Updates on the Safety of Using Newer IBD Medications during Pregnancy
IBD Clinical Pearl: June 2020
Jill K. J. Gaidos, MD
Associate Professor, Virginia Commonwealth University
Director, Inflammatory Bowel Disease
Hunter Holmes McGuire VA Medical Center
The diagnosis of inflammatory bowel diseases (IBD) overlaps with key childbearing years. Approximately 50% of patients are under 35 years of age when they are diagnosed with IBD.1 Within the IBD population, there is a high rate of voluntary childlessness due to concerns about the safety of continuing IBD medications during pregnancy.2 Studies have shown that discussing the safety of IBD medications and the importance of medication adherence during pregnancy with patients prior to conception improves medication adherence, leads to less disease activity, and contributes to a lower risk for low birth weight infants.3
Older IBD therapy recommendations during pregnancy (methotrexate, steroids, aminosalicylates, anti-TNF agents, and thiopurines)
For the older IBD therapies, the recommendations for use in pregnancy have not changed much in the last few years. Methotrexate continues to be contraindicated during pregnancy and should be discontinued at least 3 months prior to conception.4 Steroids should be avoided during pregnancy unless they are needed to treat a flare as their use has been associated with an increased risk for gestational diabetes and low birth weight. 5 Steroid use, however, is not associated with an increase in congenital anomalies including cleft lip or cleft palate.5 Aminosalicylate medications, including mesalamine and sulfasalazine, are safe to continue throughout pregnancy. However, patients on sulfasalazine should have their folate supplement increased to 2 mg daily. Given the possible risk for adverse side effects and the long onset of action with thiopurines, they should not be started during pregnancy, but can be safely continued for maintenance of disease remission.
Anti-tumor necrosis factor (anti-TNF) agents (including infliximab, adalimumab, certolizumab pegol, golimumab, and biosimilars), have been shown to be safe to continue throughout pregnancy. 6 There is a decreased risk of disease flare when anti-TNF agents are continued throughout the 3rd trimester and there is no increased risk of infection in infants following intrauterine exposure.6 The dosing interval of an infusion or injectable medication can be adjusted slightly for the longest duration between medication administration and delivery without missing any doses. These medications should be resumed 1-2 days after delivery with dosing based on the pre-pregnancy weight. Consideration should be given to discontinuing thiopurines in patients who are in stable disease remission and who are on combination thiopurine and anti-TNF medications because there is an increased risk for infections in the newborn up to 1 year of age7. However, this consideration should be decided on a case-by-case basis depending on the patient’s IBD severity and medication needs to stay in clinical remission.
Newer IBD therapy recommendations during pregnancy (vedolizumab, ustekinumab, and tofacitinib)
Data on the safety of using the newer IBD medications during pregnancy is slowly becoming available only after the therapies receive FDA-approval for use. As clinical trials on investigational medications exclude women who are pregnant or breastfeeding, information on medication safety for this population typically comes from post-marketing registries and clinical experience.
Vedolizumab is an α4β7 anti-integrin medication that was approved for the treatment of Crohn’s disease and ulcerative colitis in 2014. A recent retrospective, multicenter, case-control study, including 79 pregnancies in women treated with vedolizumab compared to 186 pregnancies in women treated with anti-TNF medications and 184 pregnancies in women who were not exposed to immunomodulators or anti-TNF medications, found no increase in the rates of spontaneous abortion; gestational age; birth weight; Appearance,Pulse, Grimace, Activity, and Respiration (APGAR) scores; congenital anomalies;, or infections in infants in the first year of life8. Ustekinumab is an anti-IL 12/23 antibody that was approved for the treatment of Crohn’s disease in 2016 and for the treatment of ulcerative colitis in 2019. A review of the pharmaceutical company safety database, including the outcomes of 206 pregnancies (164 with psoriasis, 6 with psoriatic arthritis and 36 with Crohn’s disease) with exposure to ustekinumab, found no difference in spontaneous abortions, live births, or congenital anomalies compared to the general population in the United States.9 Tofacitinib is the newest medication to receive FDA approval for the treatment of ulcerative colitis in 2018 and as such, there is limited data on the safety of use during pregnancy. In a small study, including 11 pregnancies in women treated with tofacitinib at the time of conception or during pregnancy, there was no signal for an increase in stillbirth, congenital malformation, or spontaneous abortion.10 However, because there is so little information right now, it is recommended that women discontinue tofacitinib at least 1 week prior to conception if another treatment option is available to maintain disease remission4.
IBD therapy recommendations while nursing
The use of these medications while nursing mirrors their use in pregnancy. Methotrexate and tofacitinib are not recommended to be used while nursing, but azathioprine/6-mercaptopurine and the biologic agents (including anti-TNFs, vedolizumab, and ustekinumab) can all safely be continued. There are no longer any recommendations to adjust the timing of breastfeeding based on medication dosing and there is no evidence to support “pumping and dumping.”4 Any infant with intrauterine exposure to a biologic agent, except certolizumab pegol, should avoid live vaccines for the first 6 months of life. 11 Certolizumab pegol is only passively transported across the placenta and is found in much lower levels in infant cord blood at the time of birth.11
We are continuing to learn more about the safety of using IBD medications during pregnancy as research and clinical experience grow. Studies continue to show an increased risk of adverse pregnancy and fetal outcomes in women with active disease at conception and during pregnancy including preterm birth, low birth weight, and stillbirth.12 For this reason, women with IBD should be in clinical and endoscopic remission on a steroid-free medication regimen for at least 3 months prior to conception and should stay on their IBD medications throughout their pregnancy. Discussing the importance and safety of continuing IBD medications with patients will lead to better outcomes for the mother and for the baby.