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

Fabien Rollot
  • Function : Author
Romain Casey
Marc Debouverie
  • Function : Author
Emmanuelle Le Page
  • Function : Author
Jonathan Ciron
Jerome de Seze
  • Function : Author
Aurélie Ruet
  • Function : Author
Elisabeth Maillart
Pierre Labauge
  • Function : Author
Helene Zephir
  • Function : Author
Caroline Papeix
  • Function : Author
Gilles Defer
  • Function : Author
Christine Lebrun-Frenay
Thibault Moreau
  • Function : Author
David Axel Laplaud
  • Function : Author
Eric Berger
  • Function : Author
Bruno Stankoff
  • Function : Author
Pierre Clavelou
  • Function : Author
Eric Thouvenot
Olivier Heinzlef
  • Function : Author
Abdullatif Al Khedr
  • Function : Author
Olivier Casez
  • Function : Author
Bertrand Bourre
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
Fabien Subtil
  • Function : Author
Sandra Vukusic
  • 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.
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Dates and versions

hal-03963580 , version 1 (30-01-2023)

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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, pp.10.1212/WNL.0000000000206774. ⟨10.1212/WNL.0000000000206774⟩. ⟨hal-03963580⟩
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