Adverse pregnancy outcomes associated with in utero exposure to multiple sclerosis disease-modifying therapies in France: a nationwide cohort study

Background: Exposure to disease-modifying therapies (DMTs) among pregnant women with multiple sclerosis (MS) has markedly increased over the past years, however data on their safety profile during pregnancy are limited.

Objectives: This study aimed to assess the risks of adverse pregnancy outcomes associated with exposure to the various available MS DMTs, regardless of whether their use during pregnancy is unrestricted (beta-interferon [IFNB], glatiramer acetate [GA], natalizumab [NZ]), non-recommended (dimethyl fumarate [DF], ocrelizumab/rituximab [anti-CD20]) or contraindicated (fingolimod [FG], teriflunomide [TRF]).

Methods: Using data of the Mother-Child EPI-MERES Register built from comprehensive data of the National Health Data System (SNDS), we included all pregnancies ended between 2010 and 2022 in women with MS. Pregnancies were considered exposed if they fell within DMT coverage period, estimated considering each DMT half-life. Pregnancies exposed to >1 DMT were not considered. Pregnancy outcomes, including therapeutic/elective and spontaneous abortion, mode of delivery, vital status at birth, birth term and weight for gestational age, were compared between pregnancies exposed to each DMT and those unexposed, using weighted generalized estimating equation (GEE) models accounting for sociodemographic, MS and comorbidity characteristics.

Results: Among a total of 22,413 pregnancies in women with MS, 8,477 were exposed to a single DMT: 3,099 to IFNB, 2,005 to GA, 1,607 to NZ, 789 to DF, 447 to FG, 293 to TRF, and 237 to anti-CD20. Pregnancy outcomes of pregnancies exposed to IFNB or GA did not differ from those of unexposed pregnancies. Compared to unexposed pregnancies, those exposed to NZ, DF, FG, TRF, and anti-CD20 were more frequently interrupted (therapeutic/elective abortion: adjusted odds ratio aOR 1.51 [1.30-1.75], 2.04 [1.72-2.43], 5.87 [4.71-7.31], 3.87 [3.02-4.96] and 2.35 [1.74-3.16], respectively). Pregnancies exposed to NZ resulted more frequently in spontaneous abortion (aOR 1.29 [1.05-1.58]), small weight for gestational age at birth (aOR 1.21 [1.01-1.46]), and in moderate prematurity (aOR 1.24 [0.97-1.59]). Pregnancies exposed to anti-CD20 resulted more frequently in spontaneous abortion (aOR 1.63 [0.99-2.70]) and in preterm birth (aOR 1.76 [1.03-3.00]). Pregnancies exposed to TRF resulted more frequently in small weight for gestational age at birth (aOR 1.57 [1.03-2.40]).


Conclusions: In conclusion, exposure to the various available MS DMTs (except IFNB and GA) during pregnancy is associated with increased risks of adverse pregnancy outcomes including spontaneous abortion, prematurity and small weight for gestational age at birth.