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. 2019 Jul 23;7(7):CD012711.
doi: 10.1002/14651858.CD012711.pub2.

The impact of surgical therapies for inflammatory bowel disease on female fertility

Sangmin Lee  1 , Megan Crowe, Cynthia H Seow, Paulo G Kotze, Gilaad G Kaplan, Amy Metcalfe, Amanda Ricciuto, Eric I Benchimol, M Ellen Kuenzig
Affiliations

The impact of surgical therapies for inflammatory bowel disease on female fertility

Sangmin Lee et al. Cochrane Database Syst Rev. .

Abstract

Background: Women with inflammatory bowel disease (IBD) may require surgery, which may result in higher risk of infertility. Restorative proctocolectomy with ileal anal pouch anastomosis (IPAA) may increase infertility, but the degree to which IPAA affects infertility remains unclear, and the impact of other surgical interventions on infertility is unknown.

Objectives: Primary objective• To determine the effects of surgical interventions for IBD on female infertility.Secondary objectives• To evaluate the impact of surgical interventions on the need for assisted reproductive technology (ART), time to pregnancy, miscarriage, stillbirth, prematurity, mode of delivery (spontaneous vaginal, instrumental vaginal, or Caesarean section), infant requirement for resuscitation and neonatal intensive care, low and very low birth weight, small for gestational age, antenatal and postpartum hemorrhage, retained placenta, postpartum depression, gestational diabetes, and gestational hypertension/preeclampsia.

Search methods: We searched MEDLINE, Embase, CENTRAL, and the Cochrane IBD Group Specialized Register from inception to September 27, 2018, to identify relevant studies. We also searched references of relevant articles, conference abstracts, grey literature, and trials registers.

Selection criteria: We included observational studies that compared women of reproductive age (≥ 12 years of age) who underwent surgery to women with IBD who had a different type of surgery or no surgery (i.e. treated medically). We also included studies comparing women before and after surgery. Any type of IBD-related surgery was permitted. Infertility was defined as an inability to become pregnant following 12 months of unprotected intercourse. Infertility at 6, 18, and 24 months was included as a secondary outcome. We excluded studies that included women without IBD and those comparing women with IBD to women without IBD..

Data collection and analysis: Two review authors independently screened studies and extracted data. We used the Newcastle-Ottawa Scale to assess bias and GRADE to assess the overall certainty of evidence. We calculated the pooled risk ratio (RR) and 95% confidence interval (CI) using random-effects models. When individual studies reported odds ratios (ORs) and did not provide raw numbers, we pooled ORs instead.

Main results: We identified 16 observational studies for inclusion. Ten studies were included in meta-analyses, of which nine compared women with and without a previous IBD-related surgery and the other compared women with open and laparoscopic IPAA. Of the ten studies included in meta-analyses, four evaluated infertility, one evaluated ART, and seven reported on pregnancy-related outcomes. Seven studies in which women were compared before and after colectomy and/or IPAA were summarized qualitatively, of which five included a comparison of infertility, three included the use of ART, and three included other pregnancy-related outcomes. One study included a comparison of women with and without IPAA, as well as before and after IPAA, and was therefore included in both the meta-analysis and the qualitative summary. All studies were at high risk of bias for at least two domains.We are very uncertain of the effect of IBD surgery on infertility at 12 months (RR 5.45, 95% CI 0.41 to 72.57; 114 participants; 2 studies) and at 24 months (RR 3.59, 95% CI 1.32 to 9.73; 190 participants; 1 study). Infertility was lower in women who received laparoscopic surgery compared to open restorative proctocolectomy at 12 months (RR 0.70, 95% CI 0.38 to 1.27; 37 participants; 1 study).We are very uncertain of the effect of IBD surgery on pregnancy-related outcomes, including miscarriage (OR 2.03, 95% CI 1.14 to 3.60; 776 pregnancies; 5 studies), use of ART (RR 25.09, 95% CI 1.56 to 403.76; 106 participants; 1 study), delivery via Caesarean section (RR 2.23, 95% CI 1.00 to 4.95; 20 pregnancies; 1 study), stillbirth (RR 1.96, 95% CI 0.42 to 9.18; 246 pregnancies; 3 studies), preterm birth (RR 1.91, 95% CI 0.67 to 5.48; 194 pregnancies; 3 studies), low birth weight (RR 0.61, 95% CI 0.08 to 4.83), and small for gestational age (RR 2.54, 95% CI 0.80 to 8.01; 65 pregnancies; 1 study).Studies comparing infertility before and after IBD-related surgery reported numerically higher rates of infertility at six months (before: 1/5, 20.0%; after: 9/15, 60.0%; 1 study), at 12 months (before: 68/327, 20.8%; after: 239/377, 63.4%; 5 studies), and at 24 months (before: 14/89, 15.7%; after: 115/164, 70.1%; 2 studies); use of ART (before: 5.3% to 42.2%; after: 30.3% to 34.3%; proportions varied across studies due to differences in which women were identified as at risk of using ART); and delivery via Caesarean section (before: 8/73, 11.0%; after: 36/75, 48.0%; 2 studies). In addition, women had a longer time to conception after surgery (two to five months; 2 studies) than before surgery (5 to 16 months; 2 studies). The proportions of women experiencing miscarriage (before: 19/123, 15.4%; after: 21/134, 15.7%; 3 studies) and stillbirth (before: 2/38, 5.3%; after: 3/80: 3.8%; 2 studies) were similar before and after surgery. Fewer women experienced gestational diabetes after surgery (before: 3/37, 8.1%; after: 0/37; 1 study), and the risk of preeclampsia was similar before and after surgery (before: 2/37, 5.4%; after: 0/37; 1 study). We are very uncertain of the effects of IBD-related surgery on these outcomes due to poor quality evidence, including confounding bias due to increased age of women after surgery.We rated evidence for all outcomes and comparisons as very low quality due to the observational nature of the data, inclusion of small studies with imprecise estimates, and high risk of bias among included studies.

Authors' conclusions: The effect of surgical therapy for IBD on female infertility is uncertain. It is also uncertain if there are any differences in infertility among those undergoing open versus laparoscopic procedures. Previous surgery was associated with higher risk of miscarriage, use of ART, Caesarean section delivery, and giving birth to a low birth weight infant, but was not associated with risk of stillbirth, preterm delivery, or delivery of a small for gestational age infant. These findings are based on very low-quality evidence. As a result, definitive conclusions cannot be made, and future well-designed studies are needed to fully understand the impact of surgery on infertility and pregnancy outcomes.

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Conflict of interest statement

Sangmin Lee: none known.

Megan Crowe: none known.

Cynthia H Seow: Dr. Seow has served as a consultant and on advisory boards for Janssen Pharmaceuticals, Abbvie, Takeda, Actavis, Ferring, Shire, and Pfizer. She has received an educational grant through Janssen Pharmaceuticals. Dr. Seow has also provided lectures for Janssen Pharmaceuticals, Abbvie, Ferring, Shire, and Takeda.

Paulo G. Kotze: Dr. Kotze has received speaking and consultancy honoraria from Abbvie, Janssen, Pfizer, Takeda, and UCB.

Gilaad G Kaplan: Dr. Kaplan has received honoraria for speaking or consultancy from Abbvie, Janssen, Pfizer, and Takeda. He has received research support from Janssen, Abbvie, GlaxoSmith Kline, Merck, and Shire. He shares ownership of a patent: TREATMENT OF INFLAMMATORY DISORDERS, AUTOIMMUNE DISEASE, AND PBC. UTI Limited Partnership, assignee. Patent 62/555,397. September 7, 2017.

Amy Metcalfe: none known.

Amanda Ricciuto: none known.

Eric I Benchimol: none known.

M Ellen Kuenzig: none known.

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1 Any surgery versus no surgery, Outcome 1 Infertiltiy at 12 Months.
1.2
1.2. Analysis
Comparison 1 Any surgery versus no surgery, Outcome 2 Infertility at 24 Months.
1.3
1.3. Analysis
Comparison 1 Any surgery versus no surgery, Outcome 3 Miscarriage.
1.4
1.4. Analysis
Comparison 1 Any surgery versus no surgery, Outcome 4 Miscarriage ‐ Sensitivity Analysis Based on Source of Participants.
1.5
1.5. Analysis
Comparison 1 Any surgery versus no surgery, Outcome 5 Miscarriage ‐ Sensitivity Analysis Including Only Women in Remisson at Conception.
1.6
1.6. Analysis
Comparison 1 Any surgery versus no surgery, Outcome 6 Stillbirth.
1.7
1.7. Analysis
Comparison 1 Any surgery versus no surgery, Outcome 7 Stillbirth ‐ Sensitivity Analysis Based on Source of Participants.
1.8
1.8. Analysis
Comparison 1 Any surgery versus no surgery, Outcome 8 Stillbirth ‐ Sensitivity Analysis Including Only Women in Remission at Conception.
1.9
1.9. Analysis
Comparison 1 Any surgery versus no surgery, Outcome 9 Use of ART.
1.10
1.10. Analysis
Comparison 1 Any surgery versus no surgery, Outcome 10 Caesarean Section.
1.11
1.11. Analysis
Comparison 1 Any surgery versus no surgery, Outcome 11 Preterm Delivery.
1.12
1.12. Analysis
Comparison 1 Any surgery versus no surgery, Outcome 12 Preterm Delivery ‐ Sensitivity Analysis Based on Source of Participants.
1.13
1.13. Analysis
Comparison 1 Any surgery versus no surgery, Outcome 13 Preterm Delivery ‐ Sensitivity Analysis Including Only Women in Remisson at Conception.
1.14
1.14. Analysis
Comparison 1 Any surgery versus no surgery, Outcome 14 Low Birth Weight.
1.15
1.15. Analysis
Comparison 1 Any surgery versus no surgery, Outcome 15 Small for Gestational Age.
2.1
2.1. Analysis
Comparison 2 Laparoscopic versus open surgery, Outcome 1 Infertiltiy at 12 Months.
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