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Investigating the Long-term Effect of Pregnancy on the Course of Multiple Sclerosis Using Causal Inference
Antoine Gavoille1, Fabien Rollot2, Romain Casey2
1From the Service de Neurologie (A.G., F.R., R.C., S.V.), Sclérose en Plaques, Pathologies de La Myéline et Neuro-inflammation, Hôpital Neurologique Pierre-Wertheimer, Hospices Civils de Lyon, Bron; Université de Lyon (A.G., M.R., F.S.), Université Claude Bernard Lyon 1, CNRS, Laboratoire de Biométrie et Biologie Évolutive UMR 5558, Villeurbanne; Service de Biostatistique-Bioinformatique (A.G., M.R., F.S.), Hospices Civils de Lyon; Université de Lyon (F.R., R.C., S.V.), Université Claude Bernard Lyon 1; Observatoire Français de La Sclérose en Plaques (F.R., R.C., S.V.), Centre de Recherche en Neurosciences de Lyon, INSERM 1028 et CNRS UMR; EUGENE DEVIC EDMUS Foundation Against Multiple Sclerosis (F.R., R.C., S.V.), State-approved Foundation, Bron; Nancy University Hospital (M.D.), Department of Neurology, Université de Lorraine, APEMAC; CHU Pontchaillou (E.L.P.), CIC1414 INSERM, Rennes; CHU de Toulouse (J.C.), Hôpital Pierre-Paul Riquet, Department of Neurology, CRC-SEP, Toulouse; Infinity (J.C.), INSERM UMR1291-CNRS UMR5051, Université Toulouse III; CHU de Strasbourg (J.D.S.), Department of Neurology and Clinical Investigation Center, CIC 1434, INSERM 1434; Univ. Bordeaux (A.R.), F-33000 Bordeaux INSERM U1215, Neurocentre Magendie, F-33000 Bordeaux CHU de Bordeaux, Department of Neurology, CIC Bordeaux CIC1401; Département de Neurologie (E.M.), Hôpital Pitié-Salpêtrière, APHP, Paris; Centre de Ressources et de Compétences SEP Paris (E.M.); CHU de Montpellier (P.L.), MS Unit; University of Montpellier (MUSE) (P.L.); CHU Lille (H.Z.), CRCSEP Lille, Univ Lille, U1172; Fondation Rotschild (C. Papeix), Department of Neurology, Paris; CHU de Caen (G.D.), MS Expert Centre, Department of Neurology, Avenue de La Côte-de-Nacre, Normandy University, Caen; Neurology (C.L.-F.), UR2CA, Centre Hospitalier Universitaire Pasteur2, Université Nice Côte d'Azur, Nice; CHU de Dijon (T.M.), Department of Neurology, EA4184; CHU de Nantes (D.A.L.), Service de Neurologie & CIC015 INSERM; CRTI-Inserm U1064 (D.A.L.), Nantes; CHU de Besançon (E.B.), Service de Neurologie; Sorbonne Universités (B.S.), UPMC Paris 06, Brain and Spine Institute, ICM, Hôpital de La Pitié Salpêtrière, Inserm UMR S 1127, CNRS UMR 7225, and Department of Neurology, AP-HP, Saint-Antoine Hospital; CHU Clermont-Ferrand (Pierre Clavelou), Department of Neurology, F-63000 Clermont-Ferrand Université Clermont Auvergne, Inserm, Neuro-Dol, F-63000 Clermont-Ferrand; Department of Neurology (E.T.), Nimes University Hospital; Institut de Génomique Fonctionnelle (E.T.), UMR5203, INSERM 1191, Univ. Montpellier; Hôpital de Poissy (O.H.), Department of Neurology; Aix Marseille Univ (J.P.), APHM, Hôpital de La Timone, Pôle de Neurosciences Cliniques, Service de Neurologie; CHU d'Amiens (A.A.K.), Department of Neurology; CHU Grenoble Alpes (O.C.), Department of Neurology, La Tronche/Grenoble; CHU de Rouen (B.B.), Department of Neurology; CHU de La Martinique (Philippe Cabre), Department of Neurology, Fort-de-France; APHP (A.W.), Hôpital Henri Mondor, Department of Neurology, Créteil; CHU de Limoges (L.M.), Hôpital Dupuytren, Department of Neurology; CHU de Saint-Étienne (J.-P.C.), Hôpital Nord, Department of Neurology; CHU de Tours (A.M.), Hôpital Bretonneau, CRC SEP and Department of Neurology; CHU de Reims (S.M.), CRC-SEP, Department of Neurology; Hôpital Sud Francilien (N.H.B.), Department of Neurology, Corbeil Essonnes; CHU Bicêtre (D.D.B.), Department of Neurology, Le Kremlin Bicêtre; Department of Neurology (K.H.), Hôpital Pierre Delafontaine, Centre Hospitalier de Saint-Denis; CHU La Milétrie (J.-P.N.), Hôpital Jean Bernard, Department of Neurology, Poitiers; CH de Pontoise (C. Pottier), Hôpital René Dubos, Department of Neurology; and Centre Hospitalier de Versailles (C.N.), Department of Neurology, F-78150 Le Chesnay, France. ant.gavoille@gmail.com.
Background And Objectives:
The question of the long-term safety of pregnancy is a major concern in patients with multiple sclerosis (MS), 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 patients with MS and secondarily the short-term effects (during the perpartum and postpartum years) and delayed effects (occurring beyond 1 year after delivery).
Methods:
We conducted an observational cohort study with data from patients with MS followed in the Observatoire Français de la Sclérose en Plaques registry between 1990 and 2020. We included female patients with MS 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 score 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 1 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 3 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 1 pregnancy. Pregnancy had no significant long-term causal effect on the mean EDSS score at 9 years (causal mean difference [95% CI] = 0.00 [-0.16 to 0.15]) or 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 perpartum year and significantly increased it during the postpartum year, but no significant delayed effect was found on the 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.
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