities of the biological clock and ensure they have realistic expectations about natural and assisted fertility rates if they choose to delay child-bearing into their later reproductive years. REFERENCES 1. Statistics Canada. The Daily. Ottawa: Statistics Canada; 24 Sep 2008. Available at: http:// www.statcan.gc.ca/daily-quotidien/080924/ dq080924a-eng.htm. Accessed August 31, 2011. 2. Statistics Canada. The Daily. Ottawa: Statistics Canada; 26 Sep 2008. Available at: http:// www.statcan.gc.ca/daily-quotidien/080926/ dq080926a-eng.htm. Accessed August 31, 2011. 3. Maher J, Macfarlane A. Trends in live births and birthweight by social class, marital status and mother’s age, 1976–2000. Health Stat Q 2004;(23):34–42. 4. Menken J, Trussell J, Larsen U. Age and infertility. Science 1986;233(4771):1389–94.

5. Leridon H. Can assisted reproduction technology compensate for the natural decline in fertility with age? A model assessment. Hum Reprod 2004;19:1548–53. 6. Gilbert WM, Nesbitt TS, Danielsen B. Childbearing beyond age 40: pregnancy outcome in 24,032 cases. Obstet Gynecol 1999;93(1):9–14. 7. Baker TG. A quantitative and cytological study of germ cells in human ovaries. Proc R Soc Lond B Biol Sci 1963;158:417–33. 8. Richardson SJ, Senikas V, Nelson JF. Follicular depletion during the menopausal transition: evidence for accelerated loss and ultimate exhaustion. J Clin Endocrinol Metab 1987; 65:1231–7. 9. Faddy MJ, Gosden RG, Gougeon A, Richardson SJ, Nelson JF. Accelerated disappearance of ovarian follicles in mid-life: implications for forecasting menopause. Hum Reprod 1992;7:1342–6. 10. Hansen KR, Knowlton NS, Thyer AC, Charleston JS, Soules MR, Klein NA. A new model of reproductive aging: the decline in ovarian non-growing follicle number from birth to menopause. Hum Reprod 2008;23:699–708. 11. Nikolaou D, Templeton A. Early ovarian ageing: a hypothesis. Detection and clinical relevance. Hum Reprod 2003;18:1137–9. 12. Broekmans FJ, Soules MR, Fa BC. Ovarian aging: mechanisms and clinical consequences. Endocr Rev 2009;30:465–93. 13. Johnson NP, Bagrie EM, Coomarasamy A, Bhattacharya S, Shelling AN, Jessop S, et al. Ovarian reserve tests for predicting fertility outcomes for assisted reproductive technology: the International Systematic Collaboration of Ovarian Reserve Evaluation protocol for a systematic review of ovarian reserve test accuracy. BJOG 2006;113:1472–80. 14. te Velde ER, Pearson PL. The variability of female reproductive ageing. Hum Reprod Update 2002;8:141–54. 15. Stein ZA. A woman’s age: childbearing and child rearing. Am J Epidemiol 1985; 121:327–42. 16. Klein NA, Battaglia DE, Miller PB, Branigan EF, Giudice LC, Soules MR. Ovarian follicular development and the follicular fluid hormones and growth factors in normal women of advanced reproductive age. J Clin Endocrinol Metab 1996;81:1946–51. 17. Klein NA, Battaglia DE, Fujimoto VY, Davis GS, Bremner WJ, Soules MR. Reproductive aging: accelerated ovarian follicular development associated with a monotropic follicle-stimulating hormone rise in normal older women. J Clin Endocrinol Metab 1996;81:1038–45. 18. Klein NA, Harper AJ, Houmard BS, Sluss PM, Soules MR. Is the short follicular phase in older women secondary to advanced or accelerated dominant follicle development? J Clin Endocrinol Metab 2002;87:5746–50. 19. de Bruin JP, Bovenhuis H, van Noord PA, Pearson PL, van Arendonk JA, te Velde ER, et al. The role of genetic factors in age at natural menopause. Hum Reprod 2001;16:2014–8. 20. Pellestor F, Andreo B, Arnal F, Humeau C, Demaille J. Maternal aging and chromosomal abnormalities: new data drawn from in vitro unfertilized human oocytes. Hum Genet 2003; 112:195–203. 21. Volarcik K, Sheean L, Goldfarb J, Woods L, bdul-Karim FW, Hunt P. The meiotic competence of in-vitro matured human oocytes is influenced by donor age: evidence that folliculogenesis is compromised in the reproductively aged ovary. Hum Reprod 1998;13:154–60. 22. Gougeon A, Chainy GB. Morphometric studies of small follicles in ovaries of women at different ages. J Reprod Fertil 1987;81:433–42. 23. Warburton D. Biological aging and the etiology of aneuploidy. Cytogenet Genome Res 2005;111(3–4):266–72. 24. Broekmans FJ, Faddy MJ, Scheffer G, te Velde ER. Antral follicle counts are related to age at natural fertility loss and age at menopause. Menopause 2004;11(6 Pt 1):607–14.

NOVEMBER JOGC NOVEMBRE 2011 l 1173

SOGC Clinical Practice Guideline

25. Tietze C. Fertility after discontinuation of intrauterine and oral contraception. Int J Fertil 1968;13:385–9. 26. Tietze C. Reproductive span and rate of reproduction among Hutterite women. Fertil Steril 1957;8:89–97. 27. Gunby J, Bissonnette F, Librach C, Cowan L; IVF Directors Group of the Canadian Fertility and Andrology Society. Assisted reproductive technologies (ART) in Canada: 2006 results from the Canadian ART . Fertil Steril 201;93(7):2189–201. 28. Schwartz D, Mayaux MJ. Female fecundity as a function of age: results of artificial insemination in 2193 nulliparous women with azoospermic husbands. Federation CECOS. N Engl J Med 1982;306:404–6. 29. Shenfield F, Doyle P, Valentine A, Steele SJ, Tan SL. Effects of age, gravidity and male infertility status o n cumulative conception rates following artificial insemination with cryopreserved donor semen: analysis of 2998 cycles of treatment in one centre over 10 years. Hum Reprod 1993;8:60–4. 30. van Noord-Zaadstra BM, Looman CW, Alsbach H, Habbema JD, te Velde ER, Karbaat J. Delaying childbearing: effect of age on fecundity and outcome of pregnancy. BMJ 1991;302(6789):1361–5.

42. Aging and infertility in women. Fertil Steril 2006;86(5 Suppl 1):S248–S252. 43. Dovey S, Sneeringer RM, Penzias AS. Clomiphene citrate and intrauterine insemination: analysis of more than 4100 cycles. Fertil Steril 2008;90:2281–6. 44. Harris ID, Missmer SA, Hornstein MD. Poor success of gonadotropininduced controlled ovarian hyperstimulation and intrauterine insemination for older women. Fertil Steril 2010; 94:144–8. 45. Tsafrir A, Simon A, Margalioth EJ, Laufer N. What should be the first-line treatment for unexplained infertility in women over 40 years of age—ovulation induction and IUI, or IVF? Reprod Biomed Online 2009;19(Suppl 4):4334. 46. Hourvitz A, Machtinger R, Maman E, Baum M, Dor J, Levron J. Assisted reproduction in women over 40 years of age: how old is too old? Reprod Biomed Online 2009;19:599–603. 47. Serour G, Mansour R, Serour A, Aboulghar M, Amin Y, Kamal O, et al. Analysis of 2,386 consecutive cycles of in vitro fertilization or intracytoplasmic sperm injection using autologous oocytes in women aged 40 years and above. Fertil Steril 2010;94:1707–12. 48. Assisted Human Reproduction Act, S.C. 2004, c. 2, s.7.

31. Virro MR, Shewchuk AB. Pregnancy outcome in 242 conceptions after artificial insemination with donor sperm and effects of maternal age on the prognosis for successful pregnancy. Am J Obstet Gynecol 1984;148:518–24.

49. Assisted Human Reproduction Act, S.C. 2004, c. 2, s.12.

32. Gunby J, Bissonnette F, Librach C, Cowan L; IVF Directors Group of the Canadian Fertility and Andrology Society. Assisted reproductive technologies (ART) in Canada: 2007 results from the Canadian ART . Fertil Steril 2011;95(2):542–7.

51. Paulson RJ, Thornton MH, Francis MM, Salvador HS. Successful pregnancy in a 63-year-old woman. Fertil Steril 1997;67:949–51.

33. United States Centers for Disease Control and Prevention. Assisted Reproductive Technology (ART) Report, National Summary. Available at: http:// www.apps.nccd.cdc.gov/art/Apps/Marquee.aspx. Accessed May 19, 2010. 34. Noci I, Borri P, Chieffi O, Scarselli G, Biagiotti R, Moncini D, et al. I. Aging of the human endometrium: a basic morphological and immunohistochemical study. Eur J Obstet Gynecol Reprod Biol 1995;63:181–5. 35. Broekmans FJ, Kwee J, Hendriks DJ, Mol BW, Lambalk CB. A systematic review of tests predicting ovarian reserve and IVF outcome. Hum Reprod Update 2006;12:685–718. 36. Sherman BM, West JH, Korenman SG. The menopausal transition: analysis of LH, FSH, estradiol, and progesterone concentrations during menstrual cycles of older women. J Clin Endocrinol Metab 1976;42:629–36. 37. Sabatini L, Zosmer A, Hennessy EM, Tozer A, Al-Shawaf T. Relevance of basal serum FSH to IVF outcome varies with patient age. Reprod Biomed Online 2008;17:10–9.

50. United States Centers for Disease Control and Prevention. 2005 assisted reproductive technology report. Available at: http://www.cdc.gov/ART/ ART2005/section4.htm. Accessed April 23, 2010.

52. Jacobsson B, Ladfors L, Milsom I. Advanced maternal age and adverse perinatal outcome. Obstet Gynecol 2004;104:727–33. 53. Simchen MJ, Yinon Y, Moran O, Schiff E, Sivan E. Pregnancy outcome after age 50. Obstet Gynecol 2006;108(5):1084–8. 54. Cleary-Goldman J, Malone FD, Vidaver J, Ball RH, Nyberg DA, Comstock CH, et al. Impact of maternal age on obstetric outcome. Obstet Gynecol 2005;105(5 Pt 1):983–90. 55. Joseph KS, Allen AC, Dodds L, Turner LA, Scott H, Liston R. The perinatal effects of delayed childbearing. Obstet Gynecol 2005;105:1410–8. 56. Schutte JM, Schuitemaker NW, Steegers EA, van RJ. Maternal death after oocyte donation at high maternal age: case report. Reprod Health 2008;5:12. 57. Smajdor A. The ethics of egg donation in the over fifties. Menopause Int 2008;14:173–7. 58. Hook EB. Rates of chromosome abnormalities at different maternal ages. Obstet Gynecol 1981;58:282–5. 59. McLachlan RI. The endocrine control of spermatogenesis. Baillieres Best Pract Res Clin Endocrinol Metab 2000;14:345–62.

38. Lee TH, Liu CH, Huang CC, Hsieh KC, Lin PM, Lee MS. Impact of female age and male infertility on ovarian reserve markers to predict outcome of assisted reproduction technology cycles. Reprod Biol Endocrinol 2009;7:100.

60. Kidd SA, Eskenazi B, Wyrobek AJ. Effects of male age on semen quality and fertility: a review of the literature. Fertil Steril 2001;75:237–48.

39. Broekmans FJ, de ZD, Howles CM, Gougeon A, Trew G, Olivennes F. The antral follicle count: practical recommendations for better standardization. Fertil Steril 2010;94:1044–51.

62. Ford WC, North K, Taylor H, Farrow A, Hull MG, Golding J. Increasing paternal age is associated with delayed conception in a large population of fertile couples: evidence for declining fecundity in older men. The ALSPAC Study Team (Avon Longitudinal Study of Pregnancy and Childhood). Hum Reprod 2000;15:1703–8.

40. Hehenkamp WJ, Looman CW, Themmen AP, de Jong FH, te Velde ER, Broekmans FJ. Anti-Mullerian hormone levels in the spontaneous menstrual cycle do not show substantial fluctuation. J Clin Endocrinol Metab 2006;91:4057–63. 41. Sowers MR, Eyvazzadeh AD, McConnell D, Yosef M, Jannausch ML, Zhang D, et al. Anti-mullerian hormone and inhibin B in the definition of ovarian aging and the menopause transition. J Clin Endocrinol Metab 2008;93(9):3478–83.

1174 l NOVEMBER JOGC NOVEMBRE 2011

61. Goldman N, Montgomery M. Fecundability and husband’s age. Soc Biol 1989;36(3–4):146–66.

63. Klonoff-Cohen HS, Natarajan L. The effect of advancing paternal age on pregnancy and live birth rates in couples undergoing in vitro fertilization or gamete intrafallopian transfer. Am J Obstet Gynecol 2004;191:507–14. 64. de La RE, de MJ, Thepot F, Thonneau P. Fathers over 40 and increased failure to conceive: the lessons of in vitro fertilization in . Fertil Steril 2006;85:1420–4.

Advanced Reproductive Age and Fertility

65. Spandorfer SD, Avrech OM, Colombero LT, Palermo GD, Rosenwaks Z. Effect of parental age on fertilization and pregnancy characteristics in couples treated by intracytoplasmic sperm injection. Hum Reprod 1998;13:334–8. 66. Aboulghar M, Mansour R, Al-Inany H, Abou-Setta AM, Aboulghar M, Mourad L, et al. Paternal age and outcome of intracytoplasmic sperm injection. Reprod Biomed Online 2007;14:588–92.

81. Astolfi P, De PA, Zonta LA. Paternal age and preterm birth in Italy, 1990 to 1998. Epidemiology 2006;17:218–21. 82. Orioli IM, Castilla EE, Scarano G, Mastroiacovo P. Effect of paternal age in achondroplasia, thanatophoric dysplasia, and osteogenesis imperfecta. Am J Med Genet 1995;59:209–17. 83. North K. Neurofibromatosis type 1: review of the first 200 patients in an Australian clinic. J Child Neurol 1993;8:395–402.

67. Gallardo E, Simon C, Levy M, Guanes PP, Remohi J, Pellicer A. Effect of age on sperm fertility potential: oocyte donation as a model. Fertil Steril 1996;66:260–4.

84. Bunin GR, Needle M, Riccardi VM. Paternal age and sporadic neurofibromatosis 1: a case-control study and consideration of the methodologic issues. Genet Epidemiol 1997;14:507–16.

68. Paulson RJ, Milligan RC, Sokol RZ. The lack of influence of age on male fertility. Am J Obstet Gynecol 2001;184:818–22.

85. Jadayel D, Fain P, Upadhyaya M, Ponder MA, Huson SM, Carey J, et al. Paternal origin of new mutations in von Recklinghausen neurofibromatosis. Nature 1990;343(6258):558–9.

69. Dain L, Auslander R, Dirnfeld M. The effect of paternal age on assisted reproduction outcome. Fertil Steril 2011;95:1–8. 70. Luna M, Finkler E, Barritt J, Bar-Chama N, Sandler B, Copperman AB, et al. Paternal age and assisted reproductive technology outcome in ovum recipients. Fertil Steril 2009;92:1772–5. 71. Frattarelli JL, Miller KA, Miller BT, Elkind-Hirsch K, Scott RT Jr. Male age negatively impacts embryo development and reproductive outcome in donor oocyte assisted reproductive technology cycles. Fertil Steril 2008;90:97–103. 72. Kleinhaus K, Perrin M, Friedlander Y, Paltiel O, Malaspina D, Harlap S. Paternal age and spontaneous abortion. Obstet Gynecol 2006;108:369–77. 73. Maconochie N, Doyle P, Prior S, Simmons R. Risk factors for first trimester miscarriage—results from a UK-population-based case-control study. BJOG 2007;114:170–86. 74. Erickson JD. Paternal age and Down syndrome. Am J Hum Genet 1979;31:489–97. 75. Erickson JD, Bjerkedal TO. Down syndrome associated with father’s age in Norway. J Med Genet 1981;18:22–8. 76. Hook EB, Cross PK. Paternal age and Down’s syndrome genotypes diagnosed prenatally: no association in New York state data. Hum Genet 1982;62:167–74. 77. Stene J, Fischer G, Stene E, Mikkelsen M, Petersen E. Paternal age effect in Down’s syndrome. Ann Hum Genet 1977;40:299–306. 78. Toriello HV, Meck JM. Statement on guidance for genetic counseling in advanced paternal age. Genet Med 2008;10:457–60. 79. Tough SC, Faber AJ, Svenson LW, Johnston DW. Is paternal age associated with an increased risk of low birthweight, preterm delivery, and multiple birth? Can J Public Health 2003;94:88–92. 80. Basso O, Wilcox AJ. Paternal age and delivery before 32 weeks. Epidemiology 2006;17:475–8.

86. Riccardi VM, Dobson CE, Chakraborty R, Bontke C. The pathophysiology of neurofibromatosis: IX. Paternal age as a factor in the origin of new mutations. Am J Med Genet 1984;18:169–76. 87. Carothers AD, McAllion SJ, Paterson CR. Risk of dominant mutation in older fathers: evidence from osteogenesis imperfecta. J Med Genet 1986;23:227–30. 88. Lauritsen MB, Pedersen CB, Mortensen PB. Effects of familial risk factors and place of birth on the risk of autism: a nationwide -based study. J Child Psychol Psychiatry 2005;46:963–71. 89. Reichenberg A, Gross R, Weiser M, Bresnahan M, Silverman J, Harlap S, et al. Advancing paternal age and autism. Arch Gen Psychiatry 2006;63:1026–32. 90. Croen LA, Najjar DV, Fireman B, Grether JK. Maternal and paternal age and risk of autism spectrum disorders. Arch Pediatr Adolesc Med 2007;161:334–40. 91. Malaspina D, Harlap S, Fennig S, Heiman D, Nahon D, Feldman D, et al. Advancing paternal age and the risk of schizophrenia. Arch Gen Psychiatry 2001;58:361–7. 92. Byrne M, Agerbo E, Ewald H, Eaton WW, Mortensen PB. Parental age and risk of schizophrenia: a case-control study. Arch Gen Psychiatry 2003;60:673–8. 93. Tsuchiya KJ, Takagai S, Kawai M Matsumoto H, Nakamura K, Minabe Y, et al. Advanced paternal age associated with an elevated risk for schizophrenia in offspring in a Japanese population. Schizophr Res 2005;76(2–3):337–42. 94. Zammit S, Allebeck P, Dalman C, Lundberg I, Hemmingson T, Owen MJ, et al. Paternal age and risk for schizophrenia. Br J Psychiatry 2003;183:405–40. 95. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

NOVEMBER JOGC NOVEMBRE 2011 l 1175

SOGC CLINICAL PRACTICE GUIDELINE SOGC Clinical Practice Guideline

No. 249, October 2010

Asymptomatic Endometrial Thickening Abstract This Clinical Practice Guideline has been prepared by the Clinical Practice Gynaecology Committee and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada.

Objective: To formulate clinical recommendations for the assessment of endometrial thickening when it is found on ultrasound in a postmenopausal patient without bleeding.

PRINCIPAL AUTHOR

Outcomes: Ensure that women with asymptomatic thickening and endometrial polyps found on ultrasound are managed appropriately.

Wendy Wolfman, MD, Toronto ON CLINICAL PRACTICE GYNAECOLOGY COMMITTEE Nicholas Leyland, MD (Chair), North York ON Wendy Wolfman, MD, Toronto ON Mark Heywood, MD, Vancouver BC Sukhbir S. Singh, MD, Ottawa ON David Allan Rittenberg, MD, Halifax NS Renée Soucy, MD, Chandler QC Catherine Allaire, MD, Vancouver BC Alaa Awadalla, MD, Winnipeg MB Carolyn Best, MD, Toronto ON Sheila Dunn, MD, Toronto ON Nathalie Leroux, MD, Montreal QC Frank Potestio, MD, Thunder Bay, ON Vyta Senikas, MD, Ottawa ON Disclosure statements have been received from all of the committee. SPECIAL CONTRIBUTORS Sarah Wallace, MD, Sudbury ON Rebecca Menzies, MSc, Toronto ON The literature searches and bibliographic for this guideline were undertaken by Becky Skidmore, Medical Research Analyst, Society of Obstetricians and Gynaecologists of Canada.

Evidence: Published literature was retrieved through searches of English language articles from the EMBASE, Cochrane, and PubMed databases for relevant peer-reviewed articles dating from 1970 to 2009, using appropriate controlled vocabulary (e.g., “asymptomatic endometrial thickness,” “endometrial cancer,” “postmenopausal bleeding,” “transvaginal ultrasonography,” “endometrial biopsy” and “endometrial polyp”). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. Searches were updated on a regular basis and incorporated in the guideline to April 2010. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Values: The level of evidence was determined according to the criteria established by the Canadian Task Force on Preventative Health Care (Table). Recommendations are ranked according to this method. Benefits, harms, and costs: It is anticipated that the adoption of these recommendations would save postmenopausal women unnecessary anxiety, pain, and risk of procedural complication. It is also expected to decrease the cost to the health system by eliminating unnecessary interventions. Key Words: Asymptomatic endometrial thickening, asymptomatic endometrial polyp, endometrial cancer, transvaginal ultrasonography, hysteroscopy, endometrial biopsy tamoxifen, postmenopausal polyps Recommendations 1. Transvaginal ultrasound should not be used as screening for endometrial cancer. (II-1E) 2. Endometrial sampling in a postmenopausal woman without bleeding should not be routinely performed. (II-1E) 3. Indications for tissue sampling of the endometrium in bleeding postmenopausal women with an endometrial thickness of greater than 4 to 5 mm should not be extrapolated to asymptomatic women. (II-2E)

Key Words: Asymptomatic endometrial thickening, asymptomatic endometrial polyp, endometrial cancer, transvaginal ultrasonography, hysteroscopy, endometrial biopsy tamoxifen, postmenopausal polyps

4. A woman who has endometrial thickening and other positive findings on ultrasound, such as increased vascularity, inhomogeneity of endometrium, particulate fluid, or thickened endometrium over 11 mm, should be referred to a gynaecologist for further investigations. (II-1A) 5. Decisions about further investigations should be made on a case-by-case basis in asymptomatic women with increased

This document reflects emerging clinical and scientific advances on the date issued, and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

990

l OCTOBER JOGC OCTOBRE 2010

Asymptomatic Endometrial Thickening

Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

D. There is fair evidence to recommend against the clinical preventive action E. There is good evidence to recommend against the clinical preventive action L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.71 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the The Canadian Task Force on Preventive Health Care.71

endometrial thickening and risk factors for endometrial cancer such as obesity, hypertension, and late menopause. (II-1B) 6. In asymptomatic women on tamoxifen, a routine ultrasound for endometrial thickening should not be performed. (II-2E) 7. Not all postmenopausal women who have asymptomatic endometrial polyps require surgery. Women found to have asymptomatic polyps on ultrasound should be triaged for intervention according to size of the polyp, age, and other risk factors. (II-1A) J Obstet Gynaecol Can 2010;32(10):990–999

INTRODUCTION

n this guideline, asymptomatic endometrial thickening is defined as an endometrium of > 5 mm discovered on ultrasound in a postmenopausal woman who is not bleeding.1–3 Current ultrasound literature suggests that asymptomatic endometrial thickness of 8 to 11 mm in a postmenopausal women is not abnormal.4–8 The measurement of the endometrium is made at its maximal thickness on a midline sagittal image of the uterus obtained by transvaginal ultrasound. It is a bilayer measurement combining the width of both the anterior and the posterior layers of the endometrium. It has been suggested that the normal endometrial thickness in a postmenopausal woman is 5 mm. There is controversy about the normal measurement in

I

ABBREVIATIONS HT

hormone therapy

TVUS

transvaginal ultrasound

women on hormone therapy. Studies have shown a normal range from 5.4 to 10.8 mm.4–6,9 An endometrium 2 mm thicker in women who use sequential therapy may be normal.10 The endometrium may normally be thicker in the first year after the last menstrual period, reflecting some residual hormonal activity.11 The finding of asymptomatic endometrial thickening on ultrasound presents a clinical management dilemma and is a frequent reason for referral by family physicians. Concern is raised when an endometrium of > 5 mm is discovered during an ultrasound examination, often one that is undertaken for non-gynaecologic reasons. Subsequent radiologic reports prompt interventions that can be invasive and involve risk. The incidence of endometrial thickening (³ 4.5 mm) in postmenopausal women ranges from 3% to 17%,1–3 while the incidence of endometrial cancer in an unselected postmenopausal population is 1.3 to 1.7/1000.12–14 The American Cancer Society does not recommend routine screening of asymptomatic patients for endometrial cancer.15 The Canadian Cancer Society reports that there is inadequate evidence that screening by ultrasonography or endometrial sampling would reduce the mortality from endometrial cancer.16 The 2001 consensus statement on bleeding published by the Society of Radiologists in Ultrasound included a caveat that the 5 mm threshold does not apply to asymptomatic women with incidentally observed thickened endometrium.17 In 2009, the American College of Obstetricians and Gynecologists stated that there was OCTOBER JOGC OCTOBRE 2010 l

991

SOGC Clinical Practice Guideline

no evidence to recommend routine investigations for asymptomatic endometrial thickening.18 Despite this recommendation, clinicians are concerned when the ultrasound report states that endometrial cancer cannot be ruled out because of endometrial thickening found in an asymptomatic postmenopausal woman. Goldstein, in 2010,19 recommended postmenopausal asymptomatic endometrial thickening be evaluated on a case-by-case basis. The clinician must consider risk factors for endometrial cancer including obesity, polycystic ovary syndrome, and diabetes mellitus in their decision making. Goldstein19 emphasized that it is inappropriate to investigate every asymptomatic patient with thickened endometrium > 5 mm. ENDOMETRIAL CANCER AND RISK FACTORS

Endometrial cancer is the most common gynaecologic malignancy.20 The incidence in Canada is 19/100 000 women. The Canadian Cancer Society estimated that in 2009 there would be 4400 cases of endometrial cancer and 720 deaths due to the disease in Canada.16 Approximately 80% of endometrial cancers occur in postmenopausal women.21 Ninety percent of women with endometrial cancer present with bleeding.22 Most women (72%) have stage I cancer when diagnosis is made,22 and the survival rate depends on the stage, grade, and type of cancer. Five-year survival rates for localized, regional, and metastatic endometrial cancer are 95%, 67%, and 23%, respectively, and the overall 5-year survival rate is 86%.20 Individual risk factors are obesity, high-fat diet, reproductive factors such as nulliparity and polycystic ovary syndrome, early menarche, and late menopause.23 Tamoxifen use also increases the risk of developing endometrial cancer by 2.3 per 1000 women.24 Women with hereditary nonpolyposis colorectal cancer syndrome have an estimated cumulative incidence of endometrial cancer ranging from 20% to 60% by the age of 70 years. The mean age of developing cancer is 47 in carriers versus 60 years in those with non-inherited endometrial cancer.25 No studies have yet shown the benefit of screening for endometrial cancer in female carriers of hereditary nonpolyposis colorectal cancer syndrome.26 The incidence of endometrial cancer is lower in Black women. However, the overall mortality due to the disease is higher among this group.27 A Swedish longitudinal evaluation of postmenopausal women found that a history of bleeding incurs a 64-fold increased risk of endometrial cancer.28,29 For any woman presenting with postmenopausal bleeding there is approximately a 10% risk of endometrial carcinoma.29 If the woman is on hormone therapy and bleeds, the risk is 1%.29 992

l OCTOBER JOGC OCTOBRE 2010

It is unknown how many women who have endometrial cancer are diagnosed in the absence of bleeding. Diagnosis of cancer in asymptomatic women has been estimated by Smith-Bindman to be 5% to 10% of all cases.30 It is also unknown if diagnosing endometrial cancer before a woman bleeds would improve overall survival. In 1981 Koss et al.2 initiated a screening study of 1280 asymptomatic women aged 45 and older via endometrial sampling in a New York Medical Center. Carcinoma was found in only 8 patients (6/1000). In 1997 Korhonen et al.31 published their results of pathologic findings for endometrial biopsy in 2964 perimenopausal and postmenopausal women who were candidates for hormone therapy. Endometrial biopsy findings were 68.7% atrophic, 23.5% proliferative, 0.5% secretory, 0% hyperplastic, and < 0.07% malignant. Of the biopsy samples, 6.6 % were insufficient for classification, reflecting the low incidence of pathology in the general population. A necropsy study found an occult incidence of endometrial cancer of 22 to 31/10 000 women (0.22% to 0.31%).32 These studies indicate a background incidence of endometrial cancer of 0.6 to 6/1000 women (0.2% to 0.6%).2,32 SIGNIFICANCE OF ASYMPTOMATIC ENDOMETRIAL THICKENING

In a menstruating woman the endometrium changes with the phase of the menstrual cycle. It ranges from 3 mm after menses to a thickness of 15 mm in the luteal phase. In the first year after the last menstrual period the normal endometrium is often thicker than it will be several years after menopause, reflecting fluctuating levels of estrogen. Descriptions of the endometrium on ultrasound examination include global thickening, heterogeneity, thickening, focal areas of thickening, fluid collections, increased vascularity, and myometrial associated findings such as myometrial cysts, and submucosal fibroids. After menopause, endometrial thickening may reflect proliferative endometrium, cystic hyperplasia, complex hyperplasia, atypical hyperplasia, or carcinoma of the endometrium. Ultrasound evidence of thickened endometrium may also indicate structural abnormalities such as a uterine septum, submucous myomas, polyps, or adenomyosis. Ultrasound technology, by identifying vascular flow, now allows differentiation of polyps from other abnormalities.33 Increased vascularity and fluid accumulation in association with endometrial thickening are cause for greater concern than other findings.34

Asymptomatic Endometrial Thickening

SCREENING STUDIES OF ASYMPTOMATIC WOMEN

The purpose of performing ultrasound in non-bleeding postmenopausal women may be to investigate abdominal pain or masses or to delineate the adnexae when pelvic examination is inadequate. Screening studies have been undertaken to assess whether ultrasound can detect endometrial cancer in large populations of asymptomatic women.3,35,36 The American Cancer Society concluded that there was insufficient evidence to recommend any routine screening for endometrial cancer with TVUS or endometrial biopsy.37 Screening asymptomatic women will result in unnecessary additional examinations because of low specificity. Most cases of endometrial cancer are diagnosed as a result of symptoms reported by patients, and a high proportion of these cases are diagnosed at an early stage, with high rates of survival. In 1995, Ciatto and colleagues35 performed TVUS on 2025 women to evaluate the feasibility of using this modality to screen for endometrial carcinoma solely on the basis of endometrial thickness. In this study, 117 women (5.8%) showed abnormal thickness of > 4 mm. Of these, 98 underwent endometrial biopsy, but 32 had imable cervical stenosis. It was decided that evaluation of the endometrium by dilatation and curettage was not warranted. These women underwent repeat transvaginal ultrasound examination. The positive predictive value was 3.3%, with 3 endometrial carcinomas found out of 66 biopsies. A 1999 study by Vuento et al.3 focused on the feasibility of TVUS to screen for endometrial cancer in asymptomatic postmenopausal women using multiple criteria, one of which was endometrial thickness. In this study, 291 of 1074 women (29%) had an abnormal thickness > 4 mm, uterine artery pulsatility index < 1.0, or fluid accumulation in the endometrial cavity. However, after biopsy, only 23 women were found to have endometrial pathology, and only 3 were found to have endometrial cancer. Endometrial fluid was found in 12%. Another case of carcinoma was found 2.5 years later in a patient who had refused biopsy. The authors concluded that TVUS, while sensitive for detecting early endometrial cancer, has a low specificity that precludes its utility as a screening modality. Doppler ultrasound did not improve detection of abnormal endometrial pathology. A study by Fleischer et al.36 of 1926 women who underwent ultrasound examination as part of the workup for an osteoporosis prevention trial found that 93 women had an endometrium > 6 mm. When endometrial aspiration of 42 of these women was undertaken, there were abnormal findings in only 1 case. A further 1750 of 1833 women with endometrial thickness of < 6 mm underwent sampling,

yielding 5 abnormal results (1 endometrial cancer). The sensitivity was 17% for 6 mm and 33% using 5 mm as a threshold. The positive predictive value was 2%. The negative predictive value at < 6 mm was 99%. Smith-Bindman et al.30 calculated a 6.7% risk of endometrial cancer if the endometrium was > 11 mm, and a 0.002 % risk if the endometrium was thin (< 11 mm). This theoretical risk was calculated on the basis of a review of published and unpublished data and an estimate of 15% of total cases of endometrial cancer occurring in women who have no bleeding. The risk is also related to age, with women > 70 years, with a thicker endometrium having a higher risk (9.3% with 11 mm endometrium). Gambacciani et al.1 undertook a retrospective review of 850 postmenopausal women who were investigated with outpatient hysteroscopy for various causes of thickening. The authors focused on the 148 asymptomatic postmenopausal women with endometrium > 4 to 5 mm, and found 1 case of adenocarcinoma (0.7%) (endometrium 16 mm) and 9 cases of hyperplasia (6.1%). In this study 24/27 cases of adenocarcinoma presented with bleeding, 2/27 had an abnormal Papanicolaou smear, and 1/27 (3.7%) had thickened endometrium. One hundred forty-seven hysteroscopies were performed for benign pathology; the false positive rate was 93.2%. Gerber et al.38 in a retrospective analysis discovered 16 patients (13%) had endometrial cancer when an endometrial thickening of 10 mm was used as a cut-off in the investigation of 123 asymptomatic women; 21 of the women (17%) had hyperplasia. Asymptomatic women without symptoms had no prognostic advantage over the symptomatic women if bleeding had occurred for < 8 weeks. Duration of postmenopausal bleeding was correlated with increasing tumour stage and reduced survival time. Endometrial screening often resulted in unnecessary operations with increased morbidity and cost. Archer et al.12 attempted to obtain endometrial samples in 801 asymptomatic perimenopausal and postmenopausal women prior to enrolment in a multicentre hormone replacement therapy study. Of the samples, 75% contained sufficient tissue for diagnosis. One endometrial cancer was diagnosed, illustrating the low incidence of disease in asymptomatic women and the low incidence of disease in asymptomatic women. The endometrium was atrophic in 46.9%, proliferative in 16.7%, secretory in 6.8%, and hyperplastic in 5.2%. Tsuda et al.39 screened 1400 asymptomatic postmenopausal Japanese women and found a prevalence of endometrial disease of 2.3% in asymptomatic and 21% in symptomatic women. At a cut-off of 3 mm in non-bleeding women, sensitivity was 90%, specificity 84%, and positive predictive OCTOBER JOGC OCTOBRE 2010 l

993

SOGC Clinical Practice Guideline

value 12%. With an endometrial thickness < 3 mm, the probability that endometrial disease would be missed was 0.003. A review of the literature therefore does not indicate that routine screening via transvaginal ultrasound for endometrial cancer is recommended. There is a baseline incidence of thickening (³ 4.5 mm) of up to 17%, with a low incidence of cancer < 1%.1,12,36–38 WOMEN WITH RISK FACTORS

Increased lifetime estrogen exposure has been associated with an increased risk of endometrial cancer. Early menarche, late menopause, obesity, and unopposed estrogen use have been linked to an increased risk. Should endometrial thickening on ultrasound be more aggressively investigated in women with risk factors? A regression analysis by Maatela et al.40 of endometrial thickening in asymptomatic postmenopausal women found an increased risk of pathological findings in the presence of obesity (BMI > 26) and late menopause. In a 1993 study of ultrasonic thickness of the endometrium in 300 asymptomatic postmenopausal women, Andolf et al.41 found that endometrial thickness correlated significantly with BMI. In the same study, Andolf and colleagues found a non-significant trend towards a higher prevalence of predisposing factors (hypertension, nulliparity, diabetes) in women with a thick endometrium. The Women’s Health Initiative data, however, showed that the interactions of age, race/ethnicity, BMI, hypertension, smoking status, pack-years of smoking, prior use of unopposed estrogen, or prior use of estrogen and progesterone had no significant effect on the observed incidence rate of endometrial cancer.42 There was a insignificant decrease in the number of endometrial cancer cases in women taking HT rather than placebo (13 fewer cases per 10 000). Martinez-Rubio and Alcazar43 prospectively compared the prevalence of abnormal endometrium in 187 postmenopausal asymptomatic, normotensive women and 182 asymptomatic postmenopausal women receiving anti-hypertensive drugs. The endometrium was assessed via office endometrial biopsy and TVUS when the definition of abnormal ultrasound was > 5 mm. Women taking antihypertensive medications were significantly more likely than normotensive women to have endometrial thickness > 5 mm (26.9% vs. 12.8%; P 0.001), heterogeneous endometrial polyps (23.1 vs. 12.8%; P < 0.001), and endometrial polyps (17.6 vs. 9.6%; P < 0.001). These results were independent of body mass index. Sit et al.44 evaluated asymptomatic thickening as an estrogen biomarker as a part of the Prostate, Lung, Colorectal and 994

l OCTOBER JOGC OCTOBRE 2010

Ovarian Cancer Screening Trial in 1271 women. Thickness ranged from 1 to 32 mm (median 3 mm). Frequency of thicker endometrium was independently associated with increasing BMI and current use of HT. The time from menopause is a factor in investigating the significance of the findings. Tsuda et al.11 found histologic findings of a proliferative endometrium in 28% of women < 5 years post-menopause and in 4.8% in women ³ 5 years post-menopause. Andolf and colleagues41 found only an insignificant trend towards decreasing endometrial thickness with time after menopause. ENDOMETRIAL THICKENING IN WOMEN ON HT

Hänggi et al.10 compared TVUS with histological findings in endometrial evaluation of postmenopausal women using hormone therapy to evaluate the safety of 3 hormone therapy regimens versus no therapy. Patients on oral micronized 17b-estradiol/oral sequential dydrogesterone were compared with those using transdermal 17b-estradiol/oral sequential dydrogesterone, or oral tibolone. If endometrial thickness was < 5 mm, endometrial biopsy sample was either inactive/atrophic or insufficient for diagnosis. Hyperplastic or malignant change was not reported. After 24 months, endometrial thickness was increased both in the oral and the transdermal 17b-estradiol/dydrogesterone groups. The tibolone group showed no difference from the control group. In the Postmenopausal Estrogen and Progestin Interventions Trial, 448 participants underwent both TVUS and endometrial biopsy over 4 years.45 They were randomized to placebo or to cyclic or sequential HT. Langer et al.45 found that at a threshold value of 5 mm for endometrial thickness, TVUS had 90% sensitivity and 48% specificity. No cancer or atypical hyperplasia was found in 261 women with endometrial thickness of < 5 mm. Two cases of atypical hyperplasia and 1 case of cancer were found in 307 women with endometrial thickness ³ 5 mm. The majority of serious disease cases were found in women with endometrial thickness > 10 mm. Eight cases of complex hyperplasia, 3 cases of atypical hyperplasia, and 1 case of adenocarcinoma were found in the study population. Using this threshold, more than one half of the women would undergo a biopsy, while only 4% had serious disease. Gull et al.46 evaluated a random sample of 1000 women between the ages of 45 and 80 who underwent screening ultrasound in Sweden; 559 were postmenopausal. The current use of HT was associated with increasing endometrial thickness. Kurtay et al.47 assessed the effects of hormone therapy on endometrial thickness in asymptomatic postmenopausal

Asymptomatic Endometrial Thickening

women between 1997 and 2001. Three hundred seven women received oral equine HT, oral equine estrogen, oral 17b-estradiol, or oral tibolone. All women on estrogen also received a progestin. Patients with endometrial thickness > 7 mm underwent a biopsy. Patients taking tibolone did not have a statistically significant increased thickness of endometrium compared with those in the other arms of the study. The authors suggested that tibolone closely mimics the natural atrophic state of the postmenopausal endometrium and could be considered as an alternative to HT. In a 10-year (1991 to 2001) study undertaken in by Mossa et al.,48 the threshold of endometrial thickness was investigated in 587 women on HT. An increased endometrial thickness and increased incidence of bleeding was found in the HT group. However, no difference in the prevalence of endometrial cancer was found between the HT and control groups. The authors recommended that women with bleeding on HT undergo hysteroscopy and biopsy only if endometrial thickness is > 8 mm. STUDIES IN WOMEN WITH ENDOMETRIAL POLYPS

The estimated prevalence of polyps in women with postmenopausal bleeding ranges from 13% to 50%.49 Several studies have also shown that polyps are highly prevalent in asymptomatic postmenopausal women.49–52 The molecular and pathological etiology of endometrial polyps is evolving. Most lesions are benign, but some may be pre-malignant (simple or complex hyperplasia with cytological atypia) or malignant.53 Malignant pathology is identified in 0.5% to 4.8% of polyps found in postmenopausal women.53,54 However, polyps are a known risk factor for the subsequent development of endometrial cancer.49–53 Fernández-Parra et al.55 conducted a retrospective chart review to determine the incidence of malignant polyps in postmenopausal women. Of 1870 hysteroscopies conducted at the study centre, 653 had confirmed polyps. The majority of women had postmenopausal bleeding, and only 117 women were asymptomatic. No cases of cancer in a polyp were found in asymptomatic women. In a Norwegian study of 411 pre- and postmenopausal patients, pathological analysis of hysteroscopically resected endometrial polyps was conducted.49 Thirty-one percent of study participants were symptomatic in postmenopause, and 18.5% were asymptomatic in postmenopause. In the group of postmenopausal women with symptoms, 5.5% of polyps were malignant or had atypical hyperplasia compared with 2.6% in women with no symptoms. The authors concluded that hysteroscopic resection of both symptomatic and asymptomatic polyps should be performed since the natural course of malignant polyps is still unknown.

Antunes et al.53 sought to determine factors associated with malignancy in endometrial polyps in their 2007 study. A retrospective chart review of 475 surgical patients of any age who underwent hysteroscopy for endometrial polyp removal were included in the study. Overall, 78.53% of the polyps were benign, 13.47% had simple or complex hyperplasia, and 2.74% were malignant. Statistical subanalysis showed that women over 60 years of age were 3.28 times more likely than their younger counterparts to have malignant endometrial polyps. Women over 60 with postmenopausal bleeding were 5.31 times more likely than asymptomatic younger women to have malignant polyps. The authors did not find a significant difference in the prevalence of malignant polyps associated with arterial hypertension, diabetes mellitus, obesity, HT, or tamoxifen use. Antunes et al.53 concluded that older women with postmenopausal bleeding are at greatest risk for malignancy and should have hysteroscopic resection of the polyps. In 2009, Ferrazzi et al.54 sought to elucidate the risk of malignancy in endometrial polyps in a large sample of asymptomatic and symptomatic postmenopausal women. A total of 1155 asymptomatic women and 770 bleeding women who had undergone polypectomy were included in the retrospective clinical chart review study. The authors found only one case of a cancerous polyp in the asymptomatic group. The polyp in this case was large, with a mean diameter of 40 mm. There was a significantly (P < 0. 001) higher prevalence of malignant polyps in the symptomatic group. The authors concluded that women with incidentally found polyps do not require polypectomy unless the polyps have a large diameter. In 2009, Gregoriou et al.56 published a retrospective analysis of 516 cases of women who underwent hysteroscopic polypectomy to determine risk factors for malignancy. The final pathology report after polyp resection was compared with each patient chart. The majority of polyps were benign (96.9%), and a small percentage were premalignant (1.2%) or malignant (1.9%). Obesity (BMI > 30) (P = 0.001), diabetes mellitus (P = 0.04), menopause (P = 0.005), and age > 60 years (P = 0.001) were all significant risk factors for the development of malignant polyps. Gregoriou et al.56 suggested that all clinical parameters must be considered to assess the risk of the malignancy potential of a polyp in a postmenopausal woman. Baiocchi et al.57 also conducted a large-scale retrospective study to determine the clinical factors associated with malignant polyps. Inclusion criteria for this study were diagnosis of an endometrial polyp or endometrial postmenopausal thickening of ³ 5 mm. In total, 1242 cases were included in this study run from January 1995 to December 2006. The majority of patients (95.2%) had OCTOBER JOGC OCTOBRE 2010 l

995

SOGC Clinical Practice Guideline

benign polyps. Hyperplastic polyps with atypia occurred in 1.3% of patients and cancer in 3.5%. Postmenopausal status, age > 60, and hypertension were all significantly correlated with cancer in the polyp. Other clinical factors such as diabetes mellitus, HT, tamoxifen, and bleeding symptoms were not significantly different between the benign and cancerous polyp groups. In fact, the 2 most important factors appear to be advanced age and postmenopausal status. Baiocci et al.57 concluded that older menopausal patients with hypertension are at the greatest risk of developing a malignant polyp. However, in both the Gregoriou et al.56 and Baiocci et al.57 studies the incidence of cancer in polyps was low (1.9% and 3.5% respectively). IMPLICATIONS OF TAMOXIFEN FOR ENDOMETRIAL THICKENING

Women taking tamoxifen have a greater risk of endometrial cancer. This risk is augmented further if those women were previously taking estrogen replacement therapy.58 Routine endometrial biopsy is not necessary in asymptomatic women who are taking tamoxifen.24 Endometrial thickening can be confused with stromal hypertrophy in these women. However, any abnormal bleeding should be evaluated. Endometrial cancers that occur in these women are similar to endometrial cancers occurring in the general population with respect to stage, grade, and histology. Prognosis tends to be good. To date there have been no published studies evaluating the effect of endometrial cancer screening modalities on mortality among women taking tamoxifen for the treatment or prevention of breast cancer. Fishman et al.59 found that endometrial thickness increased with increasing duration of tamoxifen use at a rate of 0.75 mm/yr. The mean endometrial thickness after 5 years of tamoxifen use was 12 mm (range 6 to 21 mm). After discontinuation of tamoxifen treatment the endometrium decreased by 1.27 mm/yr. Gerber et al.60 investigated the effect on the endometrium in women with breast cancer when they switched from tamoxifen to an aromatase inhibitor, anastrozole. A total of 226 postmenopausal women who had received tamoxifen 20 mg/d for ³ 12 months, £ 48 months and had developed abnormal vaginal bleeding and/or asymptomatic endometrial thickness >10 mm underwent hysteroscopy and dilatation and curettage. One hundred seventy-one were randomized to continue tamoxifen (88) or changed to anastrozole (83). Patients were monitored for £ 42 months via TVUS at 6-monthly intervals. There was no difference in recurrent vaginal bleeding between groups: 4/83 on tamoxifen and 9/88 on anastrozole. Mean endometrial thickness for patients who switched to anastrozole was significantly less than for those on tamoxifen. Repeat hysteroscopy and 996

l OCTOBER JOGC OCTOBRE 2010

dilatation and curettage revealed endometrial atrophy in all 4 cases in the anastrozole group, and there were 14 polyps, 8 hyperplasias, and 7 atrophies in the tamoxifen group. Women on long-term tamoxifen therapy are thought to have higher risk of developing endometrial cancer. Berlière et al.61 enrolled 575 women with estrogen receptor-positive breast cancer into a prospective study of endometrial pathology. Prior to tamoxifen treatment, all women had TVUS, and if endometrial thickness was > 5 mm, hysteroscopy was performed to remove polyps or lesions. In the study by Berlière et al.,61 women who had lesions before initiating tamoxifen therapy were found at 2-year follow-up to be at significantly higher risk (P < 0.001) of developing atypical lesions. The lesions in the women who had lesions originally were also more severe than any developed in the women who were initially lesion-free. The authors concluded that women with initial lesions may be at greater risk for the oncologic effects of tamoxifen on their endometrium. Garuti et al.62 also conducted a prospective study of estrogenpositive breast cancer patients who were being prescribed tamoxifen adjuvant therapy. The authors enrolled 99 asymptomatic patients and evaluated the endometrium using hysteroscopy if their endometrial thickness was > 4 mm. Thirty-four women had thickness > 4 mm, 10 had polyps, 4 had simple hyperplasia, and 3 had complex hyperplasia. Thus, 18.6% of the patients had asymptomatic endometrial pathology before tamoxifen treatment. Garuti et al.62 suggested routine endometrial screening for all women before initiation of tamoxifen therapy since subclinical endometrial pathology is prevalent in this group of women. The most recent American College of Obstetricians and Gynecologists guideline for tamoxifen use and endometrial cancer risk has several recommendations for postmenopausal women.24 Women may be stratified into 2 risk groups based on whether they have initial endometrial lesions. Women with initial lesions are at higher risk for developing endometrial cancers on tamoxifen therapy. Routine endometrial screening is not recommended for women taking tamoxifen because of the costs incurred and risk of unnecessary further investigation. Instead, women should be educated regarding the symptoms of endometrial cancer and instructed to consult their doctor if they develop any spotting or postmenopausal bleeding. If a woman develops endometrial hyperplasia, the use of tamoxifen should be re-assessed. COMPLICATIONS OF INVESTIGATION

Endometrial biopsy may result in pain, bleeding, infection, and uterine perforation, and office-based endometrial biopsy has false negative rates of 5% to 15%.63 Dilatation

Asymptomatic Endometrial Thickening

and curettage has false negative rates of 2% to 6%.46 Endometrial sampling may be limited or impossible because of virginal status, cervical stenosis, small introitus, pain, or anatomical abnormalities such as fibroids aberrating the canal. The finding of insufficient tissue in the face of endometrial thickening prompts further investigations such as hysterosonogram, office hysteroscopy, dilatation and curettage, and diagnostic and therapeutic hysteroscopy under general anaesthetic.63–66 Each of these procedures has its own complications, including untimely hysterectomy. In a study designed to compare blind biopsy, hysteroscopy with biopsy, and ultrasound in 683 women who were experiencing bleeding, discomfort and distress was reported in 16% of women who had hysteroscopy and in 10% who had blind biopsy.67 No major complications were reported in the Shushan et al.68 study of 300 women who underwent hysteroscopic polyp removal. Minor complications reported in the study included bradycardia during general anaesthetic and postoperative hemorrhage that was treated conservatively with uterine tamponade for 8 hours. Two of the 300 patients were reitted to hospital with postoperative fever and treated with antibiotic combination therapy for pelvic inflammatory disease. Lev-Sagie et al.69 reported a complication rate of 3.6% in a retrospective study of women who underwent hysteroscopy after incidental finding of endometrial polyp on ultrasound examination. The complications reported in the study were uterine perforation in 2 women and complication of general anaesthetic due to difficult intubation. Ferrazzi et al.54 reported a particularly low rate of complications in the literature. Only the minor complications of cervical tears and false ages were reported in 0.6% and 0.3% of asymptomatic patients respectively. False age complications were reported in 0.8% of symptomatic patients in the Ferrazzi et al. study.54 In the 2007 Lieng et al.70 study, 92.2% of hysteroscopies performed to remove endometrial polyps were complicationfree. The complications that did occur included uterine perforation, creation of false age, moderate bleeding, endometritis, failed procedure, and uterine perforation including bowel injury. Thus, some of the complications of hysteroscopy carry significant morbidity and possible mortality. CONCLUSION

Asymptomatic endometrial thickening found on ultrasound examination in postmenopausal women often poses a clinical management dilemma. Although the prevalence of endometrial cancer is relatively low in women with no bleeding, the disease has the best outcome when it is found at an early stage. The disease is usually diagnosed at an early stage when postmenopausal women present with bleeding. Routine

ultrasound screening for asymptomatic women is not recommended. Current evidence suggests that certain subsets of women at high risk of developing endometrial cancer who have endometrial thickening on ultrasound and other positive findings (increased vascularity, inhomogeneity of endometrium, particulate fluid, excessively thickened endometrium > 11 mm) should be referred to gynaecologists for further investigations. Women with risk factors for endometrial cancer and endometrial thickening such as tamoxifen use, obesity, hypertension, and late menopause should be triaged on an individual basis. Polyps found in asymptomatic postmenopausal women need not be removed routinely. However, factors such as polyp size and histopathology, and patient age must be incorporated into the decision for polypectomy. Investigations for asymptomatic endometrial thickening are not risk free, and serious complications such as bowel injury and uterine perforation have been reported in the literature. Thus, adoption of these recommendations may reduce anxiety, pain and risk of procedural complication to the postmenopausal patient. Recommendations 1. Transvaginal ultrasound should not be used as screening for endometrial cancer. (II-1E) 2. Endometrial sampling in a postmenopausal woman without bleeding should not be routinely performed. (II-1E) 3. Indications for tissue sampling of the endometrium in bleeding postmenopausal women with an endometrial thickness of greater than 4 to 5 mm should not be extrapolated to asymptomatic women. (II-2E) 4. A woman who has endometrial thickening and other positive findings on ultrasound, such as increased vascularity, inhomogeneity of endometrium, particulate fluid, or thickened endometrium over 11 mm, should be referred to a gynaecologist for further investigations. (II-1A) 5. Decisions about further investigations should be made on a case-by-case basis in asymptomatic women with increased endometrial thickening and risk factors for endometrial cancer such as obesity, hypertension, and late menopause. (II-1B) 6. In asymptomatic women on tamoxifen, a routine ultrasound for endometrial thickening should not be performed. (II-2E) 7. Not all postmenopausal women who have asymptomatic endometrial polyps require surgery. Women found to have asymptomatic polyps on ultrasound should be triaged for intervention according to size of the polyp, age, and other risk factors. (II-1A) OCTOBER JOGC OCTOBRE 2010 l

997

SOGC Clinical Practice Guideline

REFERENCES 1. Gambacciani M, Monteleone P, Ciaponi M, Sacco A, Genazzani AR. Clinical usefulness of endometrial screening by ultrasound in asymptomatic postmenopausal women. Maturitas 2004;48:4221–4. 2. Koss L, Schreiber K, Oberlander S, Mamdouh M, Herbert, S. Screening of asymptomatic women for endometrial cancer. CA Cancer J Clin 1981;31:300–17. 3. Vuento MH, Pirhonen JP, Mäkinen JI, Tyrkkö JE, Laippala PJ, Grönroos M, et al. Screening for endometrial cancer in asymptomatic postmenopausal women with conventional and colour Doppler sonography. Br J Obstet Gynaecol 1999;106:14–20. 4. Smith-Bindman R, Weiss E, Feldstein V. How thick is too thick? When endometrial thickness should prompt biopsy in postmenopausal women without vaginal bleeding. Ultrasound Obstet Gynecol 2004;24:558–65. 5. Levine D, Gosink BB, Johnson LA. Change in Endometrial Thickness In postmenopausal women undergoing hormone replacement therapy. Radiology 1995; 197:603–8. 6. Shipley CF 3rd, Simmons CL, Nelson GH. Comparison of transvaginal sonography with endometrial biopsy in asymptomatic postmenopausal women. J Ultrasound Med 1994;13:99–104. 7. Lin MC, Gosink BB, Wolf SI, Feldesman MR, Stuenkel CA, Braly PS, et al. Endometrial thickness after menopause: effect of hormone replacement. Radiology 1991;180:427–32. 8. Aleem F, Predanic M, Calame R, Moukhtar M, Pennisi J. Transvaginal color and pulsed Doppler sonography of the endometrium: a possible role in reducing the number of dilatation and curettage procedures. J Ultrasound Med 1995;14:139–45. 9. Varner RE, Sparks JM, Cameron CD, Roberts LL, Soong SJ. Transvaginal sonography of the endometrium in postmenopausal women. Obstet Gynecol 1991;78:195–9. 10. Hänggi W Bersinger N, Altermatt HJ, Birkha MH. Comparison of transvaginal ultrasonography and endometrial biopsy in surveillance in postmenopausal HRT s. Maturitas 1997;27:133–43. 11. Tsuda H, Kawabata M, Kawabata K, Yamamoto K, Umesaki N. Improvement of diagnostic accuracy of transvaginal ultrasound for identification of endometrial malignancies by using cutoff level of endometrial thickness based on length of time since menopause. Gynecol Oncol 1997;64:35–7. 12. Archer D, McIntyre-Seltman K, Wilborn W, Dowling E, Conce F, Creasy G. Endometrial morphology in asymptomatic postmenopausal women. Am J Obstet Gynecol 1991;165: 317–20. 13. Gull B, Karlsson B, Milsom I, Wikland M, Granberg S. Transvaginal sonography of the endometrium in a representative sample of postmenopausal women. Ultrasound Obstet Gynecol 1996;7:322–7. 14. Koss LG, Schreiber K, Oberlander SG, Moussouris HF, Lesser M. Detection of endometrial carcinoma and hyperplasia in asymptomatic women. Obstet Gynecol 1984;64:1–11. 15. American Cancer Society. Cancer Facts & Figures 2009. Atlanta, GA: American Cancer Society; 2009.

21. Gallup DG, Stock RJ. Adenocarcinoma of the endometrium in women 40 years of age or younger. Obstet Gynecol 1984;64:417–20. 22. ACOG practice bulletin, clinical management guidelines for obstetrician-gynecologists, number 65, August 2005: management of endometrial cancer. Obstet Gynecol 2005;106:413–7. 23. Linkov F, Edwards R, Balk J, Yurkovetsky Z, Stadterman B, Lokshin A, Taioli E. Endometrial hyperplasia, endometrial cancer and prevention: gaps in existing research of modifiable risk factors. Eur J Cancer 2008;44:1632–44. 24. Tamoxifen and uterine cancer. ACOG Committee Opinion No. 336. American College of Obstetricians and Gynecologists. Obstet Gynecol 2006;107:1475–8. 25. Meyer LA, Broaddus RR, Lu KH. Endometrial cancer and Lynch syndrome: clinical and pathologic considerations. Cancer Control 2009;16:14–22. 26. Schmeler KM, Lu KH. Gynecologic cancers associated with Lynch syndrome/HNPCC. Clin Trans Oncol 2008;10:313–7. 27. Allard JE, Maxwell GL. Race disparities between black and white women in the incidence, treatment, and prognosis of endometrial cancer. Cancer Control 2009;16:53–6. 28. Karlsson B, Granberg S, Wikland M, Ryd W, Norstrom A. Endovaginal scanning of the endometrium compared to cytology and histology in women with postmenopausal bleeding. Gynecol Oncol 1993;50:173–8. 29. Karlsson B, Granberg S, Wikland M, Ylöstalo P, Torvid K, Marsal K, et al. Transvaginal ultrasonography of the endometrium in women with postmenopausal bleeding—a Nordic multicenter study. Am J Obstet Gynecol 1995;172:1488–94. 30. Smith-Bindman R, Kerlikowske K, Feldstein V, Subak L, Scheidle J, Segal M, et al. Endovaginal ultrasound to exclude endometrial cancer and other endometrial abnormalities. JAMA 1998;280:1510–7. 31. Korhonen MO, Symons JP, Hyde BM, Rowan JP, Wilborn WH. Histologic classification and pathologic findings for endometrial biopsy specimens obtained from 2964 perimenopausal and postmenopausal women undergoing screening for continuous hormones as replacement therapy (CHART 2 Study). Am J Obstet Gynecol 1997;176:377–80. 32. Horwitz RI, Horwitz SM, Feinstein R, Robboy SJ. Necropsy diagnosis of endometrial cancer and detection-bias in case/control studies. Lancet 1981;2(8237):66–8. 33. Alcazar JL, Galvan R. Three-dimensional power Doppler ultrasound scanning for the prediction of endometrial cancer in women with postmenopausal bleeding and thickened endometrium. Am J Obstet Gynecol 2009;200:44.e1–6. Epub 2008 Oct 30. 34. Opolskiene G, Sladkevicius P, Valentin L. Ultrasound assessment of endometrial morphology and vascularity to predict endometrial malignancy in women with postmenopausal bleeding and sonographic endometrial thickness > 4.5 mm Ultrasound Obstet Gynecol 2007;30:332–40.

16. Canadian Cancer Society/National Cancer Institute of Canada. Canadian Cancer Statistics 2008. Toronto: Canadian Cancer Society; 2008.

35. Ciatto S, Cecchini S, Bonardi R, Grazzini G, Mazotta A, Zappa M. A feasibility study of screening for endometrial carcinoma in postmenopausal women by ultrasonography. Tumori 1995;81:334–7.

17. Goldstein RB, Bree RL, Benson CB, Benacerraf BR, Bloss JD, Carlos R, et al. Evaluation of the woman with postmenopausal bleeding: Society of Radiologists in Ultrasound-sponsored consensus conference statement. J Ultrasound Med 2001;20:1025–36.

36. Fleischer AC, Wheeler JE, Lindsay I, Hendrix SL, Grabill S, Kravitz B, et al. An assessment of the value of ultrasonographic screening for endometrial disease in postmenopausal women without symptoms. Am J Obstet Gynecol 2001;184:70–5.

18. American College of Obstetricians and Gyneoclogists. The role of transvaginal ultrasonography in the evaluation of postmenopausal bleeding. ACOG Committee Opinion No. 426. Obstet Gynecol 2009;113:462–4.

37. Smith RA, Cokkinides V, Brawley OW. Cancer screening in the United States, 2008: a review of current American Cancer Society guidelines and cancer screening issues, 2008. CA Cancer J Clin 2008;58:161–79.

19. Goldstein SR. Modern evaluation of the endometrium. Obstet Gynecol 2010; 116:168–76.

38. Gerber B, Krause A, Mueller H, Reimer T, Kuelz T, Kundt G, et al. Ultrasonographic detection of asymptomatic endometrial cancer in postmenopausal patients offers no prognostic advantage over symptomatic disease discovered by uterine bleeding. Eur J Cancer 2001;37:64–71.

20. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer Statistics. CA Cancer J Clin 2008;58:71–96.

998

l OCTOBER JOGC OCTOBRE 2010

Asymptomatic Endometrial Thickening

39. Tsuda H, Nakamura H, Inoue T, Kawamura N, Ken-ichi A. Transvaginal ultrasonography of the endometrium in postmenopausal Japanese women. Gynecol Obstet Invest 2005;60:218–23.

55. Fernández-Parra J, Rodríguez Oliver A, López Criado S, Parrilla Fernández F, Montoya Ventoso F. Hysteroscopic evaluation of endometrial polyps. Int J Gynaecol Obstet 2006;95:144–8.

40. Maatela J, Aromaa A, Salmi T, Pohja M, Vuento M, Gronroos M. The risk of endometrial cancer in diabetic and hypertensive patients: a nationwide record-linkage study in Finland. Ann Chir Gynaecol Suppl 1994;208:20–4.

56. Gregoriou O, Konidaris S, Vrachnis N, Bakalianou K, Salakos N, Papadias K, et al. Clinical parameters linked with malignancy in endometrial polyps. Climacteric 2009; 12:454–8.

41. Andolf E, Dahlander K, Aspenberg P. Ultrasound thickness of the endometrium correlated to body weight in asymptomatic postmenopausal women. Obstet Gynecol 1993;82:936–40.

57. Baiocchi G, Manci N, Pazzaglia M, Giannone L, Burnelli L, Giannone E, et al. Malignancy in endometrial polyps: a 12-year experience. Am J Obstet Gynecol 2009; 201:e1-e4.

42. Anderson GL, Judd HL, Kaunitz AM, Barad DH, Beresford SAA, Pettinger M, et al.; Women’s Health Initiative Investigators. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: The Women’s Health Initiative Randomized Trial. JAMA 2003;290:1739–48.

58. Bernstein L, Deapen D, Cerhan JR, Schwartz SM, Liff J, McGann-Maloney E, et al. Tamoxifen therapy for breast cancer and endometrial cancer risk. Natl Cancer Inst 1999;91(19):1654–62.

43. Martinez Rubio M, Alcazar J. Ultrasonographic and pathological endometrial findings in asymptomatic postmenopausal women taking antihypertensive drugs. Maturitas 2003;46:27–32.

59. Fishman M, Mona B, Sheiner E, Rotmensch J, Abramoxicz J. Changes in the sonographic appearance of the uterus after discontinuation of tamoxifen therapy. J Ultrasound Med 2006;25:469–73.

44. Sit AS, Modugno F, Hill LM, Martin J, Weissfeld JL. Transvaginal ultrasound measurement of endometrial thickness as a biomarker for estrogen exposure. Cancer Epidemiol Biomarkers Prev 2004;13:1459–65.

60. Gerber B, Krause A, Reimer T, Mylonas I, Makovitzky J Kundt G, et al. Anastrozole versus tamoxifen treatment in postmenopausal women with endocrine-responsive breast cancer and tamoxifen-induced endometrial pathology. Clin Cancer Res 2006;12:1245–50.

45. Langer RD, Pierce JJ, O’Hanlan KA, Johnson SR, Espeland MA, Trabal JF, et al. Transvaginal ultrasonography compared with endometrial biopsy for the detection of endometrial disease. Postmenopausal Estrogen/Progestin Intervention Trial. N Engl J Med 1997;337:1792–8.

61. Berlière M, Radikov G, Galant C, Piette P, Marbaix E, Donnez J. Identification of women at high risk of developing endometrial cancer on tamoxifen. Eur J Cancer 2000; 36:S35–36.

46. Gull B, Karlsson B, Milsom I, Granber S. Can ultrasound replace dilation and curettage: a longitudinal evaluation of postmenopausal bleeding and transvaginal sonographic measurement of the endometrium as predictors of endometrial cancer. Am J Obstet Gynecol 2003;188:401–8. 47. Kurtay G, Berker B, Demirel C. Transvaginal ultrasonographic assessment of the endometrium in asymptomatic, postmenopausal women using different HRT regimens containing tibolone or estrogen. J Reprod Med 2004;49:893–8.

62. Garuti G, Cellani F, Centinaio G, Sita G, Nalli G, Luerti M. Baseline endometrial assessment before tamoxifen for breast cancer in asymptomatic menopausal women. Gynecol Oncol 2005; 98:63–70. 63. Gull B, Carlsson SA, Karlsson B, Ylostalo P, Milsom I, Granberg S. Transvaginal ultrasonography of the endometrium in women with postmenopausal bleeding: is it always necessary to perform an endometrial biopsy? Am J Obstet Gynecol 2000; 182:509–15. 64. Goldstein S, Nachtigall M, Snyder J. Endometrial assessment by vaginal ultrasonography before endometrial sampling in patients with postmenopausal bleeding. Am J Obstet Gynecol 1990;163:119–23.

48. Mossa B, Imperato F, Marziani R, Perniola F, Melluso J, Perniola G, et al. Hormonal replacement therapy and evaluation of intrauterine pathology in postmenopausal women: a ten-year study. Eur J Gynaecol Oncol 2003;24:507–12.

65. Goldstein S. The endometrial echo revisited: have we created a monster? Am J Obstet Gynecol 2004;191:1092–6.

49. Tjarks M, Van Voorhis BJ. Treatment of endometrial polyps. Obstet Gynecol 2000; 96:886–9.

66. Goldstein SR. Postmenopausal endometrial fluid collections revisited: look at the doughnut rather than the hole. Obstet Gynecol 1994; 83:738–40.

50. Bakour SH, Khan KS, Gupta JK. The risk of premalignant and malignant pathology in endometrial polyps. Acta Obstet Gynecol Scand 2000;79:317–20.

67. Critchley HO, Warner P, Lee AJ, Brechin S, Guise J, Graham B. Evaluation of abnormal uterine bleeding: comparison of three outpatient procedures within cohorts defined by age and menopausal status. Health Technol Assess 2004;8(34):iii-iv,1–139.

51. Savelli L, De Iaco P, Santini D, Rosati F, Ghi T, Pignotti E, et al. Histopathological features and risk factors for benignity, hyperplasia and cancer in endometrial polyps. Am J Obstet Gynecol 2003;188:927–31. 52. Domingues AP, Lopes H, Dias I, De Olivera CF. Endometrial polyps in postmenopausal women. Acta Obstet Gynecol 2009;88:618–20. 53. Antunes A, Costa-Paiva L, Arthuso M, Costa JV, Pinto-Neto AM. Endometrial polyps in pre- and postmenopausal women: factors associated with malignancy. Maturitas 2007;57:415–21. 54. Ferrazzi E, Zupi E, Leone FP, Savelli L, Omodei U, Moscarini M, et al. How often are endometrial polyps malignant in asymptomatic postmenopausal women? A multicenter study. Am J Obstet Gynecol 2009;200:1–6.

68. Shushan A, Revel A, Rojansky N. How often are endometrial polyps malignant? Gynecol Obstet Invest 2004;58:212–5. 69. Lev-Sagie A, Hamani Y, Imbar T, Hurwitz A, Lavy Y. The significance of intrauterine lesions detected by ultrasound in asymptomatic postmenopausal patients. BJOG 2005;112:379–81. 70. Lieng M, Qvigstad E, Sandvik L, Jorgensen H, Langebrekke A, Istre O. Hysteroscopic resection of symptomatic and asymptomatic endometrial polyps. J Min Invas Gynecol 2007;14:189–94. 71. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8

OCTOBER JOGC OCTOBRE 2010 l

999

SOGC Policy Statement No. 263, August 2011

Maternity Leave in Normal Pregnancy This policy statement has been prepared by the Clinical Practice Obstetrics Committee, reviewed by the Family Physicians Advisory Committee, and approved by the Executive of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHOR Dean Leduc, MD, Ottawa ON CLINICAL PRACTICE OBSTETRICS COMMITTEE Dean Leduc, MD (Co-Chair), Ottawa ON Glenn H. Gill, MD (Co-Chair), Williams Lake BC Anne Biringer, MD, Toronto ON Louise Duperron, MD, Kirkland QC Ahmed M. Ezzat, MD, Saskatoon SK Donna Jones, MD, Calgary AB

Abstract Objective: To assist maternity care providers in recognizing and discussing health- and illness-related issues in pregnancy and their relationship to maternity benefits. Evidence: Published literature was retrieved through searches of PubMed or Medline, CINAHL, and The Cochrane Library in 2009 using appropriate controlled vocabulary (e.g., maternity benefits) and key words (e.g., maternity, benefits, pregnancy). Results were restricted to systematic reviews, randomized controlled trials/controlled clinical trials, and observational studies. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to December 2009. Grey (unpublished) literature was identified through searching the web sites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies.

Lily Lee, MSN, Vancouver BC Suzanne Muise, MD, St. Thomas ON Barbara Mary Parish, MD, Halifax NS Lexy Regush, MD, Saskatoon SK Vyta Senikas, MD, Ottawa ON Kathi Wilson, RM, Ilderton ON

J Obstet Gynaecol Can 2011;33(8):864–866

BACKGROUND

T

Cindy Marshall, MD, Lower Sackville NS

he role of obstetrical care providers in Canada is to promote and apply best practices in caring for the pregnant woman in order to minimize risk and maximize positive outcomes for both mother and infant. Pregnant women often seek input from their caregivers on the topic of maternity leave to plan cessation of work. In Canada, the importance of child care in the first year of life is recognized with benefit programs that provide financial to families. In addition, many employers have extended these benefits through insurance plans or collective agreements to promote healthy beginnings.

Disclosure statements have been received from all of the committees.

CESSATION OF WORK AND PARENTAL BENEFITS

Grace Yeung, MD, London ON FAMILY PHYSICIANS ADVISORY COMMITTEE William Ehman, MD (Chair), Nanaimo BC Anne Biringer, MD, Toronto ON Andrée Gagnon, MD, Blainville QC Lisa Graves, MD, Sudbury ON Jonathan Hey, MD, Saskatoon SK Jill Konkin, MD, Edmonton AB Francine Léger, MD, Montreal QC

Key Words: Pregnancy, maternity benefits

The Federal Employment Insurance program1 provides maternal benefits for up to 15 weeks. In order to qualify, a woman must have worked 600 hours within the preceding 42 weeks. These benefits can be collected up to 8 weeks

This document reflects emerging clinical and scientific advances on the date issued, and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

864 l AUGUST JOGC AOÛT 2011

Maternity Leave in Normal Pregnancy

before the expected due date and “within 17 weeks of the actual or expected week of birth.” 1 The employment insurance program provides parental benefits to either parent for up to 35 weeks. The benefits can be claimed concurrently or consecutively but must be claimed within the 52 weeks following the birth. In addition, many employers will supplement benefits so that parents receive up to 95% of their salary. Quebec is the only province that has a program that provides financial benefits for women with uncomplicated pregnancies whose work or work environment may pose a threat to them or their unborn child.2 Currently, a woman with an uncomplicated pregnancy is deemed to be unfit for work and to qualify for benefits at the onset of labour. Women who experience complications of pregnancy or other illness-related problems and who are deemed unable to continue working are eligible for sickness benefits rather than maternal benefits. Healthy women with uncomplicated pregnancies often ask their care providers to a period of absence from work before delivery, because they want to prepare for labour; however, such a leave of absence would be considered a health-related rather an illness-related leave. There are few guidelines or standards governing the timing or duration of health-related maternity leave. In addition, there is no conclusive evidence for the ideal length of health-related prenatal maternity leave, and there are no data suggesting that such a leave of absence improves outcomes. This leads to uncertainty for care providers, resulting in inconsistent practices. The timing of cessation of work before delivery is unique for each pregnancy and should be discussed between patient and care provider. The SOGC Clinical Practice Obstetrics Committee has reviewed and endorses the document published by the Alberta Perinatal Health Program: Health-Related Maternity Leave in the Uncomplicated Pregnancy and Birth.3 This document summarizes current evidence regarding work-related risks and presents a summary of current practices and recommendations for health-related maternity leave in the antepartum and the postpartum period. It s the federal definition, stating that women with uncomplicated pregnancies are deemed unfit to work no later than at the onset of labour. The document also expands this definition by stating that for uncomplicated singleton pregnancies, health-related maternity leave may be required for 2 to 6 weeks before the estimated date of birth.

When complications arise in the antepartum period, physicians can recommend a medical absence from the workplace if they feel it is in the best interests of the patient. Even in uncomplicated pregnancies a health-related leave may be required to optimize maternal and fetal health, although there is no conclusive evidence of improved outcomes.3 Health care providers should initiate a discussion early in the pregnancy to educate women about the difference between health-related and illness-related leaves of absence. This provides an opportunity to advise women about the possible medical complications that would an illness-related leave of absence and to inform them that issues such as discomfort, poor sleep, fatigue, and musculoskeletal pain are an unfortunate but normal part of a healthy pregnancy. When a patient requests a medical leave of absence for an uncomplicated pregnancy, the physician is not required to this demand. The patient should also be made aware that it is not a recommended practice for care providers to advocate an illness-related leave for women with uncomplicated pregnancy without justification. However, physicians can and should a healthrelated leave to enable a woman to prepare for the eventual delivery, although she may not receive benefits for the entire period of the leave. If care providers do a health-related leave, the woman should be advised that it cannot be defined as an illness-related medical leave and that she would not, therefore, be entitled to receive any medical benefits. In effect, this health-related leave to prepare for childbirth would be voluntary. A woman would receive employment insurance benefits if this leave began within 8 weeks of her expected due date. The issue of benefits is beyond the scope of maternity care providers. If a physician does recommend a leave of absence, he or she should advise the patient that she may or may not be entitled to employee benefits for the entire period. Women should be aware of the maternity benefits they are entitled to through their employer or government agency, and should be advised that a recommendation to take health-related leave in preparation for delivery does not guarantee benefits. RECOMMENDATIONS FOR OBSTETRICAL CARE PROVIDERS

1. Understand the difference between a health-related and an illness-related leave of absence. 2. Initiate a routine discussion early in pregnancy about the issues that can present in an uncomplicated AUGUST JOGC AOÛT 2011 l 865

SOGC Policy Statement

pregnancy (e.g., discomfort, poor sleep, fatigue, etc.) so that women can plan their cessation of work. 3. women in taking health-related leave to prepare for labour and delivery. 4. Advise women that they can begin maternity benefits up to 8 weeks before the onset of labour. 5. Advise women that physicians cannot an illness-related leave in an uncomplicated pregnancy and that this leave would be voluntary.

866 l AUGUST JOGC AOÛT 2011

REFERENCES 1. Human Resources and Skills Development Canada. Employment Insurance (EI) and maternity, parental and sickness benefits. Available at: http://www.servicecanada.gc.ca/eng/ei/types/special.shtml#Who. Accessed April 29, 2011. 2. Government of Quebec. Quebec Parental Insurance Plan. Available at: http://www.formulaire.gouv.qc.ca/cgi/affiche_doc.cgi?dossier=3967. Accessed April 29, 2011. 3. Alberta Perinatal Health Program. Health-related maternity leave in the uncomplicated pregnancy and birth, February 2008. Available at: http://www.aphp.ca/publications_links_pub.html. Accessed April 29, 2011.

SOGC CLINICAL PRACTICE GUIDELINE No. 258, May 2011

Magnesium Sulphate for Fetal Neuroprotection This clinical practice guideline has been prepared by the Guidelines Consensus Group, reviewed by the Maternal Fetal Medicine Committee, and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. This document has been reveiwed by the Fetus and Newborn Committee of the Canadian Paediatric Society. PRINCIPAL AUTHORS

MATERNAL FETAL MEDICINE COMMITTEE Robert Gagnon, MD (Co-Chair), Montreal QC Lynda Hudon, MD (Co-Chair), Montreal QC Melanie Basso, RN, Vancouver BC Hayley Bos, MD, London ON Joan M. Crane, MD, St. John’s NL Gregory Davies, MD, Kingston ON

Laura Magee, MD, Vancouver BC

Marie- Delisle, MD, Vancouver BC

Diane Sawchuck, RN, PhD, Vancouver BC

Savas Menticoglou, MD, Winnipeg MB

Anne Synnes, MD, Vancouver BC

William Mundle, MD, Windsor ON

Peter von Dadelszen, MBChB, Vancouver BC

Annie Ouellet, MD, Sherbrooke QC

THE MAGNESIUM SULPHATE FOR FETAL NEUROPROTECTION CONSENSUS COMMITTEE

Tracy Pressey, MD, Vancouver BC

Melanie Basso, RN, Vancouver BC

Christy Pylypjuk, MD, Saskatoon SK

Joan M. Crane, MD, St. John’s NL

Anne Roggensack, MD, Calgary AB

Lex Doyle, MD, Victoria, Australia

Frank L. Sanderson, MD, Saint John NB

William Ehman, MD, Nanaimo BC

Disclosure statements have been received from all of the committees.

Robert Gagnon, MD, Montreal QC

The literature searches and bibliographic for this guideline were undertaken by Becky Skidmore, Medical Research Analyst, Society of Obstetricians and Gynaecologists of Canada.

William Grobman, MD, Chicago IL Michael Helewa, MD, Winnipeg MB KS Joseph, MD, Vancouver BC M. Jocelyne Martel, MD, Saskatoon SK Steven Miller, MD, Vancouver BC Nan Okun, MD, Toronto ON Dwight Rouse, MD, Providence RI Vyta Senikas, MD, Ottawa ON Rebecca Sherlock, MD, Vancouver BC

Abstract Objective: To provide guidelines for the use of antenatal magnesium sulphate (MgSO4) for fetal neuroprotection of the preterm infant.

Sandrine Wavrant, MD, Montreal QC

Options: Antenatal MgSO4 istration should be considered for fetal neuroprotection when women present at ≤ 31+6 weeks with imminent preterm birth, defined as a high likelihood of birth because of active labour with cervical dilatation ≥ 4 cm, with or without preterm pre-labour rupture of membranes, and/or planned preterm birth for fetal or maternal indications.

R. Douglas Wilson, MD, Calgary AB



Amanda Skoll, MD, Vancouver BC Graeme Smith, MD, Kingston ON Brenda Wagner, MD, Richmond BC

Jennifer Hutcheon, PhD, Vancouver BC

Key Words: Magnesium sulphate, preterm birth, cerebral palsy, death, neuroprotection

There are no other known fetal neuroprotective agents.

Outcomes: The outcomes measured are the incidence of cerebral palsy () and neonatal death. Evidence: Published literature was retrieved through searches of PubMed or Medline, CINAHL, and the Cochrane Library in May 2010, using appropriate controlled vocabulary and key words (magnesium sulphate, cerebral palsy, preterm birth). Results were restricted to systematic reviews, randomized controlled

This document reflects emerging clinical and scientific advances on the date issued, and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

516 l MAY JOGC MAI 2011

Magnesium Sulphate for Fetal Neuroprotection

trials, and relevant observational studies. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to August 2010. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Values: The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). Benefits, harms, and costs: Antenatal magnesium sulphate for fetal neuroprotection reduces the risk of “death or ” (RR 0.85; 95% CI 0.74 to 0.98; 4 trials, 4446 infants), “death or moderatesevere ” (RR 0.85; 95% CI 0.73 to 0.99; 3 trials, 4250 infants), “any ” (RR 0.71; 95% CI 0.55 to 0.91; 4, trials, 4446 infants), “moderate-to-severe ” (RR 0.60; 95% CI 0.43 to 0.84; 3 trials, 4250 infants), and “substantial gross motor dysfunction” (inability to walk without assistance) (RR 0.60; 95% CI 0.43 to 0.83; 3 trials, 4287 women) at 2 years of age. Results were consistent between trials and across the meta-analyses. There is no anticipated significant increase in health care-related costs, because women eligible to receive antenatal MgSO4 will be judged to have imminent preterm birth. Validation: Australian National Clinical Practice Guidelines were published in March 2010 by the Antenatal Magnesium Sulphate for Neuroprotection Guideline Development . Antenatal MgSO4 was recommended for fetal neuroprotection in the same dosage as recommended in these guidelines. However, MgSO4 was recommended only at < 30 weeks’ gestation, based on 2 considerations. First, no one gestational age subgroup was considered to show a clear benefit. Second, in the face of uncertainty, the committee felt it was prudent to limit the impact of their clinical practice guidelines on resource allocation. Also in March 2010, the American College of Obstetricians and Gynecologists issued a Committee Opinion on MgSO4 for fetal neuroprotection. It stated that, “the available evidence suggests that magnesium sulphate given before anticipated early preterm birth reduces the risk of cerebral palsy in surviving infants.” No official opinion was given on a gestational age cut-off, but it was recommended that physicians develop specific guidelines around the issues of inclusion criteria, dosage, concurrent tocolysis, and monitoring in accordance with one of the larger trials. Sponsors: Canadian Institutes of Health Research (CIHR).

Summary Statement 1. “Imminent preterm birth” is defined as a high likelihood of birth due to one or both of the following conditions (II-2): • Active labour with ≥ 4 cm of cervical dilation, with or without PPROM. • Planned preterm birth for fetal or maternal indications. Recommendations 1. For women with imminent preterm birth (≤ 31+6 weeks), antenatal magnesium sulphate istration should be considered for fetal neuroprotection. (I-A) 2. Although there is controversy about upper gestational age, antenatal magnesium sulphate for fetal neuroprotection should be considered from viability to ≤ 31+6 weeks. (II-1B) 3. If antenatal magnesium sulphate has been started for fetal neuroprotection, tocolysis should be discontinued. (III-A) 4. Magnesium sulphate should be discontinued if delivery is no longer imminent or a maximum of 24 hours of therapy has been istered. (II-2B) 5. For women with imminent preterm birth, antenatal magnesium sulphate for fetal neuroprotection should be istered as a 4g IV loading dose, over 30 minutes, followed by a 1g/hr maintenance infusion until birth. (II-2B) 6. For planned preterm birth for fetal or maternal indications, magnesium sulphate should be started, ideally within 4 hours before birth, as a 4g IV loading dose, over 30 minutes, followed by a 1g/hr maintenance infusion until birth. (II-2B) 7. There is insufficient evidence that a repeat course of antenatal magnesium sulphate for fetal neuroprotection should be istered. (III-L) 8. Delivery should not be delayed in order to ister antenatal magnesium sulphate for fetal neuroprotection if there are maternal and/or fetal indications for emergency delivery. (III-E) 9. When magnesium sulphate is given for fetal neuroprotection, maternity care providers should use existing protocols to monitor women who are receiving magnesium sulphate for preeclampsia/ eclampsia. (III-A) 10. Indications for fetal heart rate monitoring in women receiving antenatal magnesium sulphate for neuroprotection should follow the fetal surveillance recommendations of the SOGC 2007 Fetal Health Surveillance: Antepartum and Intrapartum Consensus Guideline. (III-A) 11. Since magnesium sulphate has the potential to alter the neonate’s neurological evaluation, causing hypotonia or apnea, health care providers caring for the neonate should have an increased awareness of this effect. (III-C) J Obstet Gynaecol Can 2011;33(5):516–529

BACKGROUND ABBREVIATIONS APH

antepartum hemorrhage



cerebral palsy

IQR

interquartile range

IUGR

intrauterine growth restriction

NNT

number needed to treat

PPROM preterm pre-labour rupture of membranes PTL

preterm labour

The Importance of Preterm Birth

T

he Canadian preterm birth rate overall reached 8.2 % of live births in 2004, with births at < 32 weeks representing 1.2 % of live births in Canada.1 The survival of infants born preterm has improved with interventions such as antenatal corticosteroids and surfactant. However, survival has been associated with substantial risk of medical and neurodevelopmental impairment. MAY JOGC MAI 2011 l 517

SOGC CLINICAL PRACTICE GUIDELINE

Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well–designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action

* The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.47 † Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the The Canadian Task Force on Preventive Health Care.47

Two identified patterns of injury appear to underlie the central nervous system complications of preterm infants: (1) intraventricular hemorrhage and (2) white matter injury. Severe intraventricular hemorrhage (grades 3 and 4) is reliably detected by ultrasound and occurs primarily among babies who are born at or before 28 weeks’ gestation. Although the incidence of severe intraventricular hemorrhage is highest at 24 to 25 weeks, severe intraventricular hemorrhage is still a relevant problem up to 28 weeks, because there are more births at 26 to 28 weeks than at 24 to 25 weeks. MRI is required for reliable detection of white matter injury, which has a peak prevalence at 28 weeks. Its severity is associated with adverse motor and cognitive outcomes.2 Clinically, the most frequent adverse neurological outcomes associated with preterm birth are cerebral palsy and cognitive impairment. Other adverse outcomes include blindness, deafness, developmental delay, and/or other neurological impairment. More than 50% of very preterm babies suffer from learning or motor disabilities or school difficulties, compared with about 20% of normal birthweight controls.3 The Importance of Cerebral Palsy

3. Ataxic (problems with balance and depth perception) 4. Mixed The most common pattern is spasticity plus athetoid movements.5 can be reliably diagnosed by the age of 2 years. The prevalence of is 2 to 2.5 per 1000 live births.6 The risk of is highest at earlier gestational ages. Compared with infants born at term, infants born preterm have a risk that is approximately 3-fold higher at 34 to 36 weeks,7 8-fold7 to 14-fold8 higher at 30 to 33 weeks, 46-fold higher at 28 to 30 weeks,8 and as high as 30-fold4 to 80-fold8 higher at < 28 weeks.9 The gestational age-related risk is associated, in part, with very low birth weight (i.e., < 1500 g) and intraventricular hemorrhage.10–12 Multiples are also at heightened risk.13 Temporal trends in the prevalence of among infants born very preterm are a matter of controversy. Rates have been reported to be both falling14,15 and rising,10,16 possibly because perinatal mortality rates are decreasing, so that the rate of “death or ” among infants born at < 30 weeks has appeared to be stable.6

Cerebral palsy is a symptom complex of non-progressive motor impairment syndromes secondary to brain injury or anomalies arising in early development.4 The typical signs of include spasticity, movement disorders, muscle weakness, ataxia, and rigidity. There are 4 main types of cerebral palsy:

What is agreed upon, however, is that the economic burden associated with is enormous. The US Centers for Disease Control and Prevention estimate that lifetime health care, productivity, and social costs for a person with are US$921 000 (2003).17

1. Spastic (increased muscle tone) 2. Athetoid or dyskinetic (slow, uncontrolled movements)

There is no known cure for , which makes effective preventive measures of primary importance. To date, no

518 l MAY JOGC MAI 2011

Magnesium Sulphate for Fetal Neuroprotection

Table 2. Inclusion criteria in the randomized controlled trials of magnesium sulphate for fetal neuroprotection Inclusion criteria*

Study

Women, n

Multiple pregnancy, %

Gestational age, weeks

Delivery likely within 24 hours

PTL, %

PPROM

Chorioamnionitis

Preeclampsia

Severe IUGR

APH

Neuroprotective intent ACTOMgSO4 Crowther et al. 200335

1062

17

< 30

Yes

63

9%

14%

15%

9%

14%

PREMAG Marrett et al. 200636

564

22

< 33

Yes

85

61%

11%

Excluded

Excluded

19%

MAGnet Mittendorf et al. 2002— neuroprotective intent arm37

57

4

25 to 33+6

NA

100†

If associated with PTL

Excluded

Excluded

NA

NA

2241

9

24 to 31+6

NA

10

87%

NA

Excluded

Included by % NA

NA

NA

100

If associated with PTL

Yes‡

Excluded

NA

Yes‡

< 37 NA (but subgroup analyses were possible for lower gestational age categories)

NA

NA

NA

100%

NA

NA

BEAM Rouse et al. 200838

Other primary intent MAGnet Mittendorf et al. 2002, tocolytic arm37

92

15

MAGPIE 200641

10 141

4

25to 33+6

LD: loading dose; NA: not available * indications for at least 90% of study population listed. † With cervical dilatation > 4 cm and therefore not eligible for tocolysis. ‡ 71.1% had PPROM and 50.8% had chorioamnionitis, but the results were not presented according to whether women were in the tocolytic or neuroprotective intent arms.

antenatal interventions have been identified that effectively decrease risk among preterm infants. Magnesium Sulphate for Neuroprotection

In two studies published in the 1980s, preterm infants born to women with preeclampsia had a lower incidence of adverse CNS outcomes than gestational age-matched neonates born to mothers without preeclampsia.18,19 In 1995, a seminal case–control study20 was conducted with data derived from the California Cerebral Palsy project.21 It demonstrated an association between antenatal magnesium sulphate istration prior to preterm birth and fewer cases of among infants born < 1500 g.20 It has been proposed that use of magnesium sulphate for eclampsia treatment and prophylaxis may underlie the potential association between antenatal istration of magnesium sulphate and ,20,22 but the findings of subsequent observational studies investigating the association have been inconsistent.23–25 Although the effectiveness of magnesium sulphate for prevention and treatment of maternal eclampsia is well proven, there remains a lack of understanding of how it may act as a neuroprotective agent.26,27 Magnesium acts in many intracellular processes, and its actions include cerebral

vasodilation, reduction in inflammatory cytokines and/or oxygen free radicals, and/or inhibition of calcium influx into cells.28,29 Animal studies have shown a neuroprotective effect.30,31 From 2002 to 2008, 5 randomized controlled trials (6145 babies) studied magnesium sulphate for fetal neuroprotection (Table 2). In 2009, a milestone was reached with the publication of 3 meta-analyses, all of which concluded that magnesium sulphate for fetal neuroprotection decreases the risk of childhood .32–34 Four trials used magnesium sulphate specifically for fetal neuroprotection among women likely to deliver within 24 hours.35–38 The fifth trial26 evaluated the effectiveness of magnesium sulphate for eclampsia prevention in women with preeclampsia. Of the 4 trials with neuroprotective intent, one also included a tocolytic arm.37 Three of these 4 trials enrolled primarily women with preterm labour (with or without PPROM),35–37 whereas the fourth focused on women with PPROM.38 Children were followed-up to the age of 2 years for assessment, and 3 trials undertook cognitive testing.26,35,38 Study quality was good.32 Importantly, 4 of the 5 trials (and all neuroprotective intent trials) described an adequate MAY JOGC MAI 2011 l 519

SOGC CLINICAL PRACTICE GUIDELINE

Table 3a. Magnesium sulphate versus placebo: perinatal outcomes in neuroprotection trials only

Doyle et al.34 Death or Death or moderatesevere Death or substantial gross motor dysfunction Death

0.85 (0.74 to 0.98)

Moderate-severe

0.84 (0.71 to 1.00) 0.95 (0.80 to 1.12) 0.71 (0.55 to 0.91) Not presented

Substantial gross motor dysfunction Any neurological impairment

0.60 (0.43 to 0.83) 1.03 (0.87 to 1.21)

IVH

0.96 (0.86 to 1.07) 0.83 (0.62 to 1.13) 0.93 (0.68 to 1.28)



Severe IVH (grade 3 or 4) PVL

Developmental delay or intellectual impairment Major neurological disability Blindness Deafness

1.00 (0.91 to 1.09) 1.14 (0.86 to 1.51) 0.97 (0.14 to 6.90) 0.51 (0.05 to 4.96)

RR (95%CI) Costantine and Weiner33 0.86 (0.75 to 0.99) 0.85 (0.73 to 0.99) Not presented

Conde-Agudelo and Romero32 Primary outcomes Not presented Not presented Not presented

0.95 (0.80 to 1.13) 0.71 (0.55 to 0.91) 0.60 (0.43 to 0.84) Not presented

0.95 (0.80 to 1.12) 0.71 (0.55 to 0.91) Not presented

Not presented

Not presented

Not presented

Doyle et al.34 4 trials, 4446 infants Not presented 3 trials, 4387 infants 4 trials, 4446 infants 4 trials, 4446 infants Not presented 3 trials; 4387 infants 1 trial, 1255 infants

Other neonatal CNS outcomes Not presented Not presented 4 trials to 4446 infants Not presented Not presented 2 trials; 3699 infants Not presented Not presented 4 trials to 4446 infants Other infant/child neurodevelopmental outcomes Not presented Not presented 3 trials, 4387 infants Not presented 1.09 1 trial, (0.83 to 1.43) 1255 infants Not presented 0.97 2 trials, (0.14 to 6.90) 1943 infants Not presented 0.51 2 trials, (0.05 to 4.96) 1943 infants

Trials, n, Infants, n Costantine and Weiner33

Conde-Agudelo and Romero32

4 trials, 4314 infants 3 trials, 4250 infants Not presented

Not presented

4 trials, 4324 infants 4 trials, 4314 infants 3 trials, 4250 infants Not presented

4 trials, 4446 infants 4 trials, 4446 infants Not presented

Not presented

Not presented

Not presented

Not presented

Not presented

Not presented

Not presented

Not presented

Not presented

Not presented

Not presented

2 trials, 2060 infants 2 trials, 1943 infants 2 trials, 1943 infants

Not presented Not presented

Not presented Not presented

Not presented

CNS: central nervous system; IVH: intraventricular hemorrhage; PVL: periventricular leukomalacia.

method of allocation concealment.26,35,36,38 All but the tocolytic arm of Mittendorf et al.37 described doublemasking of outcome assessment. Magnesium Sulphate Use in Obstetrics

Magnesium sulphate is widely available and commonly used in Canadian obstetric practice for eclampsia prophylaxis and treatment.26,27,39 Magnesium sulphate is no longer recommended for tocolysis, because it is ineffective.34 This document summarizes the relevant evidence and provides practice recommendations related to the use of antenatal magnesium sulphate for fetal neuroprotection among women with imminent preterm birth. Summary Statement

1. “Imminent preterm birth” is defined as a high likelihood of birth due to one or both of the following conditions (II-2): 520 l MAY JOGC MAI 2011



• Active labour with ≥ 4 cm of cervical dilation, • with or without PPROM.



• Planned preterm birth for fetal or maternal • indications. Recommendation

1. For women with imminent preterm birth (≤ 31+6 weeks), antenatal magnesium sulphate istration should be considered for fetal neuroprotection. (I-A) Table 3a presents the results of the 3 relevant metaanalyses of neuroprotective trials,32–34 and shows that antenatal magnesi um sulphate reduced the risk of “death or ,” “death or moderate-severe ,” “any ,”

Magnesium Sulphate for Fetal Neuroprotection

Table 3b. Magnesium sulphate versus placebo: perinatal outcomes in all trials of antenatal magnesium sulphate Doyle et al.34 RR (95% CI) Death or Death or moderatesevere Death or substantial gross motor dysfunction Death

0.94 (0.78 to 1.12) Not presented

Moderate-severe

0.92 (0.75 to 1.12) 1.01 (0.82 to 1.23) 0.69 (0.54 to 0.87) Not presented

Substantial gross motor dysfunction Any neurological impairment

0.60 (0.43 to 0.83) 1.01 ( 0.86 to 1.19 )

IVH

0.96 (0.86 to 1.08) 0.83 (0.62 to 1.13) 0.93 (0.68 to 1.28)



Severe IVH (grade 3/4) PVL

Developmental delay or intellectual impairment Major neurological disability Blindness Deafness

0.99 (0.91 to 1.09) 1.07 (0.82 to 1.40) 0.74 (0.17 to 3.30) 0.79 (0.24 to 2.56)

Costantine and Weiner33

Trials, n Infants, n

Trials, n RR (95% CI) Infants n Primary outcomes 5 trials, 0.92 5 trials, 6145 infants (0.83 to 1.03) 5225 infants Not presented 0.85 3 trials, (0.73 to 0.99) 4250 infants 4 trials, Not presented Not presented 5980 infants 5 trials, 0.95 4 trials, 6145 infants (0.80 to 1.13) 4324 infants 5 trials, 0.71 4 trials, 6145 infants (0.55 to 0.91) 4314 infants Not presented 0.60 3 trials, (0.43 to 0.84) 4250 infants 4 trials, Not presented Not presented 4387 infants 2 trials, Not presented Not presented 2848 infants Other neonatal CNS outcomes 4 trials, Not presented Not presented 4552 infants 2 trials, Not presented Not presented 3699 infants 4 trials, Not presented Not presented 4552 infants Other infant/child neurodevelopmental outcomes 4 trials, Not presented Not presented 5980 infants 2 trials, Not presented Not presented 2848 infants 3 trials, Not presented Not presented 3536 infants 3 trials, Not presented Not presented 3536 infants

Conde-Agudelo and Romero32 RR (95% CI)

Trials, n Infants n

0.92 (0.83 to 1.02) Not presented

5 trials, 5357 infants Not presented

Not presented

Not presented

1.01 (0.89 to 1.14) 0.69 (0.55 to 0.88) 0.64 (0.44 to 0.92) 0.60 (0.43 to 0.83) 1.02 (0.86 to 1.20)

5 trials, 5357 infants 5 trials, 5357 infants 3 trials, 4387 infants 3 trials, 4387 infants 2 trials, 2060 infants

0.96 (0.86 to 1.08)) 0.83 (0.61 to 1.11) 0.93 (0.68 to 1.28)

5 trials, 4552 infants 4 trials, 3864 infants 5 trials, 4552 infants

Not presented

Not presented

1.09 (0.83 to 1.43) 0.97 (0.14 to 6.90) 0.51 (0.05 to 4.96)

2 trials, 2060 infants 2 trials, 1943 infants 2 trials, 1943 infants

CNS: central nervous system; IVH: intraventricular hemorrhage; PVL: periventricular leukomalacia.

“moderate-severe ,” and “substantial gross motor dysfunction” (inability to walk without assistance) at 2 years of age. The direction of effect was the same for death or substantial gross motor dysfunction, but this did not reach statistical significance. Results were consistent between trials and across the meta-analyses. Use of magnesium sulphate was not associated with an increase in pediatric death. The tocolytic arm of one study37 was stopped early because of an increase in pediatric mortality; although this is consistent with the effects of magnesium sulphate istered as a tocolytic in other studies,34 there were other quality issues with the Mittendorf et al. tocolytic arm. These included the confounding effect of multiple births (i.e., more in the magnesium sulphate arm), the low quality score (Jahad score of 2/8 when the other neuroprotective intent trials scored 7–8/8), the lack

of a placebo arm, that crossover was allowed, and that 3 of the 8 neonatal deaths in the magnesium sulphate arm were related to congenital anomalies (n = 1) or twin-totwin transfusion (n = 2). When the tocolytic arm of the MAGnet Trial40 and results of the preeclampsia prophylaxis trial (MAGPIE)41 were included in the meta-analyses, antenatal magnesium sulphate was shown to reduce the risk of death or moderatesevere , any , moderate-severe , and substantial gross motor dysfunction; the outcome of death or no longer reached statistical significance (Table 3b). Although such analyses the use of magnesium sulphate to decrease , the results of the neuroprotective intent trials suggest a change in clinical practice. MAY JOGC MAI 2011 l 521

SOGC CLINICAL PRACTICE GUIDELINE

For antenatal magnesium sulphate given specifically for fetal neuroprotection, the NNT to prevent one case of death or is 43 (based on an event rate of 14.9% overall in the magnesium arm of trials and 17.2% among placebo-treated controls). The NNT to prevent one case of is 63 (based on an event rate of 3.4% overall in the magnesium arm of the trials and 5.0% among placebo-treated controls). These compare favourably with other established obstetric interventions, such as the NNT of 50 (95% CI 34 to 100) for use of magnesium sulphate to prevent eclampsia among women with severe preeclampsia.26 While the 3 meta-analyses demonstrate significant results for antenatal magnesium sulphate reducing the risk of death or , death or moderate-severe , any , moderate-severe , and substantial gross motor dysfunction at 2 years of age, it is important to note that no single trial demonstrated a statistically significant decrease in the combined outcome of death or . Despite these favourable results, strong evidence is lacking with respect to 4 clinical issues: 1. The gestational age below which this therapy should be offered. 2. The optimal loading and maintenance doses. 3. Antenatal magnesium sulphate has not been associated with a decrease in central nervous system pathology associated with , cognitive impairment (i.e., intraventricular hemorrhage or white matter injury measured as cystic periventricular leukomalacia), and other adverse developmental outcomes associated with preterm birth (e.g., developmental delay, neurological impairment, blindness, or deafness). However, confidence intervals in these trials35–38 were reasonably wide and compatible with any of the following: a protective effect (38% reduction), harmful effect (13% increase), or no effect at all. Further evidence is needed to determine whether there is an association between magnesium sulphate and decreased CNS pathology. 4. There is no information on the effect of magnesium sulphate on learning disabilities, school difficulties, or other common school-age disabilities, because none of the trials reported on outcomes beyond 2 years of age; follow-up to school-age is planned for 2 of the trials.35,36 Neurological follow-up was conducted to the age of 2 years in 3 trials, 2 of which undertook detailed neurocognitive testing.35,38 However, learning disabilities and developmental coordination disorder, which are prevalent among extremely low birth weight babies born preterm, cannot be reliably detected until school age. 522 l MAY JOGC MAI 2011

Recommendations

2. Although there is controversy about upper gestational age, antenatal magnesium sulphate for fetal neuroprotection should be considered from viability to ≤ 31+6 weeks. (II-1B) 3. If antenatal magnesium sulphate has been started for fetal neuroprotection, tocolysis should be discontinued. (III-A) There is some uncertainty about the gestational age at which magnesium sulphate should be istered. A lower gestational age limit for viability has not been specified in these studies35,37 so that clinical decisions can take into consideration both parental preference and institutionally defined thresholds. Each of the trials in the meta-analyses32–34 had a different upper gestational age limit for study eligibility, ranging from < 30 weeks35 to ≤ 33+6,37 making it challenging to recommend an upper age limit. It is uncertain whether the neuroprotective effect of magnesium sulphate depends on gestational age at birth. Table 4a presents the results of trials with neuroprotective intent. The outcome of death or was significantly decreased by magnesium sulphate when therapy was istered at < 34 weeks. The outcome of was significantly decreased at all gestational ages. Results for all trials are shown in Table 4b; the < 30 week and < 28 week analyses include post hoc analyses of the MAGPIE and BEAM trials, as randomization was not stratified by these gestational age groupings. No effect of magnesium sulphate was seen on the outcome of death or , but was significantly decreased at all gestational ages. There are 2 key considerations when determining a gestational cut-off: (1) the potential for effect modification by gestational age (i.e., the potential for magnesium sulphate to have a different effect at different gestational ages), and (2) the baseline prevalence of at different gestational ages (since the NNT will be lower with a higher baseline prevalence of a disease). Table 4a (neuroprotective intent trials) and Table 4b (all relevant trials) both show that the point estimate for the effect of magnesium sulphate on risk reduction appears to be lower at < 28 weeks. Since the prevalence of is also higher at < 28 weeks, the NNT to prevent one case of is lowest at < 28 weeks. The NNT appears to fall for istration of magnesium at earlier gestational ages, with a more obvious trend among all trials rather than among only neuroprotective trials. Regardless, the NNT to prevent one case of is low at all gestational ages at < 34 weeks.

Magnesium Sulphate for Fetal Neuroprotection

Table 4a. Subgroup analyses by gestational age at randomization: neuroprotective trials only35–38 RR (95% CI) Weeks < 34

NNT to prevent harm

Death or



Death or



Trials, n, infants, n

0.85 (0.74 to 0.98)

0.71 (0.55 to 0.91)

43

53

5 trials, 6145 infants

< 32

0.86 (0.74 to 1.00)

0.68 (0.52 to 0.91)

43

50

3 trials, 3981 infants

< 30*

0.87 (0.74 to 1.03)

0.69 (0.48 to 0.99)

36

53†

3 trials, 2475 infants

< 28*

0.95 (0.74 to 1.22)

0.45 (0.23 to 0.87)

91

30

1 trial, 938 infants

* Includes the < 28 week subgroup of Rouse et al.38 which had women as the denominator. † Inclusion of only the Crowther et al.35 trial and exclusion of the BEAM data (Rouse et al.38) give an NNT of 24.

Table 4b. Subgroup analyses by gestational age at randomization: all trials26,35-38,41 RR (95% CI) Weeks

NNT to prevent harm

Death or



Death or



Trials, n, infants, n

< 34

0.94 (0.78 to 1.12)

0.68 (0.54 to 0.87)

105

63

5 trials, 6145 infants

< 32

0.95 (0.76 to 1.18)

0.69 (0.52 to 0.91)

71

56

3 trials, 3981 infants

< 30*

0.97 (0.78 to 1.21)

0.70 (0.49 to 0.99)

71

56†

3 trials, 2475 infants

< 28*

0.95 (0.74 to 1.22)

0.45 (0.23 to 0.87)

91

30

1 trial, 938 infants

* Includes the < 28 week subgroup of Rouse et al., which had women as the denominator. 38

This also includes the < 30 week subgroup data provided by the MAGPIE trial. † In the Cochrane review,34 the < 30 week subgroup did not include the BEAM trial data for < 28 week38 and the NNT was 50.

A more useful post hoc analysis would be to examine risk reduction within gestational age strata (32 to 33 weeks, 30 to 31 weeks, 28 to 29 weeks, and < 28 weeks) to identify the gestational age at which babies may be most likely to benefit. In the BEAM trial,38 analyses were stratified by gestational age (< 28 vs. 28 to 31 weeks). Although it appeared as if the decrease in was confined to the < 28-week subgroup, the test for interaction by gestational age was actually not significant. This should be interpreted as revealing no difference in magnesium effect on rate by gestational age up to 31+6 weeks. In MAGPIE,41 which was not a neuroprotective intent trial and which underreported , risk was similar at < 30 weeks (RR 1.04; 95% CI 0.06 to 16.06) and at 30 to 33 weeks (RR 0.95; 95% CI 0.71 to 1.27). In summary, risk is highest at earlier gestational ages, but these very preterm infants are fewer in number. Use of magnesium sulphate at gestational ages closer to 34 weeks has the potential to substantially increase overuse of magnesium sulphate for women with threatened preterm birth who do not deliver in the subsequent 24 to 48 hours. Therefore, consensus was reached to recommend an upper gestational age cut-off of < 32 weeks (i.e., ≤ 31+6 weeks) to strike a balance between appropriate use of magnesium sulphate at earlier gestational ages and potential overuse of magnesium sulphate at later gestational ages, when neurological morbidity is lower. Institutions may choose different thresholds (< 34 weeks) according to other

considerations, including the accuracy of gestational age determination and resource allocation. Table 2 presents the baseline characteristics of women who were enrolled in the relevant randomized controlled trials. In 3 of the 4 neuroprotective intent trials, most women had preterm labour with anticipated delivery within 24 hours. This is not equivalent to threatened preterm labour for which tocolysis is an option in the hope/expectation of being able to arrest labour; this must be emphasized to prevent potential overuse of magnesium sulphate for neuroprotection in patients who are not truly in labour. The other major indications for very preterm delivery (APH or IUGR) were present in a minority of women enrolled in the relevant trials. Although many women also had PPROM, only the BEAM trial38 enrolled women with PPROM without associated preterm labour. In this guideline, these women are not included as eligible for magnesium sulphate for neuroprotection. First, in the BEAM trial, retreatment with magnesium was istered for 59.1% of women. Second, women with PPROM who are not in labour are not necessarily in a delivery suite and receiving one-to-one nursing care; istration of magnesium for neuroprotective intent could have significant hospital resource implications for these women. All trials excluded women with the usual contraindications to magnesium sulphate (i.e., hypersensitivity to the drug, hepatic MAY JOGC MAI 2011 l 523

SOGC CLINICAL PRACTICE GUIDELINE

Table 5. Inclusion and exclusion criteria for antenatal magnesium sulphate istration in randomized controlled trials Inclusion criteria

Exclusion criteria

Singleton and multiple pregnancies

Magnesium sulphate already istered for preeclampsia/ eclampsia

Nulliparous and parous

< 12 hours since discontinuation of previous magnesium sulphate infusion

Anticipated vaginal or Caesarean delivery

Magnesium sulphate contraindicated

Any reason for anticipated preterm birth

Fetus unlikely to benefit

much lower, at 6.5 g (IQR of 4.5 to 14.0 g),35 when women were enrolled primarily for preterm labour, reflecting a very short median time from enrolment to delivery. There have been no direct comparisons of different dosing regimens of magnesium sulphate for neuroprotection. A loading dose of 4 g IV with a maintenance infusion of 1 g/hr has been recommended to (1) resemble current clinical practice and hospital protocols for magnesium sulphate for eclampsia prophylaxis and treatment, and (2) minimize concerns about maternal safety, particularly as higher dosing regimens have not been associated with greater neuroprotection. Trials that istered maintenance infusions treated for a maximum of 24 hours antenatally.

coma, myasthenia gravis) and those whose fetus was unlikely to benefit from potential neuroprotection (i.e., severe fetal malformations or chromosomal abnormalities). Antenatal magnesium sulphate for fetal neuroprotection should be used with caution in women who have renal impairment, and serum magnesium levels should be monitored.

For women with planned preterm birth, for fetal or maternal indications, it is recommended that magnesium sulphate be started as close as possible to 4 hours before birth, as this was the mean time from randomization to birth in subgroup analysis.35 No trials randomized women with planned preterm birth to different durations of magnesium sulphate therapy.

Magnesium sulphate for neuroprotection should be istered regardless of singleton or multiple gestation, as women with multiple pregnancies were enrolled in all trials.

Risk of medication errors may be decreased if magnesium sulphate is prepared in the central pharmacy rather than in the labour and delivery suite.

The inclusion and exclusion criteria from the published trials are summarized in Table 5.

Magnesium sulphate for fetal neuroprotection should be discontinued at delivery.

Recommendations

4. Magnesium sulphate should be discontinued if delivery is no longer imminent or a maximum of 24 hours of therapy has been istered. (II-2B) 5. For women with imminent preterm birth, antenatal magnesium sulphate for fetal neuroprotection should be istered as a 4g IV loading dose, over 30 minutes, followed by a 1g/hr maintenance infusion until birth. (II-2B) 6. For planned preterm birth for fetal or maternal indications, magnesium sulphate should be started, ideally within 4 hours before birth, as a 4g IV loading dose, over 30 minutes, followed by a 1g/hr maintenance infusion until birth. (II-2B) As shown in Table 6, 4 trials of magnesium sulphate istered a 4 g IV loading dose over 20 to 30 min35–37,41 Maintenance dosing varied from none36,37 to 1 g/hr35,41 or 2 g/hr38 for 12 hr38 or 24 hr.35,41 The median dose received was as high as 31.5 g (IQR of 29.0 to 44.6), but this was the trial primarily of women who had PPROM without labour, and 59.1% of women were re-treated when delivery was again considered to be imminent.38 The median dose was 524 l MAY JOGC MAI 2011

The one trial (Rouse et al.38) in which re-treatment was performed enrolled primarily women who had PPROM without labour, and 59.1% of women were re-treated when delivery was again considered to be imminent.38 Magnesium sulphate was infused for neuroprotective intent as quickly as 20 minutes before delivery. Recommendations

7. There is insufficient evidence that a repeat course of antenatal magnesium sulphate for fetal neuroprotection should be istered. (III-L) 8. Delivery should not be delayed in order to ister antenatal magnesium sulphate for fetal neuroprotection if there are maternal and/or fetal indications for emergency delivery. (III-E) 9. When magnesium sulphate is given for fetal neuroprotection, maternity care providers should use existing protocols to monitor women who are receiving magnesium sulphate for preeclampsia/ eclampsia. (III-A) Existing protocols developed for eclampsia prophylaxis and treatment may be used for women given magnesium sulphate for fetal neuroprotection. Close monitoring of

Magnesium Sulphate for Fetal Neuroprotection

Magnesium sulphate for fetal neuroprotection in imminent preterm birth (≤ 31+6 weeks)

Woman ≤ 31+6 weeks gestation AND imminent preterm birth • Active labour with ≥ 4 cm cervical dilation with either failure or contraindication to tocolysis • ≥ 4 cm dilation with documented progressive change in cervical dilation • PPROM with active labour • Planned delivery for fetal or maternal indications

YES

NO

• ister MgSO4 loading dose, 4g IV over 30 minutes • Follow with MgSO4 maintenance infusion of 1g/hour IV until birth or a maximum of 24 hours of therapy • ister corticosteroids for fetal lung maturation (if not already given) • Monitor maternal vital signs as per existing MgSO4 protocols • Provide continuous fetal heart surveillance

Woman currently not eligible for MgSO4 for neuroprotection

CLINICAL TIPS

• • •

MgSO4 may be istered before tocolytic drugs have been cleared from the maternal circulation. If nifedipine has been used for tocolysis or hypertension, there is NO contraindication to the use of MgSO4 for fetal neuroprotection. Delivery should NOT be delayed in order to ister antenatal MgSO4 for fetal neuroprotection if there are maternal and/or fetal indications for urgent delivery. Monitoring of serum Mg levels is NOT required.

“Imminent preterm birth” is defined as a high likelihood of birth, due to one or both of the following conditions: active labour with ≥4 cm of cervical dilation, with or without PPROM; planned preterm birth for fetal or maternal indications.

maternal urine output should not be required to the same degree (i.e., no requirement for Foley catheter) when magnesium sulphate is given with neuroprotective intent.

observed but are more frequent when magnesium sulphate is prepared in the delivery suite rather than by a central pharmacy.

Magnesium sulphate produces peripheral vasodilation when infused intravenously. In neuroprotective intent trials, dose-related effects were common, particularly flushing, problems at the injection site, sweating, and nausea and vomiting (Table 7). Serious maternal side effects were uncommon, with only maternal hypotension and tachycardia reaching statistical significance. Few women discontinued magnesium sulphate because of side effects. Neither maternal death nor cardiorespiratory arrest was reported in the magnesium sulphate arm of these trials.

Because of their underlying condition, women with imminent preterm birth require continuous fetal heart rate monitoring, in accordance with the SOGC fetal health surveillance guidelines.42

Monitoring of maternal serum magnesium levels is not required when magnesium sulphate is istered solely for fetal neuroprotection. Maternal adverse effects are dose-related, with respiratory or cardiac arrest associated with levels in excess of 5 mmol/L. Levels of this magnitude are not anticipated when magnesium contraindications are

   Recommendations

  10. Indications for fetal heart rate monitoring in women receiving antenatal magnesium sulphate for neuroprotection should follow the fetal surveillance recommendations of the SOGC’s 2007 Fetal Health Surveillance: Antepartum and Intrapartum Consensus Guideline. (III-A)   11. Since magnesium sulphate has the potential to alter the neonate’s neurological evaluation, causing hypotonia or apnea, health care providers caring for the neonate should have an increased awareness of this effect. (III-C) MAY JOGC MAI 2011 l 525

SOGC CLINICAL PRACTICE GUIDELINE

Table 6. Magnesium sulphate dosing in the randomized controlled trials of magnesium sulphate for fetal neuroprotection Intervention: MgSO4 Study

Women who received the LD, %

Maintenance dose

Median (IQR) dose received (g)

Women, n

Loading dose

ACTOMgSO4 Crowther et al. 200335

1062

4g IV over 20 mins

90%

1g/hr IV for 24 hr or until delivery, whichever comes first

6.5 (4.5, 14)

PREMAG Marrett et al. 200636

564

4g IV over 30 mins

99%

None given

4 g IV over 30 mins

MAGnet Mittendorf et al. 2002—neuroprotective intent arm37

57

4g IV bolus

Not reported

2241

6g IV over 20–30 mins*

> 90%†

Neuroprotective intent

BEAM Rouse et al. 200838

Neuroprotective arm: none (Tocolysis arm: 2–3g/hr)

Not reported

2 g/hr IV for a maximum of 12 hr or until delivery†

31.5 (29.0, 44.6)

Other primary intent MAGnet Mittendorf et al. 2002—tocolytic arm37 MAGPIE 200641

92

4g IV “bolus”

Not known

2–3 g/hr

Not reported

10 141

4g IV over 10 to15 mins

96%

1g/hr IV (or 5g/4hrs IM) for 24 hours

18 (9, 29)‡

LD: loading dose; NA: not available. * 71.5% of women were eligible for re-treatment. 59.1% of women were re-treated and were on magnesium sulphate at delivery. † Based on the fact that 91% of women were on magnesium sulphate for at least three hours. ‡ Estimated as value uncertain from published data.33

The relevant randomized controlled trials34 raise no concerns about short-term neonatal adverse effects of antenatal exposure, and no additional neonatal assessment or care is required. Neonates with hypermagnesemia may present with symptoms of apnea or hypoventilation, weakness, hypotonia, absent or reduced deep tendon reflexes, and stupor or coma. This symptom complex has been described in the neonates of mothers istered large doses of IV magnesium sulphate for eclampsia with neonatal serum levels > 4.5 mEq/L.43 However, antenatal magnesium sulphate istered specifically for fetal neuroprotection did not affect the incidence of Apgar score < 7 at 5 minutes (RR 1.03; 95% CI 0.90 to 1.18; 3 trials, 4387 infants), neonatal hypotonia (RR 1.02; 95% CI 0.77 to 1.36; 1 trial, 2444 infants), or the need for ongoing ventilatory (RR 0.94; 95% CI 0.89 to 1.00; 3 trials; 4387 women). None of the main trial publications reported on the need for active resuscitation at birth,34 but a subanalysis of the BEAM trial found no correlation between cord blood magnesium levels and the need for bag-mask ventilation, intubation, or chest compressions.44 It is unknown whether magnesium sulphate exposure would affect the need for ventilation in neonatal intensive care units using protocols to minimize ventilation. The relevant randomized controlled trials35–38 demonstrated no other differences in neonatal morbidity, including seizures, respiratory distress syndrome, bronchopulmonary dysplasia, or necrotizing enterocolitis. 526 l MAY JOGC MAI 2011

Few newborn subjects with in utero exposure to magnesium sulphate remote from delivery were included in the relevant trials. There is no clear rationale for any additional assessment of these newborns. There should be an ongoing registry of children exposed to antenatal magnesium sulphate for neuroprotection. This would allow evaluation of the following: 1. Effects on delivery room resuscitation, especially in units with ventilation-avoidance protocols 2. Anticipated reduction in 3. Effect on the high prevalence of school age morbidities among infants born preterm. SPECIAL CONSIDERATIONS REGARDING THE USE OF MAGNESIUM SULPHATE FOR FETAL NEUROPROTECTION Transport

When maternal transport is being considered, magnesium istration should be decided on in consultation with the receiving centre, on a case-by-case basis. Drug Interactions

Antenatal corticosteroids should be istered for fetal lung maturation. When tocolysis has been employed to attempt to arrest preterm labour, magnesium sulphate can be used once

Magnesium Sulphate for Fetal Neuroprotection

Table 7. Maternal outcomes in trials of magnesium sulphate for fetal neuroprotection in neuroprotective intent trials (adapted from Conde-Agudelo and Romero32) MgSO4 n (%)

Placebo n (%)

RR (95% CI)

Trials n

1356/1917 (70.7)

343/1950 (17.6)

5.05 (2.06 to 12.39)

3

Flushing

1119/1917 (58.4)

162/1950 (8.3)

7.56 (3.39 to 16.88)

3

Problems at injection site

614/1631 (37.6)

68/1672 (4.1)

9.12 (7.19 to 11.57)

2

Sweating

411/1631 (25.2)

57/1672 (3.4)

6.37 (1.96 to 20.68)

2

Nausea or vomiting

312/1917 (16.3)

76/1950 (3.9)

4.60 (1.54 to 13.75)

3

Clinical and self-assessed maternal side effects

Any side effect Minor side effects

Serious side effects

Hypotension

80/821 (9.7)

52/805 (6.5)

1.51 (1.09 to 2.09)

2

Tachycardia

56/535 (10.5)

36/527 (6.8)

1.53 (1.03 to 2.29)

1

Respiratory depression

41/1631 (2.5)

31/1672 (1.9)

1.31 (0.83 to 2.07)

2

Pulmonary edema

8/1096 (0.7)

3/1145 (0.3)

2.79 (0.74 to 10.47)

1

123/1631 (7.5)

44/1672 (2.6)

2.81 (2.01 to 3.93)

2

Death

0/1917

1/1950

0.32 (0.01 to 7.92)

3

Cardiac or respiratory arrest

0/1917

0/1950

—*

3

Infusion stopped due to adverse effects Serious maternal adverse effects

* Not estimable.

tocolysis has been discontinued because delivery is considered imminent. If nifedipine has been used for tocolysis or hypertension, there is no contraindication to the use of magnesium sulphate for fetal neuroprotection. Although case reports have described neuromuscular blockade with concomitant use of magnesium sulphate and nifedipine or other calcium channel blockers, a controlled study and synthesis of the literature failed to demonstrate an increased risk.42 Potential Obstetrical Adverse Outcomes

In the Conde-Agudelo and Romero meta-analysis,32 magnesium sulphate given with neuroprotective intent was not associated with a difference in Caesarean section (822 [42.9%] in the magnesium arm vs. 834 [42.8%] for placebo; RR 1.0; 95% CI 0.9 to 1.1; 3 trials, 3867 women) or severe postpartum hemorrhage (28 [3.4%] in the magnesium arm vs. 26 [3.2%] for placebo; RR 1.1; 95% CI 0.6 to 1.8; 2 trials, 1626 women). None of the trials reported on length of labour or augmentation of labour. CLINICAL PRACTICE GUIDELINES AND COMMITTEE OPINION

Australian National Clinical Practice Guidelines45 were published in March 2010 by the Antenatal Magnesium Sulphate for Neuroprotection Guideline Development . They recommended antenatal magnesium sulphate

for fetal neuroprotection (excellent evidence) in the same dosage as recommended in these guidelines. However, magnesium was recommended only at < 30 weeks’ gestation (good evidence) on the basis of two considerations. First, no one gestational age subgroup (of the < 34, < 33, < 32, and < 30 week categories considered) was considered to show a clear benefit, although the < 28 week subgroup of Rouse et al.38 was not included, because the committee felt that the predominance of PPROM in that study population limited generalizability to the target population of women with imminent preterm labour (which the committee defined as planned or definitely expected within 24 hours). Second, in the face of uncertainty, the committee felt it was prudent to limit the impact of their clinical practice guidelines on resource allocation. Also in March 2010, the American College of Obstetricians and Gynecologists issued a committee opinion on magnesium sulphate for fetal neuroprotection. It stated that “the available evidence suggests that magnesium sulphate given before anticipated early preterm birth reduces the risk of cerebral palsy in surviving infants.” No official opinion was given on a gestational age cut-off, but it was recommended that physicians develop specific guidelines around the issues of inclusion criteria, dosage, concurrent tocolysis, and monitoring in accordance with one of the larger trials.46 MAY JOGC MAI 2011 l 527

SOGC CLINICAL PRACTICE GUIDELINE

REFERENCES 1. Public Health Agency of Canada. Canadian Perinatal Health Report. Ottawa: Minister of Public Works and Government Services Canada, 2008. 2. Woodward LJ, Anderson PJ, Austin NC, Howard K, Inder TE. Neonatal MRI to predict neurodevelopmental outcomes in preterm infants. N Engl J Med 2006;355:685–94. 3. Anderson P, Doyle LW. Neurobehavioral outcomes of school-age children born extremely low birth weight or very preterm in the 1990s. JAMA 2003;289:3264–72. 4. Kuban KC, Leviton A. Cerebral palsy. N Engl J Med 1994;330:188–95. 5. Center for Disease Control and Prevention. What is cerebral palsy? Available at: http://www.cdc.gov/ncbddd/dd/dd.htm. Accessed March 3, 2011.

22. Kuban KC, Leviton A, Pagano M, Fenton T, Strassfeld R, Wolff M. Maternal toxemia is associated with reduced incidence of germinal matrix hemorrhage in premature babies. J Child Neurol 1992;7:70–6. 23. Grether JK, Hoogstrate J, Walsh-Greene E, Nelson KB. Magnesium sulfate for tocolysis and risk of spastic cerebral palsy in premature children born to women without preeclampsia. Am J Obstet Gynecol 2000;183:717–25. 24. O’Shea TM, Klinepeter KL, Dillard RG. Prenatal events and the risk of cerebral palsy in very low birth weight infants. Am J Epidemiol 1998;147:362–9. 25. Schendel DE, Berg CJ, Yeargin-Allsopp M, Boyle CA, Decoufle P. Prenatal magnesium sulfate exposure and the risk for cerebral palsy or mental retardation among very low-birth-weight children aged 3 to 5 years. JAMA 1996;276:1805–10.

6. Vincer MJ, Allen AC, Joseph KS, Stinson DA, Scott H, Wood E. Increasing prevalence of cerebral palsy among very preterm infants: a population-based study. Pediatrics 2006;118(6):e1621-e1626.

26. Altman D, Carroli G, Duley L, Farrell B, Moodley J, Neilson J, et al. Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: a randomised placebo-controlled trial. Lancet 2002;359(9321):1877–90.

7. Petrini JR, Dias T, McCormick MC, Massolo ML, Green NS, Escobar GJ. Increased risk of adverse neurological development for late preterm infants. J Pediatr 2009;154:169–76.

27. Duley L, Carroli G, Belizan J, Gonzalez L, Campodonico L, Bergel, E et al. Which anticonvulsant for women with eclampsia—evidence from the Collaborative Eclampsia Trial. Lancet 1995;345(8963):1455–63.

8. Moster D, Lie RT, Markestad T. Long-term medical and social consequences of preterm birth. N Engl J Med 2008;359:262–73.

28. Gathwala G. Neuronal protection with magnesium. Indian J Pediatr 2001;68:417–9.

9. Stanley FJ. Survival and cerebral palsy in low birthweight infants: implications for perinatal care. Paediatr Perinat Epidemiol 1992;6:298–310.

29. Nelson KB, Grether JK. Causes of cerebral palsy. Curr Opin Pediatr 1999;11:487–91.

10. Drummond PM, Colver AF. Analysis by gestational age of cerebral palsy in singleton births in north-east England 1970–94. Paediatr Perinat Epidemiol 2002;16:172–80.

30. Burd I, Breen K, Friedman A, Chai J, Elovitz MA. Magnesium sulfate reduces inflammation-associated brain injury in fetal mice. Am J Obstet Gynecol 2010;202:292–9.

11. Pharoah PO, Cooke T, Johnson MA, King R, Mutch L. Epidemiology of cerebral palsy in England and Scotland, 1984–9. Arch Dis Child Fetal Neonatal Ed 1998;79(1):F21-F25.

31. McDonald JW, Silverstein FS, Johnston MV. Magnesium reduces N-methyl-D-aspartate (NMDA)-mediated brain injury in perinatal rats. Neurosci Lett 1990;109(1–2):234–8.

12. Winter S, Autry A, Boyle C, Yeargin-Allsopp M. Trends in the prevalence of cerebral palsy in a population-based study. Pediatrics 2002;110(6):1220–5.

32. Conde-Agudelo A, Romero R. Antenatal magnesium sulfate for the prevention of cerebral palsy in preterm infants less than 34 weeks’ gestation: a systematic review and metaanalysis. Am J Obstet Gynecol 2009;200:595–609.

13. Petterson B, Nelson KB, Watson L, Stanley F. Twins, triplets, and cerebral palsy in births in Western Australia in the 1980s. BMJ 1993;307(6914):1239–43. 14. Hack M, Costello DW. Trends in the rates of cerebral palsy associated with neonatal intensive care of preterm children. Clin Obstet Gynecol 2008;51:763–74. 15. Robertson CM, Watt MJ, Yasui Y. Changes in the prevalence of cerebral palsy for children born very prematurely within a population-based program over 30 years. JAMA 2007;297(24):2733–40. 16. Hagberg B, Hagberg G, Beckung E, Uvebrant P. Changing panorama of cerebral palsy in Sweden. VIII. Prevalence and origin in the birth year period 1991–94. Acta Paediatr 2001;90:271–7. 17. Economic costs associated with mental retardation, cerebral palsy, hearing loss, and vision impairment—United States, 2003. MMWR Morb Mortal Wkly Rep 2004;53:57–9.

33. Costantine MM, Weiner SJ. Effects of antenatal exposure to magnesium sulfate on neuroprotection and mortality in preterm infants: a metaanalysis. Obstet Gynecol 2009;114(2 Pt 1):354–64. 34. Doyle LW, Crowther CA, Middleton P, Marret S, Rouse D. Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus. Cochrane Database Syst Rev 2009;(1):CD004661. 35. Crowther CA, Hiller JE, Doyle LW, Haslam RR. Effect of magnesium sulfate given for neuroprotection before preterm birth: a randomized controlled trial. JAMA 2003; 290(20):2669–76. 36. Marret S, Marpeau L, Zupan-Simunek V, Eurin D, Leveque C, Hellot MF, et al. Magnesium sulphate given before very-preterm birth to protect infant brain: the randomised controlled PREMAG trial*. BJOG 2007;114:310–8.

18. Leviton A, Kuban KC, Pagano M, Brown ER, Krishnamoorthy KS, Allred EN. Maternal toxemia and neonatal germinal matrix hemorrhage in intubated infants less than 1751 g. Obstet Gynecol 1988;72:571–6.

37. Mittendorf R, Dambrosia J, Pryde PG, Lee KS, Gianopoulos JG, Besinger RE, et al. Association between the use of antenatal magnesium sulfate in preterm labor and adverse health outcomes in infants. Am J Obstet Gynecol 2002;186:1111–8.

19. Van de B or [Van de Bor M, ] M, Verloove-Vanhorick SP, Brand R, Keirse MJ, Ruys JH. Incidence and prediction of periventricular-intraventricular hemorrhage in very preterm infants. J Perinat Med 1987;15:333–9.

38. Rouse DJ, Hirtz DG, Thom E, Varner MW, Spong CY, Mercer BM, et al. A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy. N Engl J Med 2008; 359(9):895–905.

20. Nelson KB, Grether JK. Can magnesium sulfate reduce the risk of cerebral palsy in very low birthweight infants? Pediatrics 1995; 95:263–9.

39. Magee LA, Helewa M, Rey E, Cote AM, Douglas J, Gibson P, et al. Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy. SOGC Clinical Practice Guideline no. 206, March 2008. J Obstet Gynaecol Can 2008;30(Suppl 1):S1-S48.

21. Grether JK, Cummins SK, Nelson KB. The California Cerebral Palsy Project. Paediatr Perinat Epidemiol 1992;6:339–51.

528 l MAY JOGC MAI 2011

Magnesium Sulphate for Fetal Neuroprotection

40. Mittendorf R, Covert R, Boman J, Khoshnood B, Lee KS, Siegler M. Is tocolytic magnesium sulphate associated with increased total paediatric mortality? Lancet 1997;350(9090):1517–8. 41. The Magpie Trial: a randomised trial comparing magnesium sulphate with placebo for pre-eclampsia. Outcome for children at 18 months. BJOG 2007;114:289–99. 42. Liston R, Sawchuck D, Young D; SOGC Fetal Health Surveillance Consensus Committee. Fetal health surveillance: antepartum and intrapartum consensus guideline. SOGC clinical practice guideline no. 197, September 2007. J Obstet Gynaecol Can 2007;29(Suppl 4):S1-S58. 43. Volpe JJ. Neurology of the newborn. 4th ed. Philadelphia: W.B. Saunders; 2001. 44. Johnson L; for the Eunice Kennedy Shriver, National Institute of Child Health and Human Development Maternal Fetal Medicine Units Network,

Bethesda MD. Correlation of cord blood magnesium level with neonatal resuscitation requirements in preterm infants. Presented at: Pediatric Academic Societies Meeting; May 2010; Vancouver BC. 45. The Antenatal Magnesium Sulphate for Neuroprotection Guideline Development . Antenatal magnesium sulphate prior to preterm birth for neuroprotection of the fetus, infant and child: national clinical practice guidelines. The Australian Research Centre for Health of Women and Babies, The University of Adelaide; 2010. 46. Magee LA, Miremadi S, Li J, Cheng C, Ensom MH, Carleton B, et al. Therapy with both magnesium sulfate and nifedipine does not increase the risk of serious magnesium-related maternal side effects in women with preeclampsia. Am J Obstet Gynecol 2005;193:153–63. 47. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

MAY JOGC MAI 2011 l 529

SOGC CLINICAL PRACTICE GUIDELINE SOGC CLINICAL PRACTICE GUIDELINE

No. 256, April 2011

Substance Use in Pregnancy This clinical practice guideline has been prepared by the Working Group on Problematic Substance Use in Pregnancy, reviewed by the Maternal Fetal Medicine Committee, the Family Physicians Advisory Committee and the Medico-Legal Committee, and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Suzanne Wong, MD, Toronto ON Alice Ordean, MD, Toronto ON Meldon Kahan, MD, Toronto ON MATERNAL FETAL MEDICINE COMMITTEE Robert Gagnon, MD (Chair), Montreal QC Lynda Hudon, MD (Co-Chair), Montreal QC Melanie Basso, RN, Vancouver BC Hayley Bos, MD, London ON Joan Crane, MD, St. John’s NL Gregory Davies, MD, Kingston ON Marie- Delisle, MD, Vancouver BC Dan Farine, MD, Toronto ON Savas Menticoglou, MD, Winnipeg MB William Mundle, MD, Windsor ON Lynn Murphy-Kaulbeck, MD, Allison NB Annie Ouellet, MD, Sherbrooke QC Tracy Pressey, MD, Vancouver BC Anne Roggensack, MD, Calgary AB Frank Sanderson, MD, Saint John NB FAMILY PHYSICIANS ADVISORY COMMITTEE William Ehman, MD (Chair), Nanaimo BC Anne Biringer, MD, Toronto ON Andrée Gagnon, MD, Blainville QC Lisa Graves, MD, Sudbury ON

J Obstet Gynaecol Can 2011;33(4):367–384 Key Words: Pregnancy, substance-related disorders, substance use, neonatal abstinence syndrome

Jonathan Hey, MD, Saskatoon SK Jill Konkin, MD, Edmonton AB Francine Léger, MD, Montreal QC Cindy Marshall, MD, Lower Sackville NS MEDICO-LEGAL COMMITTEE Deborah Robertson, MD (Chair), Toronto ON Douglas Bell, MD, Ottawa ON George Carson, MD, Regina SK Donna Gilmour, MD, Halifax NS Owen Hughes, MD, Ottawa ON Caroline Le Jour, MD, Calgary AB Dean Leduc, MD, Orleans ON Nicholas Leyland, MD, Hamilton ON Paul Martyn, MD, Calgary AB André Masse, MD, Montreal QC AD HOC REVIEWERS Ron Abrahams, MD, Vancouver BC Sanja Avdic, MD, Toronto ON Howard Berger, MD, Toronto ON Mike Franklyn, MD, Sudbury ON Samuel Harper MD, Montreal QC Georgia Hunt, MD, Vancouver BC Patricia Mousmanis, MD, Richmond Hill ON Kellie Murphy, MD, Toronto ON Sarah Payne, MA, Vancouver BC SPECIAL CONTRIBUTORS Deana Midmer, EdD, Toronto ON Sandra de la Ronde, MD, Calgary AB The literature searches and bibliographic for this guideline were undertaken by Becky Skidmore, Medical Research Analyst, Society of Obstetricians and Gynaecologists of Canada. Disclosure statements have been received from all of the committees. Dr Alice Ordean received funding from National Institute on Drug Abuse grant R01 DA015741.

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

APRIL JOGC AVRIL 2011 l 367

SOGC CLINICAL PRACTICE GUIDELINE

Abstract

4.

Objective: To improve awareness and knowledge of problematic substance use in pregnancy and to provide evidence-based recommendations for the management of this challenging clinical issue for all health care providers.

Health care providers should employ a flexible approach to the care of women who have substance use problems, and they should encourage the use of all available community resources. (II-2B)

5.

Women should be counselled about the risks of periconception, antepartum, and postpartum drug use. (III-B)

6.

Smoking cessation counselling should be considered as a first-line intervention for pregnant smokers. (I-A) Nicotine replacement therapy and/or pharmacotherapy can be considered if counselling is not successful. (I-A)

7.

Methadone maintenance treatment should be standard of care for opioid-dependent women during pregnancy. (II-IA) Other slow-release opioid preparations may be considered if methadone is not available. (II-2B)

8.

Opioid detoxification should be reserved for selected women because of the high risk of relapse to opioids. (II-2B)

9.

Opiate-dependent women should be informed that neonates exposed to heroin, prescription opioids, methadone, or buprenorphine during pregnancy are monitored closely for symptoms and signs of neonatal withdrawal (neonatal abstinence syndrome). (II-2B) Hospitals providing obstetric care should develop a protocol for assessment and management of neonates exposed to opiates during pregnancy. (III-B)

Options: This guideline reviews the use of screening tools, general approach to care, and recommendations for clinical management of problematic substance use in pregnancy. Outcomes: Evidence-based recommendations for screening and management of problematic substance use during pregnancy and lactation. Evidence: Medline, PubMed, CINAHL, and The Cochrane Library were searched for articles published from 1950 using the following key words: substance-related disorders, mass screening, pregnancy complications, pregnancy, prenatal care, cocaine, cannabis, methadone, opioid, tobacco, nicotine, solvents, hallucinogens, and amphetamines. Results were initially restricted to systematic reviews and randomized control trials/controlled clinical trials. A subsequent search for observational studies was also conducted because there are few RCTs in this field of study. Articles were restricted to human studies published in English. Additional articles were located by hand searching through article reference lists. Searches were updated on a regular basis and incorporated in the guideline up to December 2009. Grey (unpublished) literature was also identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Values: The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on the Preventive Health Care. Recommendations for practice were ranked according to the method described in that report (Table 1). Benefits, harms, and costs: This guideline is intended to increase the knowledge and comfort level of health care providers caring for pregnant women who have substance use disorders. Improved access to health care and assistance with appropriate addiction care leads to reduced health care costs and decreased maternal and neonatal morbidity and mortality. Recommendations 1.

All pregnant women and women of childbearing age should be screened periodically for alcohol, tobacco, and prescription and illicit drug use. (III-A)

2.

When testing for substance use is clinically indicated, urine drug screening is the preferred method. (II-2A) Informed consent should be obtained from the woman before maternal drug toxicology testing is ordered. (III-B)

3.

Policies and legal requirements with respect to drug testing of newborns may vary by jurisdiction, and caregivers should be familiar with the regulations in their region. (III-A)

ABBREVIATIONS HCV

hepatitis C virus

MMT

methadone maintenance therapy

NAS

neonatal abstinence syndrome

NRT

nicotine replacement therapy

UDS

urine drug screening

368 l APRIL JOGC AVRIL 2011

10. Antenatal planning for intrapartum and postpartum analgesia may be offered for all women in consultation with appropriate health care providers. (III-B) 11. The risks and benefits of breastfeeding should be weighed on an individual basis because methadone maintenance therapy is not a contraindication to breastfeeding. (II-3B)

Introduction

S

ubstance use during pregnancy is common. In national prevalence surveys, 14% of Canadian women reported using alcohol during their last pregnancy, and 17% reported smoking during pregnancy.1,2 The prevalence of illicit drug use among Canadian women of childbearing age is less but not insignificant. In United States population surveys ~5% of pregnant women reported illicit drug use during the preceding month.3 Marijuana remains the most commonly used illegal drug, followed by cocaine. Women report higher rates than men of prescription drug use, including pain relievers (23.1%), opioid analgesics (2.1%), sleeping pills (1.7%), tranquilizers (1.1%), and antidepressants (2.1%).2 The use of alcohol and drugs by pregnant women can result in significant maternal, fetal, and neonatal morbidity.4–17 In general, pregnant women with substance use disorders are less likely to seek prenatal care, and they have higher rates of infectious diseases such as HIV, hepatitis, and other sexually transmitted infections.17–19 There are numerous direct and indirect costs of perinatal substance exposure. In 2002, the overall social cost of substance abuse in Canada, including burden on health care, law enforcement, and loss of productivity due to premature death and ill health, totalled ~$40 billion.20 Data

Substance Use in Pregnancy

Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well–designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.161 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the The Canadian Task Force on Preventive Health Care.161

from American studies have indicated that the increase in cost of neonatal care for infants born to mothers who smoke cigarettes is ~$700, and the increase in cost for those exposed to cocaine is $5110 per patient.21–23 Because of the prevalence of substance use and its clinical and economic impact, health care providers need to know how to identify and care for the affected patient population. Management of substance use disorders is complicated because of the associated comorbid conditions and psychosocial and socioeconomic factors, such as mental health problems, poor housing, financial stressors, and lack of s. Canadian physicians have identified a lack of knowledge and training regarding the effects of and treatments for substance use during pregnancy as another barrier to providing care for these patients.24 Perinatal care providers have several opportunities during pregnancy to identify and assist women who have substance use problems. Although most physicians enquire routinely about alcohol, tobacco, and other drug use during pregnancy, many do not use a specific screening tool and are not making referrals to other treatment resources.25–28 As motivation to change unhealthy or harmful behaviours is increased during pregnancy, it is an ideal time to intervene with women who have substance use problems. This guideline provides a unified approach to care for perinatal substance use disorders.

DEFINITIONS

Substance abuse and dependence have well-defined criteria based on the DSM-IV guide (Table 2).29 Substance dependence is characterized by compulsive drug use, loss of control over use, and physical, social, and psychological consequences.30 Physical dependence is characterized by tolerance and withdrawal; however, it is not in itself sufficient to make a diagnosis of substance dependence. Substance withdrawal consists of a combination of drugspecific symptoms and signs that occur within hours to days of stopping drug use (Table 3). identification of substance-related disorders in pregnancy

Screening and Assessment

All pregnant women regardless of socioeconomic status should be asked about past and current alcohol, nicotine, and illicit and prescribed drug use. A high index of suspicion for potential substance use during pregnancy is required in various clinical situations.31 There is no optimal screening tool for identifying substance use in pregnancy. Maternal interview using open-ended, non-judgemental questioning is more likely to elicit disclosure of perinatal substance use.31,32 Health care providers should develop their own level of comfort and style in asking their patients about this sensitive topic. The T-ACE and TWEAK questionnaires were developed for screening at-risk perinatal alcohol use APRIL JOGC AVRIL 2011 l 369

SOGC CLINICAL PRACTICE GUIDELINE

(Figure 1).33,34 The ALPHA tool incorporates the CAGE questionnaire to screen for maternal recreational drug use, as well as validated questions to identify associated psychosocial risk factors such as family violence or postpartum depression (Appendix).35,36 If the woman acknowledges substance use, a more complete assessment is then recommended to determine if there is a history of substance abuse or dependence (Figure 2).

Table 2. Definitions of substance-related disorders Substance use disorder Substance dependence

2. withdrawal 3. substance taken in larger amounts or over a longer period than was intended

Drug toxicology testing is not recommended for universal screening (i.e., routine testing of all women) because it has numerous limitations (Figure 3), and it should be considered only after a comprehensive assessment if there is a clinical indication.37 If a woman is concerned about providing a sample or is reluctant to do so, clinicians should focus on developing a trusting relationship before suggesting toxicology testing. Vulnerable women may feel threatened if clinicians wish to gather detailed information through drug testing and psychosocial histories.

UDS has several clinical indications. Evidence shows that the addition of urine drug testing to the structured maternal interview can increase the detection of problematic substance use in pregnancy.42,43 Detection can facilitate early intervention, including treatment of maternal and neonatal withdrawal and counselling and referral for longterm outpatient treatment. For example, an unexpected positive UDS result for opioids may prompt an assessment for opioid dependence and observation of the neonate for signs of withdrawal. Ongoing outpatient monitoring with UDS is also used to advocate on behalf of patients with child protection services and to monitor compliance with prescribed medications (e.g., opioids).34,38 In addition, it can be performed on maternal request. Informed consent must be obtained and documented in the medical record before any maternal drug testing is performed (except in life-threatening situations where informed consent is impossible).44 If the mother refuses, 370 l APRIL JOGC AVRIL 2011

A pattern of substance use, leading to clinically significant impairment or distress, as manifested by ≥ 3 of the following, occurring at any time in the same 12-month period: 1. tolerance

Role of Toxicology Testing

Urine, hair, and meconium samples are sensitive biological markers of substance use. Urine drug screening can detect only recent substance exposure, while neonatal hair and meconium testing can document intrauterine use because meconium and hair form in the second and third trimester, respectively.38–41 By itself, a single positive test result cannot be used to diagnose substance dependence. Although child protection agencies sometimes request hair analyses, neither hair nor meconium is appropriate for routine clinical use because of the high costs and propensity for false positive results.

Definition

4. persistent desire or unsuccessful efforts to cut down or control substance use 5. a great deal of time spent in activities necessary to obtain the substance (e.g., visiting multiple doctors or driving long distances), use the substance (e.g., chainsmoking), or recover from its effects 6. important social, occupational, or recreational activities given up or reduced because of substance use 7. continued use despite knowledge of harm Substance abuse

A pattern of substance use leading to clinically significant impairment or distress, as manifested by ≥ 1 of the following, occurring within a 12-month period: 1. recurrent substance use resulting in a failure to fulfill major role obligations at work, school, or home 2. recurrent substance use in situations in which it is physically hazardous 3. recurrent substance-related legal problems 4. persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of the substance

Tolerance

Characterized by a need for markedly increased amounts of the substance to achieve desired effect or diminished effect with continued use of the same amount of the substance

this should be documented, and testing should not be performed. Neonatal toxicology testing may be performed without consent of the parent(s) if the person requesting this testing has a legislative right to make decisions for the infant to be tested. However, the mother should be informed that the neonate is being tested.34 Once consent is obtained, any drug toxicology testing to be performed must be ordered by the physician responsible for maternal and/or neonatal care. Recommendations

1. All pregnant women and women of childbearing age should be screened periodically for alcohol, tobacco, and prescription and illicit drug use. (III-A)

Substance Use in Pregnancy

Table 3. Withdrawal syndromes Substance

Withdrawal symptoms and signs

Nicotine

Irritability, restlessness, anxiety, insomnia, fatigue, poor concentration

Marijuana

Irritability, insomnia, anorexia, anxiety

Opioids

Influenza-like symptoms: myalgias, rhinorrhea, goosebumps, diaphoresis, nausea, vomiting, diarrhea Psychological symptoms: insomnia, anxiety, strong cravings, dysphoria Obstetrical symptoms: abdominal cramping, uterine irritability

Benzodiazepines

Seizures (high dose), anxiety, panic attacks, insomnia, emotional lability

Cocaine/amphetamines

Crash phase: fatigue, increased appetite Withdrawal dysphoria phase: dysphoria, irritability, insomnia, strong cravings

Inhalants

Similar to alcohol withdrawal: tremor, malaise, gastrointestinal symptom

2. When testing for substance use is clinically indicated, urine drug screening is the preferred method. (II-2A) Informed consent should be obtained from the woman before maternal drug toxicology testing is ordered. (III-B) 3. Policies and legal requirements with respect to drug testing of newborns may vary by jurisdiction, and caregivers should be familiar with the regulations in their region. (III-A) Components of office management

Obstetrical care providers need to establish rapport with substance-using pregnant women through good communication and a willingness to be flexible in providing prenatal care and ongoing . These women face a number of barriers to receiving optimal prenatal care (Figure 4).45–48 Flexibility with respect to patient scheduling and understanding late arrivals and missed appointments are key to engaging these women for prenatal care. Women are likely to seek and commit to prenatal care if health care providers are welcoming and non-judgemental, and if they acknowledge the women’s courage and persistence in the face of very difficult personal circumstances. Studies have shown that comprehensive care provided at one site is costeffective and produces better outcomes for both mother and child.9,19,49–58 It is also important to address women’s substance use because pregnancy is an ideal time for women to make a change. Harm reduction is defined as a program or policy designed to reduce the drug-related harm without requiring the cessation of drug use.30 The philosophy of care for women with problematic substance use in pregnancy is harm reduction. Components of this philosophy include encouragement of abstinence or reduction of use, safe

use, treatment of withdrawal symptoms, counselling and/ or pharmacotherapy. Pregnancy may motivate women to abstain from or reduce drug use, given the potential effects on fetal outcomes. Pregnant substance-using women are also at increased risk of infectious diseases. Injection drug use remains the most dominant mode of hepatitis C virus acquisition. Approximately, 70% to 80% of HCV-infected patients report a history of current or past injection drug use.59 HCV-negative women should be advised about ways to prevent exposure to HCV. Women should be told not to share materials to prepare, inject, or inhale drugs, and that they should not engage in higher risk sexual behaviours (e.g., unprotected sex with multiple sexual partners or unprotected sex with HCV-positive partners). Pregnant HCV-infected women have a 5% chance of transmitting the virus to their infants.60 There are no ways to decrease the risk of vertical transmission. Furthermore, mode of delivery and breastfeeding do not affect mother-to-infant transmission. Procedures that promote mixing of maternal and fetal blood, such as use of scalp electrodes, should be avoided, if possible. Serology testing of infants at 12 to 18 months of age is recommended to determine HCV status. The prevalence of sexually transmitted infections is also higher among pregnant women with a history of substance abuse related to high-risk sexual behaviours.61,62 Screening for Chlamydia, gonorrhea, syphilis, hepatitis, and HIV should be repeated throughout pregnancy if historical factors warrant it.63 There are numerous adverse effects associated with prenatal drug exposure (Table 4). These effects may also be linked to other factors such as inadequate prenatal care, poor social circumstances, and concomitant use of other substances.64,65 Therefore, long-term studies are difficult to APRIL JOGC AVRIL 2011 l 371

SOGC CLINICAL PRACTICE GUIDELINE

Figure 1. T-ACE and TWEAK for problematic alcohol use T-ACE T How many drinks does it take to make you feel high? (Tolerance) A Have people annoyed you by criticizing your drinking? C Have you felt you ought to cut down on your drinking? E Have you ever had a drink first thing in the morning to steady your nerves or get rid of a hangover? (Eye-opener) Scoring: T: 2 points if > 3 drinks; A,C,E: 1 point for each yes answer A total of 2 or more points indicates patient is likely to have an alcohol problem. TWEAK T Tolerance W Have friends or relatives complained about your drinking? (Worried) E Eye-opener A Has a friend or family member ever told you about things you said or did while you were drinking that you could not ? (Amnesia or black-out) K Cut-down Scoring: T: 2 points if > 3 drinks; W, E, A, K: 1 point for each yes answer A total of score of 3 or more points indicates patient is at-risk drinking

Figure 2. Assessment for substance-related disorders Complete drug history: name of drug, amount, frequency, duration, route(s), last use, injection drug use, sharing needles/paraphernalia, withdrawal symptoms Stage of change with respect to substance use

• Consequences of drug use: medical, social, personal • Previous treatment programs, mutual aid groups (e.g., AA) Medical history: HIV, Hepatitis B and C, STIs

• Chronic medical conditions (e.g., chronic pain), medications Psychiatric history: eating disorders, sexual/physical abuse, mood and anxiety disorders Obstetrical history: cycle regularity, LMP, past obstetrical outcomes and complications Social history: family situation (partner and number of children), custody status, housing situation, legal status (current charges and court dates), finances, nutrition, child protection agency involvement, child safety concerns FIFE: feelings, impressions/ideas, functioning, expectations about pregnancy and drug use

interpret because effects may be due to these confounders and environmental deprivation rather than the drug itself. In addition to routine care, patients should be given counselling regarding the drug-specific fetal, neonatal, and maternal effects of substance use. Antenatal fetal surveillance should be based on obstetrical indications rather than solely on substance use. Substance use during pregnancy has been associated with obstetrical complications such as preterm labour, placental abruption, and intrauterine growth restriction (Table 4), and these adverse effects may lead to an increased risk of perinatal morbidity and mortality. Therefore, the method and 372 l APRIL JOGC AVRIL 2011

frequency of antenatal testing will be determined by the presence or absence of these complications.66 There are two phases to the management of substance use disorders. The first addresses treatment of withdrawal syndromes. Pregnant women who are dependent on alcohol, opioids, or high-dose benzodiazepines (> 50 mg daily diazepam equivalent) may require medical detoxification under the supervision of a physician (Table 5).30 Women who are in withdrawal from other substances, such as cocaine or marijuana, may also benefit from a ive ission to a non-medical withdrawal management centre, if available.

Substance Use in Pregnancy

Figure 3. Limitations of drug toxicology • Women can avoid detection of substances in urine samples through simple measures such as abstaining for 1–3 days before testing, drinking lots of water to lower the concentration of the drug in the urine, or substituting samples of another person’s urine for their own • Alcohol is very hard to detect with laboratory testing (blood and urine sampling) because of its short half-life • The amount of drug in a hair sample correlates with degree of drug use (which is not the case with urine drug testing); however, a positive finding is not diagnostic of addiction • Hair analysis can have false-positive results due to ive exposure to smoked drugs in environment • A false positive result can have serious legal and emotional consequences for the mother

Figure 4. Barriers to prenatal care for pregnant substance-using women • Personal factors: shame, stigma, guilt, lack of family , substance using male partner, fear of losing children, concomitant psychosocial issues (e.g., transportation, child care) • Systemic factors: lack of appropriate treatment services for pregnant women, negative attitudes of health care providers

The second phase focuses on relapse prevention by encouraging substance abuse treatment and development of a ive network. Brief interventions can range from simple physician advice to motivation counselling sessions consisting of goal setting, problem solving with respect to triggers, and information on potential harms. These interventions are effective in reducing alcohol use among pregnant women.67,68 Currently, there are no research data on the effectiveness of similar interventions for illicit substance use in pregnancy. However, systematic reviews have shown that outpatient psychotherapy for cannabis dependence is moderately effective at reducing substance use in non-pregnant patients.69,70 Therefore, physician counselling may also be of benefit to pregnant women. Pharmacological maintenance options are available for management of nicotine and opioid dependence. Evidence suggests that enhanced treatment programs for opioid dependence that combine methadone maintenance therapy, group psychotherapy, and obstetrical care result in less overall illicit substance use, improved prenatal care, and lower rates of obstetrical complications.19,52,71–73 Evaluation of comorbid conditions should include screening for depression, anxiety, and other mental health disorders, domestic violence and abuse, and psychosocial system. Most women in substance abuse treatment programs report a past history of trauma (including physical and sexual abuse), and approximately 25% have been diagnosed with posttraumatic stress disorder.74–76 Partner involvement in prenatal care and addiction treatment is critical to recovery.56 A partner’s active drug use has been linked to delayed treatment time for women seeking care.77,78 Similarly, women with fewer social s are less likely to seek and to remain in treatment.79,80 Appropriate referrals may include counselling to deal with pre-existing trauma and assistance with other social determinants of

health (e.g., food and housing). The cornerstone of care of problematic substance use in pregnant women is harm reduction. Components of this include encouragement of abstinence or reduction of use, safe use, treatment of withdrawal, counselling, and/or pharmacotherapy. Any health care provider who has a clinical suspicion based on history and/or physical examination that a child is or may be in need of protection because of abuse or neglect must make a report to child protection services.81 Health care professionals should be aware of province-specific legislation with respect to child welfare and reporting responsibilities. Clinicians are not required to report until birth, because unborn babies do not have any legal rights, but antenatal self-reporting is encouraged to increase maternal self-determination, dignity, and stability and the establishment of a treatment plan. However, if other children present in the home are deemed to be at risk, earlier referral to child protection is indicated to ensure the safety of these children. Health care professionals should advocate on behalf of women involved with child protection agencies and should encourage a positive relationship between mothers and workers. A history of substance dependence is not incompatible with ability to parent. Recommendations 4. Health care providers should employ a flexible approach to the care of women who have substance use problems, and they should encourage the use of all available community resources. (II-2B) 5. Women should be counselled about the risks of periconception, antepartum, and postpartum drug use. (III-B) APRIL JOGC AVRIL 2011 l 373

SOGC CLINICAL PRACTICE GUIDELINE

Table 4. Effects of antenatal substance use Drug

Antenatal complications

Neonatal effects

Long-term effects

Nicotine

• SA • PTL, PROM • Placenta previa and placental abruption • IUGR, LBW

• Increased perinatal mortality • SIDS

• Childhood asthma • Behavioural problems • ADHD

Marijuana

• Inconsistent effects

• • Neurobehavioural effects: decreased self-quieting ability, increased fine tremors and startles, increased hand-to-mouth activity, sleep pattern changes

• Disturbed nocturnal sleep • Behaviour problems: inattention, impulsivity and hyperactivity, delinquency and externalizing problems self-reported depressive and anxiety symptoms

Heroin

• Premature labour • IUGR, LBW • Toxemia • Antepartum and postpartum hemorrhage

• Increased perinatal mortality rate

• Increased inattention, hyperactivity and behavioural problems • Difficulty in physical, social, and selfadjustment and learning processes

Methadone

• NAS • Strabismus

Cocaine

• Spontaneous abortion • PROM, PTL • IUGR • Placental abruption

• Congenital anomalies: genitourinary malformations • Transient increase in central and autonomic nervous system symptoms and signs • Lower birth weight, length and head circumference (dose-dependent)

• Expressive language delays

Amphetamines

• Maternal hypertension • Fetal demise (at any gestational age) • IUGR

• Congenital anomalies:central nervous system, cardiovascular, oral clefts, limbs • Neurobehavioural effects: decreased arousal, increased stress and poor quality of movement (dose-response relationship)

• Behavioural problems

Hallucinogens (MDMA, LSD)

• Congenital anomalies: cardiovascular, MSK defects

ADHD: attention-deficit hyperactivity disorder; IUGR: intrauterine growth restriction; LBW: low birth weight; LSD: lysergic acid diethylamide; MDMA: 3,4-methylenedioxymethamphetamine; MSK: medullary sponge kidney; PTL: preterm labour; PROM: premature rupture of membranes; SA: spontaneous abortion; SIDS: sudden infant death syndrome.

nicotine DEPENDENCE

Smoking Cessation Counselling

Smoking cessation interventions are effective in reducing the number of women smoking during pregnancy regardless of intensity or provider delivering the intervention.82–87 Lower rates of preterm delivery and low birth weight infants are additional benefits of smoking cessation interventions. A variety of interventions have been studied ranging from simple advice to cognitive behavioural strategies for quitting smoking. Women also often received pregnancyspecific self-help materials and telephone counselling to smoking cessation. These interventions are estimated to be highly cost-effective with savings of US$3 in health-related costs for every US$1 spent on smoking cessation for pregnant women.88 However, brief interventions are ineffective in preventing postpartum relapse to smoking.89

374 l APRIL JOGC AVRIL 2011

Pharmacotherapy

Controlled trials have failed to demonstrate that nicotine replacement therapy increases smoking cessation rates, although it may reduce the number of cigarettes smoked.90,91 NRT (gum, lozenge, or patch), combined with cognitive behavioural therapy, results in higher quit rates during pregnancy than counselling alone.92 The safety of NRT is unknown since the link between NRT and congenital anomalies and poor perinatal outcomes is uncertain.90,92–96 However, women may be offered NRT if they continue to smoke despite counselling and after an informed discussion regarding the benefits and risks during pregnancy.82,83,97,98 Intermittent dosage NRT preparations such as nicotine gum or nasal spray may be preferable to the patch, which gives a continuous dose of nicotine. The lowest effective dose of NRT is advised. If the patch is used, the patient may consider removing it at night. NRT should be discontinued if the woman continues to smoke at the same rate.

Substance Use in Pregnancy

Table 5. Management of withdrawal Substance

Management recommendation

Alcohol

• Thiamine 100 mg po od × 3 days, folic acid 5 mg po od • Diazepam 20 mg po q1–2h until minimal symptoms • Use lorazepam 2–4 mg sl/po q2–4h prn during labour • Monitor hydration status and electrolyte levels

High-dose benzodiazepines

• Start at 2/3–3/4 of diazepam equivalent dose • Taper by 10% per day

Opioids

• Offer symptomatic therapy including gravol for nausea and vomiting, acetaminophen/ NSAIDs for myalgias • Consider methadone or buprenorphine initiation • Can use morphine 5–10 mg po q4–6h prn if methadone is not available

NSAIDs: non-steroidal anti-inflammatories

Buproprion and varenicline are effective in non-pregnant populations. There are limited safety data on the use of these medications during pregnancy.82,83,97 To date, bupropion has not been associated with malformations during pregnancy.83,97,99 Preliminary evidence from a small study suggests that bupropion is effective for smoking cessation during pregnancy.100 Further research is needed on the safety and efficacy of bupropion and varenicline before they can be recommended for routine use in pregnancy. Recommendation

6. Smoking cessation counselling should be considered as a first-line intervention for pregnant smokers. (I-A) Nicotine replacement therapy and/or pharmacotherapy can be considered if counselling is not successful. (I-A) OPIOID DEPENDENCE

Opioid Detoxification

Opioid detoxification is defined as medication-assisted withdrawal for opioid-dependent patients. There is good evidence that detoxification in the second and third trimesters of pregnancy is not linked to increased adverse perinatal events. Recent studies have failed to show any significant increased rates of obstetrical complications following opioid detoxification.91,93,94,101 Regardless, opioid detoxification is not advisable during pregnancy primarily because of the high rate of relapse.102–106 Opioid detoxification should be performed only after the first trimester and with informed consent based on a discussion of the potential risks and benefits. Methadone maintenance treatment is associated with longer adherence to treatment and decreased risk of relapse to opioid use; therefore, the standard of care for pregnant opioid-dependent women is opiate substitution therapy. Methadone Maintenance Treatment

Currently, methadone maintenance treatment is the standard of care for opioid dependence in pregnancy. Methadone is

a full opioid agonist that has an increasing effect with higher doses. There are numerous benefits of methadone use during pregnancy, including improved prenatal care,12,107–109 longer gestation,50,110 higher birth weight,111,112 and increased rates of infants discharged home in the care of their mothers.4,12,18,49,101,108,113–118 Although infants of methadonetreated women tend to be smaller (lower birth weight, length, and head circumference) than drug-free controls, studies have shown a catch-up of growth by 12 months of age.118,119 Urgent consultation with an addiction medicine specialist should be sought to facilitate rapid access to MMT during pregnancy. Close monitoring of methadone dosing during pregnancy is recommended, especially during the third trimester when methadone metabolism and clearance are increased and dose augmentation is required.120,121 Pregnant women should receive the methadone dose that is required for their opioid dependence, because the literature reports inconsistent results regarding the association between maternal methadone dose and severity of neonatal withdrawal. Prenatal discussion with the methadone prescribing physician is recommended to plan for intrapartum methadone dosing. Any regular, daily antenatal opioid exposure (e.g., morphine, codeine, oxycodone, methadone, or buprenorphine) can produce neonatal withdrawal, also known as neonatal abstinence syndrome. Estimates show that up to 96% of infants display withdrawal symptoms, and a smaller proportion require pharmacotherapy.4,68,116,117,120,121 NAS is characterized by respiratory, gastrointestinal, central nervous system, and autonomic symptoms (Table 6). Onset of withdrawal symptoms is dependent on the opiate’s halflife; the longer the half-life, the later the onset of withdrawal. Heroin-exposed infants may demonstrate symptoms within 24 hours of birth. In comparison, methadone-maintained infants have a delayed presentation at more than 24 hours, usually within 48 to 72 hours after birth and at up to 4 weeks of age.122 The length of monitoring is based on APRIL JOGC AVRIL 2011 l 375

SOGC CLINICAL PRACTICE GUIDELINE

the specific drug exposure. Treated neonatal withdrawal has not been associated with any long-term complications. A variety of standards of practice have been documented in Canadian hospitals with variability by region and practitioner. Little research is available to validate current practices. Several scoring scales have been developed for evaluation of NAS and response to therapy. The Finnegan scoring tool (also known as the Finnegan Neonatal Abstinence Scoring System) is the method most commonly used by Canadian hospitals.123 Nonpharmacologic therapy is the standard of care for all opioid-exposed infants.124 For a smaller subset of infants, pharmacotherapy may be needed to treat severe symptoms. Opioid agonist medications are the most effective agents for treatment of NAS.122,125 Options include morphine, methadone, and diluted tincture of opium (contains small amount of alcohol). Morphine is the most frequently used medication.122,123 Phenobarbital may be used as an adjunct to treat infants who are not well-controlled using an opioid alone. One half of Canadian hospitals care for substanceexposed infants in the neonatal care unit or special care nursery. The other half provide care for asymptomatic infants with the mother as part of rooming-in. One retrospective cohort study demonstrated that roomingin, under the care of ive nursing and medical staff, was associated with decreased rates and length of morphine treatment, decreased need for ission to an NICU, decreased mean neonatal length of stay in hospital, and increased likelihood of discharge in the custody of the mother.126 Additional large-scale prospective studies are required to determine the optimal management of neonatal withdrawal. Buprenorphine

Buprenorphine represents an alternative opioid replacement treatment. Buprenorphine is a partial agonist with a ceiling effect. It has typical opioid effects with less sedation than methadone and a threshold after which a higher dose has no further effect, thereby reducing the risk of overdose on this medication.127 The main rationale for buprenorphine use for treating opioid dependence during pregnancy is reports of reduced incidence and severity of NAS128–131; however, there are limited data regarding the long-term effects of in utero exposure to buprenorphine.132,133 Buprenorphine should be prescribed by a physician who has experience with substitution treatment for opioid dependence. The only preparation of buprenorphine readily available in Canada is Suboxone, which is a combination of buprenorphine and naloxone. There is limited information on the safety of this medication in pregnancy; therefore, the use of buprenorphine as a single agent (Subutex) is recommended 376 l APRIL JOGC AVRIL 2011

Table 6. Neonatal abstinence syndrome System

Symptoms and signs

Respiratory

Respiratory distress

Central nervous system

Increased tone, tremors, seizure

Gastrointestinal

Poor feeding, vomiting, regurgitation, diarrhea

Autonomic

Sweating

during pregnancy. The availability of buprenorphine during pregnancy is limited through Health Canada’s Special Access Program. OPIOIDS FOR CHRONIC NON-CANCER PAIN

Pregnant women with a history of chronic pain need to be managed according to evidence-based recommendations for chronic non-cancer pain.134,135 The goal of therapy is to use the lowest effective dose of scheduled controlledrelease opioids.134 Most women who use opioids for chronic non-cancer pain are not psychologically dependent on these medications. Risk factors for dependence on prescription opioids include past history of drug dependence and psychiatric comorbid conditions such as posttraumatic stress disorder and eating disorders. Regular opioid use for pain management during pregnancy is associated with neonatal withdrawal.136,137 Methadone is the first-line treatment for chronic non-cancer pain and concurrent opioid dependence. Recommendations

7. Methadone maintenance treatment should be standard of care for opioid-dependent women during pregnancy. (II-IA) Other slow-release opioid preparations may be considered if methadone is not available. (II-2B) 8. Opioid detoxification should be reserved for selected women because of the high risk of relapse to opioids. (II-2B) 9. Opiate-dependent women should be informed that neonates exposed to heroin, prescription opioids, methadone, or buprenorphine during pregnancy are monitored closely for symptoms and signs of neonatal withdrawal (neonatal abstinence syndrome). (II-2B) Hospitals providing obstetric care should develop a protocol for assessment and management of neonates exposed to opiates during pregnancy. (III-B)

Substance Use in Pregnancy

PERIPARTUM PAIN MANAGEMENT

Women with substance use disorders, especially those with opioid dependence, face numerous peripartum pain management challenges, including increased pain sensitivity, inadequate analgesia, difficult intravenous access, and anxiety about suffering pain due to their history of addiction.138–142 Inappropriate pain management is more likely than provision of opioid analgesics for treatment of acute pain to lead to a relapse. Women on MMT should be continued on the same dose of methadone, although this is ineffective for acute pain management.138,142 Opioids have been found to be safe and effective even in opioiddependent women; however, these women may require higher doses and more frequent analgesics for pain relief.138,142,143 Epidural analgesia is an ideal choice for pain management for opioid-dependent women. Agonistantagonist medications (e.g., butorphanol, nalbuphine, and pentazocine) should not be used in opioid-dependent individuals because of the risk of precipitating acute withdrawal. For more complicated cases (e.g., poor venous access, contraindications to epidural), referral to an anaesthesiologist should be arranged antenatally to discuss, in advance, alternatives for pain management. Recommendation

10. Antenatal planning for intrapartum and postpartum analgesia may be offered for all women in consultation with appropriate health care providers. (III-B) MANAGEMENT OF OPIOID OVERDOSE

Education about prevention of opioid overdose should also be provided routinely. This includes advising patients that they could overdose if they suddenly stop or markedly reduce their opioid medication and then resume their usual dose. They are also at risk of overdose if they combine opioids with other sedatives, such as benzodiazepines. They should be warned never to give or sell their opioid medication to anyone else, because others may lack tolerance to opioids. Finally, they should be advised to a physician immediately at the first signs of overdose (“nodding off,” slurred speech, drowsiness). Acute opioid overdose during pregnancy can be managed with respiratory and the use of naloxone, a shortacting opioid antagonist, as a last resort after an airway has been established. The dose of naloxone should be based on response to treatment and duration of action of ingested opioid. Naloxone may be required on a continuous basis until the effects of the opioid have diminished. Care should be taken to prevent acute withdrawal symptoms, which

can cause fetal distress.144 On the basis of gestational age and viability, the fetus should be monitored throughout treatment. Similarly, during neonatal resuscitation, naloxone should not be istered to a newborn of an opioiddependent mother because of the risk of precipitating acute withdrawal and seizures. POSTPARTUM CARE

Substance-using women require additional s from health care professionals in the postpartum period. More frequents visits may be required to deal with their complex medical and psychosocial needs. Areas to review include the following: • of breastfeeding, as appropriate (see paragraph below for more details) • Follow-up of other medical problems such as liver disease and sexually transmitted infections • Discussion of contraceptive needs • Surveillance and appropriate referral for treatment of postpartum mood and anxiety disorders • Assessment of substance use and encouragement to continue attending drug treatment programs • with child protection services involvement • Assistance with referrals for ongoing primary care and social services BREASTFEEDING

Although there are numerous benefits of breastfeeding, alcohol and illicit substances that are commonly abused (e.g., marijuana, cocaine, amphetamines) have been detected in breast milk.145–148 There have been reports documenting neonatal effects due to breast milk exposure; therefore, the decision to breastfeed should be made on an individual basis after discussing the potential risks and benefits.146,147149,150 Breastfeeding may be delayed after maternal use of any of these agents and any neonatal exposure to any fumes in the environment. Women who are regular substance s should be encouraged to remain abstinent while nursing and counselled regarding the increased risks for neonatal effects. All opiates have been documented in breast milk in small amounts and are unlikely to be of any clinical significance.106,121,151–157 Specifically, the presentation APRIL JOGC AVRIL 2011 l 377

SOGC CLINICAL PRACTICE GUIDELINE

and treatment of neonatal withdrawal is not affected by exposure to methadone or buprenorphine in breast milk. Therefore, maternal opiate use is considered compatible with breastfeeding. Codeine should be used with caution by women who are breastfeeding. Neonatal toxicity symptoms and signs such as drowsiness, apnea, and bradycardia have been demonstrated in women who have been prescribed codeine and who have a genetic predisposition to convert codeine to morphine at a faster rate (i.e., CYP2D6 ultrarapid metabolizers).158,159 Symptoms and signs worsen after 4 days of codeine use, and alternate pain management should be considered after that time.160 Recommendation

11. The risks and benefits of breastfeeding should be weighed on an individual basis because methadone maintenance therapy is not a contraindication to breastfeeding. (II-3B) CONCLUSION

Problematic substance use in pregnancy is prevalent in the Canadian population. Perinatal health care providers can make a significant impact on improving pregnancy outcomes by providing non-judgemental ive care within a harm reduction model to address substance use issues and social determinants of health. Ongoing education in this area and development of comprehensive care models are essential for the optimal care of patients in these challenging circumstances. REFERENCES 1. Health Canada. Canadian perinatal health report, 2003. Ottawa: Minister of Public Works and Government Services Canada; 2003. 2. Statistics Canada. Canadian community health survey (CCHS), Cycle 1.1. Ottawa: Statistics Canada; 2002. Available at: www.statcan.ca/english/ concepts/health/index.htm. Accessed December 22, 2010. 3. Substance Abuse and Mental Health Services istration. Results from the 2007 National Survey on Drug Use and Health: National Findings (Office of Applied Studies, NSDUH Series H-34, DHHS Publication No. SMA 08–4343). Rockville, MD;2008. 4. Giles W, Patterson T, Sanders F, Batey R, Thomas D, Collins J. Outpatient methadone programme for pregnant heroin using women. Aust N Z J Obstet Gynaecol 1989;29 (3 Pt 1):225–9.

8. Makarechian N, Agro K, Devlin J, Trepanier E, Koren G, Einarson TR. Association between moderate alcohol consumption during pregnancy and spontaneous abortion, stillbirth and premature birth: a meta-analysis. Can J Clin Pharmacol 1998;5:169–76. 9. Kuhn L, Kline J, Ng S, Levin B, Susser M. Cocaine use during pregnancy and intrauterine growth retardation: new insights based on maternal hair tests. Am J Epidemiol 2000;152(2):112–9. 10. Ernst M, Moolchan ET, Robinson ML. Behavioral and neural consequences of prenatal exposure to nicotine. J Am Acad Child Adolesc Psychiatry 2001;40(6):630–41. 11. US Centers for Disease Control and Prevention. The health consequences of smoking: a report of the Surgeon General. Office on Smoking and Health; 2004 [cited 2009 April 4]. Available at: http://www.cdc.gov/ tobacco/data_statistics/sgr/sgr_2004/index.htm. Accessed December 22, 2010. 12. Fajemirokun-Odudeyi O, Sinha C, Tutty S, Pairaudeau P, Armstrong D, Phillips T, et al. Pregnancy outcome in women who use opiates. Eur J Obstet Gynecol Reprod Biol 2006;126:170–5. 13. Araojo R, McCune S, Feibus K. Substance abuse in pregnant women: making improved detection a good clinical outcome. Clin Pharmacol Ther 2008;83:520–2. 14. Binder T, Vavrinkova, B. Prospective randomised comparative study of the effect of buprenorphine, methadone and heroin on the course of pregnancy, birthweight of newborns, early postpartum adaptation and course of the neonatal abstinence syndrome (NAS) in women followed up in the outpatient department. Neuro Endocrinol Lett 2008; 29:80–6. 15. Delpisheh A, Brabin L, Drummond S, Brabin BJ. Prenatal smoking exposure and asymmetric fetal growth restriction. Ann Hum Biol 2008;35:573–83. 16. Floyd RL, Jack BW, Cefalo R, Atrash H, Mahoney J, Herron A, et al. The clinical content of preconception care: alcohol, tobacco, and illicit drug exposures. Am J Obstet Gynecol 2008;199(6 Suppl 2):S333–9. 17. Vucinovic M, Roje D, Vucinovic Z, Capkun V, Bucat M, Banovic I. Maternal and neonatal effects of substance abuse during pregnancy: our ten year experience. Yonsei Med J 2008;49:705–13. 18. Edelin KC, Gurganious L, Golar K, Dellerich D, Kyei-Aboagye K, Hamid MA. Methadone maintenance in pregnancy: consequences to care and outcome. Obstet Gynecol 1988;71:399–404. 19. Chang G, Carroll KM, Behr HM, Kosten TR. Improving treatment outcome in pregnant opiate-dependent women. J Subst Abuse Treat 1992;9:327–30. 20. Rehm J, Baliunas D, Brochu S, Fischer B, Gnam W, Patra J, et al. The costs of substance abuse in Canada 2002: highlights. Canadian Centre on Substance Abuse, April 2006. Available at: http://www.ccsa.ca/Eng/ Priorities/Research/CostStudy/Pages/default.aspx. Accessed December 27, 2010. 21. Chiu TT, Vaughn AJ, Carzoli RP. Hospital costs for cocaine-exposed infants. J Fla Med Assoc 1990;77:897–900.

5. Lutiger B, Graham K, Einarson TR, Koren G. Relationship between gestational cocaine use and pregnancy outcome: a meta-analysis. Teratology 1991;44:405–11.

22. Adams EK, Miller VP, Ernst C, Nishimura BK, Melvin C, Merritt R. Neonatal health care costs related to smoking during pregnancy. Health Econ 2002;11:193–206.

6. DiFranza JR, Lew RA. Effect of maternal cigarette smoking on pregnancy complications and sudden infant death syndrome. J Fam Pract 1995;40:385–94.

23. Hutson J. A prenatal perspective on the cost of substance abuse in Canada. JFAS Int 2006;4(e9):1–4.

7. Little BB, Wilson G, Jackson G. Is there a cocaine syndrome? Dysmorphic and anthropometric assessment of infants exposed to cocaine. Teratology 1996;54:145–9.

378 l APRIL JOGC AVRIL 2011

24. Lefebvre LG, Ordean A, Midmer D, Kahan M, Tolomiczenko G. Physicians’ knowledge of alcohol, tobacco and folic acid in pregnancy. J Subst Abuse 2007;28:3–9.

Substance Use in Pregnancy 25. Leversha AM, Marks RE. Alcohol and pregnancy: doctors’ attitudes, knowledge and clinical practice. NZ Med J 1995;108:428–30.

44. Gehringer K. Informed consent: hospitals must obtain informed consent prior to drug testing pregnant patients. J Law Med Ethics 2003;31:455–7.

26. Gehshan S. Missed opportunities for intervening in the lives of pregnant women addicted to alcohol or other drugs. J Am Med Womens Assoc 1995;50:160–3.

45. Mikhail BI. Perceived impediments to prenatal care among low-income women. West J Nurs Res 1999;21:335–50; discussion 351–5.

27. Public Health Agency of Canada. Knowledge and attitudes of health professionals about fetal alcohol syndrome: results of a national survey. Available at: http://www.phac-aspc.gc.ca/publicat/fasdsurv-etcafenquete/index.html. Accessed November 23, 2010. 28. Nevin AC, Christopher P, Nulman I, Koren G, Einarson A. A survey of physicians knowledge regarding awareness of maternal alcohol use and the diagnosis of FAS. BMC Fam Pract 2002;3:2–6. 29. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed, Text Revision (DSM-IV-TR). Arlington: American Psychiatric Publishing Inc.; 2000. 30. Brands B, Kahan M, Selby P, Wilson L, eds. Management of alcohol, tobacco and other drug problems: a physician’s manual. Toronto: Centre for Addiction and Mental Health; 2000. 31. Office of Maternal and Child Health (2008 A). Substance abuse during pregnancy: guidelines for screening. Washington State Department of Health. Available at: http://www.doh.wa.gov/cfh/mch/documents/ ScreenGuideline.pdf. Accessed April 2, 2009. 32. Hinderliter SA, Zelenak JP. A simple method to identify alcohol and other drug use in pregnant adults in a prenatal care setting. J Perinatol 1993;13:93–102.

46. Milligan R, Wingrove BK, Richards L, Rodan M, Monroe-Lord L, Jackson V, et al. Perceptions about prenatal care: views of urban vulnerable groups. BMC Public Health 2002;2:25. 47. Currie JC. Best practices treatment and rehabilitation for women with substance use problems. 2001, Ottawa: Minister of Public Works and Government Services Canada. Available at: http://www.cds-sca.com. Accessed November 23,2010. 48. Roberts G, Nanson J. Best practices: fetal alcohol syndrome/fetal alcohol effects and the effects of other substance use during pregnancy. Ottawa: Minister of Public Works and Government Services Canada;2001. 49. Ellwood DA, Sutherland P, Kent C, O’Connor M. Maternal narcotic addiction: pregnancy outcome in patients managed by a specialized drugdependency antenatal clinic. Aust NZ J Obstet Gynaecol 1987;27:92–8. 50. Kandall SR, Albin S, Lowinson J, Berle B, Eidelman AI, Gartner LM. The narcotic-dependent mother: fetal and neonatal consequences. Early Hum Dev 1977;1:159–69. 51. Lee MI, Stryker JC, Sokol RJ. Perinatal care for narcotic-dependent gravidas. Perinatol Neonatol 1985;9(6):35–40. 52. Burkett G, Gomez-Marin O, Yashin SY, Martinez M. Prenatal care in cocaine-exposed pregnancies. Obstet Gynecol 1998;92:193–200.

33. Chang G, Wilkins-Haug L, Berman S, Goetz MA, Behr H, Hiley A. Alcohol use and pregnancy: improving identification. Obstet Gynecol 1998;91:892–8.

53. Jansson LM, Svikis D, Lee J, Paluzzi P, Rutiglioano P, Hackerman F. Pregnancy and Addiction. A comprehensive care model. J Subst Abuse Treat 1996;13:321–9.

34. Chang G, Wilins-Halig L, Berman S, Goetz MA. The TWEAK: Application in a prenatal setting. J Stud Alcohol 1999;60:306–9.

54. Sweeney PJ, Schwartz RM, Mattis NG, Vohr B. The effect of integrating substance abuse treatment with prenatal care on birth outcome. J Perinatol 2000;20:219–24.

35. Carroll JC, Reid AJ, Biringer A, Midmer D, Glazier RH, Wilson L, et al. Effectiveness of the Antenatal Psychosocial Health Assessment (ALPHA) form in detecting psychosocial concerns: a randomized controlled trial. CMAJ 2005;173:253–9.

55. Reece EA, Leguizamon G, Silva J, Whiteman V, Smith D. Intensive interventional maternity care reduces infant morbidity and hospital costs. J Matern Fetal Neonatal Med 2002;11:204–10.

36. Reid AJ, Biringer A, Carroll JD, Midmer D, Wilson LM, Chalmers B, et al. Using the ALPHA form in practice to assess antenatal psychosocial health. Antenatal Psychosocial health assessment. CMAJ 1998;159:677–84.

56. Suffet F, Brotman R. A comprehensive care program for pregnant addicts: obstetrical, neonatal, and child development outcomes. Int J Addict 1984;19:199–219.

37. Office of Maternal and Child Health (2008 B). Guidelines for Testing and Reporting Drug Exposed Newborns. Washington State Department of Health. Available at: http://www.doh.wa.gov/cfh/mch/documents/ HospTestDrug.pdf. Accessed April 2, 2009.

57. McLaughlin FJ, Altemeier WA, Christensen MJ, Sherrod KB, Dietrich MS, Stern DT. Randomized trial of comprehensive prenatal care for lowincome women: effect on infant birth weight. Pediatrics 1992;89:128–32.

38. Ostrea EM, Knapp DK, Tannenbaum L, Ostrea AR, Romero A, Salari V, et al. Estimates of illicit drug use during pregnancy by maternal interview, hair analysis, and meconium analysis. J Pediatr 2001;138:344–8. 39. Gourlay D, Heit HA, Caplan YH. Urine drug testing in primary care. USA: PharmaCom Group Inc., 2002. 40. Callahan CM, Grant TM, Phipps P, Clark G, Novack AH, Streissguth AP, et al. Measurement of gestational cocaine exposure: sensitivity of infants’ hair, meconium, and urine. J Pediatr 1992;120:763–8. 41. Vinner E, Vignau J, Thibault D, Codaccioni X, Brassart C, Humbert L, et al. Neonatal hair analysis contribution to establishing a gestational drug exposure profile and predicting a withdrawal syndrome. Ther Drug Monit 2003;25:421–32. 42. Christmas JT, Knisely JS, Dawson KS, Dinsmoor MJ, Weber SE, Schnoll SH. Comparison of questionnaire screening and urine toxicology for detection of pregnancy complicated by substance use. Obstet Gynecol 1992;80:750–4. 43. Kwong TC, Shearer D. Detection of drug use during pregnancy. Obstet Gynecol Clin North Am 1998;25:43–64.

58. Scholl TO, Hediger ML, Belsky DH. Prenatal care and maternal health during adolescent pregnancy: a review and meta-analysis. J Adolesc Health 1994;15:444–56. 59. Wong T, Lee SS. Hepatitis C: a review for primary care physicians. CMAJ 2006; 174:649–59. 60. Robinson JL. Vertical transmission of the hepatitis C virus: current knowledge and issues. Paediatr Child Health 2008;13:529–36. 61. Substance Abuse and Mental Health Services istration, Office of Applied Studies. The NSDUH report: sexually transmitted diseases and substance use. Rockville, MD; 2007. 62. Fichtner R Carson D, Brackbill R. Behavioural risks for HIV/STD and birth outcomes among pregnant women who abuse substances: evidence from intensive outreach—Atlanta, Georgia. Int Conf AIDS 1996;11:362 (abstract). 63. Bolnick JM, Rayborn JM, Rayborn WF. Substance use disorders in women: special considerations during pregnancy. Obstet Gynecol Clin North Am 2003;30:545–58. 64. Schempf AH, Strobino DM. “Illicit drug use and adverse birth outcomes: is it drugs or context? J Urban Health 2008;85:858–73.

APRIL JOGC AVRIL 2011 l 379

SOGC CLINICAL PRACTICE GUIDELINE 65. Bailey BA, Daugherty RA. Intimate partner violence during pregnancy: incidence and associated health behaviors in a rural population. Matern Child Health J 2007;11:495–503.

85. McBride CM, Baucom DH, Peterson BL, Pollak KI, Palmer C, Westman E, et al. Prenatal and postpartum smoking abstinence a partner-assisted approach. Am J Prev Med 2004;27:232–8.

66. Liston R, Sawchuck D, Young D; SOGC Fetal Health Surveillance Consensus Committee. Fetal health surveillance: antepartum and intrapartum consensus guideline. SOGC Clinical Practice Guideline No. 197, September 2007. J Obstet Gynaecol Can 2007;29(Suppl 4):S1-S56.

86. Rigotti NA, Park ER, Regan S, Chang Y, Perry K, Loudin B, et al. Efficacy of telephone counseling for pregnant smokers: a randomized controlled trial. Obstet Gynecol 2006;108:83–92.

67. Chang G, Goetz MA, Wilkins-Haug L, Berman S. A brief intervention for prenatal alcohol use: an in-depth look. J Subst Abuse Treat 2000;18:365–9.

87. Melvin CL, Dolan-Mullen P, Windsor RA, Whiteside HP Jr, Goldenberg RL. Recommended cessation counselling for pregnant women who smoke: a review of the evidence. Tob Control 2000;9(Suppl 3):1180–4.

68. The Project CHOICES Intervention Research Group. Reducing the risk of alcohol-exposed pregnancies: a study of a motivational intervention in community settings. Pediatrics 2003;111:1131–5.

88. Ruger JP Emmons KM. Economic evaluations of smoking cessation and relapse prevention programs for pregnant women: a systematic review. Value Health 2008;11: 180–90.

69. Nordstrom BR, Levin FR. Treatment of cannabis disorders: a review of the literature. Am J Addict 2007;16:331–42.

89. Hajek P, Stead LF, West R, Jarvis M, Lancaster T. Relapse prevention interventions for smoking cessation (Review). Cochrane Database System Rev 2009; Issue 1. Art No.: CD003999. DOI: 10.1002/14651858. CD003999.pub3.

70. Dutra L, Stathopolou G, Basden SL, Leyro TM, Powers MB, Otto MW. A meta-analytic review of psychosocial interventions for substance use disorders. Am J Psychiatry 2008;165:179–87. 71. Carroll KM, Chang G, Behr H, Clinton B, Kosten TR. Improving treatment outcome in pregnant, methadone-maintained women: results from a randomized clinical trial. Am J Addict 1995;4:56–9. 72. Davis MM, Brown BS, Glendinning ST. Neonatal effects of heroin addiction and methadone-treated pregnancies. Preliminary report on 70 live births. Proc Natl Conf Methadone Treat 1973;2:1153–64. 73. Harper RG, Solish GI, Sang E, Purow H. The effect of a methadone treatment program upon pregnant addicts and their infants. Proc Natl Conf Methadone Treat 1973; 2:1133–7. 74. Johnson H. Measuring violence against women: statistical trends 2006. Statistics Canada catalogue no. 85–570-XWE, Ottawa. 75. Messer K, Clarke KA, Martin SL. Characteristics associated with pregnant women’s utilization of substance abuse treatment services. Am J Drug Alcohol Abuse 1996;22: 403–22. 76. Martin SL, Beaumont JL, Kuper LL. Substance use before and during pregnancy: links to intimate partner violence. Am J Drug Alcohol Abuse 2003;29:599–617. 77. Tuten M, Jones HE. A partner’s drug-using status impacts women’s drug treatment outcome. Drug Alcohol Depend 2003;70:327–30. 78. Kissin WB, Svikis DS, Morgan GD, Haug NA. Characterizing pregnant drug-dependent women in treatment and their children. J Subst Abuse Treat 2001;21:27–34. 79. Kissin WB, Svikis DS, Moylan P, Haug NA, Stitzer ML. Identifying pregnant women at risk for early attrition from substance abuse treatment. J Subst Abuse Treat 2004; 27:31–8. 80. Tough SC, Siever JE, Johnston DW. Retaining women in a prenatal care randomized controlled trial in Canada: implications for program planning. BMC Public Health 2007;7:148. 81. Ontario Ministry of Children and Youth Services. Reporting child abuse and neglect: it’s your duty. Queen’s Printer for Ontario; 2005. Available at: http://www.children.gov.on.ca/htdocs/English/topics/childrensaid/ reportingabuse/abuseandneglect/abuseandneglect.aspx. Accessed December 22, 2010.

90. Oncken C, Dornelas E, Greene J, Sankey H, Glasmann A, Feinn R, et al. Nicotine gum for pregnant smokers: a randomized controlled trial. Obstet Gynecol 2008;112:859–67. 91. Kapur B, Hackman R, Selby P, Klein J, Koren G. Randomized, doubleblind, placebo-controlled trial of nicotine replacement therapy in pregnancy. Curr Ther Res Clin Exp 2001;62:274–8. 92. Pollak KI, Oncken CA, Lipkus IM, Lyna P, Swamy GK, Pletsch PK, et al. Nicotine replacement and behavioral therapy for smoking cessation in pregnancy. Am J Prev Med 2007;33:297–305. 93. Dwyer JB, Broide RS, Leskie FM. Nicotine and brain development. Birth Defects Res C Embryo Today 2008;84:30–44. 94. Slotkin TA. If nicotine is a developmental neurotoxicant in animal studies, dare we recommend nicotine replacement therapy in pregnant women and adolescents? Neurotoxicol Teratol 2008;30:1–19. 95. Gaither KH, Huber LR, Thompson ME, Huet-Hudson YM. Does the use of nicotine replacement therapy during pregnancy affect pregnancy outcomes? Matern Child Health J 2008;13:497–504. 96. Morales-Suárez-Valera MM, Bille C, Christensen K, Olsen J. Smoking habits, nicotine use, and congenital malformations. Obstet Gynecol 2006;107:51–7. 97. Pauley JR, Slotkin TA. Maternal tobacco smoking, nicotine replacement and neuro-behavioural development. Acta Pediatr 2008;97:1331–7. 98. Coleman T. Recommendations for the use of pharmacological smoking cessation strategies in pregnant women. CNS Drugs 2007;21:983–93. 99. Chun-Fai-Chan B, Koren G, Fayez I, Kalra S, Voyer-Lavigne S, Boshier A, et al. Pregnancy outcome of women exposed to bupropion during pregnancy: a prospective comparative study. Am J Obstet Gynecol 2005;192:932–6. 100. Chan B, Einarson A, Koren G. Effectiveness of bupropion for smoking cessation during pregnancy. J Addict Dis 2005;24(2):19–23. 101. Luty J, Nikolaou V, Bearn J. Is opiate detoxification unsafe in pregnancy? J Subst Abuse Treat 2003;24:363–7.

82. Rore C, Brace V, Danielian P, Williams D. Smoking cessation in pregnancy. Expert Opin Drug Saf 2008;7:727–37.

102. Kashiwagi M, Arlettaz R, Lauper U, Zimmermann R, Hebisch G. Methadone maintenance program in a Swiss perinatal center: (I): management and outcome of 89 pregnancies. Acta Obstet Gynecol Scand 2005;84:140–4.

83. Crawford JT, Tolosa JE, Goldenberg RL. Smoking cessation in pregnancy: why, how, and what next. Clin Obstet Gynecol 2008;51:419–35.

103. Dashe JS, Jackson GL, Olscher DA, Zane EH, Wenderl GD Jr. Opioid detoxification in pregnancy. Obstet Gynecol 1998;92:854–8.

84. Lumley J, Oliver S, Chamberlain C, Oakley L. Interventions for promoting smoking cessation during pregnancy. Cochrane Database System Rev 2004; Issue 4. Art No.: CD001055. DOI:10.1002/14651858. CD001055. pub2.

104. Maas U, Katner E, Weingart-Jesse B, Schafer A, Obladen M. Infrequent neonatal opiate withdrawal following maternal methadone detoxification during pregnancy. J Perinat Med 1990;18:111–8.

380 l APRIL JOGC AVRIL 2011

Substance Use in Pregnancy 105. Allen MH. Detoxification consideration in the medical management of substance abuse in pregnancy. Bull N Y Acad Med 1991;67:270–6. 106. Blinick G, Inturrisi CE, Jerez E, Wallach RC. Methadone assays in pregnant women and progeny. Am J Obstet Gynecol 1975;121:617–21. 107. Stern R. The pregnant addict. A study of 66 case histories, 1950–1959. Am J Obstet Gynecol 1966;94:253–7. 108. Wilson GS, Desmond MM, Wait RB. Follow-up of methadone-treated and untreated narcotic-dependent women and their infants: health, developmental, and social implications. J Pediatr 1981;98:716–22. 109. Jones HE, O’Grady KE, Malfi D, Tuten M. Methadone maintenance vs. methadone taper during pregnancy: maternal and neonatal outcomes. Am J Addict 2008;17:372–86. 110. Hagopian GS, Wolfe HM, Sokol RJ, Ager JW, Wardell JN, Cepeda EE. Neonatal outcome following methadone exposure in utero. J Matern Fetal Med 1996;5:348–54. 111. Kandall SR, Albin S, Lowinson J, Berle B, Eidelman AI, Gartner LM. Differential effects of maternal heroin and methadone use on birthweight. Pediatrics 1976;58:681–5. 112. Hulse GK, Milne E, English DR, Holman CDJ. The relationship between maternal use of heroin and methadone and infant birth weight. Addiction 1997;92:1571–9. 113. Zelson C, Lee SJ, Casalino M. Neonatal narcotic addiction. Comparative effects of maternal intake of heroin and methadone. N Eng J Med 1973;289(23):1216–20. 114. Rahbar F. Observations on methadone withdrawal in 16 neonates. Clin Pediatr (Phila) 1975;14:369–71.

126. Abrahams R, Kelly SA, Payne S, Thiessen PN, Mackintosh J, Janssen PA. Rooming-in compared with standard care for newborns of mothers using methadone or heroin. Can Fam Physician 2007;53:1722–30. 127. Srivastava A, Kahan M. Buprenorphine: a potential new treatment option for opioid dependence. CMAJ 2006;174:1835–6. 128. Johnson R, Jones H, Fischer G. Use of buprenorphine in pregnancy: patient management and effects on the neonate. Drug Alcohol Depend 2003;70(2 Suppl):S87-S101. 129. Lacroix I, Berrebi C, Chaumerliac C, Lapeyre-Mestre M, Montastruc JL, Damase-Michel C. Buprenorphine in pregnant opioid dependent women: first results of a prospective study. Addiction 2004;99:209–14. 130. Lejeune C, Simmat Durand L, Gourarier L, Aubisson S; the Groupe d’Etudes Grossesse et Addictions (GEGA). Prospective multicenter observational study of 260 infants born to 259 opiate dependent mothers on methadone or high dose buprenorphine substitution. Drug Alcohol Depend 2006;82:250–7. 131. Jones H, Johnson R, Jasinski DR, O’Grady KE, Chisholm CA, Choo RE, et al. Buprenorphine versus methadone in the treatment of pregnant opioid dependent patients: effects on the neonatal abstinence syndrome. Drug Alcohol Depend 2005;79:1–10. 132. Reisinger M. Use of buprenorphine during pregnancy. Research and Clinical Forums 1997;19:43–5. 133. Schindler SD, Eder H, Ortner R, Rohrmeister K, Langer M, Fischer G. Neonatal outcome following buprenorphine maintenance during conception and throughout pregnancy. Addiction 2003;98:103–10.

115. Malpas TJ, Darlow BA, Lennox R, Horwood LJ. Maternal methadone dosage and neonatal withdrawal. A NZ J Obstet Gynaecol 1995;35:175–7.

134. National Opioid Use Guideline Group (NOUGG). Canadian guideline for safe and effective use of opioids for chronic non-cancer pain. April 2010. Available at: http://nationalpaincentre.mcmaster.ca/opioid. Accessed November 23, 2010.

116. Brown HL, Britton KA, Mahaffey D, Brizendine E, Hiett AK, Turnquest MA. Methadone maintenance in pregnancy: a reappraisal. Am J Obstet Gynecol 1998;179: 459–63.

135. College of Physicians and Surgeons of Ontario. Methadone for pain guidelines. Nov 2004. Avialable at: http://www.so.on.ca/policies/ guidelines/default.aspx?id=1986. Accessed January 21, 2011.

117. Arlettaz R, Kashiwagi M, Das-Kundu S, Fauchere JC, Lang A, Bucher HU. Methadone maintenance program in pregnancy in a Swiss perinatal center (II): neonatal outcome and social resources. Acta Obstet Gynecol Scand 2005;84:145–50.

136. Hadi I, da Silva O, Natale R, Boyd D, Morley-Foster PK. Opioids in the parturient with chronic nonmalignant pain: a retrospective review. J Opioid Manag 2006;2:31–4.

118. Hunt RW, Tzioumi D, Collins E, Jeffery HE. Adverse neurodevelopmental outcome of infants exposed to opiate in-utero. Early Hum Dev 2008;84:29–35. 119. Vance JC, Chant DC, Tudehope DI, Gray PH, Hayes AJ. Infants born to narcotic dependent mothers: physical growth patterns in the first 12 months of life. J Paediatr Child Health 1997;33:504–8. 120. Lifshitz M, Gavrilov V, Galil A, Landau D. A four-year survey of neonatal narcotic withdrawal: evaluation and treatment. Isr Med Assoc J 2001;3:17–20. 121. McCarthy JJ, Leamon MH, Parr MS, Anania B. High-dose methadone maintenance in pregnancy: maternal and neonatal outcomes. Am J Obstet Gynecol 2005;193(3 Pt 1): 606–10. 122. Jansson LM, Velez M, Harrow C. The opioid-exposed newborn: assessment and pharmacologic management. J Opioid Manag 2009;5:47–55. 123. Marcellus L. Care of the substance-exposed infants: the current state of practice in Canadian hospitals. J Perinat Neonatal Nurs 2002;16:51–68. 124. Velez M, Jansson LM. The opioid dependent mother and newborn dyad: nonpharmacologic care. J Addict Med 2008;2(3):113–120. 125. Osborn DA, Jeffery HE, Cole M. Opiate treatment for opiate withdrawal in newborn infants. Cochrane Database System Rev 2005; Issue 3. Art No.: CD002059. DOI: 10.1002/14651858.CD002059.pub2.

137. Sharpe C, Kuschel C. Outcomes of infants born to mothers receiving methadone for pain management in pregnancy. Arch Dis Child Fetal Neonatal Ed 2004;89:F33-F36. 138. Cassidy B, Cyna AM. Challenges that opioid-dependent women present to the obstetric anaesthetist. Anaesth Intensive Care 2004;32:494–501. 139. May JA, White HC. Leonard-White A, Warltier DC, Pagel PS. The patient recovering from alcohol or drug addiction: special issues for the anesthesiologist. Anesth Analg 2001;92:1601–8. 140. Mao J. Opioid-induced abnormal pain sensitivity: implications in clinical opioid therapy. Pain 2002;100:213–7. 141. Rapp SE, Ready LB, Nessly ML. Acute pain management in patients with prior opioid consumption: a case-controlled retrospective review. Pain 1995;6:195–201. 142. Mehta V, Langford RM. Acute pain management for opioid dependent patients. Anaesthesia 2006;61:269–76. 143. Meyer M, Wagner K, Benvenuto A, Plante D, Howard D. Intrapartum and postpartum analgesia for women maintained on methadone during pregnancy. Obstet Gynecol 2007;110:261–6. 144. Center for Substance Abuse Treatment. Medication-assisted treatment for opioid addiction in opioid treatment programs. Treatment improvement protocol (TIP) 43. DHHS Publication No. (SMA) 05–4048. Rockville, MD: Substance Abuse and Mental Health Services istration; 2005. Available at: http://store.samhsa.gov/product/SMA09–4341. Accessed January 5, 2011.

APRIL JOGC AVRIL 2011 l 381

SOGC CLINICAL PRACTICE GUIDELINE 145. Perez-Reyes M, Wall ME. Presence of delta9-tetrahydrocannabinol in human milk. N Engl J Med 1982;307:819–20.

154. Geraghty B, Graham EA, Logan B, Weiss EL. Methadone levels in breast milk. J Hum Lact 1997;13:227–30.

146. Astley SJ, Little RE. Maternal marijuana use during lactation and infant development at one year. Neurotoxicol Teratol 1990;12:161–8.

155. Johnson RE, Jones HE, Jasinki DR, Svikis DS, Haug NA, Jansson LM, et al. Buprenorphine treatment of pregnant opioid-dependent women: maternal and neonatal outcomes. Drug Alcohol Depend 2001;63:97–103.

147. Chasnoff IJ, Lewis DE, Squires L. Cocaine intoxication in a breast-fed infant. Pediatrics 1987;80:836–8. 148. Steiner E, Villen T, Hallberg M, Rane A. Amphetamine secretion in breast milk. Eur J Clin Pharmacol 1984;27:123–4. 149. Chaney NE, Franke J, Wadlington WB. Cocaine convulsions in a breastfeeding baby. J Pediatr 1988;112:134–5. 150. Hopkinson JM, Schanler RJ, Fraley JK, Garza C. Milk production by mothers of premature infants: influence of cigarette smoking. Pediatrics 1992;90:934–8. 151. Robieux I, Koren G, Vanderbergh H, Schneiderman J. Morphine excretion in breast milk and resultant exposure of a nursing infant. J Toxicol Clin Toxicol 1990;28:365–70. 152. Kreek MJ, Schecter A, Gutjahr CL, Bowen D, Field F, Queenan J, et al. Analyses of methadone and other drugs in maternal and neonatal body fluids: use in evaluation of symptoms in a neonate of mother maintained on methadone. Am J Drug Alcohol Abuse 1974;1:409–19. 153. Pond SM, Kreek MJ, Tong TG, Raghunath J, Benowitz N. Altered methadone pharmacokinetics in methadone-maintained pregnant women. J Pharmacol Exp Ther 1985;233:1–6.

382 l APRIL JOGC AVRIL 2011

156. Marquet P, Chevrel J, Lavignasse P, Merle L, Lacatre G. Buprenorphine withdrawal syndrome in a newborn. Clin Pharmacol Ther 1997;62:569–71. 157. McCarthy JJ, Posey BL. Methadone levels in human milk. J Hum Lact 2000;16: 115–20. 158. Madadi P, Koren G. Pharmacogenetic insights into codeine analgesia: implications to pediatric codeine use. Pharmacogenomics 2008;9:1267–84. 159. Madadi P, Ross CJ, Hayden MR, Carleton BC, Gaedigk A, Leeder JS, et al. Pharmacogenetics of neonatal opioid toxicity following maternal use of codeine during breastfeeding: a case-control study. Clin Pharmacol Ther 2009;85:31–5. 160. Madadi P, Moretti M, Djokanovic N, Bozzo P, Nulman I, Ito S, et al. Guidelines for maternal codeine use during breastfeeding. Can Fam Physician 2009;55:1077–8. 161. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

Substance Use in Pregnancy

Appendix

Antenatal Psychosocial Health Assessment (ALPHA)

Addressograph

Antenatal psychosocial problems may be associated with unfavorable postpartum outcomes. The questions on this form are suggested ways of inquiring about psychosocial health. Issues of high concern to the woman, her family or the caregiver usually indicate a need for additional s or services. When some concerns are identified, follow-up and/or referral should be considered. Additional information can be obtained from the ALPHA Guide. *Please consider the sensitivity of this information before sharing it with other caregivers. ANTENATAL FACTORS

CONCERN

COMMENTS / PLAN

FAMILY FACTORS Social (CA, WA, PD) How does your partner/family feel about your pregnancy? Who will be helping you when you go home with your baby?

Low Some High

Recent stressful life events (CA, WA, PD, PI) What life changes have you experienced this year? What changes are you planning during this pregnancy?

Low Some High

Couple’s relationship (CD, PD, WA, CA) How would you describe your relationship with your partner? What do you think your relationship will be like after the birth?

Low Some High

MATERNAL FACTORS Prenatal care (late onset) (WA) First prenatal visit in third trimester? (check records)

Low Some High

Prenatal education (refusal or quit) (CA) What are your plans for prenatal classes?

Low Some High

Feelings toward pregnancy after 20 weeks (CA, WA) How did you feel when you just found out you were pregnant? How do you feel about it now?

Low Some High

Relationship with parents in childhood (CA) How did you get along with your parents? Did you feel loved by your parents?

Low Some High

Self esteem (CA, WA) What concerns do you have about becoming/being a mother?

Low Some High

History of psychiatric/emotional problems (CA, WA, PD) Have you ever had emotional problems? Have you ever seen a psychiatrist or therapist?

Low Some High

Depression in this pregnancy (PD) How has your mood been during this pregnancy?

Low Some High

ASSOCIATED POSTPARTUM OUTCOMES The antenatal factors in the left column have been shown to be associated with the postpartum outcomes listed below. Bold, Italics indicates good evidence of association. Regular text indicates fair evidence of association. CA – Child Abuse CD – Couple Dysfunction PI – Physical Illness PD – Postpartum Depression WA – Woman Abuse APRIL JOGC AVRIL 2011 l 383

SOGC CLINICAL PRACTICE GUIDELINE

ANTENATAL FACTORS

CONCERN

COMMENTS / PLAN

SUBSTANCE USE Alcohol/drug abuse (WA, CA) (1 drink=11/2 oz liquor, 12 oz beer, 5 oz wine) How many drinks of alcohol do you have per week? Are there times when you drink more than that? Do you or your partner use recreational drugs? Do you or your partner have a problem with alcohol or drugs? Consider CAGE (Cut down, Annoyed, Guilty, Eye opener)

Low Some High

FAMILY VIOLENCE Woman or partner experienced or witnessed abuse (physical, emotional, sexual) (CA, WA) What was your parents’ relationship like? Did your father ever scare or hurt your mother? Did your parents ever scare or hurt you? Were you ever sexually abused as a child?

Low Some High

Current or past woman abuse (WA, CA, PD) How do you and your partner solve arguments? Do you ever feel frightened by what your partner says or does? Have you ever been hit/pushed/slapped by a partner? Has your partner ever humiliated you or psychologically abused you in other ways? Have you ever been forced to have sex against your will?

Low Some High

Previous child abuse by woman or partner (CA) Do you/your partner have children not living with you? If so, why? Have you ever had involvement with a child protection agency (ie. Children’s Aid Society)?

Low Some High

Child discipline (CA) How were you disciplined as a child? How do you think you will discipline your child? How do you deal with your kids at home when they misbehave?

Low Some High

FOLLOW UP PLAN ive counselling by provider Additional prenatal appointments Additional postpartum appointments Additional well baby visits Public Health referral Prenatal education services Nutritionist Community resources / mothers’ group

Homecare Parenting classes / parents’ group Addiction treatment programs Smoking cessation resources Social Worker Psychologist / Psychiatrist Psychotherapist / marital / family therapist Assaulted women’s helpline / shelter / counseling

COMMENTS:

Date Completed

Signature

© ALPHA Group, April, 2005; Department of Family & Community Medicine, University of Toronto http://dfcm19.med.utoronto.ca/research/alpha Used with permission.

384 l APRIL JOGC AVRIL 2011

Legal advice Children’s Aid Society Other: Other: Other: Other:

SOGC TECHNICAL UPDATE

SOGC TECHNICAL UPDATE

No. 254, February 2011

Transvaginal Mesh Procedures for Pelvic Organ Prolapse Abstract This technical update has been prepared by the Urogynaecology Committee and approved by the Executive of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHOR Jens-Erik Walter, MD, Montreal QC UROGYNAECOLOGY COMMITTEE Danny Lovatsis, MD (Chair), Toronto ON Jens-Erik Walter, MD (Co-Chair), Montreal QC William Easton, MD, Scarborough ON Annette Epp, MD, Saskatoon SK Scott A. Farrell, MD, Halifax NS Lise Girouard, RN, Winnipeg MB Chander K. Gupta, MD, Winnipeg MB Marie-Andrée Harvey, MD, Kingston ON Annick Larochelle, MD, St-Lambert QC Magali Robert, MD, Calgary AB Sue Ross, PhD, Calgary AB Joyce Schachter, MD, Ottawa ON Jane A. Schulz, MD, Edmonton AB David H.L. Wilkie, MD, Vancouver BC Disclosure statements have been received from all of the committee.

Objective: To provide an update on transvaginal mesh procedures, newly available minimally invasive surgical techniques for pelvic floor repair. Options: The discussion is limited to minimally invasive transvaginal mesh procedures. Evidence: PubMed and Medline were searched for articles published in English, using the key words “pelvic organ prolapse,” transvaginal mesh,” and “minimally invasive surgery.” Results were restricted to systematic reviews, randomized control trials/ controlled clinical trials, and observational studies. Searches were updated on a regular basis, and articles were incorporated in the guideline to May 2010. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Values: The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on the Preventive Health Care. Recommendations for practice were ranked according to the method described in that report (Table 1). Benefits, harms, and costs: Counselling for the surgical treatment of pelvic organ prolapse should consider all benefits, harms, and costs of the surgical procedure, with particular emphasis on the use of mesh. Recommendations 1. Patients should be counselled that transvaginal mesh procedures are considered novel techniques for pelvic floor repair that demonstrate high rates of anatomical cure in uncontrolled shortterm case series. (II-2B) 2. Patients should be informed of the range of success rates until stronger evidence of superiority is published. (II-2B) 3. Training specific to transvaginal mesh procedures should be undertaken before procedures are performed. (III-C)

J Obstet Gynaecol Can 2011;33(2):168-174

Key Words: Pelvic organ prolapse, transvaginal mesh, minimally invasive surgery

4. Patients should undergo thorough preoperative counselling regarding (a) the potential serious adverse sequelae of transvaginal mesh repairs, including mesh exposure, pain, and dyspareunia; and (b) the limited data available comparing transvaginal mesh systems with traditional vaginal prolapse repairs or with traditional use of graft material in the form of augmented colporrhaphy and sacral colpopexy. (III-C) 5. Until appropriate ive data are available, new trocarless kits should be considered investigative. (III-C)

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

168 l FEBRUARY JOGC FÉVRIER 2011

Transvaginal Mesh Procedures for Pelvic Organ Prolapse

Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well–designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.36 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the The Canadian Task Force on Preventive Health Care.36

INTRODUCTION

T

he prevalence of pelvic organ prolapse increases with age and is approximately 31% across all age groups.1 The likelihood of requiring surgical repair by age 80 is approximately 11%,2 and 29% to 40% undergo reoperation within 3 years following traditional surgery.2,3 Traditional non-augmented vaginal techniques include, but are not limited to, anterior and posterior colporrhaphy, McCall culdoplasty, and sacrospinous and uterosacral ligament apical vault suspensions. Persistently high failure rates have led to graft use,4 but non-standardized techniques have resulted in varied outcomes and complication rates.5 Graft use for pelvic floor surgery is commonly accepted, mainly in the form of sacral colpopexy and tension-free vaginal tape, both of which demonstrate longevity of successful repair.6,7 However, sacral colpopexy can carry significant morbidity that may be increased if performed by laparotomy.6 Its laparoscopic counterpart may provide comparable success rates and expedite convalescence.8 This technical update does not focus on the specific issue of graft use, because its use in sacral colpopexy is already accepted in general practice and because grafts may be of various types: synthetic (polypropylene), xenografts (porcine dermis or porcine small intestinal submucosa), or allografts (cadaveric). This update focuses on the rapidly expanding area of transvaginal mesh (TVM) systems that employ graft material, usually polypropylene mesh, placed vaginally, using trocars.

The novel TVM procedures have been part of a surgical evolution attempting to maintain durability of repair, minimize morbidity and invasiveness, allow regional anaesthesia, and address appropriate anatomical defects of pelvic floor dysfunction.9 They are intended to be minimally invasive surgical techniques for pelvic organ prolapse repair that facilitate a tension-free placement of a broad coverage polypropylene implant without trimming of the vagina or suturing of the mesh to the vagina. The involved “systems” allow selective application of anterior, posterior, or total vaginal implants, and the need for hysterectomy is potentially eliminated. The mesh implants have arms that are delivered with trocars through anatomical landmarks via the obturator membrane or the ischiorectal fossa. The currently available commercial kits are listed in Table 2. Early literature with short-term follow-up has shown the TVM systems to be relatively effective, but there is limited long-term follow-up to demonstrate their potential longevity or safety profile.9-17 The issues of mesh erosion, dyspareunia, pelvic pain, mesh shrinkage, and de novo stress incontinence have been introduced in early studies. Modifications of the TVM procedure were carried out (elimination of hysterectomy and creating only longitudinal incisions) upon review of initial case series in attempts to reduce rates of vaginal mesh exposure.15 Even newer technology has allowed the development of single-incision trocarless TVM systems. These include the

FEBRUARY JOGC FÉVRIER 2011 l 169

SOGC TECHNICAL UPDATE

Elevate system from AMS and the Pinnaclesystem from Boston Scientific (both approved by the FDA). Their intent is to lower rates of nerve and vascular injury associated with trocar placement, expedite operating time, and potentially reduce rates of pelvic pain and dyspareunia. As no literature yet exists on their risks and effectiveness, they are not discussed in this update. TVM PROCEDURE

Table 2. Commercial TVM kits available Company

Device

Implant material

Apogee/ Perigee

Intepro polypropylene InteXen porcine dermis

Gynecare/Ethicon, Johnson & Johnson, Somerville, NJ

Prolift

Gynemesh-PS polypropylene

CR Bard Inc., Murray Hill, NJ

AvaultaPlus

Polypropylene +Porcine collagen

American Medical Systems Inc., Minnetonka, MN

*Trocarless not included: see Recommendation 5.

The TVM procedure addresses midline, paravaginal, and apical defects through placement of a macroporous monofilament polypropylene implant. Characteristics of the available TVM systems are listed in Table 3. Typically hydrodissection guides creation of a full-thickness longitudinal vaginal incision through which the paravesical and/or pararectal spaces are then accessed. Arms of the mesh implant are delivered through the obturator membrane and/or ischiorectal fossa via trocars. Positioning of the mesh is performed, and the vaginal epithelium is closed without trimming. A mid-urethral sling can then be carried out through a separate incision. There are variations of this procedural technique. TVM OUTCOMES

Currently the vast majority of the published studies are limited to short-term follow-up (typically 3 to 12 months) through either observational or retrospective studies.11-15,17-25 Initial rates of anatomical cure (typically defined as less than POP-Q stage II) in all compartments combined range from 79% to 100%.11-15,17-23,26 These results are comparable to subjective satisfaction rates from the procedure. The only published randomized clinical trial in this area compared the Perigee system from AMS with traditional anterior colporrhaphy for anterior compartmental prolapse.27 Seventy-five patients were randomized to either traditional anterior colporrhaphy (n = 38) or a Perigee procedure (n = 37). Anatomic failure was defined as recurrent POP-Q stage II prolapse or greater. Optimal repair was achieved in 55% of the colporrhaphy group and 87% of the Perigee group (P = 0.005). Rates of dyspareunia and voiding symptoms were not different. Mesh exposure rate was 5% in the Perigee group, and all were managed as outpatients. Number needed to treat analysis was carried out and determined that 9 anterior colporrhaphy patients would have recurrent anterior vaginal wall prolapse to prevent 1 mesh erosion. A summary of outcomes is shown in Table 4. 170 l FEBRUARY JOGC FÉVRIER 2011

TVM COMPLICATIONS

TVM procedures have introduced postoperative complications that initially received little attention. These include higher rates of mesh exposure than previous procedures (4.7%), mesh shrinkage (≤ 17%), and dyspareunia (≤ 13%).21,22 The TVM procedures have relatively low rates of intraoperative complication. A summary of perioperative complications is shown in Table 5. The following factors may increase the incidence of mesh exposure: lack of full-thickness dissection, improper mesh placement, estrogen status, patient nutritional status, BMI, age, smoking, inadequate hemostasis, and immunosuppression.12,28,29 Although visceral mesh erosion is possible, there is little evidence of it to date. Significant complications should be managed by a subspecialist. In October 2008, the FDA released a statement regarding potential serious complications associated with transvaginal placement of surgical mesh in pelvic floor surgery.30 On February 4, 2010, Health Canada issued important safety information on surgical mesh for stress urinary incontinence and pelvic organ prolapse.31 It outlined the serious potential adverse events associated with transvaginal meshes placed for pelvic organ prolapse or incontinence, using minimally invasive procedures information from over 1000 reports from 9 urogynaecologic surgical companies. These included vaginal mesh exposure, infection, pain, voiding dysfunction, pelvic floor dysfunction recurrence, and visceral or vascular perforation. The Health Canada document31 made recommendations for obtaining specialized training to carry out these procedures, being vigilant for adverse events associated with the trocars and the mesh, obtaining informed consent for surgery by advising the patient of potentially uncorrectable sequelae of mesh placement including pelvic pain and dyspareunia, and reporting complications to appropriate bodies. Relatively new long-term sequelae of pelvic floor reconstruction—vaginal scarring and mesh exposure— were also addressed in this notification. These may reduce

Transvaginal Mesh Procedures for Pelvic Organ Prolapse

Table 3. Characteristics of TVM systems Device

Trocar

Anterior attachment

Posterior attachment

Retrieval device

Prolift

Straight + cannula

Proximal & distal ATFP

Sacrospinous ligament

Y

Type I polypropylene; Anterior/posterior/total

Apogee

Straight

Ileococcygeus muscle

N

Type I polypropylene or porcine dermis

Perigee

Helical

Proximal & distal ATFP

N

Type I polypropylene or porcine dermis

AvaultaPlus

Straight & helical

Proximal & distal ATFP

Ileococcygeus + perineal body

Y (InSnare)

Mesh material

Type I polypropylene coated with porcine collagen; anterior/posterior

ATFP: arcus tendineus fascia pelvis

Table 4. Outcomes of TVM procedures Author Gauruder-Burmester et al.22 Fatton et al.

21

Altman et al.10 Abdel-Fattah and Ramsay14 Shek et al.23 Van Raalte et al. Hinoul

12

19

Lucioni

Design

N

Device

Follow-up, months

Anatomic cure, %

Retrospective

120

AMS

12

93

Retrospective

110

Prolift

6

95.3

Prospective cohort

123

Prolift

2

87 to 91

Retrospective cohort

289

Prolift/AMS

3

94 to 100

Retrospective

46

Perigee

10

87

Observational

350

Prolift

6

90

Observational

48

Prolift

95.2

Observational

12

Prolift

10

92

Gabriel et al.11

Case series

73

Avaulta

4

100

Nguyen and Burchette27

RCT vs. AR

75

Perigee

12

87 vs. 55

Retrospective cohort cf colpocleisis

90

Prolift

24

97.8 vs. 93.3

Elmer et al.26

Prospective cohort

261

Prolift

12

79 to 86

Cosson et al.4

Retrospective

687

Prolift

3

94

Kdous et al.

Observational

45

Prolift

24

93

20

Murphy18

Davila

16

Observational

55

Apogee

3

91

Rane et al.17

Observational

70

Perigee

36

95.7

Moore et al.24

Observational

42

Perigee

12

93

Davila

Observational

298

AMS

9

96

13

25

patients’ quality of life through debilitating discomfort and dyspareunia. Several studies have investigated this issue with conflicting results.12,13,19,27,32-34 DISCUSSION

While numerous short-term observational and retrospective studies are emerging that demonstrate the potential effectiveness of the TVM systems, there is a need to demonstrate their longevity and safety profiles, particularly in comparison with traditional and established procedures for pelvic floor repair. Appropriately designed and adequately powered prospective and randomized

trials with sufficient long-term follow-up comparing TVM with accepted “gold-standard” procedures such as sacral colpopexy would allow accurate assessment of success with appropriate subjective and objective outcome measures and complication rates. TVM procedures must be more thoroughly evaluated before it is assumed they offer benefits over traditional repairs. The ethical issues associated with the introduction of new surgical devices are discussed in a commentary by Ross et al.35 The purported intent of the TVM systems is to further reduce the invasiveness and potential morbidity of the FEBRUARY JOGC FÉVRIER 2011 l 171

SOGC TECHNICAL UPDATE

Table 5. Complications of TVM procedures Author

Device

N

Follow-up, months

Intraoperative, %

Postoperative, %

Exposure rate, %

Cosson et al.4

Prolift

687

3

6.7

6.7

6.7

Gauruder-Burmester et al.22

AMS

120

12

–

2.8 hematoma

8 to 11

Fatton et al.21

Prolift

110

3

1 cystotomy 2 hematoma

6

4.7 2.8 granuloma

Altman et al.34

Prolift

248

6

4 viscus injury 0.4 EBL >1L

14.5 total (UTI, retention, fever)

2

Prolift 76% AMS 24%

289

3

1.6 cystotomy 1.1 rectal injury 0.06 vascular

5.2 buttock pain 0.07 sepsis

10 vaginal 0.06 bladder

Prolift

350

6

–

6 dyspareunia 2 de novo SUI

1

Davila13

Apogee

55

3

–

4 granulation 4 dyspareunia

11

Rane et al.17

Perigee

70

36

–

1.4 pain

7.1

Moore et al.24

Perigee

42

12

–

11 de novo SUI

7

AMS

298

9

–

1 pain

12

Prolift

48

–

13 de novo SUI 15 dyspareunia

10.4

Gabriel et al.11

Avaulta

73

4

2.7 EBL > 500 mL 1.4 cystotomy

–

3.1

Shek et al.23

Perigee

46

10

–

10.9 mesh arm dislodgement

6.5

Abdel-Fattah and Ramsay14

Van Raalte et al.12

Davila

25

Hinoul19

laparoscopic sacral colpopexy by delivering the mesh vaginally as opposed to using an intraperitoneal approach and to eliminate the need for general anaesthesia and concurrent hysterectomy. Comparison of these procedures with traditional techniques by adequately trained pelvic floor surgeons is the first step towards elucidating the effectiveness and appropriateness of the use of these novel surgical techniques in our common urogynaecologic practices. The evolution of graft materials with interwoven absorbable mesh, such as monocryl, addition of barrier layers, such as bovine collagen, and xenografts, such as porcine dermis or small intestinal submucosa further complicates the challenge of determining the best materials and techniques for pelvic floor surgery. These graft materials mimic to a certain extent the anatomical considerations of the transvaginal mesh systems and warrant further evaluation and comparison with TVM systems as an alternate minimally invasive novel vaginal approach to pelvic floor repair. The more than 1000 reports of mesh complication referenced in the FDA notification30 raise concerns about

172 l FEBRUARY JOGC FÉVRIER 2011

adequacy of training and ability to prevent complications. Traditionally, advanced pelvic floor reconstructive surgery (such as laparoscopic sacral colpopexy, pubovaginal slings, vaginal paravaginal repairs, and to a lesser extent colpocleisis) has been the domain of the trained pelvic floor reconstructive surgeon and, less commonly, the general gynaecologist who feels competent to carry out these procedures from experience or extra training. The role of the subspecialist has included mentoring and training of generalists interested in novel techniques. The TVM systems assume familiarity with pelvic floor anatomy and surgical techniques not typically known to most generalists. Familiarity with these procedures does require surgical expertise, knowledge of pertinent anatomy, and experience with the procedure itself. These elements would facilitate the trained pelvic floor surgeon’s dissemination of his or her knowledge and skill to the interested generalist. Adequate training programs would ensure that trainees could perform competently and safely. Until adequate effectiveness and safety evidence is available, the use of new TVM devices for prolapse repair should be considered experimental and restricted to use in investigative trials.

Transvaginal Mesh Procedures for Pelvic Organ Prolapse

Recommendations

1. Patients should be counselled that transvaginal mesh procedures are considered novel techniques for pelvic floor repair that demonstrate high rates of anatomical cure in uncontrolled short-term case series. (II-2B) 2. Patients should be informed of the range of success rates until stronger evidence of superiority is published. (II-2B) 3. Training specific to transvaginal mesh procedures should be undertaken before procedures are performed. (III-C) 4. Patients should undergo thorough preoperative counselling regarding (a) the potential serious adverse sequelae of transvaginal mesh repairs, including mesh exposure, pain, and dyspareunia; and (b) the limited data available comparing transvaginal mesh systems with traditional vaginal prolapse repairs or with traditional use of graft material in the form of augmented colporrhaphy and sacral colpopexy. (III-C) 5. Until appropriate ive data are available, new trocarless kits should be considered investigative. (III-C) REFERENCES 1. Samuelsson EC, Victor FT, Tibblin G, Svardsudd KF. Signs of genital prolapsed in a Swedish population of women 20 to 59 years of age and possible related factors. Am J Obstet Gynecol 1999;180(2 Pt 1):299–305. 2. Olson AL, Smith VJ, Bergstrom JO, Colling JC, Clark AL. Epidemiology of surgically managed pelvic organ prolapse and urinary incontinence. Obstet Gynecol 1997;89:501–6. 3. Clark AL, Gregory T, Smith VJ, Edwards R. Epidemiologic evaluation of reoperation for surgically treated pelvic organ prolapse and urinary incontinence. Am J Obstet Gynecol 2003;189:1261–7. 4. Cosson M, Debodinanace P, Boukerrou M, Chauvet MP, Lobry P, Crépin G, et al. Mechanical properties of synthetic implants used in the repair of prolapse and urinary incontinence in women: which is the ideal material? Int Urogynecol J Pelvic Floor Dysfunct 2003;14:169–78. 5. Birch C. The use of prosthetics in pelvic reconstructive surgery. Best Pract Res Clin Obstet Gynaecol 2005;19:979–91. 6. Nygaard IE, McCreery R, Brubaker L, Connolly A, Cundiff G, Weber AM, et al. Abdominal sacrocolpopexy: a comprehensive review. Obstet Gynecol 2004;104:805–23. 7. Nilsson CG, Palva K, Rezapour M, Falconer C. Eleven years prospective follow-up of the tension-free vaginal tape procedure for treatment of stress urinary incontinence. Int Urogynecol J Pelvic Floor Dysfunct 2008;19:1043–7. 8. Paraiso MF, Walters MD, Rackley RR, Melek S, Hugney C. Laparoscopic and abdominal sacral colpopexies: a comparative cohort study. Am J Obstet Gynecol 2005;192:1752–8. 9. Altman D, Falconer C. Perioperative morbidity using transvaginal mesh in pelvic organ prolapsed repair. Obstet Gynecol 2007;109(2 Pt 1):303–8.

10. Altman D, Väyrynen T, Engh ME, Axelsen S, Falconer C. Nordic Transvaginal Mesh Group Short-term outcome after transvaginal mesh repair of pelvic organ prolapse. Int Urogynecol J Pelvic Floor Dysfunct 2008;19:787–93. 11. Gabriel B, Farthmann J, Brintrup B, Fünfgeld C, Jezek P, Kraus A, et al. Surgical repair of posterior compartment prolapse: preliminary results of a novel transvaginal procedure using a four-armed polypropylene mesh with infracoccygeal and pararectal suspension. Acta Obstet Gynecol Scand 2007;30:1–7. 12. van Raalte H, Lucente V, Haff R, Murphy M. Prolift: an innovative delivery system for transvaginal placement of synthetic grafts for the repair of pelvic organ prolapse. J Pelvic Med Surg 2007;13:351–60. 13. Davila G. Restoration of vaginal apical and posterior wall with the apogee system. J Minim Invasive Gynecol 2005;12:42. 14. Abdel-Fattah M, Ramsay I. Retrospective multicentre study of the new minimally invasive mesh repair devices for pelvic organ prolapsed. BJOG 2008;115:22. 15. Cosson M, Caquant F, Collinet P, Rosenthal C, Clave H, Debodinance P, et al. Prolift mesh (Gynecare) for pelvic organ prolapse surgical treatment using the TVM group technique: a retrospective study of 687 patients. Neurourol Urodyn 2005;24:590–1. 16. Kdous M, Zhioua F. Transobturator subvesical mesh: tolerance and mid-term results. A prospective study. J Gynecol Obstet Biol Reprod (Paris) 2008;37:758–69. 17. Rane A, Kannan K, Barry C, Balakrishnan S, Lim Y, Corstiaans A. Prospective study of the Perigee system for the management of cystocoeles—medium-term follow up. Aust N Z J Obstet Gynaecol 2008;48:427–32. 18. Murphy M. Quality of life and surgical satisfaction after vaginal reconstructive vs obliterative surgery for the treatment of advanced pelvic organ prolapse. Am J Obstet Gynecol 2008;198(5):573.e1–7. 19. Hinoul P. A prospective study to evaluate the anatomic and functional outcome of a transobturator mesh kit (prolift anterior) for symptomatic cystocele repair. J Minim Invasive Gynecol 2008;15:615–20. 20. Lucioni A. The surgical technique and early postoperative complications of the Gynecare Prolift pelvic floor repair system. Can J Urol 2008;15:4004–8. 21. Fatton B, Amblard J, Debodinance P, Cosson M, Jacquetin B. Transvaginal repair of genital prolapse: preliminary results of a new tension-free vaginal mesh (Prolift technique)—a case series multicentric study. Int Urogynecol J Pelvic Floor Dysfunct 2007;18:743–52. 22. Gauruder-Burmester A, Koutouzidou P, Rohne J, Gronewold M, Tunn R. Follow-up after polypropylene mesh repair of anterior and posterior compartments in patients with recurrent prolapse. Int Urogynecol J Pelvic Floor Dysfunct 2007;18:1059–64. 23. Shek KL, Dietz HP, Rane A, Balakrishnan S. Transobturator mesh for cystocele repair: a short to medium-term follow-up using 3D/4D ultrasound. Ultrasound Obstet Gynecol 2008;32(1):82–6. 24. Moore RD, Beyer RB, Miklos JR, Jacoby KJ, Freedman SF, McCammon KM, et al. Prospective, multicenter trial evaluating the Perigee system with polypropylene mesh for cystocele repair. Int Urogynecol J 2006;18(Suppl 1):S068. 25. Davila GW. Introduction to the 2005 IUGA Grafts Roundtable. Int Urogynecol J 2006;17(Suppl 1):S4–5. 26. Elmer C, Altman D, Engh ME, Axelsen S, Vayrynen T, Falconer C. Trocar-guided transvaginal mesh repair of pelvic organ prolapse. Obstet Gynecol 2009; 113:117–26. 27. Nguyen JN, Burchette RJ. Outcome after anterior vaginal prolapse repair: a randomized controlled trial. Obstet Gynecol 2008;111:891–8.

FEBRUARY JOGC FÉVRIER 2011 l 173

SOGC TECHNICAL UPDATE 28. Araco F, Gravante G, Sorge R, Overton J, De Vita D, Primicerio M, et al. The influence of BMI, smoking, and age on vaginal erosions after synthetic mesh repair of pelvic organ prolapses. A multicentre study. Acta Obstet Gynecol Scand 2009;88:772–80.

32. Sentilhes L, Berthier A, Sergent F, Verspyck E, Descamps P, Marpeau L. Sexual function in women before and after transvaginal mesh repair for pelvic organ prolapse. Int Urogynecol J Pelvic Floor Dysfunct 2008;19:763–72.

29. Collinet P, Belot F, Debodinance P, Ha Duc E, Lucot JP, Cosson M. Transvaginal mesh technique for pelvic organ prolapsed repair: mesh exposure management and risk factors. Int Urogynecol J Pelvic Floor Dysfunct 2006;17:315–20.

33. Lowman JK, Jones LA, Woodman PJ, Hale DS. Does the Prolift system cause dyspareunia? Am J Obstet Gynecol 2008;199:707.e1–6.

30. Medical Devices Safety Alerts and Notices. Available at: http://www.fda.gov/ MedicalDevices/Safety/AlertsandNotices/PublicHealthNotifications/ ucm061976.htm. Accessed November 25,2010. 31. Health Canada. Drugs & health products. Advisories, warnings & recalls. Surgical Mesh - Complications Associated with Transvaginal Implantation of Surgical Mesh for the Treatment of Stress Urinary Incontinence and Pelvic Organ Prolapse - Notice to Hospitals. February 4, 2010. Available at: http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/ prof/_2010/surgical-mesh_nth-aah-eng.php. Accessed January 21, 2011.

174 l FEBRUARY JOGC FÉVRIER 2011

34. Altman D, Elmer C, Kiilholma P, Kinne I, Tegerstedt G, Falconer C. Sexual dysfunction after trocar-guided transvaginal mesh repair of pelvic organ prolapse. Obstet Gynecol 2009;113:127–33. 35. Ross S, Robert M, Harvey M, Farrell S, Schulz J, Wilkie D, et al. Ethical issues associated with the introduction of new surgical devices, or just because we can, doesn’t mean we should. J Obstet Gynaecol Can 2008;30:508–13. 36. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

SOGC CLINICAL PRACTICE GUIDELINE No. 257, May 2011

Ultrasonographic Cervical Length Assessment in Predicting Preterm Birth in Singleton Pregnancies This clinical practice guideline has been prepared by the Diagnostic Imaging Committee, reviewed by the Family Physicians Advisory Committee and the Maternal Fetal Medicine Committee, and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Kenneth Lim, MD, Vancouver BC Kimberly Butt, MD, Fredericton NB Joan M. Crane, MD, St. John’s NL DIAGNOSTIC IMAGING COMMITTEE Lucie Morin, MD (Chair), Montreal QC Stephen Bly, PhD, Ottawa ON

MATERNAL FETAL MEDICINE COMMITTEE Robert Gagnon, MD (Chair), Verdun QC Lynda Hudon, MD (Co-Chair), Montreal QC Melanie Basso, RN, Vancouver BC Hayley Bos, MD, London ON Joan M. Crane, MD, St. John’s NL Gregory Davies, MD, Kingston ON Marie- Delisle, MD, Vancouver BC Savas Menticoglou, MD, Winnipeg MB William Mundle, MD, Windsor ON Annie Ouellet, MD, Sherbrooke QC

Kimberly Butt, MD, Fredericton NB

Tracy Pressey, MD, Vancouver BC

Yvonne Cargill, MD, Ottawa ON

Christy Pylypjuk, MD, Saskatoon SK

Gregory Davies, MD, Kingston ON

Anne Roggensack, MD, Calgary AB

Nanette Denis, RDMS, CRGS, Saskatoon SK

Frank Sanderson, MD, Saint John NB

Kenneth Lim, MD, Vancouver BC

Disclosure statements have been received from all of the committees.

Annie Ouellet, MD, Sherbrooke QC Shia Salem, MD, Toronto ON Vyta Senikas, MD, Ottawa ON FAMILY PHYSICIANS ADVISORY COMMITTEE William Ehman, MD (Chair), Nanaimo BC

The literature searches and bibliographic for this guideline were undertaken by Becky Skidmore, Medical Research Analyst, Society of Obstetricians and Gynaecologists of Canada.

Anne Biringer, MD, Toronto ON Andrée Gagnon, MD, Blainville QC Lisa Graves, MD, Sudbury ON Jonathan Hey, MD, Saskatoon SK Jill Konkin, MD, Edmonton AB Francine Léger, MD, Montreal QC Cindy Marshall, MD, Lower Sackville NS

Abstract Objectives: To review (1) the use of ultrasonographic-derived cervical length measurement in predicting preterm birth and (2) interventions associated with a short cervical length. Outcomes: Reduction in rates of prematurity and/or better identification of those at risk, as well as possible prevention of unnecessary interventions.

Key Words: Preterm birth, prediction, ultrasonography, transvaginal, cervical cerclage

Evidence: Published literature was retrieved through searches of PubMed and The Cochrane Library up to December 2009, using appropriate controlled vocabulary and key words (preterm

These guidelines reflect emerging clinical and scientific advances as of the date issued and are subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of the contents may be reproduced in any form without prior written permission of SOGC.

486 l MAY JOGC MAI 2011

Ultrasonographic Cervical Length Assessment in Predicting Preterm Birth in Singleton Pregnancies

labour, ultrasound, cervix, incompetent cervix, transvaginal, transperineal, cervical length, fibronectin). Results were restricted to general and systematic reviews, randomized controlled trials/controlled clinical trials, and observational studies. There were no date or language restrictions. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Values: The evidence and this guideline were reviewed by the Diagnostic Imaging Committee and the Maternal Fetal Medicine Committee of the Society of Obstetricians and Gynaecologists of Canada, and the recommendations were made according to the guidelines developed by The Canadian Task Force on Preventive Health Care (Table 1). Benefits, harms, and costs: Preterm birth is a leading cause of perinatal morbidity and mortality. Use of the ultrasonographic technique reviewed in this guideline may help identify women at risk of preterm birth and, in some circumstances, lead to interventions that may reduce the rate of preterm birth. Sponsors: The Society of Obstetricians and Gynaecologists of Canada Summary Statements 1. Cervical length in the general obstetrical population is relatively stable over the first 2 trimesters. The natural history of cervical length change may be useful in identifying women at increased risk of spontaneous preterm birth. Because there may be different patterns or a delay in cervical length shortening, repeat assessment of cervical length may be useful. (II-2) 2. There is no consensus on the optimal timing or frequency of serial evaluations of cervical length. If repeat measurements are performed, they should be done at suitable intervals to minimize the likelihood of observation error. (II-2) 3. Transvaginal sonography can be used to assess the risk of preterm birth in women with a history of spontaneous preterm birth and to differentiate those at higher and lower risk of preterm delivery. The gestational age of a prior preterm birth affects the cervical length in a future pregnancy. (II–2) 4. Cervical length measurement can be used to identify increased risk of preterm birth in asymptomatic women at < 24 weeks who have other risk factors for preterm birth (previous excisional treatment for cervical dysplasia, uterine anomaly, or prior multiple dilatation and evacuation procedures beyond 13 weeks’ gestation). However, there is insufficient evidence to recommend specific management strategies, such as cerclage, in these women. (II-2) 5. No specific randomized trials have evaluated any interventions in asymptomatic women at > 24 weeks’ gestation who are at increased risk of preterm birth (e.g., those who have a history of prior spontaneous preterm birth, previous excisional treatment for cervical dysplasia, uterine anomaly, or prior multiple dilatation and evacuation procedures beyond 13 weeks’ gestation) and who have a short cervical length. This information may help with

ABBREVIATIONS

LEEP loop electrical excision procedure TP transperineal TV transvaginal

empiric management of these women, including reduction of activity level, work, or travel, relocation, increased surveillance, and istration of corticosteroids. (III) 6. Transvaginal ultrasound appears to be safe in preterm premature rupture of membranes, but its clinical predictive value is uncertain in this context. (II-2) 7. It is unclear whether ultrasonographic cervical length assessment has significant advantages over clinical examination alone after elective or emergency cervical cerclage placement, although some signs, such as funnelling to the stitch, are associated with a high risk of preterm premature rupture of membranes. There is no consensus on the frequency or timing of ultrasonographic cervical length assessment post cerclage. (II-2) 8. It is unclear whether a policy of cervical length surveillance is equivalent to clinical assessment of the need for elective cerclage in those at risk of preterm delivery. (I) 9. Ultrasonographic cervical length assessment and fetal fibronectin appear to be similar in predictive ability, and the combination of both in a high-risk population may be of value. However, further research is needed in this area. (II-2) Recommendations 1. Transabdominal ultrasonography should not be used for cervical length assessment to predict preterm birth. (II-2D) 2. Transvaginal ultrasonography is the preferred route for cervical assessment to identify women at increased risk of spontaneous preterm birth and may be offered to women at increased risk of preterm birth. (II-2B) 3. Transperineal ultrasonography may be offered to women at increased risk of preterm birth if transvaginal ultrasonography is either unacceptable or unavailable. (II-2B) 4. Because of poor positive predictive values and sensitivities and lack of proven effective interventions, routine transvaginal cervical length assessment is not recommended in women at low risk. (II-2E) 5. In women presenting with suspected preterm labour, transvaginal sonographic assessment of cervical length may be used to help in determining who is at high risk of preterm delivery and may be helpful in preventing unnecessary intervention. It is unclear whether this information results in a reduced risk of preterm birth. (II-2B) 6. In asymptomatic women with a history of spontaneous preterm birth and an ultrasonographically diagnosed short cervical length (< 25 mm) prior to 24 weeks of gestation, cervical cerclage should be considered to reduce the risk of preterm birth. (I-B) 7. In all asymptomatic women who present with membranes at or protruding past the external cervical os, an emergency cerclage should be considered to reduce the risk of preterm delivery. (I-B)

J Obstet Gynaecol Can 2011;33(5):486–499

INTRODUCTION

P

reterm birth is the leading cause of perinatal morbidity and mortality.1–5 Despite advances in perinatal care, the incidence of preterm birth continues to rise, primarily because of the increased multiple pregnancies resulting from assisted reproduction.6–9 Tocolytics prolong pregnancy minimally once preterm labour has begun, and they can be associated with significant undesirable maternal, fetal, MAY JOGC MAI 2011 l 487

SOGC CLINICAL PRACTICE GUIDELINE

Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well–designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action

* The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.141 † Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the The Canadian Task Force on Preventive Health Care.141

and neonatal consequences.10–19 In order to address the prematurity problem, it is important to identify those at increased risk. The following are risk factors for spontaneous preterm birth: • Reproductive history (previous spontaneous preterm birth and use of assisted reproductive technologies)8,20–22 • Antepartum bleeding, rupture of membranes, cervical/uterine factors (cervical insufficiency, uterine anomalies,22 fibroids, and excisional cervical treatment for cervical intraepithelial neoplasia)23–25 • Fetal/intrauterine factors (multifetal gestation, fetal anomaly, and polyhydramnios) • Infection (chorioamnionitis, bacteruria, periodontal disease,26 current bacterial vaginosis with a prior preterm birth27) • Demographic factors (low socioeconomic status, single marital status, low level of education, First Nations ethnicity, or maternal age < 18 years or > 35 years) • Lifestyle issues (cigarette smoking, illicit drug use, stress, physical abuse28) • Inadequate prenatal care, low pre-pregnancy weight and poor weight gain in pregnancy.29 However, many women who deliver preterm do not have any known risk factors.8,22 Research has focused on combined risk scoring systems that use multiple serum markers, ultrasound, and maternal 488 l MAY JOGC MAI 2011

demographic factors, but these have not been fully validated in large scale studies.30–42 Other screening strategies that have been suggested include measuring biochemical markers such as fetal fibronectin and screening for infections.27,43–46 In the 1980s, an objective, ultrasound-based measurement was developed to identify women at increased risk of preterm birth. The risk of preterm birth was inversely correlated to the length of the cervix as measured by ultrasound. This observation has been confirmed in multiple studies using different techniques; however, the most widely accepted and used technique is transvaginal ultrasound.34,47–57 A number of interventions based on this observation have been studied in randomized trials. A recent meta-analysis58 has looked at its efficacy in preventing preterm birth. Since the publication of the 2001 SOGC guideline,36 there have been numerous studies on imaging, natural history, and use of transvaginal ultrasound in common clinical scenarios, as well as a number of randomized trials looking at interventions for a short cervix. This updated guideline provides a comprehensive review of studies of shortened cervical length diagnosed on transvaginal ultrasound and is broader in scope than the 2001 guideline.36 ULTRASONOGRAPHY COMPARED WITH DIGITAL ASSESSMENT OF CERVICAL LENGTH

Digital assessment of the cervix has been commonly used to diagnose premature labour or to evaluate women perceived to be at increased risk of preterm labour. Digital assessment of cervical length is subjective, varies between

Ultrasonographic Cervical Length Assessment in Predicting Preterm Birth in Singleton Pregnancies

examiners, and underestimates true anatomic length. In one study, digital examinations before hysterectomy underestimated cervical length by approximately 14 mm, whereas ultrasonography measured length accurately.59 Investigations using transvaginal ultrasound measurement as the standard confirmed that digital examination underestimates cervical length.57,60 This underestimation may result from an inability to assess the cervix length digitally beyond the vaginal fornices unless there is 2 cm or more of dilatation and the entire intracervical canal is examined. The majority of studies have found that ultrasound assessment of cervical length is superior to clinical examination for the prediction of preterm birth.61–64 Therefore, ultrasound assessment of cervical length is more reliable and more clinically predictive of preterm birth than manual examination of the cervix. COMPARISON OF TRANSVAGINAL, TRANSABDOMINAL, AND TRANSPERINEAL ULTRASONOGRAPHIC CERVICAL LENGTH ASSESSMENT

Ultrasound assessment of the cervix was initially performed transabdominally, but specific disadvantages led to a preference for transvaginal ultrasound assessment. Both TP and TV cervical assessments have been studied, with most studies evaluating TV assessment.65,66 The patient’s bladder must be full for transabdominal ultrasonography to assess the cervix adequately, but this may spuriously lengthen the cervix by opposing the anterior and posterior lower uterine segments65 and concealing cervical shortening or funnelling. In contrast, TV ultrasound is performed with the bladder empty.66 Transabdominal ultrasound is significantly less likely than the other 2 methods to provide adequate imaging and measurements.67 Visualization of the cervix by transabdominal ultrasonography is hampered significantly by maternal obesity, shadowing from fetal parts, and the need for lower frequency transducers. Recommendations

1. Transabdominal ultrasonography should not be used for cervical length assessment to predict preterm birth. (II-2D) TP ultrasonography has been found to be as accurate as transabdominal ultrasound for examining the cervix, and one study found it was more acceptable to women than TV scanning.55,67 Other studies, however, have found both TV and TP techniques acceptable to women.55,68–70 TP assessment is more accurate than digital examination for predicting preterm birth, and, when adequate images can

be obtained, TP ultrasonography can predict preterm birth as accurately as TV ultrasonography.56,63 However, most authors suggest that adequate images can be obtained more frequently with TV than with TP technique,55,67,71,72 that TV assessment is easier to obtain and more reproducible, and that TV correlates better with true cervical length than TP assessment.69,71,72 Since the TV technique is more studied and more likely to be obtainable, TP ultrasonography should be reserved for women at increased risk of preterm birth for whom vaginal assessment is unavailable or unacceptably invasive or uncomfortable. Recommendations

2. Transvaginal ultrasonography is the preferred route for cervical assessment to identify women at increased risk of spontaneous preterm birth and may be offered to women at increased risk of preterm birth. (II-2B) 3. Transperineal ultrasonography may be offered to women at increased risk of preterm birth if transvaginal ultrasonography is either unacceptable or unavailable. (II-2B) NORMAL CERVICAL LENGTH

Cervical length is normally distributed and remains relatively constant in pregnancy until the third trimester.73–75 If there is any statistically significant reduction in length, it is not clinically significant (< 0.5 mm /week).73–77 Heath et al.52 found a mean length of 38 mm at 23 weeks. Iams et al.34 found a mean length of 35 mm at 24 weeks and of 34 mm at 28 weeks. If funnelling is present, measurement should exclude the funnel and be taken from the funnel tip to the external os.47 CERVICAL CHANGE IN WOMEN WHO DELIVER PRETERM

In women who deliver preterm or require cerclage, the rate of cervical length change may be predictive of preterm birth. The rate of cervical shortening is faster in women who deliver preterm than in those who deliver at term; however, the difference can be quite small.76–80 The range of cervical length decline in those who go on to preterm delivery, preterm labour, or pregnancy intervention varies from 0.5 mm/week to 8 mm/week.76–80 In a cross-sectional, longitudinal study, Yoshizato et al.81 examined cervical change in women whose cervix became short (< 25 mm) in either the early (< 26 weeks) or the late preterm period (26 to 30 weeks). They found that “rapid CL shortening occurred between 16–20 and 21–25 weeks in the early group and between 21–25 and 26–30 weeks in the late group”81 Intervention in of tocolytics or cerclage was MAY JOGC MAI 2011 l 489

SOGC CLINICAL PRACTICE GUIDELINE

used in 19 of 20 in the early group, and 10 of 19 in the late group. More interesting was that the longitudinal cervical length change (mm/week) in the late group was statistically the same as in controls between 16 and 25 weeks, and then accelerated 3-fold in the next observation period. This study suggests that cervical length may be stable for a period of time and then undergo a phase of rapid decline prior to the onset of symptoms.81 Hence, repeat evaluation of the cervical length may be reasonable to screen for those who may be at increased risk of late preterm delivery.

perhaps even 2, to avoid observation error. The shorter the interval of time between measurements, the higher the rate of observation error: either not enough time has elapsed between assessments to detect change in the cervical length, or a small observed change is really observational error. The current evidence and the regional differences in resources, access, and practice across the country do not allow the development of a national consensus surveillance protocol.

Summary Statement

2. There is no consensus on the optimal timing or frequency of serial evaluations of cervical length. If repeat measurements are performed, they should be done at suitable intervals to minimize the likelihood of observation error. (II-2)

1. Cervical length in the general obstetrical population is relatively stable over the first 2 trimesters. The natural history of cervical length change may be useful in identifying women at increased risk of spontaneous preterm birth. Because there may be different patterns or a delay in cervical length shortening, repeat assessment of cervical length may be useful. (II-2) FREQUENCY OF CERVICAL LENGTH MEASUREMENT

The natural history of cervical shortening in women who will deliver preterm may be used to determine when serial measurements should be performed. These studies may make it possible to time reassessment and perhaps stratify follow-up according to length of measurement and the desired target threshold for intervention. Studies report thresholds for intervention ranging from 15 mm to 25 mm.82–87 Thus depending on the initial cervical length, the chosen threshold for intervention, and knowledge of natural history, it is possible to estimate when the next measurement should be performed. For example, if the measured cervical length is 36 mm and the threshold for intervention is 20 mm, then it is reasonable to wait 2 weeks to reassess cervical length, assuming the greatest velocity of cervical decline (8 mm/week). Using a mid-range estimate of cervical decline (5 mm/week), it would be reasonable to wait at least 3 weeks between ultrasound assessments. If the initial cervical length is greater than that, the interval between assessments could be longer. Minimum Interval of Time Between Cervical Assessments

Since the published rates of cervical decline in those destined to deliver preterm are quite small (1 to 8 mm/week)76–80 and fall within the 95% CI of interobserver and intraobserver variability (intraobserver repeatability coefficient of approximately ± 6 mm and the interobserver limits of agreement of approximately ± 10 mm),88 the interval should be at least 1 week, and 490 l MAY JOGC MAI 2011

Summary Statement

TRANSVAGINAL SONOGRAPHIC CERVICAL LENGTH ASSESSMENT IN ASYMPTOMATIC WOMEN AT LOW RISK

Cervical length is inversely related to the risk of preterm birth in asymptomatic women.34,47–49,52,54,57 The largest study of this relationship34 noted that when compared with women who had values above the 75th percentile of cervical length, those with a shorter cervix at 24 weeks had the following relative risks: approximately 4 if length was < 30 mm (25th percentile), 6 if < 26 mm (10th percentile), 9 if < 22 mm (5th percentile), and 14 if < 13 mm (1st percentile). However, the positive predictive values (6 to 44%) and sensitivities (47%) were poor in this low-risk population. Davies et al.,89 in a Canadian, prospective, blinded observational trial of 964 women (general obstetrical population), found a sensitivity of 57% and a specificity of 82% for preterm birth, using a 30 mm cut-off at 24 to 28 weeks. The positive predictive value for preterm birth (< 35 weeks) was only 4.5%, because preterm birth was infrequent. The authors concluded that using TV ultrasonographic cervical length to screen for preterm birth in a general obstetrical population was unwarranted. Also, no studies have shown that cervical cerclage is beneficial in women at low risk who have a short cervix.87,89,90 Because of the low incidence of preterm birth in this low-risk population34 routine screening of cervical length as a predictor of preterm birth in this population is not recommended.35 Recommendation

4.  Because of poor positive predictive values and sensitivities and lack of proven effective interventions, routine transvaginal cervical length assessment is not recommended in women at low risk. (II-2E)

Ultrasonographic Cervical Length Assessment in Predicting Preterm Birth in Singleton Pregnancies

TRANSVAGINAL SONOGRAPHIC CERVICAL LENGTH ASSESSMENT IN ASYMPTOMATIC WOMEN WITH A HISTORY OF SPONTANEOUS PRETERM BIRTH

Cervical length is a better predictor of preterm birth in women at increased risk, such as those with a history of spontaneous preterm birth, than in asymptomatic women at low risk.35,49,87,91–95 In studies of women with a history of preterm birth, using a cervical length cut-off of 25 to 30 mm to predict preterm birth < 37 weeks of gestation, sensitivity is 60% to 80%, positive predictive value is 55% to 70%, and negative predictive value is 89% to 94%. Thus, a long cervix (at least 25 to 30 mm) is reassuring and can help to reduce unnecessary and costly interventions, such as activity restriction, maternal transfer, steroids, and tocolytics. A study published in 2009 found that the gestational age at which the prior preterm delivery occurred affects the frequency and rate of cervical shortening in the current pregnancy. A prior spontaneous early preterm birth (< 24 weeks) puts women at a higher risk of cervical shortening. Women in this group also have a higher rate of cervical decline that begins at an earlier gestational age than women with a history of a later preterm birth (24 to 32 weeks).96 Summary Statement

3. Transvaginal sonography can be used to assess the risk of preterm birth in women with a history of spontaneous preterm birth and to differentiate those at higher and lower risk of preterm delivery. The gestational age of a prior preterm birth affects the cervical length in a future pregnancy. (II–2) TRANSVAGINAL SONOGRAPHIC CERVICAL LENGTH ASSESSMENT IN OTHER ASYMPTOMATIC WOMEN AT HIGH RISK

Transvaginal cervical length assessment has been found to be effective in predicting preterm birth in asymptomatic high-risk groups, including those with uterine anomalies,97 excisional cervical treatment for cervical intraepithelial neoplasia (LEEP and cone biopsy),23,98 and prior multiple dilatation and evacuation procedures (beyond 13 weeks of gestation).23,51,92,97–100 There is no evidence that cervical cerclage placement is beneficial in these women if they are found to have a short cervix on transvaginal ultrasound. Summary Statement

4. Cervical length measurement can be used to identify increased risk of preterm birth in asymptomatic women at < 24 weeks who have other risk factors for preterm birth (previous excisional treatment for

cervical dysplasia, uterine anomaly, or prior multiple dilatation and evacuation procedures beyond 13 weeks’ gestation). However, there is insufficient evidence to recommend specific management strategies, such as cerclage, in these women. (II-2) DIAGNOSIS OF SHORT CERVIX BEYOND 24 WEEKS’ GESTATION IN ASYMPTOMATIC WOMEN AT HIGH RISK

The finding of a short cervix in asymptomatic women at increased risk of preterm birth can be divided into 2 categories according to when the diagnosis is made: < 24 weeks of gestation and ≥ 24 weeks of gestation. No randomized trials have evaluated specific management strategies for women at > 24 weeks with a short cervix; however, having this information may help with empiric management of these women. This may include altering activity level, work, and travel, increased surveillance, relocation close to a tertiary care centre, and istration of corticosteroids. Summary Statement

5. No specific randomized trials have evaluated any interventions in asymptomatic women at > 24 weeks’ gestation who are at increased risk of preterm birth (e.g., those who have a history of prior spontaneous preterm birth, previous excisional treatment for cervical dysplasia, uterine anomaly, or prior multiple dilatation and evacuation procedures beyond 13 weeks’ gestation) and who have a short cervical length. This information may help with empiric management of these women, including reduction of activity level, work, or travel, relocation, increased surveillance, and istration of corticosteroids. (III) ULTRASONOGRAPHIC CERVICAL LENGTH ASSESSMENT IN CLINICAL MANAGEMENT Ultrasonographic Cervical Assessment in Women Suspected of Being in Preterm Labour

The use of cervical length measurement has been studied in women presenting with suspected preterm labour. The goal of these studies was to attempt to differentiate between women who were likely to deliver preterm and those who were not. This information may help women avoid unnecessary interventions of limited or unproven value, such as tocolysis, hospitalization, and activity restriction. Spontaneous preterm birth is unlikely if the cervical length is ≥ 30 mm.39,101–103 Fuchs et al.104 showed that a cervical length of < 15 mm in a population presenting with painful contractions (< 32 MAY JOGC MAI 2011 l 491

SOGC CLINICAL PRACTICE GUIDELINE

weeks) had a 5.5-fold increased risk (44%) of delivery within a week, and those with a cervical length of ≥ 15 mm had a 2% risk.104 In other studies, delivery occurred within 7 days of presentation in 37% of 43 women with cervical length < 15 mm,102 and a cervical length of < 20 mm had a 93.7% and 87.5% positive predictive value for preterm birth in primiparous and multiparous women respectively.105 In all these studies, the cervical length was an independent predictor of preterm delivery.102–105 In 2010, Sotiriadis et al.106 published a meta-analysis on the use of cervical length measurements in patients presenting with symptoms of preterm labour. They included prospective cohort and/or case–control studies that evaluated transvaginal ultrasonographic assessment of cervical length for the prediction of preterm birth in women with a singleton pregnancy and intact membranes (studies with < 20% premature rupture of membranes and multiples were included, however). Studies involving the use of tocolytics and/or prophylactic steroid istration were also included. They used a weighted analysis to determine test performance. The cumulative data suggest that the cervical length measurement in symptomatic women can be used to discriminate between those at higher and those at lower risk of preterm delivery, which may help to rationalize their management; however, there was considerable heterogeneity across the studies. Table 2 presents data from the study by Sotiriadis et al.106 On the basis of the weighted estimates, and using a pooled prevalence of 11.1% for birth within 1 week of presentation, Sotiriadis et al.106 calculated that the negative predictive values of 15 mm, 20 mm, and 25 mm would be 94.8%, 96.3%, and 95.8%, respectively. Use of Transvaginal Ultrasound to Stratify Women Presenting With Preterm Labour

In a prospective cohort study among several hospitals using different protocols for threatened preterm labour, the use of ultrasound assessment of cervical length appeared to shorten hospital stay without compromising patient care.107 In a small (N = 41) trial,108 women with threatened preterm labour were randomized to a control group, who received tocolytics and steroids in keeping with the hospital’s protocol, or to an assessment group who had cervical length measured by transvaginal ultrasound. Women in the assessment group who were found to have a cervical length of < 15 mm were given tocolytics and steroids. Those with cervical length of ≥15 mm were not given tocolytics and steroids. No babies in the group considered to be at low risk of preterm birth were born prematurely without a full course of antenatal corticosteroid therapy, and babies in this group had significantly lower rates of exposure to steroids and tocolytics. 492 l MAY JOGC MAI 2011

The results suggest that it may be safe to use ultrasonographic cervical length assessment to prevent unnecessary use of tocolytics and steroids.108 However, the small sample size of this study does not provide adequate power to assess uncommon outcomes such as preterm birth at < 34 weeks and to determine whether this approach could cause harm. A meta-analysis by Berghella et al.58 evaluated the efficacy of cervical length measurements to prevent preterm birth by asking whether the knowledge of ultrasonographic cervical length affected the rate of preterm birth.58 This was studied in 2 groups: those that presented in preterm labour and those with preterm rupture of membranes. Knowledge of TV ultrasonographic cervical length results was associated with a non-significant decrease in preterm birth at < 37 weeks (22.3% and 34.7%, respectively; RR 0.59; 95% CI 0.26 to 1.32). Delivery occurred at a later gestational age in the knowledge than in the no-knowledge group (mean difference 0.64 weeks; 95% CI 0.03 to 1.25). The authors concluded that there was insufficient evidence to recommend routine screening of asymptomatic or symptomatic pregnant women with transvaginal ultrasound. However, it should be noted that the total number of women in the study was small (total N = 290 in preterm labour, n = 92 in premature preterm rupture of membranes). Also, the study did not determine whether progesterone or cerclage was used, and it included clinical presentations in which neither of those interventions would likely be used. In summary, it appears that TV ultrasonography can be used to stratify risk in women presenting with preterm labour, and there is some evidence that suggests this can be done safely and with some benefit. Recommendation

5. In women presenting with suspected preterm labour, transvaginal sonographic assessment of cervical length may be used to help in determining who is at high risk of preterm delivery and may be helpful in preventing unnecessary intervention. It is unclear whether this information results in a reduced risk of preterm birth. (II-2B) Ultrasonographic Cervical Assessment in Women With Suspected Preterm Premature Rupture of Membranes

Preterm premature rupture of membranes conveys an increased risk of chorioamnionitis and preterm birth.27,28 In such circumstances, uterine contractions causing cervical change are difficult to assess because the digital cervical examination is associated with an increased risk

Ultrasonographic Cervical Length Assessment in Predicting Preterm Birth in Singleton Pregnancies

Table 2. Meta-analysis of the use of cervical length measurements (Sotiriadis et al.106) Performance based on a 15 mm threshold Outcome

Studies

n

Prevalence

Sens

Spec

LR+

LR−

PPV

NPV

< 48 hours

3

1266

7.1

71.1

86.6

5.92

0.35

28.8*

97.5*

< 7 days

6

1781

11.1

59.9

90.5

5.71

0.51

44.03*

94.7*

< 34 wks

4

429

18.18

46.2

93.7

4.31

0.63

62.2*

88.7*

Outcome

Studies

n

Prevalence

Sens

Spec

LR+

LR−

PPV

NPV

< 7 days

4

1263

9.3

75.4

79.6

3.74

0.33

27.6*

96.9*

< 34 wks

2

385

20.5

49.4

93.1

n/a

n/a

65*

88.5*

Outcome

Studies

n

Prevalence

Sens

Spec

LR+

LR−

PPV

NPV

< 7 days

4

856

9.7

78.3

70.8

2.81

0.36

22.3*

96.8*

< 34 wks

5

735

11.40

64.3

68.4

n/a

n/a

20.8*

93.7*

Performance based on a 20 mm threshold

Performance based on a 25 mm threshold

* Extrapolations based on unweighted data presented for each horizontal category Sens: sensitivity; Spec: specificity; LR: likelihood ratio; PPV: positive predictive value; NPV: negative predictive value.

of infection and should be postponed until labour is established. Several cohort studies have shown that the cervical length measured by TV predicts latency to delivery in preterm premature rupture of membranes.109,110 In a much smaller study, cervical length measurements by TP ultrasound did not correlate with latency duration to delivery.111 Transvaginal cervical length measurement in a randomized trial was not found to increase the risk of infection in patients with preterm premature rupture of membranes. This study did not find that cervical length had predictive value for latency. This is not consistent with the findings of another study.112 Summary Statement

6. Transvaginal ultrasound appears to be safe in preterm premature rupture of membranes, but its clinical predictive value is uncertain in this context. (II-2) The Use of Progesterone in Women With a Short Cervical Length by Ultrasonographic Assessment

Recent studies have evaluated the use of progesterone in patients with a short cervix to prevent preterm delivery. In a study by Fonseca et al.,83 250 women (24 to 34 weeks’ gestation) who were determined to have a cervical length of < 15 mm were randomized to either vaginal progesterone (200 mg each night) or placebo. The primary outcome was spontaneous delivery before 34 weeks. Delivery before 34 weeks of gestation was less frequent in the progesterone group than in the placebo group (19.2% vs. 34.4%; RR 0.56; 95% CI 0.36 to 0.86). However, there was no statistically significant reduction in neonatal morbidity (8.1% vs. 13.8%; RR 0.59; 95% CI 0.26 to 1.25; P = 0.17). There were no serious adverse events associated with the use of progesterone.83 In a secondary analysis of a randomized,

double-blind, placebo-controlled trial of progesterone to prevent preterm birth in patients with a history of preterm birth,113 the use of progesterone when cervical length was < 28 mm was associated with a reduction in preterm birth prior to 32 weeks (0% vs. 29.6%, P = 0.014), fewer NICU issions (15.8% vs. 51.9%, P = 0.016), and shorter NICU stays (1.1 vs. 16.5 days, P = 0.013). A recent randomized trial compared cerclage and 17 α-hydroxyprogesterone for short cervix (< 25 mm) in a high-risk population and showed no difference in rates of preterm birth; however, this study was small (N = 79) and underpowered, because recruitment was halted at the midpoint of the study. In a sub-analysis of that data set, it was shown that cerclage may be better if the cervix is < 15 mm.114 In 2009, the  United States Food and Drug istration declined approval of this use of progesterone, because of concerns about possible adverse effects, but in February 2011, intramuscular progesterone was approved for the prevention of preterm birth.115 Although progesterone supplementation in women  with a previous preterm birth  and a  short cervix appears promising,  more data are needed to better demonstrate benefit and a number of studies are in progress.116 A committee consensus could not be reached to recommend its use in this population. Ultrasonographic Cervical Length Assessment and Cervical Cerclage

Several studies have evaluated the value of cervical cerclage in women with ultrasonographically diagnosed short cervix. A prospective cohort study was the first to show benefits in those who had a cerclage versus those who had usual care, with significantly lower rates of prematurity and no fetal losses.84 Subsequently, 3 randomized trials had disparate findings, although their patient populations were different.87,90,117 A meta-analysis of patient level data of MAY JOGC MAI 2011 l 493

SOGC CLINICAL PRACTICE GUIDELINE

those 3 studies showed that in women with a history of spontaneous preterm birth and a cervical length < 25 mm before 24 weeks’ gestation, placement of a cervical cerclage was associated with a significant decrease in preterm birth < 35 weeks of gestation (from 39% to 23%).86 A recent National Institutes of Health-sponsored multicentre trial confirmed these findings, noting a significant reduction in preterm birth < 35 weeks and/or previable delivery in women with a prior spontaneous preterm birth and midtrimester transvaginal cervical length < 25 mm, with findings most pronounced when cervical length was < 15mm.118 In patients with membrane prolapse at or beyond the external os of the cervix, there may be benefit to emergency cerclage compared with conservative management. Several retrospective studies119–122 suggest that pregnancy outcomes are better with emergency cerclage, and a small randomized trial82 also showed significant prolongation of pregnancy and reduced preterm delivery rates. Recommendations

6. In asymptomatic women with a history of spontaneous preterm birth and an ultrasonographically diagnosed short cervical length (< 25 mm) prior to 24 weeks of gestation, cervical cerclage should be considered to reduce the risk of preterm birth. (I-B) 7. In all asymptomatic women who present with membranes at or protruding past the external cervical os, an emergency cerclage should be considered to reduce the risk of preterm delivery. (I-B) Ultrasonographic Cervical Length Assessment After Cervical Cerclage Placement

There is limited information on the use of ultrasonographic cervical length assessment after cervical cerclage placement. Studies involve a combination of both elective and emergency cerclage, which can confuse the results. It is unclear whether ultrasound assessment is superior to clinical examination in determining the need for cerclage.123 Cervical length significantly increases post cerclage,124–126 but the overall length post cerclage does not seem to predict preterm birth.124,126 There is some evidence that absent or short cervical length above the cerclage123,125 or the appearance of funnelling to the level of the cerclage123,126 (at 24 to 28 weeks) increases the risk of preterm delivery. In particular, 2 studies have shown that funnelling down to the cerclage has a 50% risk of preterm premature rupture of membranes.123,126 Progressive shortening may also indicate an increased risk of preterm birth, but the difference between women who deliver preterm and those who deliver at term, is slight.123–126 There is considerable disagreement about when to initiate, how frequently to reassess, and when to stop performing transvaginal cervical length assessments after cerclage, and its 494 l MAY JOGC MAI 2011

value is therefore in doubt.123,124 O’Brien et al.126 empirically suggest every 2 to 4 weeks post cerclage placement until 28 weeks of gestation, whereas other authors suggest that cervical length shortening after 28 weeks is most diagnostic of preterm delivery.123,124 Although the assessment of the cervix may help identify those at increased risk of preterm birth, it cannot predict when it will occur. Summary Statement

7. It is unclear whether ultrasonographic cervical length assessment has significant advantages over clinical examination alone after elective or emergency cervical cerclage placement, although some signs, such as funnelling to the stitch, are associated with a high risk of preterm premature rupture of membranes. There is no consensus on the frequency or timing of ultrasonographic cervical length assessment post cerclage. (II-2) Serial Ultrasonographic Cervical Length Assessment Compared With Clinical Assessment of Need for Elective Cerclage Placement

Several authors have noted that if a policy of surveillance is used in women at high risk, with urgent or emergency cerclage for those who develop a short cervix, approximately 60% of those patients would not have required cerclage. In small studies, this approach of using cervical cerclage in only women with a short cervix had perinatal outcomes equivalent to those in women who had elective cerclage.117,127 The CIRCLE trial128 was a randomized trial of either serial TV ultrasound measurements with cerclage when cervical length was < 20 mm or clinician-based assessment of need for elective cerclage. Its findings, published in 2009, were not consistent with those of earlier studies: the TV ultrasound group was found to have significantly more interventions, including cerclage, hospitalization, and progesterone use with no difference in outcomes.128 Summary Statement

8. It is unclear whether a policy of cervical length surveillance is equivalent to clinical assessment of the need for elective cerclage in those at risk of preterm delivery. (I) ULTRASONOGRAPHIC CERVICAL LENGTH COMBINED WITH FETAL FIBRONECTIN IN THE PREDICTION OF PRETERM BIRTH

Multiple studies have considered association between ultrasonographic assessment of cervical length and the presence of fetal fibronectin. It appears they are independently associated with an increased risk of preterm birth although there is some overlap.42,50,129–132 Direct comparison of these tests can be difficult. Depending

Ultrasonographic Cervical Length Assessment in Predicting Preterm Birth in Singleton Pregnancies

on the threshold of cervical length or fetal fibronectin concentration used, the sensitivities and specificities will vary. The definitions of preterm birth and/or the outcome of interest (delivery within a certain interval of time) differ from study to study. These tests have a low sensitivity in a low-risk population and should be used in women at high risk rather than for general screening.133 Study findings vary, so it is unclear whether one is more predictive than the other.129,134,135 The combination of both (sequentially or in tandem) may be more effective than using one alone, but again conflicting results have been found.31,50,129,133–137 Whether these screening strategies result in reduced interventions and use of resources remains uncertain.138–140 Summary Statement

9. Ultrasonographic cervical length assessment and fetal fibronectin appear to be similar in predictive ability, and the combination of both in a high-risk population may be of value. However, further research is needed in this area. (II-2) CONCLUSION

Ultrasonographic cervical measurement is a safe and effective technique to predict increased risk of preterm delivery in selected women. The transvaginal route appears to be the most well studied and is acceptable to women; however, the transperineal route can also be used if the patient declines the transvaginal route. It can also be used to prevent unnecessary interventions in women at increased risk of preterm delivery if the result is reassuring. In contrast, routine prenatal transvaginal ultrasound screening of cervical length in low-risk populations is not ed by available evidence. Evidence from randomized trials s the recommendation of cerclage in patients with a prior preterm birth and a short cervix. The thresholds proposed vary from 15 mm to 28 mm. The use of progesterone in patients with a short cervix appears promising, but consensus recommendation awaits further evidence and/or analysis. Further evidence is also needed with respect to the utility of measuring fetal fibronectin in conjunction with measurements of cervical length. REFERENCES 1. Alexander GR, Kogan M, Bader D, Carlo W, Allen M, Mor J. US birth weight/gestational age-specific neonatal mortality: 1995–1997 rates for whites, hispanics, and blacks. Pediatrics 2003;111:e61-e66. 2. Behrman RE, Butler AS. Preterm birth: causes, consequences, and prevention. National Academies Press: Committee on Understanding Premature Birth and Assuring Healthy Outcomes, Board on Health Sciences Policy, Institute of Medicine of the National Academies; 2007. 3. Lawn JE, Cousens S, Zupan J. 4 million neonatal deaths: when? Where? Why? Lancet 2005;365:891–900.

4. McCormick MC. The contribution of low birth weight to infant mortality and childhood morbidity. N Engl J Med 1985;312:82–90. 5. Berkowitz GS, Papiernik E. Epidemiology of preterm birth. Epidemiol Rev 1993;15:414–43. 6. Joseph KS, Kramer MS, Marcoux S, Ohlsson A, Wen SW, Allen A, et al. Determinants of preterm birth rates in Canada from 1981 through 1983 and from 1992 through 1994. N Engl J Med 1998;339:1434–9. 7. Births 2005. Ottawa: Statistics Canada; 2007. Cat no 84F0210XIE. 2007. 8. Allen VM, Wilson RD. Pregnancy outcomes after assisted reproductive technology. t SOGC-CFAS Guideline no. 173, March 2007. J Obstet Gynaecol Can 2007;28:220–33. 9. Public Health Agency of Canada. Canadian perinatal health report. 2008 ed. Ottawa: Health Canada; 2009. Cat no HP10–12/2008E. 10. Haas DM. Preterm birth. Clin Evid 2006;1966–85. 11. King JF, Flenady VJ, Papatsonis DN, Dekker GA, Carbonne B. Calcium channel blockers for inhibiting preterm labour. Cochrane Database Syst Rev 2003;CD002255. 12. Papatsonis DN, Van Geijn HP, Ader HJ, Lange FM, Bleker OP, Dekker GA. Nifedipine and ritodrine in the management of preterm labor: a randomized multicenter trial. Obstet Gynecol 1997;90:230–4. 13. King J, Flenady V, Cole S, Thornton S. Cyclo-oxygenase (COX) inhibitors for treating preterm labour. Cochrane Database Syst Rev 2005;CD001992. 14. Loe SM, Sanchez-Ramos L, Kaunitz AM. Assessing the neonatal safety of indomethacin tocolysis: a systematic review with meta-analysis. Obstet Gynecol 2005;106:173–9. 15. Smith GN, Walker MC, Ohlsson A, O’Brien K, Windrim R. Randomized double-blind placebo-controlled trial of transdermal nitroglycerin for preterm labor. Am J Obstet Gynecol 2007;196:37–8. 16. Duckitt K, Thornton S. Nitric oxide donors for the treatment of preterm labour. Cochrane Database Syst Rev 2002;CD002860. 17. Papatsonis D, Flenady V, Cole S, Liley H. Oxytocin receptor antagonists for inhibiting preterm labour. Cochrane Database Syst Rev 2005;CD004452. 18. Anotayanonth S, Subhedar NV, Garner P, Neilson JP, Harigopal S. Betamimetics for inhibiting preterm labour. Cochrane Database Syst Rev 2004;CD004352. 19. Crowther CA, Hiller JE, Doyle LW. Magnesium sulphate for preventing preterm birth in threatened preterm labour. Cochrane Database Syst Rev 2002;CD001060. 20. Caughey AB. Definition, incidence, significance and demographic characteristics of preterm birth. UpToDate; 2007. Available at: http://www.uptodate.com/contents/demographic-factors-inpreterm-birth. Accessed December 17, 2007. 21. Lockwood CJ. Overview of preterm labor and delivery. UpToDate 2007. Available at: http://www.uptodate.com/contents/fetal-fibronectin-forprediction-of-preterm-labor-and-delivery. Accessed December 17, 2007. 22. Robinson JN, Norwitz E. Risk factors for preterm labor and delivery. UpToDate 2007. Available at: http://www.uptodate.com/contents/ risk-factors-for-preterm-labor-and-delivery. Accessed December 17, 2007. 23. Crane JM, Delaney T, Hutchens D. Transvaginal ultrasonography in the prediction of preterm birth after treatment for cervical intraepithelial neoplasia. Obstet Gynecol 2006;107:37–44. 24. Arbyn M, Kyrgiou M, Simoens C, Raifu AO, Koliopoulos G, MartinHirsch P, et al. Perinatal mortality and other severe adverse pregnancy outcomes associated with treatment of cervical intraepithelial neoplasia: meta-analysis. BMJ 2008;337:a1284. 25. Jolley JA, Wing DA. Pregnancy management after cervical surgery. Curr Opin Obstet Gynecol 2008;20:528–33. 26. Dasanayake AP, Gennaro S, Hendricks-Munoz KD, Chhun N. Maternal periodontal disease, pregnancy, and neonatal outcomes. MCN Am J Matern Child Nurs 2008;33:45–9.

MAY JOGC MAI 2011 l 495

SOGC CLINICAL PRACTICE GUIDELINE

27. Yudin MH, Money DM; SOGC Infectious Diseases Committee. Screening and management of bacterial vaginosis in pregnancy. SOGC Clinical Practice Guideline no. 211, August 2008. J Obstet Gynaecol Can 2008;30:702–16. 28. Rodrigues T, Rocha L, Barros H. Physical abuse during pregnancy and preterm delivery. Am J Obstet Gynecol 2008;198:171–6. 29. Viswanathan M, Siega-Riz AM, Moos MK, Deierlein A, Mumford S, Knaack J, et al. Outcomes of maternal weight gain. Evid Rep Technol Assess (Full Rep) 2008;1–223. 30. Berghella V, Hayes E, Visintine J, Baxter JK. Fetal fibronectin testing for reducing the risk of preterm birth. Cochrane Database Syst Rev 2008;CD006843. 31. Goldenberg RL, Iams JD, Mercer BM, Meis PJ, Moawad A, Das A, et al. The Preterm Prediction Study: toward a multiple-marker test for spontaneous preterm birth. Am J Obstet Gynecol 2001;185:643–51. 32. Lockwood CJ, Kuczynski E. Markers of risk for preterm delivery. J Perinat Med 1999;27:5–20. 33. Tekesin I, Eberhart LH, Schaefer V, Wallwiener D, Schmidt S. Evaluation and validation of a new risk score (CLEOPATRA score) to predict the probability of premature delivery for patients with threatened preterm labor. Ultrasound Obstet Gynecol 2005;26:699–706. 34. Iams JD, Goldenberg RL, Meis PJ, Mercer BM, Moawad A, Das A, et al. The length of the cervix and the risk of spontaneous premature delivery. National Institute of Child Health and Human Development Maternal Fetal Medicine Unit Network. N Engl J Med 1996;334:567–72. 35. Grimes-Dennis J, Berghella V. Cervical length and prediction of preterm delivery. Curr Opin Obstet Gynecol 2007;19:191–5. 36. Van den Hof MC, Crane JM. Ultrasound cervical assessment in predicting preterm birth. SOGC Clinical Practice Guideline no. 102, May 2001. J Soc Obstet Gynaecol Can 2001;35:418–21. 37. Johnson JR, Iams JD. Prediction of prematurity by transvaginal ultrasound assessment of the cervix. UpToDate 2007. Available at: http://www.uptodate.com/contents/cervical-insufficiency. Accessed December 17, 2007. 38. Leitich H, Brunbauer M, Kaider A, Egarter C, Husslein P. Cervical length and dilatation of the internal cervical os detected by vaginal ultrasonography as markers for preterm delivery: a systematic review. Am J Obstet Gynecol 1999;181:1465–72.

45. Leitich H, Kaider A. Fetal fibronectin—how useful is it in the prediction of preterm birth? BJOG 2003;110(Suppl 20):66–70. 46. Skoll A, St. Louis P, Delisle M-F, Amira N. The evaluation of the fetal fibronectin test for prediction of preterm delivery in symptomatic patients. J Obstet Gynaecol Can 2006;28:206–13. 47. Berghella V, Kuhlman K, Weiner S, Texeira L, Wapner RJ. Cervical funneling: sonographic criteria predictive of preterm delivery. Ultrasound Obstet Gynecol. 1997;10:161–6. 48. Berghella V, Roman A, Daskalakis C, Ness A, Baxter JK. Gestational age at cervical length measurement and incidence of preterm birth. Obstet Gynecol 2007;110:311–17. 49. Crane JM, Hutchens D. Transvaginal sonographic measurement of cervical length to predict preterm birth in asymptomatic women at increased risk: a systematic review. Ultrasound Obstet Gynecol 2008;31:579–87. 50. Goldenberg RL, Iams JD, Das A, Mercer BM, Meis PJ, Moawad AH, et al. The Preterm Prediction Study: sequential cervical length and fetal fibronectin testing for the prediction of spontaneous preterm birth. National Institute of Child Health and Human Development MaternalFetal Medicine Units Network. Am J Obstet Gynecol 2000;182:636–43. 51. Guzman ER, Walters C, Ananth CV, O’Reilly-Green C, Benito CW, Palermo A, et al. A comparison of sonographic cervical parameters in predicting spontaneous preterm birth in high-risk singleton gestations. Ultrasound Obstet Gynecol 2001;18:204–10. 52. Heath VC, Southall TR, Souka AP, Elisseou A, Nicolaides KH. Cervical length at 23 weeks of gestation: prediction of spontaneous preterm delivery. Ultrasound Obstet Gynecol 1998;12:312–7. 53. Owen J. Evaluation of the cervix by ultrasound for the prediction of preterm birth. Clin Perinatol 2003;30:735–55. 54. Ozdemir I, Demirci F, Yucel O, Erkorkmaz U. Ultrasonographic cervical length measurement at 10–14 and 20–24 weeks gestation and the risk of preterm delivery. Eur J Obstet Gynecol Reprod Biol 2007;130:176–9. 55. Cicero S, Skentou C, Souka A, To MS, Nicolaides KH. Cervical length at 22–24 weeks of gestation: comparison of transvaginal and transperinealtranslabial ultrasonography. Ultrasound Obstet Gynecol 2001;17:335–40. 56. Yazici G, Yildiz A, Tiras MB, Arslan M, Kanik A, Oz U. Comparison of transperineal and transvaginal sonography in predicting preterm delivery. J Clin Ultrasound 2004;32:225–30. 57. Andersen HF, Nugent CE, Wanty SD, Hayashi RH. Prediction of risk for preterm delivery by ultrasonographic measurement of cervical length. Am J Obstet Gynecol 1990;163:859–67.

39. Vendittelli F, Volumenie J. Transvaginal ultrasonography examination of the uterine cervix in hospitalised women undergoing preterm labour. Eur J Obstet Gynecol Reprod Biol 2000;90:3–11.

58. Berghella V, Baxter JK, Hendrix NW. Cervical assessment by ultrasound for preventing preterm delivery. Cochrane Database Syst Rev 2009;CD007235.

40. Honest H, Bachmann LM, Coomarasamy A, Gupta JK, Kleijnen J, Khan KS. Accuracy of cervical transvaginal sonography in predicting preterm birth: a systematic review. Ultrasound Obstet Gynecol 2003;22:305–22.

59. Jackson GM, Ludmir J, Bader TJ. The accuracy of digital examination and ultrasound in the evaluation of cervical length. Obstet Gynecol 1992;79:214–8.

41. Iams JD. Prediction and early detection of preterm labor. Obstet Gynecol 2003;101:402–12. 42. Smith V, Devane D, Begley CM, Clarke M, Higgins S. A systematic review and quality assessment of systematic reviews of fetal fibronectin and transvaginal length for predicting preterm birth. Eur J Obstet Gynecol Reprod Biol 2007;133:134–42.

60. Sonek JD, Iams JD, Blumenfeld M, Johnson F, Landon M, Gabbe S. Measurement of cervical length in pregnancy: comparison between vaginal ultrasonography and digital examination. Obstet Gynecol 1990;76:172–5. 61. Berghella V, Tolosa JE, Kuhlman K, Weiner S, Bolognese RJ, Wapner RJ. Cervical ultrasonography compared with manual examination as a predictor of preterm delivery. Am J Obstet Gynecol 1997;177:723–30.

43. Goldenberg RL, Iams JD, Mercer BM, Meis PJ, Moawad AH, Copper RL, et al. The preterm prediction study: the value of new vs standard risk factors in predicting early and all spontaneous preterm births. NICHD MFMU Network. Am J Public Health 1998;88:233–8.

62. Gomez R, Galasso M, Romero R, Mazor M, Sorokin Y, Goncalves L, et al. Ultrasonographic examination of the uterine cervix is better than cervical digital examination as a predictor of the likelihood of premature delivery in patients with preterm labor and intact membranes. Am J Obstet Gynecol 1994;171:956–64.

44. Honest H, Bachmann LM, Gupta JK, Kleijnen J, Khan KS. Accuracy of cervicovaginal fetal fibronectin test in predicting risk of spontaneous preterm birth: systematic review. BMJ 2002;325:301.

63. Onderoglu LS. Digital examination and transperineal ultrasonographic measurement of cervical length to assess risk of preterm delivery. Int J Gynaecol Obstet 1997;59:223–8.

496 l MAY JOGC MAI 2011

Ultrasonographic Cervical Length Assessment in Predicting Preterm Birth in Singleton Pregnancies

64. Volumenie JL, Luton D, De SM, Sibony O, Blot P, Oury JF. Ultrasonographic cervical length measurement is not a better predictor of preterm delivery than digital examination in a population of patients with idiopathic preterm labor. Eur J Obstet Gynecol Reprod Biol 2004;117:33–7. 65. Andersen HF, Karimi A, Sakala EP, Kalugdan R. Prediction of cervical cerclage outcome by endovaginal ultrasonography. Am J Obstet Gynecol 1994;171:1102–6. 66. To MS, Skentou C, Cicero S, Nicolaides KH. Cervical assessment at the routine 23-weeks’ scan: problems with transabdominal sonography. Ultrasound Obstet Gynecol 2000;15:292–6. 67. Raungrongmorakot K, Tanmoun N, Ruangvutilert P, Boriboonhirunsarn D, Tontisirin P, Butsansee W. Correlation of uterine cervical length measurement from transabdominal, transperineal and transvaginal ultrasonography. J Med Assoc Thai 2004;87:326–32. 68. Braithwaite JM, Economides DL. Acceptability by patients of transvaginal sonography in the elective assessment of the first-trimester fetus. Ultrasound Obstet Gynecol 1997;9:91–3. 69. Kurtzman JT, Goldsmith LJ, Gall SA, Spinnato JA. Transvaginal versus transperineal ultrasonography: a blinded comparison in the assessment of cervical length at midgestation. Am J Obstet Gynecol 1998;179:852–7. 70. Rosati P, Guariglia L. Acceptability of early transvaginal or abdominal sonography in the first half of pregnancy. Arch Gynecol Obstet 2000;264:80–3. 71. Carr DB, Smith K, Parsons L, Chansky K, Shields LE. Ultrasonography for cervical length measurement: agreement between transvaginal and translabial techniques. Obstet Gynecol 2000;96:554–8. 72. Owen J, Neely C, Northen A. Transperineal versus endovaginal ultrasonographic examination of the cervix in the midtrimester: a blinded comparison. Am J Obstet Gynecol 1999;181:780–3. 73. Cook CM, Ellwood DA. A longitudinal study of the cervix in pregnancy using transvaginal ultrasound. Br J Obstet Gynaecol 1996;103:16–8. 74. Smith CV, Anderson JC, Matamoros A, Rayburn WF. Transvaginal sonography of cervical width and length during pregnancy. J Ultrasound Med 1992;11:465–7. 75. Tongsong T, Kamprapanth P, Pitaksakorn J. Cervical length in normal pregnancy as measured by transvaginal sonography. Int J Gynaecol Obstet 1997;58:313–5. 76. Carvalho MH, Bittar RE, Brizot ML, Maganha PP, Borges da Fonseca ES, et al. Cervical length at 11–14 weeks’ and 22–24 weeks’ gestation evaluated by transvaginal sonography, and gestational age at delivery. Ultrasound Obstet Gynecol 2003;21:135–9. 77. Liabsuetrakul T, Suntharasaj T, Suwanrath C, Leetanaporn R, Rattanaprueksachart R, Tuntiseranee P. Serial translabial sonographic measurement of cervical dimensions between 24 and 34 weeks’ gestation in pregnant Thai women. Ultrasound Obstet Gynecol 2002;20:168–73. 78. Dilek TU, Yazici G, Gurbuz A, Tasdelen B, Gulhan S, Dilek B, et al. Progressive cervical length changes versus single cervical length measurement by transvaginal ultrasound for prediction of preterm delivery. Gynecol Obstet Invest 2007;64:175–9. 79. Guzman ER, Mellon C, Vintzileos AM, Ananth CV, Walters C, Gipson K. Longitudinal assessment of endocervical canal length between 15 and 24 weeks’ gestation in women at risk for pregnancy loss or preterm birth. Obstet Gynecol 1998;92:31–7. 80. Naim A, Haberman S, Burgess T, Navizedeh N, Minkoff H. Changes in cervical length and the risk of preterm labor. Am J Obstet Gynecol 2002;186:887–9. 81. Yoshizato T, Obama H, Nojiri T, Miyake Y, Miyamoto S, Kawarabayashi T. Clinical significance of cervical length shortening before 31 weeks’ gestation assessed by longitudinal observation using transvaginal ultrasonography. J Obstet Gynaecol Res 2008;34:805–11.

82. Althuisius SM, Dekker GA, Hummel P, van Geijn HP. Cervical incompetence prevention randomized cerclage trial: emergency cerclage with bed rest versus bed rest alone. Am J Obstet Gynecol 2003;189:907–10. 83. Fonseca EB, Celik E, Parra M, Singh M, Nicolaides KH. Progesterone and the risk of preterm birth among women with a short cervix. N Engl J Med 2007;357:462–9. 84. Heath VC, Souka AP, Erasmus I, Gibb DM, Nicolaides KH. Cervical length at 23 weeks of gestation: the value of Shirodkar suture for the short cervix. Ultrasound Obstet Gynecol 1998;12:318–22. 85. Meis PJ, Goldenberg RL, Mercer BM, Iams JD, Moawad AH, Miodovnik M, et al. The preterm prediction study: risk factors for indicated preterm births. Maternal-Fetal Medicine Units Network of the National Institute of Child Health and Human Development. Am J Obstet Gynecol 1998;178:562–7. 86. Berghella V, Odibo AO, To MS, Rust OA, Althuisius SM. Cerclage for short cervix on ultrasonography: meta-analysis of trials using individual patient-level data. Obstet Gynecol 2005;106:181–9. 87. To MS, Alfirevic Z, Heath VC, Cicero S, Cacho AM, Williamson PR, et al. Cervical cerclage for prevention of preterm delivery in women with short cervix: randomised controlled trial. Lancet 2004;363:1849–53. 88. Valentin L, Bergelin I. Intra- and interobserver reproducibility of ultrasound measurements of cervical length and width in the second and third trimesters of pregnancy. Ultrasound Obstet Gynecol 2002;20:256–62. 89. Davies G, Ottenhof C, Woodman M, Farley A, Julien N, Van VD, et al. Cervix length and relaxin as predictors of preterm birth. J Obstet Gynaecol Can 2008;30:1124–31. 90. Rust OA, Atlas RO, Jones KJ, Benham BN, Balducci J. A randomized trial of cerclage versus no cerclage among patients with ultrasonographically detected second-trimester preterm dilatation of the internal os. Am J Obstet Gynecol 2000;183:830–5. 91. Owen J, Yost N, Berghella V, Thom E, Swain M, Dildy GA III, et al. Mid-trimester endovaginal sonography in women at high risk for spontaneous preterm birth. JAMA 2001;286:1340–8. 92. Crane JM, Hutchens D. Use of transvaginal ultrasonography to predict preterm birth in women with a history of preterm birth. Ultrasound Obstet Gynecol 2008;32:640–5. 93. To MS, Palaniappan V, Skentou C, Gibb D, Nicolaides KH. Elective cerclage vs. ultrasound-indicated cerclage in high-risk pregnancies. Ultrasound Obstet Gynecol 2002;19:475–7. 94. Andrews WW, Copper R, Hauth JC, Goldenberg RL, Neely C, Dubard M. Second-trimester cervical ultrasound: associations with increased risk for recurrent early spontaneous delivery. Obstet Gynecol 2000;95:222–6. 95. Durnwald , Walker H, Lundy JC, Iams JD. Rates of recurrent preterm birth by obstetrical history and cervical length. Am J Obstet Gynecol 2005;193:1170–4. 96. Szychowski JM, Owen J, Hankins G, Iams J, Sheffield J, Perez-Delboy A, et al. Timing of mid-trimester cervical length shortening in high-risk women. Ultrasound Obstet Gynecol 2009;33:70–5. 97. Airoldi J, Berghella V, Sehdev H, Ludmir J. Transvaginal ultrasonography of the cervix to predict preterm birth in women with uterine anomalies. Obstet Gynecol 2005;106:553–6. 98. Berghella V, Pereira L, Gariepy A, Simonazzi G. Prior cone biopsy: prediction of preterm birth by cervical ultrasound. Am J Obstet Gynecol 2004;191:1393–7. 99. Visintine J, Berghella V, Henning D, Baxter J. Cervical length for prediction of preterm birth in women with multiple prior induced abortions. Ultrasound Obstet Gynecol 2008;31:198–200.

MAY JOGC MAI 2011 l 497

SOGC CLINICAL PRACTICE GUIDELINE

100. Berghella V, Daly SF, Tolosa JE, DiVito MM, Chalmers R, Garg N, et al. Prediction of preterm delivery with transvaginal ultrasonography of the cervix in patients with high-risk pregnancies: does cerclage prevent prematurity? Am J Obstet Gynecol 1999;181:809–15.

117. Althuisius SM, Dekker GA, Hummel P, Bekedam DJ, van Geijn HP. Final results of the Cervical Incompetence Prevention Randomized Cerclage Trial (CIPRACT): therapeutic cerclage with bed rest versus bed rest alone. Am J Obstet Gynecol 2001;185:1106–12.

101. Crane JM, Van den Hof M, Armson BA, Liston R. Transvaginal ultrasound in the prediction of preterm delivery: singleton and twin gestations. Obstet Gynecol 1997;90:357–63.

118. Owen J, Hankins G, Iams JD, Berghella V, Sheffield JS, Perez-Delboy A, et al. Multicenter randomized trial of cerclage for preterm birth prevention in high-risk women with shortened midtrimester cervical length. Am J Obstet Gynecol 2009;201:375–8.

102. Tsoi E, Akmal S, Rane S, Otigbah C, Nicolaides KH. Ultrasound assessment of cervical length in threatened preterm labor. Ultrasound Obstet Gynecol 2003;21:552–5. 103. Tsoi E, Fuchs IB, Rane S, Geerts L, Nicolaides KH. Sonographic measurement of cervical length in threatened preterm labor in singleton pregnancies with intact membranes. Ultrasound Obstet Gynecol 2005;25:353–6.

119. Stupin JH, David M, Siedentopf JP, Dudenhausen JW. Emergency cerclage versus bed rest for amniotic sac prolapse before 27 gestational weeks. A retrospective, comparative study of 161 women. Eur J Obstet Gynecol Reprod Biol 2008;139:32–7. 120. Wong GP, Farquharson DF, Dansereau J. Emergency cervical cerclage: a retrospective review of 51 cases. Am J Perinatol 1993;10:341–47.

104. Fuchs IB, Henrich W, Osthues K, Dudenhausen JW. Sonographic cervical length in singleton pregnancies with intact membranes presenting with threatened preterm labor. Ultrasound Obstet Gynecol 2004;24:554–7.

121. Daskalakis G, Papantoniou N, Mesogitis S, Antsaklis A. Management of cervical insufficiency and bulging fetal membranes. Obstet Gynecol 2006;107:221–6.

105. Daskalakis G, Thomakos N, Hatziioannou L, Mesogitis S, Papantoniou N, Antsaklis A. Cervical assessment in women with threatened preterm labor. J Matern Fetal Neonatal Med 2005;17:309–12.

122. Olatunbosun OA, al-Nuaim L, Turnell RW. Emergency cerclage compared with bed rest for advanced cervical dilatation in pregnancy. Int Surg 1995;80:170–4.

106. Sotiriadis A, Papatheodorou S, Kavvadias A, Makrydimas G. Transvaginal cervical length measurement for prediction of preterm birth in women with threatened preterm labor: a meta-analysis. Ultrasound Obstet Gynecol 2010;35:54–64.

123. Hedriana HL, Lanouette JM, Haesslein HC, McLean LK. Is there value for serial ultrasonographic assessment of cervical lengths after a cerclage? Am J Obstet Gynecol 2008;198:705–6.

107. Sanin-Blair J, Palacio M, Delgado J, Figueras F, Coll O, Cabero L, et al. Impact of ultrasound cervical length assessment on duration of hospital stay in the clinical management of threatened preterm labor. Ultrasound Obstet Gynecol 2004;24:756–60. 108. Alfirevic Z, len-Coward H, Molina F, Vinuesa , Nicolaides K. Targeted therapy for threatened preterm labor based on sonographic measurement of the cervical length: a randomized controlled trial. Ultrasound Obstet Gynecol 2007;29:47–50. 109. Rizzo G, Capponi A, Angelini E, Vlachopoulou A, Grassi C, Romanini C. The value of transvaginal ultrasonographic examination of the uterine cervix in predicting preterm delivery in patients with preterm premature rupture of membranes. Ultrasound Obstet Gynecol 1998;11:23–9. 110. Tsoi E, Fuchs I, Henrich W, Dudenhausen JW, Nicolaides KH. Sonographic measurement of cervical length in preterm prelabor amniorrhexis. Ultrasound Obstet Gynecol 2004;24:550–3. 111. Fischer RL, Austin JD. Cervical length measurement by translabial sonography in women with preterm premature rupture of membranes: can it be used to predict the latency period or peripartum maternal infection? J Matern Fetal Neonatal Med 2008;21:105–9. 112. Carlan SJ, Richmond LB, O’Brien WF. Randomized trial of endovaginal ultrasound in preterm premature rupture of membranes. Obstet Gynecol 1997;89:458–61. 113. Defranco EA, O’Brien JM, Adair CD, Lewis DF, Hall DR, Fusey S, et al. Vaginal progesterone is associated with a decrease in risk for early preterm birth and improved neonatal outcome in women with a short cervix: a secondary analysis from a randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol 2007;30:697–705. 114. Keeler SM, Kiefer D, Rochon M, Quinones JN, Novetsky AP, Rust O. A randomized trial of cerclage vs. 17 alpha-hydroxyprogesterone caproate for treatment of short cervix. J Perinat Med 2009;37:473–9. 115. FDA approves drug to reduce risk of preterm birth in at-risk pregnant women [press release]. United States Food and Drug istration; February 4, 2011. 116. Lee HJ, Park TC, Norwitz ER. Management of pregnancies with cervical shortening: a very short cervix is a very big problem. Rev Obstet Gynecol 2009;2:107–15.

498 l MAY JOGC MAI 2011

124. Dijkstra K, Funai EF, O’Neill L, Rebarber A, Paidas MJ, Young BK. Change in cervical length after cerclage as a predictor of preterm delivery. Obstet Gynecol 2000;96:346–50. 125. Groom KM, Shennan AH, Bennett PR. Ultrasound-indicated cervical cerclage: outcome depends on preoperative cervical length and presence of visible membranes at time of cerclage. Am J Obstet Gynecol 2002;187:445–9. 126. O’Brien JM, Hill AL, Barton JR. Funneling to the stitch: an informative ultrasonographic finding after cervical cerclage. Ultrasound Obstet Gynecol 2002;20:252–5. 127. Groom KM, Bennett PR, Golara M, Thalon A, Shennan AH. Elective cervical cerclage versus serial ultrasound surveillance of cervical length in a population at high risk for preterm delivery. Eur J Obstet Gynecol Reprod Biol 2004;112:158–61. 128. Simcox R, Seed PT, Bennett P, Teoh TG, Poston L, Shennan AH. A randomized controlled trial of cervical scanning vs history to determine cerclage in women at high risk of preterm birth (CIRCLE trial). Am J Obstet Gynecol 2009;200:623.e1–6. 129. Heath VC, Daskalakis G, Zagaliki A, Carvalho M, Nicolaides KH. Cervicovaginal fibronectin and cervical length at 23 weeks of gestation: relative risk of early preterm delivery. BJOG 2000;107:1276–81. 130. Iams JD, Goldenberg RL, Mercer BM, Moawad A, Thom E, Meis PJ, et al. The Preterm Prediction Study: recurrence risk of spontaneous preterm birth. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Am J Obstet Gynecol 1998;178:1035–40. 131. Goldenberg RL, Iams JD, Mercer BM, Meis P, Moawad A, Das A, et al. What we have learned about the predictors of preterm birth. Semin Perinatol 2003;27:185–93. 132. Hincz P, Wilczynski J, Kozarzewski M, Szaflik K. Two-step test: the combined use of fetal fibronectin and sonographic examination of the uterine cervix for prediction of preterm delivery in symptomatic patients. Acta Obstet Gynecol Scand 2002;81:58–63. 133. Iams JD, Goldenberg RL, Mercer BM, Moawad AH, Meis PJ, Das AF, et al. The preterm prediction study: can low-risk women destined for spontaneous preterm birth be identified? Am J Obstet Gynecol 2001;184:652–5.

Ultrasonographic Cervical Length Assessment in Predicting Preterm Birth in Singleton Pregnancies

134. Rizzo G, Capponi A, Arduini D, Lorido C, Romanini C. The value of fetal fibronectin in cervical and vaginal secretions and of ultrasonographic examination of the uterine cervix in predicting premature delivery for patients with preterm labor and intact membranes. Am J Obstet Gynecol 1996;175:1146–51. 135. Rozenberg P, Goffinet F, Malagrida L, Giudicelli Y, Perdu M, Houssin I, et al. Evaluating the risk of preterm delivery: a comparison of fetal fibronectin and transvaginal ultrasonographic measurement of cervical length. Am J Obstet Gynecol 1997;176:196–9. 136. Schmitz T, Maillard F, Bessard-Bacquaert S, Kayem G, Fulla Y, Cabrol D, et al. Selective use of fetal fibronectin detection after cervical length measurement to predict spontaneous preterm delivery in women with preterm labor. Am J Obstet Gynecol 2006;194:138–43. 137. Tsoi E, Akmal S, Geerts L, Jeffery B, Nicolaides KH. Sonographic measurement of cervical length and fetal fibronectin testing in threatened preterm labor. Ultrasound Obstet Gynecol 2006;27:368–72.

138. Grobman WA, Welshman EE, Calhoun EA. Does fetal fibronectin use in the diagnosis of preterm labor affect physician behavior and health care costs? A randomized trial. Am J Obstet Gynecol 2004;191:235–40. 139. Mozurkewich EL, Naglie G, Krahn MD, Hayashi RH. Predicting preterm birth: a cost-effectiveness analysis. Am J Obstet Gynecol 2000;182:1589–98. 140. Ness A, Visintine J, Ricci E, Berghella V. Does knowledge of cervical length and fetal fibronectin affect management of women with threatened preterm labor? A randomized trial. Am J Obstet Gynecol 2007;197:426–7. 141. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

MAY JOGC MAI 2011 l 499

SOGC CLINICAL PRACTICE GUIDELINE No. 260, June 2011

Ultrasound in Twin Pregnancies This Clinical Practice Guideline has been prepared by the Diagnostic Imaging Committee, reviewed by the Genetics Committee and the Maternal Fetal Medicine Committee, and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada.

Jo-Ann Johnson, MD, Calgary AB

PRINCIPAL AUTHORS

Melanie Pastuck, RN, Cochrane AB

Lucie Morin, MD, Outremont QC

MATERNAL FETAL MEDICINE COMMITTEE

Kenneth Lim, MD, Vancouver BC

Robert Gagnon, MD, Montreal QC

DIAGNOSTIC IMAGING COMMITTEE

Lynda Hudon, MD (Co-Chair), Montreal QC

Lucie Morin, MD (Chair), Outremont QC

Melanie Basso, RN, Vancouver BC

Kenneth Lim, MD (Co-Chair), Vancouver BC

Hayley Bos, MD, London ON

Stephen Bly, MD, Ottawa ON

Joan M. Crane, MD, St. John’s NL

Kimberly Butt, MD, Fredericton NB

Gregory Davies, MD, Kingston ON

Yvonne M. Cargill, MD, Ottawa ON

Marie- Delisle, MD, Vancouver BC

Gregory Davies, MD, Kingston ON

Savas Menticoglou, MD, Winnipeg MB

Nanette Denis, CRGS, Saskatoon SK

William Mundle, MD, Windsor ON

Robert Gagnon, MD, Montreal QC

Annie Ouellet, MD, Sherbrooke QC

Marja Anne Hietala-Coyle, RN, Halifax NS

Tracy Pressey, MD, Vancouver BC

Annie Ouellet, MD, Sherbrooke QC

Christy Pylypjuk, MD, Saskatoon SK

Shia Salem, MD, Toronto ON

Anne Roggensack, MD, Calgary AB

Vyta Senikas, MD, Ottawa ON

Frank Sanderson, MD, Saint John NB

SPECIAL CONTRIBUTOR

Disclosure statements have been received from all of the committees.

Jon Barrett, MD, Toronto ON

Sylvie Langlois, MD, Vancouver BC Lynn Murphy-Kaulbeck, MD, Moncton NB Nanette Okun, MD, Toronto ON

GENETICS COMMITTEE R. Douglas Wilson, MD (Chair), Calgary AB François Audibert, MD, Montreal QC Jo-Ann Brock, MD, Halifax NS June Carroll, MD, Toronto ON Lola Cartier, MSc, Montreal QC Alain Gagnon, MD, Vancouver BC

Abstract Objective: To review the literature with respect to the use of diagnostic ultrasound in the management of twin pregnancies. To make recommendations for the best use of ultrasound in twin pregnancies. Outcomes: Reduction in perinatal mortality and morbidity and short- and long-term neonatal morbidity in twin pregnancies. Optimization of ultrasound use in twin pregnancies.

Key Words: Ultrasound, twins, antenatal, prematurity, cervix, amniotic fluid

J Obstet Gynaecol Can 2011;33(6):643–656

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

JUNE JOGC JUIN 2011 l 643

SOGC CLINICAL PRACTICE GUIDELINE

Evidence: Published literature was retrieved through searches of PubMed and the Cochrane Library in 2008 and 2009 using appropriate controlled vocabulary (e.g., twin, ultrasound, cervix, prematurity) and key words (e.g., acardiac, twin, reversed arterial perfusion, twin-to-twin transfusion syndrome, amniotic fluid). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date restrictions. Studies were restricted to those with available English or French abstracts or text. Searches were updated on a regular basis and incorporated into the guideline to September 2009. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Values: The evidence collected was reviewed by the Diagnostic Imaging Committee of the Society of Obstetricians and Gynaecologists of Canada, with input from of the Maternal Fetal Medicine Committee and the Genetics Committee of the SOGC. The recommendations were made according to the guidelines developed by The Canadian Task Force on Preventive Health Care (Table 1). Benefits, harms, and costs: The benefit expected from this guideline is facilitation and optimization of the use of ultrasound in twin pregnancy. Summary Statements 1. There are insufficient data to make recommendations on repeat anatomical assessments in twin pregnancies. Therefore, a complete anatomical survey at each scan may not be needed following a complete and normal assessment. (III)

7. Although many methods of evaluating the level of amniotic fluid in twins (deepest vertical pocket, single pocket, amniotic fluid index) have been described, there is not enough evidence to suggest that one method is more predictive than the others of adverse pregnancy outcome. (II-3) 8. Referral to an appropriate high-risk pregnancy centre is indicated when complications unique to twins are suspected on ultrasound. (II-2) These complications include:

1.  Twin-to-twin transfusion syndrome



2.  Monoamniotic twins gestation



3.  Coned twins



4.  Twin reversed arterial perfusion sequence



5.  Single fetal death in the second or third trimester



6.  Growth discordance in monochorionic twins.

Recommendations 1. All patients who are suspected to have a twin pregnancy on first trimester physical examination or who are at risk (e.g., pregnancies resulting from assisted reproductive technologies) should have first trimester ultrasound performed. (II-2A) 2. Every attempt should be made to determine and report amnionicity and chorionicity when a twin pregnancy is identified. (II-2A) 3. Although the accuracy in confirmation of gestational age at the first and second trimester is comparable, dating should be done with first trimester ultrasound. (II-2A)

2. There are insufficient data to recommend a routine preterm labour surveillance protocol in of frequency, timing, and optimal cervical length thresholds. (II-2)

4. Beyond the first trimester, it is suggested that a combination of parameters rather than a single parameter should be used to confirm gestational age. (II-2C)

3. Singleton growth curves currently provide the best predictors of adverse outcome in twins and may be used for evaluating growth abnormalities. (III)

5. When twin pregnancy is the result of in vitro fertilization, accurate determination of gestational age should be made from the date of embryo transfer. (II-1A)

4. It is suggested that growth discordance be defined using either a difference (20 mm) in absolute measurement in abdominal circumference or a difference of 20% in ultrasound-derived estimated fetal weight. (II-2) 5. Although there is insufficient evidence to recommend a specific schedule for ultrasound assessment of twin gestation, most experts recommend serial ultrasound assessment every 2 to 3 weeks, starting at 16 weeks of gestation for monochorionic pregnancies and every 3 to 4 weeks, starting from the anatomy scan (18 to 22 weeks) for dichorionic pregnancies. (II-1) 6. Umbilical artery Doppler may be useful in the surveillance of twin gestations when there are complications involving the placental circulation or fetal hemodynamic physiology. (II-2)

ABBREVIATIONS

AC abdominal circumference CL cervical length EFW estimated fetal weight IUGR intrauterine growth restriction NPV negative predictive value NT nuchal translucency PPV positive predictive value TTTS twin-to-twin transfusion syndrome

644 l JUNE JOGC JUIN 2011

6. There is insufficient evidence to make a recommendation of which fetus (when discordant for size) to use to date a twin pregnancy. However, to avoid missing a situation of early intrauterine growth restriction in one twin, most experts agree that the clinician may consider dating pregnancy using the larger fetus. (III-C) 7. In twin pregnancies, aneuploidy screening using nuchal transluscency measurements should be offered. (II-2B) 8. Detailed ultrasound examination to screen for fetal anomalies should be offered, preferably between 18 and 22 weeks’ gestation, in all twin pregnancies. (II-2B) 9. When ultrasound is used to screen for preterm birth in a twin gestation, endovaginal ultrasound measurement of the cervical length should be performed. (II-2A) 10. Increased fetal surveillance should be considered when there is either growth restriction diagnosed in one twin or significant growth discordance. (II-2A) 11. Umbilical artery Doppler should not be routinely offered in uncomplicated twin pregnancies. (I-E) 12. For defining oligohydramnios and polyhydramnios, the ultrasonographer should use the deepest vertical pocket in either sac: oligohydramnios when < 2 cm and polyhydramnios when > 8 cm. (II-2B)

Ultrasound in Twin Pregnancies

Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well–designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action

* The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.100 † Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the The Canadian Task Force on Preventive Health Care.100

INTRODUCTION

T

his document was originally to be written for multiple pregnancy: twins and higher order multiples. However, since twins make up > 98% of all multiple pregnancies, and most published studies in the areas covered by this document are of twins and not higher order multiples, this guideline discusses only twins. As twins and higher order multiples were included in some studies, areas of this document are applicable to higher order multiples (e.g., determination of chorionicity and amnionicity), but others are applicable only to twin pregnancy. From the first trimester until delivery of the second fetus, the use of ultrasound in the management of twins is both ubiquitous and indispensable. Some of the most common clinical uses are determination of chorionicity, confirmation of gestational age, diagnosis of anomalies and complications, measurement of cervical length, and assessment of growth and amniotic fluid, placental localization, and fetal position for intrapartum management. Ultrasound is the only safe and reliable method for the diagnosis and assessment of twins, although improved detection of twins by routine sonographic examination has not led to a significant reduction in perinatal mortality. This may be due to lack of standardized protocols for the management of twins rather than the technology itself.1 In addition, protocols for increased surveillance in twins have not been investigated in a prospective, randomized

fashion or stratified according to chorionicity. Established guidelines for the type and frequency of testing are neither evidence-based nor uniformly followed. Nevertheless, despite the lack of level I evidence, virtually all twins are followed routinely with greater fetal surveillance than lowrisk singleton fetuses.2 SONOGRAPHIC DETERMINATION OF CHORIONICITY AND AMNIONICITY

Early and accurate determination of amnionicity and chorionicity is critical in the antenatal management of twins. Ideally, determination of chorionicity should be done in the first trimester. The management of structural anomalies, screening for and identification of aneuploidy, determination of the etiology of fetal growth and/or fluid discordance, early diagnosis of twin-to-twin transfusion syndrome, and the management of a surviving twin following intrauterine demise are examples of clinical management depending on chorionicity. The high mortality and morbidity of monoamniotic twins is well-documented, and early and intensive monitoring and intervention may improve outcomes.3–5 Before 10 weeks’ gestation, several sonographic findings can help determine chorionicity. These are (1) the number of observable gestational sacs, (2) the number of amniotic sacs within the chorionic cavity, and (3) the number of yolk sacs. JUNE JOGC JUIN 2011 l 645

SOGC CLINICAL PRACTICE GUIDELINE

1. Number of Gestational Sacs

The relationship between the number of gestational sacs and the number of embryonic heartbeats gives strong evidence of chorionicity. Each gestational sac forms its own placenta and chorion. Thus, the presence of 2 gestational sacs implies a dichorionic pregnancy, while a single gestational sac with 2 identified heartbeats implies a monochorionic twin pregnancy.6 2. Number of Amniotic Sacs Within the Chorionic Cavity

When diamniotic twins are identified before 10 weeks’ gestation, separate and distinct amnions may be visible on ultrasound. The amnion grows outward from the embryonic disk, and before 10 weeks the separate amnions of a diamniotic pregnancy will not have enlarged sufficiently to each other and create the inter-twin septum. Each single amnion is extremely thin and delicate and may be very difficult to see on transabdominal scanning; however, endovaginal imaging is often successful in differentiating separate amnions. 3. Number of Yolk Sacs

The number of yolk sacs may help diagnose the amnionicity.7 When 2 yolk sacs are seen in the extra-embryonal coeloma, the pregnancy will be diamniotic, while a single yolk sac will in most cases indicate monoamniotic twins. A single yolk sac seen when there are dual embryos should prompt a follow-up first trimester scan to definitively assign amnionicity. After 10 weeks, these sonographic signs are no longer present: gestational sacs are no longer distinctly separable, and the inter-twin membrane is formed. At this stage, a new set of sonographic findings will help determine amnionicity/chorionicity. These findings are (1) fetal genitalia, (2) placental number, (3) chorionic peak sign, and (4) membrane characteristics. The following order provides a logical sequence to determine chorionicity after 10 weeks of gestation. Of note, step 1 is not routinely used at the 10- to 14-week scan. 1. Sex Discordance

Phenotypic discordance identifies dichorionicity in all but the rarest cases. Concordance of phenotype does not rule out dichorionicity. 2. Number of Distinct Placentas

A single placental mass likely indicates monochorionicity, whereas the presence of 2 distinct, separate placentas identifies dichorionicity. Careful sonographic examination may help distinguish a single placenta from 2 placentas in abutment. 646 l JUNE JOGC JUIN 2011

3. Presence or Absence of the Chorionic Peak (also called the twin peak or lambda sign)

This represents a projecting zone of tissue of similar echotexture to the placenta, triangular in cross-section and wider at the chorionic surface of the placenta, extending into, and tapering to a point within, the intertwin membrane. The twin peak sign most often identifies dichorionicity.8,9 Monochorionicity can be determined by absence of the twin peak sign. 4. Inter-Twin Membrane Characteristics

The membrane of a dichorionic pregnancy consists of 2 layers of amnion and 2 layers of chorion. It is thicker and more reflective than the monochorionic diamniotic membrane. A membrane thickness of > 2 mm identifies dichorionicity with a positive predictive value of 95% and monochorionicity with a positive predictive value of 90% for a membrane thickness ≤ 2 mm.10 In the second trimester, the number of membranes may be counted, and if there are > 2, then dichorionicity is strongly suggested.11 If a membrane is not detected, careful evaluation to diagnose or exclude the possibility of monochorionic monoamniotic twinning is warranted. When an intertwin membrane is not visualized, possibilities include monoamniotic twinning, presence of a twin with complete oligohydramnios (stuck twin), or a diamniotic twin pregnancy in which the membrane is present but not seen owing to its thinness and orientation to the transducer. The most definitive sonographic finding in the diagnosis of monoamniotic twins is the demonstration of cord entanglement from the placental or umbilical origin. Colour Doppler may facilitate identification of this finding. Entanglement of limbs or observation of a limb circumscribing the other is suggestive of monoamnionicity. Failure to find the membrane between the 2 cord insertions in the placenta strongly s monoamnionicity. The use of transvaginal ultrasound is often a helpful adjunct to transabdominal scanning in identifying the membrane. Accuracy is improved when the assessment of chorionicity is undertaken before 14 weeks’ gestation rather than after 14 weeks. Stenhouse et al.8 in a study of 131 twin pregnancies found the sensitivity after 14 weeks was 77% for monochorionicity (10/13) and 90% for dichorionicity (26/29); before 14 weeks, accuracy was 99% for both groups (98/99 overall, 21 of 22 for monochorionics) combined. The twin peak sign alone in the second trimester can accurately identify the chorionicity in many cases, but that may not be sufficient to guide clinical management in

Ultrasound in Twin Pregnancies

all cases.9,12 Scardo et al.12 in their second trimester study found that the twin peak alone may not be sufficiently accurate. With a composite of second trimester ultrasound markers (number of placentas, fetal phenotype, membrane thickness, and twin peak sign), the sensitivity for correct identification of monochorionic pregnancies is reported at 91.7% with 97.3% specificity.12 In the second trimester, the twin peak sign becomes more difficult to visualize, and it disappears in about 7% of dichorionic pregnancies at 16 to 20 weeks. Therefore, the absence of the twin peak sign in the second or third trimester cannot exclude dichorionicity.12,13 Recommendations

1. All patients who are suspected to have a twin pregnancy on first trimester physical examination or who are at risk (e.g., pregnancies resulting from assisted reproductive technologies) should have first trimester ultrasound performed. (II-2A) 2. Every attempt should be made to determine and report amnionicity and chorionicity when a twin pregnancy is identified. (II-2A) DETERMINING GESTATIONAL AGE IN TWIN PREGNANCIES

The accurate confirmation of gestational age using ultrasound is essential to pregnancy management. It necessitates determining whether there is a high probability that the measurements of the fetus are appropriate for the estimated gestational age. Early studies of the reliability of ultrasound to confirm gestational age used menstrual dating in women with regular cycles; however, menstrual dating is fraught with biological variability. More recently, studies of this nature were done in IVF pregnancies, for which conception date is known precisely, but it is unclear whether this will work as well with natural conceptions. The literature on gestational age confirmation is also not specific to multiple pregnancies, and in general these studies were a mixture of singletons, twins, and triplets, with the vast majority of subjects being singleton.14–17 Studies assessing the benefits of confirmation of gestational age by ultrasound have been published,18 but with singleton not twin pregnancies. A comprehensive and critical review of this topic is well beyond the scope of this document. The first trimester is generally considered to be the ideal time to confirm or establish accurate gestational age dating, and it is statistically superior to second trimester dating. However, in 2 dating studies using twins, the difference in accuracy compared with IVF could be considered clinically insignificant

(underestimate 1 day from IVF dating) with both first (11 to 14 weeks) and second (18 to 22 weeks) trimester ultrasound estimates being very accurate in relation to conceptual age by IVF.15,19 Hence, in twins, although there is expert consensus that first trimester ultrasound dating is preferable, second trimester dating is also acceptable and accurate. The best parameter or parameters to use for the most accurate dating vary according to the gestational age. Many studies show that singleton dating formulas work equally well with twins, hence studies in this area are usually a mixture of singletons and multiples.14–17 In the first trimester, crown– rump length provides appropriate gestational dating within 5 to 7 days.15–17 First trimester crown–rump length and second trimester biparietal diameter provide gestational age with an error of plus or minus 7 days and are very similar in accuracy.16 In the second trimester, different combinations of each parameter demonstrate slight differences in accuracy, with the best estimate using a combination of head circumference, abdominal circumference, and femur length.14 Some centres use an average of all parameters, equally weighted, or use mathematical formulas that give different significance to each parameter used. There are more than 30 different formulas in the literature, using different combinations of parameters.14 In general, about 95% of gestational age estimates in the first and second trimester will be within 5 to 7 days of the “true” gestational age, regardless of the parameter or parameters used.14,16,17 In twin pregnancies, modest size discordance is common. Several studies have cited the need to use the larger twin for dating purposes to minimize the chance of missing a fetus that might present with IUGR.16,19 Some studies have based the estimated gestational age on the mean of the fetuses.14 Salomon et al.20 recently suggested that if the inter-twin crown–rump length discrepancy was less than the 95th percentile, according to their charts, the biometry of the smaller fetus was the more correlative with the conception date of IVF pregnancies.20 However, the majority of centres, largely on the basis of expert opinion, use the larger of the 2 fetuses to date a pregnancy, erring on the side of overestimation of gestational age and lessening the chance of missing IUGR in the smaller twin. Therefore, there is no absolute consensus on the optimal method to determine gestational age in twin pregnancies. Most academic centres use the estimated gestational age based on a known last menstrual period, corrected for a regular cycle length if the initial ultrasound falls within an accepted range of days. If the fetal biometry does not agree, new gestational age estimates can be established with an anticipated accuracy of 5 to 7 days. Further study in this area appears to be warranted. JUNE JOGC JUIN 2011 l 647

SOGC CLINICAL PRACTICE GUIDELINE

Recommendations

3. Although the accuracy in confirmation of gestational age at the first and second trimester is comparable, dating should be done with first trimester ultrasound. (II-2A) 4. Beyond the first trimester, it is suggested that a combination of parameters rather than a single parameter should be used to confirm gestational age. (II-2C) 5. When twin pregnancy is the result of in vitro fertilization, accurate determination of gestational age should be made from the date of embryo transfer. (II-1A) 6. There is insufficient evidence to make recommendation of which fetus (when discordant for size) to use to date a twin pregnancy. However, to avoid missing a situation of early intrauterine growth restriction in one twin, most experts agree that the clinician may consider dating pregnancy using the larger fetus. (III-C) SCREENING FOR ANOMALIES IN TWIN PREGNANCIES Aneuploidy Screening in First Trimester

The literature on aneuploidy screening in twins is relatively scant, consisting of small studies with < 10 abnormal fetuses.21–24 Conclusions are inconsistent, and much larger studies are required to provide definitive answers. Nuchal transluscency and maternal age in twins

In 1996, Sebire and colleagues22 evaluated NT in 448 twin pregnancies (both dichorionic and monochorionic). A total of 7.3% of fetuses had an elevated NT above the 95th percentile. In 88.4% of twin pregnancies, both fetuses had a normal NT. An elevated NT was seen in one fetus in 8.7% and in both fetuses in 2.9%. Seven of 8 Down syndrome fetuses were detected with an overall sensitivity of 88%, which is comparable with the singleton detection rate. The screen positive rate was higher in monochorionic twins at 8.4% than in dichorionic twins at 5.4%.22 In a small study of monochorionic twins, Vandecruys et al.24 suggested that the best performance was achieved using the average NT, rather than the larger or smaller NT measured within a twin pair. Using the average NT resulted in an estimated 100% sensitivity for a 4.2% false-positive rate. It would appear that NT in conjunction with maternal age has the potential to reach the standard of 75% sensitivity for a 5% screen positive rate proposed by the SOGC in 200725; however, larger studies are needed to this. 648 l JUNE JOGC JUIN 2011

NT may also be useful in the early detection or prediction of TTTS. One study suggests that an increased NT in monochorionic twins may be an early manifestation of TTTS. An NT threshold at the 95th percentile had a positive and negative predictive value of 43% and 91%, respectively.26 Recommendation

7. In twin pregnancies, aneuploidy screening using nuchal transluscency measurements should be offered. (II-2B) Aneuploidy Screening in the Second Trimester

The use of genetic sonograms to detect Down syndrome in the second trimester has been well studied in singleton pregnancies. A detailed scan is performed with a number of soft markers of Down syndrome, and if there are abnormal findings, a fetus-specific risk is calculated according to the soft marker detected. In twins, the singleton genetic sonogram principles are applied to individual fetuses, and prenatal diagnosis is offered if sufficient risk exists.27 However, there is very little, if any, information to estimate the efficacy of this approach in twins. Typically, in mixed population studies, the data in twin pregnancies are combined with the singleton data, and abstraction of efficacy specific to twins is impossible.28 In one study, soft marker discordance was sought for in twin sets discordant for Down syndrome. Of the markers studied, nuchal translucency thickness was found to correctly identify 5 of 9 Down syndrome cases, with the other markers being significantly less efficacious.29 Therefore, although there may be some utility of second trimester ultrasound in screening for Down syndrome in twins, its efficacy is uncertain. Congenital Malformations

Congenital anomalies are 1.2 to 2 times more common in twin gestation.30 In dizygotic twins the rate per fetus is the same as in singletons, whereas in monozygotic twins the rate is 2 to 3 times higher.31 The most common structural abnormalities are cardiac anomalies, neural tube and brain defects, facial clefts, and gastrointestinal and anterior abdominal wall defects. Apart from structural defects, which also occur in singletons, there are 3 types of congenital anomalies unique to twin pregnancies.30 1. Midline structural defects, believed to be a consequence of the twinning process, exemplified by coned twins. 2. Malformations resulting from vascular events as a consequence of placental anastomoses, leading to hypotension and/or ischemia. This can happen to

Ultrasound in Twin Pregnancies

Table 2. Risk of spontaneous preterm birth (< 32 to 33 weeks) given various CL thresholds Author Goldenberg et al.

Prevalence

N

CL (mm)

GA (weeks)

Sensitivity

Specitivity %

PPV %

NPV %

8.8%

147

≤ 25

24

53.8

85.8

26.9

95.0

Skentou et al.35

7.8%

434

≤ 25

22 to 24

35.3

91.8

26.7

94.3

34

Vayssiere et al.

5.4%

251

≤ 25

21 to 23

38

97

38

96

Sperling et al.37

6.0%

383

≤ 20

23

21.4

96.4

27.8

95.4

Guzman et al.38

9.2%

131

≤ 20

21 to 24

42.0

85

22.0

94

36

a surviving twin after the demise of the other twin. Anomalies seen as consequence of such events include microcephaly, periventricular leukomalacia, hydrocephalus, intestinal atresia, renal dysplasia, and limb amputation. 3. Defects or deformities from intrauterine crowding: foot deformities, hip dislocation, and skull asymmetry Edwards et al.32 evaluated the accuracy of antenatal ultrasound in the detection of fetal anomalies in 245 twins managed in a specialized multiples clinic. The prevalence of anomalies was 4.9%. In this study, antepartum ultrasound detected 88% of anomalies; ultrasound for the detection of congenital anomalies in twins therefore appears to be effective.32 Twin pregnancies will be scanned multiple times during pregnancy, predominantly to assess fetal growth. There are no data to determine whether formal reassessment of fetal anatomy at each scan is of significant value in anomaly detection in twins. Only one study of singleton pregnancies33 found that routine repeat anatomy scanning in the early third trimester resulted in further diagnosis of anomalies. In the second trimester, a major anomaly was detected in 0.36% of scanned fetuses, and anatomical reassessment in the third trimester resulted in further diagnosis in 0.22% of the fetuses previous assessed as “normal.” The anomalies detected were predominantly lesions that may develop late in pregnancy and that would not be detectable in the mid-second trimester. Given the number of ultrasound examinations per twin pregnancy and the rising rates of multiple gestations, the resource implications of a policy of repeated anatomical evaluation are significant. There are insufficient data to make a recommendation on how often repeat anatomical survey should be done in twin pregnancies. Ultrasound scanning for fetal anomalies in twins is clearly justifiable and best performed between 18 and 22 weeks’ gestation. A management plan necessitates knowledge of chorionicity and consideration of the risk to the unaffected fetus.

Summary Statement

1. There are insufficient data to make recommendations on repeat anatomical assessments in twin pregnancies. Therefore, a complete anatomical survey at each scan may not be needed following a complete and normal assessment. (III) Recommendation

8. Detailed ultrasound examination to screen for fetal anomalies should be offered, preferably between 18 and 22 weeks’ gestation, in all twin pregnancies. (II-2B) SCREENING FOR PRETERM BIRTH

Preterm birth is a major cause of mortality and morbidity in twin pregnancies. Sonographic assessment of the cervical length can identify twins at significantly elevated risk of preterm delivery. A number of studies have shown that cervical length can help identify those twins that may be at either increased or reduced risk of early delivery. Most of these studies include both monochorionic and dichorionic pregnancies, and differentiation on that basis is not known. Studies varied with respect to the cervical length threshold chosen, the gestational age at which the cervical length assessment was performed, and the definition of preterm birth. Tables 2 and 3 show information from studies that were similar with respect to these 3 variables. None of the studies included patients who had a cerclage, and all studies employed transvaginal ultrasound. The studies listed in Table 2 show that a finding of a certain cervical length measured between 21 and 24 weeks correlates highly with preterm birth at < 32 to 33 weeks. The results are fairly consistent in that the risk of preterm birth is increased 3- to 5-fold from baseline prevalence. The absolute PPV ranges from 22% to 38 %. Notably, the negative predictive values are quite high and consistent across these studies: 94% to 96%.

 

Table 3 shows studies that attempted to define a threshold at which the likelihood of delivery prior to 34 to 35 weeks is low. The results are more variable than those shown in JUNE JOGC JUIN 2011 l 649

SOGC CLINICAL PRACTICE GUIDELINE

Table 3. Probability of exceeding 34 to 35 weeks given CL > 35 mm Definition threshold weeks

Prevalence of threshold %

N

CL (mm)

GA at scan weeks

Sensitivity %

Specificity %

PPV %

Soriano et al.39

> 35

79.5

44

> 35

18 to 24

88.5

88.9

96.7

Sperling et al.

> 34

87

383

> 35

23

62.8

54

90.1

> 35

76.9

65

> 35

18 to 26

90

93.3

97.6

> 35

85.3

225

> 30

21 to 23

90

27.3

87.8

Author 37

Yang et al.40 Vayssiere et al.

36

GA: gestational age

Table 2. Given a CL > 35 mm measured around the midsecond trimester, the probability of reaching 34 to 35 weeks is quite high (88% to 98%). Cervical length decreases with increasing gestational age, and those who deliver preterm have a cervical shortening rate greater than those who do not. Fujita et al.,41 in a study of 144 twin pregnancies delivering after 34 weeks, demonstrated a cervical length decrease of 0.8 mm/week. Bergelin et al.42 found that the median rate of cervical shortening in women who delivered at term was 1.8 mm per week compared with a rate of 2.9 mm/week for those who delivered preterm. Gibson et al.43 found that a rate of cervical shortening > 2.5 mm/week predicted preterm delivery (positive likelihood ratio of 10.8). Thus, it is clear that progressive shortening greater than expected may indicate a higher risk of preterm labour. However, application to clinical practice is less clear. The 95% confidence interval of inter- and intraobserver variability (intraobserver repeatability coefficient of approximately ± 6 mm and the interobserver limits of agreement was approximately ±10 mm)44 is quite large relative to the reported rates of cervical change. Observed changes may simply be observer variability unless the interobservation interval is quite long. There is also no proven intervention in this scenario. Thus, the optimal protocol for serial CL evaluation in twins is unclear. In women with signs and symptoms of preterm labour between 23 and 33 weeks, CL was a better predictor of preterm delivery than funnelling and digital examination.45 Fuchs et al.46 found that among twin pregnancies that presented in preterm labour, the longer the CL, the less likely it was that delivery would occur within 1 week. At a cervical length of > 25 mm, there were no deliveries (0/21) that occurred within a week, whereas when cervical lengths were ≤ 15 mm, the rate of delivery was 44% (18 of 32). Summary Statement

2. There are insufficient data to recommend a routine preterm labour surveillance protocol in of frequency, timing, and optimal cervical length thresholds. (II-2) 650 l JUNE JOGC JUIN 2011

Recommendation

9. When ultrasound is used to screen for preterm birth in a twin gestation, endovaginal ultrasound measurement of the cervical length should be performed. (II-2A) ASSESSMENT OF FETAL GROWTH

The growth of twins is not significantly different from the growth of singletons in the first and second trimesters. However, there is disagreement regarding the rate of fetal growth in the third trimester in uncomplicated twin pregnancies. Most studies have described slower fetal growth after 30 to 32 weeks’ gestation.47–50 The slower growth rate in twins has been attributed to placental crowding and more frequent anomalous umbilical cord insertion. The American Congress of Obstetricians and Gynecologists technical bulletin on assessment of growth51 suggests that centres should use growth tables derived from twin gestations. However, most studies of twin growth curves are derived from a small sample size that includes pregnancies with adverse outcomes and do not take into chorionicity, race, or gender. The argument in favour of using twin growth charts is that it likely prevents the over-diagnosis of IUGR in normally grown twins (which would result in an increase in iatrogenic preterm delivery). A large cohort study52 comparing the outcome of twins and singletons, taking into chorionicity and fetal growth centiles, demonstrated that twins with growth restriction (defined using singleton growth curves) were not protected from perinatal loss; growth restricted monochorionic twins were, in fact, at increased risk of perinatal mortality. Therefore, although it is suggested that the twin growth curve pattern starts to decelerate from 32 weeks’ gestation, IUGR twins defined according to the singleton growth curve have worse outcomes than those defined as appropriately grown using the same curve. Thus, the literature still suggests that the use of biometry charts from singletons in the follow-up of twin pregnancy provide good predictors of adverse perinatal outcome.52 Further investigation in this area using twin growth charts is warranted.

Ultrasound in Twin Pregnancies

Determination of fetal growth discordance is important, because studies have shown an association with increased mortality and morbidity when there are significant differences in birthweight.53–58 Therefore, detection of antenatal growth discordance by ultrasound is useful in identifying twins that may require increased surveillance to prevent higher fetal/neonatal complications. Confounding factors in studies of twin growth discordance include chorionicity, gestational age at delivery, and growth restriction relative to expected birth weight, as well as suboptimal sample size. Growth discordance has been defined in several ways, with the most common being the difference in estimated fetal weight derived by ultrasound biometry.59 Another method uses absolute differences in abdominal circumference.59 Both methods have their strengths and weaknesses. Birthweight discordance is defined by the following formula, using the larger of the twins as the denominator. EFW larger twin − EFW smaller twin × 100% EFW largest twin 00000000 There is no single definition of growth discordance in twins. Clinically significant birthweight threshold definitions in the literature (based on morbidity and mortality in the postnatal population) range from 15%54 to 30%.57,60 The largest (more than 250 000 cases) and most recent postnatal study55 (which also corrected for IUGR) found statistically significant odds ratios of neonatal mortality for the smaller fetus at 25% birthweight discordance and for the larger fetus at 30% birth weight discordance. Study findings have not been consistent with respect to the accuracy of ultrasound to diagnose discordance.61–69 This may be due to the error associated with all of the ultrasound-derived estimated fetal weight formulas. The SOGC consensus statement on twin gestations59 suggests using an EFW discordance of > 20%. Given the relative imprecision of EFW formulas (none of which were determined from pure twin populations) and the desire to have a high index of suspicion, adopting a 20% threshold is a reasonable option. Another definition of significant growth discordance includes abdominal circumference measurement differences of > 20 mm. A large study by Caravello et al.66 compared the use of AC difference and ultrasound EFW difference to predict true birthweight discordance. This study was of twins delivered between the mid-second trimester and term. Other studies were not all concordant in term of definitions. The range of sensitivities for IUGR was 43% to 83% and 33% to 93% for AC and EFW,

respectively. The range of specificities for appropriate for gestational age was 68% to 91% versus 81% to 98% for AC and EFW, respectively.66 Studies that directly compared the 2, showed them to be equally efficacious compared with estimated fetal weight formulas.66,67 Regardless of growth curves used, increased fetal surveillance is indicated when abdominal circumference and/or EFW of one or both twins is < 10th percentile or when growth discordance is identified.19,70–72 Summary Statements

3. Singleton growth curves currently provide the best predictors of adverse outcome in twins and may be used for evaluating growth abnormalities. (III) 4. It is suggested that growth discordance be defined using either a difference (20 mm) in absolute measurement in abdominal circumference or a difference of 20% in ultrasound derived estimated fetal weight. (II-2) FETAL SURVEILLANCE

There are few published studies indicating how frequently routine reassessment should be done in twin pregnancies. Giles et al.73 in a secondary analysis of their randomized trial (all twins) reported fewer fetal deaths than expected in their routine surveillance group: 11.4/1000 live births (9/1000 live births in the Doppler group) compared with historical control subjects (85.7/1000). In that study, twins had repeat biometry scans at 30 and 35 weeks after a normal 25-week scan. Thus routine surveillance of twin pregnancies every 5 weeks appears to be beneficial. Whether more frequent surveillance would improve the results further remains to be seen; however, it is suggested that more frequent surveillance will result in significantly higher falsepositive rates for IUGR.74 In current practice, the frequency of ultrasound evaluation in twin pregnancies is determined according to chorionicity and growth pattern. In general, when monochorionic twin pregnancies are identified, ultrasound scans are scheduled every 2 to 3 weeks, starting at 16 to 18 weeks, to better ascertain early evidence of TTTS.59 For all twin pregnancies, the anomaly screening scan should be scheduled at 18 to 22 weeks. Most tertiary care centres routinely assess fetal growth every 2 to 4 weeks, depending on chorionicity, largely on the basis of expert opinion.59 Monochorionic twins are scanned more frequently to allow for earlier diagnosis of TTTS and/or growth restriction or discordance, which have greater implications for the non-affected twin than they do in dichorionic pregnancies. Some specialized centres or clinics perform growth scans more frequently than every JUNE JOGC JUIN 2011 l 651

SOGC CLINICAL PRACTICE GUIDELINE

2 weeks in uncomplicated monochorionic twin pregnancies, but there is little evidence beyond expert opinion to this practice. Some centres advocate scanning dichorionic twins every 3 weeks in the third trimester, since the growth rate slows down after 30 to 32 weeks. Grobman and Parilla75 found that in twins (of all types) the positive predictive value of a sonogram for a growth abnormality at birth significantly decreased if the 20- to 24-week sonogram was normal. Furthermore, in gestations with normal growth at 20 to 24 weeks a mean of 10.3 (± 3.9) weeks elapsed before a growth abnormality was subsequently detected.75 This suggests that some routine growth scans may be of very limited benefit while increasing the false positive rate. Increased surveillance is warranted when one or both fetuses show growth restriction or discordance. In these circumstances, serial growth scans every 2 to 3 weeks (or more frequently in monochorionic twins) and fetal surveillance testing are indicated as for singleton (Doppler, non-stress test, and/or biophysical profile). Summary Statements

5. Although there is insufficient evidence to recommend a specific schedule for ultrasound assessment of twin gestation, most experts recommend serial ultrasound assessment every 2 to 3 weeks, starting at 16 weeks of gestation for monochorionic pregnancies and every 3 to 4 weeks, starting from the anatomy scan (18 to 22 weeks) for dichorionic pregnancies. (II-1) Recommendation

10. Increased fetal surveillance should be considered when there is either growth restriction diagnosed in one twin or significant growth discordance. (II-2A) USE OF UMBILICAL ARTERY DOPPLER VELOCIMETRY IN TWINS

Because inequality of the 2 fetal-placental circulations can cause inter-twin differences in growth, umbilical artery Doppler velocimetry may improve the detection of IUGR or fetal growth discordance.65 The largest trial of Doppler assessment of twin pregnancy (n = 526) compared routine biometric ultrasound assessment to routine assessment plus umbilical artery Doppler velocimetry in a randomized fashion at 25, 30, and 35 weeks’ gestation.73 There were no differences between groups in any antenatal, intrapartum, or neonatal outcome; there were fewer unexplained fetal deaths in the Doppler group, but this was not statistically significant. Unfortunately, this study was limited by insufficient power and because monochorionic pregnancies were not analyzed separately. The available data do not show a clear benefit of Doppler 652 l JUNE JOGC JUIN 2011

velocimetry over the use of ultrasound alone; therefore, routine use of Doppler velocimetry in twin gestations cannot be recommended at this time. Of note, in uncomplicated monochorionic twins, uterine artery waveform abnormalities may be common, and they reflect retrograde transmission of arterio-arterial interference patterns in the presence of large arterioarterial anastomosis rather than fetal compromise.76,77 Summary Statement

6. Umbilical artery Doppler may be useful in the surveillance of twin gestations when there are complications involving the placental circulation or fetal hemodynamic physiology. (II-2) Recommendation

11. Umbilical artery Doppler should not be routinely offered in uncomplicated twin pregnancies. (I-E) ASSESSMENT OF AMNIOTIC FLUID

Currently available evidence78–81 is insufficient to make a formal recommendation on the best method of amniotic fluid assessment in twins. Outcome-based studies are lacking. Identification of the inter-twin membrane is vital in order to determine the fluid space around each fetus. Accepted methods for fluid estimation include subjective assessment, deepest vertical pocket, modified amniotic fluid index and 2-dimensional pockets. Another method is to ascertain the presence of fluid, caudal and rostral, and determine to which fetus it belongs and subjectively estimate if normal. When amniotic fluid volume appears reduced or increased, the vertical measurement of the largest pocket in each sac is taken. The condition is defined as oligohydramnios when the deepest vertical pocket < 2 cm and as polyhydramnios when the deepest vertical pocket is > 8 cm. These definitions correspond approximately to the 2.5th percentile and 95th percentile across all gestational ages.82 This is also a common criterion used in defining TTTS, and for these reasons, this may be the clinically useful method for assessing amniotic fluid in twins.83 Summary Statements

7. Although many methods of evaluating the level of amniotic fluid in twins (deepest vertical pocket, single pocket, amniotic fluid index) have been described, there is not enough evidence to suggest that one method is more predictive than the others of adverse pregnancy outcome. (II-3)

Ultrasound in Twin Pregnancies

Recommendation

12. For defining oligohydramnios and polyhydramnios, the ultrasonographer should use the deepest vertical pocket in either sac: oligohydramnios when < 2 cm and polyhydramnios when > 8 cm. (II-2B) Diagnosis of Twin-To-Twin Transfusion Syndrome

Prenatal diagnosis of twin-to-twin transfusion syndrome is made on the basis of specific ultrasound criteria. Monochorionic twins with an oligohydramniospolyhydramnios sequence and the presence of a large fetal bladder in the polyhydramnios twin and a small or absent fetal bladder in the oligohydramnios twin are consistent with TTTS. Discordance in fetal size with the larger twin in the polyhydramnios sac is often seen but is not essential to the diagnosis. A pathognomonic sign for the diagnosis of TTTS is the appearance of the donor as the stuck twin contained within the collapsed inter-twin membrane because of anhydramnios. Doppler studies are also part of the diagnostic evaluation. Absent or low end diastolic flow in the umbilical artery of the donor and decreased ventricular function depicted by tricuspid regurgitation, reversal of A wave in ductus venosus, and/or cardiac chamber enlargement in the recipient are seen in more advanced stages of TTTS. Currently, the Quintero classification method83 is used to stage and determine the management plan for TTTS. Stage 1 oligo-polyhydramnios sequence Stage 2 absent bladder in the donor Stage 3 abnormal fetal vascular Doppler studies Stage 4 hydrops of one fetus Stage 5 death of one fetus In the absence of oligo-polyhydramnios sequence, the diagnosis of TTTS should be entertained with caution when fetal growth discordance is seen in the presence of velamentous cord insertion, 2 vessel cord, or unequal placental partition. DIAGNOSIS OF RARE OBSTETRICAL COMPLICATIONS UNIQUE TO TWINS Monoamnionicity

This occurs in approximately 1% of all monozygotic twin pregnancies. These pregnancies are at elevated risk of fetal death because of cord entanglement. Early series reported double survival in only 46% to 65% until 30 to 32 weeks’ gestation.84,85 More recent series reported improved double perinatal survival of 92% when accurate prenatal diagnosis, serial sonography, and antenatal testing were done.86 Thus early identification is important in the management of these pregnancies.

First trimester ultrasound can predict virtually all cases of monoamniotic twins. Other sonographic indicators include the presence of a single yolk sac and detection of cord entanglement.87 In the second trimester, the diagnosis of monoamnionicity is made on the basis of the following second trimester ultrasound criteria: (1) single shared placenta, (2) fetal phenotype concordance, (3) absence of inter-twin membrane, (4) adequate amniotic fluid surrounding both fetuses, and (5) free movement of both twins within the uterine cavity. Twin Reversed Arterial Perfusion Syndrome

Also known as acardiac twinning, twin reversed arterial perfusion syndrome occurs in 1 in 35 000 deliveries, 1 in 100 monozyotic twins, and 1 in 30 monozygotic triplets.88 These pregnancies have a 90% risk of preterm birth and a 30% risk of congestive heart failure in the normal twin (also called pump twin).89 Diagnosis of acardiac twins is made when one monochorionic twin has the absence of cardiac pulsation along with poor definition of fetal parts. Definitive diagnosis is established with colour Doppler demonstrating reversal of blood flow within the abnormal fetus. Blood-flow pattern reveals a paradoxical direction of arterial flow towards rather than away from the acardiac twin and retrograde flow in the acardiac twin’s abdominal aorta. Differential diagnosis includes intrauterine fetal demise or an abnormal monochorionic twin, or placental tumours. After the diagnosis of twin reversed arterial perfusion syndrome sequence is made, fetal hemodynamic function should be assessed by fetal echocardiography; hydrops in the pump twin being a poor prognostic feature. In addition, estimation of the weight ratio of the acardiac to the pump twin should be established. In a 1990 study, Moore et al.89 found that when the weight of the acardiac twin was ≥ 70% of the weight of the normal pump twin, the incidence of preterm birth, polyhydramnios, and fetal hydrops was 90%, 40%, and 30%, respectively. When the ratio was < 70%, the rates were 70%, 30%, and 10%.89 When the weight ratio was < 50% the complication rates were 18%, 0%, and 35% compared with 44%, 25%, and 94% when > 50%.92 The overall perinatal mortality was 55% in this untreated cohort.89 A multitude of treatment options have been described in the literature, and the optimal method depends on gestational age and centre experience. In a review of all reported cases of minimally invasive therapies, Tan et al.88 reported an overall pump twin survival of 74%. Two recent series reviewed the use of radio frequency ablation and reported pump twin survival rate of around 90%.90,91 However, in one small case series of untreated, antenatally diagnosed acardiac twins, the perinatal survival of the pump twin was 90%, with 40% demonstrating spontaneous cessation of flow in the acardiac JUNE JOGC JUIN 2011 l 653

SOGC CLINICAL PRACTICE GUIDELINE

twin over time.92 Because of the complexity of these cases and the possible management options, including expectant management,92,93 referral to a tertiary care unit is indicated. Coned Twins

The incidence of coned twins varies between 1 in 50 000 and 1 in 100 000 births.94,95 The diagnosis can be made by ultrasound examination in the first trimester. If the embryo appears bifid, follow-up imaging should be performed to confirm the diagnosis. Other clues to the diagnosis include the inability to separate the fetal bodies and skin contours, lack of a separating membrane between the twins, the presence of more than 3 vessels in the umbilical cord, heads remaining at the same level and body plane, extremities in unusual proximity, and failure of the fetuses to change their relative positions over time. Of all coned twins, only those who are omphalopagus have a reasonable chance of survival.96 Single Fetal Death

It is estimated that only 50% of twin pregnancies identified in the first trimester will result in 2 live born infants.97 When the demise occurs early in pregnancy, the prognosis for the surviving fetus is excellent.98,99

Summary Statement

8. Referral to an appropriate high-risk pregnancy centre is indicated when complications unique to twins are suspected on ultrasound. (II-2) These complications include: 1. Twin-to-twin transfusion syndrome 2. Monoamniotic twins gestations 3. Coned twins 4. Twin reversed arterial perfusion sequence 5. Single fetal death in the second or third trimester 6. Growth discordance in monochorionic twins. REFERENCES 1. Chasen ST, Chervenak FA. What is the relationship between the universal use of ultrasound, the rate of detection of twins, and outcome differences? Clin Obstet Gynecol 1998;41:66–77. 2. Sherer DM. Is less intensive fetal surveillance of dichorionic twin gestations justified? Ultrasound Obstet Gynecol 2000;15:167–73. 3. Allen VM, Windrim R, Barrett J, Ohlsson A. Management of monoamniotic twin pregnancies: a case series and systematic review of the literature. BJOG 2001;108:931–36. 4. DeFalco LM, Sciscione AC, Megerian G, Tolosa J, Macones G, O’Shea A, et al. Inpatient versus outpatient management of monoamniotic twins and outcomes. Am J Perinatol 2006;23:205–11. 5. Heyborne KD, Porreco RP, Garite TJ, Phair K, Abril D. Improved perinatal survival of monoamniotic twins with intensive inpatient monitoring. Am J Obstet Gynecol 2005;192:96–101.

Demise of one fetus occurs in 2% to 5% of twin pregnancies during the second and third trimesters. The occurrence of single fetal death is 3-fold to 4-fold higher in monochorionic twins than in dichorionic twins. It is also more common in high-order multiples, complicating 14% to 17% of triplet pregnancies. The loss of a fetus in a twin gestation has been associated with adverse outcomes for the surviving fetus. The greatest risk to the surviving fetus, regardless of chorionicity, is preterm delivery and the associated complications of prematurity. Overall, 50% to 80% of surviving twins are born preterm, most often because of preterm labour. In monochorionic twins, multi-organ damage in the surviving twin can occur. Ischemic injury, which is thought to occur at the time of the demise, has been documented in the spleen, kidney, gastrointestinal tract, skin, and brain of the surviving twin. Up to 20% of surviving fetuses in monochorionic twin pregnancies may experience neurologic injury, such as multicystic encephalomalacia. These abnormalities may not be diagnosed by ultrasound until much later in pregnancy, far removed from the ischemic event. Immediate delivery may not prevent the development of such complications.

10. Winn HN, Gabrielli S, Reece EA, Roberts JA, Salafia C, Hobbins JC. Ultrasonographic criteria for the prenatal diagnosis of placental chorionicity in twin gestations. Am J Obstet Gynecol 1989;161:1540–2.

In dichorionic twin pregnancies, the risk of major perinatal morbidity or mortality to the surviving twin appears to be negligible, apart from the risk related to preterm delivery.

16. Tunón K, Eik-Nes SH, Grøttum P, Von Düring V, Kahn JA. Gestational age in pregnancies conceived after in vitro fertilization: a comparison between age assessed from oocyte retrieval, crown-rump length and biparietal diameter. Ultrasound Obstet Gynecol 2000;15:41–6.

654 l JUNE JOGC JUIN 2011

6. Monteagudo A, Roman AS. Ultrasound in multiple gestations: twins and other multifetal pregnancies. Clin Perinatol 2005;32:329–54,vi. 7. Bromley B, Benacerraf B. Using the number of yolk sacs to determine amnionicity in early first trimester monochorionic twins. J Ultrasound Med 1995;14:415–9. 8. Stenhouse E, Hardwick C, Maharaj S, Webb J, Kelly T, Mackenzie FM. Chorionicity determination in twin pregnancies: how accurate are we? Ultrasound Obstet Gynecol 2002;19:350–2. 9. Wood SL, St. Onge R, Connors G, Elliot PD. Evaluation of the twin peak or lambda sign in determining chorionicity in multiple pregnancy. Obstet Gynecol 1996;88:6–9.

11. D’Alton ME, Dudley DK. The ultrasonographic prediction of chorionicity in twin gestation. Am J Obstet Gynecol 1989;160:557–61. 12. Scardo JA, Ellings JM, Newman RB. Prospective determination of chorionicity, amnionicity, and zygosity in twin gestations. Am J Obstet Gynecol 1995;173:1376–80. 13. Sepulveda W. Chorionicity determination in twin pregnancies: double trouble. Ultrasound Obstet Gynecol 1997;10:79–81. 14. Chervenak FA, Skupski DW, Romero R, Myers MK, Smith-Levitin M, Rosenwaks Z, et al. How accurate is fetal biometry in the assessment of fetal age? Am J Obstet Gynecol 1998;178:678–87. 15. Kalish RB, Thaler HT, Chasen ST, Gupta M, Berman SJ, Rosenwaks Z, et al. First- and second-trimester ultrasound assessment of gestational age. Am J Obstet Gynecol 2004;191:975–8.

Ultrasound in Twin Pregnancies

17. Wisser J, Dirschedl P, Krone S. Estimation of gestational age by transvaginal sonographic measurement of greatest embryonic length in dated human embryos. Ultrasound Obstet Gynecol 1994;4:457–62.

37. Sperling L, Kiil C, Larsen LU, Qvist I, Bach D, Wojdemann K, et al. How to identify twins at low risk of spontaneous preterm delivery. Ultrasound Obstet Gynecol 2005;26:138–44.

18. Bennett KA, Crane JM, O’shea P, Lacelle J, Hutchens D, Copel JA. First trimester ultrasound screening is effective in reducing postterm labor induction rates: a randomized controlled trial. Am J Obstet Gynecol 2004;190:1077–81.

38. Guzman ER, Walters C, O’Reilly-Green C, Kinzler WL, Waldron R, Nigam J, et al. Use of cervical ultrasonography in prediction of spontaneous preterm birth in twin gestations. Am J Obstet Gynecol 2000;183:1103–7.

19. Sebire NJ, D’Ercole C, Soares W, Nayar R, Nicolaides KH. Intertwin disparity in fetal size in monochorionic and dichorionic pregnancies. Obstet Gynecol 1998;91:82–5.

39. Soriano D, Weisz B, Seidman DS, Chetrit A, Schiff E, Lipitz S, et al. The role of sonographic assessment of cervical length in the prediction of preterm birth in primigravidae with twin gestation conceived after infertility treatment. Acta Obstet Gynecol Scand 2002;81:39–43.

20. Salomon LJ, Cavicchioni O, Bernard JP, Duyme M, Ville Y. Growth discrepancy in twins in the first trimester of pregnancy. Ultrasound Obstet Gynecol 2005;26:512–6. 21. Gonce A, Borrell A, Fortuny A, Casals E, Martinez MA, Mercade I, et al. First-trimester screening for trisomy 21 in twin pregnancy: does the addition of biochemistry make an improvement? Prenat Diagn 2005;25:1156–61. 22. Sebire NJ, Snijders RJ, Hughes K, Sepulveda W, Nicolaides KH. Screening for trisomy 21 in twin pregnancies by maternal age and fetal nuchal translucency thickness at 10–14 weeks of gestation. Br J Obstet Gynaecol 1996;103:999–1003. 23. Spencer K, Nicolaides KH. Screening for trisomy 21 in twins using first trimester ultrasound and maternal serum biochemistry in a one-stop clinic: a review of three years experience. BJOG 2003;110:276–80. 24. Vandecruys H, Faiola S, Auer M, Sebire N, Nicolaides KH. Screening for trisomy 21 in monochorionic twins by measurement of fetal nuchal translucency thickness. Ultrasound Obstet Gynecol 2005;25:551–3. 25. Summers AM, Langlois S, Wyatt P, Wilson RD. Prenatal screening for fetal aneuploidy. J Obstet Gynaecol Can 2007;29:146–79. 26. Sebire NJ, D’Ercole C, Hughes K, Carvalho M, Nicolaides KH. Increased nuchal translucency thickness at 10–14 weeks of gestation as a predictor of severe twin-to-twin transfusion syndrome. Ultrasound Obstet Gynecol 1997;10:86–9.

40. Yang JH, Kuhlman K, Daly S, Berghella V. Prediction of preterm birth by second trimester cervical sonography in twin pregnancies. Ultrasound Obstet Gynecol 2000;15:288–91. 41. Fujita MM, Brizot ML, Liao AW, Bernath T, Cury L, Neto JD, et al. Reference range for cervical length in twin pregnancies. Acta Obstet Gynecol Scand 2002;81:856–9. 42. Bergelin I, Valentin L. Cervical changes in twin pregnancies observed by transvaginal ultrasound during the latter half of pregnancy: a longitudinal, observational study. Ultrasound Obstet Gynecol 2003;21:556–63. 43. Gibson JL, Macara LM, Owen P, Young D, Macauley J, Mackenzie F. Prediction of preterm delivery in twin pregnancy: a prospective, observational study of cervical length and fetal fibronectin testing. Ultrasound Obstet Gynecol 2004;23:561–6. 44. Valentin L, Bergelin I. Intra- and interobserver reproducibility of ultrasound measurements of cervical length and width in the second and third trimesters of pregnancy. Ultrasound Obstet Gynecol 2002;20:256–62. 45. Crane JM, Van den Hof M, Armson BA, Liston R. Transvaginal ultrasound in the prediction of preterm delivery: singleton and twin gestations. Obstet Gynecol 1997;90:357–63.

27. Bush MC, Malone FD. Down syndrome screening in twins. Clin Perinatol 2005;32:373–86,vi.

46. Fuchs I, Tsoi E, Henrich W, Dudenhausen JW, Nicolaides KH. Sonographic measurement of cervical length in twin pregnancies in threatened preterm labor. Ultrasound Obstet Gynecol 2004;23:42–5.

28. Verdin SM, Economides DL. The role of ultrasonographic markers for trisomy 21 in women with positive serum biochemistry. Br J Obstet Gynaecol 1998;105:63–7.

47. Blickstein I. Is it normal for multiples to be smaller than singletons? Best Pract Res Clin Obstet Gynaecol 2004;18:613–23.

29. Lynch L, Berkowitz GS, Chitkara U, Wilkins IA, Mehalek KE, Berkowitz RL. Ultrasound detection of Down syndrome: is it really possible? Obstet.Gynecol. 1989;73:267–70.

48. Alexander GR, Kogan M, Martin J, Papiernik E. What are the fetal growth patterns of singletons, twins, and triplets in the United States? Clin Obstet Gynecol 1998;41:114–25.

30. Sperling L, Tabor A. Twin pregnancy: the role of ultrasound in management. Acta Obstet Gynecol Scand 2001;80:287–99.

49. Blickstein I. Normal and abnormal growth of multiples. Semin Neonatol 2002;7:177–85.

31. Hall JG. Twins and twinning. Am J Med Genet 1996;61:202–4.

50. Blickstein I. Growth aberration in multiple pregnancy. Obstet Gynecol Clin North Am 2005;32:39–54,viii.

32. Edwards MS, Ellings JM, Newman RB, Menard MK. Predictive value of antepartum ultrasound examination for anomalies in twin gestations. Ultrasound Obstet Gynecol 1995;6:43–9. 33. Brocks V, Bang J. Routine examination by ultrasound for the detection of fetal malformations in a low risk population. Fetal Diagn Ther 1991;6:37–45. 34. Goldenberg RL, Iams JD, Miodovnik M, Van Dorsten JP, Thurnau G, Bottoms S, et al. The preterm prediction study: risk factors in twin gestations. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Am J Obstet Gynecol 1996;175:1047–53. 35. Skentou C, Souka AP, To MS, Liao AW, Nicolaides KH. Prediction of preterm delivery in twins by cervical assessment at 23 weeks. Ultrasound Obstet Gynecol 2001;17:7–10. 36. Vayssiere C, Favre R, Audibert F, Chauvet MP, Gaucherand P, Tardif D, et al. Cervical length and funneling at 22 and 27 weeks to predict spontaneous birth before 32 weeks in twin pregnancies: a French prospective multicenter study. Am J Obstet Gynecol 2002;187:1596–604.

51. American Congress of Obstetricians and Gynecologists. Multiple gestation: complicated twin, triplet, and high-order multifetal pregnancy. ACOG Practice Bulletin no. 56, October 2004. 52. Hamilton EF, Platt RW, Morin L, Usher R, Kramer M. How small is too small in a twin pregnancy? Am J Obstet Gynecol 1998;179:682–5. 53. Alam Machado Rde C, Brizot Mde L, Liao AW, Krebs VL, Zugaib M. Early neonatal morbidity and mortality in growth-discordant twins. Acta Obstet Gynecol Scand 2009;88:167–71. 54. Kato N, Matsuda T. The relationship between birthweight discordance and perinatal mortality of one of the twins in a twin pair. Twin Res Hum Genet 2006;9:292–7. 55. Branum AM, Schoendorf KC. The effect of birth weight discordance on twin neonatal mortality. Obstet Gynecol 2003;101:570–4. 56. Hollier LM, McIntire DD, Leveno KJ. Outcome of twin pregnancies according to intrapair birth weight differences. Obstet Gynecol 1999;94:1006–10.

JUNE JOGC JUIN 2011 l 655

SOGC CLINICAL PRACTICE GUIDELINE

57. Cheung VY, Bocking AD, Dasilva OP. Preterm discordant twins: what birth weight difference is significant? Am J Obstet Gynecol 1995;172:955–9.

78. Magann EF, Chauhan SP, Martin JN Jr, Whitworth NS, Morrison JC. Ultrasonic assessment of the amniotic fluid volume in diamniotic twins. J Soc Gynecol Investig 1995;2:609–13.

58. Fraser D, Picard R, Picard E, Leiberman JR. Birth weight discordance, intrauterine growth retardation and perinatal outcomes in twins. J Reprod Med 1994;39:504–8.

79. Magann EF, Martin JN Jr. Amniotic fluid volume assessment in singleton and twin pregnancies. Obstet Gynecol Clin North Am 1999;26:579–93.

59. Barrett J, Bocking A. Management of twin pregnancies. SOGC consensus statement: Part 1. no. 91, July 2000. J Soc Obstet Gynaecol Can 2000;22:519-29. 60. Blickstein I. The definition, diagnosis, and management of growthdiscordant twins: an international census survey. Acta Genet Med Gemellol (Roma.) 1991;40:345–51. 61. Banks CL, Nelson SM, Owen P. First and third trimester ultrasound in the prediction of birthweight discordance in dichorionic twins. Eur J Obstet Gynecol Reprod Biol 2008;138:34–8. 62. Chang YL, Chang TC, Chang SD, Cheng PJ, Chao AS, Hsieh PC, et al. Sonographic prediction of significant intertwin birth weight discordance. Eur J Obstet Gynecol Reprod Biol 2006;127:35–40. 63. Kingdom JC, Nevo O, Murphy KE. Discordant growth in twins. Prenat Diagn 2005;25:759–65. 64. MacLean M, Mathers A, Walker JJ, Cameron AD, Howat R. The ultrasonic assessment of discordant growth in twin pregnancies. Ultrasound Obstet Gynecol 1992;2:30–4. 65. Chittacharoen A, Leelapattana P, Rangsiprakarn R. Prediction of discordant twins by real-time ultrasonography combined with umbilical artery velocimetry. Ultrasound Obstet Gynecol 2000;15:118–21. 66. Caravello JW, Chauhan SP, Morrison JC, Magann EF, Martin JN Jr, Devoe LD. Sonographic examination does not predict twin growth discordance accurately. Obstet Gynecol 1997;89:529–33. 67. Blickstein I, Manor M, Levi R, Goldchmit R. Is intertwin birth weight discordance predictable? Gynecol Obstet.Invest 1996;42:105–08. 68. Sayegh SK, Warsof SL. Ultrasonic prediction of discordant growth in twin pregnancies. Fetal Diagn Ther 1993;8:241–6. 69. Chamberlain P, Murphy M, Comerford FR. How accurate is antenatal sonographic identification of discordant birthweight in twins? Eur J Obstet Gynecol Reprod Biol 1991;40:91–6. 70. Snijder MJ, Wladimiroff JW. Fetal biometry and outcome in monochorionic vs. dichorionic twin pregnancies; a retrospective crosssectional matched-control study. Ultrasound Med Biol 1998;24:197–201.

80. Devoe LD, Ware DJ. Antenatal assessment of twin gestation. Semin Perinatol 1995;19:413–23. 81. Watson WJ, Harlass FE, Menard MK, McCurdy CM, Brady K, Miller RC. Sonographic assessment of amniotic fluid in normal twin pregnancy. Am J Perinatol 1995;12:122–4. 82. Chau AC, Kjos SL, Kovacs BW. Ultrasonographic measurement of amniotic fluid volume in normal diamniotic twin pregnancies. Am J Obstet Gynecol 1996;174:1003–7. 83. Quintero RA, Morales WJ, Allen MH, Bornick PW, Johnson PK, Kruger M. Staging of twin-twin transfusion syndrome. J Perinatol 1999;19:550–5. 84. Carr SR, Aronson MP, Coustan DR. Survival rates of monoamniotic twins do not decrease after 30 weeks’ gestation. Am J Obstet Gynecol 1990;163:719–22. 85. Tessen JA, Zlatnik FJ. Monoamniotic twins: a retrospective controlled study. Obstet Gynecol 1991;77:832–4. 86. Rodis JF, McIlveen PF, Egan JF, Borgida AF, Turner GW, Campbell WA. Monoamniotic twins: improved perinatal survival with accurate prenatal diagnosis and antenatal fetal surveillance. Am J Obstet Gynecol 1997;177:1046–9. 87. Overton TG, Denbow ML, Duncan KR, Fisk NM. First-trimester cord entanglement in monoamniotic twins. Ultrasound Obstet Gynecol 1999;13:140–2. 88. Tan TY, Sepulveda W. Acardiac twin: a systematic review of minimally invasive treatment modalities. Ultrasound Obstet Gynecol 2003;22:409–19. 89. Moore TR, Gale S, Benirschke K. Perinatal outcome of forty-nine pregnancies complicated by acardiac twinning. Am J Obstet Gynecol 1990;163:907–12. 90. Lee H, Wagner AJ, Sy E, Ball R, Feldstein VA, Goldstein RB, et al. Efficacy of radiofrequency ablation for twin-reversed arterial perfusion sequence. Am J Obstet Gynecol 2007;196:459.e1–4. 91. Livingston JC, Lim FY, Polzin W, Mason J, Crombleholme TM. Intrafetal radiofrequency ablation for twin reversed arterial perfusion (TRAP): a single-center experience. Am J Obstet Gynecol 2007;197:399.e1–3.

71. Hill LM, Guzick D, Chenevey P, Boyles D, Nedzesky P. The sonographic assessment of twin growth discordancy. Obstet Gynecol 1994;84:501–4.

92. Sullivan AE, Varner MW, Ball RH, Jackson M, Silver RM. The management of acardiac twins: a conservative approach. Am J Obstet Gynecol 2003;189:1310–3.

72. Arbuckle TE, Wilkins R, Sherman GJ. Birth weight percentiles by gestational age in Canada. Obstet Gynecol 1993;81:39–48.

93. Wong AE, Sepulveda W. Acardiac anomaly: current issues in prenatal assessment and treatment. Prenat Diagn 2005;25:796–806.

73. Giles W, Bisits A, O’Callaghan S, Gill A. The Doppler assessment in multiple pregnancy randomised controlled trial of ultrasound biometry versus umbilical artery Doppler ultrasound and biometry in twin pregnancy. BJOG 2003;110:593–7.

94. Metneki J, Czeizel A. Coned twins in Hungary, 1970–1986. Acta Genet Med Gemellol (Roma) 1989;38:285–99.

74. Mongelli M, Ek S, Tambyrajia R. Screening for fetal growth restriction: a mathematical model of the effect of time interval and ultrasound error. Obstet Gynecol 1998;92:908–12. 75. Grobman WA, Parilla BV. Positive predictive value of suspected growth aberration in twin gestations. Am J Obstet Gynecol 1999;181:1139–41. 76. Gratacos E, Lewi L, Carreras E, Becker J, Higueras T, Deprest J, et al. Incidence and characteristics of umbilical artery intermittent absent and/or reversed end-diastolic flow in complicated and uncomplicated monochorionic twin pregnancies. Ultrasound Obstet Gynecol 2004;23:456–60. 77. Wee LY, Taylor MJ, Vanderheyden T, Talbert D, Fisk NM. Transmitted arterio-arterial anastomosis waveforms causing cyclically intermittent absent/reversed end-diastolic umbilical artery flow in monochorionic twins. Placenta 2003;24:772–8.

656 l JUNE JOGC JUIN 2011

95. Spitz L, Kiely EM. Coned twins. JAMA 2003;289:1307–10. 96. Newman RB, Luke B. Multifetal pregnancy: a handbook for the care of the pregnant patient. Philadelphia: Lippincott Williams & Wilkins; 2000:149–72. 97. Samuels P. Ultrasound in the management of the twin gestation. Clin Obstet Gynecol 1988;31:110–22. 98. Prompeler HJ, Madjar H, Klosa W, du BA, Zahradnik HP, Schillinger H, et al. Twin pregnancies with single fetal death. Acta Obstet Gynecol Scand 1994;73:205–8. 99. Landy HJ, Weingold AB. Management of a multiple gestation complicated by an antepartum fetal demise. Obstet Gynecol Surv 1989;44:171–6. 100. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

SOGC CLINICAL PRACTICE GUIDELINE SOGC CLINICAL PRACTICE GUIDELINENo.243, June 2010

Adhesion Prevention in Gynaecological Surgery This clinical practice guideline has been reviewed and approved by the Clinical Practice Gynaecology Committee and by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Deborah Robertson, MD, Toronto ON Guylaine Lefebvre, MD, Toronto ON CLINICAL PRACTICE GYNAECOLOGY COMMITTEE Nicholas Leyland, MD (Co-Chair), Toronto ON Wendy Wolfman, MD (Co-Chair), Toronto ON Catherine Allaire, MD, Vancouver BC Alaa Awadalla, MD, Winnipeg MB Carolyn Best, MD, Hamilton ON Elizabeth Contestabile, RN, Ottawa ON Sheila Dunn, MD, Toronto ON Mark Heywood, MD, Vancouver BC Nathalie Leroux, MD, Outremont QC Frank Potestio, MD, Thunder Bay ON David Rittenberg, MD, Halifax NS Vyta Senikas, MD, Ottawa ON Renéee Soucy, MD, Chandler QC Sukhbir Singh, MD, Ottawa ON Disclosure statements have been received from the primary authors and all committee .

Abstracts Objectives: To review the etiology and incidence of and associative factors in the formation of adhesions following gynaecological surgery. To review evidence for the use of available means of adhesion prevention following gynaecological surgery. Options: Women undergoing pelvic surgery are at risk of developing abdominal and/or pelvic adhesive disease postoperatively. Surgical technique and commercial adhesion prevention systems may decrease the risk of postoperative adhesion formation.

Outcomes: The outcomes measured are the incidence of postoperative adhesions, complications related to the formation of adhesions, and further intervention relative to adhesive disease. Evidence: Medline, EMBASE, and The Cochrane Library were searched for articles published in English from 1990 to March 2009, using appropriate controlled vocabulary and key words. Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, cohort studies, and meta-analyses specifically addressing postoperative adhesions, adhesion prevention, and adhesive barriers. Searches were updated on a regular basis and incorporated in the guideline to March 2009. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Values: The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care Summary Statements 1. Meticulous surgical technique is a means of preventing adhesions. This includes minimizing tissue trauma, achieving optimal hemostasis, minimizing the risk of infection, and avoiding contaminants (e.g., fecal matter) and the use of foreign materials (e.g., talcum powder) when possible. (II-2) 2. The risk of adhesions increases with the total number of abdominal and pelvic surgeries performed on one patient; every surgery needs to be carefully considered in this context. (II-2) 3. Polytetrafluoroethylene (Gore-Tex) barrier is more effective than no barrier or oxidized regenerated cellulose in preventing adhesion formation. (I) 4. Oxidized regenerated cellulose (Interceed) adhesion barrier is associated with a reduced incidence of pelvic adhesion formation at both laparoscopy and laparotomy when complete hemostasis is achieved. Oxidized regenerated cellulose may increase the risk of adhesions if optimal hemostasis is not achieved. (II-2) 5. Chemically modified sodium hyaluronate/carboxymethylcellulose (Seprafilm) is effective in preventing adhesion formation, especially following myomectomies. There is insufficient evidence on the effect of sodium hyaluronate/carboxymethylcellulose on long-term clinical outcomes such as fertility, chronic pelvic pain or small bowel obstruction. (II-2) 6. No adverse effects have been reported with the use of oxidized regenerated cellulose, polytetrafluoroethylene, or sodium hyaluronate/carboxymethylcellulose. (II-1)

Key Words: Hysterectomy, postoperative adhesions, adhesion barriers

7. Various pharmacological agents have been marketed as a means of preventing adhesions. None of these agents are presently available in Canada. There is insufficient evidence for the use of pharmacological agents in preventing adhesions. (III-C)

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

598

l JUNE JOGC JUIN 2010

Adhesion Prevention in Gynaecological Surgery

Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

D. There is fair evidence to recommend against the clinical preventive action E. There is good evidence to recommend against the clinical preventive action L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.1 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the The Canadian Task Force on Preventive Health Care.1

Recommendations 1. Surgeons should attempt to perform surgical procedures using the least invasive method possible in order to decrease the risk of adhesion formation. (II-1B ) When feasible, for example, a laparoscopic surgical approach is preferable to an abdominal approach, and a vaginal or laparoscopic hysterectomy is preferable to an abdominal hysterectomy. 2. Precautions should be taken at surgery to minimize tissue trauma in order to decrease the risk of postoperative adhesions. These precautions include limiting packing, crushing, and manipulating of tissues to what is strictly required for safe completion of the procedure. (III-B) 3. Surgeons could consider using an adhesion barrier for patients who are at high risk of forming clinically significant adhesions (i.e., patients who have endometriosis or pelvic inflammatory disease or who are undergoing a myomectomy). If there is a risk of ongoing bleeding from the surgical site, oxidized regenerated cellulose (Interceed) should not be used as it may increase the risk of adhesions in this situation. (II-2B) J Obstet Gynaecol Can 2010;32(6) 598–602

INTRODUCTION

dhesions have a variety of causes, including surgical procedures. Pelvic and abdominal adhesions have been associated with significant gynaecological morbidity, including infertility, chronic pelvic pain, small bowel obstruction, and difficulty with surgical access or surgical complications in the future. It is therefore important to minimize adhesions at the time of surgery. Traditionally, techniques such as meticulous hemostasis have been advocated as a means of minimizing adhesion formation. Many new products have recently been marketed to further

A

reduce the formation of adhesions, but the evidence for adhesion barriers is limited by the difficulty in assessing the impact of postoperative adhesion formation in patients. Recommendations for the prevention of adhesion formation in gynaecological surgery are quantified according to the evaluation of evidence guidelines developed by the Canadian Task Force on Preventive Health Care (Table).1 INCIDENCE OF ADHESIONS

It has been estimated that 90% of patients undergoing major abdominal surgery and 55% to 100% of women undergoing pelvic surgery develop adhesions.2 It would therefore seem that adhesions are an inevitable consequence of abdominal and pelvic surgery. Fortunately, the majority of patients with intra-abdominal adhesions are asymptomatic.3 As surgeons we are faced with the difficult task of trying to predict which patients are predisposed to symptomatic adhesion formation on the basis of the type of surgery performed and the patients’ underlying pathology. CAUSES AND ASSOCIATIONS OF ADHESIONS

Within hours of surgery, fibrin is deposited in the area of surgery.4 This fibrin is either then resorbed or becomes organized into fibrous adhesions.4 It is unclear why some patients experience resorption, while others have further formation of these adhesions. Two specific risk factors for the further organization of fibrin into adhesions have been identified: tissue injury and an inflammatory response.4 JUNE JOGC JUIN 2010 l

599

SOGC CLINICAL PRACTICE GUIDELINE

Ischemic Injury When tissue damage is associated with vascular insufficiency, adhesions form as a means of preventing ischemic injury.4 Therefore, following operations during which the tissues are crushed, sutured, or ligated, adhesions typically form in the area of injury to provide new blood supply to the devascularized organ. Inflammatory Response Contamination of the peritoneal cavity by foreign material (e.g., talcum powder, sutures, fecal material) has also been associated with the formation of adhesions because it produces an inflammatory response.4,5 Bacterial infection causes a similar inflammatory reaction.6 Averting bowel injury, preventing postoperative infections, and precluding the use of foreign materials are advocated as means of preventing inflammation but cannot always be achieved. CONSEQUENCE OF ADHESIONS

The majority of patients who develop postoperative adhesions are asymptomatic. Clinically significant outcomes associated with adhesions include chronic pelvic and abdominal pain, bowel obstruction, infertility due to the formation of adnexal adhesions, and complications at subsequent surgeries, such as difficult dissection and visceral injury.3 METHODS OF ADHESION PREVENTION

Meticulous Surgical Technique Meticulous surgical technique has long been advocated in the prevention of adhesions.4 Avoidance of tissue trauma with gentle tissue handling and prevention of thermal injury, meticulous hemostasis, prevention of bacterial infection or fecal contamination, use of copious irrigation, and avoidance of foreign objects intuitively make sense as intraoperative means of preventing postoperative adhesions.3 When possible, the omentum can be placed such that bowel is shielded from the abdominal wall before closure of the laparotomy incision.4 With every surgery, a certain amount of tissue injury inevitably occurs.7 With increasing number of surgeries there is an increased risk of adhesion formation.8 It is therefore important to attempt to minimize the total number of surgeries performed on one patient. Laparoscopic surgical procedures have been associated with fewer postoperative adhesions than open surgeries.7,9–11 Patients requiring a hysterectomy should be offered a vaginal or laparoscopic approach rather than an abdominal approach when feasible.12 Surgeons should attempt to perform surgical procedures using the least invasive method possible, while respecting the limitations of the individual patient characteristics, anticipated pathology, and their own level of skill. 600

l JUNE JOGC JUIN 2010

Adhesions are not always preventable despite meticulous surgical technique. Some conditions may increase the likelihood of forming adhesions, such as endometriosis or chronic pelvic inflammatory disease.13 Patients undergoing myomectomy are also at increased risk of adhesions, and in those women who are hoping to preserve fertility adhesions add an element of risk of interrupting tubal patency.14 When patients are at particular risk of postoperative adhesions, the use of adjuvant measures of adhesion prevention could be considered. Summary Statements 1. Meticulous surgical technique is a means of preventing adhesions. This includes mirnimizing tissue trauma, achieving optimal hemostasis, minimizing the risk of infection, and avoiding contaminants (e.g., fecal matter) and the use of foreign materials (e.g., talcum powder) when possible. (II-2) 2. The risk of adhesions increases with the total number of abdominal and pelvic surgeries performed on one patient; every surgery needs to be carefully considered in this context. (II-2) Recommendations 1. Surgeons should attempt to perform surgical procedures using the least invasive method possible in order to decrease the risk of adhesion formation. (II-1B ) When feasible, for example, a laparoscopic surgical approach is preferable to an abdominal approach, and a vaginal or laparoscopic hysterectomy is preferable to an abdominal hysterectomy. 2. Precautions should be taken at surgery to minimize tissue trauma in order to decrease the risk of postoperative adhesions. These precautions include limiting packing, crushing, and manipulating of tissues to what is strictly required for safe completion of the procedure. (III-B) Two systematic reviews have considered whether barrier agents and pharmacological agents are clinically effective in preventing the formation of postoperative adhesions in patients who have undergone pelvic surgery.15,16 Barrier Agents Barrier agents were devised to create a synthetic barrier agent between opposing pelvic structures during tissue healing that would prevent the formation of adhesions. The main theoretical concern with the use of these agents is that they could cause a foreign material reaction, thus contributing to adhesion formation. There is insufficient evidence of the effect of barrier agents on long-term clinical outcomes such as fertility, chronic pelvic pain, or small bowel obstruction. Oxidized regenerated cellulose (Interceed) Interceed is an absorbable synthetic mechanical barrier made of oxidized regenerated cellulose. When applied on

Adhesion Prevention in Gynaecological Surgery

damaged peritoneum, Interceed transforms into a gel that covers the area and is postulated to prevent adhesion formation.17 The membrane may be cut as necessary, which may allow for its use in both open and laparoscopic surgeries; however, the product monograph specifies that it has been approved only for use at laparotomy. It should be applied in a single layer between two adjacent tissues. Interceed is completely absorbed within two weeks. Meticulous hemostasis must be achieved before Interceed is applied; when mixed with blood Interceed increases fibrin deposition and may increase the formation of adhesions.18 There have been numerous studies evaluating the use of Interceed versus no treatment.19-28 When compared with no treatment, Interceed was associated with a reduced incicence of pelvic adhesion (OD 0.39; 95% CI 0.28 to 0.55) following laparotomy.15 Similar results were noted following laparoscopy, with a reduction noted in new formation (OD 0.31; 95% CI 0.23 to 0.79) and in reformation (OR 0.19; 95% CI 0.09 to 0.42) of adhesions.15 There are no data on its effects on the incidence of small bowel obstruction, chronic pelvic pain, or pregnancy rates. Polytetrafluoroethylene (Gore-Tex) Gore-Tex is a permanent, nonabsorbable membrane that must be sutured into place. Particularly at laparoscopy, the need to stabilize the membrane with sutures may result in surgical delays. There is evidence to suggest that, compared with no treatment, Gore-Tex results in a reduction in the formation of new adhesions in patients undergoing a myomectomy (OR 0.21; 95% CI 0.05 to 0.87).29 Gore-Tex has been reported to have less adhesion reformation than Interceed in women undergoing adhesiolysis (OR 0.16; 95% CI 0.03 to 0.80).15,30 Results should be interpreted with caution, as it is unclear if the surgeon was unblinded at the time of second look laparoscopy.15 Again, no studies have evaluated the incidence of small bowel obstruction and chronic pelvic pain or pregnancy rates following the use of Gore-Tex. Chemically modified sodium hyaluronate/ carboxymethylcellulose (Seprafilm) Seprafilm is an absorbable synthetic membrane made up of two polysaccharides: sodium hyaluronate and carboxymethylcellulose. Seprafilm is supplied within a plastic sleeve which must be removed before the Seprafilm is placed on the tissues. Within 24 to 48 hours, the membrane becomes gelatinous, and it is absorbed within one week. At the present time, Seprafilm is indicated only for use at laparotomy. Some surgeons use Seprafilm at laparoscopy by creating a “slurry” (i.e., a thin mixture of Seprafilm mixed with normal saline) and then flushing this preparation via a catheter

through one of the laparoscopic ports. The slurry produces a gelatinous membrane coating on any surface on which it is deposited, and it is postulated that its adhesion-preventing effects may be similar to those produced when Seprafilm is used at laparotomy. Although this slurry is being used by Canadian and international surgical experts, there is insufficient evidence to its use in preventing adhesions, and this constitutes an off-label use of the product. Trials of benefits are presently underway. The only study to examine the use of Seprafilm at laparotomy versus no treatment31 concluded that it reduced the incidence, extent, and severity of postoperative adhesions. However, the Cochrane database found that suboptimal statistical analyses were used in this study, and the results should therefore be interpreted with caution.15 No studies have yet evaluated the incidence of small bowel obstruction or chronic pelvic pain or pregnancy rates following the use of Seprafilm. Summary Statements 3. Polytetrafluoroethylene (Gore-Tex) barrier is more effective than no barrier or oxidized regenerated cellulose in preventing adhesion formation. (I) 4. Oxidized regenerated cellulose (Interceed) adhesion barrier is associated with a reduced incidence of pelvic adhesion formation at both laparoscopy and laparotomy when complete hemostasis is achieved. Oxidized regenerated cellulose may increase the risk of adhesions if optimal hemostasis is not achieved. (II-2) 5. Chemically modified sodium hyaluronate/ carboxymethylcellulose (Seprafilm) is effective in preventing adhesion formation, especially following myomectomies. There is insufficient evidence on the effect of sodium hyaluronate/carboxymethylcellulose on long-term clinical outcomes such as fertility, chronic pelvic pain, or small bowel obstruction. (II-2) 6. No adverse effects have been reported with the use of oxidized regenerated cellulose, polytetrafluoroethylene, or sodium hyaluronate/carboxymethylcellulose. (II-1) Recommendation 3. Surgeons could consider using an adhesion barrier for patients who are at high risk of forming clinically significant adhesions (i.e., patients who have endometriosis or pelvic inflammatory disease or who are undergoing a myomectomy). If there is a risk of ongoing bleeding from the surgical site, oxidized regenerated cellulose (Interceed) should not be used as it may increase the risk of adhesions in this situation. (II-2B) JUNE JOGC JUIN 2010 l

601

SOGC CLINICAL PRACTICE GUIDELINE

Pharmacological Agents The use of various pharmacological agents has been proposed to prevent the formation of adhesions. None of these agents have been approved for use in Canada. There is insufficient evidence for the use of pharmacological agents in preventing adhesions. Summary Statement 7. Various pharmacological agents have been marketed as means of preventing adhesions. None of these agents are presently available in Canada. There is insufficient evidence for the use of pharmacological agents in preventing adhesions. (III-C) SUMMARY

Meticulous surgical technique is an inexpensive and risk-free practice that may decrease likelihood of adhesion formation. Studies involving the use of commercial adhesion prevention and barrier methods such as Interceed, Gore-Tex, and Seprafilm revealed that these agents appear safe for use in gynaecological surgery. However, there is limited evidence for the long-term benefits of adhesion prevention agents in gynaecological surgery. Previous studies typically assessed only the rate of adhesion formation and did not evaluate long-term, clinically relevant outcomes such as fertility rates or abdominal or pelvic pain. Further studies of commercial adhesion prevention and barrier methods that evaluate these long-term clinical outcomes are needed. REFERENCES 1. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8. 2. Liakakos T, Thomakos N, Fine PM, Dervenis C, Young RL. Peritoneal adhesions: etiology, pathophysiology, and clinical significance. Recent advances in prevention and management. Dig Surg 2001;18:260–73. 3. Monk BJ, Berman ML, Montz FJ. Adhesions after extensive gynecologic surgery: clinical significance, etiology, and prevention. Am J Obstet Gynecol 1994;170(5 Pt 1):1396. 4. Ellis H. The causes and prevention of intestinal adhesions. Br J Surg 1982;69:241–3. 5. Luijendijk R, de Lange D, Wauters C, Hop WC, Duron JJ, Pailler JL, et al. Foreign material in postoperative adhesions. Ann Surg 1996;223:242–8. 6. Thompson JN, Whawell SA. Pathogenesis and prevention of adhesion formation. Br J Surg 1995;82:3–5. 7. Schäfer M, Krähenbühl L, Büchler MW. Comparison of adhesion formation in open and laparoscopic surgery. Dig Surg 1998;15:148–52. 8. Weibel M. Peritoneal adhesions and their relation to abdominal surgery. Am J Surg 1973;126:354–3. 9. Levrant SG, Bieber EJ, Barnes RB. Anterior abdominal wall adhesions after laparotomy or laparoscopy. Am Assoc Gyn Laparosc 1997;4:353–6. 10. Bulletti C, Polli V, Negrini V, Giacomucci E, Flamigni C. Adhesion formation after laparoscopic myomectomy. J Am Assoc Gynecol Laparosc 1996;3:533–6.

602

l JUNE JOGC JUIN 2010

11. Polymeneas G, Theodosopoulos T, Stamatiadis A, Kourias E. A comparative study of postoperative adhesion formation after laparoscopic vs open cholecystectomy. Surg Endosc 2001;15:41–3. 12. Lefebvre G, Allaire C, Jeffrey J, Vilos G; SOGC Clinical Practice Gynaecology Committee. Hysterectomy. SOGC Clinical Practice Guideline No. 109, January 2002. J Obstet Gynaecol Can 2002;24:37–48. 13. Diamond MP, Freeman ML. Clinical implications of postsurgical adhesions. Hum Reprod Update 2001;7:567–76. 14. Tulandi T, Murray C, Guralnick M. Adhesion formation and reproductive outcome after myomectomy and second-look laparoscopy. Obstet Gynecol 1993;82:213–5. 15. Ahmad G, Duffy J, Farquhar C, Vail A, Vandekerckhove P, Watson A, et al. Barrier agents for adhesion prevention after gynaecological surgery. Cochrane Database Syst Rev 2008;2:1–40. 16. Metwally M, Watson A, Lilford R, Vandekerckhove P. Fluid and pharmacological agents for adhesion prevention after gynaecological surgery. Cochrane Database Syst Rev 2006;2:1–52. 17. Al-Jaroudi D, Tulandi T. Adhesion prevention in gynecologic surgery. Obstet Gynecol Surv 2004;59:360–7. 18. DeCherney AH, diZerega GS. Clinical problem of intraperitoneal postsurgical adhesion formation following general surgery and the use of adhesion prevention barriers. Surg Clin North Am 1997;77:671–88. 19. Mais V, Ajossa S, Marongiu D, Peiretti RF, Guerriero S, Melis GB. Reduction of adhesion reformation after laparoscopic endometriosis surgery: a randomized trial with an oxidized regenerated cellulose absorbable barrier. Obstet Gynecol 1995;86:512–5. 20. Mais V, Ajossa S, Piras B, Guerriero S, Marongiu D, Melis GB. Prevention of de-novo adhesion formation after laparoscopic myomectomy: a randomized trial to evaluate the effectiveness of an oxidized regenerated cellulose absorbable barrier. Hum Reprod 1995;10:3133–5. 21. Saravelos H, Li TC. Post-operative adhesions after laparoscopic electrosurgical treatment for polycystic ovarian syndrome with the application of Interceed to one ovary: a prospective randomized controlled study. Hum Reprod 1996;11:992–7. 22. Keckstein J, Ulrich U, Sasse V, Roth A, Tuttlies F, Karageorgieva E. Reduction of postoperative adhesion formation after laparoscopic ovarian cystectomy. Hum Reprod 1996;11:579–82. 23. Azziz R. Microsurgery alone or with INTERCEED absorbable adhesion barrier for pelvic sidewall adhesion re-formation. The INTERCEED (TC7) Adhesion Barrier Study Group II. Surg Gynecol Obstet 1993;177:135–9. 24. Li TC, Cooke ID. The value of an absorbable adhesion barrier, Interceed®, in the prevention of adhesion reformation following microsurgical adhesiolysis. Br J Obstet Gynaecol 1994;101:335–9. 25. The efficacy of Interceed (TC7) for prevention of reformation of postoperative adhesions on ovaries, fallopian tubes, and fimbriae in microsurgical operations for fertility: a multicenter study. Nordic Adhesion Prevention Study Group. Fertil Steril 1995;63:709–14. 26. Franklin RR. Reduction of ovarian adhesions by the use of Interceed. Ovarian Adhesion Study Group. Obstet Gynecol 1995;86:335–40. 27. Sekiba K. Use of Interceed (TC7) absorbable adhesion barrier to reduce postoperative adhesion reformation in infertility and endometriosis surgery. The Obstetrics and Gynecology Adhesion Prevention Committee. Obstet Gynecol 1992;79:518–22. 28. Van Geldorp H. Interceed absorbable adhesion barrier reduces the formation of postsurgical adhesions after ovarian surgery. Fertil Steril 1994;62(Suppl):273. 29. An expanded polytetrafluoroethylene barrier (Gore-Tex surgical membrane) reduces post-myomectomy adhesion formation. Myomectomy Adhesion Multicenter Study Group. Fertil Steril 1995;63:491–3. 30. Haney AF, Hesla J, Hurst BS, Kettel LM, Murphy AA, Rock JA, et al. Expanded polytetrafluoroethylene (Gore-Tex Surgical Membrane) is superior to oxidized regenerated cellulose (Interceed TC7+) in preventing adhesions. Fertil Steril 1995;63:1021–6. 31. Diamond MP. Reduction of adhesions after uterine myomectomy by Seprafilm membrane (HAL-F): a blinded, prospective, randomized, multicenter clinical study. Seprafilm Adhesion Study Group. Fertil Steril 1996;66:904–10.

SOGC CLINICAL PRACTICE GUIDELINE SOGC Clinical Practice Guideline

No. 247, September 2010

Antibiotic Prophylaxis in Obstetric Procedures This Clinical Practice Guideline has been prepared by the Infectious Diseases Committee and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Julie van Schalkwyk, MD, Vancouver BC Nancy Van Eyk, MD, Halifax NS INFECTIOUS DISEASES COMMITTEE Mark H. Yudin, MD (Chair), Toronto ON Marc Boucher, MD, Montreal QC

2009 were incorporated in the guideline. Current guidelines published by the American College of Obstetrics and Gynecology were also incorporated. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Values: The evidence obtained was reviewed and evaluated by the Infectious Diseases Committee of the Society of Obstetricians and Gynaecologists of Canada under the leadership of the principal authors, and recommendations were made according to guidelines developed by the Canadian Task Force on Preventive Health Care (Table 1).

Deborah M. Money, MD, Vancouver BC

Benefits, Harms, and Costs: Implementation of this guideline should reduce the cost and harm resulting from the istration of antibiotics when they are not required and the harm resulting from failure to ister antibiotics when they would be beneficial.

Gina Ogilvie, MD, Vancouver BC

Summary Statements

Eliana Castillo, MD, Vancouver BC

1. Available evidence does not the use of prophylactic antibiotics to reduce infectious morbidity following operative vaginal delivery. (II-1)

Beatrice Cormier, MD, Montreal QC Andrée Gruslin, MD, Ottawa ON

Caroline Paquet RM, Trois-Rivières QC Audrey Steenbeek, RN, Halifax NS Nancy Van Eyk, MD, Halifax NS Julie van Schalkwyk, MD, Vancouver BC Thomas Wong, MD, Ottawa ON Disclosure statements have been received from all of the committee. The literature searches and bibliographic for this guideline were undertaken by Becky Skidmore, Medical Research Analyst, Society of Obstetricians and Gynaecologists of Canada.

2. There is insufficient evidence to argue for or against the use of prophylactic antibiotics to reduce infectious morbidity for manual removal of the placenta. (III) 3. There is insufficient evidence to argue for or against the use of prophylactic antibiotics at the time of postpartum dilatation and curettage for retained products of conception. (III) 4. Available evidence does not the use of prophylactic antibiotics to reduce infectious morbidity following elective or emergency cerclage. (II-3) Recommendations

Abstract Objective: To review the evidence and provide recommendations on antibiotic prophylaxis for obstetrical procedures. Outcomes: Outcomes evaluated include need and effectiveness of antibiotics to prevent infections in obstetrical procedures. Evidence: Published literature was retrieved through searches of Medline and The Cochrane Library on the topic of antibiotic prophylaxis in obstetrical procedures. Results were restricted to systematic reviews, randomized controlled trials/controlled clinical trials, and observational studies. Searches were updated on a regular basis and articles published from January 1978 to June

Key Words: Antibiotic prophylaxis, surgical prophylaxis, obstetrical procedures, surgical site infection, SSI, endometritis, endocarditis

1. All women undergoing elective or emergency Caesarean section should receive antibiotic prophylaxis. (I-A) 2. The choice of antibiotic for Caesarean section should be a single dose of a first-generation cephalosporin. If the patient has a penicillin allergy, clindamycin or erythromycin can be used. (I-A) 3. The timing of prophylactic antibiotics for Caesarean section should be 15 to 60 minutes prior to skin incision. No additional doses are recommended. (I-A) 4. If an open abdominal procedure is lengthy (> 3 hours) or estimated blood loss is greater than 1500 mL, an additional dose of the prophylactic antibiotic may be given 3 to 4 hours after the initial dose. (III-L) 5. Prophylactic antibiotics may be considered for the reduction of infectious morbidity associated with repair of third and fourth degree perineal injury. (I-B)

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

879

l SEPTEMBER JOGC SEPTEMBRE 2010

SOGC Clinical Practice Guideline

Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well–designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

D. There is fair evidence to recommend against the clinical preventive action E. There is good evidence to recommend against the clinical preventive action L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.40 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the The Canadian Task Force on Preventive Health Care.40

6. In patients with morbid obesity (BMI > 35), doubling the antibiotic dose may be considered. (III-B) 7. Antibiotics should not be istered solely to prevent endocarditis for patients who undergo an obstetrical procedure of any kind. (III-E) J Obstet Gynaecol Can 2010;32(9):878–884

INTRODUCTION

nfectious complications following obstetric surgical procedures are a significant source of morbidity and potential mortality. They include urinary tract infection, endometritis, wound infection, perineal infection, and sepsis, which lead to prolonged hospital stays and increased health care costs. Much work has been done to study the effect of prophylactic antibiotics in reducing infectious morbidity. A plethora of antibiotic types, dosing schedules, and routes of istration have been investigated. There is evidence to the use of prophylactic antibiotics for a number of procedures in obstetrics. Unfortunately, few comparative trials have been conducted, leaving the clinician with uncertainty as to which regimen is superior.

I

The presence of antibiotic resistant organisms is a reality in Canadian health care facilities.1 These organisms include

ABBREVIATIONS CDC

Centers for Disease Control and Prevention

IE

infective endocarditis

SSI

surgical site infection

880

l SEPTEMBER JOGC SEPTEMBRE 2010

methicillin resistant Staphylococcus aureus, vancomycin resistant Enterococcus, and extended-spectrum beta-lactamase-producing organisms. Both morbidity and mortality are increased in infections caused by these organisms, as they may be more virulent and are more difficult to treat because therapeutic options are limited. Antibiotic resistance development results mainly from the inappropriate use of antibiotics. Incomplete courses of antibiotic therapies and the unnecessary use of broader spectrum regimens play a role.2 Adherence to both treatment and prophylaxis guidelines likely assists in reducing infection and antibiotic resistance. Physician adherence to antibiotic prophylaxis guidelines is variable and usually at odds with published guidelines.3,4 In addition to antibiotic prophylaxis, it is essential to review all factors that affect infectious risk reduction in obstetrical care.5 Adherence to appropriate skin preparation procedure, including hair clipping as opposed to shaving, and effective antisepsis of both patient and staff are required.6 Sterile surgical fields must be ensured, and ongoing quality assessment of sterilization technique, air ventilation, and postoperative wound care is needed. Consistent infection control surveillance and reporting of infectious complications track ability to minimize these morbidities and possibly to identify clusters of infection and the emergence of antibiotic resistant organisms. This will dictate changes to operative routines to respond to evolving microbial diversity that seems inevitable.

Antibiotic Prophylaxis in Obstetric Procedures

PRINCIPLES OF ANTIBIOTIC PROPHYLAXIS

The purpose of antibiotic prophylaxis in surgical procedures is not to sterilize tissues but to reduce the colonization pressure of microorganisms introduced at the time of operation to a level that the patient’s immune system is able to overcome.7 Prophylaxis does not prevent infection caused by postoperative contamination. Prophylactic antibiotic use differs from treatment with antibiotics5 in that the former is intended to prevent infection, whereas the latter is intended to resolve an established infection, typically requiring a longer course of therapy. Prophylaxis is intended for elective procedures when the incision will be closed in the operating room. Before an agent can be considered for use as a prophylactic antibiotic, there must be evidence that it reduces postoperative infection. It must also be safe and inexpensive, and it must be effective against organisms likely to be encountered in the surgical procedure. The agent must be istered in a way that ensures that serum and tissue levels are adequate before an incision is made and that therapeutic levels of the agent can be maintained in serum and tissue during surgery and for a few hours (at most) after the incision is closed.7 Wound infections—surgical site infections—in the form of cellulitis, abscess, or dehiscence can occur following laparotomy. Pelvic infections, such as an abscess or infected hematoma, are a risk with any surgical procedure that enters the abdominal cavity. Cuff cellulitis is a specific risk for hysterectomy. Endometritis can result from Caesarean section or surgical abortion. Urinary tract infections can occur as a result of any procedure that involves catheterization of the bladder. A 1999 guideline published by the US Centers for Disease Control and Prevention lists the specific and stringent criteria that must be met for diagnosis of a surgical site infection.7 Accurate surveillance for SSI monitoring requires followup for 30 days postoperatively, and the trend towards early discharge from hospital makes surveillance a challenge. It is estimated that up to 84% of surgical site infections occur following discharge from hospital.7 If prophylactic antibiotics are to be given, they should be istered shortly prior to or at bacterial inoculation.8,9 The majority of studies suggest that a single dose is effective, but for lengthy procedures (> 3 hours) the dose should be repeated at intervals 1or 2 times the half-life of the drug. It has also been suggested that with large blood loss (> 1500 mL), a second dose should be given.10 USE OF ANTIBIOTIC PROPHYLAXIS IN OBSTETRICS

Procedures reviewed in this section include Caesarean section, operative vaginal delivery, manual removal of placenta,

repair of third or fourth degree perineal laceration, cervical cerclage, and postpartum dilatation and curettage. Recent changes to endocarditis prophylaxis guidelines are also be reviewed. Caesarean Section The single most important risk factor for postpartum maternal infection is Caesarean section.11 Women having Caesarean section have a 5- to 20-fold greater risk of infection than women having vaginal delivery. Rates of wound infection and serious infectious complications can be as high as 25%.12 There is no consistent application of definitions for SSI, and the practice of post-discharge surveillance varies widely.13 A recent prospective study with proper application of CDC definitions for surgical site infection with followup to 30 days post-Caesarean section identified a wound infection rate of 8.9%.14 It is likely that post- Caesarean wound infection rates are inaccurate, because up to 84% of infections occur after discharge,7 when surveillance may be lacking. Endomyometritis, urinary tract infection, wound infection, and sepsis may occur following Caesarean section. Numerous studies have investigated the use of prophylactic antibiotics to reduce these complications, the rates of which are all higher in the case of emergency Caesarean section, with or without the presence of maternal fever and/or chorioamnionitis. A Cochrane review published in 2002 included 81 randomized trials assessing antibiotic prophylaxis versus placebo or no treatment for both elective and emergency Caesarean sections. The review included just over 2000 women in each arm. When antibiotics were given rather than placebo or no treatment, the relative risk of endometritis in both elective and emergency Caesarean sections was reduced (RR 0.38; 95% CI 0.22 to 0.64 and RR 0.39; 95% CI 0.34 to 0.46), as was the risk of wound infection (RR 0.36; 95% CI 0.26 to 0.51 and RR 0.73; 95% CI 0.53 to 0.99).15 There has been debate about the benefit of prophylactic antibiotics for a woman who has an elective Caesarean section with intact membranes and without labour. A meta-analysis of 4 studies found that antibiotic prophylaxis resulted in a decrease in postoperative fever (RR 0.25; 95% CI 0.14 to 0.44) and endometritis (RR 0.05; 95% CI 0.01 to 0.38).16 Taken together, these data the recommendation to use prophylactic antibiotics for all women undergoing Caesarean section. Controversy also exists about whether prophylactic antibiotics in Caesarean section should be given prior to skin incision or at the time of the umbilical cord clamping. Traditionally, prophylaxis has been delayed in an effort to avoid masking a neonatal infection and to prevent an unnecessary septic work-up. However, recent evidence may change this practice. A randomized trial compared maternal infectious and SEPTEMBER JOGC SEPTEMBRE 2010 l

881

SOGC Clinical Practice Guideline

neonatal outcomes in women randomized to receive cefazolin 15 to 60 minutes before incision versus at cord clamp. Three hundred fifty-seven women were enrolled. Overall maternal infectious morbidity was reduced in the pre-treatment group (RR 0.4; 95% CI 0.18 to 0.87); in particular, endometritis was reduced (RR 0.2; 95% CI 0.15 to 0.94). No increase in neonatal sepsis, investigation, or length of stay was observed.17 A recent meta-analysis s the use of prophylactic antibiotics prior to Caesarean incision to prevent total infectious morbidity (RR 50; 95% CI 0.33 to 0.78, P = 0.002). Neonatal outcomes were not affected.18 The most widely studied antibiotics for surgical prophylaxis are cephalosporins. Cefazolin is a first-generation cephalosporin and is a Pregnancy Category B drug. When given intravenously, its half-life is 1.8 hours. It provides good coverage for gram positive organisms and has modest gram negative coverage. In a 1999 guideline, the US Centers for Disease Control and Prevention recommended its use at Caesarean section.7 It is recommended that 1 to 2 grams should be istered intravenously not more than 30 minutes before the skin is cut. An additional dose can be considered if blood loss exceeds 1500 mL or at 4 hours if the procedure lasts more than 4 hours (i.e., up to 2 half-lives of the drug).19 Trials have shown that broader spectrum antibiotics for Caesarean section do reduce infectious morbidity. Superiority trials with cefazolin have not been conducted. Given the potential for antibiotic resistance in both mother and neonate, recommendations for the use of broader spectrum antibiotics require further study.20 Operative Vaginal Delivery A 2004 Cochrane review investigated the use of prophylactic antibiotics for operative vaginal delivery, with either forceps or vacuum assisted deliveries, to determine if prophylaxis reduces the incidence of postpartum infections.21 The review identified only one trial of 393 women, and only 2 of 9 outcomes deemed appropriate by the reviewers were assessed in this study: endometritis and length of hospital stay. These did not differ between those who received prophylaxis and those who received no treatment. The review concluded there were insufficient data on which to base recommendations for practice and that further research is needed. No additional studies addressing this issue have been published to date. Manual Removal of Placenta There is limited information regarding the use of prophylactic antibiotics to reduce the development of postpartum endometritis following manual removal of the placenta. A Cochrane review, updated in April 2009, did not identify any randomized controlled trials.22 The World Health Organization suggests that prophylaxis should be offered but recognizes that there is no direct evidence of the value 882

l SEPTEMBER JOGC SEPTEMBRE 2010

of antibiotic prophylaxis after manual removal of the placenta and bases the recommendation on studies involving Caesarean section and abortion and on observational studies of other intrauterine manipulations.23 The effect of operator glove change before manual removal of the placenta at Caesarean section was studied in a group of 228 women, with operators changing gloves in one half of the cases. No difference in post-Caesarean endometritis was noted between the 2 groups.24 However, the incidence of endometritis was decreased when the placenta delivered spontaneously rather than being manually removed at Caesarean section in a study of 333 women, all of whom received prophylactic antibiotics (15% vs. 26%, RR 0.6; P = 0.01).25 Third or Fourth Degree Perineal Laceration A 2005 Cochrane review26 on this subject found there were no randomized trials comparing prophylactic antibiotics with placebo or no treatment in fourth degree perineal tears during vaginal birth. A well-designed randomized trial was recommended. This was undertaken by Duggal et al.27 and published in 2008. This prospective trial followed 107 women post third or fourth degree laceration repair for 2 weeks; the women had been randomly assigned to receive a single intravenous dose of cefotetan, cefoxitin, or placebo. Four of 49 (8%) who received antibiotics and 14 of 58 (24%) who received placebo developed perineal wound complication (P = 0.037). This suggests a benefit to using prophylactic antibiotics to reduce morbidity following significant perineal laceration.27 Elective and Emergency Cerclage, With or Without Exposed Membranes There is insufficient evidence to the use of prophylactic antibiotics with the placement of cervical cerclage in any clinical setting. One study28 investigated the use of continuous low-dose antibiotics in women with a history of second trimester pregnancy loss with the placement of cerclage at 14 to 24 weeks’ gestation on the basis of transvaginal sonographic findings of cervical funnelling. Each of the 10 patients had a live birth, and pregnancy was prolonged by a mean of 13.4 ± 4.2 weeks beyond the previous pregnancy. There was no control group.28 In a second retrospective study of 116 mid-trimester cerclage placements, antibiotic use was not associated with a decreased risk of delivery before 28 weeks’ gestation.29 Randomized clinical trials are needed to confirm the role of antibiotics in these high-risk pregnancies. Postpartum Dilatation and Curettage No studies were identified that investigated the use of prophylactic antibiotics for postpartum dilatation and curettage.

Antibiotic Prophylaxis in Obstetric Procedures

Table 2. Cardiac conditions associated with the highest risk of adverse outcome from endocarditis Prosthetic cardiac valve or prosthetic material used for cardiac valve repair Previous infective endocarditis Congenital heart disease (CHD) Unrepaired cyanotic CHD (including palliative shunts and conduits) Completely repaired CHD with prosthetic material < 6 months after procedure Repaired CHD with residual defects at/near site of prosthetic material Cardiac transplant recipient with cardiac valvulopathy Adapted from Wilson W, Taubert KA, Gewitz M, Lockhart PB, Baddour LM, Levison M, et al. 38

Table 3. Prophylactic antibiotic recommendations for obstetrical procedures Procedure

Antibiotic

Dosage

Level of evidence

Emergency or elective caesarean section (no labour, no rupture of membranes)

Cefazolin IV 15–60 mins prior to skin incision

1–2 g IV

I-A

Clindamycin OR erythromycin

600 mg IV 500 mg IV

None recommended

N/A

II-1C

Manual removal placenta

None recommended

N/A

III-L

Repair third or fourth degree laceration

Cefotetan Cefoxitin

1 g IV 1 g IV

I-B I-B

Postpartum dilatation and curettage

None recommended

N/A

No evidence

Cerclage

None recommended

N/A

II-3C

If penicillin allergic Operative vaginal delivery

Dosage of Antibiotic Prophylaxis in Obesity Increased BMI is associated with higher rates of both obstetric and infectious complications.30 Controlled trials assessing the required dosage for antibiotic prophylaxis based on patient BMI have not been assessed in our specialty. Expert opinion recommends twice the normal dose of prophylaxis for morbidly obese patients, who have a BMI > 35.19 Future research in this area is needed. RECOMMENDATIONS FOR PENICILLIN / CEPHALOSPORIN ALLERGY

Penicillin allergy is self-reported by up to 10 % of patients, yet only 10 % of those are actually allergic when skin testing is performed.31–33 True anaphylactic response to penicillin is rare, occurring in 1 to 4 of 10 000 istrations.34 An allergic reaction to cephalosporins in those with a penicillin allergy occurs at rates of 0.17% to 8.4%.35–37 An alternative to cephalosporins should be given only to individuals with a history of penicillin anaphylaxis (shortness of breath or evidence of airway edema rather than just rash or other allergic reaction) or cephalosporin allergy. Alternative prophylactic antibiotics include clindamycin 600 mg IV or erythromycin 500 mg IV.

PREVENTION OF INFECTIVE ENDOCARDITIS

An American Heart Association guideline38 published in 2007 found no evidence that genitourinary procedures cause IE or that istration of antibiotics prevents IE following such procedures. The American Heart Association therefore does not recommend prophylactic antibiotics for patients undergoing genitourinary procedures; this is a change from their 1997 guideline. They identified 4 conditions that are at highest risk of adverse outcome (Table 2). For patients with the conditions listed in Table 2 who have an established gastrointestinal or genitourinary tract infection or for those who receive antibiotic therapy for another reason (e.g., to prevent wound infection), they suggest it may be reasonable that the choice of antibiotic also be active against enterococci (i.e., ampicillin, piperacillin, or vancomycin). They also suggest that it may be reasonable for patients at high risk of IE who have a known enterococcal urinary tract infection or colonization to receive antibiotic treatment prior to any urinary tract manipulation. A review on this recommendation change has been recently published.39 SEPTEMBER JOGC SEPTEMBRE 2010 l

883

SOGC Clinical Practice Guideline

SUMMARY

For a number of procedures in obstetrics and gynaecology, the use of prophylactic antibiotics has been shown to reduce infectious morbidity in a safe and cost-effective manner (Table 3). There remain a number of procedures where the utility of prophylactic antibiotics is either unclear or not well studied. Appropriate antibiotics used at the correct dose and time and with the appropriate frequency will reduce infectious postoperative complications and minimize the development of antibiotic resistant organisms. Summary Statements 1. Available evidence does not the use of prophylactic antibiotics to reduce infectious morbidity following operative vaginal delivery. (II-1)

REFERENCES 1. Zoutman DE, Ford BD. A comparison of infection control program resources, activities, and antibiotic resistant organism rates in Canadian acute care hospitals in 1999 and 2005: pre and post-severe acute respiratory syndrome. Am J Infect Control 2008;36:711–7. 2. Dancer SJ. How antibiotics can make us sick: the less obvious adverse effects of antimicrobial chemotherapy. Lancet Infect Dis 2004;4:611–9. 3. Huskins WC, Ba-Thike K, Festin MR, Limpongsanurak S, Lumbiganon P, Peedicayil A, et al.; Global Network for Perinatal and Reproductive Health. An international survey of practice variation in the use of antibiotic prophylaxis in cesarean section.Int J Gynaecol Obstet 2001;73:141–5. 4. Bratzler DW, Houck PM, Richards C, Steele L, Dellinger EP, Fry DE, et al. Use of antimicrobial prophylaxis for major surgery: baseline results from the National Surgical Infection Prevention Project. Arch Surg 2005;140:174–82. 5. American College of Obstetricians and Gynecologists. ACOG practice bulleting number 47,October 2003. Prophylactic antibiotics in labor and delivery. Obstet Gynecol 2003;102:875–82. 6. Tanner J, Woodings D, Moncaster K. Preoperative hair removal to reduce surgical site infection. Cochrane Database Syst Rev 2006;3:CD004122.

2. There is insufficient evidence to argue for or against the use of prophylactic antibiotics to reduce infectious morbidity for manual removal of the placenta. (III)

7. Mangram AJ, Horan TC, Pearson ML, Silver LC, Jarvis WR. Guideline for prevention of surgical site infection, 1999. Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory Committee. Am J Infect Control 1999;27:97–134.

3. There is insufficient evidence to argue for or against the use of prophylactic antibiotics at the time of postpartum dilatation and curettage for retained products of conception. (III)

8. Classen DC, Evans RS, Pestotnik SL, Horn SD, Menlove RL, Burke JP. The timing of prophylactic istration of antibiotics and the risk of surgical-wound infection. N Engl J Med 1992;326(5):281–6.

4. Available evidence does not the use of prophylactic antibiotics to reduce infectious morbidity following elective or emergency cerclage. (II-3) Recommendations 1. All women undergoing elective or emergency Caesarean section should receive antibiotic prophylaxis. (I-A) 2. The choice of antibiotic for Caesarean section should be a single dose of a first-generation cephalosporin. If the patient has a penicillin allergy, clindamycin or erythromycin can be used. (I-A) 3. The timing of prophylactic antibiotics for Caesarean section should be 15 to 60 minutes prior to skin incision. No additional doses are recommended. (I-A) 4. If an open abdominal procedure is lengthy (> 3 hours) or estimated blood loss is greater than 1500 mL, an additional dose of the prophylactic antibiotic may be given 3 to 4 hours after the initial dose. (III-L) 5. Prophylactic antibiotics may be considered for the reduction of infectious morbidity associated with repair of third and fourth degree perineal injury. (I-B)

9. Bratzler DW, Houck PM; Surgical Infection Prevention Guidelines Writers Workgroup; American Academy of Orthopaedic Surgeons; American Association of Critical Care Nurses; American Association of Nurse Anesthetists; American College of Surgeons; American College of Osteopathic Surgeons; American Geriatrics Society; American Society of Anesthesiologists; American Society of Colon and Rectal Surgeons; American Society of Health-System Pharmacists; American Society of PeriAnesthesia Nurses; Ascension Health; Association of periOperative ed Nurses; Association for Professionals in Infection Control and Epidemiology; Infectious Diseases Society of America; Medical Letter; Premier; Society for Healthcare Epidemiology of America; Society of Thoracic Surgeons; Surgical Infection Society. Antimicrobial prophylaxis for surgery: an advisory statement from the National Surgical Infection Prevention Project. Clin Infect Dis 2004;38:1706–15. 10. Dellinger EP, Gross PA, Barrett TL, Krause PJ, Martone WJ, McGowan JE Jr, et al. Quality standard for antimicrobial prophylaxis in surgical procedures. Infectious Diseases Society of America. Clin Infect Dis 1994;18:422–7. 11. Gibbs RS. Clinical risk factors for puerperal infection. Obstet Gynecol 1980;55(Suppl 5):18S-184S. 12. Henderson E, Love EJ. Incidence of hospital-acquired infections associated with caesarean section. J Hosp Infect 1995;29 245–55. 13. Lee TB, Baker OG. Forum: surveillance of surgical site infections. Asepsis 1994:167–11. 14. Opoein HK, Valbo A, Grinde-Andersen Q, Qalberg M. Post-cesarean surgical site infections according to CDC standards: rates and risk factors. A prospective cohort study. Act Obstet Gynecol Scand 2007;86:1097–102. 15. Smaill F, Hofmeyr GJ. Antibiotic prophylaxis for cesarean section. Cochrane Database Syst Rev 2002;(3):CD000933.

6. In patients with morbid obesity (BMI > 35), doubling the antibiotic dose may be considered. (III-B)

16. Chelmow D, Ruehli MS, Huang E. Prophylactic use of antibiotics for nonlaboring patients undergoing cesarean delivery with intact membranes: a meta-analysis. Am J Obstet Gynecol 2001;184:656–61.

7. Antibiotics should not be istered solely to prevent endocarditis for patients who undergo an obstetrical procedure of any kind. (III-E)

17. Sullivan SA, Smith T, Chang E, Hulsey T, Vandorsten JP, Soper D. istration of cefazolin prior to skin incision is superior to cefazolin at cord clamping in preventing postcesarean infectious morbidity: a randomized, controlled trial. Am J Obstet Gynecol 2007;196:455.e1–5.

884

l SEPTEMBER JOGC SEPTEMBRE 2010

Antibiotic Prophylaxis in Obstetric Procedures

18. Costantine MM, Rahman M, Ghulmiyah L, Byers BD, Longo M, Wen T, et al. Timing of perioperative antibiotics for cesarean delivery: a metaanalysis. Am J Obstet Gynecol 2008;199(3):301.e1–6. 19. Gordon SM. Antibiotic prophylaxis against postoperative wound infections. Cleve Clin J Med 2006;73 (Suppl 1):S42–5. 20. Tita AT, Rouse DJ, Blackwell S, Saade GR, Spong CY, Andrews WW. Emerging concepts in antibiotic prophylaxis for cesarean delivery: a systematic review. Obstet Gynecol 2009;113:675–82. 21. Liabsuetrakul T, Choobun T, Peeyananjarassri K, Islam M. Antibiotic prophylaxis for operative vaginal delivery. Cochrane Database Syst Rev 2004;(3):CD004455. 22. Chongsomchai C, Lumbiaganon P, Laopaiboon M. Prophylactic antibiotics for manual removal of retained placenta in vaginal delivery. Cochrane Database Syst Rev 2006;(2):CD004904. 23. World Health Organisation (WHO). WHO guidelines for the management of postpartum hemorrhage and retained placenta. Geneva: WHO; 2009. Available at: http://whqlibdoc.who.int/publications/2009/ 9789241598514_eng.pdf. Accessed May 23, 2010.

immediate short-term obstetric resource implications: a meta-analysis. Obes Rev 2008;9635–83. 31. Lee CE, Zembower TR, Fotis MA, Postelnick MJ, Greenberger PA, Peterson LR, et al. The incidence of antimicrobial allergies in hospitalized patients: implications regarding prescribing patterns and emerging bacterial resistance. Arch Intern Med 2000;160:2819–22. 32. Sogn DD, Evans R 3rd, Shepherd GM, Casale TB, Condemi J, Greenberger PA, et al. Results of the National Institute of Allergy and Infectious Diseases collaborative clinical trial to test the predictive value of skin testing with major and minor penicillin derivatives in hospitalized adults. Arch Intern Med 1992;152:1025. 33. del Real GA, Rose ME, Ramirez-Atamoros MT, Hammel J, Gordon SM, Arroliga AC, Arroliga ME. Penicillin skin testing in patients with a history of beta-lactam allergy. Ann Allergy Asthma Immunol 2007;98:355–9. 34. International Rheumatic Fever Study Group. Allergic reactions to long-term benzathine penicillin propylaxis for rheumatic fever. Lancet 1991;337(8753):1308–10. 35. Dash, CH. Penicillin allergy and the cephalosporins. J Antimicrob Chemother 1975;1:107.

24. Turrentine MA, Banks TA. Effect of changing gloves before placental extraction on incidence of postcesarean endometritis. Infect Dis Obstet Gynecol 1996;4:16–9.

36. Daulat, S, Solensky, R, Earl, HS, Casey W, Gruchalla RS. Safety of cephalosporin istration to patients with histories of penicillin allergy. J Allergy Clin Immunol 2004;113:1220.

25. Lasley DS, Eblen A, Yancey MK, Duff P. The effect of placental removal method on the incidence of postcesarean infections. Am J Obstet Gynecol 1997;176:1250–4.

37. Fonacier L, Hirschberg R, Gerson S. Adverse drug reactions to a cephalosporins in hospitalized patients with a history of penicillin allergy. Allergy Asthma Proc 2005;26:135.

26. Buppasiri P, Lumbiganon P, Thinkhamrop J, Thinkhamrop B. Antibiotic prophylaxis for fourth degree perineal tear during vaginal birth. Cochrane Database Syst Rev 2005;(4):CD005125.

38. Wilson W, Taubert KA, Gewitz M, Lockhart PB, Baddour LM, Levison M, et al.; American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee; American Heart Association Council on Cardiovascular Disease in the Young; American Heart Association Council on Clinical Cardiology; American Heart Association Council on Cardiovascular Surgery and Anesthesia; Quality of Care and Outcomes Research Interdisciplinary Working Group. Prevention of Infective Endocarditis: Guidelines From the American Heart Association. Circulation 2007;116:1736–54.

27. Duggal N, Mercado C, Daniels K, Bujor A, Caughey AB, El-Sayed YY. Antibiotic prophylaxis for prevention of postpartum perineal wound complications: a randomized controlled trial. Obstet Gynecol 2008;111:1268–73. 28. Shiffman RL. Continuous low-dose antibiotics and cerclage for recurrent second-trimester pregnancy loss. J Reprod Med 2000;45:323–6. 29. Terkildsen MF, Parilla BV, Kumar P, Grobman WA. Factors associated with success of emergent second-trimester cerclage. Obstet Gynecol 2003;101:565–9. 30. Heslehurst N, Simpson H, Ells LJ, Rankin J, Wilkinson J, Lang R, et al. The impact of maternal BMI status on pregnancy outcomes with

39. Castillo E, Magee LA, von Dadelszen P, Money D, Blondel-Hill E, van Schalkwyk J. Our patients do not need endocarditis prophylaxis for genitourinary tract prodecures: insights from the 2007 Amercian Heart Association guidelines. J Obstet Gynaecol Can 2008;30:796–9. 40. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

SEPTEMBER JOGC SEPTEMBRE 2010 l

885

SOGC CLINICAL PRACTICE GUIDELINE SOGC CLINICAL PRACTICE GUIDELINENo. 240, April 2010

Cytomegalovirus Infection in Pregnancy This guideline has been reviewed by the Maternal Fetal Medicine Committee and approved by Executive and Council of the Society of Obstetricians and Gynaecologists of Canada PRINCIPAL AUTHORS Yoav Yinon, MD, Toronto ON Dan Farine, MD, Toronto ON Mark H. Yudin, MD, Toronto ON MATERNAL FETAL MEDICINE COMMITTEE Robert Gagnon, MD (Chair), Montreal QC Lynda Hudon, MD (Co-Chair), Montreal QC Melanie Basso, RN, Vancouver BC

Abstract Objectives: To review the principles of prenatal diagnosis of congenital cytomegalovirus (CMV) infection and to describe the outcomes of the affected pregnancies. Outcomes: Effective management of fetal infection following primary and secondary maternal CMV infection during pregnancy. Neonatal signs include intrauterine growth restriction (IUGR), microcephaly, hepatosplenomegaly, petechiae, jaundice, chorioretinitis, thrombocytopenia and anemia, and long-term sequelae consist of sensorineural hearing loss, mental retardation, delay of psychomotor development, and visual impairment. These guidelines provide a framework for diagnosis and management of suspected CMV infections.

Tracy Pressey, MD, Vancouver BC

Evidence: Medline was searched for articles published in English from 1966 to 2009, using appropriate controlled vocabulary (congenital CMV infection) and key words (intrauterine growth restriction, microcephaly). Results were restricted to systematic reviews, randomized controlled trials/controlled clinical trials, and observational studies. Searches were updated on a regular basis and incorporated into the guideline. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies.

Anne Roggensack, MD, Calgary AB

Recommendations

INFECTIOUS DISEASES COMMITTEE

The quality of evidence reported in this document has been assessed using the evaluation of evidence criteria in the Report of the Canadian Task Force on Preventive Health Care (Table 1).

Hayley Bos, MD, London ON Marie- Delisle, MD, Vancouver BC Dan Farine, MD, Toronto ON Savas Menticoglou, MD, Winnipeg MB William Mundle, MD, Windsor ON Annie Ouellet, MD, Sherbrooke QC

Mark H. Yudin, MD (Chair), Toronto ON Marc Boucher, MD, Montreal QC Eliana Castillo, MD, Vancouver BC Andrée Gruslin, MD, Ottawa ON Deborah M. Money, MD, Vancouver BC Kellie Murphy, MD, Toronto ON Gina Ogilvie, MD, Vancouver BC Caroline Paquet, RM, Trois-Rivières QC Nancy Van Eyk, MD, Halifax NS Julie van Schalkwyk, MD, Vancouver BC Disclosure statements have been received from all of the committees.

Key Words: Congenital infection, cytomegalovirus, CMV, prenatal diagnosis, intrauterine growth restriction, IUGR, microcephaly

1. Diagnosis of primary maternal cytomegalovirus (CMV) infection in pregnancy should be based on de-novo appearance of virus-specific IgG in the serum of a pregnant woman who was previously seronegative, or on detection of specific IgM antibody associated with low IgG avidity. (II-2A) 2. In case of primary maternal infection, parents should be informed about a 30% to 40% risk for intrauterine transmission and fetal infection, and a risk of 20% to 25% for development of sequelae postnatally if the fetus is infected. (II-2A) 3. The prenatal diagnosis of fetal CMV infection should be based on amniocentesis, which should be done at least 7 weeks after presumed time of maternal infection and after 21 weeks of gestation. This interval is important because it takes 5 to 7 weeks following fetal infection and subsequent replication of the virus in the kidney for a detectable quantity of the virus to be secreted to the amniotic fluid. (II-2A) 4. The diagnosis of secondary infection should be based on a significant rise of IgG antibody titre with or without the presence of IgM and high IgG avidity. In cases of proven secondary infection, amniocentesis may be considered, but the risk–benefit ratio is different because of the low transmission rate. (III-C)

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

348

l APRIL JOGC AVRIL 2010

Cytomegalovirus Infection in Pregnancy

5. Following a diagnosis of fetal CMV infection, serial ultrasound examinations should be performed every 2 to 4 weeks to detect sonographic abnormalities, which may aid in determining the prognosis of the fetus, although it is important to be aware that the absence of sonographic findings does not guarantee a normal outcome. (II-2B) 6. Quantitative determination of CMV DNA in the amniotic fluid may assist in predicting the fetal outcome. (II-3B) 7. Routine screening of pregnant women for CMV by serology testing is currently not recommended. (III-B) 8. Serologic testing for CMV may be considered for women who develop influenza-like illness during pregnancy or following detection of sonographic findings suggestive of CMV infection. (III-B) 9. Seronegative health care and child care workers may be offered serologic monitoring during pregnancy. Monitoring may also be considered for seronegative pregnant women who have a young child in day care. (III-B)

probability of intrauterine transmission following primary infection during pregnancy is 30% to 40%,1,8 compared with only 1% following secondary infection. 1,8 Ten to fifteen percent of congenitally infected infants will have symptoms at birth including intrauterine growth restriction, microcephaly, hepatosplenomegaly, petechiae, jaundice, chorioretinitis, thrombocytopenia, and anemia, and 20% to 30% of them will die, mostly of disseminated intravascular coagulation, hepatic dysfunction, or bacterial superinfection.8–10 Most of the congenitally infected infants (85–90%) have no signs or symptoms at birth, but 5% to 15% of them will develop sequelae such as sensorineural hearing loss, delay of psychomotor development, and visual impairment.11,12

J Obstet Gynaecol Can 2010;32(4):348–354

PRENATAL DIAGNOSIS INTRODUCTION

C

ytomegalovirus is the most common cause of intrauterine infection, occurring in 0.2% to 2.2% of all live births, and is a common cause of sensorineural hearing loss and mental retardation.1,2 Most healthy people who acquire CMV after birth experience few or no symptoms and no long-term sequelae. Some experience a mononucleosis-like syndrome with symptoms including malaise, persistent fever, myalgia, cervical lymphadenopathy, and, less commonly, pneumonia and hepatitis.3 After the primary infection, defined as CMV infection in a previously seronegative person, the virus becomes dormant and exists in a latent state, from which it can be reactivated. This is designated as recurrent (secondary) infection.4 In addition, there seem to be several strains of CMV that infect humans, so reinfection can occur, even in immunocompetent individuals. Therefore, secondary infection, defined as intermittent excretion of the virus in the presence of host immunity, may be due to either reactivation of an endogenous virus or exposure to a new virus strain from an exogenous source. Differentiation between these two kinds of secondary infection is not possible by serology but only by molecular analysis of virus isolates.3–5 Seroconversion occurs in 1% to 4% of all pregnancies and is higher in women who are of low socioeconomic status or who have poor personal hygiene.6,7 Congenital infections are the result of transplacental transmission of CMV. Transmission to the fetus may occur because of primary or secondary maternal infection. The

ABBREVIATIONS CMV

cytomegalovirus

PCR

polymerase chain reaction

IUGR

intrauterine growth restriction

The first step in the prenatal diagnosis of congenital CMV infection is determination of maternal primary and secondary infection by serological testing.12 In women with proven CMV infection, the second step is to identify fetal infection by non-invasive (ultrasound examination) and invasive (amniocentesis) prenatal tests12 (Figure). Diagnosis of Maternal Infection Revello and Gerna13 state: The diagnosis of primary CMV infection is ascertained when seroconversion is documented, i.e., the de novo appearance of virus-specific IgG in the serum of a pregnant woman who was previously seronegative. However, such an approach is feasible only when a screening program is adopted and seronegative women are identified and prospectively monitored13 [or when maternal serum specimens are saved]. When the immune status before pregnancy is unknown, determination of primary CMV infection should be based on detection of specific IgM antibody. However, IgM can also be detected in 10% of recurrent infections14 and can be detected for months after primary infection.15 Therefore, the group of women designated CMV-IgM positive could include women with primary infection acquired before pregnancy and a few women with recurrent infections.16 The IgG avidity assay can help distinguish primary infection from past or recurrent infection and can assist in determining when infection occurred.13,17 This assay is based on the observation that virus-specific IgG of low avidity is produced during the first months after onset of infection, whereas subsequently a maturation process occurs by which IgG antibody of increasingly higher avidity is generated. IgG antibody of high avidity is detected only in subjects with remote or recurrent CMV APRIL JOGC AVRIL 2010 l

349

SOGC CLINICAL PRACTICE GUIDELINE

Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

D. There is fair evidence to recommend against the clinical preventive action E. There is good evidence to recommend against the clinical preventive action L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.38 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the The Canadian Task Force on Preventive Health Care.38

infection. Avidity levels are reported as the avidity index, expressing the percentage of IgG bound to the antigen following treatment with denaturing agents.13 An avidity index > 60% is highly suggestive of past or secondary infection, while an avidity index < 30% is highly suggestive of a recent primary infection (duration < 3 months).17 Hence, serologic diagnosis of primary CMV infection during pregnancy is documented by either seroconversion (the appearance of CMV-specific IgG antibody in a previously seronegative woman) or detection of specific IgM antibody associated with low IgG avidity. Women who have detectable specific IgG antibodies without IgM antibodies before pregnancy and a significant rise of IgG antibody titre with or without the presence of specific IgM antibodies and with high IgG avidity can be classified as having recurrent infection.18 Diagnosis of Fetal Infection Since intrauterine transmission of the virus occurs in only 30% to 40% of pregnancies in women with primary infection and at a significantly lower rate in women with secondary infection, it is important in cases of proven maternal infection to find out if the fetus is infected. Ultrasonographic findings are helpful but not diagnostic because CMV has features in common with other intrauterine infections and with other fetal diseases. Moreover, these abnormalities are observed in less than 25% of infected fetuses.19 The most frequently reported 350

l APRIL JOGC AVRIL 2010

Table 2. Congenital CMV infection-sonographic finding IUGR Cerebral ventriculomegaly Microcephaly Intracranial calcifications Ascites/pleural effusion Hydrop fetalis Oligohydramnios/polyhydramnios Hyperechogenic bowel Liver calcifications

sonographic findings of fetal CMV infection include fetal growth restriction, cerebral ventriculomegaly, ascites, intracranial calcifications, abnormality of amniotic fluid volume (usually oligohydramnios), microcephaly, hyperechogenic bowel, hydrops fetalis, pleural effusion, and liver calcifications19–21 (Table 2). Because of its high sensitivity and specificity, CMV isolation from amniotic fluid has been recognized as the gold standard for prenatal diagnosis of fetal CMV infection.9,13,22 To achieve the highest sensitivity, the amniocentesis should be performed until at least 7 weeks after the onset of maternal infection and after 21 weeks of gestation because a detectable quantity of the virus is not secreted to the amniotic fluid until 5 to 7 weeks after fetal infection and replication of the virus in the kidney.9,16,23 It has been repeatedly reported that

Cytomegalovirus Infection in Pregnancy

Algorithm for prenatal diagnosis of congenital CMV

prenatal diagnosis procedures performed too close to the onset of maternal infection carry a substantial risk of false negative results.24–26 The diagnosis of fetal CMV infection should be based on the results of culture and PCR testing of amniotic fluid samples. CMV isolation can be done by conventional culture on fibroblasts or by the shell vial technique, which uses monoclonal antibodies to the major immediate early protein p72 and enables detection of the virus 16 to 24 hours after amniotic fluid collection.23,27,28 Diagnosis of fetal infection by testing for fetal IgM is not recommended not only because of the risk associated with cordocentesis but also because many fetuses infected by CMV do not develop specific IgM until late in pregnancy, resulting in poor sensitivity.5,25 Although it is accepted that amniocentesis in primary maternal CMV infection is warranted because of the high risk of fetal infection, there is no consensus on whether to perform amniotic fluid viral studies in cases of secondary infection, when the risk of fetal infection is low. However, there are several cases of secondary infection with severe sequelae described in the literature; therefore, amniocentesis for prenatal diagnosis of fetal infection may be considered even in cases of secondary infection.3,29

Prognostic Markers of CMV Disease One of the major limitations of prenatal diagnosis of CMV is that positive results of amniotic fluid tests such as viral isolation and PCR do not discriminate between infants who will have symptoms at birth and those who will not. The severity of the sonographically detected abnormalities may aid in determining the prognosis of the fetus, but the absence of sonographic findings does not guarantee a normal outcome. Once fetal infection is diagnosed, serial ultrasound examinations should be done every 2 to 4 weeks to look for signs of CMV infection (Table 2) that might help in predicting the outcome. The ultrasound follow-ups should be performed in a laboratory that is capable of diagnosing the abnormalities outlined in Table 2, and preferably in a referral centre. Fetal MRI may improve the prognostic evaluation, especially when brain abnormalities are detected by ultrasound. However, the role of fetal MRI in providing useful information in fetuses with CMV still needs to be determined.30,31 The clinical significance of the viral load in amniotic fluid as a prognostic factor has been investigated by several studies, which showed that the CMV DNA load values in amniotic fluid samples were significantly higher in the group of APRIL JOGC AVRIL 2010 l

351

SOGC CLINICAL PRACTICE GUIDELINE

symptomatic than in the group of asymptomatic fetuses.32 However, a great number of values were found to overlap between the two groups33,34; thus the role of quantitative determination of CMV DNA in the amniotic fluid as a prognostic factor of CMV disease still awaits confirmation. PRENATAL TREATMENT AND PREVENTION OF CONGENITAL CMV INFECTION

Despite advances in the diagnosis of fetal CMV infection, there is no effective therapy, and the option of pregnancy termination is often raised once fetal infection is detected by ultrasound or amniocentesis or once a fetus is determined or suspected to be affected. A recent multicentre prospective cohort study of 157 pregnant women with confirmed primary CMV infection evaluated the use of CMV-specific hyperimmune globulin for the treatment and prevention of fetal CMV infection.32 Forty-five women had a primary infection more than 6 weeks before enrolment, underwent amniocentesis, and had CMV detected in the amniotic fluid. Thirty-one of these women elected to receive intravenous treatment with CMV-hyperimmune globulin (200 U/kg of the mother’s body weight). Fourteen women declined treatment with hyperimmune globulin, and 7 of them had infants who were symptomatic at delivery. In contrast, only 1 of the 31 treated women had an infant with clinical CMV disease at birth although 15 of them were carrying fetuses with ultrasonographic evidence of CMV disease.32 In the prevention group, 37 received hyperimmune globulin, 6 (16%) of whom had infants with congenital CMV infection, compared with 19 of 47 women (40%) who did not receive hyperimmune globulin. No adverse effects of hyperimmune globulin were observed.32 These results offer a potential measure to treat and prevent congenital CMV infection. However, this was not a randomized controlled trial, and further study is necessary prior to widespread adoption of this strategy. Regarding postnatal therapy, there is some evidence suggesting a limited beneficial role for ganciclovir treatment of neonates with symptomatic congenital CMV infection. A few studies have demonstrated some hearing improvement and less hearing deterioration in infants treated with ganciclovir.33–35 The ultimate goal in prevention of congenital CMV infection is to develop a vaccine, which would be istered to seronegative women of childbearing age to prevent the occurrence of primary CMV infection during pregnancy. Until an effective vaccine is available, recommendations for seronegative pregnant women with respect to CMV infection include practising good personal hygiene such as avoiding intimate with salivary secretions and urine from 352

l APRIL JOGC AVRIL 2010

young children and careful hand washing after changing diapers and wiping secretions.33 Despite our assumption that changing protective behaviours prevents child to mother transmission of CMV during pregnancy, Adler et al. did not show any benefit for such intervention.34 However, their data also demonstrated that intervention is more effective during pregnancy than before pregnancy, because pregnant women are more motivated to adhere to recommendations than non-pregnant women.35 The Question of Screening Screening for CMV by serology has been and still is a debated issue. Routine serologic screening for pregnant women has never been recommended by any public health authority.13 The screening, if done, should be performed at the beginning of pregnancy or even prior to a planned pregnancy. If a woman is seronegative, repeated examinations during pregnancy should be done when there is clinical suspicion. However, screening is usually done before pregnancy for diseases such as rubella and varicella against which immunization can be provided, whereas there is currently no effective and safe immunization against CMV. Moreover, because effective prenatal treatment options are not yet available, the choices when a women is carrying a baby with CMV infection or disease are limited to elective termination of the pregnancy or expectant observation until delivery. Prenatal testing, however, offers an opportunity to educate women about behaviours, and precautionary measures can be suggested to seronegative women.36 Moreover, routine antibody testing, especially if done before pregnancy, may help to differentiate between primary and secondary infection in cases of suspected CMV infection during pregnancy.29 Naessens et al. evaluated a screening program for CMV in which serological testing was performed at the first prenatal visit; they showed that such screening allows the detection of 82% of all congenital CMV infections.37 Nevertheless, routine serologic testing of all pregnant women for CMV to identify those who have acquired primary infection during pregnancy is not currently recommended. Therefore, serological testing for CMV should be used only in women who develop influenza-like symptoms during pregnancy or following detection of sonographic findings that are suggestive of CMV infection and that cannot be explained by another cause (placental insufficiency in case of IUGR and oligohydramnios and fetal anemia in case of ascites etc.). SUMMARY

Congenital CMV infection is the leading infectious cause of mental retardation and sensorineural deafness. Once primary maternal CMV infection has been diagnosed, fetal infection can be accurately determined by amniocentesis. Prenatal counselling in case of fetal infection is difficult

Cytomegalovirus Infection in Pregnancy

because of our limited ability to predict outcome. Because 20% to 25% of infected fetuses will develop sequelae, termination of pregnancy should be discussed as one of the management options. Currently, routine serologic testing of all pregnant women is not recommended, and use of serologic testing should be used only in pregnant women who develop influenza-like illness or following detection of sonographic findings suggestive of CMV infection. RECOMMENDATIONS

The quality of evidence reported in this document has been assessed using the evaluation of evidence criteria in the Report of the Canadian Task Force on Preventive Health Care (Table 1). 1. Diagnosis of primary maternal cytomegalovirus (CMV) infection in pregnancy should be based on de-novo appearance of virus-specific IgG in the serum of a pregnant woman who was previously seronegative, or on detection of specific IgM antibody associated with low IgG avidity. (II-2A) 2. In case of primary maternal infection, parents should be informed about a 30% to 40% risk for intrauterine transmission and fetal infection, and a risk of 20% to 25% for development of sequelae postnatally if the fetus is infected. (II-2A)

8. Serologic testing for CMV may be considered for women who develop influenza-like illness during pregnancy or following detection of sonographic findings suggestive of CMV infection. (III-B) 9. Seronegative health care and child care workers may be offered serologic monitoring during pregnancy. Monitoring may also be considered for seronegative pregnant women who have a young child in day care. (III-B) REFERENCES 1. Stagno S, RF, Cloud G, Britt WJ, Henderson RE, Walton PD, et al. Primary cytomegalovirus infection in pregnancy. Incidence, transmission to fetus, and clinical outcome, JAMA 1986;256:1904–8. 2. Pultoo A, Jankee H, Meetoo G, Pyndiah MN, Khittoo G. Detection of cytomegalovirus in urine of hearing-impaired and mentally retarded children by PCR and cell culture. J Commun Dis 2000;32:101–8. 3. Gaytant MA, Steegers EA, Semmekrot BA, Merkus HM, Galama JM. Congenital cytomegalovirus infection: review of the epidemiology and outcome. Obstet Gynecol Surv 2002; 57:245–56. 4. Alford CA, Stagno S, RF, Britt WJ. Congenital and perinatal cytomegalovirus infections, Rev Infect Dis 1990;12(Suppl 7):S745–53. 5. Daniel Y, Gull I, Peyser MR, Lessing JB. Congenital cytomegalovirus infection. Eur J Obstet Gynecol Reprod Biol 1995;63:7–16. 6. Hagay ZJ, Biran G, Ornoy A, Reece EA. Congenital cytomegalovirus infection: a long-standing problem still seeking a solution. Am J Obstet Gynecol 1996;174:241–5. 7. Hanshaw JB. Cytomegalovirus infections. Pediatr Rev 1995;16:43–48; quiz 49. 8. Raynor BD. Cytomegalovirus infection in pregnancy. Semin Perinatol 1993;17:394–402.

3. The prenatal diagnosis of fetal CMV infection should be based on amniocentesis, which should be done at least 7 weeks after presumed time of maternal infection and after 21 weeks of gestation. This interval is important because it takes 5 to 7 weeks following fetal infection and subsequent replication of the virus in the kidney for a detectable quantity of the virus to be secreted to the amniotic fluid. (II-2A)

10. RF. Cytomegalovirus infection. Pediatr Rev 2002;23:163–70.

4. The diagnosis of secondary infection should be based on a significant rise of IgG antibody titre with or without the presence of IgM and high IgG avidity. In cases of proven secondary infection, amniocentesis may be considered, but the risk–benefit ratio is different because of the low transmission rate. (III-C)

13. Revello MG, Gerna G. Diagnosis and management of human cytomegalovirus infection in the mother, fetus, and newborn infant. Clin Microbiol Rev 2002;15:680–715.

5. Following a diagnosis of fetal CMV infection, serial ultrasound examinations should be performed every 2 to 4 weeks to detect sonographic abnormalities, which may aid in determining the prognosis of the fetus, although it is important to be aware that the absence of sonographic findings does not guarantee a normal outcome. (II-2B) 6. Quantitative determination of CMV DNA in the amniotic fluid may assist in predicting the fetal outcome. (II-3B) 7. Routine screening of pregnant women for CMV by serology testing is currently not recommended. (III-B)

9. Nigro G, Mazzocco M, Anceschi MM, La Torre R, Antonelli G, Cosmi EV. Prenatal diagnosis of fetal cytomegalovirus infection after primary or recurrent maternal infection. Obstet Gynecol 1999;94:909–14.

11. Boppana SB, RF, Britt WJ, Stagno S, Alford CA. Symptomatic congenital cytomegalovirus infection: neonatal morbidity and mortality. Pediatr Infect Dis J 1992;11:93–9. 12. Lazzarotto T, Varani S, Guerra B, Nicolosi A, Lanari M, Landini MP. Prenatal indicators of congenital cytomegalovirus infection. J Pediatr 2000;137:90–5.

14. Griffiths PD, Stagno S, RF, Smith RJ, Alford CA Jr. Infection with cytomegalovirus during pregnancy: specific IgM antibodies as a marker of recent primary infection. J Infect Dis 1982;145:647–53. 15. Drew WL. Diagnosis of cytomegalovirus infection. Rev Infect Dis 1988;10(Suppl 3):S468–76. 16. Liesnard C, Donner C, Brancart F, Gosselin F, Delforge ML, Rodesch F. Prenatal diagnosis of congenital cytomegalovirus infection: prospective study of 237 pregnancies at risk. Obstet Gynecol 2000;95:881–8. 17. Grangeot-Keros L, Mayaux MJ, Lebon P, Freymuth F, Eugene G, Stricker R, et al. Value of cytomegalovirus (CMV) IgG avidity index for the diagnosis of primary CMV infection in pregnant women. J Infect Dis 1997;175:944–6. 18. Yinon Y, Yagel S, Tepperberg-Dikawa M, Feldman B, Schiff E, Lipitz S. Prenatal diagnosis and outcome of congenital cytomegalovirus infection in twin pregnancies. BJOG 2006;113:295–300.

APRIL JOGC AVRIL 2010 l

353

SOGC CLINICAL PRACTICE GUIDELINE

19. Lipitz S, Achiron R, Zalel Y, Mendelson E, Tepperberg M, Gamzu R. Outcome of pregnancies with vertical transmission of primary cytomegalovirus infection. Obstet Gynecol 2002;100:428–33. 20. Crino JP. Ultrasound and fetal diagnosis of perinatal infection. Clin Obstet Gynecol 1999; 42:71–80; quiz 174–5. 21. Malinger G, Lev D, Zahalka N, Ben Aroia Z, Watemberg N, Kidron D, et al. Fetal cytomegalovirus infection of the brain: the spectrum of sonographic findings. AJNR Am J Neuroradiol 2003;24:28–32. 22. Hohlfeld P, Vial Y, Maillard-Brignon C, Vaudaux B, Fawer CL. Cytomegalovirus fetal infection: prenatal diagnosis. Obstet Gynecol 1991;78:615–8. 23. Revello MG, Gerna G. Pathogenesis and prenatal diagnosis of human cytomegalovirus infection. J Clin Virol 2004;29:71–83. 24. Bodeus M, Hubinont C, Bernard P, Bouckaert A, Thomas K, Goubau P. Prenatal diagnosis of human cytomegalovirus by culture and polymerasec chain reaction: 98 pregnancies leading to congenital infection. Prenat Diagn 1999;19:314–7. 25. Lipitz S, Yagel S, Shalev E, Achiron R, Mashiach S, Schiff E. Prenatal diagnosis of fetal primary cytomegalovirus infection. Obstet Gynecol 1997;89:763–7. 26. Nicolini U, Kustermann A, Tassis B, Fogliani R, Galimberti A, Percivalle E, et al. Prenatal diagnosis of congenital human cytomegalovirus infection. Prenat Diagn 1994;14:903–6. 27. Gleaves CA, Smith TF, Shuster EA, Pearson GR. Rapid detection of cytomegalovirus in MRC-5 cells inoculated with urine specimens by using low-speed centrifugation and monoclonal antibody to an early antigen. J Clin Microbiol 1984;19:917–9. 28. Lazzarotto T, Varani S, Gabrielli L, Spezzacatena P, Landini MP. New advances in the diagnosis of congenital cytomegalovirus infection. Intervirology 1999;42:390–7.

354

l APRIL JOGC AVRIL 2010

29. Ornoy A, Diav-Citrin O. Fetal effects of primary and secondary cytomegalovirus infection in pregnancy. Reprod Toxicol 2006;21:399–409. 30. Picone O, Simon I, Benachi A, Brunelle F, Sonigo P. Comparison between ultrasound and magnetic resonance imaging in assessment of fetal cytomegalovirus infection. Prenat Diagn 2008;28:753–8. 31. Benoist G, Salomon LJ, Mohlo M, Suarez B, Jacquemard F, Ville Y. Cytomegalovirus-related fetal brain lesions: comparison between targeted ultrasound examination and magnetic resonance imaging. Ultrasound Obstet Gynecol 2008; Epub ahead of print. 32. Nigro G, Adler SP, La Torre R, Best AM. ive immunization during pregnancy for congenital cytomegalovirus infection. N Engl J Med 2005;353:1350–62. 33. Adler SP, Finney JW, Manganello AM, Best AM. Prevention of child-to-mother transmission of cytomegalovirus by changing behaviors: a randomized controlled trial. Pediatr Infect Dis J 1996;15:240–6. 34. Adler SP, Finney JW, Manganello AM, Best AM. Prevention of child-to-mother transmission of cytomegalovirus among pregnant women. J Pediatr 2004;145:485–91. 35. Adler SP, Nigro G, Pereira L. Recent advances in the prevention and treatment of congenital cytomegalovirus infections. Semin Perinatol 2007;31:10–8. 36. Demmler GJ. Screening for congenital cytomegalovirus infection: a tapestry of controversies, J Pediatr 2005;146:162–4. 37. Naessens A, Casteels A, Decatte L, Foulon W. A serologic strategy for detecting neonates at risk for congenital cytomegalovirus infection. J Pediatr 2005;146:194–7. 38. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169(3):207–8.

SOGC CLINICAL PRACTICE GUIDELINE SOGC CLINICAL PRACTICE GUIDELINENo. 239, February 2010

Obesity in Pregnancy Abstract This Clinical Practice Guideline has been prepared by the Maternal Fetal Medicine Committee, reviewed by the Clinical Practice Obstetrics Committee, and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada PRINCIPAL AUTHORS Gregory A.L. Davies, MD, Kingston ON Cynthia Maxwell, MD, Toronto ON Lynne McLeod, MD, Halifax NS MATERNAL FETAL MEDICINE COMMITTEE Robert Gagnon, MD (Chair), Montreal QC Melanie Basso, RN, Vancouver BC Hayley Bos, MD, London ON Marie- Delisle, MD, Vancouver BC Dan Farine, MD, Toronto ON Lynda Hudon, MD, Montreal QC Savas Menticoglou, MD, Winnipeg MB William Mundle, MD, Windsor ON Lynn Murphy-Kaulbeck, MD, Allison NB Annie Ouellet, MD, Sherbrooke QC Tracy Pressey, MD, Vancouver BC

Objective: To review the evidence and provide recommendations for the counselling and management of obese parturients. Outcomes: Outcomes evaluated include the impact of maternal obesity on the provision of antenatal and intrapartum care, maternal morbidity and mortality, and perinatal morbidity and mortality. Evidence: Literature was retrieved through searches of Statistics Canada, Medline, and The Cochrane Library on the impact of obesity in pregnancy on antepartum and intrapartum care, maternal morbidity and mortality, obstetrical anaesthesia, and perinatal morbidity and mortality. Results were restricted to systematic reviews, randomized controlled trials/controlled clinical trials, and observational studies. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to April 2009. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Values: The evidence obtained was reviewed and evaluated by the Maternal Fetal Medicine and Clinical Practice Obstetric Committees of the SOGC under the leadership of the principal authors, and recommendations were made according to guidelines developed by the Canadian Task Force on Preventive Health Care.

Anne Biringer, MD, Toronto ON

Benefits, Harms, and Costs: Implementation of the recommendations in this guideline should increase recognition of the issues clinicians need to be aware of when managing obese women in pregnancy, improve communication and consultation amongst the obstetrical care team, and encourage federal and provincial agencies to educate Canadians about the values of entering pregnancy with as healthy a weight as possible.

Louise Duperron, MD, Montreal QC

Recommendations

Donna Jones, MD, Calgary AB

1. Periodic health examinations and other appointments for gynaecologic care prior to pregnancy offer ideal opportunities to raise the issue of weight loss before conception. Women should 2 be encouraged to enter pregnancy with a BMI < 30 kg/m , and 2 ideally < 25 kg/m . (III-B)

Anne Roggensack, MD, Calgary AB CLINICAL PRACTICE OBSTETRICS Dean Leduc, MD (Chair), Ottawa ON Charlotte Ballerman, MD, Edmonton AB

Lily Shek-Yun Lee, MSN, Vancouver BC Debra Shepherd, MD, Regina SK Kathleen Wilson, RM, Ilderton ON Disclosure statements have been received from all of the committees.

2. BMI should be calculated from pre-pregnancy height and weight. 2 Those with a pre-pregnancy BMI > 30 kg/m are considered obese. This information can be helpful in counselling women about pregnancy risks associated with obesity. (II-2B)

Key Words: Obesity, pregnancy, obstetric anaesthesia, Caesarean section, body mass index, ultrasound, decision to delivery interval

3. Obese pregnant women should receive counselling about weight gain, nutrition, and food choices. (II-2B)

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

FEBRUARY JOGC FÉVRIER 2010 l

165

SOGC CLINICAL PRACTICE GUIDELINE

Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case-control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

D. There is fair evidence to recommend against the clinical preventive action E. There is good evidence to recommend against the clinical preventive action L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.79 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the The Canadian Task Force on Preventive Health Care.79

4. Obese women should be advised that they are at risk for medical complications such as cardiac disease, pulmonary disease, gestational hypertension, gestational diabetes, and obstructive sleep apnea. Regular exercise during pregnancy may help to reduce some of these risks. (II-2B) 5. Obese women should be advised that their fetus is at an increased risk of congenital abnormalities, and appropriate screening should be done. (II-2B) 6. Obstetric care providers should take BMI into consideration when arranging for fetal anatomic assessment in the second trimester. Anatomic assessment at 20 to 22 weeks may be a better choice for the obese pregnant patient. (II-2B) 7. Obese pregnant women have an increased risk of Caesarean section, and the success of vaginal birth after Caesarean section is decreased. (II-2B) 8. Antenatal consultation with an anaesthesiologist should be considered to review analgesic options and to ensure a plan is in place should a regional anaesthetic be chosen. (III-B) 9. The risk of venous thromboembolism for each obese woman should be evaluated. In some clinical situations, consideration for thromboprophylaxis should be individualized. (III-B) J Obstet Gynaecol Can 2010;32(2):165–173

INTRODUCTION

T

he people of industrialized nations, including Canada, have experienced a dramatic increase in obesity in recent times1 The proportion of overweight and obese women in Canada rose from 34% in 1978 to 40% in 1992, and in 2004 it was 53%.2,3 Of particular concern is the rapid increase in overweight and obesity in Canada’s adolescents, in whom rates have risen 100% since 1978.4 Rising rates of obesity are associated with increasing time spent in front of 166

l FEBRUARY JOGC FÉVRIER 2010

the television and computer, a sedentary lifestyle, and poor nutrition.4 The lifestyle that leads to obesity has a direct effect on indicators of health. Women who are overweight or obese are significantly more likely to suffer from high blood pressure, diabetes, and heart disease.3 Concordantly, rates of obesity in pregnancy are increasing.5 This guideline examines the impact of obesity on maternal, fetal, and neonatal outcomes. Recommendations for the management of obese patients in pregnancy are quantified according to the evaluation of evidence guidelines developed by the Canadian Task Force on Preventive Health Care (Table 1). DEFINING OBESITY

The most clinically relevant definition of obesity is the body mass index. BMI is weight in kilograms divided by height in meters squared (kg/m2).6 Canadian guidelines for appropriate BMI are aligned with those of the World Health Organization and separated into six categories (Table 2).3 Studies of the non-pregnant population show that increasing values of BMI are associated with an increased risk for cardiovascular disease, diabetes, osteoarthritis, and cancer.3 The definition of obesity in pregnancy varies by author and includes women who are 110% to 120% of their ideal body weight or > 91 kg (200 lbs) or who have a BMI > 30 kg/m2. There is a paucity of information describing the prevalence of overweight and obesity specifically in the pregnant population. However, BMI data from the 2004 Canadian

Obesity in Pregnancy

Community Health Survey estimate rates of obesity between 11% and 21% for women of child-bearing age.3 Women who were more active and had higher fruit and vegetable consumption had lower rates of obesity.3 Obesity in pregnancy is increasing. According to Nova Scotia’s Atlee perinatal database, using a definition of obesity as > 90 kg, the rate of obesity rose from 3.2% in 1988 to 10.2% in 2002.7 Most obstetrical caregivers in Canada record prepregnancy weight in the antenatal record, although documentation of maternal height is inconsistent.7 Recent evidence from the United States suggests that many obstetrician- gynaecologists use BMI data to screen for obesity.8 The identification of women at risk is not routinely followed by interventions. Suggested strategies include behavioural weight loss treatments and specific counselling regarding exercise, diet, and pregnancy weight gain.8

Table 2. BMI classification

Underweight

BMI range

Risk of developing health problems

< 18.5

Increased

Normal weight

18.5 to 24.9

Least

Overweight

25.0 to 29.9

Increased

Obese Class I

30.0 to 34.9

High

Obese Class II

35.0 to 39.9

Very high

Obese Class III

³ 40.0

Extremely high

Table 3. Pregnancy weight gain based on BMI BMI range

Suggested weight gain (kg)

< 18.5

12.5 to 18

Normal weight

18.5 to 24.9

11.5 to 16

Overweight

25.0 to 29.9

7 to 11.5

Women should set pregnancy weight gain goals based on their pre-pregnancy BMI as shown in Table 3.9

Obese Class I

30.0 to 34.9

7

Obese Class II

35.0 to 39.9

7

To achieve these goals women should be at the healthiest weight possible when they enter pregnancy. During well-woman checks and other health care interactions, non-pregnant women of child-bearing age can be advised of their BMI. An evaluation of dietary intake and exercise habits can provide insight into women at risk.10 According to the t guidelines on exercise in pregnancy by the SOGC and the Canadian Society for Exercise Physiology, all pregnant women without contraindications should participate in regular exercise.11 During prenatal visits women can be questioned and advised about their diet and exercise habits. Where available, nutritional counselling can be a helpful adjunct for women not meeting the weight gain guidelines in Table 3.12 Pregnancy outcomes are related to maternal weight gain.13 Fifty-two percent of a Canadian cohort of women gained more than the recommended weight in pregnancy. Depending on pre-pregnancy BMI, these pregnancies were at increased risk of macrosomia > 4000 g, augmentation of labour, gestational hypertension, and neonatal metabolic abnormalities. Regardless of BMI, those women who gained the recommended amount of weight in pregnancy had fewer adverse outcomes (Caesarean section, gestational hypertension, birth weight < 2500 g or ³ 4000 g).13

Obese Class III

³ 40.0

7

WEIGHT GAIN IN PREGNANCY

IMPACT OF OBESITY ON OBSTETRIC OUTCOMES Ultrasound

With the exception of women who are underweight, most women are best assessed at 18 to 22 weeks to allow better

Underweight

evaluation of fetal structures.14,15 The sonographer’s ability to evaluate fetal structures is largely dependent on maternal size. Approximately 15% of normally visible structures will be suboptimally seen in women with a BMI above the 90th percentile.15 In women with a BMI above the 97.5th percentile, only 63% of structures are well visualized. The anatomic structures commonly less well seen with increasing BMI include the fetal heart, spine, kidneys, diaphragm, and umbilical cord.16 Repeat examinations 2 to 4 weeks later to assess the fetal cardiac anatomy will reduce the number of suboptimally viewed fetuses; however, 12% to 20% (depending on BMI class) will remain poorly visualized.15 Obstetric care providers should take BMI into consideration when arranging for fetal anatomic assessment in the second trimester. Anatomic assessment at 20 to 22 weeks may be a better choice for the obese pregnant patient. The challenge of fetal ultrasound in obese mothers is further complicated by evidence suggesting an increased rate of fetal anomalies. Nuthalapaty and Rouse17 reviewed 17 studies published between 1978 and 2003 associating maternal pre-pregnancy BMI with congenital anomalies. They reported a two-fold increase in neural tube defects in the offspring of obese women. A dose-response was noted, with heavier women having an even higher risk. Their report is ed by the findings of Anderson et al.18 Alarmingly, the protective effects of periconceptional folic FEBRUARY JOGC FÉVRIER 2010 l

167

SOGC CLINICAL PRACTICE GUIDELINE

acid do not appear to benefit the obese woman.19 It is unknown whether an increased dose of folic acid would reduce the risk to that of a lean woman. In their review, Nuthalapaty and Rouse17 also found associations between obesity and risk of other congenital malformations such as heart defects, ventral wall defects, and orofacial clefts but commented that these data were less consistent.

increasing levels of exercise both during the pregnancy and in the year prior to conception.24,25 Postulations on the protective mechanisms of exercise against preeclampsia include enhanced placental growth and vascularity, prevention and reduction of oxidative stress, and correction of vascular endothelial dysfunction.26

Ultrasound estimation of fetal weight is not superior to clinical estimation in the obese population.20 Although both methods have an associated error of approximately 10%, in the series reported by Field et al.,20 30% of obese women had an ultrasound estimated fetal weight within 5 days of delivery that was > 10% different from the actual birth weight.

Gestational Diabetes

PREGNANCY COMPLICATIONS Spontaneous Abortion

The risk of spontaneous abortion is increased in obese women. Using a retrospective case–control model and a sample size of 4932, Lashen et al.21 identified an odds ratio for spontaneous abortion of 1.2 (95% CI 1.01 to 1.46) for obese women (BMI > 30 kg/m2). The authors also identified an increased risk of recurrent early miscarriages (more than 3 successive miscarriages < 12 weeks’ gestation) in the obese population, odds ratio 3.5 (95% CI 1.03 to 12.01).21 Similar risks have been identified in obese women undergoing in vitro fertilization therapy.22 Hypertensive Disorders of Pregnancy

Robinson et al.7 reviewed pregnancy outcomes stratified by maternal pre-pregnancy weight, comparing women whose weight was 55 to 75 kg with those whose weight was > 90 kg.7 In this 15-year retrospective review (1988–2002), there were 79 005 women between 55 and 75 kg, 9355 women between 90 and 120 kg (moderate obesity) and a further 779 women > 120 kg (severe obesity). Compared with the normal weight group, the odds ratio of pregnancy induced hypertension for the moderate obesity group was 2.38 (95% CI 2.24 to 2.52). The odds ratio for the severe obesity group was 3.00 (95% CI 2.49 to 3.62). Obesity also increased the likelihood that women would experience more severe forms of hypertensive complications. For the moderate obesity group the odds ratio of severe pregnancy induced hypertension, including HELLP syndrome, was 1.56 (95% CI 1.35 to 1.80) and for the severe obesity group was 2.34 (95% CI 1.59 to 3.46). Relative to non-obese women there was 1 excess case of pregnancy induced hypertension for every 10 moderately obese women and every 7 severely obese women.7 These findings have been confirmed by others.23 In contrast, retrospective cohorts show a 24% to 60% reduction in preeclampsia in nulliparous women who had 168

l FEBRUARY JOGC FÉVRIER 2010

It is well documented that rising rates of obesity in North America are responsible for the concordant rise in type 2 diabetes in the general population.27 Pre-gestational diabetes is more prevalent in obese women. Therefore, testing in women with risk factors early in pregnancy is recommended.28 Obese women are also at increased risk of developing gestational diabetes.29 In a cohort of 16 102 women, Weiss et al.23 found that in contrast to control subjects (BMI < 30 kg/m2), the odds ratio for obese women (BMI 30 to 34.9 kg/m2) to develop gestational diabetes is 2.6 (95% CI 2.1 to 3.4) and for morbidly obese women (BMI ³ 35 kg/m2) is 4.0 (95% CI 3.1 to 5.2). Not surprisingly, obese women are also at increased risk of having a macrosomic child. The likelihood of delivering an infant weighing more than 4000 g was 1.7 times (95% CI 1.4 to 2.0) greater for obese and 2.0 times (95% CI 1.5 to 2.3) greater for morbidly obese patients. The odds of delivering an infant weighing more than 4500 g was 2.0 times (95% CI 1.4 to 3.0) and 2.4 times (95% CI 1.5 to 3.8) greater for obese and morbidly obese patients, respectively.22 Physical activity is inexpensive and can significantly reduce the risk of gestational diabetes. Zhang et al.29 reported a significant inverse relationship between the amount of weekly vigorous activity and the risk for gestational diabetes. More relevant to the obese population, they also reported a 34% reduction in the development of gestational diabetes in women who did not participate in vigorous exercise but who did participate in brisk walking compared with those who participated in easy pace walking.28 At a Canadian centre, regular walking has been used in addition to diet and insulin as part of therapy for gestational diabetes. Compared with a non-exercising matched control group, those who included walking 25 to 40 minutes 3 to 4 times per week were able to significantly reduce fasting and 1-hour postprandial glucose levels using less insulin over fewer injections. The study design did not permit comment on perinatal outcomes.30 INTRAPARTUM COMPLICATIONS AND MANAGEMENT Macrosomia and Shoulder Dystocia

Sheiner et al.31 analyzed pregnancy outcomes in a cohort of 126 080 deliveries. Patients with hypertension and diabetes were excluded. Obese women (BMI > 30 kg/m2) had an

Obesity in Pregnancy

increased risk of fetal macrosomia with an odds ratio of 1.4 (95% CI 1.2 to 1.7). Sheiner et al.31 did not find an increased risk for shoulder dystocia in the obese population. Jensen et al.32 found similar results in their cohort. The use of antenatal ultrasound to detect fetal macrosomia is associated with increased obstetric interventions such as induction of labour and Caesarean section.33 Delpapa and Mueller-Heubach33 reported 86 women with an estimated fetal weight > 4000 g within 3 days of delivery. In 77%, the ultrasound estimate was greater than the actual birth weight.33 The rate of Caesarean section is affected when sonographic examination indicates a macrosomic fetus.34 Parry et al.34 compared the rate of Caesarean section when fetal macrosomia was incorrectly predicted by antenatal ultrasound with the rate of Caesarean section in pregnancies when antenatal ultrasound correctly predicted the fetal weight not to be macrosomic. The estimated fetal weight for the predicted macrosomic group was significantly greater than that of the non-macrosomic group: 42.3% versus 24.3%, RR 1.74, (95% CI, 1.09 to 2.78).34 Although fetal macrosomia is a risk factor for shoulder dystocia, the absolute risk of a severe shoulder dystocia associated with permanent impairment, or death, remains low.35 When the sensitivity and specificity of ultrasound to predict a birth weight > 4500 g are included, it is estimated that 3695 non-diabetic women would require Caesarean section to prevent a single case of permanent brachial plexus injury due to shoulder dystocia.35 Fetal Monitoring

External fetal monitoring is at times more difficult in the presence of maternal obesity given the challenge of transducing the fetal heart through the maternal pannus. There is no evidence to the routine use of internal fetal monitoring in this population, but it may be more effective in some women. Uterine Monitoring

There is increasing evidence that uterine contractility in obese women, compared with normal weight women, may be altered or impaired.36,37 It is unclear whether these alterations in myometrial response may lead to abnormal labour and the observed increase in risk of Caesarean delivery. Monitoring contractions and ensuring adequate labour in obese women poses a special challenge. Although most obstetric care providers rely on manual palpation and/or external tocometry, the use of an intrauterine pressure catheter may be advantageous in some cases. Newer techniques, such as electrohysterography, may prove superior to both tocodynometry and intrauterine pressure assessment for labour monitoring in this population.38

Caesarean Section

The risk of Caesarean section is increased in the obese parturient. Dietz et al.39 analyzed 24 423 nulliparous women stratified by pre-pregnancy BMI and pregnancy complications. The Caesarean section rate was 14.3% for lean women (BMI < 19.8 kg/m2) and 42.6% for very obese women (BMI ³ 35 kg/m2). Among women without any complications, the relative risk of Caesarean section was 1.4 (95% CI 1.0 to 1.8) for overweight women (BMI 25 to 29.9 kg/m2), 1.5 (95% CI 1.1 to 2.1) for obese women (BMI 30 to 34.9 kg/m2), and 3.1 (95% CI 2.3 to 4.8) for very obese women (BMI ³ 35 kg/m2).39 Large cohorts from differing jurisdictions show similar findings.22,40 The increase in the rate of Caesarean section may be due, in part, to the fact that overweight and obese nulliparous women progress more slowly through the first stage of labour.41 When faced with lack of descent in the second stage of labour, some practitioners may opt for Caesarean section rather than operative vaginal delivery because of concerns about fetal macrosomia and shoulder dystocia. This may explain the decreased operative vaginal delivery rate in some series.42 Obese women undergoing Caesarean section experience more complications, including blood loss > 1000 mL, increased operative time, increased postoperative wound infection and endometritis, and need for vertical skin incision.43,44 Those obese women with diabetes who undergo Caesarean section have an odds ratio for postoperative wound infection of 9.3 (95% CI 4.5 to 19.2), and those who require a vertical skin incision have a 12% rate of wound complication serious enough to require opening the incision.43,45 Postoperative infections are even increased in those obese women who have elective Caesarean section with prophylactic antibiotics.46 Hospitals should ensure that there is an operating room table that can accommodate morbidly obese parturients. Similarly, hospitals and obstetrical caregivers should ensure there are appropriate surgical instruments to adequately visualize and operate on obese patients who require Caesarean section. Vaginal Birth After Caesarean Section

In the absence of contraindications, women who have had their first child by Caesarean section are asked to consider vaginal birth in subsequent pregnancies.47 The success of vaginal birth after Caesarean section is commonly quoted at 80%.48 Obese women are less likely than their lean peers to be successful in delivering vaginally after previous Caesarean section. In women with a BMI > 29 kg/m2 the success rate is 54% to 68%.49,50 The rate of success is further reduced in even heavier women. Chauhan et al.51 found a 13% VBAC success rate in women > 300 lbs (136 kg). When FEBRUARY JOGC FÉVRIER 2010 l

169

SOGC CLINICAL PRACTICE GUIDELINE

discussing VBAC, obstetric care providers should consider the longer time required to prepare for and commence Caesarean section in obese patients. This includes longer time for patient transport and set-up in an operating room, longer time for establishment of anaesthesia, and longer time from incision to delivery of the fetus. Obese women would benefit from knowing the success rates for women in their BMI group when they make a decision about vaginal birth after Caesarean section. Obstetric Anaesthesia

Rates of difficult or failed tracheal intubations are increased in obese parturients.52 A 6-year review of failed intubations in obstetric patients in a United Kingdom region reported 36 cases of failed intubation; the average BMI of these women was found to be 33.53 The equipment and expertise required to manage a difficult intubation should be readily available. In obese patients the risk of epidural failure is increased. The initial failure rate for epidural catheter placement can be very high (42%),54 and multiple attempts at catheter placement may be required. More than a single attempt is necessary for successful epidural placement in approximately 75% of morbidly obese parturients. and more than three attempts are needed in 14%.55 The use of regional anaesthesia may require significant time and staff resources, which may limit its use in some health care settings. Techniques to improve the success of regional anaesthesia in obese pregnant women, such as ultrasound guidance, will require further investigation in obstetrics.56 Given the increased risks of regional anaesthesia in this population, and dependent on the wishes of the patient, consideration should be given to early epidural in labour. Obese women have an increased risk for sleep apnea, which may influence the choice of location for postoperative care for obese parturients. Caesarean Section and Decision to Delivery Interval

The decision to delivery interval may be longer when an emergent or urgent Caesarean section is required for an obese parturient. Causes for this delay may include patient transport and bed transfer, the establishment of adequate analgesia, and the operative time from incision to delivery. The performance of emergent Caesarean section within 30 minutes is an arbitrary threshold rather than an evidence-based standard. Thomas et al.57 reviewed 17 780 emergency Caesarean sections performed in 2000 in England and Wales. Only 22% of women were delivered within 30 minutes. Of the 4622 Caesarean sections performed for immediate threat to the life of the mother or fetus only 46% were achieved within 30 minutes. There was no difference noted in the rate of 5-minute Apgar scores < 4 or < 7, or the rate of stillbirth between those delivered less than 15 170

l FEBRUARY JOGC FÉVRIER 2010

minutes and those delivered between 16 and 75 minutes after the decision to proceed to Caesarean section.57 There are no published data from Canadian centres that indicate whether obstetric providers can reliably meet this arbitrary standard. There are no published data that address decision to delivery interval in obese patients. Thromboembolism

The risk of thromboembolism is increased in obese parturients. Edwards et al.58 reported 683 obese women (BMI > 29 kg/m2) who were matched to 660 women of normal weight (BMI 19.8 to 26.0 kg/m2). The incidence of thromboembolism was 2.5% in the obese women, and only 0.6% in the control subjects.58 The Royal College of Obstetricians and Gynaecologists (RCOG) in the United Kingdom recommends thromboprophylaxis for 3 to 5 days, using low molecular weight heparin after vaginal delivery for women who are over age 35 and have a pre-pregnancy or early pregnancy BMI > 30 kg/m2 or weight > 90 kg.59 In addition, the RCOG recommends thromboprophylaxis before and for 3 to 5 days following Caesarean section for women with a pre-pregnancy or early pregnancy BMI > 30 kg/m2 or with a current weight > 80 kg. The RCOG also recommends considering thromboprophylaxis in “extremely obese” women who are hospitalized antenatally.59,60 However, the Pregnancy and Thrombosis Working Group in the United States does not concur with the RCOG guidelines. This group recommends consideration of thromboprophylaxis for patients who are obese, on bed rest, or having surgery.61 There have been no randomized controlled trials regarding thromboprophylaxis when there are additional factors to consider in the obese parturient. Therefore, the risk of venous thromboembolism for each obese woman should be evaluated. Depending on the clinical situation, consideration for thromboprophylaxis should be individualized. PERINATAL OUTCOMES

The most prevalent risk factor for unexplained stillbirth is pre-pregnancy obesity.62 The odds ratio for stillbirth is 2.79 (95% CI 1.94 to 4.02) for morbidly obese women (BMI ³ 35 kg/m2).63 The mechanisms suggested for increased stillbirth risk in the obese woman include a decreased ability to perceive a reduction in fetal movement, hyperlipidemia leading to atherosclerosis affecting placental blood flow, and increased snoring and sleep apnea associated with oxygen desaturation and hypoxia.57 There is a growing body of literature demonstrating the in utero environment is a predictor of future neonatal, child, and adult health.64 In the Growing Up Today Study, a cohort of over 14 000 adolescents in the United States, a 1 kg increment in birth weight in full-term infants was

Obesity in Pregnancy

associated with an approximately 50% increase in the risk of being overweight at ages 9 to 14 years.65 This is especially true for the offspring of women who experienced gestational diabetes during the pregnancy.63 In the Hypertension in Pregnancy Offspring Study, Himmelmann et al.66 reported that neonates born to women who were hypertensive during pregnancy appear to have a propensity to impaired glucose tolerance in later childhood.66 Taittonen et al.67 have also reported an increased risk of hypertension in the children of women who are hypertensive during pregnancy . THERAPY AND MANAGEMENT

All women should be encouraged to participate in regular physical exercise during their pregnancy.11 t recommendations by the SOGC and the Canadian Society for Exercise Physiology were published in 2003.11 It is recommended that women exercise four times weekly at moderate intensity. The actual effect of these recommendations is hard to measure because of the difficulty of behavioural change assessment; however, the rising obesity rate in the Canadian pregnant population and the maternal and neonatal sequelae described above are most disturbing. Heart rate target zones for previously sedentary obese pregnant women have recently been developed, using a Canadian population. Davenport et al. recommend target heart rate zones of 102 to 124 beats per minute in obese women aged 20 to 29, and 101 to 120 beats per minute in those aged 30 to 39.68 Nutritional counselling and dietary records may be helpful in guiding overweight and obese women with respect to adequate weight gain during pregnancy. Ideally these should be offered prior to pregnancy so that health status can be optimized before conception.69 The role of behavioural therapy and caloric restriction in obese women to prevent excess weight gain has not been established. Randomized controlled studies using behavioural intervention in normal weight and obese women with the goal of preventing excess weight gain have been inconclusive.70 A systematic review examining energy and protein restriction as preventive strategies to avoid adverse perinatal outcomes concluded these measures are unlikely to be beneficial and may pose harm to the developing fetus.71 The rate of unintended pregnancy increases following bariatric or gastric by surgery in morbidly obese women. Although this therapy is not recommended during pregnancy, it may arise as a discussion point during pre-pregnancy or postpartum visits. New evidence and systematic reviews suggest that weight loss surgery is more effective than conventional treatments in morbid obesity (Table 2). Thus, women who meet the criteria may benefit from counselling and consultation with obesity surgery

specialists.72 A limited but growing body of literature regarding pregnancy outcomes in women who have undergone obesity surgery suggests reassuring outcomes; however, there are reports of significant complications such as nutrient deficiency, severe fetal growth restriction, and maternal bowel obstruction.73–78 SUMMARY

It is critical that women be informed prior to pregnancy about the need to be as healthy as possible before becoming pregnant, which includes having a normal BMI, eating a balanced diet, and participating in regular exercise. It is also critical that provincial and federal authorities recognize the impact on future populations and health care costs of pregnancies complicated by obesity. A long-term national information campaign is required to exploit women’s interest in having as healthy a pregnancy as possible by giving them the information they need to become fit and have a normal BMI before they consider pregnancy. Only a national strategy can change the complacency about pre-pregnancy weight and inform women about the significant increase in risks for themselves and their children. Recommendations 1. Periodic health examinations and other appointments for gynaecologic care prior to pregnancy offer ideal opportunities to raise the issue of weight loss before conception. Women should be encouraged to enter pregnancy with a BMI < 30 kg/m2, and ideally < 25 kg/m2. (III-B) 2. BMI should be calculated from pre-pregnancy height and weight. Those with a pre-pregnancy BMI > 30 kg/m2 are considered obese. This information can be helpful in counselling women about pregnancy risks associated with obesity. (II-2B) 3. Obese pregnant women should receive counselling about weight gain, nutrition, and food choices. (II-2B) 4. Obese women should be advised that they are at risk for medical complications such as cardiac disease, pulmonary disease, gestational hypertension, gestational diabetes, and obstructive sleep apnea. Regular exercise during pregnancy may help to reduce some of these risks. (II-2B) 5. Obese women should be advised that their fetus is at an increased risk of congenital abnormalities, and appropriate screening should be done. (II-2B) 6. Obstetric care providers should take BMI into consideration when arranging for fetal anatomic assessment in the second trimester. Anatomic assessment at 20 to 22 weeks may be a better choice for the obese pregnant patient. (II-2B) FEBRUARY JOGC FÉVRIER 2010 l

171

SOGC CLINICAL PRACTICE GUIDELINE

7. Obese pregnant women have an increased risk of Caesarean section, and the success of vaginal birth after Caesarean section is decreased. (II-2B) 8. Antenatal consultation with an anaesthesiologist should be considered to review analgesic options and to ensure a plan is in place should a regional anaesthetic be chosen. (III-B) 9. The risk of venous thromboembolism for each obese woman should be evaluated. In some clinical situations, consideration for thromboprophylaxis should be individualized. (III-B) REFERENCES 1. Flegal KM. The obesity epidemic in children and adults: current evidence and research issues. Med Sci Sports Exerc 1999;31:509–14. 2. Torrance GM, Hooper MD, Reeder BA. Trends in overweight and obesity among adults in Canada (1970–1992): evidence from national surveys using measured height and weight. Int J Obes Relat Metab Disord 2002;26:797–804. 3. Statistics Canada. Adult obesity in Canada: measured height and weight. 2005. Available at: http://www.statcan.gc.ca/pub/82-620-m/2005001/article/ adults-adultes/8060-eng.htm. Accessed January 6, 2010. 4. Statistics Canada. Overweight Canadian children and adolescents. 2005. Available at: http://www.calgaryhealthregion.ca/programs/childobesity/pdf/ cobesity%5B1%5D.pdf. Accessed January 6, 2010. 5. Lu GC, Rouse DJ, Dubard M, Cliver S, Kimberlin D, Hauth JC. The effect of increasing prevalence of maternal obesity on perinatal morbidity. Am J Obstet Gynecol 2001;185:845–9. 6. Gilmore J. Body mass index and health. Health Reports (Statistics Canada, Catalogue 82–003) 1999;11(1):31–43. 7. Robinson HE, O’Connell CM, Joseph KS, McLeod NL. Maternal outcomes in pregnancies complicated by obesity. Obstet Gynecol 2005;106:1357–64. 8. Power M, Cogswell M, Schulkin J. Obesity prevention and treatment practices of US obstetrician-gynecologists. Obstet Gynecol 2006;108:961–8. 9. Cunningham FG, Gant NF, Leveno KJ, Gilstrap LC III, Hauth JC, Wenstrom KD. Prenatal care. In: William’s Obstetrics. 21st ed. New York: Appleton and Lange;2001:232.

18. Anderson JL, Waller DK, Canfield MA, Shaw GM, Watkins ML, Werler MM. Maternal obesity, gestational diabetes, and central nervous system birth defects. Epidemiology 2005;16:87–92. 19. Werler MM, Louik C, Shapiro S, Mitchell AA. Prepregnant weight in relation to risk of neural tube defects. JAMA 1996;275:1127–8. 20. Field NT, Piper JM, Langer O. The effect of maternal obesity on the accuracy of fetal weight estimation. Obstet Gynecol 1995;86:102–7. 21. Lashen H, Fear K, Sturdee DW. Obesity is associated with increased risk of first trimester and recurrent miscarriage: matched case-control study. Hum Reprod 2004;19:1644–6. 22. Bellver J, Rossal LP, Bosch E, Zuniga A, Corona JT, Melendez F, et al. Obesity and the risk of spontaneous abortion after oocyte donation. Fertil Steril 2003;79:1136–40. 23. Weiss JL, Malone FD, Emig D, Ball RH, Nyberg DA, Comstock CH, et al. FASTER Research Consortium. Obesity obstetric complications and cesarean delivery rate—a population based screening study. Am J Obstet Gynecol 2004;190:1091–7. 24. Sorenson TK, Williams MA, Lee IM, Dashow EE, Thompson ML, Luthy DA. Recreational physical activity during pregnancy and risk of preeclampsia. Hypertension 2003;41:1273–80. 25. Maiorana A, O’Driscoll G, Dembo L, Cheetham C, Goodman C, Taylor R, et al. Effect of aerobic and resistance exercise training on vascular function in heart failure. Am J Physiol Heart Circ Physiol 2000;279:H1999–2005. 26. Weissgerber TL, Wolfe LA, Davies GAL. The role of regular physical activity in preeclampsia prevention. Med Sci Sports Exerc 2004;36:2024–31. 27. Colditz GA, Willett WC, Rotnitzky A, Manson JE. Weight gain as a risk factor for clinical diabetes mellitus in women. Ann Intern Med 1995;122:481–6. 28. Berger H, Crane J, Farine D. Screening for gestational diabetes mellitus. SOGC Clinical Practice Guideline. J Obstet Gynaecol Can 2002;24:894–903. 29. Zhang C, Solomon CG, Manson JE, Hu FB. A prospective study of pregravid physical activity and sedentary behaviors in relation to the risk for gestational diabetes mellitus. Arch Intern Med 2006;166:543–8. 30. Davenport MH, Mottola MF, McManus R, Gratton R. A walking intervention improves capillary glucose control in women with gestational diabetes mellitus: a pilot study. Appl Physiol Nutr Metab 2008;33:511–7.

10. Handbook for physical activity guide to healthy active living. Ottawa: Health Canada; 1998. Available at: http://www.eatwellbeactive.gc.ca. Accessed December 1, 2009.

31. Sheiner E, Levy A, Menes TS, Silverberg D, Katz M, Mazor M. Maternal obesity as an independent risk factor for caesarean delivery. Paediatr Perinat Epidemiol 2004;18:196–201.

11. Davies GAL, Wolfe LA, Mottola MF, MacKinnon C. Exercise in pregnancy and the postpartum period. J Obstet Gynaecol Can 2003;25:516–22.

32. Jensen DM, Damm P, Sorensen B, Molsted-Pedersen L, Westergaard JG, Ovesen P, et al. Pregnancy outcome and pre-pregnancy body mass index in 2459 glucose-tolerant Danish women. Am J Obstet Gynecol 2003;189:239–44.

12. Piirainen T, Isolauri E, Lagstrom H, Laitinen K. Impact of dietary counselling on nutrient intake during pregnancy: a prospective cohort study. Br J Nutr 2006;96: 1095–104. 13. Crane JMG, White J, Murphy P, Burrage L, Hutchens D. The effect of gestational weight gain by body mass index on maternal and neonatal outcomes. J Obstet Gynaecol Can 2009;31:28–35.

33. Delpapa EH, Mueller-Heubach E. Pregnancy outcome following ultrasound diagnosis of macrosomia. Obstet Gynecol 1991;78:340–3. 34. Parry S, Severs , Sehdev HM, Macones GA, White LM, Morgan MA. Ultrasonographic prediction of fetal macrosomia. Association with Cesarean delivery. J Reprod Med 2000;45:17–22.

14. Lantz ME, Chisholm CA. The preferred timing of second trimester obstetric sonography based on maternal body mass index. J Ultrasound Med 2004;23:1019–22.

35. Sacks DA, Chen W. Estimating fetal weight in the management of macrosomia. Obstet Gynecol Survey 2000;55:229–39.

15. Wolfe HM, Sokol RJ, Martier SM, Zador IE. Maternal obesity: a potential source of error in sonographic prenatal diagnosis. Obstet Gynecol 1990;76:339–42.

36. Zhang J, Bricker L, Wray S, Quenby S. Poor uterine contractility in obese women. BJOG 2007;114:343–8.

16. Hendler I, Blackwell SC, Bujold E, Treadwell MC, Mittal P, Sokol RJ, et al. Suboptimal second-trimester ultrasonographic visualization of the fetal heart in obese women: should we repeat the examination? J Ultrasound Med 2005;24:1205–9.

37. Moynihan AT, Hehir MP, Glavey SV, Smith TJ, Morrison JJ. Inhibitory effect of leptin on human uterine contractility in vitro. Am J Obstet Gynecol 2006;195:504–9.

17. Nuthalapaty FS, Rouse DJ. The impact of obesity on obstetrical practice and outcome. Clin Obstet Gynecol 2004;47:898–913.

172

l FEBRUARY JOGC FÉVRIER 2010

38. Euliano TY, Nguyen MT, Marossero D, Edwards RK. Monitoring contractions in obese parturients: electrohysterography compared with traditional monitoring. Obstet Gynecol 2007;109:1136–4.

Obesity in Pregnancy

39. Dietz PM, Callaghan WM, Morrow B, Cogswell ME. Population-based assessment of the risk of primary cesarean delivery due to excess pre-pregnancy weight among nulliparous women delivering term infants. Matern Child Health J 2005;9:237–44. 40. Dempsey JC, Ashiny Z, Qiu CF, Miller RS, Sorensen TK, Williams MA. Maternal pre-pregnancy overweight status and obesity as risk factors for cesarean delivery. J Matern Fetal Neonatal Med 2005;17:179–85.

59. Nelson-Piercy C. Thromboprophylaxis during pregnancy, labour and after vaginal delivery. RCOG Guideline No. 37, 2004. 60. Lewis G, ed. The confidential enquiry into maternal and child health (CEMACH). Saving mothers’ lives: reviewing maternal deaths to make motherhood safer—2003–2005. The Seventh Report on Confidential Enquiries into Maternal Deaths in the United Kingdom. London: CEMACH; 2007.

41. Vahration A, Zhang J, Troendle JF, Savitz DA, Siega-Riz AM. Maternal pre-pregnancy overweight and obesity and the pattern of labor progression in term nulliparous women. Obstet Gynecol 2004;104:943–51.

61. Duhl AJ, Paidas MJ, Ural SH, Branch W, Casele H, Cox-Gill J, et al. Antithrombotic therapy and pregnancy: consensus report and recommendations for prevention and treatment of venous thromboembolism and adverse pregnancy outcomes. Am J Obstet Gynecol 2007;197:457e1–457e21.

42. Steinfeld JD, Valentine S, Lerer T, Ingardia CJ, Wax JR, Curry SL. Obesity-related complications of pregnancy vary by race. J Matern Fetal Med 2000;9:238–41.

62. Fretts RC. Etiology and prevention of stillbirth. Am J Obstet Gynecol 2005;193:1923–35.

43. Perlow JH, Morgan MA. Massive maternal obesity and perioperative cesarean morbidity. Am J Obstet Gynecol 1994;170:560–5. 44. Wall PD, Deucy EE, Glantz JC, Pressman EK. Vertical skin incisions and wound complications in the obese parturient. Obstet Gynecol 2003;102:952–6. 45. Schneid-Kofman N, Sheiner E, Levy A, Holcberg G. Risk factors for wound infection following Cesarean deliveries. Int J Gynaecol Obstet 2005;90:10–5. 46. Myles TD, Gooch J, Santolaya J. Obesity as an independent risk factor for infectious morbidity in patients who undergo cesarean delivery. Obstet Gynecol 2002;100:959–64. 47. Martel M, MacKinnon CJ; SOGC Clinical Practice Obstetrics Committee. Guidelines for vaginal birth after previous Caesarean birth. Society of Obstetricians and Gynaecologists of Canada G No. 155, February 2005. J Obstet Gynaecol Can 2005;27:164–74. 48. Dodd J, Crowther C. Vaginal birth after Caesarean versus elective repeat Caesarean for women with a single prior Caesarean birth: a systematic review of the literature. A N Z J Obstet Gynaecol 2004;44:387–91. 49. Durnwald , Ehrenberg HM, Mercer BM. The impact of maternal obesity and weight gain on vaginal birth after cesarean section success. Am J Obstet Gynecol 2004;191:954–7. 50. Juhasz G, Gyamfi C, Gyamfi P, Tocce K, Stone JL. Effect of body mass index and excessive weight gain on success of vaginal birth after Cesarean delivery. Obstet Gynecol 2005;106:741–6. 51. Chauhan SP, Magann EF, Carroll CS, Barrilleaux PS, Scardo JA, Martin JN Jr. Mode of delivery for the morbidly obese with prior cesarean delivery: vaginal versus repeat cesarean section. Am J Obstet Gynecol 2001;185:349–54. 52. Saravanakumar K, Rao SG, Cooper GM. Obesity and obstetric anaesthesia. Anaesthesia 2006;61:36–48. 53. Barnardo PD, Jenkins JG. Failed tracheal intubation in obstetrics: a 6 year review in a UK region. Anaesthesia 2000;55:685–94. 54. Hood DD, Dewan DM. Anesthestic and obstetric outcome in morbidly obese parturients. Anesthesiology 1993;79:1210–8. 55. Jordan H, Perlow MD, Mark A, Morgan MD. Massive maternal obesity and perioperative cesarean morbidity. Am J Obstet Gynecol 1994;170:560–5. 56. Grau T, Bartusseck, E, Conradi R, Martin E, Motsch J. Ultrasound imaging improves learning curves in obstetrical epidural anaesthesia: a preliminary study. Can J Anaesth 2003;50(10):1047–50. 57. Thomas J, Paranjothy S, James D. National cross sectional survey to determine whether the decision to delivery interval is critical in emergency caesarean section. BMJ 2004; doi:10.1136/bmj.38031.775845.7C. 58. Edwards LE, Hellerstedt WL, Alton IR, Story M, Himes JH. Pregnancy complications and birth outcomes in obese and normal-weight women: effects of gestational weight change. Obstet Gynecol 1996;87:389–94.

63. Cedergren MI. Maternal morbid obesity and the risk of adverse pregnancy outcome. Obstet Gynecol 2004;103:219–24. 64. Simmons R. Perinatal programming of obesity. Exp Gerontol 2005;40:863–6. 65. Gillman MW, Rifas-Siman SL, Berkey CS, Field AE, Colditz GA. Maternal gestational diabetes, and adolescent obesity. Pediatrics 2003;111:E221–6. 66. Himmelmann A, Himmelmann K, Svensson A, Hansson L. Glucose and insulin levels in young subjects with different maternal histories of hypertension: the Hypertension in Pregnancy Offspring Study. J Int Med 1997;241:19–22. 67. Taittonen L, Nuutinen M, Turtinen J, Uhari M. Prenatal and postnatal factors in predicting later blood pressure among children: cardiovascular risk in young Finns. Pediatr Res 1996;40:627–32. 68. Davenport MH, Charlesworth S, Vanderspank D, Sopper MM, Mottola MF. Development and validation of target heart rate zones for overweight and obese pregnant women. Appl Physiol Nutr Metab 2008;33:984–9. 69. Olafsdottir A, Skuladottir G, Thorsdottir I, Hauksoon A, Steingrimsdottir L. Maternal diet in early and late pregnancy in relation to weight gain. Int J Obes 2006;30:492–9. 70. Polley BA, Wing RR, Sims CJ. Randomized controlled trial to prevent excessive weight gain in pregnant women. Int J Obes Relat Metab Disord 2002;26:1494–502. 71. Kramer M. Energy/protein restriction for high weight-for-height or weight gain during pregnancy. Cochrane Database Syst Rev 2000;(1):CD00080. 72. Colquitt J, Clegg A, Loveman E, Royle P, Sidhu MK. Surgery for morbid obesity. Cochrane Database Syst Rev 2005 Oct 19;(4):CD003641. 73. Bar-Zohar D, Azem F, Klausner J, Abu-Abeid S. Pregnancy after laparoscopic adjustable gastric banding: perinatal outcome is favorable also for women with relatively high gestational weight gain. Surg Endosc 2006;20:1580–3. 74. Martin L, Finigan K, Nolan T. Pregnancy after adjustable gastric banding. Obstet Gynecol 2000;95:927–30. 75. Gurewitsch E, Smith-Levitin M, Mack J. Pregnancy following gastric by surgery for morbid obesity. Obstet Gynecol 1996;88:658–61. 76. Weissman A, Hagay Z, Schacter M, Dreazen E. Severe maternal and fetal electrolyte imbalance in pregnancy after gastric surgery for morbid obesity: a case report. J Rep Med 1995;40(11):813–6. 77. Granstrom L, Granstrom L, Backman L. Fetal growth retardation after gastric banding. Acta Obstet Gynecol Scand 1990;69(6):533–6. 78. Moore K, Ouyang D, Whang E. Maternal and fetal deaths after gastric by surgery for morbid obesity. N Engl J Med 2004;351(7):721–2. 79. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169(3):207–8.

FEBRUARY JOGC FÉVRIER 2010 l

173

SOGC CLINICAL PRACTICE GUIDELINE SOGC CLINICAL PRACTICE GUIDELINE

No. 252, December 2010

Oral Contraceptives and the Risk of Venous Thromboembolism: An Update This clinical practice guideline has been reviewed by the Clinical Practice Gynaecology Committee and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHOR Robert Reid, MD, Kingston, ON CLINICAL PRACTICE GYNAECOLOGY COMMITTEE Nicholas Leyland, MD (Co-Chair), North York ON Wendy Wolfman, MD (Co-Chair), Toronto ON

contraceptives, hormonal contraception. Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. Searches were updated on a regular basis and incorporated in the guideline to May 2010. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Values: The quality of evidence was rated using the criteria described by the Canadian Task Force on Preventive Health Care (Table).

Catherine Allaire, MD, Vancouver BC

Summary Statements

Alaa Awadalla, MD, Winnipeg MB

1. Modern oral contraceptives offer highly effective contraception and a range of non-contraceptive benefits. (I)

Carolyn Best, MD, Toronto ON Sheila Dunn, MD, Toronto ON Madeleine Lemyre, MD, Quebec QC Violaine Marcoux, MD, Ville Mont-Royal QC Chantal Menard, RN, Ottawa ON Frank Potestio, MD, Thunder Bay ON David Rittenberg, MD, Halifax NS Sukhbir Singh, MD, Ottawa ON Vyta Senikas, MD, Ottawa ON Disclosure statements have been received from all of the committee. The literature searches and bibliographic for this guideline were undertaken by Becky Skidmore, Medical Research Analyst, Society of Obstetricians and Gynaecologists of Canada.

Abstract Objective: To provide current and emerging evidence on oral contraceptives and the risk of venous thromboembolism. Evidence: Articles published in English from 2005 were retrieved through searches of PubMed and Medline, using the following : venous thromboembolism, VTE, contraception, oral

Key Words: Venous thromboembolism, VTE, contraception, oral contraceptives, hormonal contraception

2. Venous thromboembolism, although rare, remains one of the serious adverse consequences of hormonal contraception. Best evidence indicates that venous thromboembolism rates in non-s of reproductive age approximate 4–5/10 000 women per year; rates in oral contraceptive s are in the range of 9–10/10 000 women per year. For comparison, venous thromboembolism rates in pregnancy approach 29/10 000 overall and may reach 300–400/10 000 in the immediate postpartum period. (II-1) 3. Research demonstrates that oral contraceptives with £ 35 µg of ethinyl estradiol carry a lower risk of venous thromboembolism than oral contraceptives with 50 µg. (II-2) Although preliminary data suggest a possible further reduction in venous thromboembolism with oral contraceptives with < 35 µg ethinyl estradiol, robust data to this conclusion are presently lacking. 4. Recent contradictory evidence and the ensuing media coverage of the venous thromboembolism risk attributed to the progestin component of certain newer oral contraceptive products have led to fear and confusion about the safety of oral contraceptives in general and drospirenone-containing oral contraceptives in particular. “Pill scares” of this nature have occurred in the past, with panic stopping of the pill, increased rates of unplanned pregnancy, and no subsequent decrease in venous thromboembolism rates. (II-3) 5. Two high quality research studies that addressed the venous thromboembolism risk associated with various oral contraceptives found comparable venous thromboembolism rates with drospirenone-containing oral contraceptives and other approved products. (II-1) 6. Two reports suggesting an increased risk of venous thromboembolism with drospirenone-containing oral contraceptives have significant

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

1192

l DECEMBER JOGC DÉCEMBRE 2010

Oral Contraceptives and the Risk of Venous Thromboembolism: An Update

Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

D. There is fair evidence to recommend against the clinical preventive action E. There is good evidence to recommend against the clinical preventive action L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.35 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the The Canadian Task Force on Preventive Health Care.35

methodological flaws that render their conclusions suspect. It seems likely that residual confounding could have distorted both the results and the conclusions of these reports. (II-3) J Obstet Gynaecol Can 2010;32(12):1192–1197

INTRODUCTION

odern oral contraceptives afford not only excellent contraception but also a variety of non-contraceptive benefits, ranging from regulation and reduction of both menstrual bleeding and dysmenorrhea to treatment of premenstrual syndrome, menstrual migraines, acne, and hirsutism. Long-term benefits include reduced rates of endometrial, ovarian, and colorectal cancer.1 Modern OCs are well tolerated (serious side effects are rare), and adherence to prescribed regimens is generally excellent. As a result, OC s are able to prevent pregnancy and the considerable risks associated with being pregnant while enjoying the non-contraceptive benefits of hormonal contraception.

M

ABBREVIATIONS FDA

US Food and Drug istration

OC

oral contraceptives

VTE

venous thromboembolism

VENOUS THROMBOEMBOLISM

Risk Factors Venous thromboembolism is a rare but potentially serious condition, usually involving a blood clot in the deep veins of the legs or pelvis. If the clot breaks away into the circulation it may block blood flow to the lungs (pulmonary embolism) with potentially fatal consequences. Known risk factors for VTE include advancing age,2 cigarette smoking,3 immobility (such as that associated with travel or hospitalization),4 obesity,5 and pregnancy and the peripartum period.6,7 Hormonal Effects on Venous Thromboembolism Hormonal contraceptives increase the risk of VTE above the background rate (from 5/10 000 woman years in nons8 to 9–10/10 000 woman years in OC s9). To keep the risks of VTE for OC s in perspective, it is important to that the risk of VTE in pregnancy may reach 29/10 000,9,10 and in the peripartum period the risk has been reported to be as high as 300–400/10 000.6,7 Among the most widely used and effective contraceptive methods, OCs reduce rates of unplanned pregnancies and actually decrease the overall rate of VTE in the population compared with rates in populations without access to effective contraception.11 Older OCs, which contained higher levels of estrogen, carried a slightly greater risk than currently available OCs, most of

DECEMBER JOGC DÉCEMBRE 2010 l 1193

SOGC CLINICAL PRACTICE GUIDELINE

which contain < 50 µg of ethinyl estradiol. Sub-50 µg pills have a lower risk of VTE than pills with ³ 50 µg.12 Although, in theory, greater reductions in the dosage of estrogen might further decrease the risk of VTE, this benefit has not been clearly established. A non-significant decrease in VTE was noted in the European Active Surveillance Study when OCs containing 30µg ethinyl estradiol were compared with those containing 20µg.9 Lidegaard et al.13 also reported that “a reduction in estrogen dose from 30–40 µg to 20 µg for OCs containing desogestrel or gestodene reduced the risk of venous thromboembolism by 18%”; however, the validity of the VTE diagnoses in the Danish National Patient Registry (1 of 4 registries used by the Lidegaard et al. study) has been questioned.14 Many pills with ethinyl estradiol levels lower than 35 µg are currently on the market, and although they may be associated with fewer estrogen-related nuisance side effects (such as nausea or breast tenderness) in the first months of use, no conclusive data exist to establish that they result in a lower risk of VTE. Pills with £ 20 µg of ethinyl estradiol have the potential to cause more breakthrough (unscheduled) bleeding, and this may be a deterrent to consistent use for some women.15 Innovations in hormonal contraception in recent years have largely involved the use of new progestins, and this has brought the progestin component of the OC under increasing scrutiny. New progestins are, in part, responsible for some of the most desired non-contraceptive benefits, while maintaining a low risk of serious side effects. Third generation pills have been promoted as being less androgenic and as possibly having fewer adverse effects on cardiovascular and metabolic parameters and therefore as being safer than existing pills. Shortly after the introduction of these third generation pills, reports of a possible increased risk of VTE began to appear, bringing the progestin component of these pills under scrutiny. A phenomenon called “stimulated reporting” occurred: physicians with patients on these new pills were more likely to send their patients for assessment of any leg pain and more likely to report any VTE episodes to regulatory authorities because of heightened awareness of the possible risk. What followed was the “pill scare” in 1995, when regulatory authorities issued an alert about the possible increased risk of VTE with third generation pills. The abrupt rise in births and abortions16,17 (each associated with an increased risk of VTE) that resulted from unplanned pregnancies indicated that many women stopped taking OCs because of this scare. The history of this unfortunate episode is well-documented.18,19 Subsequent analysis and/or replication has shown systematic error in the epidemiological studies that examined VTE risks. The precise effects of different hormonal contraceptives on the hemostatic 1194 l DECEMBER JOGC DÉCEMBRE 2010

system continue to be studied and debated,20 but because there were no compelling data demonstrating an increased risk, third generation pills remain on the market and are widely prescribed.21 Assessing Venous Thromboembolism Risks of Oral Contraceptives VTE remains one of the few serious side effects of OC use. Because VTE is so rare, valid information about the risks associated with a given pill cannot be adequately gleaned from pre-marketing research, which may involve only 1000 to 3000 women. Information on serious but rare side effects like VTE must come from post-marketing surveillance. The current Canadian system requires that health care providers voluntarily report unexpected or severe adverse reactions to drugs to Health Canada. Although such a system can alert regulatory authorities to rare unexpected side effects of a medication, it cannot provide valid information about the rates of complications or inform consumers about the comparative risks of available products. This is because newer products tend to be prescribed for women who already have risk factors. For example, drospirenonecontaining pills, which are effective in reducing acne and hair growth, tend to be prescribed for women who are obese and who therefore already have an independent risk factor for a blood clot. Isolated reports of serious side effects of a specific OC may motivate health care providers to be more vigilant in looking for and reporting similar cases (stimulated reporting). Numerators in adverse event reporting are therefore selectively biased towards certain products, which may give a misleading impression of risk. Since denominators (the number of women using a particular product) and risk factors in the entire population of women prescribed a specific type of OC are unknown, voluntary reports of individual cases cannot provide valid information on comparative risks for rare but serious side effects. Another suggested methodology is to try to obtain more comprehensive data by retrospectively searching large databases for use of specific products and establish links between their use and complications like VTE. These techniques may be useful if the original data set includes information on age, weight, duration of use, etc., which are important independent risk factors that might influence risks for VTE. In the absence of quality data on such variables, it is possible that a risk apparently associated with a specific OC is actually associated with the characteristics of the women who were taking that OC. Databases, especially those developed for istrative purposes, may lack adequate validation of discharge diagnoses. A 2010 study has shown that conditions signed out as VTEs in an istrative database are often found to be something else when testing is completed.14 A valid comparison of VTE risk with

Oral Contraceptives and the Risk of Venous Thromboembolism: An Update

different OCs must consider the fact that the risk for VTE is greatest in the first months of use and declines thereafter.9,22–24 This same effect was noted in the largest randomized clinical trial to examine VTE in menopausal women receiving hormone therapy at the time of menopause.25 Comparisons of the VTE risks for different OCs must for duration of use and ensure that new s of one pill are truly being compared with new s of the other pill. RECENT RESEARCH

Legitimate information on these rare risks is most likely to come from research that uses a prospective approach with subjects who are all new s of various OCs. Careful followup by active surveillance (regular patient ) and validation of all suspected cases (through examination of the medical records) is critical. The European Active Surveillance Study was conducted by the manufacturer of a new drospirenone-containing OC with an independent advisory board and after approval by European regulatory authorities. This prospective noninterventional active surveillance study followed 59 674 new s of different OCs for a total of 142 475 woman years, with a loss to follow-up of only 2.4%. The study demonstrated that drospirenone-containing OCs were prescribed more often to heavier women and that despite this there was no difference in VTE rates between s of this new drospirenone- containing OC and other OCs. Another large prospective study used a propensity (risk factor) scoring system to match new s of different pills according to baseline VTE risk.26,27 This study matched new OC prescriptions (drospirenone-containing OCs vs. other OCs in a 2:1 ratio) and evaluated the medical records of all potential VTE episodes. No differences in VTE rates were found between drospirenone-containing OCs and other OCs. Recent publicity about class action litigation in the US and Canada over complications related to drospirenonecontaining OCs has again raised questions about whether VTE rates are higher with drospirenone-containing OCs. Critical analysis of the 2 studies responsible for this adverse publicity,13,28 however, suggests that the conclusions could have resulted from methodologic flaws and/or misinterpretation of findings, a view shared by the FDA.29 The Dutch Mega Study,28 a retrospective case-control study, was designed to evaluate environmental and genetic factors influencing VTE and the effects of different OCs on VTE. Controls were found in an unusual way: many were the partners of men who were seen in a thrombosis clinic, and the remainder were recruited through random-digit dialling. The authors showed hazard ratios for various OCs with wide and overlapping 95% confidence intervals indicating

no statistically significant differences between drospirenone and so-called second generation progestins. Duration of use information was not available on all women, so it is not clear that all were new s. In addition, the risk estimates were not adjusted for important risk factors (such as obesity). Despite this the authors concluded that second generation OCs were safer than third generation as far as VTE was concerned. The FDA has recently revised the product labelling for a drospirenone-containing OC, and with respect to the Dutch Mega Study notes that “The number of [drospirenonecontaining OC] cases (in the Dutch Mega Study) was very small (1.2% of all cases) making the risk estimates unreliable.”29 The other study reporting increased rates of VTE with drospirenone-containing and other third generation OCs was a large Danish national cohort study.13 It consisted of a retrospective examination of Danish women who had prescriptions for hormonal contraception and subsequent hospital diagnostic codes for deep vein thrombosis between 1995 and 2005 in a number of interrelated databases maintained by the Danish national health service. This comprehensive data set included 3.4 million woman years of hormonal contraceptive use. The investigators identified 2045 hormonal contraceptive-related VTEs during this time period. In keeping with prior reports, they found that the risk of VTE decreased with duration of use and with pills containing lower estrogen dosages. In contrast to the prospective studies reported above, they found that drospirenone-containing OCs and other third generation OCs (those containing desogestrel, gestodene) carried an increased risk of VTE compared with levonorgestrelcontaining OCs. Several significant methodological weaknesses have been identified since the publication of that report.13 First, detailed information on confounders such as obesity was not available for the analysis. This is important: obesity rates in the Danish population have almost tripled in the past decade, and evidence from other research suggests that obese women are more likely to be prescribed drospirenone-containing OCs because of the perceived beneficial effects on androgenic symptoms that affect many obese women and on body weight (diuretic effect). In addition, the investigators had no information on OC use before 1995. Therefore, they classified all levonorgestrel use in 1995 as short-term use, but others have estimated that 60% of those levonorgestrel s should have been classified as long-term s.30 ing this premise was the finding that the expected first year elevation of VTE risk was seen with all OCs except the levonorgestrel products. More importantly, the incidence of VTE could not reliably be assessed in the Danish registry.14 Severinsen et al.14 examined the medical records of patients with a diagnosis of DECEMBER JOGC DÉCEMBRE 2010 l 1195

SOGC CLINICAL PRACTICE GUIDELINE

VTE in the same Danish registry used for the Lidegaard et al.13 study and could confirm only 31% of diagnoses made through emergency room visits and only 71% of those made in women itted to the ward for diagnostic testing. The Danish database was designed as an istrative database rather than as a medical research database, and the diagnostic codes were primarily intended to capture costs related to hospitalization. Many physicians were incorrectly entering a diagnostic code for VTE rather than the intended code of “itted for evaluation of possible VTE.”14 The increased rate ratio of VTEs with drospirenonecontaining OCs compared with levonorgestrel containing OCs was 1.64 (95% CI 1.27 to 2.10). With the potential methodological issues identified above and with rate ratios that in epidemiological are very small (relative risks of £ 2), it is extremely difficult to exclude bias or residual confounding as the explanation for the findings.30–33 Despite the recent serious allegations about the validity of the VTE diagnostic codes in the Danish database, the authors of this research have yet to acknowledge the possibility that their data were invalid and their conclusions incorrect.34 The new FDA-endorsed product labelling for a drospirenonecontaining OC addresses the Lidegaard et al. study and concludes, “The risk estimates may not be reliable because the analysis may include women of varying risk levels.”29 CONCLUSION

The highest quality scientific studies evaluating the risk of VTE in OC s show a baseline risk of approximately 4–5/10 000 woman years in women who do not use hormonal contraception. In the absence of reliable contraception, women of reproductive age face risks of VTE associated with pregnancy of up to 29/10 000 woman years, and in the immediate postpartum period this risk is as high as 300–400/10 000 woman years. Prospective observational studies have shown that all currently available OCs increase the risk of VTE to the range of 9–10/10 000 woman years of use and that this risk is highest in the first months of use, with a fall towards baseline risk thereafter. Modern OCs offer excellent contraceptive efficacy, and adherence is good because of their many non-contraceptive benefits. The occurrence of serious risks such as VTE, including pulmonary embolism, are rare with contemporary OCs, but individualized risk assessment should always be unertaken to identify women who would be better advised to use other forms of contraception. For most healthy women of reproductive age, the benefits of OCs will outweigh the risks. 1196 l DECEMBER JOGC DÉCEMBRE 2010

Summary Statements 1. Modern oral contraceptives offer highly effective contraception and a range of non-contraceptive benefits. (I) 2. Venous thromboembolism, although rare, remains one of the serious adverse consequences of hormonal contraception. Best evidence indicates that venous thromboembolism rates in non-s of reproductive age approximate 4–5/10 000 women per year; rates in oral contraceptive s are in the range of 9–10/10 000 women per year. For comparison, venous thromboembolism rates in pregnancy approach 29/10 000 overall and may reach 300–400/10 000 in the immediate postpartum period. (II-1) 3. Research demonstrates that oral contraceptives with £ 35 µg of ethinyl estradiol carry a lower risk of venous thromboembolism than oral contraceptives with 50 µg. (II-2) Although preliminary data suggest a possible further reduction in venous thromboembolism with oral contraceptives with < 35 µg ethinyl estradiol, robust data to this conclusion are presently lacking. 4. Recent contradictory evidence and the ensuing media coverage of the venous thromboembolism risk attributed to the progestin component of certain newer oral contraceptive products have led to fear and confusion about the safety of oral contraceptives in general and drospirenone-containing oral contraceptives in particular. “Pill scares” of this nature have occurred in the past, with panic stopping of the pill, increased rates of unplanned pregnancy, and no subsequent decrease in venous thromboembolism rates. (II-3) 5. Two high quality research studies that addressed the venous thromboembolism risk associated with various oral contraceptives found comparable venous thromboembolism rates with drospirenone-containing oral contraceptives and other approved products. (II-1) 6. Two reports suggesting an increased risk of venous thromboembolism with drospirenone-containing oral contraceptives have significant methodological flaws that render their conclusions suspect. It seems likely that residual confounding could have distorted both the results and the conclusions of these reports. (II-3) REFERENCES 1. ACOG Noncontraceptive uses of hormonal contraception. ACOG Practice Bulletin No. 110, Jan 2010. Obstet Gynecol 2010;115:206–18. 2. Silverstein MD, Heit JA, Mohr DN, Petterson TM, O’Fallon WM, Melton L J 3rd. Trends in the incidence of deep vein thrombosis and pulmonary

Oral Contraceptives and the Risk of Venous Thromboembolism: An Update

embolism. A 25-year population-based study. Arch Intern Med 1998;158:585–93. 3. Pomp ER, Rosendaal FR, Doggen CJM. Smoking increases the risk of venous thrombosis and acts synergistically with oral contraceptive use. Am J Hematol 2008;83:97–102. 4. Cannegieter SC, Doggen CMJ, van Houwelingen HC, Rosendaal FR. Travel-related venous thrombosis: results from a large population-based case control study (MEGA Study). PLoS Med 2006;3(8):e307. DOI:10.1371/journal.pmed. 0030307. 5. Pomp ER, le Cessie S, Rosendaal FR, Doggen CJR. Risk of venous thrombosis: obesity and its t effect with oral contraceptive use and prothrombotic mutations. Br J Haematol 2007;139:289–96. 6. Ros HS, Lichtenstein P, Belloco R, Petersson G, Cnattingius S. Increased risks of circulatory diseases in late pregnancy and puerperium. Epidemiology 2001;12:456–60. 7. Pomp ER, Lenselink AM, Rosendaal FR, Doggen CJM. Pregnancy, the postpartum period and prothrombotic defects: risk of venous thrombosis in the MEGA study. J Thromb Haemost 2008;6:632–7. 8. Heinemann LAJ, Dinger JC. Range of published estimates of venous thromboembolism incidence in young women. Contraception 2007;75:328–36. 9. Dinger JC, Heinemann LAJ, Kuhl-Habich D. The safety of a drospirenone-containing oral contraceptive: final results from the European Active Surveillance study on Oral Contraceptives based on 142,475 women-years of observation. Contraception 2007;75:344–54. 10. Heit JA, Kobbervig CE, James AH, Petterson TM, Bailey KR, Melton LJ 3rd. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med 2005;143:697–706. 11. Ory HW. Mortality associated with fertility and fertility control: 1983. Fam Plann Perspect 1983;15:57–63. 12. Gerstman BB, Piper JM, Tomita DK, Ferguson WJ, Stadel BV, Lundin FE. Oral contraceptive estrogen dose and the risk of deep venous thromboembolic disease. Am J Epidemiol 1991;133:32–7. 13. Lidegaard Ø, Løkkegaard E, Svendsen AL, Agger C. Hormonal contraception and risk of venous thromboembolism: national follow-up study. BMJ 2009;339: b2890. 14. Severinsen MT, Kristensen SR, Overvad K, Dethlefsen C, Tjønneland A, Johnsen SP. Venous thromboembolism discharge diagnoses in the Danish National Patient Registry should be used with caution. J Clin Epidemiol 2010;63:223–8. 15. Gallo MF, Nanda K, Grimes DA, Schulz KF. Twenty micrograms vs. > 20 microg estrogen oral contraceptives for contraception: systematic review of randomized controlled trials. Contraception 2005;71:162–9. 16. Mills A. Combined oral contraception and the risk of venous thromboembolism. Hum Reprod 1997;12:2595–8. 17. Goodyear-Smith A, Arroll B. Termination of pregnancy following panic-stopping of oral contraceptives. Contraception 2002;66:163–7.

20. Hennessy S, Berlin JA, Kinman JL, Margolis DJ, Marcus SM, Strom BL. Risk of venous thromboembolism from oral contraceptives containing gestodene and desogestrel versus levonorgestrel: a meta-analysis and formal sensitivity analysis. Contraception 2001;64:125–33. 21. Spitzer WO. The 1995 pill scare revisited: anatomy of a non-epidemic. Hum Reprod 1997;12:2347–57. 22. Suissa S, Blais L, Spitzer WO, Cusson J, Lewis M, Heineman L. First time use of newer oral contraceptives and the risk of venous thromboembolism. Contraception 1997;56:141–6. 23. Herings RM, Urquhart J, Leufkens HG. Venous thromboembolism among new s of different oral contraceptives. Lancet 1999;354:127–8. 24. Bloemenkamp KW, Rosendaal FR, Helmerhorst FM, Vandenbroucke JP. Higher risk of venous thrombosis during early use of oral contraceptives in women with inherited clotting defects. Arch Intern Med 2000;160:49–52. 25. Cushman M, Kuller LH, Prentice R, Rodabough RJ, Psaty BM, Stafford RS, et al.; for the WHI Investigators. Estrogen plus progestin and the risk of venous thrombosis. JAMA 2004;292:1573–80. 26. Seeger JD, Loughlin J, Eng PM, Clifford CR, Cutone J, Walker AM. Risk of thromboembolism in women taking ethinyl estradiol/drospirenone and other oral contraceptives. Obstet Gynecol 2007;110:587–93. 27. Eng PM, Seeger JD, Loughlin J, Clifford CR, Mentor S, Walker AM. Supplementary data collection with case-cohort analysis to address potential confounding in a cohort study of thromboembolism in oral contraceptive initiators matched on claims-based propensity scores. Pharmacoepidemiol Drug Saf 2008;17:297–305. 28. Van Hylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP, Doggen CJM, Rosendaal FR. Effects of oestrogen dose and progestogen type on venous thrombotic risk associated with oral contraceptives: results of the MEGA case-control study. BMJ 2009;339:b2921. 29. Yasmin physician labeling. Available at: http://www.yasmin-us.com/index.html. Accessed September 29, 2010. 30. Shapiro S, Dinger J. Risk of VTE among s of oral contraceptives [reply to letter to editor]. J Fam Plann Reprod Health Care 2010:36:104–5. 31. Spitzer WO. Bias or causality: Interpreting recent evidence of oral contraceptive studies. Am J Obstet Gynecol 1998;179:S43–S50. 32. Dinger J. Oral contraceptives and venous thromboembolism: old questions revisited. J Fam Plann Reprod Health Care 2009;35:211–3. 33. Shapiro S. Causation, bias and confounding: a hitchhiker’s guide to the epidemiological galaxy. Part 3: principles of causality in epidemiological research: statistical stability, dose- and duration-response effects, internal and external consistency, analogy and biological plausibility. J Fam Plann Reprod Health Care 2008:34:261–4.

18. Spitzer WO. The aftermath of a pill scare: regression to reassurance. Hum Reprod Update 1999;5:736–45.

34. Lidegaard O. Risk of venous thromboembolism among s of oral contraceptives: a review of two recently published studies. J Fam Plann Reprod Health Care 2010;36:103–4.

19. Lewis MA, MacRae KD, Kuhl-Habichl D, Bruppacher R, Heinemann LA, Spitzer WO. The differential risk of oral contraceptives: the impact of full exposure history. Hum Reprod 1999;14:1493–9.

35. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

DECEMBER JOGC DÉCEMBRE 2010 l 1197

SOGC CLINICAL PRACTICE GUIDELINE SOGC Clinical Practice Guideline

No. 242, May 2010

Ovulation Induction in Polycystic Ovary Syndrome This Clinical Practice Guideline has been prepared by the Reproductive Endocrinology and Infertility Committee and approved by Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Tannys D.R. Vause, MD, Ottawa ON Anthony P. Cheung, MD, Vancouver BC REPRODUCTIVE ENDOCRINOLOGY AND INFERTILITY COMMITTEE Anthony P. Cheung, MD (Chair), Vancouver BC Sony Sierra, MD (Co-Chair), Toronto ON Paul Claman, MD, Ottawa ON James Graham, MD, Calgary AB Jo-Anne Guillemin, RN, Regina SK Louise Lapensée, MD, Outremont QC Sabrina Stewart, MD, Saskatoon SK Tannys D.R.Vause, MD, Ottawa ON

Options: This guideline reviews the evidence for the various options for ovulation induction in PCOS. Outcomes: Ovulation, pregnancy and live birth rates, risks, and side effects are the outcomes of interest. Evidence: Published literature was retrieved through searches of Medline using appropriate controlled vocabulary and key words. Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. Grey (unpublished) literature was identified through searching the websites of health technology assessment and of health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Values: The evidence gathered was reviewed and evaluated by the Reproductive Endocrinology and Infertility Committee of the Society of Obstetricians and Gynaecologists of Canada. The quality of evidence was quantified using the Canadian Task Force on Preventive Health Care. Benefits, Harms, and Costs: Benefits include weight reduction and improvements in ovulation, pregnancy, and live birth rates. Potential harms include medication side effects and multiple pregnancies.

CANADIAN FERTILITY AND ANDROLOGY SOCIETY

Validation: These guidelines have been reviewed and approved by the Reproductive Endocrinology and Infertility Committee of the SOGC.

Jason Min, MD (président), Ottawa (Ont.)

Sponsor: The Society of Obstetricians and Gynaecologists of Canada.

Ken Cadesky, MD, Toronto (Ont.)

Recommendations

Ellen Greenblatt, MD, Toronto (Ont.)

1. Weight loss, exercise, and lifestyle modifications have been proven effective in restoring ovulatory cycles and achieving pregnancy in overweight women with PCOS and should be the first-line option for these women. (II-3A) Morbidly obese women should seek expert advice about pregnancy risk. (III-A)

Benjamin Chee-Man Wong, MD, Calgary AB

Jon Havelock, MD, Burnaby (C.-B.) Jeff Roberts, MD, Burnaby (C.-B.) Disclosure statements have been received from all of the committee.

Abstract Objective: To review current non-pharmacologic and pharmacologic options for ovulation induction in women with polycystic ovary syndrome (PCOS).

Key Words: Polycystic ovary syndrome, ovulation induction, infertility

2. Clomiphene citrate has been proven effective in ovulation induction for women with PCOS and should be considered the first-line therapy. Patients should be informed that there is an increased risk of multiple pregnancy with ovulation induction using clomiphene citrate. (I-A) 3. Metformin combined with clomiphene citrate may increase ovulation rates and pregnancy rates but does not significantly improve the live birth rate over that of clomiphene citrate alone.(I-A) Metformin may be added to clomiphene citrate in women with clomiphene resistance who are older and who have visceral obesity. (I-A) 4. Gonadotropin should be considered second-line therapy for fertility in anovulatory women with PCOS. The treatment requires ultrasound and laboratory monitoring. High costs and the risk of multiple pregnancy and ovarian hyperstimulation syndrome are drawbacks of the treatment. (II-2A)

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

MAY JOGC MAI 2010 l

495

SOGC Clinical Practice Guideline

Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well–designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

D. There is fair evidence to recommend against the clinical preventive action E. There is good evidence to recommend against the clinical preventive action L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.69 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the The Canadian Task Force on Preventive Health Care.69

5. Laparoscopic ovarian drilling may be considered in women with clomiphene-resistant PCOS, particularly when there are other indications for laparoscopy. (I-A) Surgical risks need to be considered in these patients. (III-A) 6. In vitro fertilization should be reserved for women with PCOS who fail gonadotropin therapy or who have other indications for IVF treatment. (II-2A) J Obstet Gynaecol Can 2010;32(5):495–502

INTRODUCTION

olycystic ovary syndrome is a heterogeneous endocrine condition that affects approximately 5% to 10% of women in the reproductive age group.1–3 Depending on the population being examined, however, prevalence rates as high as 26% have been reported.4 Although debate on what constitutes PCOS continues, the Rotterdam Consensus on Diagnostic Criteria for PCOS published in 2003 is the most current definition. According to this consensus, a diagnosis of PCOS is based on at least 2 of the following 3 criteria:

P

oligo-ovulation or anovulation, clinical or biochemical evidence of hyperandrogenism, and polycystic ovaries on ultrasound assessment (> 12 small antral follicles in an ovary), with the exclusion of medical conditions such as congenital adrenal hyperplasia, androgen-secreting tumours, or Cushing’s syndrome.5 Patients who fulfill these criteria are often plagued by infertility secondary to both ovulatory dysfunction and the effects of hyperandrogenism. Several methods have been effective for ovulation induction and fertility treatment in women with PCOS: • Weight loss, exercise, and lifestyle modifications • Clomiphene citrate • Metformin • Gonadotropins • Ovarian drilling • IVF This guideline addresses the sequential steps that should be undertaken, as well as the pregnancy rates, risks, and benefits of each method.

ABBREVIATIONS

WEIGHT LOSS AND LIFESTYLE MODIFICATIONS

CC

clomiphene citrate

FSH

follicle stimulating hormone

hCG

human chorionic gonadotropin

LH

luteinizing hormone

LOD

laparoscopic ovarian drilling

PCOS

polycystic ovary syndrome

Obesity is strongly associated with PCOS and may be present in up to 50% of cases.6–10 Obese women with PCOS are more likely than thin women with PCOS to suffer from anovulation.6 This effect on ovulation may be secondary to insulin resistance, which in turn results in hyperinsulinemia and stimulation of excess androgen production from the

496

l MAY JOGC MAI 2010

Ovulation Induction in Polycystic Ovary Syndrome

ovaries. Intraovarian hyperandrogenism in turn inhibits follicular maturation.10 Weight loss through exercise and diet has been proven effective in restoring ovulatory cycles and achieving pregnancy for many of these patients.11–13 In obese, anovulatory women with PCOS, weight loss of even 5% to 10% of body weight often restores ovulatory cycles.7,9,14,15 Studies also show that overweight women are less likely to respond to pharmacologic ovulation induction methods.7,16 Obese women often report difficulty in achieving and maintaining weight loss. The extent to which their obesity reflects an inherent metabolic disturbance, making it more challenging for them to lose weight, remains a question. The current recommendation is to reduce weight gradually to increase the chances of maintaining the weight loss. Preferential diet composition has been evaluated in 2 small studies.17,18 These studies compared a high carbohydrate (55%), low protein (15%) hypocaloric diet with a low carbohydrate (40%), high protein (30%) hypocaloric diet and found similar weight loss and decrease in circulating androgen and insulin levels. Although the patient sample size was small, these 2 studies suggest that patients can safely pursue either dietary composition, despite the need for larger confirmatory studies. Routine exercise is also very important in the reproductive health of women with PCOS. Exercise increases insulin sensitivity and helps achieve and maintain weight loss.19 Other lifestyle factors such as excessive caffeine intake, alcohol consumption, and smoking should also be addressed.8 Once patients have achieved weight loss, they should be encouraged to maintain this in the long term and to have normal weight gain during pregnancy. Obesity contributes to poor obstetric outcome (increased risk of spontaneous abortion and preterm labour) and also increases maternal complications, including gestational hypertension, gestational diabetes mellitus, thromboembolism, and wound infection.6 Long-term lifestyle modifications can decrease predisposition to health conditions such as type 2 diabetes mellitus and modify risk factors for cardiovascular disease.8 Recommendation 1. Weight loss, exercise, and lifestyle modifications have been proven effective in restoring ovulatory cycles and achieving pregnancy in overweight women with PCOS and should be the first-line option for these women. (II-3A) Morbidly obese women should seek expert advice about pregnancy risk. (III-A) CLOMIPHENE CITRATE

Clomiphene citrate has been used as a first-line ovulation induction agent for over 40 years.20,21 It is a selective estrogen

receptor modulator that stimulates endogenous FSH production and secretion by interrupting estrogen to the hypothalamus and pituitary. PCOS patients can be sensitive to ovulation induction medications because of a large number of antral follicles. This places some women with PCOS at risk of overresponse with multiple follicular development and ovarian hyperstimulation; however, other women have a poor response without development of a dominant follicle, despite using higher doses of CC. The starting dose of clomiphene citrate is 50 mg per day for 5 days, commencing between day 2 and 5 of menses.22 Menses may be induced with a progestin if required. If this dose produces multiple follicular development, the dose can be lowered to 25 mg. If ovulation is not achieved using 50 mg per day, the dose can be increased in increments of 50 mg. The manufacturer does not recommend exceeding 100 mg per day23; however, many clinicians use doses up to 150 mg and some even up to 250 mg per day for 5 days,24 taking into that alternatives treatments such as gonadotropins are more costly and have greater risk (see below). Cycle monitoring should be considered in at least the first cycle and when the treatment dose has to be increased because of failure to ovulate. Common indications of an ovulatory response are a biphasic pattern on basal body temperature charting and a serum progesterone measurement in the expected luteal phase of > 10 nmol/L if tested 6 to 8 days before the onset of menses.25 However, in some circumstances, detection of the pre-ovulatory LH surge with urinary kits, and ovarian follicle and endometrial assessment with transvaginal ultrasound during the late follicular phase can be useful. If ovulation cannot be achieved with CC, the patient should be offered further options. Although 60% to 85% of patients will ovulate on CC, only about one half will conceive.26,27 Approximately 50% of conceptions will occur on 50 mg, with another 20% to 25% and 10% occurring on 100 mg and 150 mg, respectively.15,28 Lack of conception despite evidence of ovulation may be due to anti-estrogenic effects of CC on the endometrium, which may manifest as a thin endometrium on ultrasound.29 In one study, no pregnancies occurred when the endometrium was < 6 mm at midcycle,30 but others have not found a similar association.31 Nevertheless, alternatives for ovulation induction should be considered if the periovulatory endometrium is persistently thin on CC therapy. Similarly, if pregnancy does not occur within 6 ovulatory cycles, another ovulation induction method should be considered. Other drawbacks of CC include an increased rate of twin (7% to 9%) and triplet (0.3%) pregnancy, and side effects such as vasomotor hot flashes.32 Unusual visual symptoms (visual blurring or persistent after-images) are also noted in MAY JOGC MAI 2010 l

497

SOGC Clinical Practice Guideline

1% to 2% of patients taking CC, which are likely due to anti-estrogenic effects of CC on the visual cortex.33 Although more studies are required, it is best to limit a patient’s lifetime exposure to CC to 12 treatment cycles, as additional cycles may place the patient at increased risk of borderline ovarian tumours.34 Recommendation 2. Clomiphene citrate has been proven effective in ovulation induction for women with PCOS and should be considered the first-line therapy. Patients should be informed that there is an increased risk of multiple pregnancy with ovulation induction using clomiphene citrate. (I-A) INSULIN SENSITIZING AGENTS

The recognition of an association between PCOS and hyperinsulinemia has led to the use of insulin-sensitizing agents in ovulation induction. Metformin, the most widely studied agent used in PCOS, is a biguanide insulin-sensitizing agent that acts by inhibiting hepatic glucose production and increasing peripheral glucose uptake.35 It does not stimulate secretion of insulin or cause hypoglycemia. Many earlier studies examining the use of metformin alone or in conjunction with CC in ovulation induction showed promising results,36–42 but most of these studies had relatively small sample sizes. A meta-analysis of 13 randomized controlled trials by Lord et al.43 in 2003 concluded that metformin is effective in achieving ovulation in women with PCOS, with odds ratios of 3.88 (95% CI 2.25 to 6.69) for metformin compared with placebo and 4.41 (95% CI 2.37 to 8.22) for metformin and CC compared with CC alone. Pregnancy rates were not significantly better with metformin than with placebo (OR 2.76; 95% CI 0.85 to 8.98), but an improvement was seen with metformin plus CC over CC alone (OR 4.4; CI 1.96 to 9.85).43 A more recent meta-analysis published in April 200844 comparing CC and metformin, both alone and in combination, found that metformin alone increased the odds of ovulation compared with placebo (OR 2.94; 95% CI 1.43 to 6.02) but did not result in a statistically significant difference in pregnancy rates (OR 1.56; 95% CI 0.74 to 3.33). When CC and metformin were compared with CC alone, both ovulation and pregnancy rates were statistically increased to 4.39 (95% CI 1.94 to 9.96) and 2.67 (95% CI 1.45 to 4.94), respectively. This meta-analysis also included studies that reported live birth rates. Ng et al.45 in 2001 compared metformin and placebo in 20 women and found that women who received metformin were less likely to achieve a live birth, although this difference did not reach statistical significance (OR 0.44; 95% CI 0.03 to 5.88). Four of the included trials examined 498

l MAY JOGC MAI 2010

live birth rates with CC and metformin versus CC alone.41,46–48 Collectively, the combination of CC and metformin suggested an increase in live birth rate over CC alone, but this increase was not statistically significant (OR 1.74; 95% CI 0.79 to 3.86). The only trial adequately powered to assess live birth rates was the large randomizedcontrolled trial published by Legro et al. in 2007.46 This trial included 626 patients and demonstrated that although the live birth rate following up to 6 months of treatment with metformin and CC was increased (26.8%), it was not significantly different from that with CC alone (22.5%). Live birth rates using CC alone or with metformin were significantly higher than rates with metformin alone (7.2%). The evidence s the use of clomiphene citrate over metformin as first-line pharmacologic therapy following lifestyle modification in women with PCOS. However, there may be a role for the addition of metformin to CC in women who are clomiphene-resistant. Siebert et al.49 examined 6 trials in which metformin was randomized with either placebo or CC in clomiphene-resistant patients and found an overall statistically significant improvement in ovulation with combination therapy (OR 6.82; 95% CI 3.59 to 12.96). Further, a recent study also suggested that women with PCOS who are older and have increased visceral obesity may benefit from the additional use of metformin.50 Patients on metformin often experience unpleasant side effects of nausea, bloating, cramps, and diarrhea, and they should be counselled to start with 250 mg to 500 mg PO daily and increase as tolerated to the optimal daily dose of 500 mg to 750 mg 3 times daily with food. Metformin can also be dosed 850 mg PO twice daily or a long-acting formulation (Glumetza) can be used to improve compliance. Although some studies have shown that continuing metformin in pregnancy may decrease the spontaneous abortion rate,42,51–53 none of these are prospective, randomized trials. Randomized controlled trials are needed in this area before sustained metformin treatment throughout pregnancy can be recommended. Recommendation 3. Metformin combined with clomiphene citrate may increase ovulation rates and pregnancy rates but does not significantly improve the live birth rate over that of clomiphene citrate alone.(I-A) Metformin may be added to clomiphene citrate in women with clomiphene resistance who are older and who have visceral obesity. (I-A) GONADOTROPINS

Use of intramuscular gonadotropins began in the 1960s. These preparations, from the purified urine of postmenopausal women, contained both FSH and LH.

Ovulation Induction in Polycystic Ovary Syndrome

Over the last decade, recombinant human FSH has been the main preparation, and it can be self-istered subcutaneously.54 Gonadotropins are used when PCOS patients fail either to ovulate or to conceive with oral ovulation inducing medications. Daily injections of gonadotropins are combined with concurrent blood and ultrasound monitoring with the aim of monofollicular growth and development. However, because of the inherent nature of exogenous gonadotropin treatment, multifollicular development is not uncommon, despite careful dose adjustment and monitoring. Once the dominant follicle has reached the appropriate size, hCG is istered to trigger ovulation. Injectable gonadotropins are very expensive and require frequent monitoring, with serum estradiol and ultrasound assessments to minimize the risks from excessive follicular growth and development. Because of the high number of antral follicles in women with PCOS, it is not uncommon that treatment is cancelled to minimize the occurrence of multiple pregnancy and also of ovarian hyperstimulation syndrome.55 Pregnancy rates with gonadotropins are 20% to 25% per cycle.54 Drawbacks to gonadotropin treatment, as mentioned earlier, are requirements for intensive monitoring, cost, multiple pregnancy, and ovarian hyperstimulation. Gonadotropins should be istered by physicians with specific training in reproductive medicine and with ready access to ultrasound monitoring and rapid hormone testing. Recommendation 4. Gonadotropin should be considered second-line therapy for fertility in anovulatory women with PCOS. The treatment requires ultrasound and laboratory monitoring. High costs and the risk of multiple pregnancy and ovarian hyperstimulation syndrome are drawbacks of the treatment. (II-2A) OVARIAN DRILLING

Surgical ovarian wedge resection by open laparotomy was one of the first treatments for anovulation due to PCOS.56 It was thought to induce ovulation by decreasing the ovarian theca and thus reducing androgen production. Because of the operative morbidity of the procedure and the risk of postoperative adhesions,57 ovarian wedge resection by laparotomy has largely been abandoned as more effective medical therapies for ovulation induction have become available. With the popularity of minimally invasive surgery, laparoscopic ovarian drilling is thought to be less destructive to the ovary and has a lower risk of adhesion formation. Laparoscopic ovarian drilling uses either cautery or laser to create approximately 10 superficial perforations per ovary.58

A Cochrane review published in 2007 examined 16 randomized controlled trials evaluating ovulation induction in clomiphene-resistant PCOS with LOD. The dose at which clomiphene resistance was defined ranged from 100 mg to 200 mg in the various studies. Approximately 80% of PCOS patients will become ovulatory after LOD. There was no difference found in the rates of miscarriage, ongoing pregnancy, or live birth between patients who underwent LOD and patients treated with gonadotropins for ovulation induction. There were significantly fewer multiple pregnancies in the LOD than in the gonadotropin treatment groups (1% vs. 16%; OR 0.13; 95% CI 0.03 to 0.59).58 In one of the included trials, adjuvant therapy with CC or gonadotropins was required to achieve equivalent pregnancy and live birth rates in patients remaining anovulatory 8 weeks after LOD or those who subsequently became anovulatory.59 Despite this evidence that LOD may be equivalent to gonadotropins in achieving ovulation, the effects of LOD on postoperative adhesion formation remain a concern,60 although it has been shown that in women who respond to this treatment, the rate of cessation of ovulation is low.61 Recommendation 5. Laparoscopic ovarian drilling may be considered in women with clomiphene-resistant PCOS, particularly when there are other indications for laparoscopy. (I-A) Surgical risks need to be considered in these patients. (III-A) AROMATASE INHIBITORS

Aromatase inhibitors have been used for the last decade as adjunctive treatments in breast cancer.62 They block the conversion of testosterone and androstenedione to estradiol and estrone, respectively, and hence inhibit the estrogen-negative on the hypothalamic–pituitary axis. This leads to increased gonadotropin secretion, which in turn leads to ovarian follicular growth and development.62 The use of aromatase inhibitors in ovulation induction was first introduced in 2001.63 Ovulation and pregnancy rates with aromatase inhibitors such as letrozole and anastrozole appear to be promising, and these agents appear to have less anti-estrogen effect on the endometrium, but the evidence on endometrial effects is conflicting, and most studies show equivalence with clomiphene citrate.62–65 In 2005, however, Health Canada and the manufacturing company of letrozole issued a “Physician Warning Letter” on the off-label use of letrozole for fertility and the possibility of embryotoxicity, fetotoxicity, and teratogenicity found in rats.66 This followed preliminary research findings by Biljan et al.67 comparing congenital malformations in babies conceived with letrozole with or without gonadotropins with those in babies born to a low-risk population of women MAY JOGC MAI 2010 l

499

SOGC Clinical Practice Guideline

without known fertility treatments. These findings reported a higher incidence of both cardiac and bone abnormalities in the letrozole group.67 More recently, however, Tulandi et al.68 retrospectively evaluated 911 newborns from letrozole and CC pregnancies. They found a 2.4% incidence of congenital malformations and chromosomal abnormalities in the letrozole group versus 4.8% in the CC group.68 However, until aromatase inhibitors have been approved for ovulation induction by Health Canada, they should be used with caution, and patients should be carefully counselled, given potential medico–legal implications. IN VITRO FERTILIZATION

IVF, with or without intracytoplasmic sperm injection, is the next treatment option for women with PCOS who fail to conceive with gonadotropin treatment or in the presence of other indications for advanced reproductive technologies. In IVF, gonadotropins are istered to achieve multifollicular development for oocyte retrieval and generation of embryos for transfer into the uterus. Pregnancy rates can approach 40% to 50% per cycle with IVF, but, as with fertility in general, success is significantly influenced by the women’s age.54 PCOS patients achieve pregnancy and live birth rates similar to those of non-PCOS patients during conventional IVF cycles. Side effects include multiple pregnancy when multiple embryos are transferred, and a higher risk of ovarian hyperstimulation; however, the risk of multiple pregnancy is more easily controlled with IVF than with ovulation induction with gonadotropins, because the number of embryos transferred into the patient’s uterus can be limited and surplus good quality embryos cryopreserved for future transfer. Recommendation 6. In vitro fertilization should be reserved for women with PCOS who fail gonadotropin therapy or who have other indications for IVF treatment. (II-2A) SUMMARY

Patients with polycystic ovary syndrome commonly present with a history of infertility due to oligo-ovulation or anovulation. First-line management of infertility should always include weight loss and exercise and lifestyle modifications in the overweight patient. This is beneficial in the patient’s overall health, it may lead to spontaneous ovulation, and it will improve response to ovulation-induction medications. Clomiphene citrate has been used for many years and remains the first-line medication despite potential anti-estrogenic effects on the endometrium and cervical mucous. Recent evidence indicates that insulin-sensitizing agents should not be used as a first-line therapy, although they may be beneficial in PCOS patients who are older and 500

l MAY JOGC MAI 2010

who have increased visceral obesity as assessed by increased waist-to-hip ratios, and in those who have failed to ovulate on clomiphene citrate alone. Laparoscopic ovarian drilling should be considered in women who are resistant to clomiphene citrate because of the lower risk of multifetal gestation compared with gonadotropin therapy. Further trials are needed in the area of aromatase inhibitors if they are to be used routinely for ovulation induction. Clinicians should always consider a patient’s age and duration of infertility as they progress through the different treatment options available. If a patient does not become pregnant in a timely manner, referral to a fertility clinic and appropriate uses of gonadotropins and IVF are effective options. REFERENCES 1. Knochenhauer ES, Key TJ, Kahsar-Miller M, Waggoner W, Boots LR, Azziz R. Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study. J Clin Endocrinol Metab 1998;83:3078–82. 2. Diamanti-Kandarakis E, Kouli CR, Bergiele AT, Filandra FA, Tsianateli TC, Spina GG, et al. A survey of the polycystic ovary syndrome in the Greek island of Lesbos: hormonal and metabolic profile. J Clin Endocrinol Metab 1999;84:4006–11. 3. Asuncion M, Calvo RM, San Millan JL, Sancho J, Avila S, Escobar-Morreale HF. A prospective study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain. J Clin Endocrinol Metab 2000;86:2434–8. 4. Michelmore KF, Balen AH, Dunger DB, Vessey MP. Polycystic ovaries and associated clinical and biochemical features in young women. Clin Endocrinol (Oxf)1999;51:779–86. 5. The Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004;81:19–25. 6. Al-Azemi M, Omu FE, Omu AE. The effect of obesity on the outcome of infertility management in women with polycystic ovary syndrome. Arch Gynecol Obstet 2004;270:205–10. 7. Norman RJ, Noakes M, Wu R, Davies MJ, Moran L, Wang JX. Improving reproductive performance in overweight/obese women with effective weight management. Hum Reprod Update 2004;10:267–80. 8. Norman RJ. Davies MJ. Lord J. Moran LJ. The role of lifestyle modification in polycystic ovary syndrome. Trends Endocrinol Metab 2002;13:251–7. 9. Hoeger KM. Obesity and lifestyle management in polycystic ovary syndrome. Clin Obstet Gynecol 2007;50:277–94. 10. Pasquali R, Gambineri A, Pagotto U. The impact of obesity on reproduction in women with polycystic ovary syndrome. BJOG 2006;113:1148–59. 11. Tolino A, Gambardella V, Caccavale C, D’Ettore A, Giannotti F, D’Anto V, et al. Evaluation of ovarian functionality after a dietary treatment in obese women with polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol 2005;119:87–93. 12. Bates GW, Whitworth NS. Effect of body weight reduction on plasma androgens in obese, infertile women. Fertil Steril 1982;38:406–9. 13. Clark AM, Thornley B, Tomlinson L, Galletley C, Norman RJ. Weight loss in obese infertile women results in improvement in reproductive outcome for all forms of fertility treatment. Hum Reprod 1998;13:1502–5. 14. Kiddy DS, Hamilton-Fairley D, Bush A, Short F, Anyaoku V, Reed MJ, Franks S, et al. Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 1992;36:105–11.

Ovulation Induction in Polycystic Ovary Syndrome

15. Speroff L, Fritz MA. Clinical gynecologic endocrinology and infertility. 7th ed. Pennsylvania: Lippincott Williams & Wilkins;2005.

34. Rossing MA, Daling JR, Weiss NS, Moore DE, Self SG. Ovarian tumors in a cohort of infertile women. N Engl J Med 1994;331:771–6.

16. Lobo RA, Gysler M, March CM, Goebelsmann U, Mishell DR Jr. Clinical and laboratory predictors of clomiphene response. Fertil Steril 1982; 37(2):168–74.

35. Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450c17a activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med 1996;335:617–23.

17. Stamets K, Taylor DS, Kunselman A, Demers LM, Pelkman CL, Legro RS. A randomized trial of the effects of two types of short-term hypocaloric diets on weight loss in women with polycystic ovary syndrome. Fertil Steril 2004;81:630–7.

36. Moghetti P, Castello R, Negri C, Tosi F, Perrone F, Caputo M, et al. Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomized, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation. J Clin Endocrinol Metab 2000; 85:139–46.

18. Moran LJ, Noakes M, Clifton PM, Tomlinson L, Norman RJ. Dietary composition in restoring reproductive and metabolic physiology in overweight women with polycystic ovary syndrome. J Clin Endocrinol Metab 2003;88:812–9. 19. Huber-Buchholz MM, Carey DGP, Norman RJ. Restoration of reproductive potential by lifestyle modification in obese polycystic ovary syndrome: role of insulin sensitivity and luteinizing hormone. J Clin Endocrinol Metab 1999;84:1470–4. 20. Kafy S, Tulandi T. New advances in ovulation induction. Curr Opin Obstet Gynecol 2007;19:248–52. 21. Kousta E, White DM, Franks S. Modern use of clomiphene citrate in induction of ovulation. Hum Reprod Update 1997;3:359–65. 22. Wu CH, Winkel CA. The effect of therapy initiation day on clomiphene citrate therapy. Fertil Steril 1989;52:564–8. 23. Sanofi-aventis Canada Inc. Product monograph, Clomid. Revised: July 21, 2009. April 7, 2006, Submission Control No. 105030. Submission Control No. 130346. Available at: http://www.sanofi-aventis.ca/live/ca/ en/layout.jsp?scat=526069AB-1A0D-49BB-87BB-310894DBE97E. Accessed March 5, 2010. 24. ACOG Practice Bulletin 34. Management of infertility caused by ovulatory dysfunction. Obstet Gynecol 2002;99:347–58. 25. Israel R, Mishell DR Jr, Stone SC, Thorneycroft IH, Moyer DL. Single luteal phase serum progesterone assay as an indicator of ovulation. Am J Obstet Gynecol 1972; 112:1043–6. 26. Neveu N, Granger L, St.-Michel P, Lavoie HB. Comparison of clomiphene citrate, metformin, or the combination of both for first-line ovulation induction and achievement of pregnancy in 154 women with polycystic ovary syndrome. Fertil Steril 2007;87:113–20. 27. Gysler M, March CM, Mishell DR Jr, Bailey E. A decade’s experience with an individualized clomiphene treatment regimen including its effect on the postcoital test. Fertil Steril 1982;37:161–7. 28. Rostami-Hodjegan A, Lennard MS, Tucker GT, Ledger, WL. Monitoring plasma concentrations to individualize treatment with clomiphene citrate. Fertil Steril 2004; 81:1187–93. 29. Randall JM, Templeton A. Transvaginal sonographic assessment of follicular and endometrial growth in spontaneous and clomiphene citrate cycles. Fertil Steril 1991; 56:208–12. 30. Dickey RP, Olar TT, Taylor SN, Curole DN, Matulich EM. Relationship of endometrial thickness and pattern to fecundity in ovulation induction cycles: effect of clomiphene citrate alone and with human menopausal gonadotropin. Fertil Steril 1993; 59: 756–60. 31. Kolibianakis EM, Zikopoulos KA, Fatemi HM, Osmanagaoglu K, Evenpoel J, Van Steirteghem A, et al. Endometrial thickness cannot predict ongoing pregnancy achievement in cycles stimulated with clomiphene citrate for intrauterine insemination. Reprod Biomed Online 2004;8:115–8.

37. Velazquez E, Acosta A, Mendoza SG. Menstrual cyclicity after metformin therapy in polycystic ovary syndrome. Obstet Gynecol 1997;90:392–5. 38. Essah PA, Apridonidze T, Iuorno MJ, Nestler JE. Effects of short-term and long-term metformin treatment on menstrual cyclicity in women with polycystic ovary syndrome. Fertil Steril 2006;86:230–2. 39. Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. N Engl J Med 1998;338:1876–80. 40. Kocak M, Caliskan E, Simsir C, Haberal A. Metformin therapy improves ovulatory rates, cervical scores, and pregnancy rates in clomiphene citrate-resistant women with polycystic ovary syndrome. Fertil Steril 2002;77:101–6. 41. Vandermolen DT, Ratts VS, Evans WS, Stovall DW, Kauma SW, Nestler JE. Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone. Fertil Steril 2001;75:310–5. 42. Glueck CJ, Wang P, Goldenberg N, Sieve-Smith L. Pregnancy outcomes among women with polycystic ovary syndrome treated with metformin. Hum Reprod 2002; 17:2858–64. 43. Lord JM, Flight IHK, Norman RJ. Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ 2003;327(7421):951–3. 44. Creanga AA, Bradley HM, McCormick C, Takacs Witkop C. Use of metformin in polycystic ovary syndrome A metaanalysis. Obstet Gynecol 2008;111:959–68. 45. Ng EH, Wat NM, Ho PC. Effects of metformin on ovulation rate, hormonal and metabolic profiles in women with clomiphene-resistant polycystic ovaries: a randomized, double-blinded placebo-controlled trial. Hum Reprod 2001;16:1625–31. 46. Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, et al. Clomiphene, metformin or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007;356:551–66. 47. Sahin Y, Yirmibes U, Kelestimur F, Aygen E. The effects of metformin on insulin resistance, clomiphene-induced ovulation and pregnancy rates in women with polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol 2004;113:214–20. 48. Hwu YM, Lin SY, Huang WY, Lin MH, Lee RK. Ultra-short metformin pretreatment for Clomiphene citrate-resistant polycystic ovary syndrome. Int J Gynecol Obstet 2005; 90:39–43. 49. Siebert TI, Kruger TF, Steyn DW, Nosarka S. Is the addition of metformin efficacious in the treatment of clomiphene citrate-resistant patients with polycystic ovary syndrome? A structured literature review. Fertil Steril 2006;86:1432–7.

32. Dickey RP, Holtkamp DE. Development, pharmacology and clinical experience with clomiphene citrate. Hum Reprod Update 1996;2:483–506.

50. Moll E, Korevaaur JC, Bossuyt PMM, van der Veen F. Does adding metformin to clomifene citrate lead to higher pregnancy rates in a subset of women with polycystic ovary syndrome? Human Reprod 2008;23:1830–4.

33. Racette L, Casson P, Claman P, Zackon P, Casson E. Bilateral visual disturbances in patients on clomiphene citrate arise from the central nervous system. Fertil Steril 2010;93:1169–72. Epub 2009, Jan 9.

51. Jakubowicz DJ, Iuorno MJ, Jakubowicz S, Roberts KA, Nestler JE. Effects of metformin on early pregnancy loss in the polycystic ovary syndrome. J Clin Endocrinol Metab 2002;87:524–9.

MAY JOGC MAI 2010 l

501

SOGC Clinical Practice Guideline

52. Thatcher SS, Jackson EM. Pregnancy outcome in infertile patients with polycystic ovary syndrome who were treated with metformin. Fertil Steril 2006;85:1002–9.

62. Bayar U, Basaran M, Kiran S, Coskun A, Gezer S. Use of an aromatase inhibitor in patients with polycystic ovary syndrome: a prospective randomized trial. Fertil Steril 2006;86:1447–51.

53. Khattab S, Mohsen IA, Foutouh IA, Ramadan A, Amaz M, Al-Inany H. Metformin reduces abortion in pregnant women with polycystic ovary syndrome. Gynecol Endocrinol. 2006;22:680–4.

63. Mitwally MFM, Casper RF. Use of aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate. Fertil Steril 2001;75:305–9.

54. Guzick DS. Ovulation induction management of PCOS. Clin Obstet Gynecol 2007;50:255–67. 55. Heijnen EMEW, Eijkemans MJC, Hughes EG, Laven JSE, Macklon NS, Fa BCJM. A meta-analysis of outcomes of conventional IVF in women with polycystic ovary syndrome. Hum Reprod Update 2006;12:13–21. 56. Stein IF, Cohen MR. Surgical treatment of bilateral polycystic ovaries. Am J Obstet Gynecol 1939;38:465–73. 57. Buttram VC Jr, Vaquero C. Post-ovarian wedge resection adhesive disease. Fertil Steril 1975;26:874–6. 58. Farquhar C, Lilford RJ, Marjoribanks J, Vandekerckhove P. Laparoscopic ‘drilling’ by diathermy or laser for ovulation induction in anovulatory polycystic ovary syndrome. Cochrane Database Syst Rev 2007;3:CD001122. 59. Bayram N, van Wely M, Kaaijk EM, Bossuyt PM, Veen van der F. Using an electrocautery strategy or recombinant follicle stimulating hormone to induce ovulation in polycystic ovary syndrome: randomized controlled trial. BMJ 2004;328:192. 60. Mercorio F, Mercorio A, Di Spiezio Sardo A, Barba GV, Pellicano M, Mappi C. Evaluation of ovarian adhesion formation after laparoscopic ovarian drilling by second-look minilaparoscopy. Fertil Steril 2008;89:1229–33. 61. Gjonnaess H. Ovarian electrocautery in the treatment of women with polycystic ovary syndrome (PCOS). Factors affecting the results. Acta Obstet Gynecol Scand 1994;73:407–12.

502

l MAY JOGC MAI 2010

64. Al-Fozen H, Al-Khadouri M, Tan SL, Tulandi T. A randomized trial of letrozole versus clomiphene citrate in women undergoing superovulation. Fertil Steril 2004;82:1561–3. 65. Badawy A, Elnashar A, Totongy M. Clomiphene citrate or aromatase inhibitors for superovulation in women with unexplained infertility undergoing intrauterine insemination: a prospective randomized trial. Fertil Steril 2009;92:1355–9. Epub2008 Aug 9. 66. Health Canada Endorsed Important Safety Information on Femara (letrozole). Published November 17, 2005. Available at: http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2005/ femara_hpc-s-eng.php. Health Canada website Accessed July 31, 2007. 67. Biljan MM, Hemmings R, Brassard N. The outcome of 150 babies following the treatment with letrozole or letrozole and gonadotropins. Fertil Steril 2005;84:S95. 68. Tulandi T, Martin J, Al-Fadhli R, Kabli N, Forman R, Hitkari J, et al. Congenital malformations among 911 newborns conceived after infertility treatment with letrozole or clomiphene citrate. Fertil Steril 2006;85:1761–5. 69. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

SOGC CLINICAL PRACTICE GUIDELINE No. 325, June 2015

Guidelines for the Management of a Pregnant Trauma Patient This clinical practice guideline has been prepared by the Maternal Fetal Medicine Committee, reviewed by the Clinical Practice – Obstetrics, Medico-Legal, and Family Physician Advisory Committees, and approved by Executive and Board of the Society of Obstetricians and Gynaecologists of Canada PRINCIPAL AUTHORS Venu Jain, MD, Edmonton AB Radha Chari, MD, Edmonton AB Sharon Maslovitz, MD, Tel Aviv, Israel Dan Farine, MD, Toronto ON MATERNAL FETAL MEDICINE COMMITTEE Emmanuel Bujold (Co-Chair), MD, Quebec QC Robert Gagnon (Co-Chair), MD, Montreal QC Melanie Basso, RN, Vancouver BC Hayley Bos, MD, Victoria BC Richard Brown, MD, Montreal QC Stephanie Cooper, MD, Calgary AB Katy Gouin, MD, Quebec QC N. Lynne McLeod, MD, Halifax NS Savas Menticoglou, MD, Winnipeg MB William Mundle, MD, Windsor ON Christy Pylypjuk, MD, Winnipeg MB Anne Roggensack, MD, Calgary, AB

Abstract Objective: Physical trauma affects 1 in 12 pregnant women and has a major impact on maternal mortality and morbidity and on pregnancy outcome. A multidisciplinary approach is warranted to optimize outcome for both the mother and her fetus. The aim of this document is to provide the obstetric care provider with an evidencebased systematic approach to the pregnant trauma patient. Outcomes: Significant health and economic outcomes considered in comparing alternative practices. Evidence: Published literature was retrieved through searches of Medline, CINAHL, and The Cochrane Library from October 2007 to September 2013 using appropriate controlled vocabulary (e.g., pregnancy, Cesarean section, hypotension, domestic violence, shock) and key words (e.g., trauma, perimortem Cesarean, Kleihauer-Betke, supine hypotension, electrical shock). Results were restricted to systematic reviews, randomized control trials/ controlled clinical trials, and observational studies published in English between January 1968 and September 2013. Searches were updated on a regular basis and incorporated in the guideline to February 2014.

Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technologyrelated agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies.

Values: The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). Benefits, harms, and costs: This guideline is expected to facilitate optimal and uniform care for pregnancies complicated by trauma.

Frank Sanderson, MD, Saint John, NB

SUMMARY STATEMENT

Disclosure statements have been received from all contributors.

Specific traumatic injuries At this time, there is insufficient evidence to the practice of disabling air bags for pregnant women. (III)

J Obstet Gynaecol Can 2015;37(6):553–571

RECOMMENDATIONS Primary survey

Key words: Abruption, electrical, fall, fetal, injury, maternal, MVC, penetrating, perimortem, pregnancy.

  1. Every female of reproductive age with significant injuries should be considered pregnant until proven otherwise by a definitive pregnancy test or ultrasound scan. (III-C)

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

JUNE JOGC JUIN 2015 l 553

SOGC clinical practice guideline

Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category

D. There is fair evidence to recommend against the clinical preventive action

III:

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

E. There is good evidence to recommend against the clinical preventive action L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

*The quality of evidence reported in here has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.133 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care.133

  2. A nasogastric tube should be inserted in a semiconscious or unconscious injured pregnant woman to prevent aspiration of acidic gastric content. (III-C)   3. Oxygen supplementation should be given to maintain maternal oxygen saturation > 95% to ensure adequate fetal oxygenation. (II-1B)   4. If needed, a thoracostomy tube should be inserted in an injured pregnant woman 1 or 2 intercostal spaces higher than usual. (III-C)   5. Two large bore (14 to 16 gauge) intravenous lines should be placed in a seriously injured pregnant woman. (III-C)   6. Because of their adverse effect on uteroplacental perfusion, vasopressors in pregnant women should be used only for intractable hypotension that is unresponsive to fluid resuscitation. (II-3B)   7. After mid-pregnancy, the gravid uterus should be moved off the inferior vena cava to increase venous return and cardiac output in the acutely injured pregnant woman. This may be achieved by manual displacement of the uterus or left lateral tilt. Care should be taken to secure the spinal cord when using left lateral tilt. (II-1B)   8. To avoid rhesus D (Rh) alloimmunization in Rh-negative mothers, O-negative blood should be transfused when needed until cross-matched blood becomes available. (I-A)   9. The abdominal portion of military anti-shock tros should not be inflated on a pregnant woman because this may reduce placental perfusion. (II-3B) Transfer to health care facility 10. Transfer or transport to a maternity facility (triage of a labour and delivery unit) is advocated when injuries are neither lifenor limb-threatening and the fetus is viable (≥ 23 weeks), and to the emergency room when the fetus is under 23 weeks’ gestational age or considered to be non-viable. When the injury is major, the patient should be transferred or transported to the trauma unit or emergency room, regardless of gestational age. (III-B)

554 l JUNE JOGC JUIN 2015

11. When the severity of injury is undetermined or when the gestational age is uncertain, the patient should be evaluated in the trauma unit or emergency room to rule out major injuries. (III-C) Evaluation of a pregnant trauma patient in the emergency room 12. In cases of major trauma, the assessment, stabilization, and care of the pregnant women is the first priority; then, if the fetus is viable (≥ 23 weeks), fetal heart rate auscultation and fetal monitoring can be initiated and an obstetrical consultation obtained as soon as feasible. (II-3B) 13. In pregnant women with a viable fetus (≥ 23 weeks) and suspected uterine contractions, placental abruption, or traumatic uterine rupture, urgent obstetrical consultation is recommended. (II-3B) 14. In cases of vaginal bleeding at or after 23 weeks, speculum or digital vaginal examination should be deferred until placenta previa is excluded by a prior or current ultrasound scan. (III-C) Adjunctive tests for maternal assessment 15. Radiographic studies indicated for maternal evaluation including abdominal computed tomography should not be deferred or delayed due to concerns regarding fetal exposure to radiation. (II-2B) 16. Use of gadolinium-based contrast agents can be considered when maternal benefit outweighs potential fetal risks. (III-C) 17. In addition to the routine blood tests, a pregnant trauma patient should have a coagulation including fibrinogen. (III-C) 18. Focused abdominal sonography for trauma should be considered for detection of intraperitoneal bleeding in pregnant trauma patients. (II-3B) 19. Abdominal computed tomography may be considered as an alternative to diagnostic peritoneal lavage or open lavage when intra-abdominal bleeding is suspected. (III-C) Fetal assessment 20. All pregnant trauma patients with a viable pregnancy (≥ 23 weeks) should undergo electronic fetal monitoring for at least 4 hours. (II-3B)

Guidelines for the Management of a Pregnant Trauma Patient

21. Pregnant trauma patients (≥ 23 weeks) with adverse factors including uterine tenderness, significant abdominal pain, vaginal bleeding, sustained contractions (> 1/10 min), rupture of the membranes, atypical or abnormal fetal heart rate pattern, high risk mechanism of injury, or serum fibrinogen < 200 mg/dL should be itted for observation for 24 hours. (III-B) 22. Anti-D immunoglobulin should be given to all rhesus D-negative pregnant trauma patients. (III-B) 23. In Rh-negative pregnant trauma patients, quantification of maternal–fetal hemorrhage by tests such as Kleihauer-Betke should be done to determine the need for additional doses of anti-D immunoglobulin. (III-B) 24. An urgent obstetrical ultrasound scan should be undertaken when the gestational age is undetermined and need for delivery is anticipated. (III-C) 25. All pregnant trauma patients with a viable pregnancy who are itted for fetal monitoring for greater than 4 hours should have an obstetrical ultrasound prior to discharge from hospital. (III-C) 26. Fetal well-being should be carefully documented in cases involving violence, especially for legal purposes. (III-C) Obstetrical complications of trauma 27. Management of suspected placental abruption should not be delayed pending confirmation by ultrasonography as ultrasound is not a sensitive tool for its diagnosis. (II-3D) Specific traumatic injuries 28. Tetanus vaccination is safe in pregnancy and should be given when indicated. (II-3B) 29. Every woman who sustains trauma should be questioned specifically about domestic or intimate partner violence. (II-3B) 30. During prenatal visits, the caregiver should emphasize the importance of wearing seatbelts properly at all times. (II-2B) Perimortem Caesarean section 31. A Caesarean section should be performed for viable pregnancies (≥ 23 weeks) no later than 4 minutes (when possible) following maternal cardiac arrest to aid with maternal resuscitation and fetal salvage. (III-B)

ABBREVIATIONS CNS

central nervous system

CT

computerized tomography

DPL

diagnostic peritoneal lavage

ECG

electrocardiogram

EFM

electronic fetal monitoring

ER

emergency room

FAST

focused abdominal sonography for trauma

ICU

intensive care unit

KB

Kleihauer-Betke

L&D

labour and delivery

MAST

military anti-shock tros

MFH

maternal-fetal hemorrhage

MVC

motor vehicle collision

Rh

rhesus D

INTRODUCTION

T

rauma during pregnancy is the leading cause of nonobstetric maternal mortality, with 20% of maternal deaths directly attributable to injuries.1 Non-lethal injuries occur in 1 in every 12 pregnant women and are most commonly the result of an MVC or of domestic or intimate partner violence.1–3 Other common causes of trauma in a pregnant patient are penetrating injuries and falls.4–6 Health Canada reported maternal mortality as 6.1 per 100 000 live births during 1997–2000.7 During that period 15 maternal deaths (an incidence of 1.5/100 000) were attributed to MVC. There was no other single diagnosis (pulmonary embolism, preeclampsia, hemorrhage, etc.) with such a high mortality rate. A Swedish national population-based study (1991–2001) reported an MVC incidence of 207/100 000 pregnancies that was associated with a maternal mortality of 1.4 per 100 000 pregnancies and a perinatal mortality of 3.7 per 100 000 pregnancies (an odds ratio of 3.55 compared with the background risk).8 There was no significant difference in fatal injury risk among pregnant and nonpregnant women involved in an MVC.8 A report by the National Trauma Data Bank (2001–2005) indicated that trauma-related mortality among pregnant women is lower than that among non-pregnant women.9 This difference has been attributed to protective hormonal and physiologic effects of pregnancy as well as a higher likelihood of hospital ission of pregnant versus nonpregnant trauma victims.9,10 The management of a pregnant trauma patient warrants consideration of several issues specific to pregnancy such as alterations in maternal physiology and anatomy, exposure to radiation and other possible teratogens, the need to assess fetal well-being, and conditions that are unique to pregnancy and are related to trauma (Rh isoimmunization, placental abruption, and preterm labour). Optimization of outcome in severe trauma cases mandates a multidisciplinary team approach involving trauma surgeons, emergency medicine physicians, obstetricians, neonatologists, nursing staff, and technicians. The obstetrician (or other obstetric care provider) plays a major role in determining gestational age, optimizing uteroplacental perfusion, assessing fetal well-being, providing information about the risks of radiation exposure and use of medications, and deciding upon and executing an emergency Caesarean section. A systematic, evidence-based approach to the management of maternal trauma is hereby provided to assist and guide physicians involved in such cases, either as primary caregivers or consultants. JUNE JOGC JUIN 2015 l 555

SOGC clinical practice guideline

PRIMARY SURVEY

Seriously injured trauma victims are occasionally unable to communicate with the primary caregiver. In addition, some women may be unaware of their pregnancy status. One study showed that 3% of women itted to a trauma unit were pregnant, and of these 11% were incidental pregnancies.11 Therefore, it is recommended that every injured female of childbearing years should be considered pregnant until proven otherwise. Following ission of the patient for further care in a health care facility, a pregnancy test should be performed.12 The confirmation of pregnancy may have a major impact on future decisions regarding diagnostic imaging, use of medications, and other treatment modalities. As with non-pregnant women, the initial assessment of an acutely injured pregnant woman should include securing her airway, ensuring breathing, and maintaining adequate circulation. The most important lifesaving primary interventions might include, for example, intubation and controlling severe external hemorrhage. Airway

The pregnant patient has a greater risk for airway management problems and difficult intubation than the non-pregnant patient.13 Weight gain, respiratory tract mucosal edema, decreased functional residual capacity, reduced respiratory system compliance, increased airway resistance, and increased oxygen requirements are pregnancy-induced changes that place the injured pregnant woman at risk for failure to maintain a patent airway and secured ventilation.14 An early intubation should be considered in whenever airway problems are anticipated. Injured pregnant women with an unsecured airway are at increased risk for aspiration of gastric contents. Gastric emptying is delayed in pregnancy and pregnant women should be considered to have a full stomach for up to 24 hours after their last meal. Intubation is more difficult in pregnant patients, with failed intubations being 8 times more likely.15 A smaller size of endotracheal tube is recommended.15 Cricoid pressure can be considered during intubation to decrease the risk of regurgitation of gastric contents into the pharynx and for manipulation of laryngoscopic view.15,16 However, adjustment of pressure or early release may be necessary if the view is poor. In addition, early placement of a nasogastric tube is warranted in an unconscious or semiconscious pregnant patient to avoid aspiration in light of decreased gastric motility, compression of the upper gastrointestinal tract, elevated gastric acid, decreased pH, and relaxation of the lower esophageal sphincter.17 556 l JUNE JOGC JUIN 2015

Breathing

Marked increases in basal oxygen consumption and extreme sensitivity of the fetus to maternal hypoxia mandate supplemental oxygen by a nasal cannula, mask, or endotracheal tube to all pregnant trauma patients to maintain oxygen saturation above 95%. Taking into the displacement of the diaphragm during pregnancy, it may be advisable to insert a thoracostomy tube, when indicated, one to 2 intercostal spaces higher than usual.18 Circulation

istration of fluids and blood products during resuscitation should proceed according to standard trauma protocols.19 Nevertheless, some modifications should be made in the pregnant trauma victim. Insertion of 2 large bore needles (14–16 gauge) is recommended for all seriously injured trauma patients to facilitate initial rapid crystalloid infusion, intravascular volume expansion, and possible further blood transfusion as required. The uteroplacental vasculature is highly responsive to vasopressors, and their istration may decrease placental perfusion. In cases of maternal hypotension vasopressors should be avoided unless the patient is unresponsive to replenishment of intravascular volume by fluid istration.20 Bicarbonate should be used with caution, because rapid correction of maternal acidosis can reduce the compensatory hyperventilation.21 To further facilitate the evaluation of maternal hypovolemia, the pregnant trauma patient should be undressed and a thorough examination for sources of blood loss should be undertaken. Care must be taken to avoid supine hypotension in the pregnant trauma patient after mid-pregnancy. Compression of the vena cava by the uterus can cause up to 30% reduction in cardiac output.22 The displacement of the uterus off of the inferior vena cava and abdominal aorta enhances maternal venous return and cardiac output, and consequently improves uterine perfusion.19,23 This can be achieved either by placing the patient in the left lateral position or by manual displacement of the uterus while the injured patient is secured in the supine position. The latter may allow more effective chest compressions while cardiopulmonary resuscitation is in progress.24 A third option is to use a backboard for lateral tilt with secured spine in suspected spinal injuries. Fetal risks from maternal defibrillation are small, especially if all fetal monitors have been removed.25 In the setting of acute blood loss necessitating immediate istration of blood products in a pregnant trauma

Guidelines for the Management of a Pregnant Trauma Patient

patient, O-negative blood should be transfused in order to avoid Rh sensitization in Rh-negative women until typespecific or cross-matched donor blood becomes available. Inflation of the abdominal portion of the MAST is contraindicated during pregnancy as it may lead to reduced placental perfusion and increased cardiac workload.26 Recommendations

1. Every female of reproductive age with significant injuries should be considered pregnant until proven otherwise by a definitive pregnancy test or ultrasound scan. (III-C) 2. A nasogastric tube should be inserted in a semiconscious or unconscious injured pregnant woman to prevent aspiration of acidic gastric content. (III-C) 3. Oxygen supplementation should be given to maintain maternal oxygen saturation > 95% to ensure adequate fetal oxygenation. (II-1B) 4. If needed, a thoracostomy tube should be inserted in an injured pregnant woman 1 or 2 intercostal spaces higher than usual. (III-C) 5. Two large bore (14 to 16 gauge) intravenous lines should be placed in a seriously injured pregnant woman. (III-C) 6. Because of their adverse effect on uteroplacental perfusion, vasopressors in pregnant women should be used only for intractable hypotension that is unresponsive to fluid resuscitation. (II-3B) 7. After mid-pregnancy, the gravid uterus should be moved off the inferior vena cava to increase venous return and cardiac output in the acutely injured pregnant woman. This may be achieved by manual displacement of the uterus or left lateral tilt. Care should be taken to secure the spinal cord when using left lateral tilt. (II-1B) 8. To avoid rhesus D (Rh) alloimmunization in Rhnegative mothers, O-negative blood should be transfused when needed until cross-matched blood becomes available. (I-A) 9. The abdominal portion of military anti-shock tros should not be inflated on a pregnant woman because this may reduce placental perfusion. (II-3B) TRANSFER TO HEALTH CARE FACILITY

Following successful initial maternal stabilization, the primary care provider should organize further appropriate referral, consultation, and transfer of care as required. The dilemma is not only whether and how

to transfer patient care between different health facilities, but also where further care should be provided: in the trauma unit, ER, or community-designated emergency care facility/personnel unit, in an ICU, or in the maternity/L&D unit or community-designated maternity facility/personnel unit. Although most injuries are not categorized as life threatening, they may still be extensive or mandate immediate intervention to prevent long-term consequences for the mother. Factors that should be taken into consideration are severity of the injuries and gestational age. Maternal health should always take priority over interventions for the fetus. When major maternal trauma is evident or suspected, the patient should be transferred without delay to the trauma unit or ER. The same applies for women with pregnancies of under 23 weeks’ gestation, when the fetus is considered nonviable and serious obstetric complications are uncommon. Women over 23 weeks’ gestation without life- or limbthreatening injuries should be transported to a maternity or L&D unit as soon as possible. However, the diagnosis of pregnancy is not always certain or obvious. Many seriously injured trauma victims cannot communicate, and some are unaware of their pregnancy status. Gestational age may be unobtainable or uncertain, complicating the process of decision making. The primary care provider should try to assess the gestational age by verbal communication with the patient or her companion or through documentation found in her possession. Fundal height may give a rough estimate of gestational age in most cases of a singleton gestation. Occasionally, injury-related distention of the abdomen may interfere with the estimation of fundal height. Multiple systems for scoring the severity of trauma have been proposed in the literature,27 but most of them are cumbersome and are not applicable for on-scene decision making. Severity assessment scoring systems frequently used in trauma and intensive care patients to predict outcome are often not useful in pregnant women itted to a general ICU.28 The standard Injury Severity Score assessment is also not accurate in predicting placental abruption and fetal demise. Buchsbaum described simple and applicable criteria that essentially distinguish between major maternal injuries that require further assessment in a trauma centre and minor injuries for which obstetrical surveillance takes precedence.29 Buchsbaum used criteria such as hematuria, suspected internal bleeding, loss of conscious, and fractures to delineate major trauma. We suggest that these simple parameters should be considered along with common sense when deciding upon patient transfer and transport arrangements for a pregnant woman after 23 weeks’ gestation. JUNE JOGC JUIN 2015 l 557

SOGC clinical practice guideline

Recommendations

10. Transfer or transport to a maternity facility (triage of a labour and delivery unit) is advocated when injuries are neither life- nor limb-threatening and the fetus is viable (≥ 23 weeks), and to the emergency room when the fetus is under 23 weeks’ gestational age or considered to be non-viable. When the injury is major, the patient should be transferred or transported to the trauma unit or emergency room, regardless of gestational age. (III-B) 11. When the severity of injury is undetermined or when the gestational age is uncertain, the patient should be evaluated in the trauma unit or emergency room to rule out major injuries. (III-C) EVALUATION OF A PREGNANT TRAUMA PATIENT IN THE ER

Assessment of a pregnant trauma patient in the ER may require the involvement of a multidisciplinary team that may include an emergency physician or trauma specialist (or the designated emergency care provider), an obstetrician (or obstetrical care provider), a neonatologist, an anaesthetist, and skilled nursing staff. The pregnant patient should be fully assessed, as is a non-pregnant patient, with a thorough history, examination, laboratory tests, imaging studies, and invasive diagnostic procedures as indicated. In addition, special attention should be given to fetal evaluation when gestational age is ≥ 23 weeks and to trauma complications that are unique to pregnancy such as placental abruption. Communication between health care providers can be facilitated by incorporating the emergency triage protocol in the management of pregnancy trauma patients.30 History

As in the non-pregnant trauma patient, a thorough history is of utmost importance to delineate the mechanism of injury and possible concealed damage in a pregnant patient. The caregiver should also obtain information about past obstetrical history (e.g., scarred uterus, previous obstetrical complications) and the course of the current pregnancy. Certain pregnancy complications will affect the management of traumarelated injuries. For example, patients with preeclampsia have reduced intravascular volume and are extremely sensitive to hypovolemia and anemia. These patients may also have compromised renal function on the one hand and increased capillary permeability with proneness to pulmonary edema on the other. Awareness of these factors may lead to modification of fluid management 558 l JUNE JOGC JUIN 2015

with regard to the method and rate of volume replacement and the means of monitoring intravascular volume and cardiac output. The history should also include inquiries into specific complications of trauma in pregnancy: leakage of fluid, vaginal bleeding, abdominal pain or cramping, intensity and frequency of contractions, and maternal perception of fetal movements. Physical Examination

The physical examination of pregnant trauma patients is similar to that of non-pregnant patients with modifications for pregnancy-related complications. We endorse the recommendations proposed by the Advanced Trauma Life Course of the American College of Surgeons’ Committee on Trauma.19 All body parts of the pregnant trauma patient should be exposed and thoroughly examined. In recording vital signs it is helpful to keep in mind that the heart rate increases by 15% during pregnancy. Tachycardia and hypotension, typical of hypovolemic shock, may appear late in the pregnant trauma patient because of her increased blood volume.31 During pregnancy, maternal vital signs and perfusion may be preserved at the expense of uteroplacental perfusion, delaying the occurrence of signs of hypovolemic shock.32 Not uncommonly, noticeable alterations in vital signs occur only after significant blood loss that may have already diminished uteroplacental perfusion. In these instances, an atypical or abnormal fetal heart rate pattern, in addition to indicating impending fetal hypoxemic injury or even death, may be the first indicator of significant maternal hypovolemia due to hemorrhage.32–34 Therefore, in a pregnant patient ≥ 23 weeks’ gestation, fetal heart rate monitoring should be initiated as soon as possible. This may require having staff from the maternity or L&D unit visit the unit where the pregnant woman is receiving care for her injuries. For those < 23 weeks’ gestation, a brief assessment of fetal viability is adequate. Continuous monitoring of oxygen saturation is advised since maternal desaturation may compromise oxygenation of the fetus. Oxygen supplementation should be given to increase oxygen saturation. Special attention should be paid to the abdomen since serious injuries may involve the gravid uterus as well as other abdominal organs. The contour of the abdomen should be carefully inspected for abnormal distension as a sign of intraabdominal hemorrhage or perforation of hollow viscus. Meticulous documentation of the location of entrance and exit wounds of penetrating trauma is of paramount importance. The uterus and its contents usually cushion the impact of penetrating trauma; therefore, in women

Guidelines for the Management of a Pregnant Trauma Patient

after mid-pregnancy mortality and incidence of visceral injury with penetrating abdominal trauma are substantially lower than in the general population.35 However, injuries below the fourth intercostal space anteriorly, or the tip of the scapula posteriorly, should be carefully evaluated for potential thoraco-abdominal penetrating injuries. Risk factors associated with maternal death include bruising injuries to the abdomen, pelvis, or lower back, pelvic fractures, intraabdominal injuries, and penetrating trauma.34,36 Clinical signs of peritoneal irritation are less evident in the pregnant woman; therefore, in cases of suspected abdominal injury, physical examination is less informative in ruling out major organ damage and further investigations should be conducted.37 The uterus should be assessed for fundal height, shape, hypertonus, and tenderness. Tenderness over the uterus is an important sign suggestive of abruption of the placenta. Irregularities on the abdomen may represent fetal body parts in cases of traumatic uterine rupture. In these cases, rapid response of the medical team can significantly reduce maternal and fetal risks, and urgent obstetrical consultation is recommended.33,38,39 In some communities, the consultant who can perform a Caesarean and other requisite surgical procedures may be a family physician or a surgeon. Vaginal examination should be performed for cervical dilatation, effacement, fetal presentation, and station. However, in cases of vaginal bleeding after 23 weeks, speculum or digital vaginal examination should be deferred until placenta previa is excluded by an ultrasound scan. A speculum examination should be performed to assess for vaginal bleeding, pooling of amniotic fluid, cervical dilatation, vaginal or cervical lacerations, and expulsion of gestational tissue. Recommendations

12. In cases of major trauma, the assessment, stabilization, and care of the pregnant women is the first priority; then, if the fetus is viable (≥ 23 weeks), fetal heart rate auscultation and fetal monitoring can be initiated and an obstetrical consultation obtained as soon as feasible. (II-3B) 13. In pregnant women with a viable fetus (≥ 23 weeks) and suspected uterine contractions, placental abruption, or traumatic uterine rupture, urgent obstetrical consultation is recommended. (II-3B) 14. In cases of vaginal bleeding at or after 23 weeks, speculum or digital vaginal examination should be deferred until placenta previa is excluded by a prior or current ultrasound scan. (III-C)

Table 2. Estimated fetal radiation doses during some common radio-diagnostic procedures Fetal dose (mrad)

Examination X-ray Upper gastrointestinal series

100

Cholecystography

100

Lumbar spine radiography

400

Pelvic radiography

200

Hip and femur radiography

300

Retrograde pyelography

600

Abdominal radiography

250

Lumbar spine,

Anteroposterior

750

Lateral

91

Oblique

100

Barium enema

1000

Intravenous pyelogram

480

Computed tomography Head

0

Chest

16

Abdomen

3000

(Adapted from Ratnapalan S, Bona N, Koren G; Motherisk Team. Ionizing radiation during pregnancy. Can Fam Physician. 2003 Jul;49:873–4. By permission of Canadian Family Physician.) mrad: milli-rad (radiation absorbed dose)

ADJUNCTIVE TESTS FOR MATERNAL ASSESSMENT Radiographic Studies

Plain radiographs of the cervical spine, chest, and pelvis are first line radiological studies.19 Clinicians are often reluctant to order imaging studies for pregnant patients out of concern about fetal exposure to ionizing radiation. Patients’ attitudes may also reflect anxieties that are disproportionate to the actual risks. Ionizing radiation has the highest teratogenic potential during the period of organogenesis (5–10 weeks), with an increased risk of miscarriage before this period.40–42 After 10 weeks, radiation is more likely to produce growth restriction or CNS effects than teratogenenic changes.40,43 Fetal exposure from the radiological examinations that are routinely used in the evaluation of pregnant trauma patients presents a very low risk to the developing fetus (Table 2).40,44,45 Radiation exposure with a cumulative dose of > 5–10 rads (50–100 mGy) is associated with an increased risk of fetal malformation or CNS effects, limited usually to a gestational age < 18 weeks.40,42,46–48 Concerns about fetal exposure to radiation should not preclude or delay any indicated radiological evaluation. CT studies are associated JUNE JOGC JUIN 2015 l 559

SOGC clinical practice guideline

with increased fetal radiation exposure depending on the body part being scanned, the gestational age, the number and thickness of slices, and the equipment used. With abdominal CT during the third trimester the fetal exposure is around 3.5 rads, which is still under the threshold for fetal damage.49 Use of gadolinium-based contrast agents has shown fetal toxicity in animal studies, though no adverse effects have been reported in human fetuses.50 Their use can be considered when the maternal benefit outweighs potential fetal risks. The carcinogenic effects of ionizing radiation exposure are still in dispute. Some studies have suggested an increased risk with exposure to even a low dose of ionizing radiation in utero, especially before 8 weeks.48,51–53 However, the lifetime cancer risk from prenatal exposure is considered to be similar to that from exposure during childhood.48 Further, at an exposure level of < 5 rad, the additional lifetime risk was < 2% (< 0.6% during childhood), over and above the background lifetime risk of around 40%.46 Other studies, including a large Ontario-based cohort, could not confirm an increased risk.54,55 Therefore, if there is any carcinogenic potential of ionizing radiation exposure at levels usually used in diagnostic procedure, it is thought to be quite low. However, careful consideration of alternative forms of evaluation, accurate completion of ionizing studies to avoid duplication, and limitation of the number of CT cuts or area studied may be beneficial in limiting fetal exposure to radiation. Laboratory Tests

In all trauma patients, laboratory tests are often ordered by protocol, but in pregnant patients the clinician should be aware of alterations in the normal range of a few laboratory values. The white blood count is usually elevated and counts up to 20 × 109/L may represent the physiologic response to pregnancy. Leukocytosis should be correlated with clinical findings, other lab tests, and imaging studies to confirm the suspicion of infection or inflammation. Fibrinogen values are often more than 4 g/L during pregnancy,56 therefore the normal values of 2.5 to 3 g/L for a non-pregnant patient may actually signify mild hypofibrinogenemia, and levels below 2 g/L may indicate disseminated intravascular coagulation, a frequent comorbidity of significant placental abruption.57 D-dimer measurement is a marker for venous thromboembolism. However, during pregnancy, the D-dimer is often positive and therefore is of little value in the diagnosis or exclusion of venous thromboembolism. Normal range for the partial pressure of CO2 is decreased during pregnancy to 27 to 32 mmHg, thus normal non-pregnant values of 40 mmHg may result from mild hypoventilation. Serum creatinine levels are decreased during pregnancy to 50 to 560 l JUNE JOGC JUIN 2015

60 µmol/L, and even a value as low as 90 µmol/L may be abnormal. Alkaline phosphatase is secreted by the placenta, thus levels that are twice the upper limit for non-pregnant patients are within the normal range during pregnancy (up to 140 IU/L).58,59 In addition to the routine laboratory studies for trauma evaluation, it is advisable to order a coagulation profile including fibrinogen.57 Additional Investigations

Abdominal ultrasound FAST is a useful aid for the detection of intraperitoneal fluid in pregnant trauma patients with suspected intraabdominal injury. The sensitivity of FAST in detecting intraperitoneal fluid in pregnant blunt trauma patients was 83% in a study that reviewed 127 pregnant trauma patients.60 This rate is similar to that in a previously published study of non-pregnant trauma patients.61,62 FAST is an easy and rapid modality that has the added advantage of avoiding fetal exposure to ionizing radiation, it should therefore be part of the secondary survey in pregnant patients with major trauma. Peritoneal lavage and laparotomy DPL is a very rapid and sensitive test with sensitivity of 96% to 100% for detection of traumatic intra-abdominal injury.63 The main disadvantages of this low cost, easily interpretable test are that it does not provide information about specific organ damage, and abdominal injuries that can be managed conservatively following CT would require operative intervention based upon DPL. For these reasons, CT is the most widely used screening modality for blunt abdominal trauma. CT identifies specific organ injury, evaluates the retroperitoneum as well and is less invasive than DPL. Concerns over fetal exposure to radiation during pregnancy may lead to a more frequent use of DPL. The open lavage technique is preferable over a blind needle insertion in the pregnant patient in order to minimize uterine injury.64 When significant abdominal blood is detected, an exploratory laparotomy with a midline incision should be performed. Recommendations

15. Radiographic studies indicated for maternal evaluation including abdominal computed tomography should not be deferred or delayed due to concerns regarding fetal exposure to radiation. (II-2B) 16. Use of gadolinium-based contrast agents can be considered when maternal benefit outweighs potential fetal risks. (III-C) 17. In addition to the routine blood tests, a pregnant trauma patient should have a coagulation including fibrinogen. (III-C)

Guidelines for the Management of a Pregnant Trauma Patient

18. Focused abdominal sonography for trauma should be considered for detection of intraperitoneal bleeding in pregnant trauma patients. (II-3B) 19. Abdominal computed tomography may be considered as an alternative to diagnostic peritoneal lavage or open lavage when intra-abdominal bleeding is suspected. (III-C) FETAL ASSESSMENT

Assessment of a viable fetus (≥ 23 weeks gestational age) should be initiated immediately following, or in parallel with the physical examination of the stabilized mother since it has been shown that most placental abruptions occur shortly after the insult.33 The objectives are: •• identification of impending hypoxemic fetal injury or death as a result of uteroplacental compromise or placental abruption, •• detection of trauma-related complications of pregnancy such as placental abruption, preterm delivery and spontaneous rupture of the membranes, •• evaluation of the degree of maternal–fetal hemorrhage and resultant fetal anemia, •• delineation of fetal injuries, and •• identification of compensated maternal hypovolemia first manifested by decreased placental perfusion. Knowledge of the estimated gestational age is essential for appropriate interpretation of tests for fetal viability and well-being. Along with clinical examination of fundal height and palpation for uterine contractions and tone, in absence of certainty regarding the gestational age, an ultrasound examination should be undertaken. Electronic monitoring of the fetal heart rate should be initiated on viable fetuses (≥ 23 weeks) as soon as possible. With a confirmed pre-viable fetus, it may be sufficient to demonstrate the presence of fetal cardiac activity. Monitoring of Fetal Heart Rate and Uterine Activity

EFM allows assessment of fetal well-being and uterine activity, with abnormality of either being predictive of potential obstetrical complications such as placental abruption, fetal hypoxic injury or fetal death. Rothenberger et al reported fetal loss in 61% of cases with major maternal injuries and 27% with minor injuries, with no effect on pregnancy outcome following insignificant maternal injuries.39 Hospital-based studies have suggested a 5% to 19% risk of fetal death as opposed to a 1.3% risk in population-based studies. This difference may result from the fact that more serious injuries are more likely to be assessed in a hospital.8,65–67 Fetal death may be an

expected consequence of maternal death.33,38 However, a high Injury Severity Score, serious abdominal injury and hemorrhagic shock all increase the risk of fetal loss.33,38 Maternal trauma resulting in hypovolemic shock can reduce uterine perfusion, a direct function of systemic blood pressure.68 This can be further compounded by visceral vasoconstriction. Placental abruption can further reduce transplacental oxygenation. A combination of these factors can lead to fetal hypoxemic injury. Compromised fetal perfusion and oxygenation usually presents with abnormalities in the fetal heart rate pattern. An abnormality in the fetal heart rate pattern may also be the first sign of maternal hemodynamic compromise.67 Occasional uterine contractions are the most common finding with trauma during pregnancy, occurring in 40% of cases,69 and resolving in 90% of cases with no adverse fetal outcome.70 The intensity and frequency of contractions are predictive of complications such as traumatic placental abruption and preterm labour. Elevated basal uterine tone also raises the suspicions for placental abruption. Abnormal EFM tracings following trauma are not reliable in predicting adverse obstetrical outcome (sensitivity of 62% and specificity of 49%).69,71 However, the combination of a normal tracing and physical examination has a negative predictive value of 100% in excluding major adverse fetal outcome.33,69,72 Atypical or abnormal fetal heart rate patterns such as decelerations, bradycardia, tachycardia or loss of variability mandate further testing, in utero resuscitation with supplemental oxygen, IV fluids and left lateral decubitus positioning or delivery, depending on the severity of the abnormal pattern, the presumed cause and gestational age. About 2.4% to 7.2% of maternal trauma patients require a Caesarean delivery shortly after trauma.34,38 Need for a Caesarean section shortly after trauma is also a risk factor for maternal death.34 The duration of fetal monitoring following maternal trauma remains disputed. For many years it has been suggested that fetal monitoring should continue for at least 24 hours following the insult33,64,73,74 and some even suggested a 48-hour period of close fetal monitoring.75 In a prospective study of pregnant trauma patients that had EFM for a minimum of 4 hours, the majority demonstrated uterine activity during that period.70 Contractions then abated in most patients. Patients were discharged home if contractions ceased or were less frequent than once every 15 minutes. These patients had pregnancy outcomes similar to that in an uninjured control group. The sensitivity of predicting placental JUNE JOGC JUIN 2015 l 561

SOGC clinical practice guideline

abruption by the frequency of uterine activity in the first 4 hours after trauma was 100%. The study suggested that 4 hours of monitoring was a sensitive method of predicting immediate post-traumatic adverse obstetrical outcomes. Another retrospective study of 271 pregnant patients, suggested monitoring for at least 24 hours only for a selected group of patients at high risk for fetal demise, preterm labour, and placental abruption.76 This high risk group consisted of patients involved in motorcycle, pedestrian or high velocity collisions, those ejected from motor vehicles and patients demonstrating maternal tachycardia, abnormal fetal heart rate pattern, and high injury severity scores. In a study of 317 patients with minor trauma (48% with falls), 14% had frequent contractions requiring observation for 24 hours.77 Delivery information was available in 80%. Only one case of placental abruption occurred, remote from the trauma. There were no other trauma-related adverse events. We suggest hospitalization and intermittent fetal heart rate and uterine activity monitoring by EFM for 24 hours for patients with •• uterine tenderness, •• significant abdominal pain, •• vaginal bleeding, •• a contraction frequency of more than once per 10 minutes during a monitoring period of 4 hours, •• rupture of the membranes, •• atypical or abnormal fetal heart rate pattern (fetal tachycardia, bradycardia or decelerations), •• high risk mechanism of injury (motorcycle, pedestrian, high speed crash), or •• serum fibrinogen < 200 mg/dL •• Monitoring for 4 hours is sufficient to rule out major trauma-related complications in low risk patients without the above mentioned risk factors.69,72,78 Prevention of Rh Alloimmunization and Evaluation of Maternal-fetal Hemorrhage

Traumatic placental injury can result in MFH. MFH occurs in 10% to 30% of pregnant trauma patients.79 Massive MFH is a rare complication of trauma and is usually clinically evident, with fetal demise, abnormal fetal heart rate pattern (bradycardia or recurrent decelerations), or abrupt fetal anemia and cardiac failure. The vast majority of post-traumatic transplacental hemorrhages are smaller and subclinical. The quantification of the amount of fetal blood cells in the maternal circulation enables the obstetric care provider to roughly estimate the degree of transplacental hemorrhage. This may be important in prevention of Rh 562 l JUNE JOGC JUIN 2015

alloimmunization in Rh-negative mothers. It has also been suggested that a larger MFH may be predictive of other adverse obstetrical outcomes.80 The Rh antigen is well developed by 6 weeks gestation81 and as little as 0.001 mL of fetal blood can cause sensitization of the Rh-negative mother. Even minor trauma in pregnancy may cause sensitizing MFH. Several studies have demonstrated reduced Rh alloimmunization after routine istration of anti-D immune globulin G (IgG) to Rh-negative mothers.81–83 Therefore, anti-D IgG should be given to all Rh-negative pregnant trauma patients.84 A single dose of 300 mg, istered within 72 hours of injury, provides protection against sensitization for up to 30 mL of fetal blood in the maternal circulation.84–86 The feto-placental blood volume is estimated to be 120 mL/kg of fetal weight. In most cases of traumatic maternal–fetal hemorrhage, the estimated volume of fetal blood in the maternal circulation is less than 15 mL and in more than 90% of cases it is less than 30 mL.70,78 Therefore, the vast majority of Rh-negative patients are protected by one ampule. The KB test has been used to quantify MFH, so that Rhnegative women could receive appropriate Rh immune prophylaxis. If the KB test indicates transplacental hemorrhage in excess of 30 mL fetal blood, additional doses of anti-D IgG may be required. According to the SOGC recommendations for prevention of Rh alloimmunization,84 KB test may be considered following events potentially associated with placental trauma and disruption of the maternal–fetal interface (e.g., placental abruption, blunt trauma to the abdomen). A novel approach for detecting MFH, using flow cytometry as a simpler, more objective, and more precise alternative to the KB method has been advocated.87,88 Another study has shown that both manual KB test and flow cytometry have good sensitivity in detecting and quantifying fetal red cells.89 Taking into consideration that flow cytometry is not available in most medical facilities and its added value is still being investigated, we cannot recommend its routine use at this time. The universal use of KB testing for all pregnant trauma patients, regardless of their Rh status had been advocated by some,80,90 hypothesizing that the magnitude of MFH reflects severity of injury and therefore would be predictive of trauma-related obstetrical complication such as preterm labour. In one study of maternal trauma, of the 46 patients with a positive KB test, 44 had contractions (of which 25 had preterm labour), and of the 25 patients with a negative KB test, none

Guidelines for the Management of a Pregnant Trauma Patient

had contractions or preterm labour.80 No information was available in this study regarding the incidence of preterm delivery. The authors concluded that KB test accurately predicted the risk of preterm labour, and clinical examination did not. However, it can be argued that since all women with contractions had a positive test, and those without contractions did not, presence of uterine contractions can be used as a surrogate marker for occurrence of MFH. Therefore the utility of KB test in rhesus-positive women is not clear. Another review suggested that KB test should be performed in all maternal trauma cases, although the basis for this recommendation for rhesus-positive women was not apparent.90 Others have suggested the KB test is only useful in Rh-negative women.69,91 A study comparing incidence of a positive KB test in women with history of trauma and that in a low risk population found no significant difference (2.6% vs. 5.1%, respectively).92 Based on the evidence, we suggest that KB testing should be done in all rhesusnegative pregnant trauma patients. Though EFM is more likely to be clinically useful in rhesus-positive women, KB test can be considered as an optional test to determine the need for prolonged monitoring. Given the high incidence of a false-positive KB test, in rhesus-positive women, assessment of MFH by flow cytometry could be a useful adjunct in differentiating true positive KB tests from the false-positive ones. The Role of Ultrasound

Ultrasonography is a rapid, non-invasive, valuable tool in the assessment of pregnant trauma patients and it does not require transport of the patient from the trauma unit. An obstetrical ultrasound scan should be done urgently in cases where the gestational age cannot be determined with certainty and need for delivery is anticipated based on an atypical or abnormal fetal heart rate pattern or suspicion of placental abruption. However, it is not sensitive in diagnosing placental abruption.70,72 Between 50% and 80% of traumatic abruptions will be missed and those detected by sonography are usually the clinically apparent ones, which pose no diagnostic challenge.70,78 The role of the biophysical profile in predicting adverse obstetrical outcome following trauma is yet to be studied.93 However, in the setting of trauma, EFM is a more sensitive tool not only to rule out a placental abruption but also for assessment of fetal well-being as compared to ultrasound.70,74,78 Nevertheless, ultrasound is an important adjunctive to the physical examination and fetal assessment tests. Ultrasonography may assist in: •• determination of gestational age •• demonstration of fetal cardiac rate and rhythm

•• placental localization and exclusion of placenta previa •• assessment of amniotic fluid volume •• cervical length assessment •• fetal well-being (biophysical profile) •• detection of fetal anemia by peak systolic flow velocity in the middle cerebral artery •• delineation of possible fetal injury, and •• confirmation of fetal demise. Therefore, an obstetrical ultrasound examination is recommended in all cases of significant maternal trauma that are itted for monitoring for more than 4 hours. However, ultrasound should only be used to complement EFM, the latter being more sensitive in predicting adverse outcomes such as placental abruption or fetal hypoxic injury.69–72 In cases where severe MFH occurred, generally there is no time for diagnostic tests such as KB test or middle cerebral artery Doppler. Fetal heart tracing is usually abnormal, and prompt delivery is recommended. Ultrasound needs to be done on an urgent basis only in cases where fetal viability is in question, in all other cases, it can be undertaken as a non-urgent follow-up examination prior to discharge of the patient from the hospital. A reassuring biophysical profile should never be used as a surrogate for EFM. After discharge from hospital, a followup obstetric ultrasound examination in 2 weeks should be considered for all patients who needed hospital ission for maternal or fetal factors (regardless of gestational age), this is to document normalcy after the traumatic event, especially of fetal intracranial anatomy and to assess fetal growth in the interval.94 Recommendations

20. All pregnant trauma patients with a viable pregnancy (≥ 23 weeks) should undergo electronic fetal monitoring for at least 4 hours. (II-3B) 21. Pregnant trauma patients (≥ 23 weeks) with adverse factors including uterine tenderness, significant abdominal pain, vaginal bleeding, sustained contractions (> 1/10 min), rupture of the membranes, atypical or abnormal fetal heart rate pattern, high risk mechanism of injury, or serum fibrinogen < 200 mg/dL should be itted for observation for 24 hours. (III-B) 22. Anti-D immunoglobulin should be given to all rhesus D-negative pregnant trauma patients. (III-B) 23. In Rh-negative pregnant trauma patients, quantification of maternal–fetal hemorrhage by tests such as Kleihauer-Betke should be done to determine the need for additional doses of anti-D immunoglobulin. (III-B) JUNE JOGC JUIN 2015 l 563

SOGC clinical practice guideline

24. An urgent obstetrical ultrasound scan should be undertaken when the gestational age is undetermined and need for delivery is anticipated. (III-C) 25. All pregnant trauma patients with a viable pregnancy who are itted for fetal monitoring for greater than 4 hours should have an obstetrical ultrasound prior to discharge from hospital. (III-C) 26. It is important to have careful documentation of fetal well-being in cases involving violence, especially for legal purposes. (III-C) OBSTETRICAL COMPLICATIONS OF TRAUMA Placental Abruption

Abruption of the placenta is a major complication of maternal trauma, occurring in 5-50% of cases, depending on the severity of injury.70,78 It is the most common cause of fetal death in cases of blunt trauma. Resulting from the difference in physical properties of the relatively inelastic placental tissue versus the elastic myometrium, significant abruption of the highly vascular uteroplacental interface can mediate rapid maternal and in some cases fetal exsanguination. Most abruptions occur within 2 to 6 hours after the injury, and almost all of them with 24 hours of injury.33,95 Abruption may follow even minor trauma and requires high index of suspicion to detect. The diagnosis of abruption is based on clinical impression, laboratory tests and fetal evaluation. Typical findings include abdominal pain, uterine tenderness, uterine contractions or hypertonicity, vaginal bleeding, preterm labour, or an atypical or abnormal EFM tracing. Specific sonographic findings are uncommon; retroplacental hematoma is seen in 2% to 25% of abruptions. Treatment should never be delayed for ultrasound confirmation because ultrasonography is not reliable in diagnosing placental abruption. In a study of 149 women with vaginal bleeding, the sensitivity, specificity, and positive and negative predictive values of sonography in diagnosing placental abruption were 24%, 96%, 88%, and 53%, respectively.96 Some have suggested that traumatic abruption tends to be occult without uterine tenderness or vaginal bleeding but with a higher incidence of coagulopathy.97 Abruption, occult or concealed, may lead to major maternal bleeding and consumption coagulopathy with thrombocytopenia, prolonged coagulation tests and hypofibrinogenemia.57 Although severe placental abruption can be lethal to the fetus, a timely and prompt Caesarean section may result in considerable survival rates of up to 75%.34,98 Delay in recognition of non-reassuring fetal status, in such cases, was able for 60% of potentially preventable perinatal deaths. In cases of a non-viable fetus, vaginal 564 l JUNE JOGC JUIN 2015

birth is preferable. Although placental abruption, particularly with greater than 50% placental separation, increases the risk of fetal death, it more often results in preterm labour. Placental abruption is often associated with a rapid cervical dilation and delivery, induction or augmentation of labour with a trial of vaginal birth may be reasonable in a hemodynamically stable mother at or near term with a normal fetal heart rate pattern. However, in the presence of fetal or maternal compromise, prompt delivery by Caesarean is often indicated. Maternal bleeding and coagulation abnormalities should be aggressively treated to optimize maternal and fetal outcome. Abruption remote from term is challenging to manage. Deterioration in fetal condition or maternal hemodynamic instability is indications for immediate delivery, even at the expense of prematurity.95 Uterine Rupture

Post-trauma uterine rupture is rare (0.6% of all maternal injuries), but seen more frequently with a scarred uterus or with direct abdominal impact during the latter half of pregnancy.74 Most (75%) uterine ruptures involve the fundal area. The degree of rupture may vary from complete avulsion of the uterus to serosal hemorrhage and abrasions. Symptoms and signs suggestive of uterine rupture include: maternal shock, abdominal distension, irregular uterine contour, palpable fetal parts, sudden abnormal fetal heart rate pattern, ascent of fetal presenting part and peritoneal irritation (abdominal rigidity, guarding and tenderness). Maternal mortality has been described with traumatic uterine rupture and fetal mortality is almost universal. It is the cause of MVCrelated perinatal death in 17.5% of the cases.8 Suspected uterine rupture with maternal and/or fetal comprise should prompt urgent laparotomy to control bleeding and facilitate resuscitation. Preterm Labour

Traumatic injury during pregnancy can result in preterm labour through several mechanisms. Placental abruption may culminate in preterm labour in 20% of cases.99 The extravasation of blood at the placental margin may lead to decidual necrosis, which, in turn, could initiate the production of prostaglandin, thereby leading to preterm labour.99 Traumatic injury to the uterus may also result in destabilization of lysosomal enzymes which can initiate prostaglandin production.68 Preterm premature rupture of membranes is also associated with preterm labour. Regardless of the mechanism, trauma (even with minor injuries) is associated with a 2-fold higher risk of preterm delivery.100 The risk is higher with increasing injury severity and among those injured early in gestation.100 Signs of

Guidelines for the Management of a Pregnant Trauma Patient

preterm labour should be sought in every patient with a viable fetus. EFM should be used to assess regularity and frequency of contractions. When regular contractions are noted, the fetal fibronectin test or cervical length assessment to determine the risk for preterm labour should be considered. Rupture of the membranes, when suspected, should be ruled out by a speculum examination including assessment with nitrazine paper and the ferning test. If risk of preterm delivery is high because of preterm labour or preterm premature rupture of membranes, steroids (and any other indicated medications such as antibiotics and magnesium sulfate), transfer to a tertiary care centre, and neonatology consultation should be considered based on gestational age and current location of the patient. In many cases, iatrogenic preterm delivery may be indicated to improve fetal or maternal outcome. Direct Fetal Injury

Direct fetal injury is seen in less than 1% of blunt maternal trauma.101 Maternal soft tissues, uterus, and amniotic fluid serve to diminish the force delivered to the fetus. Direct fetal injury from blunt abdominal trauma often involves the fetal skull and brain. One possible mechanism involves fracture of the maternal pelvis in late gestation with an engaged fetal head resulting in fetal skull fracture.102 A deceleration injury of an unengaged head can also occur.103 Fetal injuries in other modes of maternal trauma are considered in the section below. Recommendation

27. Management of suspected placental abruption should not be delayed pending confirmation by ultrasonography; ultrasound is not a sensitive tool for its diagnosis. (II-3B) ADDITIONAL CONSIDERATIONS REGARDING SPECIFIC TRAUMATIC INJURIES Penetrating Trauma

Penetrating trauma during pregnancy is becoming more common. Penetrating abdominal injuries are caused primarily by gunshot or stab wounds. As in non-pregnant individuals, stab wounds tend to have a better prognosis than gunshot wounds. The maternal bowel is less likely to be involved with penetrating injuries after the second trimester due to the protection provided by the large uterus. The incidence of maternal visceral injury with penetrating abdominal trauma is only 15% to 40% compared with 80% to 90% in non-pregnant women.35 Although the visceral organs are displaced upwards and are less likely to be injured, upper abdominal stab wounds can result in more complex bowel injury. Thoraco-abdominal penetrating injuries, below the fourth intercostal space anteriorly, or the

tip of the scapula posteriorly, may cause visceral injuries that are easily missed. At the same time that the gravid, abdominal uterus provides protection to the abdominal viscera, it is susceptible, along with the fetus, to direct injury. According to Buchsbaum, the uterine musculature absorbs a great amount of the projectile’s velocity and diminishes its ability to damage the viscera.29 Therefore, depending on the gestational age and the size of the uterus, the fetus is much more likely than the mother to sustain significant injury (and to die) after a penetrating abdominal trauma. In general, the fetus sustains injury in 60% to 70% of cases, while visceral maternal injuries are seen only in 20% of penetrating abdominal trauma. Gunshot wounds produce transient shock waves and cavitations in displacement of kinetic energy to body tissue, causing more damage and thus higher mortality for both mother and fetus than low-velocity injuries: 70% of abdominal gunshot wounds result in fetal injury, and 40% to 65% of these fetuses die.104 Fetal mortality generally results from premature delivery, maternal shock, uteroplacental injury, or direct fetal injury.105 A study of 321 pregnant trauma patients showed that 9% had penetrating trauma, of which 73% were gunshot wounds.4 The risk of maternal death was not significantly higher with penetrating trauma than with blunt trauma (7% vs. 2%); however, fetal mortality was significantly higher (75% vs. 10%) with penetrating trauma. Penetrating injuries in pregnant trauma patients are managed in essentially the same way as in non-pregnant patients. The standard of care is to prioritize the emergent treatment of the gravid patient above that of her fetus. The hemodynamically stable patient should be assessed by non-invasive diagnostic methods such as ultrasound and triple contrast CT scan. The same indications for surgical exploration apply as in the non-pregnant patient (positive findings on lavage, free air under the diaphragm before lavage, progressive abdominal distention with a declining hematocrit, or abdominal wall disruption or perforation). In cases of exploration, the decision to proceed with Caesarean section should be weighed against the likelihood for fetal survival and long-term complications of prematurity and should be made in consultation with the trauma surgeon, neonatologist, and pediatric surgeon. Factors that can influence the decision to proceed with Caesarean section are gestational age, extent and severity of fetal injury, degree of uteroplacental compromise, parameters of fetal well-being, and the need for hysterectomy with extensive uterine injury. A dead or injured fetus is not considered an indication for exploration, as the fetus will usually spontaneously JUNE JOGC JUIN 2015 l 565

SOGC clinical practice guideline

abort or can be delivered vaginally. Tetanus vaccination is safe in pregnancy and should be given, when indicated, according to the usual protocol.106,107 Domestic or Intimate Partner Violence

The incidence of domestic or intimate partner violence increases during pregnancy and is clustered in the third trimester.6,108 Domestic violence was reported by 6.6% of pregnant women in Ontario.108 The most commonly struck body area was the abdomen (64%), a risk factor for both maternal and fetal adverse outcome. Other studies have reported an even higher incidence of abuse during pregnancy (10–30%), with 5% resulting in fetal death.109,110 Every woman who sustains trauma, particularly penetrating abdominal trauma, should be questioned specifically about domestic violence. Careful, detailed, and contemporaneous documentation is essential. Such inquiry should occur in the absence of the partner. Motor Vehicle Collision

In the pregnant population, MVC is the leading cause of maternal death, and after placental abruption, maternal death is the leading cause of fetal death.111,112 Of 351 maternal deaths from non-obstetric causes in a trauma centre registry, 72% resulted from MVC.113 Documentation of the nature of the injury and of maternal and fetal status is important for reasons that include evaluating whether any subsequent adverse outcome should be attributed to the MVC. The outcome of MVC can range from no trauma at all to severe multi-organ damage and death. The outcome is related to various factors including the mechanism of the collision itself, the acceleration-deceleration velocities of the vehicles involved, and the use of protective mechanisms, such as seat belts, air bags, and other safety features. Wearing a seat belt in a motor vehicle during pregnancy is useful and effective in reducing the risk of adverse pregnancy outcomes including maternal death.113,114 Crosby and Costiloe reported a reduction in the maternal death rate from 33% to 5% with the use of a two-point seatbelt, and that finding was reproduced by a more recent study.112,115 During prenatal visits, the caregiver should emphasize the importance of wearing a properly adjusted and positioned seatbelt at all times and refute any misconception about the use of seatbelts during pregnancy.116 Ejection from the vehicle increases the risk to both the woman and the fetus. The lap belt should be positioned below the abdomen and not over the uterus. The shoulder belt should be placed between the breasts. The belt should be comfortable, but not tight. Air bags are a relatively newer modality in preventing and reducing injuries in MVC. In a simulated study, a combination of 566 l JUNE JOGC JUIN 2015

seatbelts and air bag was the most beneficial, and could be lifesaving in severe MVC.117 Deployment of airbags has been associated with adverse events such as uterine rupture, placental abruption, and fetal death that were attributed to the air bags.113,118,119 However, this is more likely a reflection of the severity of traumatic force rather than a causal association. At this point there are not enough data to make a recommendation about disabling air bags during pregnancy. Furthermore, when the risk of fetal death or injury is balanced against risks to the mother, the latter should take precedence, recognizing the fact that fetal well-being is dependent on maternal well-being. Although organ damage, fractures, and hemorrhage can occur in MVC, the most common mechanism of injury is blunt trauma, which can cause both maternal and fetal morbidity and mortality. The mechanism of trauma often involves the uterus. A force applied to the uterus can deform the shape of the uterus due to its elasticity, but can have a smaller deforming effect on the less elastic placenta. This can result in a shearing force that may separate the attached placenta from the uterus. Abrupt changes in amniotic fluid pressure may further contribute to placental separation. The end result of this kind of mechanism is placental abruption. One report suggested that up to 37% of life-threatening maternal injuries after MVC are complicated by abruption, whereas in non– life-threatening injuries, the incidence of abruption was only 1.6%.120 Uterine contractions may also result from blunt trauma and lead to preterm labour. Relatively minor injuries may be associated with a grave pregnancy outcome.121 Maternal–fetal hemorrhage may be a serious complication of blunt trauma. Exsanguination into maternal circulation can occasionally culminate in fetal demise. Direct fetal intracranial injury is another, albeit uncommon, mechanism of fetal injury.122 This type of injury may be attributed to a direct trauma to the fetal head but may also result from a massive maternal–fetal hemorrhage and significant fetal hypotension with subsequent hypoxic-ischemic intracranial injury. Falls

Falls are the cause in 3% to 31% of cases of maternal trauma.69,123 Less than 10% of falls are associated with significant maternal or fetal complications.124 They are more common in the latter half of pregnancy, particularly after 32 weeks.69,74 The increase in lumbar lordosis that is seen in pregnancy moves the centre of gravity forward and contributes to an increased incidence of falls.123 Therefore, aggressive high-impact activity should be avoided in advanced pregnancy. Complications associated

Guidelines for the Management of a Pregnant Trauma Patient

with falls include preterm labour, placental abruption, uterine rupture, fetal growth restriction, and fetal death.123 Electrical Trauma

Electrical shock is the fifth leading cause of fatal occupational injuries in the United States and most commonly result from failure to ground appliances properly or from using electrical devices while wet.125 The literature on maternal electrical trauma is scarce and possibly misleading due to publication bias stemming from the tendency to report adverse outcomes rather than uneventful insults. Nevertheless, several case series have emphasized poor fetal outcome of electrical trauma. Fatovich reviewed the literature and found 15 cases of maternal electric shock with a fetal mortality rate of 73% and only 1 normal pregnancy outcome.126 The Motherisk Program published a prospective cohort study of 31 pregnant women with electric shock who sought experts’ advice via telephone127; 28 of those women delivered healthy newborns. One spontaneous abortion was temporally related to the insult, another was probably unrelated to the injury, and a third baby was born with a ventricular septal defect. Mean birth weight, gestational age at delivery, rates of Caesarean section, and incidence of neonatal distress were similar between electric shock and control groups.127 Several risk factors for adverse perinatal outcome were identified. The magnitude of the current obviously has an impact on outcome. The pathway of the current in the body, from entrance to exit points, is of utmost importance. A current that travels from the hand to the foot will probably go through the uterus, stimulating myometrial contractions, which may culminate in preterm labour.127 Electrical current that traverses the amniotic fluid (an excellent conductor) may lead to spontaneous abortion, fetal demise, or fetal burns.128 Other risk factors include maternal body weight, blunt trauma following the electrical insult, and being wet. Maternal and fetal assessment is warranted in cases of electrical injury during pregnancy.129 Electrocardiography, urine tests for major muscle injury, X-ray imaging, and sometimes CT are all part of the initial evaluation of the mother. With a viable fetus, EFM is recommended for 24 hours if the injury involved loss of consciousness, abnormal maternal ECG, or known maternal cardiovascular illness. In most other cases, and especially if the insult involved low voltage, immediate fetal effects are unlikely. Summary Statement

At this time, there is insufficient evidence to the practice of disabling air bags for pregnant women. (III)

Recommendations

28. Tetanus vaccination is safe in pregnancy and should be given when indicated. (II-3B) 29. Every woman who sustains trauma should be questioned specifically about domestic or intimate partner violence. (II-3B) 30. During prenatal visits, the caregiver should emphasize the importance of wearing seatbelts properly at all times. (II-2B) PERIMORTEM CAESAREAN SECTION

The concept of performing Caesarean section concurrent with maternal resuscitation was introduced in 1986 when it was recommended that the procedure should be done no later than 4 minutes following maternal cardiac arrest.130,131 The rationale for the recommendation was improved efficacy of maternal chest compression after delivery by alleviating the aortocaval compression exerted by the gravid uterus and allowing adequate venous return. Neurologic injury in the mother begins 6 minutes after cessation of cerebral blood flow; to obtain cardiac return by 5 minutes and avoid neurological damage the Caesarean section should be started 4 minutes after the maternal pulse ceases.24,41,132 A perimortem Caesarean section is recommended for viable pregnancies (≥ 23 weeks, or fundal height 2 or more fingerbreadths above the umbilicus).132 In these cases, not only is the uterus large enough to cause significant aortocaval compression (its emptying therefore allowing improved maternal cardiac output), the baby is also mature enough that it may survive the event even if the mother does not.132 Prolonged resuscitation is not recommended if no pulse can be obtained, and the uterus should be emptied to increase the likelihood of successful maternal resuscitation and a healthy infant. In many trauma cases, resuscitation will be futile because of a fatal cause. In such cases, there is no reason to delay Caesarean section to save a viable fetus. It should be emphasized that many studies and case reports relate non-traumatic cardiac arrests in which the maternal resuscitation efforts were the major indication for delivery. Trauma patients with cardiac arrest are less likely to respond to resuscitation; in these cases, perimortem Caesarean is performed primarily for fetal salvage. Delivery of a viable neonate is less likely when no maternal vital signs have been recorded for 15 to 20 minutes.131,132 A multi-institutional retrospective cohort study showed that of 33 fetuses delivered by emergency Caesarean section in the setting of maternal trauma, 13 had no fetal heart tones at the initiation of the Caesarean section and none survived. When no fetal JUNE JOGC JUIN 2015 l 567

SOGC clinical practice guideline

heart tones can be demonstrated at initial assessment of a pregnant trauma patient after 23 weeks’ gestation, Caesarean section is likely to be futile in of fetal survival.34 Recommendation

31. A Caesarean section is recommended for viable pregnancies (≥ 23 weeks) no later than 4 minutes (when possible) following maternal cardiac arrest to aid with maternal resuscitation and fetal salvage. (III-B) REFERENCES 1. Kuhlmann RD, Cruikshank DP. Maternal trauma during pregnancy. Clin Obstet Gynecol 1994;37:274–93. 2. Mendez-Figueroa H, Dahlke JD, Vrees RA, Rouse DJ. Trauma in pregnancy: an updated systematic review. Am J Obstet Gynecol 2011;209:1–10. 3. Weinber L, Steele RG, Pugh R, Higgins S, Herbert M, Story D. The pregnant trauma patient. Anaesth Intensive Care 2005;33:167–80. 4. Petrone P, Talving P, Browder T, Teixeira PG, Fisher O, Lozornio A, et al. Abdominal injuries in pregnancy: a 155-month study at two level 1 trauma centers. Injury 2011;42:47–9. 5. Lavery JP, Staten-McCormick M. Management of moderate to severe trauma in pregnancy. Obstet Gynecol Clin North Am 1995;22:69–90. 6. Poole GV, Martin JN Jr, Perry KG Jr, Griswold JA, Lambert CJ, Rhodes RS. Am J Obstet Gynecol 1996;174:1873–8. 7. Health Canada. Special report on maternal mortality and severe morbidity in canada- enhanced surveillance: the path to prevention. Ottawa: Minister of Public Works and Government Services Canada; 2004. 8. Kvarnstrand L, Milsom I, Lekander T, Druid H, Jacobsson B. Maternal fatalities, fetal and neonatal deaths related to motor vehicle crashes during pregnancy: a national population-based study. Acta Obstet Gynecol Scand 2008;87:946–52. 9. John PR, Shiozawa A, Haut ER, Efron DT, Haider A, Cornwell EE 3rd, et al. An assessment of the impact of pregnancy on trauma mortality. Surgery 2011;149:94–8. 10. Sela HY, Weiniger CF, Hersch M, Smueloff A, Laufer N, Einav S. The pregnant motor vehicle accident casualty: adherence to basic workup and ission guidelines. Ann Surg 2011;254(2):346–52. 11. Bochicchio GV, Napolitano LM, Haan J, Champion H, Scalea T. Incidental pregnancy in trauma patients. J Am Coll Surg 2001;192:566–9.

18. Tsuei BJ. Assessment of the pregnant trauma patient. Injury 2006;37(5):367–73. 19. American College of Surgeons Committee on Trauma. Trauma in women. In: Advanced trauma life for doctors: student course manual. 8th edition. Chicago: American College of Surgeons; 2008:259–68. 20. Sperry JL, Minei JP, Frankel HL, West MA, Harbrecht BG, Moore EE, et al. Early use of vasopressors after injury: caution before constriction. J Trauma 2008;64:9–14. 21. Atta E, Gardner M. Cardiopulmonary resuscitation in pregnancy. Obstet Gynecol Clin North Am 2007;34:585–97. 22. Pearlman M, Faro S. Obstetric septic shock: a pathophysiologic basis for management. Clin Obstet Gynecol 1990;33:482–92. 23. Bamber JH, Dresner M. Aortocaval compression in pregnancy: the effect of changing the degree and direction of lateral tilt on maternal cardiac output. Anesth Analg 2003;97:256–8. 24. Hui D, Morrison LJ, Windrim R, Lausman AY, Hawryluck L, Dorian P, et al. The American Heart Association 2010 guidelines for the management of cardiac arrest in pregnancy: consensus recommendations on implementation strategies. J Obstet Gynaecol Can 2011;33:858–63. 25. Wang YC, Chen CH, Su HY, Yu MH. The impact of maternal cardioversion on fetal haemodynamics. Eur J Obstet Gynecol Reprod Biol 2006;126:268–9. 26. Davis SM. Antishock tros: a collective review. J Emerg Med 1986;4:145–55. 27. Van Camp LA, Delooz HH. Current trauma scoring systems and their applications. Eur J Emerg Med 1998;5:341–53. 28. Lapinsky SE, Kruczynski K, Seaward GR, Farine D, Grossman RF. Critical care management of the obstetric patient. Can J Anaesth 1997;44:325–9. 29. Buchsbaum HJ. Accidental injury, complicating pregnancy. Am J Obstet Gynecol 1968;102:752–69. 30. Bullard MJ, Unger B, Spence J, Grafstein E; CTAS Working Group. Revisions to the Canadian emergency department triage and acuity. CJEM 2008;10:136–42. 31. Norwitz ER, Robinson JN. Pregnancy-induced physiologic alterations. In: Belfort MA, Saade GR, Foley MR, Phelan JP, Dildy GA, eds. Critical care obstetrics. 5th ed. Malden, MA: Wiley-Blackwell; 2010:30–52. 32. Scorpio RJ, Esposito TJ, Smith LG, Gens DR. Blunt trauma during pregnancy: factors affecting fetal outcome. J Trauma 1992;32:213–6. 33. Shah KH, Simons RK, Holbrook T, Fortlage D, Winchell RJ, Hoyt DB. Trauma in pregnancy: maternal and fetal outcomes. J Trauma 1998;45:83–6.

12. Hirsh HL. Routine pregnancy testing: is it a standard of care? South Med J 1980;73:1365–6.

34. Morris JA Jr, Rosenbower TJ, Jurkovich GJ, Hoyt DB, Harviel JD, Knudson MM, et al. Infant survival after cesarean section for trauma. Ann Surg 1996;223:481–91.

13. Suresh MS, Wali A. Failed intubation in obstetrics: airway management strategies. Anesthesiol Clin North Am 1998;16:477–98.

35. Stone IK. Trauma in the obstetric patient. Obstet Gynecol Clin North Am 1999;26:459–67.

14. McAuliffe F, Kametas N, Costello J, Rafferty GF, Greenough A, Nicolaides K. Respiratory function in singleton and twin pregnancy. BJOG 2002;109:765–9.

36. Vivian-Taylor J, Roberts CL, Chen JS, Ford JB. Motor vehicle accidents during pregnancy: a population-based study. BJOG 2012;119:499–503.

15. Ramsay G, Paglia M, Bourjeily G. When the heart stops: a review of cardiac arrest in pregnancy. J Intensive Care Med 2013;28:204–14.

37. Epstein FB. Acute abdominal pain in pregnancy. Emerg Med Clin North Am 1994;12:151–65.

16. Lockey DJ, Crewdson K, Lossius HM. Pre-hospital anaesthesia: the same but different. Br J Anaesth 2014;113:211–9.

38. Rogers FB, Rozycki GS, Osler TM, Shackford SR, Jalbert J, Kirton O, et al. A multi-institutional study of factors associated with fetal death in injured pregnant patients. Arch Surg 1999;134(11):1274–7.

17. Johnson MD, Ostheimer GW. Airway management in obstetric patients. Sem Anesth 1992;1:1–12.

39. Rothenberger D, Quattlebaum FW, Perry JF Jr, Zabel J, Fischer RP. Blunt maternal trauma: a review of 103 cases. J Trauma 1978;18:173–9.

568 l JUNE JOGC JUIN 2015

Guidelines for the Management of a Pregnant Trauma Patient

40. Puri A, Khadem P, Ahmed S, Yadav P, Al-Dulaimy K. Imaging of trauma in a pregnant patient. Semin Ultrasound CT MR 2012;33:37–45. 41. Vaizey CJ, Jacobson MJ, Cross FW. Trauma in pregnancy. Br J Surg 1994;81:1406–15. 42. Brent RL. The effect of embryonic and fetal exposure to x-ray, microwaves, and ultrasound: counseling the pregnant and nonpregnant patient about these risks. Semin Oncol 1989;16:347–68. 43. Mossman KL, Hill LT. Radiation risks in pregnancy. Obstet Gynecol 1982;60:237–42. 44. Osei EK, Faulkner K. Fetal doses from radiological examinations. Br J Radiol 1999;72:773–80. 45. Ratnapalan S, Bona N, Koren G; Motherisk Team. Ionizing radiation during pregnancy. Can Fam Physician. 2003;49:873–4 46. Lowe SA. Diagnostic radiography in pregnancy: risks and reality. Aust N Z J Obstet Gynaecol 2004;44:191–6. 47. ACOG Committee on Obstetric Practice. ACOG Committee Opinion, No.299, September 2004. Guidelines for diagnostic imaging during pregnancy. Obstet Gynecol 2004;104:647–51. 48. Donnelly EH, Smith JM, Farfán EB, Ozcan I. Prenatal radiation exposure: background material for counseling pregnant patients following exposure to radiation. Disaster Med Public Health Prep 2011;5:62–8. 49. De Santis M, Di Gianantonio E, Straface G, Cavaliere AF, Caruso A, Schiavon F, et al. Ionizing radiations in pregnancy and teratogenesis: a review of literature. Reprod Toxicol 2005;20:323–9. 50. Patel SJ, Reede DL, Katz DS, Subramaniam R, Amorosa JK. Imaging of pregnant patient for nonobstetric conditions: algorithm and radiation dose considerations. Radiographics 2007;27:1705–22. 51. Shu XO, Jin F, Linet MS, Zheng W, Clemens J, Mills J, et al. Diagnostic X-ray and ultrasound exposure and risk of childhood cancer. Br J Cancer 1994;70:531–6.

61. Goletti O, Ghiselli G, Lippolis PV, Chiarugi M, Braccini G, Macaluso C, et al. The role of ultrasonography in blunt abdominal trauma: results in 250 consecutive cases. J Trauma 1994;36:178–81. 62. Kimura A, Otsuka T. Emergency center ultrasonography in the evaluation of hemoperitoneum: a prospective study. J Trauma 1991;31:20–3. 63. Meyer DM, Thal ER, Weigelt JA, Redman HC. Evaluation of computed tomography and diagnostic peritoneal lavage in blunt abdominal trauma. J Trauma 1989;29:1168-72. 64. Esposito TJ, Gens DR, Smith LG, Scorpio R. Evaluation of blunt abdominal trauma occurring during pregnancy. J Trauma 1989;29:1628–32. 65. Aboutanos MB, Aboutanos SZ, Dompkowski D, Duane TM, Malhotra AK, Ivatury RR. Significance of motor vehicle crashes and pelvic injury on fetal mortality: a five-year institutional review. J Trauma 2008;65(3):616–20. 66. Ali J, Yeo A, Gana TJ, McLellan BA. Predictors of fetal mortality in pregnant trauma patients. J Trauma 1997;42:782–5. 67. Hoff WS, D’Amelio LF, Tinkoff GH, Lucke JF, Rhodes M, Diamond DL, et al. Maternal predictors of fetal demise in trauma during pregnancy. Surg Gynecol Obstet 1991;172:175–80. 68. Pearlman MD, Tintinalli JE, Lorenz RP. Blunt trauma during pregnancy. N Engl J Med 1990;323:1609. 69. Connolly AM, Katz VL, Bash KL, McMahon MJ, Hansen WF. Trauma and pregnancy. Am J Perinatol 1997;14:331–6. 70. Pearlman MD, Tintinalli JE, Lorenz RP. A prospective controlled study of outcome after trauma during pregnancy. Am J Obstet Gynecol 1990;162:1502–10. 71. Biester EM, Tomich PG, Esposito TJ, Weber L. Trauma in pregnancy: normal Revised Trauma Score in relation to other markers of maternofetal status—a preliminary study. Am J Obstet Gynecol 1997;176:1206–10.

52. Doll R, Wakeford R. Risk of childhood cancer from fetal irradiation. Br J Radiol 1997;70:130–9.

72. Dahmus MA, Sibai BM. Blunt abdominal trauma: are there any predictive factors for abruptio placentae or maternal-fetal distress? Am J Obstet Gynecol 1993;169:1054–9.

53. Ju YJ, Du LQ, Cao J, Wang Y, Miao XD, Wang H, et al. The impact of early life exposure to diagnostic and therapeutic radiation on childhood cancer risk. Phys Med 2013;29:221–3.

73. Farmer DL, Adzick NS, Crombleholme WR, Crombleholme TM, Langaker MT, Harrison MR. Fetal trauma: relation to maternal injury. J Pediatr Surg 1990;25:711–4.

54. Ray JG, Schull MJ, Urquia ML, You JJ, Guttmann A, Vermeulen MJ. Major radiodiagnostic imaging in pregnancy and the risk of childhood malignancy: a population-based cohort study in Ontario. PLoS Med 2010;7:e1000337.

74. Williams KJ, McClain L, Rosemurgy AS, Colorado WM. Evaluation of blunt abdominal trauma in the third trimester of pregnancy: maternal and fetal considerations. Obstet Gynecol 1990;75:33–7.

55. Schonfeld SJ, Tsareva YV, Preston DL, Okatenko PV, Gilbert ES, Ron E, et al. Cancer mortality following in utero exposure among offspring of female Mayak Worker Cohort . Radiat Res 2012;178:160–5. 56. Hellgren M, Blombäck M. Studies on blood coagulation and fibrinolysis in pregnancy, during delivery and in the puerperium. I. Normal condition. Gynecol Obstet Invest 1981;12:141. 57. Doan-Wiggens L. Trauma in pregnancy. In: Benrubi GI, ed. Obstetric and gynecologic emergencies. Philadelphia: Lippencott; 1994:57–76. 58. Van Buul EJ, Steegers EA, Jongsma HW, Eskes TK, Thomas CM, Hein PR. Haematological and biochemical profile of uncomplicated pregnancy in nulliparous women; a longitudinal study. Neth J Med 1995;46:73–85. 59. Grossman NB. Blunt trauma in pregnancy. Am Fam Physician 2004;70:1303–10. 60. Goodwin H, Holmes JF, Wisner DH. Abdominal ultrasound examination in pregnant blunt trauma patients. J Trauma 2001;50:689–93.

75. Higgins SD, Garite TJ. Late abruptio placenta in trauma patients: implications for monitoring. Obstet Gynecol 1984;63(3 Suppl):10S–12S. 76. Curet MJ, Schermer CR, Demarest GB, Bieneik EJ 3rd, Curet LB. Predictors of outcome in trauma during pregnancy: identification of patients who can be monitored for less than 6 hours. J Trauma 2000;49:18–24. 77. Cahill AG, Bastek JA, Stamilio DM, Odibo AO, Stevens E, Macones GA. Minor trauma in pregnancy—is the evaluation unwarranted? Am J Obstet Gynecol 2008;198:208.e1–e5. 78. Goodwin TM, Breen MT. Pregnancy outcome and fetomaternal hemorrhage after noncatastrophic trauma. Am J Obstet Gynecol 1990;162:665–71. 79. Hull SB, Bennett S. The pregnant trauma patient: assessment and anesthetic management. Int Anesthesiol Clin 2007;45(3):1–18. 80. Muench MV, Baschat AA, Reddy UM, Mighty HE, Weiner , Scalea TM, et al. Kleihauer-Betke testing is important in all cases of maternal trauma. J Trauma 2004;57(5):1094–8. 81. Urbaniak SJ. The scientific basis of antenatal prophylaxis. Br J Obstet Gynaecol 1998;105(Suppl 18):11–8.

JUNE JOGC JUIN 2015 l 569

SOGC clinical practice guideline

82. Bowman J. The prevention of Rh immunization. Transfus Med Rev 1998;2:129–50. 83. Ghosh S, Murphy WG. Implementation of the rhesus prevention program: a prospective study. Scot Med J 1994;39:147–9. 84. Fung Kee Fung K, Eason E, Crane J, Armson A, De La Ronde S, Farine D, et al. Prevention of Rh alloimmunization. J Obstet Gynaecol Can 2003;25:765–73. 85. ACEP Clinical Policies Committee and Clinical Policies Subcommittee on Early Pregnancy. American College of Emergency Physicians. Clinical policy: critical issues in the initial evaluation and management of patients presenting to the emergency department in early pregnancy. Ann Emerg Med 2003;41:122–33. 86. Stern K, Goodman H, Berger M. Experimental iso-immunization to hemo-antigens in man. J Immunol 1961;87:189–98. 87. Chen JC, Davis BH, Wood B, Warzynski MJ. Multicenter clinical experience with flow cytometric method for fetomaternal hemorrhage detection. Cytometry 2002;50(6):285–90. 88. Porra V, Bernaud J, Gueret P, Bricca P, Rigal D, Follea G, et al. Identification and quantification of fetal red blood cells in maternal blood by a dual-color flow cytometric method: evaluation of the Fetal Cell Count kit. Transfusion 2007;47:1281–9. 89. Savithrisowmya S, Singh M, Kriplani A, Agarwal N, Mehra NK, Bhatla N. Assessment of fetomaternal hemorrhage by flow cytometry and Kleihauer-Betke test in Rh-negative pregnancies. Gynecol Obstet Invest 2007;65:84–8. 90. Weintraub AY, Leron E, Mazor M. The pathophysiology of trauma in pregnancy: a review. J Matern Fetal Neonatal Med 2006;19:601–5. 91. Towery R, English TP, Wisner D. Evaluation of pregnant women after blunt injury. J Trauma 1993;35:731–6.

104. Sandy EA, Koemer M. Self inflicted gunshot wound to the pregnant abdomen: report of a case and review of the literature. Am J Perinatol 1989;6:30–1. 105. Awwad JT, Azar GB, Seoud MA, Mroueh AM, Karam KS. High-velocity penetrating wounds of the gravid uterus: review of 16 years of civil war. Obstet Gynecol 1994;83:259–64. 106. Czeizel AE, Rockenbauer M. Tetanus toxoid and congenital abnormalities. Int J Gynaecol Obstet 1999;64:253–8. 107. Centers for Disease Control and Prevention (CDC). Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) in pregnant women—Advisory Committee on Immunization Practices (ACIP), 2012. MMWR Morb Mortal Wkly Rep. 2013;62:131–5. 108. Stewart DE, Cecutti A. Physical abuse in pregnancy. CMAJ 1993;149(9):1257-63. 109. Guth AA, Pachter L. Domestic violence and the trauma surgeon. Am J Surg 2000;179:134–40. 110. McFarlane J, Parker B, Soeken K, Bullock L. Assessing for abuse during pregnancy. Severity and frequency of injuries and associated entry into prenatal care. JAMA 1992;267:3176–8. 111. Muench MV, Canterino JC. Trauma in pregnancy. Obstet Gynecol Clin North Am 2007;34:555–83. 112. Crosby WM, Costiloe JP. Safety of lap-belt restraint for pregnant victims of automobile collisions. N Engl J Med 1971;284:632–6. 113. Brookfield KF, Gonzalez-Quintero VH, Davis JS, Schulman CI. Maternal death in the emergency department from trauma. Arch Gynecol Obstet 2013;288:507–12.

92. Dhanraj D, Lambers D. The incidences of positive Kleihauer-Betke test in low-risk pregnancies and maternal trauma patients. Am J Obstet Gynecol 2004;190:1461–3.

114. Hyde KH, Cook LJ, Olson LM, Weiss HB, Dean JM. Effect of motor vehicle crashes on adverse fetal outcomes. Obstet Gynecol 2003;102:279–86.

93. Pak LL, Reece EA, Chan L. Is adverse pregnancy outcome predictable after blunt abdominal trauma? Am J Obstet Gynecol 1998;179:1140–4.

115. Luley T, Fitzpatrick CB, Grotegut CA, Hocker MB, Myers ER, Brown HL. Perinatal implications of motor vehicle accident trauma during pregnancy: identifying populations at risk. Am J Obstet Gynecol 2013;208(6):466.e1–e5.

94. Leroy-Malherbe V, Bonnier C, Papiernik E, Groos E, Landrieu P. The association between developmental handicaps and traumatic brain injury during pregnancy: an issue that deserves more systematic evaluation. Brain Inj 2006;20(13–14):1355–65. 95. Oyelese Y, Ananth CV. Placental abruption. Obstet Gynecol 2006;108:1005–16. 96. Glantz C, Purnell L. Clinical utility of sonography in the diagnosis and treatment of placental abruption. J Ultrasound Med 2002;21:837–40. 97. Kettel LM, Branch DW, Scott JR. Occult placental abruption after maternal trauma. Obstet Gynecol 1988;71(3 Pt 2):449–53. 98. Ananth CV, Berkowitz GS, Savitz DA, Lapinski RH. Placental abruption and adverse perinatal outcomes. JAMA 1999;282:1646–51. 99. Wolf EJ, Mallozzi A, Rodis JF, Campbell WA, Vintzileos AM. The principal pregnancy complications resulting in preterm birth in singleton and twin gestations. J Matern Fetal Med 1992;14:206–12. 100. Sperry JL, Casey BM, McIntire DD, Minei JP, Gentilello LM, Shafi S. Long-term fetal outcomes in pregnant trauma patients. Am J Surg 2006;192:715–21. 101. Van Hook JW. Trauma in pregnancy. Clin Obstet Gynecol 2002;45:414–24. 102. Fries MH, Hankins GDV. Motor vehicle accidents associated with minimal maternal trauma but subsequent fetal demise. Ann Emerg Med 1989;18:301–4. 103. Palmer JD, Sparrow OC. Extradural haematoma following intrauterine trauma. Injury 1994;25:671–3.

570 l JUNE JOGC JUIN 2015

116. Johnson HC, Pring DW. Car seatbelts in pregnancy: the practice and knowledge of pregnant women remain causes for concern. BJOG 2000;107:644–7. 117. Moorcroft DM, Stitzel JD, Duma GG, Duma SM. Computational model of the pregnant occupant: predicting the risk of injury in automobile crashes. Am J Obstet Gynecol 2003;189:540–4. 118. Schultze PM, Stamm CA, Roger J. Placental abruption and fetal death with airbag deployment in a motor vehicle accident. Obstet Gynecol 1998;92(4 Pt 2):719. 119. Fusco A, Kelly K, Winslow J. Uterine rupture in a motor vehicle crash with airbag deployment. J Trauma 2001;51:1192–4. 120. Pearlman MD. Motor vehicle crashes, pregnancy loss and preterm labor. Int J Gynecol Obstet 1997;57:127–32. 121. Schiff MA, Holt VL. The injury severity score in pregnant trauma patients: predicting placental abruption and fetal death. J Trauma 2002;53:946–9. 122. Hagmann CF, Schmitt-Mechelke T, Caduff JH, Berger TM. Fetal intracranial injuries in a preterm infant after maternal motor vehicle accident: a case report. Pediatr Crit Care Med 2004;5:396–8. 123. Tweddale CJ. Trauma during pregnancy. Crit Care Nurs Q 2006;29:53–67. 124. Fort A, Harlin R. Pregnancy outcome after noncatastrophic maternal trauma during pregnancy. Obstet Gynecol 1970;35:912–5.

Guidelines for the Management of a Pregnant Trauma Patient

125. Fish R. Electric shock. Part I: physics and pathophysiology. J Emerg Med 1993;11:309–12.

130. Katz VL, Dotters DJ, Droegemueller W. Perimortem cesarean delivery. Obstet Gynecol 1986;68:571–6.

126. Fatovich DM. Electric shock in pregnancy. J Emerg Med 1993;11:175–7.

131. Katz V, Balderston K, DeFreest M. Perimortem cesarean delivery: were our assumptions correct? Am J Obstet Gynecol 2005;192(6):1916–20.

127. Einarson A, Bailey B, Inocencion G, Ormond K, Koren G. Accidental electric shock in pregnancy: a prospective cohort study. Am J Obstet Gynecol 1997;176:678–81. 128. Jaffe R, Fejgin M, Ben Aderet N. Fetal death in early pregnancy due to electric current. Acta Obstet Gynecol Scand 1986;65:283. 129. Fish RM. Electric injury. Part III: cardiac monitoring indications, the pregnant patient, and lightning. J Emerg Med 2000;18:181–7.

132. Katz VL. Perimortem cesarean delivery: its role in maternal mortality. Semin Perinatol 2012;36:68–72. 133. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

JUNE JOGC JUIN 2015 l 571

T SOGC-APOG POLICY STATEMENT T SOGC-APOG POLICY No. 246,STATEMENT September 2010 (Replaces No. 176, April 2006)

Pelvic Examinations by Medical Students PREAMBLE This t policy statement has been reviewed by the Society of Obstetricians and Gynaecologists of Canada (SOGC) Ethics Committee, the Association of Professors of Obstetrics and Gynaecology of Canada (APOG) Undergraduate Committee, and the APOG Department Chairs Committee, and approved by the Executive and Council of the SOGC and the Board of Directors of the APOG. PRINCIPAL AUTHORS Kimberly E. Liu, MD, Toronto ON Jodi Shapiro, MD, Toronto ON Deborah Robertson, MD, Toronto ON Susan Chamberlain, MD, Kingston ON ETHICS COMMITTEE Jodi Shapiro, MD (Chair), Toronto ON Saima S. Akhtar, MD, London ON Bruno Camire, MD, Quebec QC Jan Christilaw, MD, Vancouver BC Julie Corey, RM, St Jacobs ON Erin Nelson, LLM, Edmonton AB Marianne Pierce, MD, Halifax NS Deborah Robertson, MD, Toronto ON Anne H. Simmonds, MN, Halifax NS Disclosure statements have been received from all of the committees.

GENERAL PRINCIPLES

nsuring the quality of medical education is important to ensuring that all Canadians have access to good health care today and in the future; however, patient autonomy should be respected in all clinical and educational interactions. When a medical student is involved in patient care, patients should be told what the student’s roles will be, and patients must provide consent. Patient participation in any aspect of medical education should be voluntary and non-discriminatory.

E

J Obstet Gynaecol Can 2010;32(9):872–874

Women’s health is an important element of the medical school curriculum, and all physicians must be trained in the basic knowledge and skills pertinent to the care of the female patient. Regardless of the specialty that medical students ultimately choose to pursue, as medical practitioners they need to learn to perform pelvic examinations in a sensitive, competent, and ethical manner. They need not only the capacity to perform the examination but also the ability to communicate with the patient and obtain consent for the examination. Use of standardized patients and models can be effective in teaching medical students the technique of pelvic examinations and should allow students to feel comfortable with pelvic examinations prior to patient .1 Medical students will also have the opportunity to learn pelvic examinations during clinical clerkship in the ambulatory clinic setting, as well as in hospital rotations under appropriate supervision. Pelvic examinations are an integral component of any gynaecologic consultation, and pelvic examinations under anaesthesia are a fundamental part of most gynaecologic surgery. Under anaesthesia, pelvic and abdominal muscles are relaxed, and the patient is free from discomfort, thus allowing the surgeon to fully appreciate the pelvic anatomy and clinical findings in a way that may not be possible when the patient is awake. All surgeries require a surgical team, which, in addition to the primary surgeon, may consist of an anaesthesiologist, surgical assistants, and nurses, who are all present in the operating room. Resident physicians and medical students are also of the surgical team and are involved in the preoperative, intraoperative, and postoperative care of the patient. During surgery, they are not merely observers but often play an essential role as surgical assistants. of the gynaecologic surgical team examine the patient preoperatively in order to confirm underlying pathology, determine the most appropriate surgical approach, and understand the patient’s individual anatomy.2 As an educational setting, this also provides an opportunity for the

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

872

l SEPTEMBER JOGC SEPTEMBRE 2010

Pelvic Examinations by Medical Students

student to be guided through a pelvic examination by an expert teacher.

medical students, and they must explain that they will be assisting in the surgery.

If future generations of women are to have access to adequate health care, medical students must be trained to competently examine female patients. The teaching of these examinations, however, can pose ethical problems.3 Many women undergoing pelvic surgery may not be aware of the role medical students play or of the importance of performing a pelvic examination at the time of surgery.4 The sensitivity of this issue has been recognized within the medical community for over 20 years,5 and medical societies have enacted guidelines in response to these concerns.6,7 The controversy about medical students’ performing pelvic examinations on anaesthetized women has been well documented.2,8,9

As part of the surgical consent, patients should be informed that pelvic examinations will be performed by of the gynaecologic surgical team following the induction of anaesthesia and before initiation of surgery. Verbal consent for a medical student to be part of the surgical team and to perform an examination under anaesthesia should be obtained and documented. Patient consent must be voluntary and not coerced. When possible, a discussion about the teaching environment in the operating room should take place with the patient in the office when she signs consent for surgery.

The most important consideration in this educational setting is the need to establish that the patient has consented to a pelvic examination by a medical student before that examination is performed.10 Patients have the right to refuse medical treatment and participation in medical teaching exercises. In fact, most patients are willing to participate in medical education5,11–15 but want to be informed of medical student involvement in their care.4,14,15 Physicians and students must be explicit about student participation during the consent process.16 Patient participation in medical education in an academic or any teaching centre should be nondiscriminatory and respectful of patients’ rights and autonomy.6 Race or socioeconomic status should not be the basis for selection of patients for teaching. Pelvic examinations under anaesthesia are not the primary means of teaching pelvic examinations to medical students, and students should not be brought into the operating room solely to perform a pelvic examination on an anaesthetized patient. OBTAINING INFORMED CONSENT TO PELVIC EXAMINATIONS PERFORMED BY MEDICAL STUDENTS

1. On Patients in Clinical Settings (in-patient wards, out-patient clinics, and birth units) Medical students must introduce themselves to patients and identify themselves as medical students. If a student will be performing a pelvic examination, he or she must explain the procedure that will be performed and seek the patient’s permission to perform the examination. Patient consent must be voluntary and not coerced. 2. On Patients Under Anaesthesia During Surgery All of the gynaecologic surgical team (including medical students, residents, and fellows) are expected to introduce themselves to the patient before her gynaecologic surgery. Medical students must identify themselves as

In summary, in out-patient clinics, in-patient settings, and birth units, medical students must introduce themselves and identify themselves as medical students to the patient. Verbal consent from the patient is required before a pelvic examination is performed. When pelvic examinations are to be performed during surgery while a patient is under anaesthesia, medical students must introduce themselves and identify themselves as medical students to the patient before the surgery. Consent for the pelvic examination under anaesthesia by the gynaecologic surgical team, including the medical student, must be obtained. Pelvic examinations under anaesthesia should not be the primary means of teaching pelvic examinations to medical students, and students must not be brought into the operating room solely to perform a pelvic examination on an anaesthetized patient. ENSURING ADEQUATE SUPERVISION

Medical students must perform pelvic examinations only under the supervision of an appropriately qualified health care professional (i.e., nurse, resident, midwife, or physician). Medical students may and should decline to participate if they do not feel comfortable with the circumstances of the examination. SUMMARY

The pelvic examination is an integral part of the gynaecological consultation and fundamental to planning any gynaecological surgical intervention. Competently performing the pelvic examination is an essential skill for all medical professionals, but its sensitive nature makes it challenging to teach and to learn. While educational tools such as didactic teaching sessions and the use of standardized patients and pelvic models have largely replaced the clinical patient as the initial stage of teaching medical students how to perform a pelvic examination, the best means of consolidating that SEPTEMBER JOGC SEPTEMBRE 2010 l

873

T SOGC-APOG POLICY STATEMENT

knowledge is examining a patient in a clinical setting. Indeed, our patients are our best teachers. In all settings, the patient’s consent must always be obtained by the medical student or a member of the gynaecologic surgical team before the medical student performs a pelvic examination. Medical students must introduce themselves to all patients in whose care they are participating and identify their role as medical students. Specifically, patients who are undergoing gynaecologic surgery should understand the role of a pelvic examination during the procedure and that it may be performed by of the gynaecologic surgical team, including medical students. In all settings, consent must be given voluntarily and must not be coerced. In order to maintain high standards of women’s health care in Canada, all physicians must be trained to perform an appropriate pelvic examination and to detect abnormal pathology. Medical students are of the medical team, and they should be involved in the full scope of patient care—communication, physical examination including pelvic examinations, diagnosis, and therapy. During their clinical rotations, medical students need to learn and perform pelvic examinations with adequate supervision to ensure the safety and comfort of the patient and to optimize their learning experience. REFERENCES 1. Siwe K, Wijma K, Stjernquist M, Wijma B. Medical students learning the pelvic examination: comparison of outcome in of skills between a professional patient and a clinical patient model. Patient Educ Couns 2007;68(3):211–7. 2. Wall LL, Brown D. Ethical issues arising from the performance of pelvic examinations by medical students on anesthetized patients. Am J Obstet Gynecol 2004;190(2):319–23.

874

l SEPTEMBER JOGC SEPTEMBRE 2010

3. Coldicott Y, Pope C, Roberts C. The ethics of intimate examinationsteaching tomorrow’s doctors. BMJ 2003;326(7380):97–101. 4. Wainberg S, Wrigley H, Fair J, Ross S. Teaching pelvic examinations under anaesthesia: what do women think? J Obstet Gynaecol Can 2010;32:49–53. 5. Bibby J, Boyd N, Redman CW, Luesley DM. Consent for vaginal examination by students on anaesthetised patients. Lancet 1988;2(8620):1150. 6. Professional responsibilities in obstetric-gynecologic education. ACOG Committee Opinion 2007, No. 358. American College of Obstetricians and Gynecologists. Obstet Gynecol 2007;109:239–42. Available at: http://www.acog.org/from_home/publications/ethics/c0358.pdf. Accessed February 15, 2010. 7. Gynaecological examinations: guidelines for specialist practice. London: Royal College of Obstetricians and Gynaecologists Press; 2002. 8. Ubel PA, Jepson C, Silver-Isenstadt A. Don’t ask, don’t tell: a change in medical student attitudes after obstetrics/gynecology clerkships toward seeking consent for pelvic examinations on an anesthetized patient. Am J Obstet Gynecol 2003;188(2):575–9. 9. Hicks LK, Lin Y, Robertson DW, Robinson DL, Woodrow SI. Understanding the clinical dilemmas that shape medical students’ ethical development: questionnaire survey and focus group study. BMJ 2001;322(7288):709–10. 10. Wilson RF. Autonomy suspended: using female patients to teach intimate exams without their knowledge or consent. J Health Care Law Policy 2005;8:240–63. 11. Lawton FG, Redman CW, Luesley DM. Patient consent for gynaecological examination. Br J Hosp Med 1990;44(5):326,9. 12. Ubel PA, Silver-Isenstadt A. Are patients willing to participate in medical education? J Clin Ethics 2000;11:230–5. 13. Silver-Isenstadt A, Ubel PA. Erosion in medical students’ attitudes about telling patients they are students. J Gen Intern Med 1999;14:481–7. 14. Wilson RF. Unauthorized practice: teaching pelvic examination on women under anesthesia. J Am Med Womens Assoc 2003;58:217–20; discussion 221–2. 15. Magrane D, Gannon J, Miller CT. Student doctors and women in labor: attitudes and expectations. Obstet Gynecol 1996;88:298–302. 16. O’Flynn N, Rymer J. Consent for teaching: the experience of women attending a gynaecology clinic. Med Educ 2003;37:1109–14.

SOGC CLINICAL PRACTICE GUIDELINE SOGC CLINICAL PRACTICE GUIDELINE

No. 250, November 2010

Recurrent Urinary Tract Infection Abstract This Clinical Practice Guideline has been prepared by the Urogynaecology Committee, reviewed by the Family Physicians Advisory Committee, and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Annette Epp, MD, Saskatoon SK Annick Larochelle, MD, St. Lambert QC UROGYNAECOLOGY COMMITTEE Danny Lovatsis, MD (Chair), Toronto ON Jens-Erik Walter, MD (Co-Chair), Westmount QC William Easton, MD, Scarborough ON Annette Epp, MD, Saskatoon SK Scott A. Farrell, MD, Halifax NS Lise Girouard, RN, Winnipeg MB Chander Gupta, MD, Winnipeg MB Marie-Andrée Harvey, MD, Kingston ON Annick Larochelle, MD, St. Lambert QC Magali Robert, MD, Calgary AB Sue Ross, PhD, Calgary AB

Objective: To provide an update of the definition, epidemiology, clinical presentation, investigation, treatment, and prevention of recurrent urinary tract infections in women. Options: Continuous antibiotic prophylaxis, post-coital antibiotic prophylaxis, and acute self-treatment are all efficient alternatives to prevent recurrent urinary tract infection. Vaginal estrogen and cranberry juice can also be effective prophylaxis alternatives. Evidence: A search of PubMed and The Cochrane Library for articles published in English identified the most relevant literature. Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date restrictions. Values: This update is the consensus of the Sub-Committee on Urogynaecology of the Society of Obstetricians and Gynaecologists of Canada. Recommendations were made according to the guidelines developed by the Canadian Task Force on Preventive Health Care (Table 1). Options: Recurrent urinary tract infections need careful investigation and can be efficiently treated and prevented. Different prophylaxis options can be selected according to each patient’s characteristics.

Joyce Schachter, MD, Ottawa ON

Recommendations

Jane A. Schulz, MD, Edmonton AB

1. Urinalysis and midstream urine culture and sensitivity should be performed with the first presentation of symptoms in order to establish a correct diagnosis of recurrent urinary tract infection. (III-L)

David Wilkie, MD, Vancouver BC FAMILY PHYSICIANS ADVISORY COMMITTEE William Ehman, MD (Chair), Naniamo BC Sharon Domb, MD, Toronto ON Andrée Gagnon, MD, Blainville QC Owen Hughes, MD, Ottawa ON Jill Konkin, MD, Edmonton AB Joanna Lynch, MD, Winnipeg MB Cindy Marshall, MD, Lower Sackville NS Disclosure statements have been received from all of the committees. The literature searches and bibliographic for this guideline were undertaken by Becky Skidmore, Medical Research Analyst, Society of Obstetricians and Gynaecologists of Canada.

Key Words: Recurrent urinary tract infection, prophylaxis, treatment, antibiotic, prevention

2. Patients with persistent hematuria or persistent growth of bacteria aside from Escherichia coli should undergo cystoscopy and imaging of the upper urinary tract. (III-L) 3. Sexually active women suffering from recurrent urinary tract infections and using spermicide should be encouraged to consider an alternative form of contraception. (II-2B) 4. Prophylaxis for recurrent urinary tract infection should not be undertaken until a negative culture 1 to 2 weeks after treatment has confirmed eradication of the urinary tract infection. (III-L) 5. Continuous daily antibiotic prophylaxis using cotrimoxazole, nitrofurantoin, cephalexin, trimethoprim, trimethoprimsulfamethoxazole, or a quinolone during a 6- to 12-month period should be offered to women with ³ 2 urinary tract infections in 6 months or ³ 3 urinary tract infections in 12 months. (I-A) 6. Women with recurrent urinary tract infection associated with sexual intercourse should be offered post-coital prophylaxis as an alternative to continuous therapy in order to minimize cost and side effects. (I-A)

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

1082

l NOVEMBER JOGC NOVEMBRE 2010

Recurrent Urinary Tract Infection

Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well–designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

D. There is fair evidence to recommend against the clinical preventive action E. There is good evidence to recommend against the clinical preventive action L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.82 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the The Canadian Task Force on Preventive Health Care.82

7. Acute self-treatment should be restricted to compliant and motivated patients in whom recurrent urinary tract infections have been clearly documented. (I-B) 8. Vaginal estrogen should be offered to postmenopausal women who experience recurrent urinary tract infections. (I-A) 9. Patients should be informed that cranberry products are effective in reducing recurrent urinary tract infections. (I-A) 10. Acupuncture may be considered as an alternative in the prevention of recurrent urinary tract infections in women who are unresponsive to or intolerant of antibiotic prophylaxis. (I-B) 11. Probiotics and vaccines cannot be offered as proven therapy for recurrent urinary tract infection. (II-2C) 12. Pregnant women at risk of recurrent urinary tract infection should be offered continuous or post-coital prophylaxis with nitrofurantoin or cephalexin, except during the last 4 weeks of pregnancy. (II-1B) J Obstet Gynaecol Can 2010;32(11):1082–1090

DEFINITION AND EPIDEMIOLOGY

rinary tract infection is one of the most common bacterial infections in women, and 50% to 60% of adult women experience a UTI during their lifetime.1,2 It is

U

estimated that in young women there are 0.5 episodes of acute cystitis per person per year.3 This incidence decreases with age. In postmenopausal women, it is estimated that there are 0.07 episodes of acute cystitis per person per year.4 Recurrent UTI is defined as 2 uncomplicated UTIs in 6 months or, more traditionally, as ³ 3 positive cultures within the preceding 12 months.5,6 This is estimated to affect 25% of women with a history of UTI. When there is recurrent infection with the same organism despite adequate therapy, it is considered a relapse. Reinfection is defined as recurrent UTI caused by a different bacterial isolate, or by the previously isolated bacteria after a negative intervening culture or an adequate time period (³ 2 weeks) between infections.7 Reinfection is more common than relapse.8 Most recurrences occur within the first 3 months after the primary infection, and there can often be clustering of infections.9,10 When the initial infection is caused by E. coli, there is a higher risk of reinfection within the first 6 months.11 PRESENTATION

ABBREVIATIONS E. coli

Escherichia coli

HPF

high-power field

TMP-SMX

trimethoprim-sulfamethoxazole

UTI

urinary tract infection

Classic symptoms of acute lower UTI include dysuria, urinary frequency, and suprapubic pain plus or minus hematuria. Differential diagnoses include vaginitis, acute urethritis, interstitial cystitis, and pelvic inflammatory disease. Other organisms that may be involved and mimic acute cystitis include Chlamydia, Neisseria gonorrhea, Candida, NOVEMBER JOGC NOVEMBRE 2010 l 1083

SOGC CLINICAL PRACTICE GUIDELINE

bacterial vaginosis, and herpes simplex virus.12 Classic symptoms seem to be highly predictive of true disease. If dysuria, frequency, and hematuria are present in the absence of vaginal discharge, the probability of a positive culture is 81%.12 Women with recurrent UTI can self-diagnose on the basis of symptoms very accurately, with an 84% positive culture rate.13 Positive predictive factors for recurrent UTIs in women are symptoms after intercourse, a prior history of pyelonephritis, absence of nocturia, and prompt resolution of symptoms (48 hours) after initiation of treatment. The main negative predictors are the presence of nocturia and persistence of symptoms between episodes of treated infection.5 PATHOPHYSIOLOGY

The main causative pathogen involved in recurrent UTI in women is E. coli, which is responsible for approximately 80% of all episodes of infection. Other significant pathogens include Staphylococcus saprophyticus, Klebsiella pneumoniae, and Proteus mirabilus, which each cause approximately 4% of all episodes of acute cystitis. Citrobacter and Enterococci are less likely causes of UTI in women.14 Infection with organisms that do not usually cause UTIs may be an indicator of underlying structural abnormalities or renal calculi.7 Uropathogenic E. coli have virulence factors, such as the type of fimbria, that promote binding to the epithelium of the vagina and urethra and enhance their ability to cause cystitis. Other factors increase resistance to serum bactericidal activity and host defence mechanisms. Animal models suggest that E. coli can remain dormant in large bacterial reservoirs within the host and be reactivated to cause infection in the future.15 In a 2007 study,16 midstream urine samples from women with acute uncomplicated cystitis also showed evidence of intracellular bacterial communities of uropathogenic E. coli. These communities are relatively protected from host immune response mechanisms and antibiotic therapy and may reactivate, causing recurrent UTI.16 In the classic theory for development of UTI, the uropathogen is part of the fecal flora. It colonizes the vagina and distal urethra. Subsequently, it ascends into the bladder and causes infection. This model is the same for sporadic and for recurrent UTI in women.8,17 Reservoirs of uropathogenic bacteria can remain in the gastrointestinal tract and vagina of the susceptible individual. The results of one study suggest that household , including pets, could act as reservoirs for the recolonization of a person with UTI.18 Lactobacilli in the vagina are protective, because they prevent initial colonization with uropathogens.19 1084 l NOVEMBER JOGC NOVEMBRE 2010

RISK FACTORS

Premenopausal Women In young women who suffer from recurrent UTIs there are behavioural risk factors at play. These include increased frequency of intercourse, use of a spermicide, and new sexual partners.20 Intercourse and spermicide exposure increase the rate of vaginal and periurethral colonization with E. coli. When a first UTI is caused by E. coli, the risk of a second infection within 6 months is greater than when a first infection is cause by another uropathogen.11 Dysfunctional voiding patterns in which there is increased tone of the external sphincter during micturition can also be associated with recurrent UTI in otherwise urologically normal women.21 There are also some non-behavioural risk factors for recurrent UTI in young women. These include a history of UTI before age 15 and a maternal history of UTI. This suggests that there are also anatomic and genetic factors involved.20 Most women with recurrent UTI do not have any functional or anatomic abnormalities of the urinary tract, and extensive radiologic and cystoscopic examination is not indicated.8,22 Postmenopausal Women In premenopausal women, 90% of the vaginal flora are lactobacilli, which protects against colonization with uropathogens such as E. coli. Estrogen loss at menopause results in thinning of the vaginal epithelium and decreased amounts of glycogen. The resulting environment is hostile to lactobacilli, and the numbers decrease. The vaginal pH increases, and there is an increased propensity for colonization with uropathogens.10 Women who are non-secretors of histocompatibility blood-group antigens are at increased risk of recurrent UTI. This is thought to be a result of attachment of P-fimbriated E. coli to glycolipids on vaginal and uroepithelial cells.10 Non-secretor status is a more significant risk factor in postmenopausal than in premenopausal women. Postmenopausal women who suffer from incontinence and who have significant pelvic floor prolapse and elevated post-void residual volumes are at increased risk for recurrent UTI.10 Other significant factors for recurrent UTI in postmenopausal woman are diabetes mellitus and a previous history of UTI.3 INVESTIGATION

All women with recurrent UTI should undergo a physical examination to evaluate urogenital anatomy and estrogenization of vaginal tissues and to detect prolapse. Post-void residual urine volume should be measured. Diabetes screening is indicated in patients with other risk

Recurrent Urinary Tract Infection

factors, such as family history and obesity. Most women do not require extensive urologic investigations.8,22 However, women who suffer infection with organisms that are not common causes of UTI, such as Proteus, Pseudomonas, Enterobacter, and Klebsiella may have structural abnormalities or renal calculi. They would benefit from imaging studies of the upper urinary tract and cystoscopy.7 Women who have persistent hematuria after resolution of their infection also require a complete urologic workup.8 Although empiric therapy based on symptoms is generally accurate and cost-effective, women who are felt to be in the early stages of a problem with recurrent UTI should have documented cultures.23 Urine culture not only serves as the gold standard for diagnostic accuracy but also provides specific information about the uropathogen and its antibiotic susceptibilities.6 The standard definition of a UTI on culture is > 100 000 colony forming units per HPF. This value has excellent specificity but a sensitivity of only 50%.7 In women with symptoms of a UTI > 1000 colony forming units per HPF is considered sufficient to document infection without compromising specificity. The sensitivity to detect infection is 80% and the specificity 90%.7 When a “clean-catch” or midstream technique is used to obtain a urine sample, the rates of contamination with vaginal flora are approximately 30%.24 The presence of > 20 epithelial cells per HPF on urinalysis suggests contamination by vaginal secretions.23 Because bacteria reduce urinary nitrates to nitrites, the use of urine dipstick analysis can be helpful. A positive result usually indicates infection, with a specificity of 92% to 100% and a sensitivity of 19% to 48%.25 A negative result does not rule out infection if the patient is symptomatic. Some bacteria such as Staphylococcus saprophyticus lack the enzymes to reduce nitrates. If urine has not been present in the bladder for at least 4 hours, there may not have been sufficient time for the reaction to occur.25 Leukocyte esterase is produced by neutrophils and indicates pyuria, which is associated with UTI. Organisms other than uropathogens can produce leukocyte esterase. Therefore, this is a sensitive (72% to 97%) but not specific (41% to 86%) test for UTI in women. Blood on dipstick can help to confirm infection, but this can be associated with other clinical circumstances and therefore is more sensitive (68% to 92%) than specific (42% to 46%) for UTI.25 TREATMENT OF ACUTE URINARY TRACT INFECTIONS

Ampicillin and sulfonamides generally should not be used for empiric therapy because more than one third of isolates demonstrate in vitro resistance.26,27 More than 15% to 20% of E. coli strains causing uncomplicated cystitis are now resistant to these agents in several areas of the United States

and other countries.28 The prevalence of resistance to nitrofurantoin among E. coli is < 5%, although non-E. coli uropathogens are often resistant. Resistance to the fluoroquinolones remains < 5% in most studies of uropathogenic strains. Three-day regimens are recommended because they are associated with better compliance, lower cost, and lower frequency of adverse reactions than 7- to 10-day regimens.29 Several studies and clinical experience have confirmed the effectiveness of 3-day regimens of trimethoprim, trimethoprimsulfamethoxazole, or a fluoroquinolone for treatment of acute uncomplicated cystitis, and these agents are generally recommended for empiric therapy.29 In comparison, 3-day regimens with beta-lactams are less effective than ³ 5 days of therapy.29 Nitrofurantoin is a safe and generally effective agent, but it should be istered for a minimum of 7 days. Single-dose regimens are somewhat less effective than 3- to 7-day regimens, even with fluoroquinolones.27,29 First-line treatment suggested by the Infectious Disease Society of America in 1999 was TMP-SMX in a 3-day regimen.29 Given the increasing prevalence of TMP-SMX resistance among uropathogens, it is important to examine risk factors predicting in vitro resistance. These are diabetes, recent hospitalization, antibiotic use in the past 3 to 6 months (for any reason), and recent TMP-SMX use.30 Fluoroquinolones (norfloxacin, ciprofloxacin, ofloxacin, fleroxacin) are generally not recommended as first-line treatment because of their greater expense and concerns regarding the promotion of quinolone resistance. However, fluoroquinolones can become a reasonable first-line treatment for women who have or are suspected of having antimicrobial resistance or of being allergic to or not tolerating more conventional therapy, and for women in areas where resistance to TMP-SMX is > 15% to 20%.29 Other reasonable empiric choices for mild cystitis include a 7-day course of nitrofurantoin or a single-dose of fosfomycin.29 In 2007, Gupta et al. demonstrated the equivalent efficacy of a 5-day course of nitrofurantoin and a 3-day course of TMP-SMX.31 Recurrent cystitis that occurs during or within the first week following treatment suggests possible relapse and should be managed with a pre-treatment urine culture, antimicrobial susceptibility testing, and treatment with a fluoroquinolone for 7 days.8 PREVENTION OF RECURRENT URINARY TRACT INFECTIONS

Lifestyle Modification Women using spermicide-containing contraception should be offered an alternative form of contraception.27,32 Several studies have shown that there is no association between recurrent UTI and pre- and post-coital patterns, frequency NOVEMBER JOGC NOVEMBRE 2010 l 1085

SOGC CLINICAL PRACTICE GUIDELINE

of urination, delayed voiding habits, douching, use of hot tubs, bubble baths, BMI, frequent use of pantyhose or tights, use of tight clothing, type of clothing, bicycle riding, and the volume of fluid consumed.32,33 However, behavioural approaches are unlikely to be harmful.34 Antimicrobial Strategy There are as many options for prevention and management of recurrent UTI as there are studies on the issue (Table 2).8,10,33,35–39 A Cochrane review,35 of 19 trials including 1120 patients, showed that antibiotics are better than placebo in reducing the number of clinical and microbiological recurrences in pre- and postmenopausal women with recurrent UTI. Seven trials including 257 patients showed a relative risk of having a clinical UTI of 0.15 (95% CI 0.08 to 0.28) favouring antibiotic over placebo. The number needed to treat to prevent one symptomatic recurrent UTI was 2.2. Antibiotics in this review were fluoroquinolones (norfloxacin, ciprofloxacin, pefloxacin), cephalosporins (cephalexin, cefaclor), trimethoprim, sulfamethoxazole, and nitrofurantoin. No antibiotic was superior. Choice of antibiotic should rely on community patterns of resistance, adverse events, and local costs. Three main management strategies generally considered are continuous antimicrobial prophylaxis, post-coital prophylaxis, and patient-istered self-treatment.36 For patients with £ 2 UTIs per year, the acute self-treatment may be useful. Patients with ³ 3 infections annually should be offered a regimen of continuous, low-dose prophylaxis or post-coital prophylaxis.36 Continuous Prophylaxis Continuous prophylaxis can be given daily at bedtime. Some authors suggest prophylaxis on alternate nights or 3 nights per week (Table 2). One study showed that weekly prophylaxis was better than monthly prophylaxis.40 No studies compared daily and weekly prophylaxis.35 No recommendation can be made about the optimal prophylaxis. Post-coital Prophylaxis Another study41 showed that sexually active women who took post-coital ciprofloxacin had similar outcomes to women who took ciprofloxacin daily. A causal relationship between infections and intercourse can be suspected when the interval is consistently between 24 and 48 hours.42 Two studies41,43 suggest that for sexually active women with UTI related to sexual intercourse, the post-coital approach could be a better option. The authors of one study41 noted that a major advantage of post-intercourse prophylaxis was that it produced fewer side effects because women took only one third of the amount of antibiotic used in daily prophylaxis. 1086 l NOVEMBER JOGC NOVEMBRE 2010

Table 2. Antimicrobial prophylaxis regimens for women with recurrent urinary tract infections Oral regimens Continuous prophylaxis TMP-SMX

40/200 mg daily

TMP-SMX

40/200 mg 3´/week

TMP

100 mg daily

Nitrofurantoin monohydrate/macrocrystals (Macrobid)

50–100 mg daily

Nitrofurantoin macrocrystal (Macrodantin)

50–100 mg daily

Cephalexin

125–250 mg daily

Cefaclor

250 mg daily

Norfloxacin

200 mg daily

Ciprofloxacin

125 mg daily

Cinoxacin

250–500 mg daily

Post-coital prophylaxis (single dose) TMP-SMX

40/200 mg

TMP-SMX

80/400 mg

Nitrofurantoin macrocrystal (Macrodantin)

50–100 mg

Cephalexin

125–250 mg

Cinoxacin

250 mg

Ciprofloxacin

125 mg

Norfloxacin

200 mg

Ofloxacin

100 mg

Acute self-treatment TMP-SMX

160/800 mg twice daily × 3 days

Ciprofloxacin

250 mg twice daily × 3 days

Norfloxacin

200 mg twice daily × 3 days

Acute Self-treatment The self-start therapy is ideal for women who are not suitable candidates for long-term daily prophylaxis or who are unwilling to take it. However, this strategy should be restricted to those women who have clearly documented recurrent infections and who are motivated, compliant with medical instructions, and have a good relationship with a medical provider.8 Such women should be reminded to call their provider if the symptoms are not completely resolved within 48 hours. The patient identifies episodes of infection on the basis of symptoms, performs her own culture, and initiates a standard 3-day course of empiric treatment. Antimicrobial agents with minimal side effects are recommended, because this approach could lead to some degree of overtreatment (Table 2).42 The efficacy of antimicrobial agents to prevent recurrent UTIs seems to arise through 2 mechanisms. First, agents

Recurrent Urinary Tract Infection

such as TMP-SMX and norfloxacin decrease the rate of recovery of aerobic Gram-negative uropathogens such as E. coli from the fecal reservoir.44 Nitrofurantoin in contrast, decreases the recurrence rate by intermittently sterilizing the urine and possibly by inhibiting bacterial attachment.36,45,46 Adverse Events In a 2004 Cochrane Review,35 the rates of adverse events were higher in the antibiotic group than in the placebo group. The relative risk for severe side effects requiring withdrawal of treatment was 1.58 (95% CI 0.47 to 5.28) and for mild side effects the relative risk was 1.78 (95% CI 1.06 to 3.00). The most frequently reported adverse events were nausea and vaginal and oral candidiasis. Nitrofurantoin required the highest number of withdrawals, followed by cephalexin and weekly pefloxacin.35 Several adverse effects have been described with the use of nitrofurantoin, including aplastic anemia, polyneuritis, acute cholestatic and hepatocellular reactions, and pulmonary toxicity.47 Chronic pulmonary toxicity is uncommon and may develop after 1 month to 6 years of therapy. Patients who are long-term s of nitrofurantoin should be checked regularly for any complications. Most authorities advocate an antibiotic prophylaxis duration of 6 to 12 months, although in certain cases this has been extended to 2 to 5 years.48 However, as no study has looked at prophylaxis for more than 1 year, no conclusion can be made about the optimal duration. In the two studies that had a follow-up assessment at up to 6 months after the prophylaxis period,44,49 there was no difference in the microbiological recurrences between the antibiotic group and the placebo group. There were no studies that assessed clinical recurrences after prophylaxis. However, it appears that most women revert to the previous pattern of recurrent infections once prophylaxis is stopped. Estrogen Use in Postmenopausal Women Evidence from two small RCTs shows that in postmenopausal women with recurrent UTI, vaginal estrogens reduce the number of UTIs.50,51 Raz and Stamm reported a significant reduction in UTI among postmenopausal women using 0.5 mg of estriol cream vaginally every night for 2-weeks and then twice a week for 8-months compared with those using a placebo (0.5 vs. 5.9 episodes per patient-year, P < 0.001).52 Eriksen has shown a similar beneficial prophylactic effect with the use of an estradiol-releasing vaginal ring (Estring, Pharmacia & Upjohn) compared with a placebo vaginal ring.53 After 36 weeks of the study, the cumulative likelihood of remaining free of UTI was 45% in the Estring group compared with approximately 20% in the placebo group (P < 0.008).53

The mechanism of action is thought to be the reappearance of vaginal lactobacilli which, unlike placebo, decrease the vaginal pH. This results from maturation and thickening of the vaginal epithelium with increased cellular glycogen, a main substrate for lactobacilli.52,53 This process prevents overgrowth and colonization of Enterobacteriaceae in the vagina.54 It can take at least 12 weeks for the vaginal ring to be effective in reducing the occurrence of UTIs.53 Studies have provided insufficient evidence for recommending a particular type or form of vaginal estrogen.50,51 Creams are cheaper and possibly more efficient but could be more difficult to apply for some women and can produce some adverse effects (e.g., itching, burning, occasional spotting). Estradiol vaginal tablets may have fewer side effects but are more expensive. The vaginal ring is also more expensive and may require a trained professional to place it correctly.51 A recent Cochrane review51 did not show a significant difference in the number of women with UTI at the end of treatment period between oral estrogens and placebo. It seems that the route of istration may be more important than the compound itself.50 The studies comparing vaginal estrogens to antibiotics were inconclusive because of their heterogeneity.51,55,56 Cranberries Cranberries (particularly in the form of cranberry juice) have been touted as an effective home remedy for the prevention and treatment of UTIs for several decades. So far, no definite mechanism of action has been established. The main suggestion is that cranberries prevent bacteria (particularly E. coli) from adhering to uroepithelial cells.57,58 Without adhesion, the bacteria cannot infect the mucosal surface of the urinary tract. A recent Cochrane review59 of 10 studies with a total of 1049 subjects showed some evidence that cranberry juice and derivatives may decrease the number of symptomatic UTIs over a period of 12 months, particularly for women with recurrent UTIs. A meta-analysis of the results of 4 RCTs found that cranberry products significantly reduced the incidence of UTIs (RR 0.66; 95% CI 0.47 to 0.92) compared with placebo or control.60–63 Further, there is no clear evidence of the amount and concentration that must be consumed and over what period for the intervention to be most effective. No published trials have been undertaken that compare cranberry with established interventions (e.g., antibacterials) for preventing UTIs.59 Other Potential Strategies Antibiotics are usually effective in treating acute infections and are the primary means of prophylaxis for recurrent UTI patients; however, their value is being lessened by the NOVEMBER JOGC NOVEMBRE 2010 l 1087

SOGC CLINICAL PRACTICE GUIDELINE

emergence of increasing numbers of drug-resistant bacteria. Consequently, it is important that alternative prevention strategies be developed. Acupuncture Two small RCTs evaluated the role of acupuncture compared with sham acupuncture or no treatment in the prophylaxis of recurrent UTIs.64,65 During a 6-month period, both studies demonstrated that acupuncture could play a significant role in preventing recurrent UTIs. Authors concluded that it seems a worthwhile alternative to antibiotic strategy. Probiotics The instillation of Lactobacillus into the vagina is believed to stop the ascension of uropathogens into the bladder. Available studies suggest that probiotics can be beneficial, and most authors consider this approach promising, but further research is needed before probiotics can be recommended for prevention of UTI.66–70 Vaccines An injectable vaccine developed in Switzerland was found to be effective, with no adverse effects observed in pregnant women or their offspring.71 In order to obviate some adverse reactions of the parenteral vaccine, four mucosal vaccines were developed as a vaginal suppository or an oral tablet, but the vaccine’s benefits seemed to decline after the last dose.72 The only parenteral vaccine currently under development, FimCH, has proven to be safe in a phase I clinical trial.73 A phase II clinical trial has been completed, but data are not yet available.34 Others Other potential preventive strategies, which include the use of bacterial interference (E. coli 83972)74 and topical application of carbohydrates (hyaluronic acid),34,75–78 are still under development. PREGNANCY AND RECURRENT UTIs

For pregnant women with symptomatic or asymptomatic bacteriuria, the risk of a preterm delivery and low birth weight infant is significantly increased.79 Hooton and Stamm recommend a follow-up culture for test of cure a week after completion of therapy and monthly follow-up until the completion of the pregnancy.34 Indications for prophylaxis are (1) all women with a pre-pregnancy history of recurrent UTIs, (2) persistent symptomatic or asymptomatic bacteriuria after two antibiotic treatments, and (3) after only one UTI for a woman who has other conditions that potentially increase the risk of urinary complications during the episode of UTI (e.g., diabetes or sickle cell trait). Both continuous and post-coital prophylaxis regimens have been shown to 1088 l NOVEMBER JOGC NOVEMBRE 2010

be effective, and agents of choice are nitrofurantoin (50 mg) and cephalexin (250 mg).34,36,80,81 Recommendations Recommendations were made according to the guidelines developed by the Canadian Task Force on Preventive Health Care (Table 1). 1. Urinalysis and midstream urine culture and sensitivity should be performed with the first presentation of symptoms in order to establish a correct diagnosis of recurrent urinary tract infection. (III-L) 2. Patients with persistent hematuria or persistent growth of bacteria aside from Escherichia coli should undergo cystoscopy and imaging of the upper urinary tract. (III-L) 3. Sexually active women suffering from recurrent urinary tract infections and using spermicide should be encouraged to consider an alternative form of contraception. (II-2B) 4. Prophylaxis for recurrent urinary tract infection should not be undertaken until a negative culture 1 to 2 weeks after treatment has confirmed eradication of the urinary tract infection. (III-L) 5. Continuous daily antibiotic prophylaxis using cotri- moxazole, nitrofurantoin, cephalexin, trimethoprim, trimethoprimsulfamethoxazole, or a quinolone during a 6- to 12-month period should be offered to women with ³ 2 urinary tract infections in 6 months or ³ 3 urinary tract infections in 12 months. (I-A) 6. Women with recurrent urinary tract infection associated with sexual intercourse should be offered post-coital prophylaxis as an alternative to continuous therapy in order to minimize cost and side effects. (I-A) 7. Acute self-treatment should be restricted to compliant and motivated patients in whom recurrent urinary tract infections have been clearly documented. (I-B) 8. Vaginal estrogen should be offered to postmenopausal women who experience recurrent urinary tract infections. (I-A) 9. Patients should be informed that cranberry products are effective in reducing recurrent urinary tract infections. (I-A) 10. Acupuncture may be considered as an alternative in the prevention of recurrent urinary tract infections in women who are unresponsive to or intolerant of antibiotic prophylaxis. (I-B) 11. Probiotics and vaccines cannot be offered as proven therapy for recurrent urinary tract infection. (II-2C)

Recurrent Urinary Tract Infection

12. Pregnant women at risk of recurrent urinary tract infection should be offered continuous or post-coital prophylaxis with nitrofurantoin or cephalexin, except during the last 4 weeks of pregnancy. (II-1B) REFERENCES 1. Czaja CA, Hooton TM. Update on acute uncomplicated urinary tract infection in women. Postgrad Med 2006;119:39–45.

21. Minardi D, Parri G, d’Anzeo G, Fabiani A, El Asmar Z, Muzzonigro G. Perineal ultrasound evaluation of dysfunctional voiding in women with recurrent urinary tract infections. J Urol 2008;179:947–51. 22. Car J, Sheikh A. Recurrent urinary tract infection in women. BMJ 2003:327:1204. 23. Car J. Urinary tract infections in women: diagnosis and management in primary care. BMJ 2006;332:94–7. 24. Lifshitz E, Kramer L. Outpatient urine culture. Does collection technique matter? Arch Intern Med 2000;160:2537–40.

2. Foxman B, Barlow R, D’Arcy H, Gillespie B, Sobel JD. Self reported incidence of urinary tract infection and associated costs. Ann Epidemiol 2000;10:509–15.

25. Simerville JA, Maxted WC, Pahira JJ. Urinalysis: a comprehensive review. Am Fam Physician 2005;71:1153–62.

3. Hooton TM. A prospective study for risk factors for symptomatic urinary tract infection in young women. N Engl J Med 1996;335:468.

26. Drekonja DM, Johnson JR. Urinary tract infections. Prim Care 2008;35:345–67.

4. Jackson SL, Boyko IJ, Scholes D, Abraham L, Gupta K, Fihn SD. Predictors of urinary tract infection after menopause. Am J Med 2004;117:903.

27. Hooton TM, Stamm WE. Diagnosis and treatment of uncomplicated urinary tract infection. Infect Dis Clin North Am 1997;11:551–81.

5. Gopal M, Northington G, Arya L. Clinical symptoms predictive of recurrent urinary tract infection. Am J Obstet Gynecol 2007;197:74.e1–4. 6. Foster RT Sr. Uncomplicated urinary tract infections in women. Obstet Gynecol Clin North Am 2008;35:235–48. 7. American College of Obstetricians and Gynecologists. Treatment of urinary tract infection in non pregnant women. ACOG Practice Bulletin No. 91, March 2008. Obstet Gynecol 2008;11:785–94. 8. Hooton. Recurrent urinary tract infection in women. Int J Antimicrobial Agents 2001;17:259–268. 9. Kraft JK, Stamey TA. The natural history of symptomatic recurrent bacteruria in women. Medicine 1977;56:55–60. 10. Gupta K, Stamm WE. Pathogenesis and management of recurrent urinary tract infecitons in women. World J Urol 1999;17:415–20.

28. Gupta K, Scholes D, Stamm WE. Increasing prevalence of antimicrobial resistance among uropathogens causing acute uncomplicated cystitis. J Am Med Assoc 1999;281: 736–8. 29. Warren JW, Abrutyn E, Hebel JR, Johnson JR, Schaeffer AJ, Stamm WE. Guidelines for antimicrobial treatment of uncomplicated acute bacterial cystitis and acute pyelonephritis in women. Clin Infect Dis 1999;29:745–58. 30. Wright SW, Wrenn KD, Haynes ML. Trimethoprim-sulfamethoxazole resistance among urinary coliform isolates. J Gen Intern Med 1999;14:606–9. 31. Gupta K, Hooton TM, Roberts MS, Stamm WE. Short-course nitrofurantoin for the treatment of acute uncomplicated cystitis in women. Arch Intern Med 2007;167(20):2207–12. 32. Franco AV. Recurrent urinary tract infections. Best Pract Res Clin Obstet Gynaecol 2005;19:861–73.

11. Foxman B, Gillespie B, Koopman J, Zhang L, Palin K, Tallman P, et al. Risk fctors for second urinary tract infection among college women. Am J Epidemiol 2000;151:1194–205.

33. Reid G. Potential preventive strategies and therapies in urinary tract infection. World J Urol 1999;17:359–63.

12. Bent S, Nallamothu BK, Simel DL, Fihn SD, Saint S. Does this woman have an acute urinary tract infection? JAMA 2002;287:2701–10.

34. Hooton TM, Stamm WE. Urinary tract infections and asymptomatic bacteriuria in pregnancy. UpToDate 2008; version 16.2 (May 31, 2008).

13. Gupta K, Hooton TM, Roberts PL Stamm WE. Patient-initiated treatment of recurrent urinary tract infection in women. Ann Intern Med 2001;135:9–16.

35. Albert X, Huertas I, Pereiró II, San félix J, Gosalbes V, Perrota C. Antibiotics for preventing recurrent urinary tract infection in non-pregnant women. Cochrane Database Syst Rev 2004;(3):CD001209.

14. Echols RM, Tosiello RL, Haverstock DC, Tice AD. Demographic, clinical and treatment parameters influencing the outcome of acute cystitis. Clin Infect Dis 1999;29:113–9.

36. Stapleton A, Stamm WE. Prevention of urinary tract infection. Infect Dis Clin North Am 1997;11:719–33.

15. Mulvey MA, Schilling JD, Jultgren SJ. Establishment of a persistent Escherichia coli reservoir during the acute phase of a bladder infection. Infect Immun 2001;69:4572–9. 16. Rosen DA, Hooten TM, Stamm WE, Humphrey PA, Hultgren SJ. Detection of intracellular bacterial communities in human urinary tract infection. PLOS Med 2007;4:e329. 17. Fihn SD. Acute uncomplicated urinary tract infection in women. N Engl J Med 2003;349:259–66. 18. Johnson JR, Clabots C. Sharing of virulent Escherichia coli clones among household of a woman with acute cystitis. Clin Infect Dis 2006;43:e101–8. 19. Gupta K, Stapleton AE, Hooton TM, Roberts PL, Fennell CL, Stamm WE. Inverse association of H202-producing Lactobacilli and vaginal E. coli colonization in women with recurrent urinary tract infection. J Infect Dis 1998;178:446–50. 20. Scholes D, Hooton TM, Roberts PL, Stapleton AE, Gupta K, Stamm WE. Risk factors for recurrent urinary tract infection in young women. J Infect Dis 2000;182:1177–82.

37. Orenstein R, Wong ES. Urinary tract infections in adults. Am Fam Physician 1999;59(5):1225–34,1237. 38. Dwyer PL, O’Reilly M. Recurrent urinary tract infection in the female. Curr Opin Obstet Gynecol 2002;14:537–43. 39. Nicolle LE. Urinary tract infection: traditional pharmacologic therapies. Am J Med 2002;113(Suppl 1A):35S-44S. 40. Guibert J, Humbert G, Meyrier A, Jardin A, Vallancien G, Piccoli S et al. Antibioprevention of recurrent cystitis. A randomized double-blind comparative trial of 2 dosages of pefloxacin. Presse Med 1995;24:213–6. 41. Melekos MD, Asbach HW, Gerharz E, Zarakovitis IE, Weingaertner K, Naber KG. Post-intercourse versus daily ciprofloxacin prophylaxis for recurrent urinary tract infections in premenopausal women. J Urol 1997;157:935–9. 42. Engel JD, Schaeffer AJ. Evaluation of and antimicrobial therapy for recurrent urinary tract infections in women. Urol Clin North Am 1998;25:685–701. 43. Stapleton A, Latham RH, Johnson C, Stamm WE. Postcoital antimicrobial prophylaxis for recurrent urinary tract infection. A randomized, double-blind, placebo-controlled trial. JAMA 1990;264:703–6.

NOVEMBER JOGC NOVEMBRE 2010 l 1089

SOGC CLINICAL PRACTICE GUIDELINE

44. Stamm WE, Counts GW, Wagner K, Martine D, Gregory D, McKevitt M, et al. Antimicrobial prophylaxis of recurrent urinary tract infections: a double-blind, placebo-controlled trial. Ann Intern Med 1980;92:770–5.

63. Waites KB, Canupp KC, Armstrong S, DeVivo MJ. Effect of cranberry extract on bacteriuria and pyuria in persons with neurogenic bladder secondary to spinal cord injury. J Spinal Cord Med 2004; 27:35–40.

45. Nicolle LE. Prophylaxis: recurrent urinary tract infections in women. Infection 1992; 20(Suppl 3):S203–5.

64. Aune A, Alreak T, LiHua H, Baerheim A. Acupuncture in the prophylaxis of recurrent lower urinary tract infection in adult women. Scand J Prim Health Care 1998; 16:37–9.

46. Zhanel GG, Nicolle LE. Effects of sub-inhibitory antimicrobial concentration (sub-MICs) on in-vitro bacterial adherence to uroepithelial cells. J Antimicrob Chemother 1992;29:617–27. 47. Goemaere NNT, Grijm K, ThW van Hal P, Bakker MA. Nitrofurantoin-induced pulmonary fibrosis: a case-report. J Med Case Report 2008;2:169. 48. Nicolle LE, Harding GK, Thomson M, Kennedy J, Urias B, Ronald AR. Efficacy of five year of continuous, low-dose trimethoprim-sulfamethoxazole prophylaxis for urinary tract infection. J Infect Dis 1988;157:1239–42. 49. Schaeffer AJ, Jones JM, Flynn SS. Prophylactic efficacy of cinoxacin in recurrent urinary tract infection: biologic effects on the vaginal and fecal flora. J Urol 1982;127:1128–31. 50. Cardozo L, Lose G, McClish D, Versi E, de Koning Gans H. A systematic review of estrogens for recurrent urinary tract infections: third report of the hormones and urogenital therapy (HUT) committee. Int Urogynecol J Pelvic Floor Dysfunct 2001;12:15–20. 51. Perrotta C, Aznar M, Mejia R, Albert X, Ng CW. Oestrogens for preventing recurrent urinary tract infection in postmenopausal women. Cochrane Database Syst Rev 2008;(2):CD005131. 52. Raz R, Stamm WE. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. New Engl J Med 1993;329:753–6. 53. Eriksen BC. A randomized, open, parallel-group study on the preventive effect of an estradiol-releasing vaginal ring (Estring) on recurrent urinary tract infections in postmenopausal women. Am J Obstet Gynecol 1999;180:1072–9. 54. Raz R. Hormone replacement therapy or prophylaxis in postmenopausal women with recurrent urinary tract infection. J Infect Dis 2001;183(Suppl 1):S74–6. 55. Raz R, Colodner R, Rohana Y, Battino S, Rottensterich E, Wasser I, et al. Effectiveness of estriol-containing vaginal pessaries and nitrofurantoin macrocrystal therapy in the prevention of recurrent urinary tract infection in postmenopausal women. Clin Infect Dis 2003;36:1362–8. 56. Xu R, Wu Y, Hu Y. Prevention and treatment of recurrent urinary system infection with estrogen cream in postmenopausal women. Zhonghua Fu Chan Ke Za Zhi 2001;36:531–3. 57. Schmidt DR, Sobota AE. An examination of the antiadherence activity of cranberry juice on urinary and non-urinary bacterial isolates. Microbios 1988;55:173–81.

65. Alraek T, Fagerheim U, Baerheim A. Acupuncture treatment in the prevention of uncomplicated recurrent lower urinary tract infections in adult women. Am J Public Health 2002;92:1609–11. 66. Reid G, Bruce AW. Probiotics to prevent urinary tract infections: the rational and evidence. World J Urol 2006;24:28–32. 67. Reid G, Bruce AW, Taylor M. Instillation of Lactobacillus and stimulation of indigenous organisms to prevent recurrence of urinary tract infections. Microecol Ther 1995;23:32–45. 68. Uehara S, Monden K, Nomoto K, Seno Y, Kariyama R, Kumon H. A pilot study evaluating the safety and effectiveness of Lactobacillus vaginal suppositories in patients with recurrent urinary tract infection. Int J Antimicrob Agents 2006;28(Suppl 1):S30–4. 69. Baerheim A, Larsen E, Digranes A. Vaginal application of lactobacilli in the prophylaxis of recurrent urinary tract infection in women. Scand J Prim Health Care 1994;12:239–43. 70. Falagas ME, Betsi GI, Tokas T, Athanasiou S. Probiotics for prevention of recurrent urinary tract infections in women. Drugs 2006;66:1253–61. 71. Grischke EM, Rüttgers H. Treatment of bacterial infections of the female urinary tract by immunization of the patiets. Urol Int 1987;42:338–41. 72. Uehling DT, Hopkins WJ, Beierle LM, Kryger JV, Heisey DM. Vaginal mucosal immunization for recurrent urinary tract infection: extended phase II clinical trial. J Infect Dis 2001;183 (Suppl 1): S81–3. 73. Hopkins WJ, Uehling DT. Vaccine development for the prevention of urinary tract infections. Curr Infect Dis Rep 2002;4:509–13. 74. Sundén F, Håkansson L, Ljunggren E, Wullt B. Bacterial interference—is deliberate colonization with Escherichia coli 83972 an alternative treatment for patients with recurrent urinary tract infection? Int J Antimicrob Agents 2006;28(Suppl 1):S26–9. 75. Lipovac M, Kurz C, Reithmayr F, Verhoeven HC, Huber JC, Imhof M. Prevention of recurrent bacterial urinary tract infections by intravesical instillation of hyaluronic acid. Int J Gynaecol Obstet 2007;96:192–5. 76. Constantinides C, Manousakas T, Nikolopoulos P, Stanitsas A, Haritopoulos K, Giannopoulos A. Prevention of recurrent bacterial cystitis by intravesical istration of hyaluronic acid: a pilot study. BJU Int 2004;93:1262–6.

58. Zafriri D, Ofek I, Adar R, Pocino M, Sharon N. Inhibitory activity of craberry juice on adherence of type 1 and type P fimbriated Escherichia coli to eucaryotic cells. Antimicrob Agents Chemother 1989;33:92–8.

77. Eden CS, Fretr R, Hagberg L, Hull R, Hull S, Leffler H, et al. Inhibition of experimental ascending urinary tract infection by an epithelial cell-surface receptor analogue. Nature 1982;298(5874):560–2.

59. Jepson JP, Craig JC. Cranberries for preventing urinary tract infections. Cochrane Database Syst Rev 2008;(1):CD 001321.

78. Zopf D, Roth S. Oligosaccharides anti-infectives agents. Lancet 1996;347(9007):1017–21.

60. Kontiokari T, Sundqvist K, Nuutinen M, Pokka T, Koskela M, Uhari M. Randomised trial of cranberry-lingonberry juice and Lactobacillus GG drink for the prevention of urinary tract infections in women. BMJ 2001;322(7302):1571–3.

79. Romero R, Oyarzun E, Mazor M, Sirtori M, Hobbins JC, Bracken M. Meta-analysis of the relationship between asymptomatic bacteriuria and preterm delivery/low birth weight. Obstet Gynecol 1989;73:576–82.

61. McMurdo ME, Bissett LY, Price RJ, Phillips G, Crombie IK. Does ingestion of cranberry juice reduce symptomatic urinary tract infections in older people in hospital? A double-blind, placebo-controlled trial. Age Ageing 2005;34:256–61. 62. Stothers L. A randomized trial to evaluate effectiveness and cost effectiveness of naturopathic cranberry products as prophylaxis against urinary tract infection in women. Can J Urol 2002;9:1558–62.

1090 l NOVEMBER JOGC NOVEMBRE 2010

80. Pfau A, Sacks TG. Effective prophylaxis for recurrent urinary tract infections during pregnancy. Clin Infect Dis 1992;14:810–4. 81. Ovalle A, Levancini M. Urinary tract infections in pregnancy. Curr Opin Urol 2001:11:55–9. 82. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

SOGC CLINICAL PRACTICE GUIDELINE SOGC Clinical Practice Guideline No. 248, September 2010 (Replaces No. 74, July 1998)

Guidelines for the Evaluation and Treatment of Recurrent Urinary Incontinence Following Pelvic Floor Surgery Abstract This clinical practice guideline has been prepared by the Urogynaecology Committee and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Danny Lovatsis, MD, Toronto ON William Easton, MD, Scarborough ON David Wilkie, MD, Vancouver BC UROGYNAECOLOGY COMMITTEE Danny Lovatsis, MD, (Chair), Toronto ON Jens-Erik Walter, MD (Co-Chair), Montreal QC William Easton, MD, Scarborough ON Annette Epp, MD, Saskatoon SK Scott Farrell, MD, Halifax NS Lise Girouard, RN, Winnipeg MB Chander Gupta, MD, Winnipeg MB Marie-Andrée Harvey, MD, Kingston ON Annick Larochelle, MD, St-Lambert QC Magali Robert, MD, Calgary AB Sue Ross, PhD, Calgary AB Joyce Schachter, MD, Ottawa ON Jane Schulz, MD, Edmonton AB David Wilkie, MD, Vancouver BC

Objective: To provide general gynaecologists and urogynaecologists with clinical guidelines for the management of recurrent urinary incontinence after pelvic floor surgery. Options: Evaluation includes history and physical examination, multichannel urodynamics, and possibly cystourethroscopy. Management includes conservative, pharmacological, and surgical interventions. Outcomes: These guidelines provide a comprehensive approach to the complicated issue of recurrent incontinence that is based on the underlying pathophysiological mechanisms. Evidence: Published opinions of experts, and evidence from clinical trials where available. Values: The quality of the evidence is rated using the criteria described by the Canadian Task Force on Preventive Health Care (Table). Recommendations 1. Thorough evaluation of each patient should be performed to determine the underlying etiology of recurrent urinary incontinence and to guide management. (II-3B) 2. Conservative management options should be used as the first line of therapy. (III-C) 3. Patients with a hypermobile urethra, without evidence of intrinsic sphincter deficiency, may be managed with a retropubic urethropexy (e.g., Burch procedure) or a sling procedure (e.g., mid-urethral sling, pubovaginal sling). (II-2B)

Disclosure statements have been received from all of the committee.

4. Patients with evidence of intrinsic sphincter deficiency may be managed with a sling procedure (e.g., mid-urethral sling, pubovaginal sling). (II-3B)

The literature searches and bibliographic for this guideline were undertaken by Becky Skidmore, Medical Research Analyst, Society of Obstetricians and Gynaecologists of Canada.

5. In cases of surgical treatment of intrinsic sphincter deficiency, retropubic tension-free vaginal tape should be considered rather than transobturator tape. (I-B) 6. Patients with significantly decreased urethral mobility may be managed with periurethral bulking injections, a retropubic sling procedure, use of an artificial sphincter, urinary diversion, or chronic catheterization. (III-C) 7. Overactive bladder should be treated using medical and/or behavioural therapy. (II-2B)

Key Words: Urinary incontinence, recurrent, surgery

8. Urinary frequency with moderate elevation of post-void residual volume may be managed with conservative measures such as drugs

This document reflects emerging clinical and scientific advances on the date issued, and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

SEPTEMBER JOGC SEPTEMBRE 2010 l

893

SOGC Clinical Practice Guideline

Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well–designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

D. There is fair evidence to recommend against the clinical preventive action E. There is good evidence to recommend against the clinical preventive action L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.20 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the The Canadian Task Force on Preventive Health Care.20

to relax the urethral sphincter, timed toileting, and double voiding. Intermittent self-catheterization may also be used. (III-C) 9. Complete inability to void with or without overflow incontinence may be managed by intermittent self-catheterization or urethrolysis. (III-C) 10. Fistulae should be managed by an experienced physician. (III-C) J Obstet Gynaecol Can 2010;32(9):893–898

3. An intraoperative or postoperative complication of surgery (e.g., fistula). 4. Surgery was inappropriate therapy or an inappropriate procedure used. 5. Pre-existing or de novo overactive bladder causing urgency incontinence.

INTRODUCTION

6. Urinary tract infection causing urgency incontinence.

areful investigation and patient selection before primary pelvic surgery for prolapse and/or urinary incontinence will minimize the incidence of immediate or delayed failure.1 Conservative (i.e., non-surgical) or surgical intervention may be required when prior surgery has failed, although non-surgical options should first be considered.2 Patients who complain of either de novo or recurrent urinary incontinence following reconstructive pelvic floor or incontinence surgery must undergo a thorough evaluation to identify the cause of this incontinence. The causes of incontinence for most of these patients will fall into one of the following categories.

7. Voiding dysfunction causing urgency/frequency or overflow incontinence.

C

Early Causes of Urinary Incontinence 1. Surgical correction of stress incontinence either unsuccessful or not sustained. 2. Latent (occult) stress incontinence not recognized preoperatively in a patient with pelvic organ prolapse. 894

l SEPTEMBER JOGC SEPTEMBRE 2010

Long-term Progressive Causes of Urinary Incontinence 1. Deficiency of pelvic floor either through genetic predisposition or other medical condition. 2. Predisposing medical conditions (e.g., chronic obstructive pulmonary disease, obesity, chronic constipation). 3. Urogenital aging and estrogen deficiency. ASSESSMENT

Although some recurrent urinary incontinence may fit into the category outlined in the 2003 SOGC guideline, “The Evaluation of Stress Incontinence Prior to Primary Surgery,”1 specialized evaluation, including urodynamics, will permit accurate diagnosis and measurement of

Guidelines for the Evaluation and Treatment of Recurrent Urinary Incontinence Following Pelvic Floor Surgery

urodynamic variables that may significantly affect the management plan. Should a patient meet all the criteria on the following list, then assessment may proceed as suggested in the guideline1 without multichannel urodynamics. • No more than one prior surgery for incontinence • Symptoms of pure stress urinary incontinence • No symptoms of overactive bladder • No symptoms of voiding dysfunction such as urinary hesitancy, slow or interrupted stream, straining to void, or incomplete bladder emptying • Hypermobile urethra • Post-void residual urine volume < 100 mL • Normal urinalysis If any of the above requirements are not met, then a more thorough evaluation is required, using multichannel urodynamics, and referral to a subspecialist may be indicated. In all cases, the assessment must be designed to identify one or a combination of the following predisposing conditions. 1. Compromise to the urethral sphincter mechanism 2. Detrusor overactivity (overactive bladder) 3. Voiding dysfunction 4. Urogenital fistula 5. Persistent or de novo pelvic prolapse Recommendation 1. Thorough evaluation of each patient should be performed to determine the underlying etiology of recurrent urinary incontinence and to guide management. (II-3B) Investigation of Urethral Sphincter Function Extrinsic of the urethra is critical to continence, and it is provided laterally by connective tissue attachment to the pelvic side walls and posteriorly by the levator ani muscles. Urethral mobility should be assessed to evaluate extrinsic . However, continence is maintained only if extrinsic is complemented by normal intrinsic urethral function, which consists of the following: 1. Healthy urethral mucosa 2. A normal vascular plexus 3. Normal smooth muscle sphincter function 4. Normal external striated sphincter function Such factors as lack of estrogen, aging tissues, devascularization, denervation, or disruption of muscular sphincters can result in marked impairment of intrinsic urethral sphincter function. These problems may also arise from prior trauma, surgery, or pelvic radiation. Some patients may have a combination of recurrent hypermobility and deficiency of intrinsic urethral function.

The majority of surgical procedures used to treat stress incontinence are designed to restore normal anatomic relationships and re-establish extrinsic urethral . Although the exact mechanism responsible for the restoration of continence that results from successful surgery is uncertain3; the only consistent postoperative urodynamic finding is enhanced pressure transmission to the urethra. This urodynamic change is probably a consequence of better transmission of intra-abdominal pressure to the newly ed urethra. It is also speculated that of the mid-urethra results in some degree of kinking of the urethra when the proximal urethra and bladder descend during increased intra-abdominal pressure.4 Using this model, it is evident that in order for surgery to correct stress incontinence, it must stabilize the urethra at an appropriate anatomic level to allow pressure transmission to the urethra. If this stability is not established at the time of the operation or if it cannot be maintained over time, the surgery may fail. Repeated surgery may cause significant trauma to the urethra resulting in a poorly vascularized, scarred, rigid “drainpipe urethra” that has no sphincteric function (intrinsic sphincter deficiency).5 In this condition, the urethra is a poorly coapted conduit through which urine may leak with minimal increases in intra-abdominal pressure or on a nearly continuous basis. Urethroscopy will reveal a smooth rigid tube which does not coapt. The urethrovesical junction is open and can be visualized from any point along the urethra. Videocystourethrography will confirm a urethra which is immobile and open. Intrinsic sphincter deficiency (ISD) may result after prior retropubic urethropexy (e.g., Burch procedure) or needle suspension (e.g., Pereyra procedure), or less frequently after prior anterior colporrhaphy.6 The likelihood of ISD increases as the number of prior surgeries increases.6 Urethrovesical junction mobility can be assessed by Q-tip test,7 inspection and palpation of the distal anterior vaginal wall during Valsalva manoeuvre, ultrasound examination, videocystourethrography, and urethroscopy. If recurrent hypermobility is found, it may be assumed that surgery has failed either to establish or to maintain urethral . If the urethra is maintained in an elevated retropubic position, then it can be assumed that the goal of surgery has been achieved and that failure is the result of ISD. A patient with ISD will require subspecialized evaluation and management, including multichannel urodynamics. Urodynamic variables consistent with ISD include a maximum urethral closure pressure less than 20 cm of water or a leak point pressure less than 60 cm of water.6 The choice of any subsequent surgical procedure will be determined by the degree of urethral fixation by scar, the patient’s medical condition, SEPTEMBER JOGC SEPTEMBRE 2010 l

895

SOGC Clinical Practice Guideline

and the degree to which detrusor and urethral function has been compromised by denervation caused by previous surgical procedures.8

retropubic sling procedure, use of an artificial sphincter, urinary diversion, or chronic catheterization. (III-C) OVERACTIVE BLADDER

MANAGEMENT OF RECURRENT STRESS INCONTINENCE

Any decision to proceed with a specific treatment must include an assessment of the severity of the patient’s symptoms, and a trial of conservative management must be considered (as described in the SOGC guideline “Conservative Management of Urinary Incontinence”).2 Conventional retropubic urethropexy (Burch procedure)9 has a higher rate of failure in cases of suspected ISD where maximum urethral closure pressure is less than 20 cm of water. Tension-free vaginal tape has shown success rates of 74% to 82% when performed as a repeat procedure, depending on the degree of ISD present.8 Some data indicate that transobturator tape may not be as effective as tension-free vaginal tape in cases where there is an element of ISD,10 particularly if the maximum urethral closure pressure is less than 40 cm of water,11 with success rates of only approximately 50%. Patients with significant ISD, such as a fixed drainpipe urethra, may also have persistent incontinence even if undergoing a urethral sling as the repeat surgical technique. Referral to a subspecialist for a retropubic sling procedure with or without lysis of bladder neck and paraurethral scar may provide continence under these circumstances. The risk of failure and urinary retention may be increased. Periurethral bulking agents may also be injected.12 Consideration may be given to other “end-stage” options, such as placement of an artificial sphincter, urinary diversion, or chronic catheterization. Patients with recurrent stress incontinence who opt for surgical treatment should be managed according to the following recommendations.

Overactive bladder, a symptom complex consisting of urgency, frequency, nocturia, and urgency incontinence, is caused by a failure of bladder inhibition and, if unrecognized prior to surgery, may cause persistent incontinence following surgery. De novo overactive bladder may develop following surgery for stress incontinence,13 particularly if extensive vaginal dissection has been performed or as a secondary result after outlet obstruction. Patients will usually present with urinary urgency, frequency, nocturia, with or without urge incontinence. Cystoscopy may identify bladder pathology responsible for the urinary symptoms, such as suture or mesh penetrating the bladder or urethra. Although a simple cystometrogram will identify most cases of overactive bladder, multichannel subtracted cystometry is indicated if the diagnosis is uncertain. The management of overactive bladder is medical or behavioural. Medical therapy typically uses anticholinergic/ antimuscarinic medications.14 Behavioural therapy includes prompted voiding, bladder training, caffeine reduction, or bio, with or without electrostimulation.2 In some instances, overactive bladder is a result of outlet obstruction, (discussed in the next section), and urethrolysis may provide improvement.15 Some patients may have mixed urinary incontinence. Although surgery is not contraindicated in cases of mixed urinary incontinence,16 conservative management options for both the stress and urgency incontinence should be used, and benefits maximized before further surgery is undertaken.

Recommendations

Recommendation

2. Conservative management options should be used as the first line of therapy. (III-C)

7. Overactive bladder should be treated using medical and/or behavioural therapy. (II-2B)

3. Patients with a hypermobile urethra, without evidence of intrinsic sphincter deficiency, may be managed with a retropubic urethropexy (e.g., Burch procedure) or a sling procedure (e.g., mid-urethral sling, pubovaginal sling). (II-2B) 4. Patients with evidence of intrinsic sphincter deficiency may be managed with a sling procedure (e.g., mid-urethral sling, pubovaginal sling). (II-3B) 5. In cases of surgical treatment of intrinsic sphincter deficiency, retropubic tension-free vaginal tape should be considered rather than transobturator tape. (I-B) 6. Patients with significantly decreased urethral mobility may be managed with periurethral bulking injections, a 896

l SEPTEMBER JOGC SEPTEMBRE 2010

VOIDING DYSFUNCTION

Voiding dysfunction as a consequence of pelvic surgery may develop for several reasons. In general, voiding dysfunction is due to either urethral obstruction or detrusor underactivity. A patient with subclinical preoperative dysfunctional voiding may not be able to empty her bladder after surgical stabilization of the urethrovesical junction.17 Excessive elevation of the urethra in patients with a normal preoperative voiding mechanism may partially obstruct urinary outflow, causing voiding dysfunction. Mild degrees of incomplete emptying will appear as urinary frequency, hesitancy, and nocturia. More severe voiding compromise is manifested in urinary retention, bladder distension and

Guidelines for the Evaluation and Treatment of Recurrent Urinary Incontinence Following Pelvic Floor Surgery

overflow incontinence, recurrent urinary tract infections, and possible upper tract decompensation. Simple uroflowmetry including measurement of peak flow rate and post-void residual volume is sufficient to screen for voiding dysfunction.1 Post-void residual levels can be measured by catheterization, ultrasound examination, or contrast radiography. An intermittent voiding pattern on uroflowmetry, a decreased peak flow rate (< 15 mL/second), or a high post-void residual volume (> 150 mL) should prompt more sophisticated voiding studies, which may include voiding cystometry (simultaneous measurement of intravesical and abdominal pressures during voiding), urine flow rate, electromyogram, and urethral sphincter activity.15 Treatment should be individualized, and options include timed toileting, double voiding, intermittent catheterization, or urethrolysis. There are limited data on the use of urethral relaxants (e.g., benzodiazepines, lioresal, alpha-blockers). Detrusor stimulation using bethanecol is typically ineffective.18 Occasionally, voiding may be improved by use of a pessary or surgery to correct a high cystocoele if present. If detrusor hypotonia is the cause, then sacral nerve stimulation can be used. Additional anti-incontinence operations for stress incontinence should be planned cautiously in patients with marked postoperative voiding dysfunction.15 Recommendations 8. Urinary frequency with moderate elevation of post-void residual volume may be managed with conservative measures such as drugs to relax the urethral sphincter, timed toileting, and double voiding. Intermittent self-catheterization may also be used. (III-C) 9. Complete inability to void with or without overflow incontinence may be managed by intermittent self-catheterization or urethrolysis. (III-C) UROGENITAL FISTULA

Urogenital fistula following incontinence surgery is a rare complication. A fistula may exist between the vagina and the urethra, the bladder, the ureter, or a combination of these organs. Methylene blue solution may be instilled into the bladder followed by speculum examination or placement of tampons in the vagina. Direct visualization of dye or staining of the tampon will confirm the presence of a vesicovaginal fistula. Cystourethroscopy should permit the identification of a fistula in either the urethra or the bladder, as well as assessment of the precise size, location, and number of fistulae. Injection of intravenous indigo carmine followed by speculum examination or the tampon test may identify a ureterovaginal fistula if a vesicovaginal fistula has been ruled out. Intravenous pyelography or computed

tomography with intravenous contrast (CT urogram) is indicated to identify possible upper tract damage. Urogenital fistula is a surgical problem that must be corrected.19 The choice of procedure will depend on the severity and location of the fistula. Fistula and stress incontinence can co-exist. If surgery is undertaken, it should correct all incontinence and pelvic floor prolapse disorders, either concomitantly or in stages, depending on individual circumstances. Recommendations 10. Fistulae should be managed by an experienced physician. (III-C) REFERENCES 1. Farrell SA, Epp A, Flood C, Lojoie F, MacMillan B, Mainprize T, Robert M. The evaluation of stress incontinence prior to primary surgery. SOGC Guideline No. 127, Apr. 2003. J Obstet Gynaecol Can 2003;25:313–8. 2. Robert M, Ross S, Farrell SA, Easton WA, Epp A, Girouard L, et al. Conservative management of urinary incontinence. SOGC Clinical Practice Guideline No. 186, December 2006. J Obstet Gynaecol Can 2006;28:1113–25. 3. Nager CW, Schulz JA, Stanton SL, Monga A. Correlation of urethral closure pressure, leak-point pressure and incontinence severity measures. Int Urogynecol J Pelvic Floor Dysfunct 2001;12:395–400. 4. Lo TS, Wang AC, Horng SG, Liang CC, Soong YK. Ultrasonographic and urodynamic evaluation after tension free vagina tape procedure (TVT). Acta Obstet Gynecol Scand 2001;80:65–70. 5. GM Ghoniem, AN Elgamasy, R Elsergany, DS Kapoor. Grades of intrinsic sphincteric deficiency (ISD) associated with female stress urinary incontinence. Int Urogynecol J Pelvic Floor Dysfunct 2002;13:99–05. 6. McGuire EJ, Fitzpatrick CC, Wan J, Bloom D, Sanvordenker J, Ritchey M. Clinical assessment of urethral sphincter function. J Urol 1993;150:1452–4. 7. Karram MM, Bhatia NW. The Q-tip test: standardization of the technique and its interpretation in women with urinary incontinence. Obstet Gynecol 1988;71:807–11. 8. Rezapour M, Falconer C, Ulmsten U. Tension-free vaginal tape (TVT) in stress incontinent women with intrinsic sphincter deficiency (ISD)— a long-term follow-up. Int Urogynecol J Pelvic Floor Dysfunct 2001; Suppl 2:S12–14. 9. Sand PK, Bowen LW, Panganiban R, Ostergard DR. The low pressure urethra as a factor in failed retropubic urethropexy. Obstet Gynecol 1987;69:399–402. 10. Schierlitz L, Dwyer PL, Rosamilia A. Effectiveness of tension-free vaginal tape compared with transobturator tape in women with stress urinary incontinence and intrinsic sphincter deficiency. Obstet Gynecol 2008;112:1253–61. 11. Guerette NL, Bena JF, Davila GW. Transobturator slings for stress incontinence: using urodynamic parameters to predict outcomes. Int Urogynecol J Pelvic Floor Dysfunct 2008;19:97–102. 12. Herschorn S. Current status of injectable agents for female stress urinary incontinence. Can J Urol 2001;8:1281–9. 13. Bombieri L, Freeman RM, Perkins EP, Williams MP. Why do women have voiding dysfunction and de novo detrusor instability after colposuspension? BJOG 2002;109:402–12. 14. JG Ouslander. Management of overactive bladder. N Engl J Med 2004;350:786–99. 15. Carr L, Webster G. Voiding dysfunction following incontinence surgery: diagnosis and treatment with retropubic or vaginal urethrolysis. J Urol 1997;157:821–3.

SEPTEMBER JOGC SEPTEMBRE 2010 l

897

SOGC Clinical Practice Guideline

16. Rezapour M, Falconer C, Ulmsten U. Tension-free vaginal tape (TVT) in women with mixed urinary incontinence—a long-term follow-up. Int Urogynecol J Pelvic Floor Dysfunct 2001;Suppl 2:S15–18. 17. Minassian VA, Al-Badr A, Drutz HP, Lovatsis D. Tension-free vaginal tape, Burch, and slings: are there predictors for early postoperative voiding dysfunction? Int Urogynecol J Pelvic Floor Dysfunct 2004;15:183–7. 18. Farrell SA, Webster RD, Higgins LM, Steeves RA. Duration of postoperative catheterization: a randomized, double-blind trial comparing two catheter

898

l SEPTEMBER JOGC SEPTEMBRE 2010

management protocols and the effect of bethanecol. Int Urogynecol J Pelvic Floor Dysfunct 1990;1:132–5. 19. Miller EA, Webster GD. Current management of vesicovaginal fistulae. Curr Opin Urol 2001;11:417–21. 20. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.

SOGC CLINICAL PRACTICE GUIDELINE SOGC CLINICAL PRACTICE GUIDELINENo. 238, January 2010

Supracervical Hysterectomy This guideline has been reviewed by the Clinical Practice Gynaecology Committee and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Sari Kives MD, Toronto ON Guylaine Lefebvre MD, Toronto ON CLINICAL GYNAECOLOGY COMMITTEE Wendy Wolfman (Co-Chair), MD, Toronto ON Nicholas Leyland (Co-Chair), MD, Toronto ON Catherine Allaire, MD, Vancouver BC Alaa Awadalla, MD, Winnipeg MB Carolyn Best, MD, Hamilton ON Nathalie Leroux, MD, Montreal QC Frank Potestio, MD, Thunder Bay ON David Rittenberg, MD, Halifax NS Renée Soucy, MD, Chandler QC Sukhbir Singh, MD, Ottawa ON Disclosure statements have been received from all of the committee.

Abstract Objective: This guideline reviews the evidence relating to the potential benefits of the vaginal hysterectomy (VH) and supracervical hysterectomy (SCH) versus total abdominal hysterectomy (TAH) with respect to postoperative sexual function, urinary function, and peri- and postoperative complications. Laparoscopic options are not included in this guideline.

Evidence: The Cochrane Library, Medline, and Embase were searched for articles published in English from January 1950 to March 2008 specifically comparing VH and SCH with TAH in the prevention of sexual dysfunction, urinary dysfunction, and periand postoperative complications. Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. Additional publications were identified from the bibliographies of these articles. Randomized controlled trials were considered evidence of the highest quality, followed by cohort studies. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Values: The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table). Recommendations 1. Vaginal hysterectomy is generally considered the first choice of surgical approach for most benign indications for hysterectomy, as it is associated with lower rates of morbidity, fewer postoperative complications, and a faster recovery time than abdominal hysterectomy. (I-A) 2. Women contemplating a vaginal, laparoscopic, or abdominal hysterectomy for the management of benign uterine disease should be reassured that hysterectomy is usually associated with improved quality of life, including improved sexual function, whether or not the cervix is removed. (I-B) 3. Supracervical hysterectomy should not be recommended as a superior technique to total abdominal hysterectomy for the prevention of postoperative lower urinary tract symptoms. (I-B)

Options: Women considering hysterectomy for benign disease can be given the option of retaining the cervix or proceeding with a total hysterectomy.

4. Although supracervical hysterectomy may be associated with less blood loss and a shorter surgical time, these parameters have not been found to be clinically significant, and supracervical hysterectomy should not be recommended as a superior technique to total abdominal hysterectomy for the prevention of peri- and postoperative complications. (I-B)

Outcomes: The outcomes measured are postoperative sexual function and urinary function, and peri- and postoperative complications.

5. Women considering a supracervical hysterectomy should be counselled that they may continue experiencing cyclic vaginal bleeding following the surgery. (I-B) 6. Women must be advised that they require routine cytological screening following a supracervical hysterectomy. (II-B) 7. Women who require a hysterectomy and who have a current or significant history of abnormal cervical cytological results should be counselled on the advantages of vaginal hysterectomy or total abdominal hysterectomy over supracervical hysterectomy. (I-B)

Key Words: Hysterectomy, vaginal, supracervical, perioperative complications, postoperative complications

J Obstet Gynaecol Can 2010;32(1):62–68

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

62

l JANUARY JOGC JANVIER 2010

Supracervical Hysterectomy

Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of evidence assessment*

Classification of recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case-control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

D. There is fair evidence to recommend against the clinical preventive action E. There is good evidence to recommend against the clinical preventive action L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.26 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the The Canadian Task Force on Preventive Health Care.26

APPROACHES TO HYSTERECTOMY

ysterectomy involves the removal of the uterine body and cervix, referred to as total abdominal hysterectomy, or the removal of the uterine body only at or below the level of the isthmus, referred to as supracervical hysterectomy. Hysterectomy may also be associated with removal of the ovaries and fallopian tubes (bilateral salpingooophorectomy). Currently, hysterectomy is one of the most frequently performed surgical procedures in Canada.1 Since 1981, hysterectomy rates have decreased from 937 to 462 hysterectomies per year per 100 000 women ³ 20 years of age.2 Patient satisfaction following hysterectomy has been evaluated and is consistently high. Hysterectomy usually is associated with improvement in lower tract urinary symptoms, whether or not the cervix is removed. As vaginal hysterectomy is associated with lower rates of morbidity, fewer postoperative complications, and a faster recovery time than abdominal hysterectomy, it is usually the first

H

ABBREVIATIONS LAVH

laparoscopically assisted vaginal hysterectomy

LSCH

laparoscopically assisted supracervical hysterectomy

MUI

mixed urinary incontinence

RCT

randomized controlled trial

SCH

supracervical hysterectomy

SUI

stress urinary incontinence

TAH

total abdominal hysterectomy

UUI

urge urinary incontinence

VH

vaginal hysterectomy

choice of surgical approach when indications for hysterectomy are benign.3,4 In Canada, 72% of hysterectomies are still performed abdominally in women under 40 years of age.5 It is not clear how many of these are supracervical hysterectomies, as this method is not uniquely identified in the Canadian Classification of Health Interventions, but SCH likely s for 10% of all hysterectomies performed in Canada.6 The advent of minimally invasive surgeries has led to an increasing number of hysterectomies being performed laparoscopically. At present there is insufficient evidence to compare laparoscopic subtotal with laparoscopic total hysterectomy; therefore, this guideline considers operations done by laparotomy. Recommendation 1. Vaginal hysterectomy is generally considered the first choice of surgical approach for most benign indications for hysterectomy, as it is associated with lower rates of morbidity, fewer postoperative complications, and a faster recovery time than abdominal hysterectomy. (I-A) During the 1940s, SCH was replaced almost universally by TAH because of the risk of cervical stump cancer and persistent blood-stained discharge associated with retaining the cervix. Surgical skills and availability of anaesthesia and antibiotics also allowed for longer and more complex surgeries. More recently, there has been a re-emergence of SCH, as some literature has suggested that retaining the cervix offers better postoperative sexual and urinary function and may protect the integrity of the pelvic floor.7,8 In the United JANUARY JOGC JANVIER 2010 l

63

SOGC CLINICAL PRACTICE GUIDELINE

States, the number of SCHs appears to be increasing simultaneously with a decrease in TAH.9 With the advent of minimally invasive surgical options, the laparoscopic SCH may be favoured over a total laparoscopic hysterectomy because it is perceived to be technically easier laparoscopically to leave the cervix behind. The superiority of SCH over TAH still remains largely theoretical and is not ed by a review of evidence. RATIONALE FOR GUIDELINE DEVELOPMENT

This guideline provides a consolidation of a systematic review of the evidence ing or opposing the use of SCH rather than TAH, and the consensus on whether or not SCH offers our patients an advantage in the prevention of sexual dysfunction, urinary dysfunction, and peri- and postoperative complications. SEXUAL FUNCTION AND QUALITY OF LIFE

Four RCTs were identified that specifically address sexual function and/or quality of life after total versus supracervical hysterectomy.10–13 All 4 trials used objective, previously validated questionnaires to assess sexual function and/or quality of life,10,11 psychological well-being,11,12 and pain.12 These 4 trials included only women undergoing a hysterectomy for benign indications. Exclusion criteria varied, but postmenopausal women were excluded in 3 of the 4 trials.10–12 Oophorectomy was the only concomitant procedure permitted in all 4 trials. Thakar et al.11 also excluded women with comorbidities, including a body weight > 100 kg, previous pelvic surgery, and known endometriosis. Follow-up varied, ranging from a minimum of 7 months to a maximum of 24 months after surgery. One study also tested subjects 2 to 3 weeks prior to surgery.12 All trials stated the method of randomization and included an intention-to-treat analysis. Adequate follow-up of > 80% was obtained in all 4 trials. All 4 trials were graded as good because either the outcome was blinded,11 or the outcome was considered to be as objective as possible for a qualitative measure.10–13 Kupperman et al.10 conducted a randomized trial of 135 women (67 TAH and 68 SCH). Each woman was followed for 2 years. Baseline sexual functioning and quality of life variables were measured at randomization and again, with a telephone interview, at 1, 3, 9, and 15 months, and with clinic-based interviews every 6 months. At 2 years, both groups reported few problems with sexual functioning (mean score 82, SD 26 for SCH and 80, SD 26 for TAH). In addition, both randomization groups demonstrated substantial improvement in most measures of sexual functioning and health-related quality of life at 2 years. This 64

l JANUARY JOGC JANVIER 2010

study was significantly longer than the other 3 trials, and its findings suggest that these results persist beyond 1 year. The study by Thakar et al.11 of 279 women (146 TAH and 133 SCH) was the only double-blind RCT. Each woman was followed for 1 year. A short-form, previously validated 36-question health survey (SF-36) and psychological outcome measure (GHQ: general health questionnaire) were used preoperatively and at 6 and 12 months postoperatively (0–100 scale). No statistical difference was found between TAH and SCH on the SF-36 and GHQ before and after surgery. The frequency of intercourse, desire for intercourse, orgasm, and initiation of intercourse did not differ significantly between the groups. In addition, most aspects of quality of life improved in both randomization groups. All aspects of mental health improved following hysterectomy. There was also a significant increase in the frequency of intercourse in both groups after surgery (P = 0.01). Deep dyspareunia was reduced significantly in both groups (46.2% to 6.6% SCH and 39.3% to 14.3% TAH) at 12 months (P < 0.001), but there was no statistical difference between groups. Zobbe et al.13 conducted a randomized trial of 319 women (158 TAH and 161 SCH). Each woman was followed for 1 year. At the 12-month follow-up, there was no statistical difference between the 2 intervention groups regarding frequency of sexual desire, intercourse, masturbation, and orgasm, as well as quality of orgasm, vaginal lubrication, or satisfaction with sexual life (P > 0.05). Dyspareunia decreased significantly in both groups (89 women pre surgery and 22 post surgery P = 0.009). A multivariate logistic regression analysis identified preoperative satisfaction with sexual life, good relationship with partner, chronic disease, and use of hormone therapy as significant predictors of postoperative satisfaction with sexual life. Flory et al.12 conducted a randomized trial of 63 women (32 LAVH and 31 LSCH). Each woman was followed for 7 months. Two control groups of women who did not undergo hysterectomy were included. There were no differences among the 4 groups in sexual functioning overall (P > 0.05). There was significant improvement in sex drive, arousal, and sexual behaviour in the LAVH group, and significant improvement in sexual behaviour and sexual function in the LSCH group (P < 0.01). No significant difference in pain variables among the 4 groups was found (P > 0.05). Chronic pain in the abdomen and intensity of pain during gynaecologic examination was alleviated in both hysterectomy groups (P < 0.01). An overall postoperative improvement in depressive and psychological symptoms was also demonstrated in both hysterectomy groups (P < 0.001). Similarly, no statistical difference in adverse psychological effects was demonstrated among the

Supracervical Hysterectomy

4 groups (P > 0.05). While the laparoscopic approach to the surgery is more modern, the findings about sexual function specifically are consistent, regardless of the approach to surgery. Recommendation 2. Women contemplating a vaginal, laparoscopic, or abdominal hysterectomy for the management of benign uterine disease should be reassured that hysterectomy is usually associated with improved quality of life, including improved sexual function, whether or not the cervix is removed. (I-B) URINARY DYSFUNCTION

Two RCTs specifically addressed urinary dysfunction after TAH compared with SCH.14,15 Three RCTs addressed urinary dysfunction as part of a larger study that also looked at peri- and postoperative morbidity.16–18 All of these trials included only women undergoing a hysterectomy for benign indications. Only 1 trial was reported as a double-blind controlled trial.16 Two were multicentre trials, but investigators were not blinded to the treatment assignment.14,17 All 3 trials used standardized questionnaires in addition to cystometrography to assess urinary function.14,16,17 The study by Thakar et al.11 of 279 women (146 TAH and 133 SCH) was the only double-blind RCT. Each woman was followed for 1 year. Urinary function was assessed by use of twin-channel subtracted cystometrography and uroflowmetry, as well as by the women’s response to subjective standardized questionnaire. Urinary frequency, stress urinary incontinence, urgency, urgency incontinence, poor stream, interrupted stream, and incomplete emptying did not differ significantly between groups. (P > 0.05). In both groups, significantly fewer women had stress incontinence (subjective and by urodynamic testing), urgency, urinary frequency, nocturia, interrupted stream, and incomplete emptying at 1 year after surgery (P < 0.05). Gimbel et al.18 conducted an RCT of 319 women (158 TAH and 161 SCH). Each woman was followed for 1 year. A non-validated questionnaire was istered at randomization and at 2, 6, and 12 months after surgery. The comparison of the 2 hysterectomy techniques showed a lower rate of all urinary incontinence in the TAH group (OR 0.46, 95% CI 0.23 to 0.95; P = 0.03) than in the SCH at 12 months. Although there was no significant difference found between the method of operation, and the 3 categories of urinary incontinence were examined individually, the TAH did show a larger reduction in SUI and MUI than the SCH group, resulting in the demonstrated overall reduction. No other differences between the women in the TAH and SCH groups regarding lower urinary tract symptoms were observed at the 12-month follow-up. (P > 0.05).

Overall urinary frequency decreased and double/triple (repetitive emptying) voiding increased in both groups at 1 year following hysterectomy (OR not provided). A multivariate logistic regression analysis identified preoperative incontinence, duration of surgery, and size of uterus, as the most important variables predicting urinary incontinence at 1 year after surgery. Learman et al.17 conducted a randomized trial of 135 women (67 TAH and 68 SCH). Each woman was followed for 2 years. There was no differential improvement in urinary symptoms overall according to randomization group (P > 0.05). There was a statistically significant reduction of urgency incontinence, urinary urgency, sensation of incomplete emptying, frequent urination, and stress incontinence in the TAH group. There was a statistically significant reduction of urinary urgency, sensation of incomplete emptying, and frequent urination in the SCH group (P < 0.05). Recommendation 3. Supracervical hysterectomy should not be recommended as a superior technique to total abdominal hysterectomy for the prevention of postoperative lower urinary tract symptoms. (I-B) PERIOPERATIVE AND POSTOPERATIVE MORBIDITY

Three RCTs specifically addressed perioperative or postoperative complications of TAH compared with SCH.16–18 All 3 trials used objective measures abstracted from operative reports, pathology reports, and discharge summaries to estimate the intraoperative and postoperative complication rates. All 3 trials included only women undergoing hysterectomy for benign indications. Only 1 trial was reported as a double-blind controlled trial.16 Two were multicentre trials, but investigators were not blinded to the treatment assignment.15,17 Repeat hospitalizations were ascertained by cross-referencing abstracted data with diagnosis- related group codes on reission to hospitals d with each clinical centre and by assessing patients’ reports of hospitalization every 3 months.17 Learman et al.17 conducted a randomized trial of 135 women (67 TAH and 68 SCH). Each woman was followed for 2 years. There were no statistically significant differences in procedure time, estimated blood loss, febrile events, length of stay, and surgical complications between the 2 randomized groups (P > 0.05). The rate of hospital reission was somewhat greater in the SCH group, but the difference was not statistically significant (relative hazard 1.99, 95% CI 0.58 to 6.8; P > 0.5). Five percent of the SCH group experienced postoperative cyclical vaginal bleeding. JANUARY JOGC JANVIER 2010 l

65

SOGC CLINICAL PRACTICE GUIDELINE

Gimbel et al.18 conducted an RCT of 318 women (158 TAH and 161 SCH). Each woman was followed for 1 year after hysterectomy. SCH had a shorter median operation time (70 minutes; range 34–165 vs. 85 minutes; range 35–255, P < 0.001 ) and women who underwent this procedure had less median perioperative blood loss than those who underwent TAH (250 mL, range 10–2500 vs. 400 mL, range 25–4500; P < 0.001). Postoperative complications were grouped into 4 categories according to severity and showed no difference between the 2 hysterectomy methods (OR 1.02, CI 0.55 to 1.88; P = 0.95). The overall complication rate was 41%. Twenty percent of the SCH group had cyclical vaginal bleeding postoperatively.

incidence of cervical cancer of 0.3% at 10 years. Both cases of cervical cancer occurred in women over the age of 50.19 Oats et al. looked at 1515 women treated for cervical cancer between 1946 and 1972 and found a 3.6% incidence of cervical cancer in the stump.20 The incidence of cervical cancer is very low in both studies, but in view of the persistent risk, all women must continue to undergo routine cytological screening following a SCH.

In the double-blind RCT of 279 women (146 TAH and 133 SCH) by Thakar et al.,11 each woman was followed for 1 year. SCH had a shorter duration of surgery (59 minutes, range 39.6–80.2 vs. 71.1 minutes, range 47.7–84.5; P < 0.001), and women who underwent this procedure had less estimated blood loss (320.1 mL, range 49.1–591.1 vs. 422.6 mL, range 120.8–724.4; P = 0.004) and a shorter hospital stay than those who underwent TAH (5.2 days, range 4.3–6.3 vs. 6.0 days, range 1.3–10.7; P = 0.04). Immediate postoperative complications were greater in the TAH group: 9.8% (13) versus 27.4% (40) (P < 0.001), but delayed complications after discharge were greater in the SCH group: 10.5% (10) versus 6.2% (9) (P < 0.001). No visceral damage was sustained in either group. The majority of the immediate postoperative complications were pyrexia, retention of urine, and vault hematoma. Seven percent of the SCH group experienced cyclical vaginal bleeding.

There are no data to suggest that screening is less adequate or less frequent following the removal of the corpus. A retrospective cohort study on cervical screening in the US demonstrated no difference in screening between women after SCH and women who had not undergone hysterectomy.21 Women with supracervical hysterectomies had the same rate of testing—approximately one test every 2.5 years—as their non-exposed counterparts (mean difference: –0.03 tests/year, P = 0.62). Additionally, a retrospective cohort study by Hannoun-Levi et al. identified 77 patients with an infiltrating carcinoma of the cervical stump and demonstrated similar treatment results in patients with carcinoma of the cervical stump and in patients with carcinoma of the intact uterus.22 The advantages of removing the cervix when it is potentially diseased should be presented to patients who are having a hysterectomy and who have a current or significant history of abnormal cervical cytological results. In the study by Learman et al.,17 3 TAH patients had high-grade dysplasia in the cervical specimens despite the requirement for up-to-date Papanicolaou smears and the exclusion from the study of women with a previous history of cervical dysplasia. This may reflect limitations in the sensitivity of cervical cancer screening tests. It is also important to discuss the need for ongoing surveillance of the vaginal vault in women who have a total hysterectomy performed in the presence of cervical dysplasia.

Recommendation 4. Although supracervical hysterectomy may be associated with less blood loss and a shorter surgical time, these parameters have not been found to be clinically significant, and supracervical hysterectomy should not be recommended as a superior technique to total abdominal hysterectomy for the prevention of peri- and postoperative complications. (I-B) 5. Women considering a supracervical hysterectomy should be counselled that they may continue experiencing cyclic vaginal bleeding following the surgery. (I-B) ADVERSE EFFECTS Potential Harm of Leaving the Cervix at the Time of Hysterectomy Cervical cancer

We identified 2 papers that specified the incidence of cervical cancer following a SCH. A case–control study of 1104 women who underwent SCH in Denmark between 1978 and 1988 revealed 2 cases of cervical cancer, for an overall 66

l JANUARY JOGC JANVIER 2010

Recommendation 6. Women must be advised that they require routine cytological screening following a supracervical hysterectomy. (II-B)

Recommendation 7. Women who require a hysterectomy and who have a current or significant history of abnormal cervical cytological results should be counselled on the advantages of vaginal hysterectomy or total abdominal hysterectomy over supracervical hysterectomy. (I-B) Vaginal bleeding

Most surgeons routinely attempt to ablate the endocervical canal after removal of the corpus at the time of SCH. Persistent cyclical vaginal bleeding still occurs in up to 25% women with a retained cervix following SCH. In a retrospective cohort by Van Der Stege et al., 25% of women

Supracervical Hysterectomy

experienced regular vaginal bleeding following SCH.23 Three RCTs16–18 described cyclical vaginal bleeding in 5% to 20% of women following SCH. The problem of cyclical vaginal bleeding exceeded acceptability in 2 women in the study by Gimbel et al.,18 and each had her cervical stump removed at 3 months after SCH. In the study by Learman et al.,17 persistent vaginal bleeding led to a trachelectomy in one SCH patient 15 months after hysterectomy.

The 3 RCTs15–17 specifically addressing urinary dysfunction do not the suggestion that removal of the uterine cervix at hysterectomy is more detrimental to urinary function. Overall, SCH is not associated with any significant improvement in urinary function when compared with TAH; rather, women in both intervention groups had an improvement in urinary symptoms, specifically SUI and urgency.

COST

The 3 RCTs16–18 specifically addressing peri- and postoperative complications do not suggest that removal of the uterine cervix at hysterectomy is detrimental. Two studies did demonstrate a longer operating time,16,18 greater estimated blood loss,16,18 and length of stay16 with SCH than with TAH. Differences in operation time and blood loss are unlikely to be clinically significant. The variation in length of stay was less than 1 day, which is also not considered clinically relevant. Perioperative complications were greater in the TAH group in one study,16 but the most commonly documented complication was pyrexia, which may not be clinically significant. The other 2 studies failed to demonstrate a difference in postoperative complications17,18 or in reission rates.17

The direct costs following SCH have been shown to be similar to those following TAH. In a retrospective cohort study of 11 Ontario hospitals, the direct costs of TAH and SCH were comparable in community hospitals and teaching hospitals. There were, however, considerable variations in the mean direct costs for hysterectomy by surgical approach (e.g., $955–$1831 in the community hospital and $1665–$3190 in the teaching hospital for SCH). Additionally, the overall direct cost was much greater in the teaching hospitals for both SCH and TAH.6 A trial by Showstack et al. that randomized 120 women to receive either TAH or SCH found that overall resource use was similar at 12 and 24 months.24 Women who undergo SCH still require regular cervical cancer screening, which may mean additional expenses in the case of abnormal Papanicolaou smears, including repeat cytologic studies, colposcopy, and treatment not incurred with women who have their cervix removed. Women presenting for definitive management of ongoing symptoms related to the cervical stump may choose a trachelectomy, which is associated with significant additional costs. SUMMARY

Using the evidence, a November 2007 ACOG Committee Opinion states that Recently published Level 1 evidence reveals no advantage of the supracervical hysterectomy with regards to surgical complications, urinary symptoms or sexual function for women undergoing hysterectomy for symptomatic uterine leiomyomata or abnormal uterine bleeding. The supracervical hysterectomy should not be recommended as a superior technique for hysterectomy for benign disease.25 The 4 RCTs specifically addressing sexual dysfunction do not the suggestion that removal of the uterine cervix at hysterectomy is detrimental to sexual satisfaction.10–13 In fact, regardless of operative technique used, sexual function and frequency of intercourse often improved, as did quality of life, mental health, intensity and frequency of pain, and frequency of dyspareunia.

Although, in the past, data from uncontrolled series may have suggested there are benefits in preserving the cervix, a review of the recently published level 1 evidence reveals no advantage to the supracervical technique of hysterectomy with respect to sexual function, urinary symptoms, and surgical complications in women undergoing hysterectomy for benign indications. REFERENCES 1. Gentleman JF, Parsons GF, Walsh MN, Vayda E. High and low surgical procedure rates in census divisions across Canada [published erratum appears in Health Reports 1995;7(1):64]. Health Reports 1994;6(4):403–40. (Statistics Canada Cat 82–003). 2. Statistics Canada, Hospital Morbidity File, 1981/82; Canadian Institute for Health Information, 1996/97. 3. Ottosen C, Lingman G, Ottosen L. Three methods for hysterectomy: a randomized, prospective study of short term outcome. BJOG 2000;107:1380–5. 4. Lefebvre G, Allaire C, Jeffrey J,Vilos G; SOGC Clinical Practice Gynaecology Committee. Clinical practice guidelines for hysterectomy. SOGC Clinical Practice Guideline No. 109, January 2002. J Obstet Gynaecol Can 2002;24(1):37–48. 5. Brown AD, Magistretti AI, Ferris L, Steward DE. Hospital Report 2001: Preliminary study volume 2. Exploring women’s health, 2001. 6. Cohen MM, Young W. Costs of hysterectomy: does surgical approach make a difference? J Womens Health 1998 Sep;7(7):885–92. 7. Kilkku P, Grönroos M, Hirvonen T, Rauramo L. Supravaginal uterine amputation vs. hysterectomy. Effects on libido and orgasm. Acta Obstet Gynecol Scand 1983;62(2):147–52. 8. Vervest HA, Kiewiet de Jonge M, Vervest TM, Barents JW, Haspels AA. Micturition symptoms and urinary incontinence after non-radical hysterectomy. Acta Obstet Gynecol Scand 1988;67(2):141–6.

JANUARY JOGC JANVIER 2010 l

67

SOGC CLINICAL PRACTICE GUIDELINE

9. Sills ES, Saini J, Steiner CA, McGee M 3rd, Gretz HF 3rd. Abdominal hysterectomy practice patterns in the United States. Int J Gynaecol Obstet 1998 Dec;63(3):277–83. 10. Kuppermann M, Summitt RL Jr, Varner RE, McNeeley SG, Goodman-Gruen D, Learman LA, et al. and Total or Supracervical Hysterectomy Research Group. Sexual functioning after total compared with supracervical hysterectomy: a randomized trial. Obstet Gynecol 2005 Jun;105(6):1309–18. 11. Thakar R, Ayers S, Georgakapolou A, Clarkson P, Stanton S, Manyonda I. Hysterectomy improves quality of life and decreases psychiatric symptoms: a prospective and randomised comparison of total versus subtotal hysterectomy. BJOG 2004 Oct;111(10):1115–20.

Research Group. A randomized comparison of total or supracervical hysterectomy: surgical complications and clinical outcomes. Obstet Gynecol 2003 Sep;102(3):453–62. 18. Gimbel H, Zobbe V, Andersen BM, Filtenborg T, Gluud C, Tabor A. Randomised controlled trial of total compared with subtotal hysterectomy with one-year follow up results. BJOG 2003 Dec;110(12):1088–98. 19. Storm HH, Clemmensen IH, Manders T, Brinton LA. Supravaginal uterine amputation in Denmark 1978–1988 and risk of cancer. Gynecol Oncol 1992 May;45(2):198–201. 20. Oats JJ. Carcinoma of the cervical stump. Br J Obstet Gynaecol 1976 Nov;83(11):896–9.

12. Flory N, Bissonnette F, Amsel RT, Binik YM. The psychosocial outcomes of total and subtotal hysterectomy: a randomized controlled trial. J Sex Med 2006 May;3(3):483–91.

21. Eaker ED, Vierkant RA, Konitzer KA, Remington PL. Cervical cancer screening among women with and without hysterectomies. Obstet Gynecol 1998 Apr;91(4):551–5.

13. Zobbe V, Gimbel H, Andersen BM, Filtenborg T, Jakobsen K, Sørensen HC, et al. Sexuality after total vs. subtotal hysterectomy. Acta Obstet Gynecol Scand 2004 Feb;83(2):191–6.

22. Hannoun-Lévi JM, Peiffert D, Hoffstetter S, Luporsi E, Bey P, Pernot M. Carcinoma of the cervical stump: retrospective analysis of 77 cases. Radiother Oncol 1997 May;43(2):147–53.

14. Lalos O, Bjerle P. Bladder wall mechanics and micturition before and after subtotal and total hysterectomy. Eur J Obstet Gynecol Reprod Biol 1986 Mar;21(3):143–50.

23. van der Stege JG, van Beek JJ. Problems related to the cervical stump at follow-up in laparoscopic supracervical hysterectomy. JSLS 1999 Jan-Mar;3(1):5–7.

15. Gimbel H, Zobbe V, Andersen BJ, Sørensen HC, Toftager-Larsen K, Sidenius K, et al. Lower urinary tract symptoms after total and subtotal hysterectomy: results of a randomized controlled trial. Int Urogynecol J Pelvic Floor Dysfunct 2005 Jul-Aug;16(4):257–6.

24. Showstack J, Kuppermann M, Lin F, Vittinghoff E, Varner RE, Summitt RL Jr, et al. Resource use for total and supracervical hysterectomies: results of a randomized trial. Obstet Gynecol 2004 May;103(5 Pt 1):834–41.

16. Thakar R, Ayers S, Clarkson P, Stanton S, Manyonda I. Outcomes after total versus subtotal abdominal hysterectomy. N Engl J Med 2002 Oct 24;347(17):1318–25. 17. Learman LA, Summitt RL Jr, Varner RE, McNeeley SG, Goodman-Gruen D, Richter HE, et al. and Total or Supracervical Hysterectomy (TOSH)

68

l JANUARY JOGC JANVIER 2010

25. ACOG Committee Opinion No. 388 November 2007: supracervical hysterectomy. Obstet Gynecol 2007 Nov;110(5):1215–7. 26. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169(3):207–8.

SOGC CLINICAL PRACTICE GUIDELINE SOGC CLINICAL PRACTICE GUIDELINE No. 235 October 2009 (Replaces No. 88, April 2000)

Active Management of the Third Stage of Labour: Prevention and Treatment of Postpartum Hemorrhage This Clinical Practice Guideline has been prepared by the Clinical Practice Obstetrics Committee and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHOR

be relevant. Each full-text article was critically appraised with use of the Jadad Scale and the levels of evidence definitions of the Canadian Task Force on Preventive Health Care. Values: The quality of evidence was rated with use of the criteria described by the Canadian Task Force on Preventive Health Care.

Dean Leduc, MD, Ottawa ON

Sponsor: The Society of Obstetricians and Gynaecologists of Canada.

Vyta Senikas, MD, Ottawa ON

Recommendations

André B. Lalonde, MD, Ottawa ON

Prevention of Postpartum Hemorrhage

CLINICAL PRACTICE OBSTETRICS COMMITTEE

1. Active management of the third stage of labour (AMTSL) reduces the risk of PPH and should be offered and recommended to all women. (I-A)

Dean Leduc (Chair), MD, Ottawa ON Charlotte Ballerman, MD, Edmonton AB Anne Biringer, MD, Toronto ON Martina Delaney, MD, St. John’s NL Louise Duperron, MD, Montreal QC Isabelle Girard, MD, Montreal QC Donna Jones, MD, Calgary AB Lily Shek-Yun Lee, MD, Vancouver BC Debra Shepherd, MD, Regina SK Kathleen Wilson, RM, Ilderton ON Disclosure statements have been received from all of the committee.

Abstract Objective: To review the clinical aspects of postpartum hemorrhage (PPH) and provide guidelines to assist clinicians in the prevention and management of PPH. These guidelines are an update from the previous Society of Obstetricians and Gynaecologists of Canada (SOGC) clinical practice guideline on PPH, published in April 2000. Evidence: Medline, PubMed, the Cochrane Database of Systematic Reviews, A Journal Club, and BMJ Clinical Evidence were searched for relevant articles, with concentration on randomized controlled trials (RCTs), systematic reviews, and clinical practice guidelines published between 1995 and 2007. Each article was screened for relevance and the full text acquired if determined to

Key Words: Prevention, hemorrhage, obstetrics, obstetric hemorrhage

2. Oxytocin (10 IU), istered intramuscularly, is the preferred medication and route for the prevention of PPH in low-risk vaginal deliveries. Care providers should ister this medication after delivery of the anterior shoulder. (I-A) 3. Intravenous infusion of oxytocin (20 to 40 IU in 1000 mL, 150 mL per hour) is an acceptable alternative for AMTSL. (I-B) 4. An IV bolus of oxytocin, 5 to 10 IU (given over 1 to 2 minutes), can be used for PPH prevention after vaginal birth but is not recommended at this time with elective Caesarean section. (II-B) 5. Ergonovine can be used for prevention of PPH but may be considered second choice to oxytocin owing to the greater risk of maternal adverse effects and of the need for manual removal of a retained placenta. Ergonovine is contraindicated in patients with hypertension. (I-A) 6. Carbetocin, 100 mg given as an IV bolus over 1 minute, should be used instead of continuous oxytocin infusion in elective Caesarean section for the prevention of PPH and to decrease the need for therapeutic uterotonics. (I-B) 7. For women delivering vaginally with 1 risk factor for PPH, carbetocin 100 mg IM decreases the need for uterine massage to prevent PPH when compared with continuous infusion of oxytocin. (I-B) 8. Ergonovine, 0.2 mg IM, and misoprostol, 600 to 800 mg given by the oral, sublingual, or rectal route, may be offered as alternatives in vaginal deliveries when oxytocin is not available. (II-1B) 9. Whenever possible, delaying cord clamping by at least 60 seconds is preferred to clamping earlier in premature newborns (< 37 weeks’ gestation) since there is less intraventricular hemorrhage and less need for transfusion in those with late clamping. (I-A) 10. For term newborns, the possible increased risk of neonatal jaundice requiring phototherapy must be weighed against the

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

980

l OCTOBER JOGC OCTOBRE 2009

Active Management of the Third Stage of Labour: Prevention and Treatment of Postpartum Hemorrhage

Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of Evidence Assessment*

Classification of Recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case-control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

D. There is fair evidence to recommend against the clinical preventive action E. There is good evidence to recommend against the clinical preventive action L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.54 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the The Canadian Task Force on Preventive Health Care.54

physiological benefit of greater hemoglobin and iron levels up to 6 months of age conferred by delayed cord clamping. (I-C) 11. There is no evidence that, in an uncomplicated delivery without bleeding, interventions to accelerate delivery of the placenta before the traditional 30 to 45 minutes will reduce the risk of PPH. (II-2C) 12. Placental cord drainage cannot be recommended as a routine practice since the evidence for a reduction in the duration of the third stage of labour is limited to women who did not receive oxytocin as part of the management of the third stage. There is no evidence that this intervention prevents PPH. (II-1C) 13. Intraumbilical cord injection of misoprostol (800 mg) or oxytocin (10 to 30 IU) can be considered as an alternative intervention before manual removal of the placenta. (II-2C) Treatment of PPH 14. For blood loss estimation, clinicians should use clinical markers (signs and symptoms) rather than a visual estimation. (III-B) 15. Management of ongoing PPH requires a multidisciplinary approach that involves maintaining hemodynamic stability while simultaneously identifying and treating the cause of blood loss. (III-C) 16. All obstetric units should have a regularly checked PPH emergency equipment tray containing appropriate equipment. (II-2B) 17. Evidence for the benefit of recombinant activated factor VII has been gathered from very few cases of massive PPH. Therefore this agent cannot be recommended as part of routine practice. (II-3L) 18. Uterine tamponade can be an efficient and effective intervention to temporarily control active PPH due to uterine atony that has not responded to medical therapy. (III-L) 19. Surgical techniques such as ligation of the internal iliac artery, compression sutures, and hysterectomy should be used for the

management of intractable PPH unresponsive to medical therapy. (III-B) Recommendations were quantified using the evaluation of evidence guidelines developed by the Canadian Task Force on Preventive Health Care (Table 1). J Obstet Gynaecol Can 2009;31(10):980–993

INTRODUCTION

ostpartum hemorrhage is the leading cause of maternal death worldwide, with an estimated mortality rate of 140 000 per year, or 1 maternal death every 4 minutes.1 PPH occurs in 5% of all deliveries and is responsible for a major part of maternal mortality.2,3 The majority of these deaths occur within 4 hours of delivery, which indicates that they are a consequence of the third stage of labour.4,5 Nonfatal PPH results in further interventions, iron deficiency anemia, pituitary infarction (Sheehan’s syndrome) with associated poor lactation, exposure to blood products, coagulopathy, and organ damage with associated hypotension and shock.

P

Since all parturient women are at risk for PPH, care providers need to possess the knowledge and skills to practise active management of the third stage of labour to prevent PPH and to recognize, assess, and treat excessive blood loss.

ABBREVIATIONS AMTSL active management of the third stage of labour PPH

postpartum hemorrhage

RCT

randomized controlled trial

DEFINITION OF PPH

Primary PPH is defined as excessive bleeding that occurs in the first 24 hours after delivery. OCTOBER JOGC OCTOBRE 2009 l

981

SOGC CLINICAL PRACTICE GUIDELINE

Table 2. Signs and symptoms of shock resulting from blood loss Degree of shock

Blood loss < 20%

Mild

Moderate

Severe

20% to 40%

> 40%

Signs and symptoms Diaphoresis Increased capillary refilling Cool extremities Anxiety Above plus Tachycardia Tachypnea Postural hypotension Oliguria Above plus Hypotension Agitation/confusion Hemodynamic instability

Traditionally the definition of PPH has been blood loss in excess of 500 mL after vaginal delivery and in excess of 1000 mL after abdominal delivery. For clinical purposes, any blood loss that has the potential to produce hemodynamic instability should be considered PPH. The amount of blood loss required to cause hemodynamic instability will depend on the pre-existing condition of the woman. Hemodynamic compromise is more likely to occur in conditions such as anemia (e.g., iron deficiency, thalassemia) or volume-contracted states (e.g., dehydration, gestational hypertension with proteinuria). Hypovolemic Shock6

Excessive bleeding, or hemorrhage, results in net loss of intravascular volume and decreased oxygen delivery to tissues and organs. Physiological compensatory mechanisms such as reflex tachycardia, peripheral vasoconstriction, and increased myocardial contractility help to maintain tissue perfusion. Increasing blood loss results in circulatory collapse, end-organ damage, and eventual death. Ideally, care providers should be able to assess the amount of blood loss in order to estimate the volume of fluid that needs to be replaced. However, research has shown that clinicians often underestimate the actual loss.7 The signs and symptoms listed in Table 2 should be used at the bedside to evaluate the amount of blood loss since, in general, the degree of shock parallels the amount of blood loss that results in these clinical markers.6 Etiology of PPH

In regard to the underlying causes of PPH, it may be helpful to think in of the 4 Ts: • Tone: uterine atony, distended bladder • Tissue: retained placenta and clots • Trauma: vaginal, cervical, or uterine injury • Thrombin: coagulopathy (pre-existing or acquired) 982

l OCTOBER JOGC OCTOBRE 2009

The most common and important cause of PPH is uterine atony. The primary protective mechanism for immediate hemostasis after delivery is myometrial contraction causing occlusion of uterine blood vessels, the so-called living ligatures of the uterus. Thus blood flow from the vascular space to the uterine cavity via the myometrium is impeded. Maternity care providers should recognize the risk factors for PPH due to the 4 Ts, as listed in Table 3, and take appropriate action. PREVENTION OF PPH

AMTSL involves interventions to assist in expulsion of the placenta with the intention to prevent or decrease blood loss. Interventions include use of uterotonics, clamping of the umbilical cord, and controlled traction of the cord. In contrast, with expectant, or physiological, management, spontaneous delivery of the placenta is allowed, with subsequent intervention, if necessary, that involves uterine massage and use of uterotonics. Prendiville and colleagues’ meta-analysis8 demonstrated the benefits of AMTSL to prevent and reduce PPH after vaginal delivery for women at low risk of PPH. Studies included in the meta-analysis had design methods that involved routine use of uterotonics after delivery of the newborn and before delivery of the placenta, early cord clamping, and controlled cord traction. The primary goal of these interventions was to assist placental delivery, thereby allowing the uterus to contract and reduce blood flow across the myometrium. The meta-analysis concluded that active compared with expectant management significantly reduced the risk in all areas, including mild PPH (estimated blood loss > 500 mL; OR 0.38; 95% CI 0.32 to 0.46), severe PPH (estimated blood loss > 1000 mL; OR 0.32; 95% CI 0.21 to 0.50), low postpartum hemoglobin level (< 9 g/dL; OR 0.38; 95% CI 0.27 to 0.53), need for transfusion (OR 0.33; 95% CI 0.21 to 0.52), and need for additional uterotonic medication (OR 0.17; 95% CI 0.14 to 0.21). There was no difference in the incidence of retained placenta or management of this complication by manual or surgical removal. There was significantly more nausea and hypertension in the actively managed group given ergonovine (OR 1.83; 95% CI 1.51 to 2.23). A review of the data resulted in a t statement in 2004 by the International Confederation of Midwives and International Federation of Gynaecologists and Obstetricians endorsing the need for all deliveries to be attended by a caregiver trained in AMTSL, which should include routine use of uterotonics, controlled cord traction, and uterine massage.9 Delaying cord clamping by 1 to 3 minutes was

Active Management of the Third Stage of Labour: Prevention and Treatment of Postpartum Hemorrhage

Table 3. Risk factors for postpartum hemorrhage (PPH) Etiologic category and process Tone: abnormalities of uterine contraction Overdistension of uterus

Uterine muscle exhaustion

Intra-amniotic infection Functional/anatomic distortion of uterus Uterine-relaxing medications Bladder distension, which may prevent uterine contraction 4 Tissue: retained Retained products of conception Abnormal placentation Retained cotyledon or succenturiate lobe Retained blood clots Trauma: of the genital tract Lacerations of the cervix, vagina, or perineum Extensions, lacerations at cesarean section Uterine rupture Uterine inversion

Thrombin: abnormalities of coagulation Pre-existing states

Clinical risk factors Polyhydramnios Multiple gestation Macrosomia Rapid labour Prolonged labour High parity Oxytocin use Fever Prolonged rupture of membranes Fibroids Placenta previa Uterine anomalies Halogenated anesthetics Nitroglycerin Incomplete placenta at delivery Previous uterine surgery High parity Abnormal placenta seen on ultrasonography Atonic uterus Precipitous delivery Operative delivery Malposition Deep engagement Previous uterine surgery High parity Fundal placenta Excessive cord traction History of hereditary coagulopathies or liver disease

Hemophilia A Von Willebrand’s disease History of previous PPH Acquired in pregnancy Idiopathic thrombocytopenic purpura

Bruising, elevated blood pressure

Thrombocytopenia with preeclampsia Disseminated intravascular coagulation Gestational hypertensive disorder of pregnancy with adverse conditions

Elevated blood pressure

a) Dead fetus in utero

Fetal demise

b) Severe infection

Fever, neutrophilia/neutropenia

c) Abruption

Antepartum hemorrhage

d) Amniotic fluid embolus Therapeutic anticoagulation

Sudden collapse History of thrombotic disease

favoured over early cord clamping to reduce anemia in the newborn.

1. Active management should be offered to all women by skilled care providers.

A similar review of the literature in 2006 by the World Health Organization10 highlighted the most common cause of PPH as uterine atony and the fact that most women with PPH have no identifiable risk factors. The review resulted in several recommendations to minimize maternal morbidity and mortality rates.

2. Skilled attendants should offer uterotonics (oxytocin preferred over ergonovine, misoprostol, and carboprost) to prevent PPH. 3. Early cord clamping is recommended only when the newborn needs to be resuscitated. OCTOBER JOGC OCTOBRE 2009 l

983

SOGC CLINICAL PRACTICE GUIDELINE

4. Despite the lack of evidence to cord traction, this practice should be continued as part of active management. Uterotonics

During the third stage of labour the muscles of the uterus contract downward, causing constriction of the blood vessels that through the uterine wall to the placental surface and stopping the flow of blood. This action also causes the placenta to separate from the uterine wall. The absence of uterine contractions, clinically defined as atony, may result in excessive blood loss. Uterotonics promote uterine contractions to prevent atony and speed delivery of the placenta. The uterotonic agents include oxytocin, ergonovine, carbetocin, misoprostol, and Syntometrine (a combination of ergonovine and oxytocin, unavailable in Canada). Oxytocin and ergonovine

The 1997 Abu Dhabi study11 included in Prendiville and colleagues’meta-analysis8 randomly allocated low-risk women who delivered vaginally to receive either 10 IU of oxytocin IM with delivery of the anterior shoulder followed by controlled cord traction upon signs of placental separation or minimal intervention. The results revealed a benefit for the oxytocin group: a lower incidence of blood loss > 500 mL (OR 0.50; CI 0.34 to 0.73) and > 1000 mL (OR 0.22; CI 0.08 to 0.57), fewer retained placentas (OR 0.31; CI 0.15 to 0.63), and less need for additional uterotonics (OR 0.44; CI 0.24 to 0.78). A 2004 Cochrane Review12 compared the efficacy of Syntometrine and oxytocin alone, both istered IM, in AMTSL. The results showed a small benefit for Syntometrine in preventing blood loss > 500 mL (OR 0.82; 95% CI 0.71 to 0.95) but no difference in preventing losses > 1000 mL. The group receiving Syntometrine were more likely to have elevated diastolic blood pressure (OR 2.40; 95% CI 1.58 to 3.64), nausea (OR 4.07; 95% CI 3.43 to 4.84), and vomiting (OR 4.92; 95% CI 4.03 to 6.00). The authors favoured oxytocin alone on the basis of the lower incidence of maternal side effects. A 2008 meta-analysis13 included 14 studies assessing the benefits of oxytocin in AMTSL for vaginal deliveries. Seven trials comparing oxytocin and no uterotonics found a lower incidence of blood loss > 500 mL (RR 0.50; 95% CI 0.43 to 0.59) and less need for therapeutic oxytocin (RR 0.5; 95% CI 0.39 to 0.64) in the groups receiving oxytocin. Six trials found no difference between the results with oxytocin and ergonovine except that the groups receiving oxytocin had fewer manual removals of the placenta (RR 0.57; 95% CI 0.41 to 0.79) and a tendency to a lower incidence of raised blood pressure (RR 0.53; 95% CI 0.19 to 1.52) than the 984

l OCTOBER JOGC OCTOBRE 2009

groups receiving ergonovine. Five trials showed little evidence of a synergistic effect of adding oxytocin to ergonovine versus ergonovine alone. One double-blind randomized controlled trial14 compared the efficacy of 10 IU of oxytocin in saline solution with saline solution alone in cephalic vaginal deliveries in low-risk women. The oxytocin group had a lower mean blood loss (407 vs. 527 mL), a lower incidence of blood loss > 800 mL (8.8% vs. 5.2%), and a lower rate of use of additional ergonovine (3.5% vs. 2.3%). Another double-blind RCT15 found no difference in the incidence of PPH among women with low-risk vaginal deliveries given an IV bolus of oxytocin (20 IU in 500 mL of crystalloid) before or after delivery of the placenta. The use of a slow IV bolus in management of the third stage of labour has been adopted as standard practice although there is little ing evidence in the literature. The Dublin trial16 was the only study in Prendiville and colleagues’meta-analysis8 in which a uterotonic (Syntometrine) was istered IV; the result was a lower incidence of PPH but more retained placentas. There has been concern about the safety of such rapid istration of oxytocin in the third stage, although 99 women given 10 IU in an IV push after vaginal delivery did not have significant hemodynamic effects. The study, however, was underpowered to demonstrate a reduction in the incidence of PPH.17 For women undergoing elective Caesarean section, recent studies have demonstrated adverse maternal effects of an oxytocin IV bolus. One double-blind RCT found hemodynamic changes in 30 patients given 5 IU IV over 30 seconds compared with women who received the same dose over 5 minutes.18 In another double-blind RCT, 40 patients given 10 IU of oxytocin as an IV bolus manifested electrocardiographic changes consistent with myocardial ischemia when compared with pregnant women who received 0.2 mg of ergonovine and nonpregnant women; the effect was transient, with onset at 1 minute and resolution by 5 minutes after exposure to oxytocin.19 These studies suggest a potential maternal effect of the rapid istration (within 30 seconds) of oxytocin, and it may be dose-related. Oxytocin given as part of AMTSL has been shown to reduce the need for manual removal of a retained placenta compared with expectant management.8,13 The greater need for manual removal noted in the Dublin trial16 was attributed to the use of Syntometrine as an IV bolus. A 2001 Cochrane review13 of prophylactic IM oxytocin use during the third stage of labour demonstrated a significantly reduced need for manual removal of the placenta compared with ergometrine use (RR 0.57; 95% CI 0.41 to 0.79).

Active Management of the Third Stage of Labour: Prevention and Treatment of Postpartum Hemorrhage

Recommendations Recommendations were quantified using the evaluation of evidence guidelines developed by the Canadian Task Force on Preventive Health Care (Table 1). 1. AMTSL reduces the risk of PPH and should be offered and recommended to all women. (I-A) 2. Oxytocin (10 IU), istered intramuscularly, is the preferred medication and route for the prevention of PPH in low-risk vaginal deliveries. Care providers should ister this medication after delivery of the anterior shoulder. (I-A) 3. Intravenous infusion of oxytocin (20 to 40 IU in 1000 mL, 150 mL per hour) is an acceptable alternative for AMTSL. (I-B) 4. An IV bolus of oxytocin, 5 to 10 IU (given over 1 to 2 minutes), can be used for PPH prevention after vaginal birth but is not recommended at this time with elective Caesarean section. (II-B) 5. Ergonovine can be used for prevention of PPH but may be considered second choice to oxytocin owing to the greater risk of maternal adverse effects and of the need for manual removal of a retained placenta. Ergonovine is contraindicated in patients with hypertension. (I-A) Carbetocin

Carbetocin is a long-acting oxytocin studied by Dansereau et al.,20 who performed an RCT comparing the incidence of PPH in women undergoing elective Caesarean section who received either carbetocin as a 100-mg IV bolus or oxytocin as a continuous infusion for 8 hours (25 IU of oxytocin in 1000 mL of Ringer’s lactate, 125 mL per hour). The carbetocin group had a decreased incidence of PPH and of the need for therapeutic oxytocics (4.7% vs. 10.1%; P < 0.05). The recommended dose of carbetocin is 100 mg given either IM or slowly (over 1 minute), the pharmacokinetics of the 2 istration routes being almost the same.21 Boucher and colleagues’ double-blind 2003 RCT22 demonstrated that women with at least 1 risk factor for PPH who were given carbetocin (100 mg IM) immediately after placental delivery were less likely to required uterine massage as a uterotonic intervention than those given a continuous infusion of oxytocin over 2 hours: 43.4% of women in the carbocetin group (36/83 [43.4%]; 95%CI, 32.7% to 54% vs. 48/77 [62.3%] of women in the oxytocin group; 95% CI, 51.5% to 73.2%) required the massage (P = 0.02). There was no difference in the requirement for additional uterotonic medication (i.e., oxytocin, ergonovine), estimated blood loss, or difference in hemoglobin level before and after vaginal delivery. There was no significant benefit of carbetocin over oxytocin in the prevention of PPH. The

authors commented on the advantage of IM intervention in a setting where IV treatment is unavailable. A 2007 Cochrane Review23 included 4 RCTs that compared carbetocin with oxytocin for prevention of PPH. The results were consistent with the results of the trials conducted by Dansereau and Boucher and their colleagues.20,22 Since none of the trials included low-risk women, there was insufficient evidence that 100 mg of carbetocin given IV is as effective as oxytocin in the prevention of PPH in low-risk vaginal deliveries. An RCT by Leung et al.24 compared IM istration of carbetocin and Syntometrine in AMTSL for singleton vaginal deliveries after 34 weeks. The results showed no difference in the incidence of a low hemoglobin level, blood loss > 500 mL, retained placenta, or use of additional uterotonic agents. Carbetocin recipients had less nausea (RR 0.18; 95%CI 0.04 to 0.78), vomiting (RR 0.1; 95% CI 0.01 to 0.74), and hypertension 30 minutes (0 vs. 8 cases, P < 0.01) and 60 minutes (0 vs. 6 cases, P < 0.05) after delivery. There was a higher incidence of maternal tachycardia (RR 1.68; 95% CI 1.03 to 3.57) in the carbetocin group. We did not identify any published reports of trials comparing oxytocin and carbetocin, each istered IM for AMTSL, in low-risk term vaginal deliveries. Recommendations 6. Carbetocin, 100 mg given as an IV bolus over 1 minute, should be used instead of continuous oxytocin infusion in elective Caesarean section for the prevention of PPH and to decrease the need for therapeutic uterotonics. (I-B) 7. For women delivering vaginally with 1 risk factor for PPH, carbetocin 100 mg IM decreases the need for uterine massage to prevent PPH when compared with continuous infusion of oxytocin. (I-B) Misoprostol

Misoprostol is a prostaglandin that has generated considerable interest as an effective uterotonic agent owing to its ease of istration, safety profile, cost, and ease of storage. The first study of misoprostol as a uterotonic agent was an uncontrolled prospective study for prevention of PPH.25 A systematic review26 that analyzed the pharmacokinetics of misoprostol concluded the following: • There is a shorter time to peak concentration with oral and sublingual istration than with vaginal or rectal istration. • Sublingual istration results in the most rapid onset of effects and the highest peak concentration. • The initial increase in tonus is more pronounced after oral than after vaginal istration. OCTOBER JOGC OCTOBRE 2009 l

985

SOGC CLINICAL PRACTICE GUIDELINE

• The effects have a slower onset but longer duration with rectal and vaginal routes than with oral and sublingual routes. • Pyrexia is more common when the dose exceeds 600 mg. There have been 3 systematic reviews of the use of misoprostol for the prevention of PPH.27–29 The WHO multicentre trial30 and the Cochrane review27 suggested that the observed lesser efficacy of misoprostol compared with injectable uterotonics may be due to the later achievement of peak plasma levels with oral and sublingual istration of misoprostol: 30 minutes versus 1 to 2 minutes for IM or IV istration of oxytocin. All of the reviews concluded that misoprostol was not as effective as oxytocin for the prevention of PPH and that maternal pyrexia was a significant adverse effect. A 2007 study comparing 800 mg of misoprostol istered rectally with 10 IU of oxytocin istered IM in a developing country found these 2 agents to be equally effective in minimizing blood loss during the third stage of labour.31 There was more pyrexia in the misoprostol group, however. The systematic review by Joy and colleagues29 compared the efficacy of misoprostol with that of oxytocin, other uterotonic agents, and placebo in preventing PPH in the third stage of labour. Compared with placebo, misoprostol was associated with a decreased need for additional uterotonics (OR 0.64; 95% CI 0.46 to 0.90) and an increased risk of shivering and pyrexia. Oxytocin was superior to misoprostol in preventing blood loss and the need for additional agents, and the patients had less shivering and pyrexia. The authors proposed that misoprostol is a reasonable agent for management of the third stage of labour when other agents are not available for reasons of cost, storage, or difficulty of istration. There have been no studies to determine the benefit of a combination of oxytocin and misoprostol compared with either agent alone. Recommendation 8. Ergonovine, 0.2 mg IM, and misoprostol, 600 to 800 mg given by the oral, sublingual, or rectal route, may be offered as alternatives in vaginal deliveries when oxytocin is not available. (II-1B)

25% to 60% of the fetal–placental circulation is found in the placental circulation.33,34 Early cord clamping in term newborns results in a decrease of 20 to 40 mL/kg of blood, which is equivalent to 30 to 35 mg of iron. A delay in clamping, causing increased neonatal blood volume, may lead to complications such as respiratory distress, neonatal jaundice, and polycythemia. Prendiville and colleagues’ meta-analysis espousing the benefit of AMTSL8 included studies that applied early cord clamping, controlled traction, and uterotonics before delivery of the placenta. In these studies, early cord clamping was included as part of controlled traction and was not independently studied to demonstrate a benefit. A 2004 Cochrane Review by Rabe et al.35 and a prospective study by Ibrahim et al.36 demonstrated that delaying cord clamping by 30 to 120 seconds resulted in less need for transfusion because of anemia (RR 2.01; 95% CI 1.24 to 3.27) and less intraventricular hemorrhage (RR 1.74; 95% CI 1.08 to 2.81) in nonresuscitated premature infants (< 37 weeks’ gestation). A systematic review and meta-analysis comparing cord clamping done early (less than 1 minute after delivery of the infant) and late (at least 2 minutes after delivery) showed that late clamping conferred physiological benefit to the newborn that extended up to 6 months into infancy.37 Advantages included prevention of anemia over the first 3 months of life and enhanced iron stores (weighted mean difference 19.90; 95% CI 7.67 to 32.13) and ferritin concentration (weighted mean difference 17.89; 95% CI 16.58 to 19.21) for up to 6 months. There was no increase in respiratory distress, defined as tachypnea or grunting. Neonates were at increased risk of asymptomatic polycythemia (RR 3.82; 95% CI 1.11 to 13.21). There was no significant difference between the early and late groups in bilirubin levels and proportions of infants receiving phototherapy. A 2008 Cochrane review included 11 RCTs that compared the effect on maternal and neonatal outcomes of cord clamping done early (up to 60 seconds after delivery) and late (beyond 60 seconds after delivery).38 The results showed no difference in the incidence of PPH but an increased incidence of neonatal jaundice requiring phototherapy, higher newborn hemoglobin levels up to 6 months of age, and higher ferritin levels at 6 months of age after late clamping.

Management of the Placenta

Recommendations

Timing of cord clamping

9. Whenever possible, delaying cord clamping by at least 60 seconds is preferred to clamping earlier in premature newborns (< 37 weeks’ gestation) since there is less intraventricular hemorrhage and less need for transfusion in those with late clamping. (I-A)

Clamping of the umbilical cord is a necessary part of the third stage of labour. Its timing varies widely throughout the world, early clamping being the predominant practice in Western countries.32 Physiological studies have shown that 986

l OCTOBER JOGC OCTOBRE 2009

Active Management of the Third Stage of Labour: Prevention and Treatment of Postpartum Hemorrhage

10. For term newborns, the possible increased risk of neonatal jaundice requiring phototherapy must be weighed against the physiological benefit of greater hemoglobin and iron levels up to 6 months of age conferred by delayed cord clamping. (I-C) Timing of placental delivery

Placental delivery is essential to allow the uterus to contract and thus reduce blood loss in the third stage of labour. This process is completed within 5 minutes in 50% of deliveries and by 15 minutes in 90%. Failure of the placenta to be delivered in such a timely manner is a well-known risk factor of PPH.39,40 The traditional definition of retained placenta includes failure of placental delivery within 30 to 45 minutes and a requirement of intervention to assist with delivery. One study published in 2006 concluded that the risk of PPH increases if the placenta has not been delivered by 10 minutes, although research is needed to determine if the risk of PPH can be reduced by intervening at this stage.41 Recommendation 11. There is no evidence that, in an uncomplicated delivery without bleeding, interventions to accelerate delivery of the placenta before the traditional 30 to 45 minutes will reduce the risk of PPH. (II-2C) Placental cord drainage

Drainage of cord blood has been proposed to assist with delivery of the placenta. A 2005 Cochrane review42 included only 2 studies addressing this intervention, which makes it difficult to draw conclusions. The selection criteria for the review were low-risk vaginal deliveries in which a cord clamped within 30 seconds of delivery and separated was unclamped, which allowed the blood from the placenta to drain freely. The measured outcomes included incidence of retained placenta (at 30 to 45 minutes), manual removal of the placenta, PPH, length of the third stage of labour, need for blood transfusion, decrease in maternal hemoglobin level, and maternal pain. The outcomes reported were a decreased incidence of retained placenta at 30 minutes (RR 0.28; 95% CI 0.10 to 0.73) and a shorter third stage (weighted mean difference –5.46; 95% CI –8.02 to –2.90) after cord drainage. A major confounding factor was the lack of use of uterotonics and the varied definition of a prolonged third stage: from 30 to 45 minutes. Sharma et al.43 randomly assigned 958 women to either placental cord drainage or controlled traction after istration of 0.2 mg of ergonovine with delivery of the anterior shoulder and immediate cord clamping. Measured outcomes were PPH and length of the third stage. The third stage had a mean duration of 3.24 and 3.20 minutes in the

drainage group versus 8.57 and 6.20 minutes in the traction group in primigravid (P < 0.05) and multigravid (P < 0.05) women, respectively. There was no significant difference between the groups in the incidence of blood loss > 500 mL and the need for transfusion (P > 0.05), and none of the women had a retained placenta. The limited number of studies makes it difficult to recommend a change in practice to routine cord drainage, but this intervention does appear to reduce the length of the third stage of labour and the risk of a retained placenta. More research is required to determine if the length of the third stage is reduced with routine drainage after the use of uterotonics and if this intervention reduces the risk of PPH. Recommendation 12. Placental cord drainage cannot be recommended as a routine practice since the evidence for a reduction in the duration of the third stage of labour is limited to women who did not receive oxytocin as part of the management of the third stage. There is no evidence that this intervention prevents PPH. (II-1C) Injection of the umbilical vein

Injection of the umbilical vein has been proposed to assist in uterine contractions and dehiscence of the placenta from the uterine wall to effect delivery. If successful, this intervention would avoid manual removal of the placenta, an invasive procedure with potential complications, including hemorrhage, infection, and trauma. A 2001 Cochrane Review44 assessed if injection of various agents would reduce the need for manual removal of a retained placenta. The authors derived the following conclusions. • Saline versus expectant management: no difference (RR 0.97; 95% CI 0.83 to 1.14). • Saline plus oxytocin versus expectant management: nonsignificant reduction in the incidence of manual removal (RR 0.86; 95% CI 0.72 to 1.01) with the use of saline plus oxytocin. • Saline plus oxytocin versus saline: significantly lower incidence of manual removal of the placenta (RR 0.79; 95% CI 0.69 to 0.91) (number needed to treat: 8; 95% CI 5 to 20) with the use of saline plus oxytocin. • Saline plus oxytocin versus plasma expander: nonsignificantly greater incidence of manual removal of the placenta (RR 1.34; 95% CI 0.97 to 1.85) with the use of saline plus oxytocin. • Saline plus prostaglandin versus saline: significantly lower incidence of manual removal of the placenta (RR 0.05; 95% CI 0.00 to 0.73) with the use of saline plus prostaglandin but no difference in the incidence of blood loss, fever, pain, and oxytocin augmentation. OCTOBER JOGC OCTOBRE 2009 l

987

SOGC CLINICAL PRACTICE GUIDELINE

Figure 1. Pipingas technique for injection of the intraumbilical vein if the placenta has not separated or delivered within 45 minutes after delivery of the baby • Prepare a syringe of misoprostol (800 mg) or oxytocin (50 IU) dissolved in 30 mL of normal saline. • Insert a size 10 nasogastric suction catheter along the umbilical vein. If resistance is felt, retract the catheter 1 to 2 cm and advance it further, if possible. If the catheter cannot be advanced further without force, inject the solution in this position. • If most of the catheter has been inserted when resistance is felt, indicating that it has reached the placenta, retract it 3 to 4 cm to ensure that the tip is in the umbilical vein and not in a placental branch. • Connect the syringe to the catheter and inject the solution. Clamp the catheter in situ and record the time of the injection. • Allow 30 minutes for the placenta to deliver before undertaking further intervention.

• Saline plus prostaglandin versus saline plus oxytocin: no difference (RR 0.10; 95% CI 0.01 to 1.59). This review suggests that umbilical vein injection of uterotonics assists with the third stage of labour but provides no convincing evidence of the benefit; the last 3 conclusions were based on the results of a single small trial. The authors conclude that umbilical vein injection of oxytocin may reduce the need for manual removal of a retained placenta, but further investigation is required. There is an ongoing systematic review to determine if routine injection of the umbilical vein with a uterotonic within 15 minutes of birth will affect perinatal and maternal outcomes.45 An RCT compared the effect of intraumbilical vein injection of Syntocinon (synthetic oxytocin; 50 IU in 30 mL of normal saline), misoprostol (800 mg in 30 mL of normal saline), or normal saline (30 mL) on the need for manual removal of the placenta in a prolonged third stage of labour in 87 low-risk women at term.46 The Pipingas technique (Figure 1) was used for injection. All the women had AMTSL with either oxytocin or Syntometrine with delivery of the anterior shoulder, early cord clamping, and cord traction when signs of placental separation were observed. The women whose third stage exceeded 30 minutes were randomly assigned to intervention at 45 minutes with 1 of the 3 injections. The trial was stopped when the misoprostol group had many fewer instances of manual removal of the placenta (9 of 21 women) compared with the Syntocinon group (16 of 20 women) and the saline group (7 of 13 women). Recommendation 13. Intraumbilical cord injection of misoprostol (800 mg) or oxytocin (10 to 30 IU) can be considered as an alternative intervention before manual removal of the placenta. (II-2C) TREATMENT OF ESTABLISHED PPH

Research has shown that care providers poorly estimate blood loss7 and consistently underestimate the loss of a 988

l OCTOBER JOGC OCTOBRE 2009

large volume of blood.43 Clinical signs and symptoms (Table 2) are useful bedside indicators of ongoing blood loss and will assist clinicians in management. A previously established plan of action is of great value when preventive measures have failed. This plan should include aggressive fluid resuscitation, control of bleeding to minimize loss, and access to a surgical room and personnel (Table 4). The initial goal of management is to determine the cause of blood loss while instituting resuscitative measures. Evaluation of uterine tone and a complete inspection of the lower genital tract are required. The goal of resuscitative measures is to maintain hemodynamic stability and oxygen perfusion of the tissues. An IV infusion of crystalloid solution should be instituted, using large-bore tubing, along with oxygen supplementation. The “ABCs” should be observed and vital signs, oxygen saturation, and urinary output monitored. A visual assessment of clotting can be done at the bedside while blood is sent for analysis and matching for transfusion. PPH emergencies often occur unexpectedly and, depending on the volume of deliveries in each institution, may be infrequent. When a situation does not resolve with the usual interventions, there is a need for more equipment that may not be readily available when needed. For these reasons, every obstetric unit should have a readily available tray with all of the necessary equipment. Since clinicians may rarely apply these interventions, this equipment should be accompanied by appropriate diagrams illustrating the relevant anatomy and technique. A previously prepared PPH tray in a large Canadian birthing centre was used in 1 in 250 Caesarean sections and 1 in 1000 vaginal deliveries.47 Recommendations 14. For blood loss estimation, clinicians should use clinical markers (signs and symptoms) rather than a visual estimation. (III-B) 15. Management of ongoing PPH requires a multidisciplinary approach that involves maintaining hemodynamic stability while simultaneously identifying and treating the cause of blood loss. (III-C)

OCTOBER JOGC OCTOBRE 2009 l

Uterine fundus not felt abdominally OR visible vaginally

Excess bleeding or shock shortly after birth, uterus contracted

Placenta not separated or partially separated (with or without hemorrhage)

Uterus soft and relaxed

Clotting

Uterine inversion

® Laparotomy:

Uterine rupture

• Treat accordingly with blood products

Clotting disorder

® Correct inversion in theatre under general anaesthesia

• Hysterectomy

• Primary repair

® Repair tears in perineum, vagina and cervix

• Gentle curettage

• Manual exploration

• Manual vacuum aspiration

Incomplete separation

• Intraumbilical vein injection

• Controlled cord traction

• Uterotonics

Whole placenta in uterus

Uterotonic drugs

Uterine massage

Directed therapy

Low genital tract trauma

Retained placenta

Uterine atony

Assess etiology

If nonsurgical correction fails, ensure that uterus remains contracted by continued oxytocin infusion

Manual removal

Placenta still retained

• Balloon (condom) tamponade

• Uterine packing

• External aortic compression

• Bimanual uterine compression

Nonsurgical uterine compression

If bleeding continues

Adapted with permission of the World Health Organization from Postpartum Hemorrhage Technical Consultation Meeting Document55

• Blood grouping and cross

• Coagulation screen

• Complete blood count

Laboratory tests

• Empty bladder, monitor urine output

• Monitor BP, P, R

• Crystalloid, isotonic fluid replacement

• IV line

• Oxygen by mask

• Assess the “ABC”

Resuscitation

Call for help

Initial assessment and treatment for primary PPH

Table 4. Treatment of PPH

Hysterectomy

Correction via laparotomy

Surgery

Hysterectomy

Hysterectomy

Partial or complete removal of placenta through laparotomy

Placenta still retained (placenta accreta)

Uterine artery embolization

• Cho square

• Vertical compression Hysterectomy (subtotal or total)

Artery ligation (uterine, hypogastric)

Compression sutures • B-Lynch

If bleeding continues

If bleeding continues

Active Management of the Third Stage of Labour: Prevention and Treatment of Postpartum Hemorrhage

989

SOGC CLINICAL PRACTICE GUIDELINE

16. All obstetric units should have a regularly checked PPH emergency equipment tray containing appropriate equipment. (II-2B) Uterine Massage and Additional Uterotonic istration

Since the most common cause of PPH is uterine atony, the clinician’s initial efforts should be directed at preventing ongoing blood loss by performing the initial basic maneuvres of uterine massage and istering additional uterotonics, which include the following. 1. Oxytocin • 10 IU IM. Consider ability of the medication to reach a uterus with poor tissue perfusion. • 5 IU IV push • 20 to 40 IU in 250 mL of normal saline, infused IV at an hourly rate of 500 to 1000 mL. 2. 15-methyl prostaglandin (carboprost tromethamine [Hemabate])

• 250 mg IM or intramyometrially • Can be repeated every 15 minutes to a maximum of 2 mg (8 doses). • Asthma is a relative contraindication. 3. Carbetocin

• 100 mg IM or IV over 1 minute • Shown to reduce bleeding due to uterine atony in Caesarean sections but not low-risk vaginal deliveries. 4. Misoprostol (off-label use not approved for PPH by Health Canada)

• 400 to 800 mg. Onset of effects is faster with oral or sublingual than with rectal istration. • 800 to 1000 mg. Effects are longer lasting with rectal than with oral istration. • Higher incidence of pyrexia with oral than with rectal istration. 5. Ergonovine • 0.25 mg IM or IV, can be repeated every 2 hours • Contraindicated in women with hypertension and those taking certain drugs (e.g., proteases for HIV infection). 6. Recombinant activated factor VII • Has been used in women with massive PPH but in a limited number of studies, all without randomization. • A review by Franchini et al.48 suggests a potential role, although further research is required to determine this agent’s role and benefit. 990

l OCTOBER JOGC OCTOBRE 2009

Recommendation 17. Evidence for the benefit of recombinant activated factor VII has been gathered from very few cases of massive PPH. Therefore this agent cannot be recommended as part of routine practice. (II-3L) Tamponade

The quickest method of tamponade is with bimanual compression of the uterus. One hand is placed over the uterus externally; the other is placed in the vagina to apply pressure on the lower segment. Consistent compression with the 2 hands results in external compression of the uterus to reduce blood flow. This can be continued until further measures are taken or assistance arrives. In the case of uterine atony, the following can be placed inside the uterus to provide direct compression of the uterine wall and thus decrease blood loss.

• Bakri SOS tamponade balloon catheter • Sengstaken Blakemore esophageal catheter • Foley catheter filled with 60 to 80 mL of sterile solution • Rusch hydrostatic urologic balloon • Hydrostatic condom catheter • Uterine packing All the above have been reported to be successful for the temporary control of active bleeding. The insertion technique for a balloon device is relatively simple and requires the operator to ensure that the entire balloon is positioned past the cervical canal. Once inserted, the balloon is filled with sterile solution until there is no further bleeding. After successful tamponade, continued oxytocin infusion may be required to maintain uterine tone. Prophylactic antibiotic therapy should be considered. The balloon can be left in place for 8 to 48 hours and then gradually deflated and removed. Uterine packing requires greater skill and experience to properly pack the uterus with enough gauze to control bleeding while avoiding trauma to the uterine wall. Other disadvantages include risk of infection, unrecognized bleeding with blood soaking the packing material, and the possible need for another surgical procedure to remove the material. Recommendation 18. Uterine tamponade can be an efficient and effective intervention to temporarily control active PPH due to uterine atony that has not responded to medical therapy. (III-L)

Active Management of the Third Stage of Labour: Prevention and Treatment of Postpartum Hemorrhage

Figure 2. B-Lynch technique for uterine compression sutures

Reproduced from B-Lynch et al52 with permission of the Royal College of Obstetricians and Gynaecologists.

Figure 3. Cho technique for uterine compression sutures

Reproduced from Cho et al53 with permission of the Royal College of Obstetricians and Gynaecologists.

OCTOBER JOGC OCTOBRE 2009 l

991

SOGC CLINICAL PRACTICE GUIDELINE

Radiologic Methods

Percutaneous transcatheter arterial embolization is an option when there is active bleeding in a hemodynamically stable woman and before surgical intervention.49 A review of the literature found success rates of 100% after 49 vaginal deliveries and 89% after 18 Caesarean sections. This technique preserves the uterus and adnexa and thus fertility. The procedure requires rapid access to imaging technology and interventional radiologists, which is not available to all centres. Surgical Methods

Ligation of the internal iliac artery was used to control intraoperative bleeding from cervical cancer before being applied to obstetric cases.50 A retrospective study found this technique to be useful for preventing PPH in women at high risk of hemorrhage and for treating PPH due to uterine atony or genital tract injury.51 The timing of this intervention is important: it must be done without delay, before excessive blood loss has occurred. Surgical skill is required to avoid failure and complications such as damage to other vascular structures and the ureters.

3. Subtil D, Sommé A, Ardiet E, Depret-Mosser S. [Postpartum hemorrhage: frequency, consequences in of health status, and risk factors before delivery]. J Gynecol Obstet Biol Reprod (Paris) 2004;33(8 Suppl):4S9–4S16. 4. Ramanathan G, Arulkumaran S. Postpartum haemorrhage. Curr Obstet Gynaecol 2006;16(1):6–13. 5. Kane TT, el-Kady AA, Saleh S, Hage M, Stanback J, Potter L. Maternal mortality in Giza, Egypt: magnitude, causes, and prevention. Stud Fam Plann 1992;23:45–57. 6. Maier RV. Approach to the patient with shock. In: Kasper DL, Braunwald E, Fauci AS, Ha SL, Longo DL, Jameson JL, editors. Harrison’s principles of internal medicine. 16th ed. New York: McGraw-Hill; 2004:1600–6. 7. Bose P, Regan F, Paterson-Brown S. Improving the accuracy of estimated blood loss at obstetric haemorrhage using clinical reconstructions. BJOG 2006;113:919–24. 8. Prendiville WJ, Elbourne D, McDonald S. Active versus expectant management in the third stage of labour. Cochrane Database Syst Rev 2000;(3):CD000007. 9. International Confederation of Midwives, International Federation of Gynaecologists and Obstetricians. t statement: management of the third stage of labour to prevent post-partum haemorrhage. J Midwifery Womens Health 2004;49:76–77. 10. World Health Organization. Recommendations for the Prevention of Postpartum Haemorrhage. Geneva: WHO; 2007. 11. Khan GQ, John IS, Wani S, Doherty T, Sibai BM. Controlled cord traction versus minimal intervention techniques in delivery of the placenta: a randomized controlled trial. Am J Obstet Gynecol 1997;177(4):770–4.

Uterine compression sutures, described by B-Lynch52 (Figure 2) and Cho53 (Figure 3), have the benefit of preserving the uterus. Both techniques involve external compression of the uterus to control bleeding, followed by application of sutures into and over the uterus. The sutures are tied down to maintain uterine compression and control further bleeding. A hysterotomy at the lower segment is required to ensure that there are no retained products that would prevent compression of the uterus and subsequent failure of pregnancy.

12. McDonald S, Abbott JM, Higgins SP. Prophylactic ergometrine–oxytocin versus oxytocin for the third stage of labour. Cochrane Database Syst Rev 2004;(1):CD000201.

Peripartum hysterectomy is indicated when massive hemorrhage has not responded to previous interventions and requires a surgical intervention familiar to surgeons. Indications include abnormal placentation (previa, accreta), atony, trauma, rupture, and sepsis. The disadvantage of peripartum hysterectomy is the loss of fertility in women who wish to continue childbearing.

16. Begley C. A comparison of ‘active’ and ‘physiological’ management of the third stage of labour. Midwifery 1990;6:3–17.

Recommendation 19. Surgical techniques such as ligation of the internal iliac artery, compression sutures, and hysterectomy should be used for the management of intractable PPH unresponsive to medical therapy. (III-B) REFERENCES 1. AbouZahr C. Global burden of maternal death and disability. Br Med Bull 2003;67:1–11. 2. Reynders FC, Senten L, Tjalma W, Jacquemyn Y. Postpartum hemorrhage: practical approach to a life-threatening complication. Clin Exp Obstet Gynecol 2006;33:81–4.

992

l OCTOBER JOGC OCTOBRE 2009

13. Cotter A, Ness A, Tolosa J. Prophylactic oxytocin for the third stage of labour. Cochrane Database Syst Rev 2001;(4):CD001808. 14. Nordstrom L, Fogelstam K, Fridman G, Larsson A, Rydhstroem H. Routine oxytocin in the third stage of labour: a placebo controlled randomised trial. Br J Obstet Gynaecol 1997;104:781–6. 15. Jackson KW Jr, Allbert JR, Schemmer GK, Elliot M, Humphrey A, Taylor J. A randomized controlled trial comparing oxytocin istration before and after placental delivery in the prevention of postpartum hemorrhage. Am J Obstet Gynecol. 2001 Oct;185(4):873–7.

17. Davies GA, Tessier JL, Woodman MC, Lipson A, Hahn PM. Maternal hemodynamics after oxytocin bolus compared with infusion in the third stage of labor: a randomized controlled trial. Obstet Gynecol 2005;105:294–9. 18. Thomas JS, Koh SH, Cooper GM. Hemodynamic effects of oxytocin given as IV bolus or infusion on women undergoing caesarean section. Br J Anaesth 2007;98;116–9. 19. Svanström MC, Biber B, Hanes M, Johansson G, Näslund U, Balfors EM. Signs of myocardial ischemia after injection of oxytocin: a randomized double-blind comparison of oxytocin and methylergometrine during caesarean section. Br J Anaesth 2008;100:683–9. 20. Dansereau J, Joshi AK, Helewa ME, Doran TA, Lange IR, Luther ER, et al. Double-blind comparison of carbetocin versus oxytocin in prevention of uterine atony after cesarean section. Am J Obstet Gynecol 1999;180(3 Pt 1):670–6. 21. Sweeney G, Holbrook AM, Levine M, Yip M, Alfredsson K, Cappi S, et al. Pharmacokinetics of a long-acting oxytocin analogue, in non-pregnant women. Curr Ther Res 1990;47:528–40. 22. Boucher M, Nimrod CA, Tawagi GF, Meeker TA, Rennicks White RE, Varin J. Comparison of carbetocin and oxytocin for the prevention of

Active Management of the Third Stage of Labour: Prevention and Treatment of Postpartum Hemorrhage

postpartum hemorrhage following vaginal delivery: a double-blind randomized trial. J Obstet Gynaecol Can 2004;26:481–8. 23. Su LL, Chong YS, Samuel M. Oxytocin agonists for preventing postpartum hemorrhage. Cochrane Database Syst Rev 2007;(3):CD005457. 24. Leung SW, Ng PS, Wong WY, Cheung TH. A randomized trial of carbetocin versus Syntometrine in the management of the third stage of labour. BJOG 2006;113:1459–64.

40. Combs CA, Laros RK. Prolonged third stage of labor; morbidity and risk factors. Obstet Gynecol 1991;77:863–7. 41. Magann EF, Doherty DA, Briery CM, Niederha A, Morrison JC. Timing of placental delivery to prevent post-partum haemorrhage: lessons learned from an abandoned randomised clinical trial. Aust N Z J Obstet Gynaecol 2006;46:549–51.

25. El-Refaey H, O’Brien P, Morafa W, Walder J, Rodeck C. Misoprostol for third stage of labour [letter]. Lancet 1996;347:1257.

42. Soltani H, Dickinson F, Symonds I. Placental cord drainage after spontaneous vaginal delivery as part of the management of the third stage of labour. Cochrane Database Syst Rev 2005;(4):CD004665.

26. Hofmeyr GJ, Walraven G, Gülmezoglu AM, Maholwana B, Alfirevic Z, Villar J. Misoprostol to treat postpartum haemorrhage: a systematic review. BJOG 2005;112:547–53.

43. Sharma JB, Pundir P, Malhotra M, Arora R. Evaluation of placental drainage as a method of placental delivery in vaginal deliveries. Arch Gynecol Obstet 2005;271:343–5.

27. Gülmezoglu AM, Forna F, Villar J, Hofmeyr GJ. Prostaglandins for prevention of postpartum haemorrhage. Cochrane Database Syst Rev 2004;(1):CD000494.

44. Carroli G, Bergel E. Umbilical vein injection for management of retained placenta. Cochrane Database Syst Rev 2001;(4):CD001337.

28. Villar J, Gülmezoglu AM, Hofmeyr GJ, Forna F. Systematic review of randomized controlled trials of misoprostol to prevent postpartum hemorrhage. Obstet Gynecol 2002;100:1301–12. 29. Joy SD, Sanchez-Ramos L, Kaunitz AM. Misoprostol use during the third stage of labor. Int J Gynaecol Obstet 2003;82:143–52. 30. Gülmezoglu AM, Villar J, Ngoc NT, Piaggio G, Carroli G, Adetoro L, et al. WHO multicentre randomised trial of misoprostol in the management of the third stage of labour. Lancet 2001;358:689–95. 31. Parsons SM, Walley RL, Crane JMG, Matthews K, Hutchens D. Rectal misoprostol versus oxytocin in the management of the third stage of labour. J Obstet Gynaecol Can 2007;29:711–8. 32. Morley G. Cord closure: Can hasty clamping injure the newborn? OBG Manage 1998;July:29–36. 33. Dixon LR. The complete blood count: physiologic basis and clinical usage. J Perinat Neonatal Nurs 1997;11:1–18. 34. Yao AC, Moinian M, Lind J. Distribution of blood between infant and placenta after birth. Lancet 1969;2:871–3. 35. Rabe H, Reynolds G, Diaz-Rossello J. Early versus delayed umbilical cord clamping in preterm infants. Cochrane Database Syst Rev 2004;(4):CD003248.

45. Nardin JM, Carroli G, Weeks a.d., Mori R. Umbilical vein injection for the routine management of third stage of labour [Protocol]. Cochrane Database Syst Rev 2006;(4):CD006176. 46. Rogers MS, Yuen PM, Wong S. Avoiding manual removal of placenta: evaluation of intra-umbilical injection of uterotonics using the Pipingas technique for management of adherent placenta. Acta Obstet Gynecol 2007;86:48–54. 47. Baskett TF. Surgical management of severe obstetrical hemorrhage: experience with an obstetrical hemorrhage equipment tray. J Obstet Gynaecol Can 2004;26:805–8. 48. Franchini M, Lippi G, Franchi M. The use of recombinant activated factor VII in obstetric and gynaecological haemorrhage. BJOG 2007;114:8–15. 49. Vedantham S, Goodwin SC, McLucas B, Mohr G. Uterine artery embolization: an underused method of controlling pelvic hemorrhage. Am J Obstet Gynecol 1997;176:938–48. 50. Kelly HA. Ligation of both internal iliac arteries for hemorrhage in hysterectomy for carcinoma uteri. Bull Johns Hopkins Hosp 1984;5:53. 51. Joshi V, Otiv SR, Majumder R, Nikam YA, Shrivastava M. Internal iliac artery ligation for arresting postpartum haemorrhage. BJOG 2007;114:356–61.

36. Ibrahim HM, Krouskop RW, Lewis DF, Dhanireddy R. Placental transfusion: umbilical cord clamping and preterm infants. J Perinatol 2000;20:351–4.

52. B-Lynch C, Coker A, Lawal AH, Abu J, Cowen MJ. The B-Lynch surgical technique for the control of massive postpartum haemorrhage: An alternative to hysterectomy? Five cases reported. Br J Obstet Gynaecol 1997;104:372–5.

37. Hutton EK, Hassan ES. Late vs early clamping of the umbilical cord in full-term neonates: systematic review and meta-analysis of controlled trials. JAMA 2007;297:1241–52.

53. Cho JH, Jun HS, Lee CN. Hemostatic suturing technique for uterine bleeding during cesarean delivery. Obstet Gynecol 2000;96(1):129–31.

38. McDonald SJ, Middleton P. Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes. Cochrane Database Syst Rev 2008;(2):CD004074.

54. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169(3):207–8.

39. Dombrowski MP, Bottoms SF, Saleh AA, Hurd WW, Romero R. Third stage of labor: analysis of duration and clinical practice. Am J Obstet Gynecol 1995;172:1279–84.

55. Mathai M, Gulmezoglu AM. Postpartum haemorrhage and retained placenta. WHO guideline. Geneva: World Health Organization;2009.

OCTOBER JOGC OCTOBRE 2009 l

993

SOGC CLINICAL PRACTICE GUIDELINE SOGC CLINICAL PRACTICE GUIDELINE

No. 214, September 2008

Guidelines for the Management of Pregnancy at 41+0 to 42+0 Weeks This guideline was prepared by the Clinical Practice Obstetrics Committee and reviewed by the Maternal Fetal Medicine Committee and reviewed and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Martina Delaney, MD, St. John’s NL Anne Roggensack, MD, Toronto ON CLINICAL PRACTICE OBSTETRICS COMMITTEE Dean C. Leduc, MD (Chair), Ottawa ON Charlotte Ballermann, MD, Edmonton AB Anne Biringer, MD, Toronto ON Martina Delaney, MD, St. John’s NL Loraine Dontigny, MD, Lasalle QC Thomas P. Gleason, MD, Edmonton AB Lily Shek-Yn Lee, RN, Vancouver BC Marie-Jocelyne Martel, MD, Saskatoon SK Valérin Morin, MD, Cap-Rouge QC Joshua Nathan Polsky, MD, Windsor ON Carol Rowntree, MD, Sundre AB Debra-Jo Shepherd, MD, Regina SK Kathi Wilson, RM, Ilderton ON Disclosure statements have been received from all of the committee.

Abstract Objective: To provide evidence-based guidelines for the management of pregnancy at 41+0 to 42+0 weeks. Outcomes: Reduction of perinatal mortality associated with Caesarean section at 41+0 to 42+0 weeks of pregnancy. Evidence: The Medline database, the Cochrane Library, and the American College of Obstetricians and Gynecologists and the Royal College of Obstetricians and Gynecologists, were searched Key Words: Labour, induction, postdates pregnancy, post-term pregnancy

for English language articles published between 1966 and March 2007, using the following key words: prolonged pregnancy, post-term pregnancy, and postdates pregnancy. The quality of evidence was evaluated and recommendations were made according to guidelines developed by the Canadian Task Force on Preventive Health Care. Recommendations 1. First trimester ultrasound should be offered, ideally between 11 and 14 weeks, to all women, as it is a more accurate assessment of gestational age than last menstrual period with fewer pregnancies prolonged past 41+0 weeks. (I-A) 2. If there is a difference of greater than 5 days between gestational age dated using the last menstrual period and first trimester ultrasound, the estimated date of delivery should be adjusted as per the first trimester ultrasound. (I-A) 3. If there is a difference of greater than 10 days between gestational age dated using the last menstrual period and second trimester ultrasound, the estimated date of delivery should be adjusted as per the second trimester ultrasound. (I-A) 4. When there has been both a first and second trimester ultrasound, gestational age should be determined by the earliest ultrasound. (I-A) 5. Women should be offered the option of membrane sweeping commencing at 38 to 41 weeks, following a discussion of risks and benefits. (I-A) 6. Women should be offered induction at 41+0 to 42+0 weeks, as the present evidence reveals a decrease in perinatal mortality without increased risk of Caesarean section. (I-A) 7. Antenatal testing used in the monitoring of the 41- to 42-week pregnancy should include at least a non-stress test and an assessment of amniotic fluid volume. (I-A) 8. Each obstetrical department should establish guidelines dependent on local resources for scheduling of labour induction. (I-A) J Obstet Gynaecol Can 2008;30(9):800–810

INTRODUCTION

he World Health Organization defines a post-term pregnancy as one that has extended to or beyond 42 weeks (294 days) of gestation.1 In 1997, the SOGC published clinical practice guidelines recommending that women with an uncomplicated pregnancy who reach 41 to 42 weeks’ gestation should be offered elective delivery.2

T

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

800

l SEPTEMBER JOGC SEPTEMBRE 2008

Guidelines for the Management of Pregnancy at 41+0 to 42+0 Weeks

Sue-A-Quan et al. undertook a Canadian study to examine trends over time in the rates of induction in post-term pregnancies.3 The proportion of births occurring at 41 weeks’ gestation increased significantly from 11.9% in 1980 to 16.3% in 1995, and the proportion of births occurring at 42 weeks or more decreased significantly from 7.1% in 1980 to 2.9% in 1995. The authors reported that the rate of labour induction increased significantly between 1980 and 1995 among women delivering at 41 or more weeks’ gestation, which indicates that the guidelines are, for the most part, being followed. The stillbirth rate was also examined in the study by Sue-A-Quan and colleagues. Interestingly, the stillbirth rate among deliveries at 41 or more weeks’ gestation decreased significantly from 2.8/1000 total births in 1980 to 0.9/1000 total births in 1995 (P < 0.001). Concern about increased risk to the post-term (³ 42 weeks) fetus has existed since the early to mid 1900s.4 Increased PMRs for the post-term fetus have been reported in descriptive studies.4,5 However, these studies did not exclude all high-risk pregnancies or fetuses with congenital anomalies. Older descriptive studies that did correct for congenital anomalies did not find any difference in PMRs for post-term infants.6,7 More recent database studies have demonstrated an increasing risk of stillbirth with advancing gestational age.8–11 However, a Canadian database study did not demonstrate an increased post-term PMR.12 Other obstetrical and perinatal complications that were found to be higher in post-term pregnancies in these nonrandomized studies include fetal distress, non-progression, operative delivery (both operative vaginal and Caesarean), macrosomia, shoulder dystocia, low Apgar scores, and meconium aspiration.12–14 A linear decline of umbilical artery pH from term has also been described.15 Kitlinski et al.15 collected data on singleton pregnancies planned for vaginal delivery after 37 completed weeks. They defined acidemia as a pH < 7.10 and a gestational age-dependent acidemia as a pH < mean-2 SDs. Their data show that the mean umbilical cord arterial blood pH at birth decreases linearly with gestational age. The odds ratio trend curve for ABBREVIATIONS CI

confidence interval

CRL

crown–rump length

EDC

estimated date of conception

LMP

last menstrual period

NST

non-stress test

OR

odds ratio

PMR

perinatal mortality rate

RCT

randomized controlled trial

RR

relative risk

low pH according to the gestational age-dependent definition of < mean-2 SDs showed no linear association with gestational age but a significant increase after 42 weeks (OR 1.24; 95% CI 1.05–1.47). The odds ratio for pH < 7.10 among infants born after 41 weeks 3 days was also significant at 1.48 (95% CI 1.26–1.72). The RCT is the most reliable form of scientific evidence, as it is the best known design for eliminating biases that can compromise the validity of research. Controversy about the management of and the risks associated with the post-term pregnancy led to the performance of many RCTs designed to determine if induction before or at the start of the post-term period versus expectant management results in any difference in maternal or perinatal outcomes. This document updates the 1997 SOGC Guideline.2 Its recommendations refer only to otherwise uncomplicated pregnancies at 41 to 42 weeks’ gestation. This guideline reviews the following: 1. Interventions to decrease the incidence of pregnancy beyond 41+0 weeks. 2 . The evidence for induction of labour versus antenatal surveillance in an uncomplicated pregnancy at 41+0 to 42+0 weeks. 3. The role of antenatal fetal surveillance in the uncomplicated pregnancy at 41+0 to 42+0 weeks. Sources of information include Medline, the Cochrane Library, and guidelines from the American College of Obstetricians and Gynecologists and the Royal College of Obstetricians and Gynaecologists. The quality of evidence was evaluated and recommendations were made according to guidelines developed by the Canadian Task Force on Preventive Health Care (Table).16 INTERVENTIONS TO REDUCE PREGNANCY DURATION BEYOND 41+0 WEEKS Accurate Pregnancy Dating

Error is associated with pregnancy dating by LMP alone. If the gestational age is underestimated, prematurity may be misdiagnosed, and unnecessary obstetric interventions performed. However, overestimation of gestational age is more likely, increasing the risks of unnecessary induction of labour. Dating gestational age with LMP alone assumes both accurate recall of the LMP and ovulation on the 14th day of the menstrual cycle. Error in estimating LMP is due to inaccurate patient recall, maternal preference of date of LMP, and random error.17 The duration of the follicular phase is variable, ranging from 7 to 21 days. Sixty-eight percent of women originally dated at greater than 42+0 weeks by LMP SEPTEMBER JOGC SEPTEMBRE 2008 l

801

SOGC CLINICAL PRACTICE GUIDELINE

Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care Quality of Evidence Assessment*

Classification of Recommendations†

I:

A. There is good evidence to recommend the clinical preventive action

Evidence obtained from at least one properly randomized controlled trial

II-1: Evidence from well-designed controlled trials without randomization

B. There is fair evidence to recommend the clinical preventive action

II-2: Evidence from well-designed cohort (prospective or retrospective) or case-control studies, preferably from more than one centre or research group

C. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making

II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

D. There is fair evidence to recommend against the clinical preventive action E. There is good evidence to recommend against the clinical preventive action L. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making

*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.16 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the The Canadian Task Force on Preventive Health Care.16

were actually less advanced in gestational age when basal body temperature was used to determine the ovulation date.18 Delayed ovulation is an important cause of perceived prolonged pregnancy.19 Most pregnancies induced after 41+0 weeks are found not to be > 41+0 when ultrasound rather than LMP is used to date the pregnancy.20 Ultrasound biometry in the second trimester ultrasound is accurate for dating ± 10 days and is routinely used in the diagnosis of congenital anomalies. Biometry is most accurate if two or more parameters, such as biparietal diameter, abdominal circumference, and femur length, are used to estimate gestational age.21 Pregnancies noted to be term by second trimester ultrasound dating, but pregnancies post-term by LMP estimate do not have an increased risk of adverse fetal outcome.22 Induction of labour for post-term pregnancy is decreased when gestational age is estimated using second trimester biometry versus LMP alone.23–25 When pregnancies are dated from a second trimester ultrasound, delivery past 41+0 weeks occurs in 16.3%, compared with 6.7% dated from a first trimester ultrasound.26 Gestational age is most accurately determined by first trimester CRL, with an error estimated to be ± 5 days. In addition to accurate pregnancy dating, first trimester ultrasound allows for early diagnosis of missed abortion, ectopic pregnancy, multiple gestations, and limited assessment of fetal anatomy. A study involving 44 623 births in a Canadian tertiary centre demonstrated that the use of first trimester 802

l SEPTEMBER JOGC SEPTEMBRE 2008

ultrasound for dating significantly decreases the incidence of birth after 41+0 and 42+0 weeks of gestation. Different algorithms for combining LMP and CRL estimates were compared. The lowest rates for delivery at > 41+0 or > 42+0 weeks were seen with using early ultrasound alone for pregnancy dating (11.2% and 1.9%, respectively) and changing the EDC if the discrepancy was > 3 days between LMP and CRL (11.7% and 1.9%). These data are compared with the results of using LMP alone (20.9% and 6.4%) or changing the EDC if the discrepancy was > 14 days (16.9% and 3.5%).27 Bukowski et al.28 studied 3588 pregnancies in women with known LMP who had a first trimester ultrasound as part of the FASTER trial. When pregnancies were dated by the CRL rather than the LMP, pregnancies reaching ³ 41+0 were less frequent. The number of pregnancies at ³ 41+0 weeks (8.2% vs. 22.1%; [P < 0.001, RR 0.37; 95% CI 0.33–0.4]), and at ³ 42+0 weeks (1.6% vs. 12.7% [P < 0.001, RR 0.13; 95% CI 0.1–0.2]) at birth was significantly reduced when gestational age was determined by CRL, compared with determination of gestational age by LMP.28 Bennett et al.29 conducted an RCT of routine first trimester ultrasound and the rate of post-term induction in a low-risk obstetric population. Two hundred eighteen women were randomized to first trimester ultrasound (EDC changed if > 5 days different from LMP) or second trimester ultrasound (changed if > 10 days different from LMP dates) to determine the gestational age. Routine use of first trimester ultrasound demonstrated a statistically and

Guidelines for the Management of Pregnancy at 41+0 to 42+0 Weeks

clinically significant reduction in induction of labour for pregnancy ³ 41+0 from 13% to 5% (P = 0.04, RR 0.37; 95% CI 0.14–0.96). There was no difference between the two groups in induction of labour for other indications, mode of delivery, or neonatal outcomes.29 There are no studies investigating the cost-effectiveness of using first trimester ultrasound to decrease induction of labour between 41+0 and 42+0 weeks. Routine first trimester ultrasound reduces error in estimating gestational age and induction of labour between 41+0 and 42+0 weeks.30 Other benefits of early ultrasound include measurement of nuchal translucency,31 visualization of other markers of aneuploidy,32 and early diagnosis of some anatomical anomalies.33 Recommendations 1. First trimester ultrasound should be offered, ideally between 11 and 14 weeks, to all women, as it is a more accurate assessment of gestational age than last menstrual period with fewer pregnancies prolonged past 41+0 weeks. (I-A) 2. If there is a difference of greater than 5 days between gestational age dated using the last menstrual period and first trimester ultrasound, the estimated date of delivery should be adjusted as per the first trimester ultrasound. (I-A) 3. If there is a difference of greater than 10 days between gestational age dated using the last menstrual period and second trimester ultrasound, the estimated date of delivery should be adjusted as per the second trimester ultrasound. (I-A) 4. When there has been both a first and second trimester ultrasound, gestational age should be determined by the earliest ultrasound. (I-A) Sweeping of Fetal Membranes

Sweeping (or stripping) of membranes off the lower uterine segment has been reported since the 19th century and is believed to stimulate the onset of labour. During a vaginal examination, the fetal membranes are separated from the cervix and lower uterine segment as far as possible, sweeping a finger inserted through the cervical os 360º if possible. This procedure necessitates a sufficiently dilated cervix, usually representing a favourable Bishop score. When the cervix is closed, some clinicians attempt to stretch the cervix open or perform cervical massage. There are no trials comparing these different techniques. Sweeping results in the release of endogenous prostaglandins, softening the cervix and augmenting oxytocin-induced uterine contractions.34 Plasma prostaglandin concentrations after sweeping are 10% of those achieved in labour, thus possibly improving labour outcomes.35

Theoretical risks of membrane sweeping include chorioamnionitis, premature rupture of membranes, and bleeding from an undiagnosed placenta previa. However, in review of clinical trials, there was no increased incidence of fetal infection or neonatal morbidity related to the procedure. A small study did not find any increased colonization with group B streptococcus during membrane sweeping.36 Maternal morbidity is related mainly to significant discomfort or pain during procedure, bleeding, and contractions not leading to labour within 24 hours.37,38 In an RCT investigating indicated induction of labour at 39 weeks in conjunction with membrane sweeping, the beneficial effect of membrane sweeping was limited to nulliparous women with unfavourable Bishop scores. In this patient group, both the induction-to-labour interval and oxytocin use were decreased, and there was an increased rate of normal vaginal delivery.39 Weekly membrane stripping preceding induction of labour has similar effects.40 However, the need for an intervention (sweeping membranes) at 38 weeks to routinely shorten pregnancy has been widely questioned in the literature. The results of membrane sweeping are not predictable and should not be used alone for induction if the indication for induction is urgent. In several small trials, membrane stripping has been an effective outpatient method to reduce the number of patients with pregnancies exceeding 41+0.41–44 Again, membrane sweeping is generally most efficacious in nulliparous women with unfavourable Bishop scores. In a study by Berghella et al.,45 patients were randomized to weekly sweeping of membranes or gentle exams starting at 38 weeks. Time to delivery was significantly decreased with membrane stripping, and there were fewer pregnancies reaching past 41+0 weeks.45 Not all studies have noted a reduction in the need for post-term induction.46 A well-designed Canadian study enrolled patients at 38 to 40 weeks, and did not find any differences between a single membrane sweeping and routine examination with respect to onset of after 41 weeks or need for induction of labour.47 Multiple episodes of membrane sweeping may be more efficacious. There are no trials comparing single and multiple sweepings of the membranes. A recently published RCT by de Miranda et al.48 randomized 750 low-risk pregnant women from the Netherlands at 41 weeks’ gestational age to routine monitoring or membrane sweeping every two days until spontaneous labour or 42 weeks’ gestational age. Sweeping was defined as separating the lower membranes as much as possible from their cervical attachment, with three circumferential es of the examining fingers. If the cervix was closed, cervical massage was performed. Analysis was by intention-to-treat. Serial sweeping of the membranes decreased the risk of SEPTEMBER JOGC SEPTEMBRE 2008 l

803

SOGC CLINICAL PRACTICE GUIDELINE

pregnancy reaching 42+0 weeks (87/375 [23%] versus 149/367 [41%]); RR 0.57 [95% CI 0.46–0.71], NNT 6 [95% CI 4–12]).48 Benefits were noted in both nulliparous and multiparous patients. Uncomplicated vaginal bleeding was reported more frequently in the sweeping group (111/364 vs. 16/345, RR 6.58 [95% CI 3.98–10.87]). As well, 68% of treated women reported sweeping as “somewhat” to “very painful.” Of note, 88% of all women randomized to sweeping reported that they would chose sweeping in the next pregnancy, despite the discomfort. Obstetric outcomes and neonatal morbidity were similar between groups.48 A recent Cochrane review assessed 22 trials involving sweeping membranes. Sweeping of the membranes at term (38–41 weeks) reduced the frequency of pregnancies continuing after 41+0 weeks (RR 0.59; 95% CI 0.46–0.74) and after 42+0 weeks (RR 0.28; 95% CI 0.15–0.50). Eight women would need to undergo sweeping of membranes to prevent one induction of labour.38 Recommendation 5. Women should be offered the option of membrane sweeping commencing at 38 to 41 weeks, following a discussion of risks and benefits. (I-A) LABOUR INDUCTION VERSUS EXPECTANT MANAGEMENT AT 41 WEEKS

Nineteen trials randomizing women with uncomplicated pregnancies at 41 or more weeks’ gestation to induction or expectant management with surveillance were identified.49–67 A recently published trial randomized women at 41 weeks and two days of gestation to induction or expectant management; however, the authors do not specify if the pregnancies are uncomplicated.68 Two of these trials are reported as abstracts only.50,66 A trial in a Spanish journal was identified through the Cochrane Collaboration and was not reviewed for this document.65 Nine trials began enrolment at 41+0 weeks53,55,56,60–63,66,67 (two of these recruited at 41 weeks but did not randomize until 42 weeks);53,62 one trial at 41+2 weeks68; five trials at 41+3 weeks;49,50,52,54,64 two trials at 42+0 weeks;51,57 and two trials at 42+1 weeks.58,59 Dating was by various methods (menstrual cycle history, positive pregnancy tests, physical examination, and ultrasound) in each of the trials. Five trials did not use ultrasound assessment.49,54,57,59,63 It was unclear from one of the trials published only as an abstract if ultrasound was used.66 All trials reported perinatal mortality and delivery mode. Perinatal morbidities and other maternal outcomes were reported in variable detail. As the incidence of substantive outcomes, such as perinatal mortality and morbidity associated with post-term pregnancy are low, a large sample size would be required to detect a statistically significant difference between these two management methods. The largest 804

l SEPTEMBER JOGC SEPTEMBRE 2008

trial was a Canadian multi-centre trial enrolling 3407 women.60 The remainder of the trials had sample sizes ranging from 22 to 440.49–59,61–64,66–68 The Canadian trial randomized women at 41 or more weeks’ gestation to induction or to serial antenatal monitoring, with delivery indicated for non-reassuring fetal status, the development of obstetrical complications, or the attainment of 44 weeks’ gestation.60 Those assigned to the induction group were to have labour induced within four days after randomization. The primary outcome of the study was perinatal mortality and neonatal morbidity. The sample size was based on finding a reduction in the incidence of an Apgar score less than 7 at five minutes. The secondary outcome was the rate of Caesarean section. The authors concluded that there was no difference in the risk of perinatal mortality or neonatal morbidity between the two management schemes. There were two stillbirths in the monitored group and none in the induction group. The two groups did not differ significantly in the rate of neonatal morbidity. The frequency of fetal distress was lower in the induction group (10.3% vs. 12.8%, P = 0.017). The incidence of meconium staining of the amniotic fluid was significantly lower in the induction group (25% vs. 28.7%, P = 0.009). There was a statistically significant higher rate of Caesarean section among women who were monitored than among those induced (24.5% vs. 21.25%, P = 0.03; OR 1.22; 95% CI 1.02–1.45), and this difference was due to a lower rate of this procedure for fetal distress. There were limitations in this study’s methods. Prostaglandin E2 gel was not used in the monitoring group, as the authors felt there was insufficient evidence to use this preparation in the presence of fetal compromise, and they speculated that most of the women in this group requiring induction would have evidence of fetal compromise. They acknowledge that this could for the difference in the rate of Caesarean section. Also, this trial was not blinded, which introduces the potential for bias toward a higher Caesarean rate, as pregnancies are likely to be considered higher risk as they became further post-term. The authors conclude that labour induction in post-term pregnancies decreases the Caesarean rate but leads to no difference in the incidence of perinatal mortality and morbidity. As the authors of the Canadian trial point out, the perinatal mortality rate in their study was low at 0.6 per 1000. They reported that to detect a reduction of 50% in the perinatal mortality rate by inducing women with post-term pregnancy, approximately 30 000 women would need to be enrolled. Such a trial does not exist and for logistical reasons is likely not to be carried out. In the absence of such a trial, clinical practice relies on information from smaller trials and from systematic reviews.

Guidelines for the Management of Pregnancy at 41+0 to 42+0 Weeks

Three meta-analyses addressing labour induction versus expectant management of pregnancies at 41 weeks and beyond have been published.69–71 In 1993, Hannah69 published a review of the literature on post-term pregnancy. Included in this review was a meta-analysis of 11 randomized or quasi randomized trials in which a policy of routine induction at 41 weeks was compared with expectant management with serial fetal surveillance. A total of 5057 women were included in these trials. Methods of fetal surveillance and induction varied between the studies. Ten studies reported on probability of Caesarean and the results showed that inducing labour at ³ 41 weeks resulted in a significantly lower Caesarean section rate (OR 0.85; 95% CI 0.74–0.97). Inducing labour at ³ 41 weeks resulted in a lower rate of fetal distress, as defined by different authors, than expectant management (OR 0.81; 95% CI 0.68–0.97) and a lower rate of meconium staining of amniotic fluid (OR 0.79; 95% CI 0.69–0.90). Labour induction at ³ 41 weeks resulted in a lower rate of macrosomia (usually defined as birth weight < 4000 g) than expectant management (OR 0.80; 95% CI 0.69–0.92). Inducing labour at ³ 41 weeks resulted in a lower rate of fetal or neonatal death (excluding lethal congenital anomalies) than expectant management (OR 0.23; 95% CI 0.06–0.90). The reduction in perinatal death was largely due to a reduction in fetal death (OR 0.14; 95% CI 0.02–0.98). There was no difference in other measures of neonatal morbidity, such as small for gestational age, Apgar score < 7 at one minute, Apgar score < 7 at five minutes, shoulder dystocia, cord prolapse, neonatal seizures, birth trauma, ission to NICU, and meconium aspiration syndrome. The author concludes that the induction of labour groups are less likely to undergo delivery by Caesarean, to have an operative vaginal delivery, or to have fetal distress, macrosomic babies, or babies who die during the perinatal period. She states that women who reach 41 weeks should be appropriately counselled about the higher risks to themselves and to their babies if they pursue expectant management, and she suggests that a policy of labour induction is to be preferred. A meta-analysis published in 2003 compared routine labour induction with expectant management for patients at 41 weeks.70 Trials consisting of uncomplicated, singleton, live pregnancies were included. The primary outcomes assessed were perinatal mortality and Caesarean section. Sixteen trials enrolling 6588 subjects were included in the review.49–64 The trials differed in methods of antenatal fetal surveillance and means of labour induction. The meta-analysis showed that women who underwent labour induction had a significantly lower rate of Caesarean section (20.1% vs. 22%; OR 0.88; 95% CI 0.78–0.99). Those whose labour was induced

required Caesarean section secondary to fetal heart rate abnormalities at a significantly lower rate than those expectantly managed (6.2% vs. 8.0%; OR 0.77; 95% CI 0.61–0.96). Those whose labour was induced were less likely to have meconium staining of amniotic fluid (22.4% vs. 27.75; OR 0.75; 95% CI 0.66–0.84). Women whose labour was induced had a lower rate of perinatal mortality; however, this difference was not statistically significant (0.09% vs. 0.33%; OR 0.41; 95% CI 0.14–1.18). Other neonatal outcomes showed no significant differences and included meconium below the vocal cords, meconium aspiration, NICU issions, and Apgar scores < 7 at 5 minutes. The authors concluded that labour induction in women at 41 weeks’ gestation with otherwise uncomplicated pregnancies lowers the Caesarean rate without compromising perinatal outcomes. As the authors state, none of these 16 trials had adequate statistical power to assess the perinatal mortality rate. Even when combined in a meta-analysis, the statistical power for assessing this outcome remained low. They calculated that 16 000 women would need to be enrolled to detect a 50% reduction in the PMR rate of 3 per 1000 with routine labour induction, compared with expectant management at a power of 80% and allowing for a type I error of 5%. To detect an even smaller reduction in the PMR that would be clinically relevant, would require even more participants. The Cochrane Collaboration published a review in 2006 whose objective was to evaluate the benefits and harms of a policy of labour induction at term or post-term, compared with awaiting spontaneous labour or later induction of labour.71 Eligible trials were RCTs enrolling women at low risk. This review included three trials65–67 not in the meta-analysis by Sanchez-Ramos et al. and excluded three trials included in that review for methodological reasons.51,52,58 The review included 19 trials involving 7984 women undergoing induction of at various times from 38 to > 42 weeks’ gestation. The review grouped the trials by gestational age of induction at (1) 37 to 40 weeks, (2) 41 completed weeks, and (3) 42 completed weeks, and compared this with waiting until a later date for induction. Subgroup analyses were also done according to the condition of the cervix. In this document, results from the 41-week and the 42-week groups from 16 trials are reviewed.49,50,53–57,59–67 The primary outcome was perinatal mortality, which was defined as intrauterine deaths plus newborn deaths in the first week of life. Secondary infant and maternal outcomes were also assessed. Eleven trials intervened at or during the 41st completed week49,50,54–56,60,61,63,64,66,67 and five trials at or after 42 completed weeks.53,57,59,62,65 The relative risk of perinatal death in the 41st week group was 0.25 with 95% CI 0.05 to 1.18 (0/2835 vs. 6/2808), not statistically significant. When the 41- and 42-week groups were analyzed SEPTEMBER JOGC SEPTEMBRE 2008 l

805

SOGC CLINICAL PRACTICE GUIDELINE

together, the RR was 0.30 with 95% CI 0.09 to 0.99 (1/2986 vs. 9/2953), statistically significant. Labour induction significantly reduced the risk of meconium aspiration syndrome in the 41-week group (RR 0.29; 95% CI 0.12–0.68). In the 42-week group, fewer babies in the induction group had meconium aspiration syndrome, but the difference was not statistically significant (RR 0.66; 95% CI 0.24–1.81). There was no difference in neonatal intensive care issions. There was no evidence of an increased risk of Caesarean section for women induced at 41 and 42 weeks, respectively (RR 0.92; 95% CI 0.76–1.12; RR 0.97; 95% CI 0.72–1.31). There was no evidence of a statistically significant difference in the risk of assisted vaginal delivery for women induced at 41 and 42 completed weeks, respectively (RR 1.05; 95% CI 0.94–1.17; RR 0.95; 95% CI 0.65–1.38). Obstetric outcomes were also analyzed according to cervical status. This subgroup analysis was limited by the small number of trials reporting cervical status. No differences between a policy of labour induction and expectant management were identified for Caesarean section or assisted vaginal birth in these analyses. The reviewers did not produce a point estimate because of significant heterogeneity for these outcomes. The authors conclude in their discussion that routine labour induction at 41 completed weeks or later, compared with waiting for the onset of labour for at least one week is associated with fewer perinatal deaths and meconium aspiration syndrome. The absolute number of perinatal deaths was small in the induction group (1/3285, 0.03%) and in the expectant management group (11/3238, 0.33%). In this review, there was one stillbirth reported among the seven trials since 1992. Excluding congenital anomalies, there were no deaths in the labour induction group and nine deaths in the expectant management group. Regarding Caesarean rates, the authors acknowledge that the data are difficult to interpret because of heterogeneity among trials. This review also analyzed the data excluding the multicentre trial by Hannah et al., which did not use prostaglandins in the expectantly managed group,60 and reported that there did not seem to be a difference in Caesarean rates.” The authors state that the effect on Caesarean section is unclear, but the rate is not increased. With respect to fetal monitoring in the expectant arms, most trials included twice weekly non-stress tests and amniotic fluid index assessments, and the authors speculate that in centres that can offer these services, expectant management could be safely practised. In conclusion, the authors state that they think the results are valid and indicate beneficial outcomes with a policy of labour induction at 41 completed weeks. They acknowledge that the risk of the primary outcome (perinatal death) is small but that such a policy is associated with fewer perinatal deaths. They state that labour induction should be offered to women at low risk at 41 weeks and 806

l SEPTEMBER JOGC SEPTEMBRE 2008

that the pros and cons should be discussed so that women can make an informed decision. There does not seem to be any increased risk of Caesarean or assisted vaginal delivery with such a policy. The authors state that if a woman chooses to await spontaneous labour, regular fetal monitoring would be prudent as longitudinal epidemiological studies suggest that there is an increased risk of perinatal death with increasing gestational age. The evidence suggests that the rate of Caesarean section is either reduced or not increased when women are induced, compared with those expectantly managed.65,30,66 The three meta-analyses have different conclusions regarding the policy of labour induction on PMR. The Hannah review69 demonstrated a statistically significant lower PMR with induction at 41 weeks or more. The meta-analysis by Sanchez-Ramos et al. showed a lower PMR in the induced group, but it was not statistically significant.70 The most recent Cochrane review demonstrated a lower perinatal mortality rate for induction at 41 weeks and beyond.71 In this review, when the group induced at or during the 41st week was analyzed, the induced group had a lower PMR, but it did not reach statistical significance. However, even when these studies are combined in a meta-analysis, there is still low statistical power to assess this outcome. When the groups induced at or during the 41st and at or during the 42nd week were combined, the PMR was lower in those induced, just reaching statistical significance. If anything, it appears induction during the 41st week may decrease the PMR, but there are inadequate numbers of enrolled women to answer this question definitively. Given that induction does not increase the risk of Caesarean and that uncertainty remains regarding whether induction at 41 to 42 weeks decreases the PMR, it would seem reasonable to offer women induction in this gestational age range. A 2002 commentary on routine labour induction at 41 weeks’ gestation noted that aggregate data to that point showed that not all of the seven perinatal deaths in the expectantly managed groups occurred in women who received contemporary fetal testing, and it is questionable whether all causes were related to pregnancy duration.72 The stillbirth rate within the following week for women who remain undelivered at 41 weeks 0 days is about 0.1% (1.04–1.27 per 1000).72 Concern has been expressed that obstetricians have responded to the previous SOGC guideline by booking induction by one week past the expected due date.72 A proportion of women will labour spontaneously between 41 and 42 weeks. Provided there are no indications for delivery earlier, that fetal surveillance is employed and is reassuring, and if the patient chooses, induction at the latter end of this gestational age spectrum will maximize the chances of spontaneous labour. Each

Guidelines for the Management of Pregnancy at 41+0 to 42+0 Weeks

obstetrics department should establish guidelines dependent on their local resources for scheduling of labour inductions. Recommendation 6. Women should be offered induction at 41+0 to 42+0 weeks, as the present evidence reveals a decrease in perinatal mortality without increased risk of Caesarean section. (I-A) FETAL SURVEILLANCE IN THE 41 TO 42 WEEK PREGNANCY

Options for fetal surveillance include fetal movement counting, non-stress test, biophysical profile or modified biophysical profile (non-stress test plus amniotic fluid volume estimation), and contraction stress test. In each of the aforementioned randomized trials of labour induction, compared with expectant management of the post-term patient, some form of antenatal test of fetal well-being was used at varying frequencies.49–64,66–68 There is a paucity of data from randomized trials on the type and frequency of fetal surveillance in post-term pregnancy. There has been only one randomized trial on forms of antenatal testing in the post-term pregnancy.73 Alfirevic et al. randomized 145 women with singleton, uncomplicated pregnancies after 42 weeks to a modified biophysical profile defined as computerized cardiotocography, amniotic fluid index, and assessment of fetal breathing, tone, and gross body movements or to standard cardiotocography and maximum pool depth. Women were monitored at randomization and then twice weekly until 43 weeks. Outcome measures were cord pH at delivery, number of abnormal monitoring tests, intrapartum management, mode of delivery, and neonatal outcome. There were significantly more abnormal monitoring results in the modified biophysical group (47.2% vs. 20.5%; OR 3.5; 99% CI 1.3–9.1). Amniotic fluid volume was more likely to be labelled abnormal with amniotic fluid index than with maximum pool depth (44.4% vs. 15.1%; OR 4.5; 99% CI 1.6–12.8). There were no differences in cord blood gases, neonatal outcome, or outcomes related to labour and delivery between the two groups. These results suggest that monitoring pregnancies with their definition of a modified biophysical profile after 42 weeks does not improve pregnancy outcome as measured by cord pH; however, the number of patients included in this trial is insufficient to reach any definitive conclusions about the impact of fetal testing on outcomes in post-term pregnancies. There are no randomized trials regarding antepartum fetal testing between 41 and 42 weeks. The commencement of antenatal testing at 41 weeks’ gestation is ed by case-control studies. Guidetti et al.74 reported on 293

women at low risk who began twice weekly testing at 41 weeks’ gestation with an NST and amniotic fluid volume assessment. The control population consisted of 59 women at low risk delivered between 39 and 41 weeks’ gestation, who were referred for routine testing at term. The outcome parameters studied were abnormal NST, oligohydramnios, Caesarean section for fetal distress, Apgar score £ 6 at five minutes, NICU issions, and perinatal deaths. When the study group delivering at 41 to 42 weeks were compared with the control group, the former had a statistically significant increase in the incidence of abnormal NSTs, oligohydramnios, Caesarean section for fetal distress, and issions to the neonatal unit. When the study group who were delivered between 41 and 42 weeks were compared with those delivered after 42 weeks, the only significant difference was that the former had more abnormal NSTs. Bochner et al.75 compared neonatal outcomes of patients with antenatal fetal testing starting at 41 weeks’ gestation with patients who delivered between 41 and 42 weeks without testing and those who started testing at 42 weeks. All patients were at low risk. The study population consisted of 1260 women. Of these, 908 started testing at 41 weeks, and 352 started at 42 weeks. The control group consisted of 1807 women who delivered between 41 and 42 weeks without any antenatal testing. Antepartum testing consisted of twice weekly amniotic fluid assessment, NST, and contraction stress test when necessary. The total number of adverse outcomes in the untested group resulted in a significantly increased incidence of neonatal morbidity (seizures, apnea, pneumonia, severe meconium aspiration, or infection), compared with the tested group. Those who delivered after 42 weeks and whose testing started at 41 weeks had significantly fewer abnormal antepartum testing results leading to labour induction and Caesarean sections due to fetal distress than whose testing started at 42 weeks. The group whose testing started at 42 weeks had a significantly greater incidence of fetal distress. Despite the lack of evidence from RCTs that antenatal testing improves perinatal outcome in uncomplicated pregnancies at 41 to 42 weeks’ gestation, most practitioners utilize some form of monitoring in this clinical situation. The randomized trials comparing labour induction with expectant management at 41 weeks and beyond have included fetal assessment.49–64,66–68 For most trials, those women who were randomized to induction did not undergo antenatal surveillance. In eight trials, however, fetal assessment was carried out before patients were eligible for study enrolment, and they therefore had some type of fetal surveillance between 41 and 42 weeks.51,53,55,56,61,62,67,68 Therefore, for some pregnancies, fetal surveillance started at 41 weeks and for others at 42 weeks. For some women, fetal monitoring was started at 41 weeks but only if they were randomized to SEPTEMBER JOGC SEPTEMBRE 2008 l

807

SOGC CLINICAL PRACTICE GUIDELINE

expectant management. Those randomized to expectant management underwent fetal surveillance of various types and at various intervals from randomization to delivery. Most studies carried out fetal testing at least twice per week. Twelve studies included assessment of amniotic fluid volume and an NST for women randomized to expectant management.50,52,55,56,60–64,66–68 The Canadian trial, which is the largest, utilized amniotic fluid volume two to three times per week, NST three times weekly, and daily fetal movement counts.60 A reasonable approach would be at least an NST and some type of amniotic fluid assessment twice weekly. The American College of Obstetrician and Gynecologists have a Level C recommendation (consensus and expert opinion) for initiation of fetal surveillance between 41 and 42 weeks because of evidence that perinatal morbidity and mortality increase as gestational age advances and that a twice weekly assessment of amniotic fluid and a NST should be adequate.76 The Royal College of Obstetricians and Gynaecologists recommends increased antenatal surveillance consisting of a twice weekly NST and an ultrasound estimation of maximum amniotic pool depth from 42 weeks in women who decline labour induction.77 Recommendations 7. Antenatal testing used in the monitoring of the 41- to 42-week pregnancy should include at least a non-stress test and an assessment of amniotic fluid volume. (I-A) 8. Each obstetrical department should establish guidelines dependent on local resources for scheduling of labour induction. (I-A) REFERENCES 1. International Statistical Classification of Diseases and Related Health Problems, 10th revision. Geneva (CH): World Health Organization, 2006. 2. Mary Hannah M, and the Maternal-Fetal Medicine Committee of the Society of Obstetricians and Gynaecologists of Canada. Post-term pregnancy. SOGC Clinical Practice Guideline No. 15, March 1997. Available at: http://www.sogc.org//guide/library_e.asp. Accessed July 9, 2008. 3. Sue-A-Quan AK, Hannah ME, Cohen MM, Foster GA, Liston RM. Effect of labour induction on rates of stillbirth and cesarean section in post-term pregnancies. CMAJ 1999;160:1145–9. 4. McClure Browne JC. Postmaturity. Am J Obstet Gynecol 1963; 85(5):573–82. 5. Votta RA, Cibils LA. Active management of prolonged pregnancy. Am J Obstet Gynecol 1993; 168:557–63. 6. Evans TN, Koeff ST, Morley GW. Fetal effects of prolonged pregnancy. Am J Obstet Gynecol 1963; 85(6)701–09. 7. Eden RD, Seifert LS, Winegar A, Spellacy WN. Perinatal characteristics of uncomplicated postdates pregnancies. Obstet Gynecol 1987; 69:296–99.

10. Hilder L, Costeloe K, Thilaganathan B. Prolonged pregnancy: evaluating gestation-specific risks of fetal and infant mortality. Br J Obstet Gynecol 1998;105:169–73. 11. Cotzias CS, Paterson-Brown S, Fisk N. Prospective risk of unexplained stillbirth in singleton pregnancies at term: population based analysis. Br Med Journal 1999;319:287–88. 12. Usher RH, Boyd ME, McLean FH, Kramer MA. Assessment of fetal risk in postdate pregnancies. Am J Obstet Gynecol 1988;158:259–64. 13. Treger M, Hallak M, Silberstein T, Friger M, Katz M, Mazor M. Post-term pregnancy: should induction of labor be considered before 42 weeks? J Matern Fetal Med 2002;11:50–3. 14. Olesen AW, Westergaard JG, Olsen J. Perinatal and maternal complications related to postterm delivery: a national -based study, 1978–1993. Am J Obstet Gynecol 2003;189:222–7. 15. Kitlinski ML, Kallen K, Marsal K, Olofsson P. Gestational age-dependent reference values for pH in umbilical cord arterial blood at term. Obstet Gynecol 2003;102:338–45. 16. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169(3):207–8. 17. Savitz D, Terry JW, Dole N, Thorp JM, Siega-Riz AM, Herring AH. Comparison of pregnancy dating by LMP, ultrasound scanning, and their combination. Am J Obstet Gynecol 2002;187:1660–6. 18. Boyce A, Mayaux M, Schwartz. Classical and true gestational postmaturity. Am J Obstet Gynecol 1970;106:676–9. 19. Saito M, Keijiro Y, Akinori H, Takahiro K, Nozumu N, Kohei K. Time of ovulation and prolonged pregnancy. Am J Obstet Gynecol 1976;112:31–8. 20. Gardosi J, Vanner T, Francis A. Gestational age and induction of labour for prolonged pregnancy. Br J Obstet Gynaecol 1997;104(7):792–7. 21. Hadlock FP, Deter RL, Harrist RB, Seung K, Park MD. Computer-assisted analysis of fetal age in the third trimester using multiple fetal growth parameters. J Clin Ultrasound 1988;11:313–6. 22. Tunon K, Eik-Nes S, Grotten P. Fetal outcome in pregnancies defined as postterm according to the LMP estimate, but not according to the ultrasound estimate. Ultrasound Obstet Gynecol 1999;14:12–6. 23. Waldenstrom U, Axelsson O, Nilsson S, Gunnar E, Fall O, Lindeberg S, et al. Effects of routine one-stage ultrasound screening in pregnancy: a randomized controlled trial. Lancet 1988;2:585–8. 24. Saari-Kemppainen A, Karjalainen O, Ylostalo P, Heinonen OP. Ultrasound screening and perinatal mortality: controlled trial of systematic one-stage screening in pregnancy. The Helsinki Ultrasound Trial. Lancet 1990;336:387–91. 25. Ewigman BG, Crane JP, Frigoletto FD, LeFevre ML, Bain RP, McNellis D. Effect of prenatal ultrasound screening on perinatal outcome. N Engl J Med 1993;329:821–7. 26. Kramer MS, McLean F, Boyd ME, Usher RH. The validity of gestational age estimation by menstrual dating in term, preterm, and postterm gestations. JAMA 1988;260:3306–8. 27. Blondel B, Morin I, Platt RW, Kramer MS, Usher R, Breart G. Algorithms for combining menstrual and ultrasound estimates of gestational age: consequences for rates of preterm and postterm birth. BJOG 2002;109:718–20.

8. Feldman GB. Prospective risk of stillbirth. Obstet Gynecol 1992; 79:547–53.

28. Bukowski R, Saade G, Malone F, Hankins G, D’Alton M. A decrease in postdates pregnancies in an additional benefit of first trimester screening for aneuploidy. Am J Obstet Gynecol 2001;185(suppl):S148.

9. Smith GCS. Life-table analysis of the risk of perinatal death at term and post term in singleton pregnancies. Am J Obstet Gynecol 2001;184:489–96.

29. Bennett KA, Crane JMG, O’Shea P, Lacelle MD, Hutchens D, Copel J. First trimester ultrasound screening is effective in reducing postterm induction

808

l SEPTEMBER JOGC SEPTEMBRE 2008

Guidelines for the Management of Pregnancy at 41+0 to 42+0 Weeks

rates: a randomized controlled trial. Am J Obstet Gynecol 2004; 190:1077–81.

50. Suikkari Am, Jalkanen M, Heiskala H, Koskela O. Prolonged pregnancy: induction or observation. Acta Obstet Gynecol Scand Suppl 1983;116:58.

30. Crowley P. Interventions for preventing or improving the outcome of delivery at or beyond term. The Cochrane Database of Systematic Reviews 1997, Issue 1.

51. Katz Z, Yemini M, Lancet M, Mogilner BM, Ben-Hur H, Caspi B. Non-aggressive management of post-date pregnancies. Eur J Obstet Gynecol Reprod Biol 1983; 15:71–9.

31. Welch KK, Malone FD. Nuchal translucency-based screening. Clin Obstet Gynecol 2003;46:909–22.

52. Cardozo L, Fysh J, Pearce JM. Prolonged pregnancy: the management debate. Br Med J 1986;293:1059–63.

32. D’Alton M, Cleary-Goldman J. First and second trimester evaluation of risk for fetal aneuploidy: the secondary outcomes of the FASTER Trial. Sem Perinatol 2005; 29:240–6.

53. Witter FR, Weitz CM. A randomized trial of induction at 42 weeks of gestation vs. expectant management for postdates pregnancies. Am J Perinatol 1987;4:206–11.

33. Taipale P, Ammala M, Salonen R, Hiilesmaa V. Learning curve in ultrasonographic screening for selected fetal structural anomalies in early pregnancy. Obstet Gynecol 2003;101:273–8.

54. Augensen K, Bergsjo P, Eikeland T, Askvik K, Carlsen J. Randomised comparison of early versus late induction of in post-term pregnancy. Br Med J 1987;294:1192–5.

34. Mitchell MD, Flint APF, Bibby J, Brunt J, Anderson ABM, Turnbull AC. Rapid increase in plasma prostaglandin concentrations after vaginal examination and amniotomy. Br Med J 1977;2:1183–5.

55. Dyson DC, Miller PD, Armstrong MA. Management of prolonged pregnancy: Induction of labor versus antepartum testing. Am J Obstet Gynecol 1987;156:928–34.

35. McColgin SW, Bennet WA, Roach H, Cowan BD, Martin JN, Morrison JC. Parturitional factors associated with membrane stripping. Am J Obstet Gynecol 1993;169:71–7.

56. Martin JM, Sessums JK, Howard P, Martin RW, Morrison JC. Alternative approaches to the management of gravidas with prolonged-posttermpostdate pregnancies. J Miss State Med Assoc 1989;30:105–11.

36. Netta D, Visintainer P, Bayliss P. Does cervical membrane stripping increase maternal colonization of group B streptococcus? Am J Obstet Gynecol 2002;187(6):S221.

57. Bergsjo P, Gui-dan H, Su-qin Y, Zhi-zeng G, Bakketeig LS. Comparison of induced versus non-induced labor in post-term pregnancy. Acta Obstet Gynecol Scand 1989; 68:683–7.

37. Boulvain M, Irion O, Marcoux S, Fraser W. Sweeping the membranes to prevent post-term pregnancy and to induce labour: a systematic review. Br J Obstet Gynaecol 1999;106(5):481–5. 38. Boulvain M, Irion O. Stripping/sweeping the membranes for inducing or preventing post-term pregnancy. Cochrane Database Syst Rev 2004;(3):CD001328. 39. Foong LC, Vanaja K, Tan G, Chua S. Membrane sweeping in conjunction with induction. Obstet Gynecol 2000;96:539–42. 40. Doany W, McCarthy J. Outpatient management of the uncomplicated postdate pregnancy with intravaginal prostaglandin E2 gel and membrane stripping. J Matern Fetal Med 1997;6:71–8.

58. Heden L, Ingemarsson I, Ahlstrom H, Solum T. Induction of labor versus conservative management in prolonged pregnancy: controlled study. Int J Fetomaternal Med 1991;4(4):231–6. 59. Herabutya Y, Prasertsawat PO, Tongyai T, Isarangura Na Ayudthya N. Prolonged pregnancy: the management dilemma. Int J Gynecol Obstet 1992;37:253–8. 60. Hannah ME, Hannah WJ, Hellamn J, Hewson S, Milner R, Willan and the Canadian Multicenter post-term pregnancy trial group. Induction of labor as compared with serial antenatal monitoring in post-term pregnancy. A randomized controlled trial. N Engl J Med 1992;326:1587–92.

41. Wiriyasirizvaj B, Vutyavanich T, Ruangsri R. A randomized controlled trial of membrane stripping at term to promote labour. Obstet Gynecol 1996;87:767–70.

61. The national institute of child health and human development network of maternal-fetal medicine units. A clinical trial of induction of labor versus expectant management in postterm pregnancy. Am J Obstet Gynecol 1994;170:716–23.

42. Goldenberg M, Dulitzky M, Feldman B, Zolti M, Bider D. Stretching of the cervix and stripping of the membranes at term: a randomized controlled study. Eur J Obstet Gynecol Reprod Biol 1996;66:129–32.

62. Roach VJ, Rogers MS. Pregnancy outcome beyond 41 weeks gestation. Int J Gynecol Obstet 1997;59:19–24.

43. el-Torkey M, Grant JM. Sweeping of the membranes is an effective method of induction of labour in prolonged pregnancy. Br J Obstet Gynaecol 1992;99(6):455–8. 44. Cammu H, Haitsma V. Sweeping of the membranes at 39 weeks in nulliparous women: a randomized controlled trial. Br J Obstet Gynaecol 1998;105(1):41–4. 45. Berghella V, Rogers RA, Lescale K. Stripping of membranes as a safe method to reduce prolonged pregnancies. Obstet Gynecol 1996;87:927–31. 46. Wong SF, Hui SK, Choi H, Ho LC. Sweeping of membranes in formal induction of labour. BJOG 2002;109:632–5. 47. Crane J, Bennett K, Young D, Windrim R, Kravitz H. The effectiveness of sweeping membranes at term: a randomized trial. Obstet Gynecol 1997; 89:586–90.

63. James C, George SS, Guanekar N, Seshadri L. Management of prolonged pregnancy: A randomized trial of induction and antepartum foetal monitoring. Nat J India 2001;14:270–3. 64. Chanrachakul B, Herabutya Y. Postterm with favorable cervix: is induction necessary? Eur J Obstet Gynecol Reprod Biol 2003;106:154–7. 65. Ocon L, Hurtado R, Coteron JJ, Zubiria A, Ramirez O, Garcia JA. Prolonged Pregnancy: procedure guidelines. Progresos de Obstetricia y Ginecologia 1997; 40:101–6. 66. Chakravarti S, Goenka B. Conservative policy of induction of labor in uncomplicated postdated pregnancies. XVI FIGO World Congress of Obstetrics and Gynecology; 2000 Sept 3–8; Washington DC, USA (Book 3). 2000:62.

48. de Miranda E, van der Bom JG, Bonsel GJ, Bleker OP, Rosendaal FR. Membrane sweeping and prevention of post-term pregnancy in low-risk pregnancies: a randomized controlled trial. BJOG 2006;113:402–8.

67. Gelisen O, Caliskan E, Dilbaz S, Ozdas E, Dilbaz B, Ozdas E, Haberal A. Induction of labor with three different techniques at 41 weeks of gestation or spontaneous follow-up until 42 weeks in women with definitely unfavorable cervical scores. Eur J Obstet Gynecol Reprod Biol 2005;120(2):164–9.

49. Henry GR. A controlled trial of surgical induction of labor and amnioscopy in the management of prolonged pregnancy. J Obstet Gynaecol Br Cmwlth 1969;76:795–8.

68. Heimstad R, Skogvoll E, Mattson L, Johansen OJ, Eik-Nes SH, Salvesen KA. Induction of labor or serial antenatal fetal monitoring in postterm pregnancy. Obstet Gynecol 2007;109:609–17.

SEPTEMBER JOGC SEPTEMBRE 2008 l

809

SOGC CLINICAL PRACTICE GUIDELINE

69. Hannah ME. Postterm pregnancy: should all women have labour induced? A review of the literature. Fetal and Maternal Medicine Review 1993;5:3–17. 70. Sanchez-Ramos L, Olivier F, Delke I, Kaunitz AM. Labor induction versus expectant management for postterm pregnancies: a systematic review with meta-analysis. Obstet Gynecol 2003;101:1312–8. 71. Gulmezoglu AM, Crowther CA, Middleton P. Induction of labour for improving birth outcomes for women at or beyond term. Cochrane Database Syst Rev 2006 Oct 18;(4):CD004945. 72. Menticoglou SM, Hall PH. Routine induction of labour at 41 weeks gestation: nonsensus consensus. Br J Obstet Gynaecol 2002;109:485–91. 73. Alfirevic Z, Walkinshaw SA. A randomised controlled trial of simple compared with complex antenatal fetal monitoring after 42 weeks of gestation. Br J Obstet Gynaecol 1995;102:638–43.

810

l SEPTEMBER JOGC SEPTEMBRE 2008

74. Guidetti DA, Divon MY, Langer O. Postdate fetal surveillance: is 41 weeks too early? Am J Obstet Gynecol 1989;161:91–3. 75. Bochner CJ, Williams J, Castro L, Medearis A, Hobel CJ, Wade M. The efficacy of starting postterm antenatal testing at 41 weeks as compared with 42 weeks of gestational age. Am J Obstet Gynecol 1988;159:550–4. 76. American College of Obstetricians and Gynecologists. Practice Bulletin. Management of postterm pregnancy. No. 55, 2004. 77. Royal College of Obstetricians and Gynecologists. Induction of labour. Evidence based clinical Guideline No. 9, June 2001. London: RCOG Press. Available at: http://www.rcog.org.uk/resources/public/pdf/ rcog_induction_of_labour.pdf. Accessed July 9, 2008.

SOGC CLINICAL PRACTICE GUIDELINES SOGC CLINICAL PRACTICE No GUIDELINES 155 (Replaces guideline No 147), February 2005

Guidelines for Vaginal Birth After Previous Caesarean Birth This guideline has been prepared and reviewed by the Clinical Practice Obstetrics Committee and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. PRINCIPAL AUTHORS Marie-Jocelyne Martel, MD, FRCSC, Saskatoon SK Catherine Jane MacKinnon, MD, FRCSC, Brantford ON CLINICAL PRACTICE OBSTETRICS COMMITTEE Catherine Jane MacKinnon, MD, FRCSC, Brantford ON Marc-Yvon Arsenault, MD, FRCSC, Montreal QC Elias Bartellas, MD, FRCSC, St John’s NL Yvonne M. Cargill, MD, FRCSC, Ottawa ON Sue Daniels, RN, Dartmouth NS Tom Gleason, MD, FRCSC, Edmonton AB Stuart Iglesias, MD, Gibsons BC Michael C. Klein, MD, CCFP, Vancouver BC Marie-Jocelyne Martel, MD, FRCSC, Saskatoon SK Ann Roggensack, MD, Kingston ON Ann Kathleen Wilson, BHSc, RM, Ilderton ON SPECIAL CONTRIBUTOR Gregory A. Davies, MD, FRCSC, Kingston ON

Abstract Objective: To provide evidence-based guidelines for the provision of a trial of labour (TOL) after Caesarean section. Outcome: Fetal and maternal morbidity and mortality associated with vaginal birth after Caesarean (VBAC) and repeat Caesarean section. Evidence: MEDLINE database was searched for articles published from January 1, 1995, to February 28, 2004, using the key words “vaginal birth after Caesarean (Cesarean) section.” The quality of evidence is described using the Evaluation of Evidence criteria outlined in the Report of the Canadian Task Force on the Periodic Health Exam.

Key Words: Vaginal birth after Caesarean, trial of labour, uterine rupture, induced labour, oxytocin, prostaglandins, misoprostol

Recommendations: 1. Provided there are no contraindications, a woman with 1 previous transverse low-segment Caesarean section should be offered a trial of labour (TOL) with appropriate discussion of maternal and perinatal risks and benefits. The process of informed consent with appropriate documentation should be an important part of the birth plan in a woman with a previous Caesarean section (II-2B). 2. The intention of a woman undergoing a TOL after Caesarean section should be clearly stated, and documentation of the previous uterine scar should be clearly marked on the prenatal record (II-2B). 3. For a safe labour after Caesarean section, a woman should deliver in a hospital where a timely Caesarean section is available. The woman and her health care provider must be aware of the hospital resources and the availability of obstetric, anesthetic, pediatric, and operating-room staff (II-2A). 4. Each hospital should have a written policy in place regarding the notification and (or) consultation for the physicians responsible for a possible timely Caesarean section (III-B). 5. In the case of a TOL after Caesarean, an approximate time frame of 30 minutes should be considered adequate in the set-up of an urgent laparotomy (III-C). 6. Continuous electronic fetal monitoring of women attempting a TOL after Caesarean section is recommended (II-2A). 7. Suspected uterine rupture requires urgent attention and expedited laparotomy to attempt to decrease maternal and perinatal morbidity and mortality (II-2A). 8. Oxytocin augmentation is not contraindicated in women undergoing a TOL after Caesarean section (II-2A). 9. Medical induction of labour with oxytocin may be associated with an increased risk of uterine rupture and should be used carefully after appropriate counselling (II-2B). 10. Medical induction of labour with prostaglandin E2 (dinoprostone) is associated with an increased risk of uterine rupture and should not be used except in rare circumstances and after appropriate counselling (II-2B). 11. Prostaglandin E1 (misoprostol) is associated with a high risk of uterine rupture and should not be used as part of a TOL after Caesarean section (II-2A). 12. A foley catheter may be safely used to ripen the cervix in a woman planning a TOL after Caesarean section (II-2A). 13. The available data suggest that a trial of labour in women with more than 1 previous Caesarean section is likely to be successful but is associated with a higher risk of uterine rupture (II-2B). 14. Multiple gestation is not a contraindication to TOL after Caesarean section (II-2B).

These guidelines reflect emerging clinical and scientific advances as of the date issued and are subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

164

lFEBRUARY JOGC FÉVRIER 2005

Guidelines for Vaginal Birth After Previous Caesarean Birth

15. Diabetes mellitus is not a contraindication to TOL after Caesarean section (II-2B). 16. Suspected fetal macrosomia is not a contraindication to TOL after Caesarean section (II-2B). 17. Women delivering within 18 to 24 months of a Caesarean section should be counselled about an increased risk of uterine rupture in labour (II-2B). 18. Postdatism is not a contraindication to a TOL after Caesarean section (II-2B). 19. Every effort should be made to obtain the previous Caesarean section operative report to determine the type of uterine incision used. In situations where the scar is unknown, information concerning the circumstances of the previous delivery is helpful in determining the likelihood of a low transverse incision. If the likelihood of a lower transverse incision is high, a TOL after Caesarean section can be offered (II-2B). Validation: These guidelines were approved by the Clinical Practice Obstetrics and Executive Committees of the Society of Obstetricians and Gynaecologists of Canada. J Obstet Gynaecol Can 2005;27(2):164–174

BACKGROUND

his document reviews the contraindications to and maternal and fetal risks of a trial of labour (TOL) after Caesarean birth and makes recommendations for achieving vaginal birth after Caesarean (VBAC) safely. Delivery by Caesarean section occurs in 15% to 25% of births.1–5 In 2000 and 2001, the Caesarean section rate in Canada was 21.2%.6 The most frequent indications for Caesarean delivery are previous Caesarean delivery, dystocia, malpresentation, and nonreassuring fetal status.7,8 In any given region, the rate of birth by Caesarean section and the rate of VBAC tend to be inversely related.4 Schell first reported VBAC in 1923, describing the successful vaginal delivery of 34 infants in 23 mothers with previous Caesarean deliveries.9

T

A trial of labour after Caesarean should be considered in women who present for prenatal care with a history of previous Caesarean birth.10–12 In certain situations, a TOL after Caesarean will be contraindicated3 and a repeat Caesarean section will be advised, but in most cases, successful vaginal birth can be safely achieved for both mother and infant.13–15 Women and their health care providers will need to discuss the risks and benefits of VBAC when planning the birth. A Canadian consensus statement on VBAC was published in 1985, and Clinical Practice Guidelines were published by the Society of Obstetricians and Gynaecologists of Canada (SOGC) in 1997.3 This document updates the 1997 SOGC Guidelines with articles published from January 1, 1995, to February 28, 2004. Articles were obtained by searching the MEDLINE database, using the key words “vaginal birth after Caesarean (Cesarean) section.” The data are limited by 3 important factors: first, there are no randomized trials of TOL versus elective repeat Cesarean section (ERCS); second, adverse maternal or perinatal outcomes are rare, and large study populations are necessary to observe a

significant difference in maternal and perinatal outcomes; and finally, a woman’s choice to attempt TOL after Caesarean is heavily influenced by her health care provider and local resources, often leading to selection bias in published reports.12,16 The level of evidence and quality of the recommendations in this guideline have been determined using the criteria described by the Canadian Task Force on the Periodic Health Examination (Table).17 TRIAL OF LABOUR VERSUS ELECTIVE REPEAT CAESAREAN SECTION

The success rate of a TOL after Caesarean ranges between 50% and 85%.3,4,14,18–21 In a study examining 1776 women undergoing TOL after Caesarean, the overall success rate was 74%.14 A Canadian study reported similar results, quoting a success rate of 76.6%.2 Predictors of successful VBAC include nonrecurring indication for Caesarean birth, such as malpresentation (odds ratio [OR], 1.9; 95% confidence interval [CI], 1.0–3.7)22 or gestational hypertension (OR, 2.3; 95% CI, 1.0–5.8),22 and a previous vaginal delivery (OR, 1.8; 95% CI, 1.1–3.1),22 where success rates are as high as 82%.1,22,23 When the previous Caesarean birth was for dystocia, failure to progress, or cephalopelvic disproportion, some studies found the rates of successful VBAC comparable,24,25 while others reported lower-than-expected rates.14,18,22,26 In 1996 McMahon et al. published a report of maternal morbidity in TOL compared with ERCS in Nova Scotia from 1986 to 1992.1 In an examination of 3249 women undergoing a TOL and 2889 women who delivered by ERCS, the risk of major complications (for example, hysterectomy, uterine rupture, and operative injury) was almost doubled (1.6% vs. 0.8%) in the TOL group (OR, 1.8; 95% CI, 1.1–3.0).1 Complications like puerperal fever, transfusion, and abdominal wound infection were comparable. When comparing women who had a successful TOL with those who required a repeat Caesarean section after failed TOL, the risks were greater of operative injury (3.0% vs. 0.1%; OR, 5.1; 95% CI, 2.5–10.7) and fever (8.0% vs. 3.5%; OR, 1.5; 95% CI, 1.3–1.8) in the failed TOL group.1 Hibbard et al. also reported a greater rate of complication in women who attempted a TOL and failed.27 In 1999 Rageth et al. reviewed 17 613 TOL and 11 433 ERCS deliveries.20 The rates of hysterectomy (relative risk [RR], 0.36; 95% CI, 0.23–0.56), febrile morbidity (RR, 0.65; 95% CI, 0.55–0.77), and thromboembolic complications (RR, 0.52; 95% CI, 0.34–0.78) were less in the TOL group than in the ERCS group.20 There is less blood loss with a successful VBAC (OR, 0.50; 95% CI, 0.3–0.9)27 and a shorter hospital stay with a more rapid recovery and return to full activity. FEBRUARY JOGC FÉVRIER 2005 l

165

SOGC CLINICAL PRACTICE GUIDELINES

Table Criteria for quality of evidence assessment and classification of recommendations Level of results*

Classification of recommendations†

I:

A.

II-1: Evidence from well-designed controlled trials without randomization.

There is good evidence to the recommendation that the condition be specifically considered in a periodic health examination.

B.

II-2: Evidence from well-designed cohort (prospective or retrospective) or case-control studies, preferably from more than one centre or research group.

There is fair evidence to the recommendation that the condition be specifically considered in a periodic health examination.

C.

There is poor evidence regarding the inclusion or exclusion of the condition in a periodic health examination, but recommendations may be made on other grounds.

D.

There is fair evidence to the recommendation that the condition not be considered in a periodic health examination.

E.

There is good evidence to the recommendation that the condition be excluded from consideration in a periodic health examination.

Evidence obtained from at least one properly randomized controlled trial.

II-3: Evidence obtained from comparisons between times or places with or without intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category. III:

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.

*The quality of evidence reported in these guidelines has been described using the Evaluation of Evidence criteria outlined in the Report of the Canadian Task Force on the Periodic Health Exam. †Recommendations included in these guidelines have been adapted from the ranking method described in the Classification of Recommendations found in the Report of the Canadian Task Force on the Periodic Health Exam.

Rosen et al. also reported that the risk of febrile morbidity is lower in women who attempt a TOL after Caesarean (OR, 0.5; 95% CI, 0.5–0.6) and is lowest in those who succeed (OR, 0.2; 95% CI, 0.2–0.2), compared with ERCS, but is increased in those who attempt a TOL and ultimately deliver by Caesarean (OR, 2.0; 95% CI, 1.7–2.5).28 An examination of 16 938 Finnish women who had undergone a Caesarean delivery found that previous Caesarean section is associated with an increased risk of ectopic pregnancy (RR, 1.28), placenta previa (RR, 3.89), and abruptio placenta (RR, 2.41).29 A repeat Caesarean has been associated with an increase in the risk of placenta previa (OR, 1.59; 95% CI, 1.21–2.08)30 and placenta accreta in subsequent pregnancies.31 A meta-analysis published in 2000 demonstrated that the overall risk of perinatal death is increased in women attempting a TOL (OR, 1.71; 95% CI, 1.28–2.28).32 The risks of perinatal mortality and severe morbidity are directly related to uterine rupture as a sentinel event. If uterine rupture occurs, the risks of perinatal mortality and severe morbidity are increased. The risk of suspected neonatal sepsis is greater in women attempting TOL but appears to be confined to those who fail TOL and require a repeat Caesarean section (OR, 4.8; 95% CI, 2.6–9.0).33 In women who choose ERCS, the risk of respiratory problems in the newborn is increased (6% vs. 3%), compared with women who have a successful VBAC (OR, 2.3; 95% CI, 1.4–3.8).33 166

l FEBRUARY JOGC FÉVRIER 2005

CONTRAINDICATIONS TO VAGINAL BIRTH AFTER CAESAREAN SECTION

The following situations are contraindications to a TOL after Caesarean: 1. previous classical or inverted “T” uterine scar3,13; 2. previous hysterotomy or myomectomy entering the uterine cavity3,19; 3. previous uterine rupture3,19; 4. presence of a contraindication to labour, such as placenta previa or malpresentation3; 5. the woman declines a TOL after Caesarean and requests ERCS.3,19 Recommendation

1. Provided there are no contraindications, a woman with 1 previous transverse low-segment Caesarean section should be offered a trial of labour after Caesarean with appropriate discussion of maternal and perinatal risks and benefits. The process of informed consent with appropriate documentation should be an important part of the birth plan in women with a previous Caesarean section (II-2B). PLANNING A TRIAL OF LABOUR AFTER CAESAREAN SECTION

A woman and her health care provider must decide together whether an appropriate situation exists for considering TOL after Caesarean. The evaluation and discussion should address the issues outlined below and should be well documented in the prenatal record or chart.

Guidelines for Vaginal Birth After Previous Caesarean Birth

Documentation of Previous Uterine Incision

Documentation of the location and type of uterine incision used during the previous Caesarean section is ideal.3 In most cases, this information can be obtained by reviewing the operative record from the previous surgery. Other information in this record, such as the indication for the Caesarean section and the opinion of the previous surgeon, may be helpful in counselling as well. The fact that the record has been reviewed and that no contraindications to a TOL after Caesarean are present should be documented clearly on the prenatal record.34 If the operative record is not available, the scar is considered “unknown.” Review of the operative report from previous hysterotomy or myomectomy should be documented in detail. Recommendation

2. The intention of a woman undergoing a TOL after Caesarean should be clearly stated, and documentation of the previous uterine scar should be clearly marked on the prenatal record (II-2B). Facilities and Resources

A trial of labour after Caesarean is always associated with a risk of uterine rupture, however small, and a good outcome is not guaranteed under any circumstances. Further, little evidence exists about the exact timing of a Caesarean section following a suspected uterine rupture, which would prevent a poor neonatal outcome. A TOL after Caesarean can be offered to women within any hospital setting where there is an ability to perform a Caesarean section.13,34,35 This document does not intend to set a standard regarding whether staff must be “in house” or “on site” to provide safe intrapartum care and therefore makes no statements on such attendance. Facilities providing TOL after Caesarean should have a policy in place to manage such parturients, so that all resources are mobilized promptly if an intrapartum emergency occurs.23 The SOGC recognizes that in such cases of maternal fetal compromise, necessitating timely Caesarean section, an approximate time frame of 30 minutes may be required to assemble the team and commence laparotomy. This availability and time required for obstetric, anesthetic, and pediatric services to attend such an emergency should be fully discussed with the woman. Women who live in areas where local hospitals cannot provide a timely Caesarean section should be offered the opportunity for transfer to a facility where this service is available, in order to permit a TOL after Caesarean.13 The of the team who could be called urgently in the case of an intrapartum complication (anesthetic, pediatric, and obstetric services) should be notified that the woman is in hospital and in labour, and their availability should be confirmed.

Labour and delivery in women who have had a previous Caesarean section should be conducted in a hospital setting with facilities for a laparotomy. Recommendation

3. For a safe labour after Caesarean section, the woman should deliver in a hospital where a timely Caesarean section is available. The woman and her health care provider must be aware of the hospital resources and the availability of obstetric, anesthetic, pediatric, and operating-room staff (II-2A). 4. Each hospital should have a written policy in place regarding the notification and (or) consultation for the physicians responsible for a possible timely Caesarean (III-B). 5. In the case of a TOL after Caesarean, an approximate time frame of 30 minutes should be considered adequate in the set-up of an urgent laparotomy (III-C). Maternal Monitoring

Women planning a TOL after Caesarean should have appropriate monitoring in labour. The presence of a devoted birth attendant is ideal. Progress of labour should be assessed frequently, as there is some evidence that prolonged or desultory labour is associated with an increased risk of failure and uterine rupture.19,36,37 Epidural analgesia is not contraindicated.7,19,34,38 Fetal Monitoring

Continuous electronic fetal monitoring in labour is recommended for all women attempting TOL after Caesarean.19,34,39 The most reliable first sign of uterine rupture is a nonreassuring fetal heart tracing.34 This may be sudden in onset and may not be related to contractions.40 Recommendation

6. Continuous electronic fetal monitoring of women attempting TOL after Caesarean is recommended (II-2A). POSTPARTUM EVALUATION

Routine digital exploration of the Caesarean scar postpartum is not necessary, except when signs or symptoms suggest uterine rupture.41 UTERINE RUPTURE

Uterine rupture, the most serious complication of a TOL after Caesarean, is defined as complete separation of the myometrium with or without extrusion of the fetal parts into the maternal peritoneal cavity and requires emergency Caesarean section or postpartum laparotomy.19,42 It is an uncommon complication of VBAC but is associated with significant maternal and perinatal morbidity and mortality.1,7 The most common sign or symptom of uterine rupture is nonreassuring fetal heart rate monitoring.18,20,43 Other clinical signs include the cessation of contractions, FEBRUARY JOGC FÉVRIER 2005 l

167

SOGC CLINICAL PRACTICE GUIDELINES

loss of the presenting part on vaginal examination, abdominal pain, vaginal bleeding, hematuria, or maternal cardiovascular instability.16,44 The type and location of the previous uterine incision helps to determine the risk of uterine rupture. The incidence of uterine rupture is 0.2% to 1.5% in women who attempt labour after a transverse lower uterine segment incision14,16,18,27,45 and 1% to 1.6% in women who have had a vertical incision in the lower uterine segment.46–49 The risk is 4% to 9% with a classical or “T” incision; thus TOL after Caesarean is contraindicated in these situations.16,19,30 Shimonovitz et al. found the risk of uterine rupture after 0, 1, 2, and 3 VBAC deliveries to be 1.6%, 0.3%, 0.2%, and 0.35%, respectively, indicating that the risk of uterine rupture decreases after the first successful VBAC.50 Since uterine rupture is a rare event, a realistic appraisal of potential maternal and perinatal risks is difficult to accomplish outside of large series, literature reviews, or metaanalyses. The most important published reports in this area are discussed below, as well as those applicable to the Canadian population. In 1991 Rosen et al. performed a meta-analysis of 10 studies that examined a total of 4617 women who had a TOL after Caesarean compared with 3831 women who had ERCS births.28 The rate of uterine rupture was similar in the 2 groups: TOL 0.18% and ERCS 0.19% (P = 0.5). There was no difference in the rate of maternal death (0.028% vs. 0.024%) or perinatal death (0.3% vs. 0.4%) in the TOL group, compared with the ERCS group.28 In 2000 Mozurkewich and Hutton published a metaanalysis of 15 studies that examined a total of 28 813 women undergoing a TOL compared with ERCS between 1989 and 1999.32 There was an increased rate of uterine rupture (0.39% vs. 0.16%; OR, 2.1; 95% CI, 1.45–3.05) and perinatal mortality (0.58% vs. 0.28%; OR, 1.71; 95% CI, 1.28–2.28) in the TOL group. The rates of maternal mortality and low 5-minute Apgar scores were not different.32 In 2002 Keiser et al. reviewed the incidence and consequences of uterine rupture in Nova Scotia from 1988 to 1997.51 Among 4516 women undergoing a TOL, 18 (0.39%) uterine ruptures were documented over 10 years. All women underwent laparotomy, and there were no maternal deaths. Of those who had a uterine rupture, 3 women underwent hysterectomy, 10 required transfusion, and 5 suffered a cystotomy. After excluding lethal anomalies, there was 1 perinatal death (0.02%) and 6 neonates with severe asphyxia (0.13%).51 In 2002 Bujold et al. examined the risk factors for serious neonatal morbidity associated with 23 cases of uterine rupture among 2233 women attempting a TOL (rate 1.03%).52 Nine neonates (0.4%) had a pH < 7.0 (severe metabolic acidosis), 3 (0.13%) were diagnosed with hypoxic ischemic 168

l FEBRUARY JOGC FÉVRIER 2005

encephalopathy, and 1 (0.04%) died.52 The presence of placental or fetal part extrusion at laparotomy was associated with severe metabolic acidosis (P < 0.001).52 Other variables (e.g., induction, birth weight, or use of epidural) did not demonstrate an association with uterine rupture. Even in situations where very rapid decision to delivery times were recorded, some cases of perinatal acidosis could not be avoided.52 Smith et al. published a large series of 15 515 women undergoing a TOL after Caesarean compared with 9014 women who underwent ERCS between 1992 and 1997.53 The rate of perinatal death in the TOL group was 0.129%, 11.6 times higher than that of the ERCS group (OR, 11.6; 95% CI, 1.6–86.7).53 Smith compared this to the risk of perinatal death in other common obstetrical situations: TOL compared with multiparous women in labour (OR, 2.2; 95% CI, 1.3–3.5) and TOL compared with nulliparous women in labour (OR, 1.3; 95% CI, 0.8–21).53 In 2003 Chauhan et al. published a review of data on the maternal and perinatal complications of uterine rupture in those attempting a TOL after Caesarean.54 Examining 142 075 trials of labour revealed an overall rate of uterine rupture of 0.62%.54 The rate of maternal death was 0.002%; hysterectomy, 0.09%; transfusion, 0.18%; and genitourinary tract injury, 0.08%.54 In this study, the rate of neonatal acidosis was 0.15%, and the rate of perinatal death was 0.04%.54 Oxytocin was involved in 43% of the uterine ruptures in this series.54 The data indicate that the relative risk of uterine rupture, maternal morbidity, and perinatal mortality or severe morbidity is increased in women undergoing a TOL after Caesarean, compared with ERCS, but that the absolute risk remains very low. The treatment of suspected uterine rupture is timely laparotomy after maternal stabilization and anaesthesia. Urgent intervention is mandatory to obtain the best possible outcome for both mother and fetus. Once the fetus is delivered, maternal hemorrhage must be arrested, and if the uterus cannot be salvaged, hysterectomy may be required. Although the risk of uterine rupture has been found to be increased in situations of prolonged labour with augmentation,55 when Phelan et al. retrospectively examined the patterns of uterine activity before uterine rupture, no association with frequency or intensity of contractions could be discerned.40 In 1996 Rozenberg et al. examined ultrasonographic measurement of the lower uterine segment’s myometrial thickness at 36 to 38 weeks’ gestation as a predictor of uterine rupture and found that if the lower segment thickness was less than 3.5 mm, the risk of uterine rupture or dehiscence was 11.8%; if the measurement was greater than 3.5 mm, the risk of uterine rupture was minimal.56 However, the

Guidelines for Vaginal Birth After Previous Caesarean Birth

incidence of uterine rupture in this population was 2.3%, significantly greater than the usually quoted 1%. Therefore, the positive predictive value of this test in clinical practice will be much lower.56 In a follow-up open study, Rozenberg et al. found that the use of the lower-uterine-segment measurement helped clinicians select women for a TOL after Caesarean.57 The rate of successful VBAC for those with 1 previous Caesarean section did not change but was increased in those with 2 previous Caesarean deliveries.57 These findings will need to be confirmed in further randomized studies before ultrasonography can be used to make a decision about the safety of TOL after Caesarean. Recommendation

7. Suspected uterine rupture requires urgent attention and expedited laparotomy to attempt to decrease maternal and perinatal morbidity and mortality (II-2A). OXYTOCICS AND TOL AFTER CAESAREAN SECTION Augmentation

In 1987 Flamm et al. performed a multicentre examination of 485 women who received oxytocin to augment their spontaneous labour in a planned TOL after Caesarean.58 No increase in the risk of uterine rupture, maternal morbidity, or perinatal morbidity or mortality was detected.58 Zelop et al. ed the same conclusion about the risk of uterine rupture with augmentation in a 1999 study (OR, 2.3; 95% CI, 0.8–7.0).59 Goetzl et al. examined the relation between the dose of oxytocin used and the risk of uterine rupture in women undergoing a TOL after Caesarean.60 No significant association was detected between exposure to oxytocin and the risk of uterine rupture.60 Careful surveillance for progress of labour is required, especially when the diagnosis of dystocia is being considered.19,34 There are insufficient studies examining the use of other agents to augment labour, such as prostaglandins, and their safety in a TOL after Caesarean. Induction

In 2000 Ravasia et al. reviewed the risk of uterine rupture in women undergoing an induction TOL after Caesarean.61 In 575 women with a previous Caesarean section, labour was induced with prostaglandin E2 gel (n = 172), intracervical foley catheter (n = 129), or amniotomy and (or) oxytocin (n = 274).61 Outcomes were compared with women undergoing a TOL with spontaneous labour. The risk of uterine rupture was not increased in women who underwent either amniotomy/oxytocin or foley catheter induction but was significantly increased in those who underwent a prostaglandin E2 induction (P = 0.004).61 Also in 2000, Sanchez-Ramos et al. performed a metaanalysis looking at the efficacy and safety of prostaglandin

E2 for cervical ripening in women with a previous Caesarean section and found it to be effective and not associated with an increased risk of uterine rupture (OR, 1.46; 95% CI, 0.96–2.22), compared with spontaneous labour.62 In 2003 Delaney and Young reported the examination of 3746 women with a prior Caesarean delivery who underwent either induced or spontaneous labour.63 They found that induced labour was associated with a greater risk of early postpartum hemorrhage (7.3% vs. 5.0%: OR, 1.66; 95% CI, 1.18–2.32), Caesarean delivery (37.5% vs. 24.2%: OR, 1.84; 95% CI, 1.51–2.25), and ission to a neonatal intensive care unit (13.3% vs. 9.4%: OR, 1.69; 95% CI, 1.25–2.29).63 There was a trend toward a higher rate of uterine rupture, but this was not statistically significant (0.7% vs. 0.3%, P = 0.128).63 In another retrospective study of 560 women, the rate of uterine rupture in women whose labour was induced with oxytocin was 2%, with prostaglandin was 2.9%, and with both was 4.5%.59 Up to 2001, there were conflicting data on the risk of labour induction with prostaglandin E2. Several other smaller studies reported that it appeared to be safe, effective, and not associated with an increased risk of uterine rupture.45,64–66 In the largest study published to date, conducted by Lydon-Rochelle et al., the incidence of uterine rupture was reviewed retrospectively in 20 095 women with a previous Caesarean section and was reported as follows: ERCS (no labour) 0.16%; spontaneous labour 0.52% (RR, 3.3; 95% CI, 1.8–6.0); labour induced without prostaglandin 0.77% (RR, 4.9; 95% CI, 2.4–9.7); and labour induced with prostaglandin 2.45% (RR, 15.6; 95% CI, 8.1–30.0).67 As for all inductions, the indication for induction in women undergoing a planned TOL after Caesarean should be compelling and documented. The possibility that the use of oxytocin and (or) prostaglandin for labour induction in women considering TOL after Caesarean may be associated with an increased risk of uterine rupture and its sequelae must be discussed with the parturient. The absolute risks of uterine rupture are low, but the relative risks (especially with the use of prostaglandin E2, compared with spontaneous labour) are greater. Misoprostol

Misoprostol has been proposed as an effective and economical agent for cervical ripening and induction.68 In 1998 Sciscione et al. reported a case of uterine rupture in a woman with 2 previous Caesarean deliveries after misoprostol was istered as a cervical ripening agent.69 Several small series reported a risk from 0% to 11.7% of uterine rupture with misoprostol in women undergoing a TOL after Caesarean 43,70–73 Blanchette et al. compared prostaglandin E2 to misoprostol in women undergoing induction TOL after FEBRUARY JOGC FÉVRIER 2005 l

169

SOGC CLINICAL PRACTICE GUIDELINES

Caesarean and found them to be equally effective, but misoprostol was associated with a higher incidence of uterine rupture (18.8% compared to no ruptures in the prostaglandin E2 group).74 The numbers in all these studies are small, and it is difficult to draw meaningful conclusions. Until further randomized studies are completed, misoprostol should be discouraged as a method of induction or cervical ripening in women with previous Caesarean delivery.74,75 CERVICAL PREPARATION

In situations where delivery is indicated and the cervix is unfavourable, TOL after Caesarean can be considered. Various methods of cervical ripening have been examined. In a cohort study published in 2002, Ben-Aroya et al. compared women undergoing a trial of labour after Caesarean section in 3 situations: spontaneous labour (n = 1432), prostaglandin cervical ripening (n = 55), and cervical ripening by foley catheter (n = 161).76 There was a significantly higher rate of dystocia (30.4% vs. 11.6%, P < 0.01) and repeat Caesarean section in the second stage (49.1% vs. 35.2%, P < 0.01) in the foley catheter group, compared with the control group.76 There was no difference in the rate of uterine rupture, fetal distress, or Apgar scores.76 In a Canadian study published in 2004, Bujold et al. compared the rate of uterine rupture in 1807 women who presented in spontaneous labour, 417 induced with amniotomy with or without oxytocin, and 255 induced with transcervical foley catheter.77 The rate of successful vaginal birth was 78% in the spontaneous group, 77.9% in the amniotomy group, and 55.7% in the transcervical foley group (P < 0.001).77 However, the rates of uterine rupture did not differ significantly: 1.1%, 1.2%, and 1.6%, respectively (P = 0.81).77 These data the use of the foley catheter for cervical ripening of an unfavourable cervix in women undergoing a TOL after Caesarean. Recommendations

8. Oxytocin augmentation is not contraindicated in women undergoing a TOL after Caesarean (II-2A). 9. Medical induction of labour with oxytocin may be associated with an increased risk of uterine rupture and should be used carefully after appropriate counselling (II-2B). 10. Medical induction of labour with prostaglandin E2 (dinoprostone) is associated with an increased risk of uterine rupture and should not be used except in rare circumstances after appropriate counselling (II-2B). 11. Prostaglandin E1 (misoprostol) is associated with a high risk of uterine rupture and should not be used as part of a TOL after Caesarean (II-2A). 12. A foley catheter may be used safely to ripen the cervix in a woman planning a TOL after Caesarean (II-2A). 170

l FEBRUARY JOGC FÉVRIER 2005

SPECIAL CIRCUMSTANCES More Than 1 Previous Low Transverse Caesarean Section

Several authors have assessed the rate of successful VBAC and the risk of uterine rupture in women with more than 1 previous low transverse Caesarean section.8,78–84 All indicated success rates between 62% and 89% and uterine rupture rates between 0% and 3.7%. In the largest study, Miller et al. demonstrated a VBAC success rate of 75.3% in 1827 women with 2 or more previous low transverse Caesarean deliveries, with a uterine rupture rate of 1.7% versus 0.6% in the ERCS group (OR, 3.06; 95% CI, 1.95–4.79).8 Unfortunately, the use of prostaglandins or oxytocin for induction or augmentation was not considered. Caughey et al. reported a uterine rupture rate of 3.7% versus 0.8% (RR, 4.8; 95% CI, 1.8–13.2) in a retrospective review of 134 women undergoing labour after 2 previous Caesarean deliveries after correction for prostaglandin, oxytocin, and epidural use.84 Recommendation

13. The available data suggest that a trial of labour in women with more than 1 previous Caesarean is likely to be successful but is associated with a higher risk of uterine rupture (II-2B). Multiple Pregnancy

Seven studies have examined a total of 233 women attempting VBAC in multiple pregnancy.85–91 All a trial of VBAC in multiple pregnancy as being safe and effective, with success rates of 69% to 84% and without increased maternal or fetal morbidity or mortality.85–91 In one study, uterine dehiscence was noted in 1 woman on manual exploration after successful vaginal delivery of both twins, and no treatment was required.86 Each of these studies examined a small number of women, however, and greater numbers would be required to detect rare outcomes such as uterine rupture and maternal and perinatal mortality. Recommendation

14. Multiple gestation is not a contraindication to a TOL after Caesarean (II-2B). Breech Presentation

A large multicentre trial by Hannah et al. demonstrated that a planned Caesarean birth is associated with better perinatal and neonatal outcomes in breech presentation at term.92 This recommendation has been adopted by the SOGC and would therefore preclude a planned TOL after Caesarean in women presenting with a singleton fetus in breech presentation at term.92,93 Vaginal delivery of premature fetuses and the second twin were not addressed in the study; therefore, no recommendations can be made in this regard. It would seem appropriate to consider these cases individually.

Guidelines for Vaginal Birth After Previous Caesarean Birth

External cephalic version is not contraindicated in women with a previous Caesarean birth.94,95 Diabetes Mellitus

In a retrospective cohort study, Coleman et al. examined the issue of TOL after Caesarean in women with gestational diabetes mellitus (GDM).96 Coleman examined 156 women with GDM and planned TOL after Caesarean and compared them with women with no GDM and attempting TOL after Caesarean. They reported that the success rate for VBAC of 64.1% in women with GDM was lower than the 77.2% of women without GDM (P < 0.001).96 Maternal and fetal morbidities were comparable.96 A retrospective study of TOL after Caesarean in women with pregestational or gestational diabetes found similar results.97 Based on these studies, diabetes mellitus should not be considered a contraindication to TOL after Caesarean. Recommendation

15. Diabetes mellitus is not a contraindication to TOL after Caesarean (II-2B). Macrosomia

In a study examining the outcome of 365 women who underwent a TOL after Caesarean and who were giving birth to neonates weighing more than 4000 g, Zelop et al. demonstrated a success rate of 60%, with no increase in maternal or fetal morbidity and no increase in the risk of uterine rupture.98 These data previously reported findings by Flamm (success rate 58%)99 and Phelan (success rate 67%).100 In 2003 Elkousy et al. reported an examination of 9960 women with a previous Caesarean section planning a trial of labour. The study was further stratified by neonatal birth weights and birth history (primarily, whether they had a previous vaginal delivery and whether it occurred before or after their Caesarean).101 Their results indicate that the likelihood of successful VBAC decreases with increasing birth weight and is lowest in women who have never had a successful vaginal birth.101 According to these results, suspected macrosomia is not a contraindication to TOL after Caesarean, though it may be associated with a lower chance of success. Recommendation

16. Suspected fetal macrosomia is not a contraindication to a TOL after Caesarean (II-2B). Interdelivery Interval

Four studies have examined the relation between the interdelivery interval and the rate of successful VBAC and uterine rupture.102–105 Esposito et al. examined 23 cases of uterine rupture and compared them with 127 control subjects.102 There was an increased risk of uterine rupture with a short interpregnancy interval (< 6 months between pregnancies; < 15 months between deliveries), compared with

control subjects (17.4% vs. 4.7%, P = 0.05).102 Shipp et al. reviewed 311 women who underwent a TOL after Caesarean less than 18 months after their Caesarean section and compared them with 2098 women who underwent a TOL after Caesarean after more than 18 months.103 The shorter interval was associated with a threefold increase in the risk of uterine rupture (2.25% vs. 1.05%: OR, 3.0; 95% CI, 1.2–7.2).103 Huang et al. reviewed 1185 women undergoing a TOL after Caesarean and noted no difference in the success of vaginal delivery in women with a shorter interval of less than 19 months (79% vs. 85.5%, P = 0.12); however, they did note a significant difference in successful VBAC in women who underwent medical induction, compared with spontaneous labour (14.3% vs. 86.1%, P < 0.01).104 Their study noted no difference in the rate of uterine rupture.104 In 2002 Bujold et al. reported an observational study of 1527 women undergoing a planned TOL after Caesarean at different intervals from the index Caesarean delivery.105 The rates of uterine rupture were as follows: < 12 months, 4.8%; 13 to 24 months, 2.7%; 25 to 36 months, 0.9%; and > 36 months, 0.9%.105 After adjusting for such confounders as number of layers in the uterine closure, induction, oxytocin, and epidural use, the odds ratio for uterine rupture in a woman less than 24 months from her last delivery was 2.65 (95% CI, 1.08–6.46).105 Recommendation

17. Women delivering within 18 to 24 months of a Caesarean section should be counselled about an increased risk of uterine rupture in labour (II-2B). Postdatism

Three studies have examined postdatism and TOL after Caesarean.106–108 In 2 of these studies, the rate of successful VBAC and uterine rupture in women who delivered at less than 40 weeks’ gestation was compared with those who delivered at more than 40 weeks.106,107 Success rates for VBAC after 40 weeks were reported from 65.6%107 to 73.1%106 and were comparable to success rates for women who delivered before 40 weeks’ gestation.106,107 Zelop et al. also compared the risk of uterine rupture in women who delivered before and after 40 weeks’ gestation in spontaneous labour and induced labour.108 They reported that the risk of uterine rupture in a TOL after Caesarean after 40 weeks’ gestation was not significantly increased when compared with women who delivered before 40 weeks, whether in spontaneous labour (1.0 % vs. 0.5%, P = 0.2, adjusted OR, 2.1; 95% CI, 0.7–5.7) or after induction (2.6% vs. 2.1%, P = 0.7, adjusted OR, 1.1; 95% CI, 0.4–3.4).108 Recommendation

18. Postdatism is not a contraindication to a TOL after Caesarean (II-2B). FEBRUARY JOGC FÉVRIER 2005 l

171

SOGC CLINICAL PRACTICE GUIDELINES

One- Versus 2-Layer Closure of Low Transverse Caesarean Section

In 1992 Hauth et al. published data comparing operative time, endometritis, transfusion, and placement of extra hemostatic sutures in women undergoing uterine closure in 1 layer compared with 2 layers.109 The only significant difference was in operative time: 44 minutes with 1-layer closure, compared to 48 minutes with 2-layer closure (P < 0.05).109 Ohel et al. published similar findings in 1996.110 The trend shifted in many centres toward single-layer closure. In 1997 Chapman et al. published a review of 145 women who underwent a TOL after Caesarean after being randomized to either 1-layer or 2-layer closure in the previous Caesarean section.111 They reported no significant difference in the outcome of the next pregnancy.111 In a 2002 review of 2142 women who underwent a TOL after Caesarean, Bujold et al. noted that a 1-layer interlocking closure was associated with an increased risk of uterine rupture when compared with a 2-layer closure (3.1% vs. 0.5%, P < 0.001; OR, 3.95; 95% CI, 1.35–11.49).112 Further study in this area is recommended. Unknown Scar

All records available or obtainable describing the woman’s previous Caesarean section should be reviewed. If unavailable, information about the circumstances of the Caesarean section will help determine the likelihood of a vertical uterine incision.113,114 Most unknown scars will be lower transverse incisions (92%) and therefore at low risk for uterine rupture.115 If the history suggests a reasonable likelihood of a classical incision, it would be prudent to recommend a repeat Caesarean section, but in settings where the history indicates a high likelihood of lower transverse uterine incision and the woman wishes to proceed after counselling, TOL after Caesarean is acceptable.115 Recommendation

19. Every effort should be made to obtain the previous Caesarean operative report to determine the type of uterine incision used. In situations where the scar is unknown, information concerning the circumstances of the previous delivery is helpful in determining the likelihood of a low transverse incision. If the likelihood of a lower transverse incision is high, TOL after Caesarean can be offered (II-2B). Other Factors

Factors such as maternal obesity,116 presence of postpartum fever after Caesarean section,117 type of suture material, müllerian duct anomalies,118 and maternal age119 and their relation to the risk of uterine rupture have been examined in small studies, but definitive conclusions cannot yet be drawn. 172

l FEBRUARY JOGC FÉVRIER 2005

CONCLUSION

Trial of labour after Caesarean section should be considered in women who have no contraindications after appropriate discussion. The efficacy and safety of a TOL after Caesarean in appropriately selected women about to give birth in a hospital where timely Caesarean section facilities are available is well ed. of the woman in labour, including close observation of herself and her fetus for signs of complications, is recommended. Augmentation of labour with oxytocin is safe. Induction of labour may be provided when the indication for induction is compelling and the risks have been fully discussed. The use of prostaglandin E2 (dinoprostone) and prostaglandin E1 (misoprostol) in women planning a TOL is not recommended. The use of a foley catheter for cervical ripening in situations where the cervix is unfavourable is associated with a lower chance of success but no increased risk of uterine rupture. REFERENCES 1. McMahon MJ, Luthier ER, Bowes WA, Olshan AF. Comparison of a trial of labor with an elective second Cesarean section. N Engl J Med 1996;335:689–95. 2. Davies GA, Hahn PM, McGrath MM. Vaginal birth after Cesarean section: physicians’ perceptions and practice. J Reprod Med 1996;41:515–20. 3. Society of Obstetricians and Gynaecologists of Canada. Vaginal birth after previous Caesarean birth. Clinical Practice Guideline No. 68. Ottawa (ON): SOGC; December 1997. 4. Biswass A. Management of previous Cesarean section. Curr Opin Obstet Gynecol 2003;15:123–9. 5. Curtin SC, Kozak LJ, Gregory KD. U.S. Cesarean and VBAC rates stalled in the mid-1990s. Birth 2000;27:54–7. 6. Health Canada. Canadian perinatal health report 2003. Ottawa (ON): Health Canada; 2003. p. 33. 7. Weinstein D, Benshushan A, Ezra Y, Rojansky N. Vaginal birth after Cesarean section: current opinion. Int J Gynecol Obstet 1996;53:1–10. 8. Miller DA, Diaz FG, Paul RH. Vaginal birth after Cesarean: a 10-year experience. Obstet Gynecol 1994;84:255–8. 9. Schell JT. Once a Cesarean always a Cesarean? N Y Med J 1923;637. 10. Roberts LJ, Beardsworth SA, Trew G. Labour following Caesarean section: current practice in the United Kingdom. Br J Obstet Gynaecol 1994;101:153–5. 11. Norman P, Kostovcik S, Lanning A. Elective repeat Caesarean sections: how many could be vaginal births? Can Med Assoc J 1993;149:431–5. 12. Kline J, Arias F. Analysis of factors determining the selection of repeated Cesarean section or trial of labor in patients with histories of prior Cesarean delivery. J Reprod Med 1993;38:289–92. 13. National Institutes of Health. Cesarean childbirth. Bethesda (MD): NIH; 1981. Publication No. 82-2067. 14. Flamm BL, Lim OW, Jones C, Fallon D, Newman LA, Mantis JK. Vaginal birth after Cesarean section: results of a multicenter study. Am J Obstet Gynecol 1988;158:1079–84. 15. Socol ML, Peaceman AM. Vaginal birth after Cesarean: an appraisal of fetal risk. Obstet Gynecol 1999;93:674–9. 16. McMahon MJ. Vaginal birth after Cesarean. Clin Obstet Gynecol 1998;41:369–81. 17. Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Canadian Task Force on the Periodic Health Exam. Ottawa (ON): Canada Communication Group; 1994. p. xxxvii. 18. Quilligan EJ. Vaginal birth after Cesarean section: 270 degrees. J Obstet Gynecol Res 2001;27:169–73. 19. Scott JR. Avoiding labor problems during vaginal birth after Cesarean delivery. Clin Obstet Gynecol 1997;40:533–41.

Guidelines for Vaginal Birth After Previous Caesarean Birth

20. Rageth JC, Juzi C, Grossenbacher H. Delivery after previous Cesarean: a risk evaluation. Obstet Gynecol 1999;93:332–7. 21. Lovell R. Vaginal delivery after Caesarean section: factors influencing success rates. Aust N Z J Obstet Gynaecol 1996;36:4–8. 22. Weinstein D, Benshushan A, Tanos V, Zilberstein R, Rojansky N. Predictive score for vaginal birth after Cesarean section. Am J Obstet Gynecol 1996;174:192–8. 23. Flamm BL, Geiger AM. Vaginal birth after Cesarean delivery: an ission scoring system. Obstet Gynecol 1997;90:907–10. 24. Bujold E, Gauthier R. Should we allow a trial of labor after a previous Cesarean for dystocia in the second stage of labor? Obstet Gynecol 2001;98:652–5. 25. Hoskins IA, Gomez JL. Correlation between maximum cervical dilatation at Cesarean delivery and subsequent vaginal birth after Cesarean delivery. Obstet Gynecol 1997;89:591–3. 26. Shipp TD, Zelop CM, Repke JT, Cohen A, Caughey AB, Lieberman E. Labor after previous Cesarean: influence of prior indication and parity. Obstet Gynecol 2000;95:913–6. 27. Hibbard JU, Ismail MA, Wang Y, Te C, Karrison T, Ismail MA. Failed vaginal birth after Cesarean section: how risky is it? Am J Obstet Gynecol 2001;184:1365–73. 28. Rosen MG, Dickinson JC, Westhoff CL. Vaginal birth after Cesarean section: a meta-analysis of morbidity and mortality. Obstet Gynecol 1991;77:465–70. 29. Hemminki E, Merilainen J. Long-term effects of Cesarean sections: ectopic pregnancies and placental problems. Am J Obstet Gynecol 1996;174:1569–74. 30. Gilliam M, Rosenberg D, Davis D. The likelihood of placenta previa with greater number of Cesarean deliveries and higher parity. Obstet Gynecol 2002;99:976–80. 31. Miller DA, Chollet JA, Goodwin TM. Clinical risk factors for placenta previa-placenta accreta. Am J Obstet Gynecol 1997;177:210–4. 32. Mozurkewich EL, Hutton EK. Elective repeat Cesarean delivery versus trial of labor: a meta-analysis of the literature from 1989 to 1999. Am J Obstet Gynecol 2000;183:1187–97. 33. Hook B, Kiwi R, Amini SB, Fanaroff A, Hack M. Neonatal morbidity after elective repeat Cesarean section and trial of labor. Pediatrics 1997;100:348–53. 34. American College of Obstetricians and Gynecologists. Vaginal birth after previous Cesarean delivery. ACOG Practice Bulletin No. 5. Washington (DC): ACOG; 1999. 35. Wing DA, Paul RH. Vaginal birth after Cesarean section: selection and management. Clin Obstet Gynecol 1999;42:836–48. 36. Khan KS, Risvi A. The partograph in the management of labor following Cesarean section. Int J Gynecol Obstet 1995;50:151–7. 37. Guleria K, Dhall GI, Dhall K. Pattern of cervical dilatation in previous lower segment Cesarean section patients. J Indian Med Assoc 1997;95:131–4. 38. Rowbottom SJ, Critchley LAH, Gin T. Uterine rupture and epidural analgesia during trial of labor. Anaesthesia 1997;52:483–8. 39. Society of Obstetricians and Gynaecologists of Canada. Fetal health surveillance in labour. J Obstet Gynaecol Can 2002;112:250–62. 40. Phelan JP, Korst LM, Settles DK. Uterine activity patterns in uterine rupture: a case–control study. Obstet Gynecol 1998;92:394–7. 41. Kaplan B, Royburt M, Peled Y, Hirsch M, Ovadia Y, Neri A. Routine revision of uterine scar after prior Cesarean section. Acta Obstet Gynecol Scand 1994;73:473–5. 42. Bucklin BA. Vaginal birth after Cesarean delivery. Anesthesiology 2003;99:1444–8. 43. Hill DA, Chez RA, Quinlan J, Fuentes A, LaCombe J. Uterine rupture and dehiscence associated with intravaginal misoprostol cervical ripening. J Reprod Med 2000;45:823–6. 44. Yap OWS, Kim ES, Laros RK. Maternal and neonatal outcomes after uterine rupture in labor. Am J Obstet Gynecol 2001;184:1576–81. 45. Appleton B, Targett C, Rasmussen M, Rean E, Sale F, Permezel M. Vaginal birth after Caesarean section: an Australian multicentre study. Aust N Z J Obstet Gynaecol 2000;40:87–91. 46. Shipp TA, Zelop CM, Repke JT, Cohen A, Caughey AB, Lieberman E. Intrapartum uterine rupture and dehiscence in patients with prior lower uterine segment vertical and transverse incisions. Obstet Gynecol 1993;94:735–40.

47. Martin JN, Perry KG, Roberts WE, Meydrech EF. The case for trial of labor in the patient with a prior low-segment vertical Cesarean incision. Am J Obstet Gynecol 1997;177:144–8. 48. Adair CD, Sanchez-Ramos L, Whitaker D, McDyer DC, Farah L, Briones D. Trial of labor in patients with a previous lower uterine vertical Cesarean section. Am J Obstet Gynecol 1996;174:966–70. 49. Stovall TG, Shaver DC, Solomon SK, Anderson GD. Trial of labor in previous Cesarean section patients, excluding classical Cesarean sections. Obstet Gynecol 1987;70:713–7. 50. Shimonovitz S, Botosneano A, Hochner-Celnikier D. Successful first vaginal birth after Cesarean section: a predictor of reduced risk for uterine rupture in subsequent deliveries. Indian Med Assoc J 2000;2:526–8. 51. Kieser KE, Baskett TF. A 10-year population-based study of uterine rupture. Am J Obstet Gynecol 2002;100:749–53. 52. Bujold E, Gauthier RJ. Neonatal morbidity associated with uterine rupture: what are the risk factors? Am J Obstet Gynecol 2002;186:311–4. 53. Smith GCS, Pell JP, Cameron AD, Dobbie R. Risk of perinatal death associated with labor after previous Cesarean delivery in uncomplicated term pregnancies. J Am Med Assoc 2002;287:2684–90. 54. Chauhan SP, Martin JN, Henrichs CE, Morrison JC, Magann EF. Maternal and perinatal complications with uterine rupture in 142 075 patients who attempted vaginal birth after Cesarean delivery: a review of the literature. Am J Obstet Gynecol 2003;189:408–17. 55. Hamilton EF, Bujold E, McNamara H, Gauthier R, Platt RW. Dystocia among women with symptomatic uterine rupture. Am J Obstet Gynecol 2001;184:620–4. 56. Rozenberg P, Goffinet F, Philippe HJ, Nisand I. Ultrasonographic measurement of lower uterine segment to assess the risk of defects of scarred uterus. Lancet 1996;347:281–4. 57. Rozenberg P, Goffinet F, Philippe HJ, Nisand I. Thickness of the lower uterine segment: its influence in the management of patients with previous Cesarean sections. Eur J Obstet Gynecol Reprod Biol 1999;87:39–45. 58. Flamm BL, Goings JR, Fuelbirth N, Fischermann E, Jones C, Hewson SA. Oxytocin during labor after previous Cesarean section: results of a multicenter study. Obstet Gynecol 1987;70:709–12. 59. Zelop CM, Shipp TA, Repke JT, Cohen A, Lieberman E. Uterine rupture during induced or augmented labor in gravid women with one prior Cesarean delivery. Am J Obstet Gynecol 1999;181:882–6. 60. Goetzl L, Shipp TA, Cohen A, Zelop CM, Repke JT, Lieberman E. Oxytocin dose and the risk of uterine rupture in trial of labor after Cesarean. Obstet Gynecol 2001;97:381–4. 61. Ravasia DJ, Wood SL, Pollard JK. Uterine rupture during induced trial of labor among women with previous Cesarean delivery. Am J Obstet Gynecol 2000;183:1176–9. 62. Sanchez-Ramos L, Gaudier FL, Kaunitz AM. Cervical ripening and labor induction after previous Cesarean delivery. Clin Obstet Gynecol 2000;43:513–23. 63. Delaney T, Young DC. Spontaneous versus induced labor after a previous Cesarean delivery. Obstet Gynecol 2003;102:39–44. 64. Stone JL, Lockwood CJ, Berkowitz G, Alvarez M, Lapinski R, Valcamonico A, et al. Use of cervical prostaglandin E2 gel in patients with previous Cesarean section. Am J Perinatol 1994;11:309–12. 65. Flamm BL, Anton D, Goings JR, Newman J. Prostaglandin E2 for cervical ripening: a multicenter study of patients with prior Cesarean delivery. Am J Perinatol 1997;14:157–60. 66. MacKenzie JZ, Bradley S, Embrey MP. Vaginal prostaglandins and labour induction for patients previously delivered by Caesarean section. Br J Obstet Gynaecol 1984;91:7–10. 67. Lyndon-Rochelle M, Holt VL, Easterling TR, Martin DP. Risk of uterine rupture during labor among women with a prior Cesarean delivery. N Engl J Med 2001;345:3–8. 68. Katz VL, Farmer RM, Dean CA, Carpenter ME. Use of misoprostol for cervical ripening. Southern Med J 2000;93:881–4. 69. Sciscione AC, Nguyen L, Manley JS, Schlossman PA, Colmorgen GHC. Uterine rupture during preinduction cervical ripening with misoprostol in a patient with a previous Caesarean delivery. Aust N Z J Obstet Gynaecol 1998;38:96–7. 70. Choy-Hee L, Raynor BD. Misoprostol induction of labor among women with a history of Cesarean delivery. Am J Obstet Gynecol 2001;184:1115–7. 71. Cunha M, Bugalho A, Bique C, Berstrom S. Induction of labor by vaginal misoprostol in patients with previous Cesarean delivery. Acta Obstet Gynecol Scand 1999;78:653–4.

FEBRUARY JOGC FÉVRIER 2005 l

173

SOGC CLINICAL PRACTICE GUIDELINES

72. Plaut MM, Schwartz ML, Lubarsky SL. Uterine rupture associated with the use of misoprostol in the gravid patient with a previous Cesarean section. Am J Obstet Gynecol 1999;180:1535–42. 73. Wing DA, Lovett K, Paul RH. Disruption of prior uterine incision following misoprostol for labor induction in women with previous Cesarean delivery. Obstet Gynecol 1998;91:828–30. 74. Blanchette HA, Nayak S, Erasmus S. Comparison of the safety and efficacy of intravaginal misoprostol (prostaglandin E1) with that of dinoprostone (prostaglandin E2) for cervical ripening and induction of labor in a community hospital. Am J Obstet Gynecol 1999;180:1551–9. 75. American College of Obstetricians and Gynecologists. Induction of labor for vaginal birth after Cesarean delivery. Obstet Gynecol 2002;99:679–80. 76. Ben-Aroya Z, Hallak M, Segal D, Friger M, Katz M, Mazor M. Ripening of the uterine cervix in a post-Cesarean parturient: prostaglandin E2 versus foley catheter. J Matern Fetal Neonatal Med 2002;12:42–5. 77. Bujold E, Blackwell SC, Gauthier RJ. Cervical ripening with transcervical foley catheter and the risk of uterine rupture. Obstet Gynecol 2004;103:18–23. 78. Asakura H, Myers SA. More than one previous Cesarean delivery: a 5-year experience with 435 patients. Obstet Gynecol 1995;85:924–9. 79. Chattopadhay SK, Sherbeeni MM, Anokute CC. Planned vaginal delivery after two previous Caesarean sections. Br J Obstet Gynaecol 1994;101:498–500. 80. Bretelle F, Cravello L, Shojai R, Roger V, D’ercole C, Blanc B. Vaginal birth following two previous Cesarean sections. Eur J Obstet Gynecol Reprod Biol 2001;94:23–6. 81. Phelan JP, Ahn MO, Diaz F, Brar HS, Rodriguez MH. Twice a Cesarean, always a Cesarean? Obstet Gynecol 1989;73:161–5. 82. Porreco RP, Meier PR. Trial of labor in patient with multiple previous Cesarean sections. J Reprod Med 1983;28:770–2. 83. Farmakides G, Duvivier R, Schulman H, Schneider E, Biordi J. Vaginal birth after two or more previous Cesarean sections. Am J Obstet Gynecol 1987;156:565–6. 84. Caughey AB, Shipp TA, Repke JT, Zelop CM, Cohen A, Lieberman E. Rate of uterine rupture during a trial of labor in women with one or two prior Cesarean deliveries. Am J Obstet Gynecol 1999;181:872–6. 85. Miller DA, Mullin P, Hou D, Paul RH. Vaginal birth after Cesarean section in twin gestation. Am J Obstet Gynecol 1996;175:194–8. 86. Strong TH, Phelan JP, Ahn MO, Sarno AP. Vaginal birth after Cesarean section in the twin gestation. Am J Obstet Gynecol 1989;161:29–32. 87. Odeh M, Tarazova L, Wolfson M, Oettinger M. Evidence that women with a history of Cesarean section can deliver twins safely. Acta Obstet Gynecol Scand 1997;76:663–6. 88. Myles T. Vaginal birth of twins after previous Cesarean section. J Maternal Fetal Med 2001;10:171–4. 89. Wax JR, Philput C, Mather J, Steinfeld JD, Ingardia CJ. Twin vaginal birth after Cesarean. Conn Med 2000;64:205–8. 90. Sansregret A, Bujold E, Gauthier RJ. Twin delivery after a previous Caesarean: a twelve-year experience. J Obstet Gynaecol Can 2003;25:294–8. 91. Delaney T, Young DC. Trial of labour compared to elective Caesarean in twin gestations with a previous Caesarean delivery. J Obstet Gynaecol Can 2003;25:289–92. 92. Hannah ME, Hannah WJ, Hewson SA. Planned Cesarean section versus planned vaginal birth for breech presentation at term: a randomised multicenter trial. Lancet 2000;356:1375–83. 93. Society of Obstetricians and Gynaecologists of Canada. SOGC statement on vaginal breech. Ottawa (ON): SOGC; 1999. 94. de Meeus JB, Ellia F, Magnin G. External cephalic version after previous Cesarean section: a series of 38 cases. Eur J Obstet Gynecol Reprod Biol 1998;81:65–8. 95. Flamm BL, Fried MW, Lonky NM. External cephalic version after previous Cesarean section. Am J Obstet Gynecol 1991;165:370–2.

174

l FEBRUARY JOGC FÉVRIER 2005

96. Coleman TL, Randall H, Graves W, Lindsay M. Vaginal birth after Cesarean among women with gestational diabetes. Am J Obstet Gynecol 2001;184:1104–7. 97. Blackwell SC, Hassan SS, Wolfe HM, Michaelson J, Berry SM, Sorokin Y. Vaginal birth after Cesarean in the diabetic gravida. J Reprod Med 2000;45:987–90. 98. Zelop CM, Shipp TA, Repke JT, Cohen A, Lieberman E. Outcomes of trial of labor following previous Cesarean delivery among women with fetuses weighing >4000 g. Am J Obstet Gynecol 2001;185:903–5. 99. Flamm BL, Goings JR. Vaginal birth after Cesarean section: is suspected fetal macrosomia a contraindication? Obstet Gynecol 1989;74:694–7. 100. Phelan JP, Eglinton GS, Horenstein JM. Previous Cesarean birth: trial of labor in women with macrosomic infants. J Reprod Med 1984;29:36–40. 101. Elkousy MA, Sammel M, Stevens E, Peipert JF, Macones G. The effect of birth weight on vaginal birth after Cesarean delivery success rates. Am J Obstet Gynecol 2003;188:824–30. 102. Esposito MA, Menihan CA, Malee MP. Association of interpregnancy interval with uterine scar failure in labor: a case-control study. Am J Obstet Gynecol 2000;183:1180–3. 103. Shipp TA, Zelop CM, Repke JT, Cohen A, Lieberman E. Interdelivery interval and risk of symptomatic uterine rupture. Obstet Gynecol 2001;97:175–7. 104. Huang WH, Nakashima DK, Rumney PJ, Keegan KA, Chan K. Interdelivery interval and the success of vaginal birth after Cesarean delivery. Obstet Gynecol 2002;99:41–4. 105. Bujold E, Mehta SH, Bujold C, Gauthier R. Interdelivery interval and uterine rupture. Am J Obstet Gynecol 2002;187:1199–202. 106. Yeh S, Huang X, Phelan JP. Post-term pregnancy after previous Cesarean section. J Reprod Med 1984;29:41–4. 107. Callahan C, Chescheir N, Steiner BD. Safety and efficacy of attempted vaginal birth after Cesarean beyond the estimated date of delivery. J Reprod Med 1999;44:606–10. 108. Zelop CM, Shipp TA, Cohen A, Repke JT, Lieberman E. Trial of labor after 40 weeks’ gestation in women with prior Cesarean. Obstet Gynecol 2001;97:391–3. 109. Hauth JC, Owen J, Davis RO. Transverse uterine incision closure: one versus two layers. Am J Obstet Gynecol 1992;167:1108–11. 110. Ohel G, Younis JS, Lang N, Levit A. Double-layer closure of uterine incision with visceral and parietal peritoneal closure: are they obligatory? J Matern Fetal Med 1996;5:366–9. 111. Chapman SJ, Owen J, Hauth JC. One- versus two-layer closure of a low transverse Cesarean: the next pregnancy. Obstet Gynecol 1997;89:16–8. 112. Bujold E, Bujold C, Hamilton EF, Harel F, Gauthier R. The impact of a single-layer or double-layer closure on uterine rupture. Am J Obstet Gynecol 2002;186:1326–30. 113. Grubb DK, Kjos SL, Paul RH. Latent labor with an unknown uterine scar. Obstet Gynecol 1996;88:351–5. 114. Lau TK, Chan F. Unknown uterine scars, unknown risks. Aust N Z J Obstet Gynaecol 1994;34:216–7. 115. Beall M, Eglinton GS, Clark SL, Phelan JP. Vaginal delivery after Cesarean section in women with unknown types of uterine scar. J Reprod Med 1984;29(1):32–5. 116. Chauhan SP, Magann EF, Carroll CS, Barrilleaux PS, Scardo JA, Martin JN. Mode of delivery for the morbidly obese with prior Cesarean delivery: vaginal versus repeat Cesarean section. Am J Obstet Gynecol 2001;185:349–54. 117. Shipp TA, Zelop CM, Cohen A, Repke JT, Lieberman E. Post-Cesarean delivery fever and uterine rupture in a subsequent trial of labor. Am J Obstet Gynecol 2003;101: 136–9. 118. Ravasia DJ, Brain PH, Pollard JK. Incidence of uterine rupture among women with müllerian duct anomalies who attempt vaginal birth after Cesarean delivery. Am J Obstet Gynecol 1999;181:877–81. 119. Shipp TA, Zelop CM, Repke JT, Cohen A, Caughey AB, Lieberman E. Maternal age as a predictor of symptomatic uterine rupture during a trial of labor after previous Cesarean delivery. Am J Obstet Gynecol 2001;184:S186.