Background/Purpose: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Its effect in pregnant women is of interest, as tofacitinib has been shown to be fetocidal and teratogenic in rats and rabbits at exposures 146 times and 13 times (respectively) the maximum recommended human dose. There are no adequate, well-controlled tofacitinib studies in pregnant women; per the RA clinical development program protocols, all studies exclude pregnant subjects and require use of highly effective contraception by females with child-bearing potential, and study treatment discontinuation if a subject becomes pregnant. To understand potential effects of tofacitinib, pregnancies in the RA clinical development program were reviewed.

Methods: Cases were identified from Pfizer’s internal safety database through April 30, 2014, from interventional (one clinical study is ongoing; database not locked) and non-interventional studies, plus cases from post-marketing reporting. Cases were limited to females administered tofacitinib/placebo/blinded therapy at time of conception and/or fetal subjects exposed to tofacitinib/placebo/blinded therapy through maternal exposure. Potential duplicate cases were eliminated; remaining cases were reviewed for any pregnancy-related outcome and abnormalities, which were categorized as healthy newborns, spontaneous abortion, medical termination, still-birth, pending, or lost to follow‑up.

Results: A total of 35 cases were identified. In the tofacitinib RA clinical studies of ~6,000 subjects with nearly 17,000 patient-years of follow‑up, there were 32 cases of maternal tofacitinib exposure. Subject age ranged from 22 to 40 years. Of the 32 cases, 31 received tofacitinib; 13 had 5 mg BID, 1 had 5 mg QD, 12 had 10 mg BID, 2 had 20 mg QD, 1 had 15 mg BID, and 2 whose therapy at conception is still blinded. One subject received placebo/methotrexate (MTX). Ten of the 32 cases were also taking MTX. The pregnancy outcomes with tofacitinib were: 14 healthy newborns (including 1 low birth weight and 1 pre-term birth), 6 spontaneous abortions, 4 medical terminations, 1 still‑birth (at approximately 17 weeks gestation), 1 congenital malformation of pulmonary valvar stenosis reported in a 32‑year‑old subject with diabetes and hypertension, 2 pending outcome, and 3 lost to follow-up; the placebo-treated subject experienced a spontaneous abortion. The remaining 3 cases receiving tofacitinib were reported from other data sources including 2 cases from 2 non-interventional clinical studies and 1 from post-marketing reporting. Fetal subjects had maternal exposure to tofacitinib. Of the 3 cases, 1 had a spontaneous abortion; outcomes were still pending for the other 2 cases.

Conclusion: Most cases with reported outcomes had healthy newborns. Adverse outcomes including spontaneous abortions and congenital malformation were observed in RA subjects who became pregnant during tofacitinib therapy. Pregnancy outcomes in subjects receiving tofacitinib will continue to be monitored through routine pharmacovigilance and via a post-approval safety study within the Organization of Teratology Information Specialists (OTIS) registry.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/pregnancy-outcomes-in-the-tofacitinib-ra-safety-database-through-april-2014/