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