Dr Sandra VukusicSandra Vukusic, MD, PhD
New study findings suggest that patients with multiple sclerosis (MS) who are exposed to teriflunomide (Aubagio, Sanofi) during pregnancy do not face an increased risk of major birth defects and spontaneous abortions compared with the general population.1

The treatment, which was approved in September 2012, is contraindicated in pregnant women and women of childbearing age who are not using effective contraception due to a lack of human data and based on preclinical findings. In this study, the investigators, led by Sandra Vukusic, MD, PhD, professor of neurology, Lyon University Hospital, explored a larger number of pregnancies and included 5-years post-market data.

“Some pregnancies have occurred in teriflunomide clinical trials and the post-marketing setting,” Vukusic and colleagues wrote. “An earlier analysis of pregnancies in the clinical development program did not indicate an increased risk in these pregnancies, although exposure to teriflunomide was limited to the first trimester due to frequent pregnancy testing and use of [accelerated elimination procedure] in most cases.”

Out of 437 confirmed pregnancies exposed to the pyrimidine synthesis inhibitor, 222 experienced known outcomes—70 from clinical trials and 152 from post-market data. All told, 48.2% were live births, 28.4% were elective abortions, 21.2% were spontaneous abortions, 1.4% were ectopic, and 0.5% were stillbirths and maternal death leading to fetal death. More than 90% of the patients reported no previous pregnancies.

Spontaneous abortions occurred more frequently in the post-marketing setting (n = 37) compared to clinical trial cases (n = 10), which investigators noted may be related to the older age, on average, of women in the post-marketing setting versus clinical trials (32.5 years vs. 30.4 years). In comparison, the rate of spontaneous abortions in the general population is 15% to 20%.

“The findings reported here are consistent with data from leflunomide, a precursor to teriflunomide marketed worldwide since 1998 to treat active rheumatoid arthritis in adults,” the investigators detailed. “No increased risk of fetal abnormality in pregnancies exposed to leflunomide has been observed in over 1000 pregnancies in Sanofi-sponsored clinical trials or post-marketing surveillance data monitored over 20 years (Sanofi data on file) or in analyses from a pregnancy registry or other clinical trials.”

Additionally, the risk of major birth defects in prospectively reported live birth and stillbirth outcomes was 3.6% (1 of 28) in clinical trials and 0.0% (0 of 51) in post-marketing reports. One infant of 28 in the clinical trial group (3.6%) had a major congenital anomaly (male twin with ureteropyeloectasia) and was born pre-term (gestational age, 36 weeks). The baby was discharged 17 days post-hospitalization. In the post-market group, 3 of 84 infants had a birth defect (3.6%), none of which were considered major.

The frequency of reported major malformations in clinical trial cases was 3.6% (1 of 28) and 0% in the post-marketing setting, which was consistent with the general population’s frequency of 2% to 4%.

Outcomes data were available for roughly 50% of the included pregnancies in the post-marketing setting, compared with 100% of the pregnancies in clinical trial cases. Vukusic and colleagues acknowledged that due to this, they can “only speculate about the potential impact of this missing information.” Ultimately, they admit that this study cannot exclude the chance that defects occurred in the remaining 215 births of unknown outcome.

They also acknowledged that there are limitations to the findings, most notably that as the data are based on limited post-market data with a lack of extensive detail. As well, the age differences between clinical trial and post-market groups were important, as “patient adherence and monitoring may be less thorough compared with clinical trials,” they wrote.

They concluded that further data collection is needed to obtain additional information on the risks associated with teriflunomide exposure in pregnancy.
1. Vukusic S, Coyle PK, Jurgensen S, et al. Pregnancy outcomes in patients with multiple sclerosis treated with teriflunomide: Clinical study data and 5 years of post-marketing experience. Mult Scler. Published online April 10, 2019. doi: 10.1177/1352458519843055.