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\begin{document}

\title{First-trimester exposure to tofacitinib in ulcerative colitis: A case
report of a healthy newborn and literature review}



\author[1]{Arteen Arzivian}%
\author[1]{Eva Zhang}%
\author[1]{Robyn Laube}%
\author[1]{Rupert Leong}%
\affil[1]{Macquarie University Hospital}%


\vspace{-1em}



  
  \date{May 16, 2024}


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\textbf{First-trimester exposure to tofacitinib in ulcerative colitis: A
case report of a healthy newborn and literature review}

Arteen Arzivian\textsuperscript{1,2}, Eva Zhang\textsuperscript{1},
Robyn Laube\textsuperscript{1}, Rupert Leong\textsuperscript{1,2}

\textsuperscript{1} Department of Gastroenterology and Hepatology,
Macquarie University Hospital, Sydney, Australia.

\textsuperscript{2}Faculty of Medicine, Health and Human Sciences,
Macquarie Medical School, Macquarie University, Sydney, NSW, Australia.

\textbf{The corresponding author:}

Dr Arteen Arzivian

Position: Gastroenterology Advanced Trainee

Address: Suite 404, Level 4, 2 Technology Place, Macquarie Park NSW
2109.

Email: arteen.arzivian@students.mq.edu.au and arteenma@outlook.com

Telephone number: +61 4 02154418

\textbf{Co-authors emails:}

Dr Eva Zhang, Gastroenterologist and Hepatologist, email address:
eva.zhang.is@gmail.com

Dr Robyn Laube, Gastroenterologist and Hepatologist, email address:
robynlaube@hotmail.com

Prof Rupert Leong, Gastroenterologist and Hepatologist, email address:
rupertleong@hotmail.com

\textbf{Authorship List:}

Author 1, AA: acquisition of data, drafting the case report and figures.

Author 2, EZ: revising the case report critically.

Author 3, RL: revising the case report and providing up-to-date
pregnancy and breastfeeding data.

Author 4, RL: revision and final approval.

All the authors were involved in the patient's clinical care.

\textbf{Data availability statement:} The data in this case report are
not publicly available due to containing information that could
compromise the patient's privacy but are available from the
corresponding author AA upon reasonable request.

\textbf{Funding statement:} This case report did not receive financial
support.

\textbf{Conflict of interest disclosure:} Rupert W Leong reports
advisory board membership of AbbVie, Aspen, BMS, Celgene, Celltrion,
Chiesi, Ferring, Glutagen, Hospira, Janssen, Lilly, MSW, Novartis,
Pfizer, Prometheus Biosciences, Takeda and research grant support from
McCusker Charitable Foundation, Joanna Tiddy grant University of Sydney,
Celltrion, Shire, Janssen, Takeda, Gastroenterological Society of
Australia, MRFF, NHMRC, Gutsy Group, Pfizer. All the other authors have
no conflict of interest to declare.

\textbf{Ethics approval statement:} This case report was approved by the
Macquarie Health Clinical Innovation and Audit Committee. Reference
number: MQCIAC2023009.

\textbf{Patient consent statement:} The patient has provided written
consent to publish this case report and all accompanying details of her
health issue.

\textbf{Acknowledgements:} The authors have no acknowledgements to make.

\textbf{Introduction:}

Tofacitinib is approved for moderately to severely active ulcerative
colitis (UC).\textsuperscript{1} Animal studies showed increased
pregnancy loss, lower foetal weight, and congenital malformations; the
doses used were much higher than the maximum recommended dose of 10mg
twice daily in humans.\textsuperscript{2} The only evidence for use in
pregnancy in patients with inflammatory bowel disease (IBD) is from the
registration studies, which revealed 11 maternal exposures with
foeto-maternal adverse events rates comparable to the general population
and patients with similar conditions not taking tofacitinib; however,
the number of cases was small, the comparison was indirect, and subjects
received pre-emptive pregnancy testing at every study visit to permit
early treatment cessation.\textsuperscript{3} Until further advice is
available, tofacitinib should be avoided in
pregnancy.\textsuperscript{4}

We present a case of exposure to tofacitinib in the first trimester
until six weeks of gestation in a patient with UC.

\textbf{Case History/examination:}

A woman in her 20s with left-sided UC (Montreal E2) treated with
tofacitinib 10mg twice daily presented to our clinic after having a
positive pregnancy test. Her beta-human chorionic gonadotropin level was
18477 IU/L; an ultrasound confirmed pregnancy with a gestational age of
six weeks.

She was diagnosed with UC at the age of 8 years and was initially
treated with mesalazine until adolescence. Azathioprine was added due to
active colitis following the transition to the adult IBD clinic but was
ceased after the development of acute pancreatitis. She developed severe
allergic reactions to both infliximab and adalimumab. She responded well
to intravenous vedolizumab 300mg 8-weekly. However, the patient stopped
attending vedolizumab infusions due to poor venous access in 2018 before
the availability of subcutaneous vedolizumab. Six months after
non-adherence, she presented with acute severe UC that failed to respond
to intravenous hydrocortisone 100mg 4 times daily. She responded to
intravenous ciclosporin 4mg/kg infusions but was complicated by a
seizure necessitating ciclosporin cessation. Tofacitinib 10mg twice
daily was initiated, which led to significant clinical improvement. When
tofacitinib dose was reduced to 5mg twice daily, she relapsed with an
increase of faecal calprotectin to 907ug/g. Flexible sigmoidoscopy
showed Mayo 1 left-sided colitis. Tofacitinib dose was increased to 10mg
twice daily, which recaptured remission. The patient was in a stable
relationship and was advised against pregnancy whilst taking
tofacitinib, and she agreed to use contraception.

Six months into maintenance treatment on tofacitinib, the patient
performed a pregnancy test due to amenorrhea, which returned a positive
result. First-trimester ultrasound confirmed the gestational age of 6
weeks.

\textbf{Methods (differential diagnosis, investigations, and
treatment):}

Tofacitinib was ceased immediately. She and her partner were consulted
regarding the potential foeticidal and teratogenic effects of
tofacitinib and the lack of human studies on pregnancy outcomes. They
decided to continue the pregnancy. She was commenced on folic acid and
oral pre-conception multi-vitamin supplement tablets and referred to a
high-risk pregnancy clinic. After cessation of tofacitinib, despite
being in clinical remission, a follow-up faecal calprotectin had
increased to 2,000 ug/g. An unsedated flexible sigmoidoscopy showed Mayo
1 left-sided colitis at eight weeks gestation. Prednisolone 30mg daily
was commenced. Due to her previous remission on vedolizumab and the
recent introduction of subcutaneous maintenance vedolizumab, she agreed
to intravenous induction of 300mg at weeks 0, 2 and 6, followed by
subcutaneous vedolizumab 108mg every other week. At eleven weeks of
gestation, she remained in clinical remission on prednisolone 20mg
daily, and her faecal calprotectin decreased to 62ug/g. First-trimester
non-invasive prenatal tests for foetal aneuploidy and nuchal
translucency examination were unremarkable. Prednisolone was
successfully tapered over two months, and she continued subcutaneous
vedolizumab throughout her pregnancy.

\textbf{Conclusion and Results (Outcome and follow-up):}

She entered labour spontaneously at 37 weeks and delivered vaginally to
a healthy boy with an Apgar score of 10, weighing 2.265 Kg (maternal
pre-pregnancy weight was 48kg). Neonatal jaundice was treated with
phototherapy and resolved. Postpartum advice was encouragement to
breastfeed, continue subcutaneous vedolizumab and avoid rotavirus
vaccination due to in-utero exposure to vedolizumab. Neonatal growth and
weight gain were normal.

Figure 1 demonstrates the timeline of events during our patient's
pregnancy.

\textbf{Discussion:}

Tofacitinib is an oral, small-molecule Janus Kinase (JAK) inhibitor. It
is a second-generation JAK inhibitor that selectively inhibits JAK1 and
JAK3.\textsuperscript{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.\textsuperscript{6,7,8,9} Tofacitinib was approved in 2018 for
induction and maintenance of moderately to severely active
UC.\textsuperscript{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.\textsuperscript{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.\textsuperscript{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.\textsuperscript{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.\textsuperscript{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.\textsuperscript{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\%.\textsuperscript{14} Tofacitinib level in
breast milk was found to exceed maternal serum
levels.\textsuperscript{15} Tofacitinib should be avoided in
breastfeeding.\textsuperscript{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.\textsuperscript{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.\textsuperscript{17}

\textbf{References:}

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2 Pfizer Inc. Xeljanz prescribing information. 2012. Retrieved
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3 Mahadevan U, Dubinsky MC, Su C, Lawendy N, Jones TV, Marren A, Zhang
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4 Laube R, Selinger CP, Seow CH, Christensen B, Flanagan E, Kennedy D,
Mountifield R, Seeho S, Shand A, Williams AJ, Leong RW. Australian
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DOI:~10.1136/gutjnl-2022-329304

5 Ghoreschi K, Jesson MI, Li X, Lee JL, Ghosh S, Alsup JW, Warner JD,
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6 Fleischmann R, Kremer J, Cush J, Schulze-Koops H, Connell CA, Bradley
JD, Gruben D, Wallenstein GV, Zwillich SH, Kanik KS. Placebo-controlled
trial of tofacitinib monotherapy in rheumatoid arthritis. New England
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7 Gladman D, Rigby W, Azevedo VF, Behrens F, Blanco R, Kaszuba A,
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13 Torres J, Chaparro M, Julsgaard M, Katsanos K, Zelinkova Z, Agrawal
M, Ardizzone S, Campmans-Kuijpers M, Dragoni G, Ferrante M, Fiorino G.
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DOI:~10.1177/17562848211018097

\textbf{Figure 1:} The timeline of events during pregnancy in our
patient with ulcerative colitis who was in remission on tofacitinib 10mg
twice daily and found to be pregnant at six weeks of gestation.\selectlanguage{english}
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