STRUCTURED ABSTRACT

Question: How can gastroenterologists manage pregnant patients with inflammatory bowel disease (IBD)? How can they counsel patients seeking pregnancy and postpartum care?

Design: The Helmsley PIANO Expert Global Consensus group used GRADE¹ methodology to assess the quality of evidence and formulate recommendations when the evidence is available. For topics lacking data suitable for GRADE, the RAND/UCLA2 appropriateness method was applied to achieve expert consensus. The population, intervention, comparison, outcome (PICO) format was used. The consensus panel included 39 international experts including gastroenterologists, colorectal surgeons, maternal-fetal medicine specialists, teratologists, and lactation experts.

Patients: Women with IBD before conception, during pregnancy, and in the postpartum period. There is also guidance on vaccine schedules for infants born to mothers with IBD.

Interventions/Exposure: Ten topics are highlighted in this document: maternal factors impacting pregnancy, fertility, preconception counseling and optimization, management of active disease during pregnancy, management of pregnancy, use of IBD medications during pregnancy, use of IBD medications during lactation, pregnancy adverse events, fetal and neonatal adverse events, and vaccines.

Specific medications were discussed including 5-aminosalicylates, sulfasalazine, corticosteroids, methotrexate, thiopurines, anti-tumor necrosis factor agents, biosimilars, vedolizumab, ustekinumab, IL-23 agents, antibiotics, calcineurin inhibitors, sphingosine-1-phosphate receptor modulators, and Janus kinase inhibitors.

Outcomes: Outcomes discussed included pregnancy adverse events (low birth weight, preterm birth, congenital malformations, spontaneous abortion, and venous thromboembolism), mode of delivery, fetal and neonatal adverse events (neonatal intensive care unit admission, hospitalizations, childhood malignancy, developmental delay, and long-term health outcomes).

Data Analysis: Recommendations were graded as “strong” or “conditional” using the GRADE methodology. With a strong recommendation, gastroenterologists should recommend the intervention for most patients. A strong recommendation is usually accompanied by High or Moderate Level of Evidence from well-designed randomized controlled trials (RCTs) or RCTs with mild methodologic limitations. With a conditional recommendation, gastroenterologists might suggest this therapy or diagnostic test, while other doctors would not suggest this intervention in similar patients. Conditional recommendations are usually accompanied by Low quality or Very Low quality of evidence from studies without a comparator arm or placebo for comparison. The RAND panel was applied where robust evidence was lacking.

Funding: The Leona M. and Harry B. Helmsley Charitable Trust.

Results: There are 34 recommendations and 35 consensus statements (Tables 1 and 2). Topics covered include fertility, management of disease during pregnancy, medications in pregnancy, and fetal and neonatal adverse events.

Table 1. GRADE Statements 

Maternal factors impacting pregnancy to be addressed in counseling
1. We suggest counseling that children with first-degree relatives with IBD, as compared with those without, have an increased risk of development of IBD.
Recommendation: Conditional
Level of Evidence: Low

Fertility
2. We suggest counseling that women with IBD may have decreased fertility compared with women without IBD.
Recommendation: Conditional
Level of Evidence: Very low

3. In women with ulcerative colitis, we suggest counseling that prior ileal pouch anal anastomosis is associated with decreased fertility when compared with women with ulcerative colitis who have not had ileal pouch anal anastomosis.
Recommendation: Conditional
Level of Evidence: Very low

4. In women with IBD, we recommend counseling that active disease increases the risk of infertility as compared with inactive disease.
Recommendation: Strong
Level of Evidence: Very Low

5. We suggest counseling that women with IBD may have comparable effectiveness of assisted reproductive technology when compared with women without IBD as measured by live birth.
Recommendation: Conditional
Level of Evidence: Very low

6. We suggest counseling that women with IBD who have undergone pelvic surgery with IBD have similar effectiveness of in vitro fertilization when compared with women without IBD, as measured by live birth.
Recommendation: Conditional
Level of Evidence: Very low

Preconceptional counseling and optimization
7. We recommend that women with IBD undergo preconceptional counseling.
Recommendation: Strong
Level of Evidence: Low

Management of disease activity during pregnancy
8. We suggest that urgent and emergent IBD surgery during pregnancy be completed when required, and not based on trimester.
Recommendation: Conditional
Level of Evidence: Very low

Management of pregnancy
9. We suggest that pregnant women with IBD take low-dose aspirin by 12–16 weeks gestation to prevent preterm preeclampsia.
Recommendation: Conditional
Level of Evidence: Low

10. We suggest that pregnant women with Crohn’s disease and active perianal disease undergo Cesarean delivery.
Recommendation: Conditional
Level of Evidence: Very low

11. We suggest that pregnant women with IBD and prior ileal pouch anal anastomosis consider Cesarean delivery.
Recommendation: Conditional
Level of Evidence: Very low

Medications in pregnancy
12. For women with IBD who are pregnant or attempting conception, we recommend continuing maintenance 5-ASA therapy.
Recommendation: Strong
Level of Evidence: Low

13. In women with IBD who are pregnant or attempting conception, we suggest continuing maintenance sulfasalazine therapy.
Recommendation: Conditional
Level of Evidence: Very low

14. In women with IBD who are pregnant, we suggest use of corticosteroid therapy when clinically necessary with appropriate monitoring.
Recommendation: Conditional
Level of Evidence: Low

15. In women with IBD, we recommend discontinuing maintenance methotrexate therapy prior to conception.
Recommendation: Strong
Level of Evidence: Very low

16. In women with IBD who are pregnant or attempting conception, we suggest continuing maintenance thiopurine therapy as data does not demonstrate an increased risk of congenital malformations or infant infections.
Recommendation: Conditional
Level of Evidence: Very low

17. In women with IBD who are pregnant or attempting conception, we recommend continuing maintenance anti-TNF therapy throughout pregnancy.
Recommendation: Strong
Level of Evidence: Low

18. In women with IBD who are pregnant or attempting conception, we suggest continuing maintenance combination therapy with an anti-tumor necrosis factor and thiopurine therapy throughout pregnancy.
Recommendation: Conditional
Level of Evidence: Very low

19. In women with IBD who are pregnant or attempting conception, we suggest continuing maintenance vedolizumab therapy throughout pregnancy.
Recommendation: Conditional
Level of Evidence: Low

20. In women with IBD who are pregnant or attempting conception, we suggest continuing maintenance ustekinumab therapy throughout pregnancy.
Recommendation: Conditional
Level of Evidence: Low

Medications during lactation
21. We recommend breastfeeding as it is not associated with an increased risk of disease exacerbation in women with IBD.
Recommendation: Strong
Level of Evidence: Very low

22. We suggest counseling that infants born to mothers on anti-TNF therapy who breastfeed have no increased risk of infection in the first 12 months of life.
Recommendation: Conditional
Level of Evidence: Very low

Pregnancy adverse events
23. We suggest counseling that women with IBD as compared with women without IBD have an increased risk of adverse pregnancy outcomes including low birth weight and preterm delivery.
Recommendation: Conditional
Level of Evidence: Very low

24. We suggest counseling that women with IBD with moderate to severe disease activity have an increased risk of spontaneous abortion as compared with women without IBD or women with mild IBD.
Recommendation: Conditional
Level of Evidence: Very low

25. We suggest counseling that pregnant women with IBD have an increased risk of VTE during pregnancy as compared with pregnant women without IBD.
Recommendation: Conditional
Level of Evidence: Low

26. We suggest counseling that pregnant women with IBD have an increased risk of VTE during the postpartum as compared with pregnant women without IBD.
Recommendation: Conditional
Level of Evidence: Low

Fetal and neonatal adverse events
27. We suggest counseling that children born to women with IBD have an increased rate of neonatal intensive care unit admissions and hospitalizations in the first year of life compared with children born to women without IBD.
Recommendation: Conditional
Level of Evidence: Very low

28. We suggest counseling that children born to women with active IBD have an increased rate of small for gestational age and low birth weight compared with children born to women with inactive IBD.
Recommendation: Conditional
Level of Evidence: Very low

29. We suggest counseling that children born to women treated with anti-tumor necrosis factor therapy, ustekinumab, or vedolizumab during pregnancy have no increased risk for early childhood malignancy.
Recommendation: Conditional
Level of Evidence: Very low

30. We suggest counseling that children born to women treated with anti-tumor necrosis factor therapy, ustekinumab, or vedolizumab during pregnancy have no increased risk for early childhood developmental delay.
Recommendation: Conditional
Level of Evidence: Very low

31. We suggest counseling that children born to women treated with thiopurine therapy during pregnancy have no increased risk for early childhood developmental delay.
Recommendation: Conditional
Level of Evidence: Very low

Vaccines
32. We recommend that inactive vaccines be provided to children born to mothers with IBD on anti-TNF agents.
Recommendation: Strong
Level of Evidence: Very low

33. We suggest that live rotavirus vaccine may be provided in children with in utero exposure to biologics.
Recommendation: Conditional
Level of Evidence: Very low

34. We recommend that live Bacillus Calmette-Guérin vaccine be avoided in the first 6 months^a of life in children with in utero exposure to anti-TNF therapy due to risk of disseminated tuberculosis and associated mortality.
Recommendation: Strong
Level of Evidence: Very low

^aRegional risk should be considered.
5-ASA, 5-aminosalicylate; IBD, inflammatory bowel disease; TNF, tumor necrosis factor; VTE, venous thromboembolism.

Table 2. Consensus Statements 

Maternal factors impacting pregnancy
1. Children born to a parent with Crohn’s disease may have a higher risk of developing IBD than children born to a parent with UC.

Fertility
2. Women with IBD may have reduced fertility compared with women without IBD due to reduced ovarian reserve.
3. Women with IBD may undergo oocyte retrieval without increased risk of flare.

Preconceptional counseling and optimization
4. Women with IBD desiring contraception should use long-acting reversible contraception over estrogen-containing contraceptives.
5. Women with IBD should be in documented remission and medically optimized prior to elective conception.

Management of disease activity during pregnancy
6. Endoscopy during pregnancy among women with IBD is low risk but should only be performed if it may change management.
7. If cross-sectional imaging is needed during pregnancy, intestinal ultrasound and MRI without gadolinium are preferred to CT.
8. Fecal calprotectin is useful for monitoring disease activity in pregnant women with IBD.

Management of pregnancy
9. Pregnancies for women with IBD should be considered as high risk for complications.
10. Women with current or past history of rectovaginal fistulas should deliver by Cesarean delivery.
11. Women with IBD should be assessed early in pregnancy or preconception for nutritional status, weight gain, and micronutrient deficiency.

Medications during pregnancy
12. Women with IBD who are pregnant and with active disease should start or optimize the same appropriate therapies as in nonpregnant patients, except for thiopurines, methotrexate, JAKis inhibitors, and S1P receptor modulators.
13. In women with IBD who continue thiopurines during pregnancy, precaution should be taken for intrahepatic cholestasis by measurement of liver enzymes, metabolite levels, and consideration of split dosing.
14. Women with IBD who are pregnant and have infections, fistula, or pouchitis that require antibiotics may take an appropriate course of a low-risk antibiotic.
15. Women with IBD may initiate or continue calcineurin inhibitors (cyclosporine and tacrolimus) during pregnancy with careful monitoring if there are no viable alternate treatment options available.
16. Women with IBD who are pregnant or attempting conception should continue biosimilars to existing biologics.
17. Women with IBD who are pregnant or attempting conception should continue anti-interleukin (IL)-23 therapy throughout pregnancy (mirikizumab, risankizumb, guselkumab).
18. Women with IBD should discontinue ozanimod at least 3 months prior to conception unless there is no effective alternative therapy to maintain maternal health.
19. Women with IBD should discontinue etrasimod at least 1–2 weeks prior to conception unless there is no effective alternative therapy to maintain maternal health.
20. Women with IBD should discontinue tofacitinib at least 4 weeks prior to conception unless there is no effective alternative therapy to maintain maternal health.
21. Women with IBD should discontinue upadacitinib at least 4 weeks prior to conception unless there is no effective alternative therapy to maintain maternal health.
22. Women with IBD should discontinue filgotinib at least 4 weeks prior to conception unless there is no effective alternative therapy to maintain maternal health.

Medications during lactation
23. Mothers with IBD currently on 5-ASA/sulfasalazine may breastfeed.
24. Mothers with IBD currently on thiopurines may breastfeed.
25. Mothers with IBD currently on corticosteroids may breastfeed.
26. Mothers with IBD currently on anti-TNF agents (infliximab, adalimumab, golimumab, certolizumab) may breastfeed.
27. Mothers with IBD currently on anti-integrins (vedolizumab, natalizumab) may breastfeed.
28. Mothers with IBD currently on anti-interleukin-12/23 and anti-interluekin-23 agents may breastfeed (ustekinumab, risankizumab, mirikizumab, guselkumab).
29. Mothers with IBD currently on biosimilars may breastfeed.
30. Mothers with IBD currently on S1P receptor modulators (etrasimod or ozanimod) should not breastfeed.
31. Mothers with IBD currently on JAKis (tofacitinib, upadacitinib, filgotinib) should not breastfeed.

Pregnancy adverse events
32. Controlling disease activity during pregnancy among women with IBD is critical to reduce adverse outcomes.

Vaccines
33. Inactive vaccines should be given on schedule to infants of women with IBD regardless of in utero IBD medication exposure.
34. Children exposed to JAKis or S1P receptor modulators in utero may receive live vaccines after 1 month of age.
35. Live vaccines can be given to infants of mothers breastfeeding while on biologics.

Abbreviations: 5-ASA, 5-aminosalicylate; CT, computed tomography; IBD, inflammatory bowel disease; JAKis, Janus kinase inhibitors; MRI, magnetic resonance imaging; S1P, sphingosine-1-phosphate; TNF, tumor necrosis factor.

Visual abstract: Global Consensus on the Management of Pregnancy in IBD.
BCG, Bacillus Calmette-Guerin; IBD, inflammatory bowel disease; IPAA, ileal pouch anal anastomosis; NICU, neonatal intensive care unit; SGA, small gestational age; VTE, venous thromboembolism.

The guidelines still emphasize the importance of preconception counseling and achieving disease remission prior to conception to lower the risk of adverse pregnancy outcomes. Decreased fertility remains an important outcome in post-surgical patients, especially in patients with ileal pouch anal anastomosis.

Note: An author of this study are active on social media. Tag them to discuss their work and this EBGI summary.@Vasantham_A
Vasantham Chaudhary, MD