Use of Immunomodulators and Biologics Before, During, and After Pregnancy

Abstract

Immunomodulators and biologic medications, alone or in combination, form the core therapeutic strategy for managing moderate-to-severe inflammatory bowel disease (IBD). IBD incidence peaks during the prime reproductive years, raising concerns about the impact of disease and its treatment on fertility, maternal and fetal health during pregnancy, breastfeeding safety, and childhood development. Although IBD increases risk of pregnancy complications independent of disease activity, adverse pregnancy outcomes are more common when disease is active. To mitigate fetal risk, women should conceive while disease is quiescent. Aside from methotrexate, immunomodulators and biologics may be used during pregnancy to achieve and maintain disease control. Based on available safety data, there is no increased risk of congenital anomalies among infants exposed to these medications. Active thiopurine metabolites and most monoclonal antibodies cross the placenta and are detectable in neonates. They are detectable in breast milk in minute levels as well. The impact of this exposure on neonatal outcomes is discussed. Adjusted dosing schedules during gestation may reduce fetal drug exposure, though the maternal risks of such manipulation require careful consideration. Ongoing prospective studies will further inform risk assessment, including for newer medications such as the anti-integrin agents.

Understanding the Cautions and Contraindications of Immunomodulator and Biologic Therapies for Use in Inflammatory Bowel Disease

“…In fact, individuals with IBD are less fertile than their healthy counterparts, 17%–44% and 18%–50% for non-surgically-treated women and men, respectively, according to a recent systematic review by Tavernier et al 22 This decrease is attributed more to a “voluntary childlessness” stemming from IBD-centric fears and not to actual reproductive capacity, although active disease likely increases the risk of poor pregnancy outcomes. 23,24 It is also worth noting that there is a well-established reversible negative impact on spermatogenesis caused by sulfasalazine. 25–27 …”

“…AZA and 6-MP were previously classified by the United States Food and Drug Administration (FDA) category D (as an aside, such categorizations have been eliminated and replaced with the Pregnancy and Lactation Labeling Rule [PLLR] 28 ), and although neither drug is known to cross the placenta, their metabolites, 6-TGN and 6-MMP, do. 23,29 Thought to be secondary to gestational changes in hepatic metabolism, maternal serum concentrations of 6-TGN decrease and 6-MMP increase with no apparent consequence to the mother. Still, Jharap and coworkers found 60% of neonates born to mothers on thiopurines during pregnancy to be anemic at birth.…”

“…37 Nonetheless, most authors agree that thiopurines should not be commenced during pregnancy due to the risk of drug-induced pancreatitis. 23 …”

“…It is recommended that women discontinue the medication six months prior to conception for an adequate washout period. 103 Most experts consider breastfeeding a strong contraindication to MTX use due to increased risk of immunosuppression in the infant, 23,104,105 but MTX secretion into breast milk is minimal, 103 and was not discouraged in a recent study of MTX-treated mothers with lupus. 106 …”

Proper Use of Inflammatory Bowel Disease Drugs during Pregnancy

“…With respect to growth and development in children exposed to thiopurines in utero, a normal growth and development was reported in children followed up to 6 years of age [40] . Furthermore, the ongoing prospective PIANO registry did not observe an increased risk of congenital anomalies or pregnancy complications among 337 children who were exposed to a thiopurine during pregnancy [41]. In case of longstanding remission using combination therapy with an anti-TNF agent, it may be considered to stop the thiopurine before conception.…”