Pregnancy Outcomes After Maternal or Paternal Exposure to Tofacitinib Across Clinical Programs

Abstract

INTRODUCTION:

This analysis reports updated pregnancy outcomes after tofacitinib exposure in patients with immune-mediated diseases.

METHODS:

Pregnancy/partner pregnancy cases from interventional studies were identified in Pfizer safety database through March 2023.

RESULTS:

Of 184 pregnancies reported, 85 were maternal exposure events: 46 healthy newborns, 12 medical terminations, 1 fetal death, 1 congenital malformation, 14 spontaneous abortions, and 11 pending/lost to follow-up. There were 99 paternal exposure events: 67 healthy newborns, 1 fetal death, 9 spontaneous abortions, and 22 pending/lost to follow-up.

DISCUSSION:

Outcomes of maternal/paternal tofacitinib exposure were similar to those expected in the general population; tofacitinib should not be used during pregnancy unless clearly necessary.

INTRODUCTION

Tofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis (UC), rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), and juvenile idiopathic arthritis (JIA) and has been investigated for psoriasis (PsO) and Crohn's disease. Patients living with these immune-mediated diseases may face higher risks of adverse pregnancy outcomes compared with the general population, including preterm birth, low birth weight, and congenital abnormalities (1–3).

In animal studies, tofacitinib had teratogenic effects at exposures much higher than the recommended human doses of 5 and 10 mg twice daily (BID) but did not affect male fertility (4). Pregnancy outcomes after maternal/paternal exposure to tofacitinib through March 2017 were previously reported (5,6); this analysis reports updated data through March 2023.

METHODS

Pregnancies in which maternal/paternal tofacitinib exposure occurred around time of conception and/or during pregnancy were identified in the Pfizer safety database through March 2023 (further detail provided in the Supplemental Methods, http://links.lww.com/AJG/D786) and included data from randomized clinical trials and long-term extension studies (Supplemental Table 1, http://links.lww.com/AJG/D786). Patients predominantly received tofacitinib 5 or 10 mg BID, but doses ranged from 0.5 to 30 mg BID in some studies.

Follow-up continued until pregnancy completion/termination or longer on a case-by-case basis. Outcomes were categorized as healthy newborn (including preterm and otherwise healthy newborns with low birth weight), medical termination (including elective termination), fetal death (>20 weeks gestation), congenital malformation, spontaneous abortion, or pending/lost to follow-up (including refusal of consent to follow-up). The results were analyzed descriptively and as observed.

Ethics statement

All studies were conducted in compliance with the Declaration of Helsinki, International Conference on Harmonisation for Good Clinical Practice guidelines, and relevant local regulations. All patients provided informed consent, and all participating institutions provided Institutional Review Board approval before participation.

RESULTS

Characteristics of patients with pregnancy events after tofacitinib exposure are presented in Tables 1 and 2 and Supplemental Table 2 (http://links.lww.com/AJG/D786). Overall, 12,955 patients were enrolled across studies (Supplemental Table 2, http://links.lww.com/AJG/D786), including 2,756 women of childbearing age (21.3%).

Table 1.

Baseline characteristics of patients with maternal pregnancy events and the characteristics of maternal pregnancy events by each tofacitinib clinical program^a

Table 2.

Baseline characteristic of patients with paternal pregnancy events and the characteristics of paternal pregnancy events by each tofacitinib clinical program^a

Across tofacitinib clinical programs, 184 pregnancies were reported among 174 patients, including 85 maternal exposure events among 84 patients (Table 1) and 99 paternal exposure events among 90 patients (Table 2). No pregnancies were reported in the Crohn's disease trials. For maternal events in which estimated duration of exposure to tofacitinib was calculable, all but 2 events had exposure in the first trimester only (median [range]: 38.0 [1.0–109.0] days; Table 1).

Maternal pregnancy outcomes are shown in Figure 1a; the most common outcome was healthy newborn (n = 46). Pregnancy outcomes by tofacitinib dose are presented in Supplemental Table 3 (http://links.lww.com/AJG/D786). One fetal death occurred in a 32-year-old patient with PsA who had an accident of unknown cause resulting in the death of the patient and fetus (unrelated to trial). One congenital malformation (pulmonary valve stenosis) was reported in the newborn (gestational age 38 weeks; birth weight 3,155 g; normal Apgar scores) of a 32-year-old patient with RA, hypertension (treated with angiotensin II receptor antagonist), and diet-controlled gestational diabetes. There were 14 spontaneous abortions after exposure to tofacitinib in the first trimester (Supplemental Table 3, http://links.lww.com/AJG/D786). The remaining 11 events were either pending or lost to follow-up. Further information regarding cases of preterm birth and medical termination is provided in the Supplemental Results (http://links.lww.com/AJG/D786).

Figure 1.

Summary of pregnancy outcomes with (a) maternal or (b) paternal tofacitinib exposure by each tofacitinib clinical program. AS, ankylosing spondylitis; JIA, juvenile idiopathic arthritis; n, number of pregnancy events; PsA, psoriatic arthritis; PsO, psoriasis; RA, rheumatoid arthritis; UC, ulcerative colitis. ^aIncluding events delivered preterm (UC: One maternal [36 weeks] and 1 paternal [34 weeks]; RA: 2 maternal [35 and 37 weeks] and 1 paternal [36 weeks]; PsA: One maternal [37 weeks] and 1 paternal [35 weeks]; PsO: One paternal [35 weeks]) and otherwise healthy newborns with low birth weight. ^bSome of these previously reported events were listed as invalid in Pfizer internal safety database because of elective termination (no adverse events were associated; 2 UC [Event 1: The patient decided to terminate pregnancy, based on the potential risks of tofacitinib; Event 2: Reason unknown]; 2 RA [Event 1: The patient decided to terminate pregnancy, based on the potential risks of tofacitinib and unwanted pregnancy; Event 2: Reason unknown], 1 PsA [reason unknown], and 2 PsO [reasons unknown]) (5). One event in the PsO clinical program was removed since the March 2017 cutoff because of the patient not receiving tofacitinib before the pregnancy event. ^cNo new events or updates since March 2017 data cutoff (5). ^dIncludes 2 patients with 2 events each. ^eIncludes 2 AS events and 4 UC events originally reported as maternal exposure in Pfizer internal safety database; however, after a review of the event narratives, it was confirmed that for these events the study drug was taken by the father (partner's pregnancy).

Paternal exposure pregnancy events are shown in Figure 1b, including 67 healthy newborns. One fetal death occurred after a cardiac arrest postdelivery at 36 weeks; other unspecified clinical factors were noted to have contributed to the death. Nine spontaneous abortions were reported, and there were no medical terminations or congenital malformations. The remaining 22 events were either pending or lost to follow-up.

DISCUSSION

This analysis reports updated pregnancy outcomes after tofacitinib exposure in patients with UC, RA, PsA, and PsO, including data from AS and JIA for the first time. These data represent the most extensive evaluation of pregnancy outcomes after tofacitinib exposure to date; since the last analysis (through March 2017) (5), new exposure pregnancy events were reported in UC (n = 15), PsA (n = 5), AS (n = 2), and JIA (n = 5). Consistent with previous analyses, the most common outcome was healthy newborns.

These results were consistent with observations in the general population and with other oral advanced therapies. Congenital malformations were reported in ∼2% of births in England in 2020 (7) and have a reported risk of ∼3% in the United States and Europe (8,9), whereas spontaneous abortion occurs in ∼15% of clinically recognized gestations worldwide (10). In this analysis, maternal tofacitinib exposure resulted in 1 congenital malformation (1.2%) and 14 spontaneous abortions (16.5%). In recent analyses of pregnancy events after exposure to upadacitinib (Janus kinase inhibitor) or ozanimod (sphingosine 1-phosphate receptor modulator), the most common outcome was live birth, and rates of spontaneous abortion and congenital malformation were consistent with the general population (11,12).

While most cases in our study occurred after first trimester exposure, 3 case studies have reported tofacitinib exposure later in gestation (13–15). Of these, 2 reported healthy newborns (13,14). In the latter case study, tofacitinib treatment continued during breastfeeding; the infant had a normal 12-week immunological assessment and subsequently received live vaccinations; mother and baby remained well through 12-month follow-up (14). In another case study, a patient receiving tofacitinib experienced a UC flare at 18 weeks gestation, which may have contributed to a preterm delivery at week 33. The newborn had polydactyly and other findings consistent with the gestational age (15).

Limitations of this analysis include that it was retrospective, with data identified from adverse events in Pfizer internal safety database, which can result in patient recall and reporting bias, and incomplete information regarding concomitant medications. Common to these types of analyses (11,12), event numbers and duration of tofacitinib exposure were limited as contraception use was required and pregnancy resulted in discontinuation for female patients. Furthermore, disease activity before pregnancy could not be accurately assessed as assessment schedules varied across studies. Finally, there were insufficient data to include a control group, and the nature of the data source limits formal comparative or adjusted analyses.

In conclusion, this updated analysis of pregnancy outcomes after maternal or paternal exposure in the global tofacitinib clinical programs is consistent with previous publications and the general population. Tofacitinib should not be used during pregnancy unless clearly necessary, and female patients should be educated on effective contraception during treatment.

CONFLICTS OF INTEREST

Guarantor of the article: Michelle Segovia, PharmD.

Specific author contributions: M.S., X.G., N.K., J.W., I.V., and A.D.: contributed to the conception or study design. M.S., X.G., J.W., I.V., and A.D.: contributed to data acquisition and analysis. All authors contributed to data interpretation, and reviewed and approved of the final draft.

Financial support: This study was sponsored by Pfizer.

Potential competing interests: Uma Mahadevan has received consulting fees from Abbvie, Boeringher Ingelheim, Bristol Myers Squibb, Celltrion, Enveda, Gilead, Janssen, Lilly, Merck, Pfizer Inc, Protagonist, Rani Therapeutics, Roivant, and Takeda. María Chaparro has served as a speaker, consultant, or received research or education funding from AbbVie, Biogen, Dr. Falk Pharma, Eli Lilly, Ferring, Gilead, Hospira, Janssen, MSD, Pfizer Inc, Shire Pharmaceuticals, Takeda, and Tillotts Pharma. Michelle Segovia, Xiang Guo, Nicole Kulisek, Joseph Wu, Ivana Vranic, and Annette Diehl are employees and shareholders of Pfizer Inc. Arthur Kavanaugh has received consulting fees from Amgen, Bristol Myers Squibb, Eli Lilly, Janssen, Moonlake, Novartis, Pfizer, Takeda and UCB. Marla Dubinsky has received consulting fees from AbbVie, Abivax, AstraZeneca, Bristol Myers Squibb, Celltrion, Eli Lilly, Gilead, Janssen, Johnson & Johnson, Pfizer Inc, Prometheus Laboratories, Sphyre, and Takeda.

Data Sharing Statement: Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual deidentified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information.

ClinicalTrials.gov: NCT01465763, NCT01458951, NCT01458574, NCT03281304, NCT01470612, NCT00147498, NCT00847613, NCT00856544, NCT01039688, NCT02187055, NCT00413699, NCT00661661, NCT03502616, NCT02592434, NCT01500551, NCT01877668, NCT01882439, NCT03486457, NCT01976364, NCT01276639, NCT01309737, NCT01241591, NCT01186744, NCT01519089, NCT01815424, NCT01163253.

Supplementary Material

acg-121-549-s001.docx ^{(36.8KB, docx)}

ABBREVIATIONS:

AS

ankylosing spondylitis

BID

twice daily

JAK

Janus kinase

JIA

juvenile idiopathic arthritis

PsA

psoriatic arthritis

PsO

psoriasis

RA

rheumatoid arthritis

UC

ulcerative colitis