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

Antoine Gavoille (1) , Fabien Rollot , Romain Casey (2, 3) , Marc Debouverie , Emmanuelle Le Page (4, 5) , Jonathan Ciron (6) , Jerome de Seze , Aurélie Ruet (7) , Elisabeth Maillart , Pierre Labauge (8, 9) , Helene Zephir (10) , Caroline Papeix (11) , Gilles Defer (12) , Christine Lebrun-Frenay , Thibault Moreau (13) , David Axel Laplaud (14, 15) , Eric Berger (16) , Bruno Stankoff (17) , Pierre Clavelou (18) , Eric Thouvenot (19, 20) , Olivier Heinzlef (21) , Jean Pelletier (18) , Abdullatif Al Khedr , Olivier Casez , Bertrand Bourre , Philippe Cabre , Abir Wahab , Laurent Magy , Jean-Philippe Camdessanche , Aude Maurousset , Solène Moulin , Nasr Haifa Ben , Dalia Dimitri Boulos , Karolina Hankiewicz , Jean-Philippe Neau , Corinne Pottier , Chantal Nifle , Muriel Rabilloud (22, 1) , Fabien Subtil , Sandra Vukusic (2)

1 LBBE - Laboratoire de Biométrie et Biologie Evolutive - UMR 5558
2 HCL - Hospices Civils de Lyon
3 CRNL - Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center
4 CHU Pontchaillou [Rennes]
5 CIC - Centre d'Investigation Clinique [Rennes]
6 CHU Poitiers - Centre hospitalier universitaire de Poitiers
7 U1215 Inserm - UB - Neurocentre Magendie : Physiopathologie de la Plasticité Neuronale
8 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
9 UM - Université de Montpellier
10 EA 2686 - Laboratoire d'Immunologie
11 Service de Neurologie [CHU Pitié-Salpêtrière]
12 Service de Neurologie [CHU Caen]
13 Service de Neurologie générale, vasculaire et dégénérative (CHU de Dijon)
14 CIC Plurithématique de Nantes
15 U1064 Inserm - CR2TI - Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology
16 BSC - CNS - Barcelona Supercomputing Center - Centro Nacional de Supercomputacion
17 CHU Saint-Antoine [AP-HP]
18 CRMBM - Centre de résonance magnétique biologique et médicale
19 CHU Nîmes - Hôpital Universitaire Carémeau [Nîmes]
20 IGF - Institut de Génomique Fonctionnelle
21 CHI Poissy-Saint-Germain
22 Département biostatistiques et modélisation pour la santé et l'environnement [LBBE]

Background and objectives: 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). Methods: 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). Results: 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. Discussion: 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.

Keywords: All CBMRT/Null Hypothesis; Multiple sclerosis; Cohort studies

Domains: Human health and pathology; Neurons and Cognition [q-bio.NC]

Antoine Gavoille, Fabien Rollot, Romain Casey, Marc Debouverie, Emmanuelle Le Page, et al.. Investigating the Long-term Effect of Pregnancy on the Course of Multiple Sclerosis Using Causal Inference. Neurology, 2023, 100 (12), pp.e1296-e1308. ⟨10.1212/WNL.0000000000206774⟩. ⟨hal-03963580⟩