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]
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]
Fabien Rollot
- Function : Author
Romain Casey
- Function : Author
- PersonId : 1164213
- ORCID : 0000-0002-5918-9261
Marc Debouverie
- Function : Author
Jonathan Ciron
- Function : Author
- PersonId : 795646
- ORCID : 0000-0002-3386-6308
- IdRef : 137599021
Jerome de Seze
- Function : Author
Elisabeth Maillart
- Function : Author
- PersonId : 1164214
- ORCID : 0000-0001-7699-0328
Pierre Labauge
- Function : Author
- PersonId : 759958
- ORCID : 0000-0001-7759-8555
- IdRef : 059860367
Christine Lebrun-Frenay
- Function : Author
- PersonId : 770285
- ORCID : 0000-0002-3713-2416
- IdRef : 074517929
Bruno Stankoff
- Function : Author
- PersonId : 1146488
- ORCID : 0000-0002-9631-4674
- IdRef : 070067988
Eric Thouvenot
- Function : Author
- PersonId : 758070
- ORCID : 0000-0001-8671-7747
- IdRef : 094970920
Abdullatif Al Khedr
- Function : Author
Olivier Casez
- Function : Author
Bertrand Bourre
- Function : Author
- PersonId : 1164218
- ORCID : 0000-0002-2459-2480
Philippe Cabre
- Function : Author
Abir Wahab
- Function : Author
Laurent Magy
- Function : Author
Jean-Philippe Camdessanche
- Function : Author
Aude Maurousset
- Function : Author
Solène Moulin
- Function : Author
Nasr Haifa Ben
- Function : Author
Dalia Dimitri Boulos
- Function : Author
Karolina Hankiewicz
- Function : Author
Jean-Philippe Neau
- Function : Author
Corinne Pottier
- Function : Author
Chantal Nifle
- Function : Author
Muriel Rabilloud
- Function : Author
- PersonId : 181462
- IdHAL : muriel-rabilloud-ferrand
- ORCID : 0000-0003-1324-0356
- IdRef : 170401731
Fabien Subtil
- Function : Author
Abstract
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.