New Data Released on Tofacitinib in Unexpected Pregnancy

Alice Goodman

December 02, 2014

BOSTON — When women with rheumatoid arthritis who are being treated with the oral Janus kinase inhibitor tofacitinib experience an unplanned pregnancy, newborns are healthy in about half of all cases, an analysis of a large clinical trials database has shown.

"This suggests that tofacitinib should be used during pregnancy only if the potential benefit justifies potential risk to the fetus," said Amy Marren, director of global medical affairs at Pfizer in Groton, Connecticut.

Even though pregnant women are excluded from clinical trials of tofacitinib and women of childbearing age participating in tofacitinib trials are required to use contraception, 35 unintended pregnancies were identified in the analysis.

Results were presented here at the American College of Rheumatology 2014 Annual Meeting.

As of April 2014, the Pfizer internal safety database contained data on 6192 patients with rheumatoid arthritis enrolled in interventional clinical trials of tofacitinib, for a total of 16,839 patient-years of exposure.

Of the women enrolled in a clinical trial, 32 became pregnant. In addition, two women became pregnant while enrolled in a noninterventional postapproval safety study. Another pregnant woman was identified from adverse event reporting; her pregnancy was ongoing at the time of the analysis.

The age of the pregnant women ranged from 22 to 40 years. For those on tofacitinib at the time of pregnancy, total time ranged from 14 to 1404 days; for fetuses exposed to tofacitinib in utero, time ranged from 7 to 244 days.

Of the 32 women enrolled in a clinical trial, 17 were receiving tofacitinib monotherapy, 14 were receiving the combination of tofacitinib and methotrexate, and one was receiving placebo plus methotrexate.

Spontaneous Abortion

Spontaneous abortion was reported by two women in the tofacitinib monotherapy group, four in the combination group, and one in the placebo and methotrexate group. Medical termination was reported by one woman in the monotherapy group and three in the combination group.

In the clinical trials group, one woman was still pregnant at the time of the analysis and three were lost to follow-up.

Of the two women enrolled in a postapproval safety study, one experienced a spontaneous abortion and one pregnancy was ongoing at the time of analysis. The woman identified from adverse event reporting was still pregnant at the time of analysis.

Of the 29 pregnancies analyzed, 16 healthy newborns were delivered (57.1%). Of these, 11 of the mothers were receiving tofacitinib monotherapy and five were receiving tofacitinib plus methotrexate. Two of the healthy newborns were of low birth weight.

One fetal complication of pulmonary valve stenosis was reported in a newborn delivered to a woman on tofacitinib monotherapy.

"The majority of adverse pregnancy outcomes occurred in patients taking concomitant methotrexate, which is associated with adverse birth outcomes," Marren explained. She reported that the 20.6% rate of spontaneous abortion reported in the tofacitinib-treated patients, with or without methotrexate, was in line with the rate of 22.5% found in a cohort of patients with rheumatic diseases not taking methotrexate (Arthritis Rheumatol. 2014;66:1101-1110). However, that study showed that the rate of spontaneous abortion on methotrexate after conception was 42.5%, she noted.

"No delivery complications or fetal distress was reported," Marren said.

OTIS Registry to Monitor

Pfizer is using the Organization of Teratology Information Specialists (OTIS) registry to continue to monitor pregnancy outcomes in women treated with tofacitinib. However, "we are not following the children," she added.

"It is very important to have these data to counsel women on tofacitinib on pregnancy outcomes," said session moderator Gerd Burmester, MD, from the University of Medicine Berlin Free University.

"Of course, we urge our patients not to get pregnant when on a newly developed drug, especially with new mechanisms of action, but life is as it is and sometimes pregnancies occur," he explained.

"Databases taken from real-life exposure are extremely important," Dr Burmester said. However, the data "have to be put in perspective with the surprisingly high abortion and malformation rate in the normal population or the disease population at risk."

In addition, "the data are confounded by the fact that many of the patients on the new drugs are also on methotrexate, which is known to increase the risk of major birth defects and spontaneous abortion," he said.

One-third of patients were on methotrexate, which is a known teratogen.... It is also important that about half the pregnancies are reported to have had a normal delivery.

"This report is a caution that little is known about the effects of tofacitinib in pregnancy," said Eric Matteson, MD, from the Mayo Clinic in Rochester, Minnesota.

"It is important to realize that one-third of patients were on methotrexate, which is a known teratogen, and may have affected the outcomes. It is also important that about half the pregnancies are reported to have had a normal delivery," Dr Matteson said.

However, he added, "we have no idea how long the patients were exposed to tofacitinib from these data, nor do we know what prompted the medical terminations."

"The data are very preliminary, and the only conclusion I can draw is that until we have better data and follow-up, patients should be counseled to not become pregnant on this drug," Dr Matteson said.

Ms Marren is an employee of Pfizer. Dr Burmester reports financial ties to Abbott, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, Roche, and UCB. Dr Matteson reports receiving a grant from Pfizer unrelated to tofacitinib.

American College of Rheumatology (ACR) 2014 Annual Meeting. Abstract 1908. Presented November 17, 2014.


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