Patients with multiple sclerosis (MS) who were pregnant and exposed to teriflunomide, an MS drug contraindicated in pregnancy, experienced similar risks of birth defects and spontaneous abortions as that of the general population, according to a study published online on April 10 in the journal, Multiple Sclerosis.
The frequency of reported major birth defects was 3.6 percent in clinical trials and zero percent in the post-marketing setting, consistent with the general population's frequency of 2 percent to 4 percent. Overall, spontaneous abortions occurred in 21.2 percent of women who took teriflunomide. In comparison, the rate of spontaneous abortions in the general population falls between 15 percent and 20 percent.
Teriflunomide is a once-daily oral immunomodulator approved for relapsing forms of MS in 80 countries. Previous preclinical studies have found teriflunomide doses that fell in the human therapeutic range were associated with embryotoxicity and teratogenicity in rats and rabbits. The drug is contraindicated in pregnant women and women of childbearing age who do not use effective contraception.
"Current human data do not indicate a teratogenic signal in teriflunomide-exposed pregnancies," the researchers, led by Sandra Vukusic, MD, PhD, professor of neurology, Lyon University Hospital in Lyon, France, wrote in the new study.
In an effort to report outcomes of pregnancies occurring with teriflunomide use, Dr. Vukusic and her team analyzed data from teriflunomide monotherapy clinical trials and their extensions, and more than five years of post-marketing surveillance data extracted from the Sanofi Global Pharmacovigilance Database and related case files.
The researchers calculated estimates of pregnancy duration and teriflunomide exposure. The timing of teriflunomide use in relation to pregnancy outcome was based on the reported dates of teriflunomide use and the administration of cholestyramine or other agents prior to or during pregnancy intended to reduce teriflunomide concentrations in the blood to levels associated with minimal fetal risk, if available.
In addition, maternal characteristics, pregnancy outcomes, and fetal outcomes were included. Pregnancy outcomes included live birth, spontaneous abortion, elective termination, ectopic pregnancy, and fetal death. Fetal outcomes included gestational age and birth weight/length.
The researchers noted 437 pregnancies were confirmed in MS patients, including 70 from clinical trials and 367 from post-marketing data. A total of 222 pregnancies had known outcomes, including 70 from clinical trials cases and 152 post-marketing cases.
Among the findings, they reported that 48.2 percent were live births, 28.4 percent were elective abortions, 21.2 percent were spontaneous abortions, 1.4 percent were ectopic, and 0.5 percent were stillbirths and maternal death leading to fetal death. More than 90 percent of the patients reported no previous pregnancies.
Spontaneous abortions occurred more frequently in post-marketing cases than in clinical trial cases (37 versus 10). The researchers noted this may be related to the older age, on average, of women in post-marketing cases compared to clinical trials (32.5 years vs 30.4 years).
The risk of major birth defects in prospectively reported live birth/stillbirth outcomes was one out of 28 in clinical trials and 0 out of 51 in post-marketing reports. In the clinical trial group, one infant had a major congenital anomaly. In the post-marketing group, three of 84 infants had a birth defect, which none were considered as major.
The findings warrant further research to determine the risks associated with teriflunomide use during pregnancy.
The team advised caution when interpreting the findings since they are based in part on post-marketing data, with a limited number of cases, and lack extensive detail in some case reports.
Study limitations included limited data on post-marketing cases. Outcomes data was only available for approximately 50 percent of the included pregnancies, compared with 100 percent of the pregnancies in clinical trial cases. The researchers noted that this study cannot exclude the chance that defects occurred in the remaining births of unknown outcome.
In addition, age differences between clinical trial and post-marketing cases could mean patient adherence to treatment in post-marketing may be less thorough compared to women who participated in clinical trials.
Dr. Vukusic reported conflict of interests, including consultancy fees, speaker fees (nonpersonal), or honoraria from Biogen, Celgene, GeNeuro, MedDay, Merck Serono, Novartis, Roche, Sanofi Genzyme, and Teva and research grants from Biogen, GeNeuro, MedDay, Merck Serono, Novartis, Roche, Sanofi Genzyme, and Teva. Co-authors list conflicts of interest in the full study.
Link Up for More Information:
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 2019; Epub 2019 Apr 10.