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Observational Study
. 2023 Mar 21;100(12):e1296-e1308.
doi: 10.1212/WNL.0000000000206774. Epub 2022 Dec 23.

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

Antoine Gavoille  1 , Fabien Rollot  2 , Romain Casey  2 , Marc Debouverie  2 , Emmanuelle Le Page  2 , Jonathan Ciron  2 , Jerome De Seze  2 , Aurélie Ruet  2 , Elisabeth Maillart  2 , Pierre Labauge  2 , Helene Zephir  2 , Caroline Papeix  2 , Gilles Defer  2 , Christine Lebrun-Frenay  2 , Thibault Moreau  2 , David Axel Laplaud  2 , Eric Berger  2 , Bruno Stankoff  2 , Pierre Clavelou  2 , Eric Thouvenot  2 , Olivier Heinzlef  2 , Jean Pelletier  2 , Abdullatif Al Khedr  2 , Olivier Casez  2 , Bertrand Bourre  2 , Philippe Cabre  2 , Abir Wahab  2 , Laurent Magy  2 , Jean-Philippe Camdessanche  2 , Aude Maurousset  2 , Solène Moulin  2 , Nasr Haifa Ben  2 , Dalia Dimitri Boulos  2 , Karolina Hankiewicz  2 , Jean-Philippe Neau  2 , Corinne Pottier  2 , Chantal Nifle  2 , Muriel Rabilloud  2 , Fabien Subtil  2 , Sandra Vukusic  2 ; Observatoire Français de la Sclérose en Plaques (OFSEP) Investigators
Collaborators, Affiliations
Observational Study

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

Antoine Gavoille et al. Neurology. .

Erratum in

  • Corrections to Null Hypothesis Articles.
    [No authors listed] [No authors listed] Neurology. 2025 May 13;104(9):e213475. doi: 10.1212/WNL.0000000000213475. Epub 2025 Apr 4. Neurology. 2025. PMID: 40184595 Free PMC article. No abstract available.

Abstract

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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Conflict of interest statement

J. Ciron: consulting and lecturing fees and travel grants from Biogen, Novartis, Merck, Teva, Sanofi-Genzyme, Roche, BMS-Celgene, and Alexion. J. De Sèze: consulting and lecturing fees, travel grants, and unconditional research support from Biogen, Genzyme, Novartis, Roche, Sanofi Aventis, and Teva Pharma. A. Ruet: consultancy fees, speaker fees, research grants (nonpersonal), or honoraria approved by the institutions from Novartis, Biogen Idec, Genzyme, MedDay, Roche, Teva, and Merck. E. Maillart: consulting and lecturing fees from Alexion, Biogen, BMS, Merck Serono, Novartis, Roche, Sanofi, Teva Pharmaceuticals, and Ad Scientiam and research support from Biogen, Novartis, and Roche. P. Labauge: consulting and lecturing fees, travel grants, and unconditional research support from Biogen, Genzyme, Novartis, Merck Serono, Roche, and Teva Pharma. H. Zephir: consulting or lectures and invitations for national and international congresses from Biogen, Merck, Teva, Sanofi-Genzyme, Novartis, and Bayer, research support from Teva and Roche, and academic research grants from Académie de Médecine, LFSEP, FHU Imminent, and ARSEP Foundation. G. Defer: consulting and lecturing fees for Biogen, BMS, Novartis, Genzyme,Merck Serono, Roche, and Teva; funding for travel from Merck Serono, Biogen, Sanofi-Genzyme, Novartis, and Teva; research support from Merck Serono, Biogen, Genzyme, and Novartis. C. Lebrun-Frénay: fees for consulting or lectures from Novartis, Genzyme, and Roche. T. Moreau: fees as scientific adviser from Biogen, MedDay, Novartis, Genzyme, and Sanofi. D.A. Laplaud: served on the scientific advisory boards for Roche, Sanofi, Novartis, MedDay, Merck, and Biogen; received conference travel support and/or speaker honoraria from Novartis, Biogen, Roche, Sanofi, Celgene, and Merck; and received research support from Fondation ARSEP and Agence Nationale de la Recherche. E. Berger: honoraria and consulting fees from Novartis, Sanofi Aventis, Biogen, Genzyme, Roche, and Teva Pharma. B. Stankoff: consulting and lecturing fees, travel grants from Biogen Idec, Merck Serono, Novartis, and Genzyme, and unconditional research support from Merck Serono, Genzyme, and Roche. P. Clavelou: consulting and lecturing fees, travel grants, and unconditional research support from Actelion, Biogen, Genzyme, Novartis, MedDay, Merck Serono, Roche, and Teva Pharma. E. Thouvenot: consulting and lecturing fees, travel grants, or unconditional research support from the following pharmaceutical companies: Actelion, Biogen, Celgene, Genzyme, Merck Serono, Novartis, Roche, and Teva Pharma; has a patent pending for biomarkers of neurodegeneration and neuroregeneration and a patent pending for a diagnosis method of multiple sclerosis (EP18305630.8); and received academic research support from PHRC and ARSEP Foundation. O. Heinzlef: consulting and lecturing fees from Bayer Schering, Merck, Teva, Genzyme, Novartis, Almirall, and Biogen Idec, travel grants from Novartis, Teva, Genzyme, Merck Serono, and Biogen Idec, and research support from Roche, Merck, and Novartis. J. Pelletier: received fees as scientific adviser from Biogen, Merck Serono, Novartis, travel grants from Biogen, MedDay, Novartis, Genzyme, Roche, Sanofi, and Teva and unconditional research support from Merck Serono and Roche. O. Casez: funding for travel and honoraria from Biogen, Merck Serono, Novartis, Sanofi-Genzyme, and Roche. B. Bourre: served on scientific advisory board for Biogen, Genzyme, Merck Serono, Novartis, and Roche and received funding for travel and honoraria from Biogen Idec, Merck Serono, Novartis, Sanofi-Genzyme, Roche, and Teva. A. Wahab: received expert testimony from Roche and travel grants from Biogen. J.-P. Camdessanché: consulting and lecturing fees from Akcea, Alnylam, Biogen, CSL-Behring, Genzyme, Grifols, Laboratoire Français des Biotechnologies, Natus, Novartis, Pfizer, PharmAlliance, Teva, and SNF-Floerger and travel grants from Biogen, CSL-Behring, Genzyme, Laboratoire Français des Biotechnologies, Merck Serono, Novartis, Pfizer, and Teva. A. Maurousset: received funding for travel from Merck Serono, Teva, Novartis, Sanofi-Genzyme, Biogen, and Roche; served on scientific advisory board for Roche; and received honoraria from Biogen, Novartis, and Roche. N.H. Ben: honoraria and consulting fees from Novartis, Genzyme, and Roche, research support from Biogen and Novartis, and travel grants from Genzyme, Novartis, and Roche. S. Vukusic: grants, personal fees, and nonfinancial support from Biogen, grants and personal fees from GeNeuro, grants, personal fees, and nonfinancial support from Genzyme, grants and personal fees from MedDay, grants, personal fees, and nonfinancial support from Merck Serono, grants, personal fees, and nonfinancial support from Novartis, grants, personal fees, and nonfinancial support from Roche, grants, personal fees, and nonfinancial support from Sanofi, and personal fees from Teva. The other authors report no relevant disclosures. Go to Neurology.org/N for full disclosures.

Figures

Figure 1
Figure 1. Study Design: Data Structuring
Example of structuring of the follow-up into 1-year periods for a patient exposed to a pregnancy. EDSS = Expanded Disease Status Scale; MS = multiple sclerosis.
Figure 2
Figure 2. Causal DAG
Causal DAG representing the main assumptions about the relationship between pregnancy formula image, relapse formula image, and disability formula image within the same 1-year period formula image (A) and between different 1-year periods (B). DAG = directed acyclic graph; EDSS = Expanded Disease Status Scale; MS = multiple sclerosis.
Figure 3
Figure 3. Long-term Effects of Pregnancy
Mean EDSS score, annual probability of relapse, and proportion of patients exposed to pregnancy in the observed situation and the counterfactual situation without pregnancy in the exposed population. EDSS = Expanded Disease Status Scale.
Figure 4
Figure 4. Short-term and Delayed Effects of Pregnancy
Mean EDSS score, annual probability of relapse, and proportion of patients exposed to pregnancy in the observed situation with pregnancies and in the counterfactual situation without pregnancy in the early-exposed population: perpartum effect (first year), postpartum effect (second year), and delayed effect (remaining 5 years of follow-up). EDSS = Expanded Disease Status Scale.
See this image and copyright information in PMC

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