Discussion:
Tofacitinib is an oral, small-molecule Janus Kinase (JAK) inhibitor. It is a second-generation JAK inhibitor that selectively inhibits JAK1 and JAK3.5 It was first approved for moderately to severely active Rheumatoid Arthritis in 2012, followed by approval for psoriatic arthritis, active polyarticular course juvenile idiopathic arthritis and active ankylosing spondylitis 2021.6,7,8,9 Tofacitinib was approved in 2018 for induction and maintenance of moderately to severely active UC.1
Despite being approved and used for rheumatological conditions for more than a decade, there is a paucity of real-life data regarding its use in pregnancy. A review of the pregnancy cases identified in the randomised clinical trials of tofacitinib for rheumatoid arthritis and psoriatic arthritis showed a total number of 47 women who became pregnant during the trials, 33 on tofacitinib monotherapy and 13 on tofacitinib and methotrexate combination and one patient had a blinded therapy. There were 25 healthy newborns 53.2%, eight medical terminations 17% (four monotherapy, three combination therapy and one blinded therapy), seven spontaneous abortions 14.9% (four monotherapy and three combination therapy), one congenital pulmonary valve stenosis 2.1% (on monotherapy), no foetal deaths reported, and six pending or lost to follow up 12.8%. The rate of birth defects and spontaneous abortions was comparable to the general population and to patients with similar conditions who are not using tofacitinib.10 Due to the small sample size, retrospective study, and the lack of a randomised clinical trial, tofacitinib is still not considered safe to treat rheumatological conditions in pregnancy.11,12
Tofacitinib use for IBD in pregnancy is not recommended, and cessation for 4-8 weeks is advised before conception; this is based on its foeticidal and teratogenic potential in animal studies and due to the lack of evidence of use in humans.4,13 It is assumed that tofacitinib can cross the placenta due to its small molecular size, although this has yet to be formally tested and studied. Animal studies showed increased loss of pregnancy and lower mean foetal body weight. Congenital malformations included membranous ventricular septal defects, anasarca, skeletal, soft tissue, and cranial deformities. The doses used in these studies were 73 times (in rats) and 6.3 times (in rabbits) the maximum recommended dose of 10mg twice daily in humans.2
UC affects females in the reproductive age group with fewer biological therapies available, which increases the need for newer advanced therapies like tofacitinib, which is used in higher doses of 10mg twice daily in UC compared to rheumatoid arthritis. Continuation of medical treatment for UC during pregnancy is recommended due to the increased risk of active disease and poor pregnancy outcomes associated with interruption of treatment.4 In the interventional studies of tofacitinib in ulcerative colitis, there were 11 cases of maternal exposure, all patients were exposed during the first trimester, specific gestational age at the time of exposure could not be determined, and all patients except one were on 10mg twice a day dose. Four healthy newborns 36.4%, two spontaneous abortions 18.2%, and two medication terminations 18.2% were reported, and three were pending or lost to follow-up 27.2%.14 Tofacitinib level in breast milk was found to exceed maternal serum levels.15 Tofacitinib should be avoided in breastfeeding.4
There is a lack of case reports of tofacitinib exposure in pregnancy. A case of a 40-year-old patient with psoriatic arthritis who was exposed to tofacitinib was reported; the patient delivered a healthy newborn.16 However, she was treated on a lower dose of tofacitinib of 5mg twice daily and had a shorter exposure to tofacitinib while pregnant than our patient.
Real-life case reports of exposure and outcome of tofacitinib in pregnancy add to the limited available real-life evidence. Post-marketing registries are essential to obtain larger experience that might modify clinical practice guidelines in the future.17