Friday’s programme at the ECTRIMS-ACTRIMS meeting in Paris played host to an exploration of pregnancy outcomes in multiple sclerosis (MS) patients treated with teriflunomide – a once-daily oral immunomodulator approved for the treatment of relapsing-remitting MS (RMS), with its use now spanning more than 162,000 patient-years since approval.
As Sandra Vukusic (University Hospital of Lyon, France) described, teratogenicity and embryo-lethality has been observed in rats and rabbits when teriflunomide was administered during pregnancy at doses similar to those used clinically. As such, it follows that teriflunomide is contraindicated in pregnancy, and women of childbearing potential have been advised to use effective contraception whilst receiving the therapy.
Likewise, leflunomide, which is the parent compound of teriflunomide and used in rheumatoid arthritis treatment since 1998, has seen similar preclinical findings.
However, Professor Vukusic underlined that there has been no signal for human teratogenicity with teriflunomide observed in prior analyses of teriflunomide-exposed pregnancies in clinical studies. Similarly, no signal has been found in leflunomide-exposed pregnancies, as reported by over 2.4-million patient-years of post-marketing pharmacovigilance, a prospective pregnancy registry (n = 64 pregnancies), a case series (n = 45), a cohort study (n = 51) and an embryo-toxicity database report (n = 65).
With this in mind, she has been involved in a study evaluating pregnancy in female teriflunomide patients. Both monotherapy clinical study cases (CSCs) and post-marketing cases (PMCs) were included from September 2012 – May 2016, excluding known pregnancy registry cases, which will be reported elsewhere.
Of 231 pregnancies in patients exposed to teriflunomide, 62 were in the CSC arm (all prospective, and all with known outcomes). In the PMC arm (n = 169), 67 patients had known outcomes: 37 in the prospective arm (pregnancies reported prior to prenatal tests that could provide information on the status of the foetus), and 30 in the retrospective arm (those reported after having some knowledge of the status of the foetus, or if the pregnancy outcome preceded reporting).
Looking at the baseline demographics of both groups, age at pregnancy was slightly lower in the CSC arm, at 30.2 years, with standard deviation (SD) of 6 years. The PMC group had an average age of 32.6 years (SD: 5.8). Mean duration of teriflunomide treatment prior to pregnancy was significantly higher in the CSC arm (19.6 months, SD: 19.1) versus the PMC arm (4.4, SD: 6.7). The majority of patients in both groups were undergoing their first pregnancy.
Professor Vukusic stressed that because teriflunomide can remain in the body for months after cessation of treatment, an accelerated elimination procedure (AEP) using cholestyramine or activated charcoal was used where possible. “If you do that, after 11 days you reach an almost zero level in the plasma,” she said, adding that AEP had indeed been used in 81.8% of live births in the CSC arm, and 60% of the PMC arm.
“When you look at the duration of exposure, most of the patients stopped their treatment once pregnancy was diagnosed, and the majority of patients were exposed in their first trimester, of course,” she said.
Of 129 pregnancies, 54 live births were reported, including two sets of twins: 22 (35.5%) in the CSC arm; 20 (54.1%) in the prospective PMC arm; and 10 (33.3%) in the retrospective PMC arm. Pre-term live birth rates were “classical”, at 13.6% in the CSC arm, and 10% in both PMC arms. Spontaneous abortion was lowest in the CSC arm (12.9%) compared to 24.3/33.3% in the prospective/retrospective PMC arms, but Professor Vukusic noted that this was “probably compensated” by a higher elective abortion rate in the CSC arm (48.4%) versus the prospective PMC (21.6%) and retrospective PMC (30.0%) arms.
Two (3.2%) ectopic pregnancies were seen in the CSC arm, but none in either PMC arm. However, one foetal death (3.3%), cause unknown, occurred at 35 weeks in the retrospective PMC arm.
“There were three structural malformations reported for these patients,” she went on. “One obstructive defect of the renal pelvis and ureter [AEP was performed], one congenital hydrocephalus [AEP not performed], and one cystic hygroma [AEP status unknown] that was detected on ultrasound.” The child-centric outcome for the third case remains unknown, but the other two children have seen good longer-term outcomes.
Professor Vukusic emphasised that there was no pattern in the type of malformations seen in these cases, the malformations differed from those seen in animals, and no malformations were reported for the elective abortions. Finally, a preliminary review of additional data from May-November 2016 revealed no additional birth defect cases.
In summation, she concluded that pregnancy outcomes in the study, including the rates of spontaneous abortions and malformation, were similar to those observed in the general population. She continued: “The current data show no increased frequency of malformations in the patients that were exposed to teriflunomide for relapsing-remitting MS.
“Again, there were no patterns of malformations identified, and these observations are consistent with the almost 20 years of post-marketing experience with the parent compound, leflunomide, in which no teratogenic signal has been seen to date. Teriflunomide is still contraindicated in pregnancy, despite this very reassuring data.”