Investigating the Long-term Effect of Pregnancy on the Course of Multiple Sclerosis Using Causal Inference

The question of the long-term safety of pregnancy is a major concern in multiple sclerosis (MS) patients, but its study is biased by reverse causation (women with higher disability are less likely to experience pregnancy). Using a causal inference approach, we aimed to estimate the unbiased long-term effects of pregnancy on disability and relapse risk in MS patients, and secondarily the short-term effects (during the per-partum and post-partum years) and delayed effects (occurring beyond one year after delivery).We conducted an observational cohort study with data from MS patients followed in the OFSEP registry between 1990 and 2020. We included MS female patients aged 18-45 years at MS onset, clinically followed-up for more than 2 years and with ≥3 Expanded Disease Status Scale (EDSS) measurements. Outcomes were the mean EDSS at the end of follow-up and the annual probability of relapse during follow-up. Counterfactual outcomes were predicted using the longitudinal targeted maximum likelihood estimator in the entire study population. The patients exposed to at least one pregnancy during their follow-up were compared with the counterfactual situation in which, contrary to what was observed, they would not have been exposed to any pregnancy. Short-term and delayed effects were analyzed from the first pregnancy of early-exposed patients (who experienced it during their first three years of follow-up).We included 9,100 patients, with a median follow-up duration of 7.8 years, of whom 2,125 (23.4%) patients were exposed to at least one pregnancy. Pregnancy had no significant long-term causal effect on the mean EDSS at 9 years (causal mean difference [95% CI] = 0.00 [-0.16; 0.15]), nor on the annual probability of relapse (causal risk ratio [95% CI] = 0.95 [0.93; 1.38]). For the 1,253 early-exposed patients, pregnancy significantly decreased the probability of relapse during the per-partum year and significantly increased it during the post-partum year, but no significant delayed effect was found on EDSS and relapse rate.Using a causal inference approach, we found no evidence of significantly deleterious or beneficial long-term effects of pregnancy on disability. The beneficial effects found in other studies were probably related to a reverse causation bias.