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. 2025 Aug 4:e252550.
doi: 10.1001/jamaneurol.2025.2550. Online ahead of print.

Therapeutic Management During Pregnancy and Relapse Risk in Women With Multiple Sclerosis

Antoine Gavoille  1   2   3 , Fabien Rollot  1   4   5   6 , Romain Casey  1   4   5   6 , Guillaume Mathey  7 , Emmanuelle Le Page  8 , Jonathan Ciron  9 , Jérôme De Sèze  10 , Aurélie Ruet  11 , Elisabeth Maillart  12 , Pierre Labauge  13 , Hélène Zephir  14 , Arnaud Kwiatkowski  15 , Caroline Papeix  16 , Gilles Defer  17 , Christine Lebrun-Frenay  18 , Thibault Moreau  19 , David-Axel Laplaud  20 , Eric Berger  21 , Anne-Laure Dubessy  12 , Pierre Clavelou  22 , Eric Thouvenot  23 , Olivier Heinzlef  24 , Jean Pelletier  25 , Abdullatif Al-Khedr  26 , Olivier Casez  27 , Bertrand Bourre  28 , Abir Wahab  29 , Laurent Magy  30 , Solène Moulin  31 , Jean-Philippe Camdessanché  32 , Inès Doghri  33 , Mariana Sarov-Riviere  34 , Karolina Hankiewicz  35 , Corinne Pottier  36 , Amélie Dos Santos  37 , Chantal Nifle  38 , Fabien Subtil  2   3 , Sandra Vukusic  1   4   5   6 ; OFSEP Investigators
Collaborators, Affiliations

Therapeutic Management During Pregnancy and Relapse Risk in Women With Multiple Sclerosis

Antoine Gavoille et al. JAMA Neurol. .

Abstract

Importance: In women with multiple sclerosis (MS), disease-modifying therapy (DMT) management during pregnancy might impact relapse risk.

Objective: To estimate the effect of DMT management during pregnancy on MS relapse rate and compare different therapeutic strategies.

Design, setting, and participants: This was a multicenter retrospective cohort study using data from January 1990 to December 2023. Data were extracted in December 2023 from the French MS registry. Among 52 955 women in the registry, we included pregnancies identified through childbirths in patients with relapsing-onset MS who were monitored for at least 18 months before delivery and 9 months after. Pregnancies occurring less than 18 months apart or with missing month of birth were excluded.

Exposures: Mediation analysis was used to estimate the total, direct, and indirect (mediated by DMT management) effects of pregnancy. Different therapeutic strategies were compared: DMT interruption, switching to or maintaining interferon β or glatiramer acetate, switching to or maintaining natalizumab until the third trimester, and switching to or maintaining intravenous anti-CD20 and interrupting it 3 months before conception.

Main outcomes and measures: The primary outcome was the annualized relapse rate (ARR) during the preconception, gestation, and postpartum periods. Within a causal inference framework, counterfactual ARRs were estimated using longitudinal g-computation, combining a random forest algorithm for predicting DMTs, and a mixed-effects Poisson model for relapses.

Results: We included 6341 pregnancies occurring in 4998 women (mean [SD] age at conception, 31.5 [4.5] years). DMT management during pregnancy significantly increased ARR during gestation (causal rate ratio [cRR], 1.13; 95% CI, 1.06-1.22) and postpartum (cRR, 1.08; 95% CI, 1.01-1.16) periods. This led to a deleterious total effect of pregnancy on ARR, particularly in women receiving natalizumab before pregnancy with prolonged interruption (ie, interruption before the second trimester or resumption more than 3 months after delivery; cRR, 2.18; 95% CI, 1.76-2.69), and in women receiving fingolimod (cRR, 2.15; 95% CI, 1.60-2.93). Compared to DMT interruption, anti-CD20 strategy was the most effective (cRR, 0.38; 95% CI, 0.25-0.52), followed by the natalizumab strategy with short interruption (cRR, 0.80; 95% CI, 0.71-0.90), whereas interferon β (cRR, 0.93; 95% CI, 0.86-0.99) and glatiramer acetate strategies (cRR, 0.91; 95% CI, 0.84-0.99) were less effective.

Conclusion: In this study, DMT management during pregnancy significantly increased relapse risk, particularly in patients receiving natalizumab with prolonged interruption or fingolimod. The strategy based on the use of anti-CD20 before pregnancy was the most effective to mitigate this risk.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Mathey reported consulting or lectures fees and travel grants from Biogen, Novartis, Sanofi-Genzyme, Merck, Teva, Alexion, and Roche. Dr Le Page reported consulting or lecture fees and invitations for national and international congresses from Biogen, Merck, Teva, Sanofi-Genzyme, Novartis, and Alexion and research support from Teva and Biogen. Dr Ciron reported consulting for, serving on a scientific advisory board for, speaking at, or other activities with Biogen, Novartis, Merck, Sanofi-Genzyme, Roche, Alexion, and Horizon-Amgen. Dr De Sèze reported consulting and lecturing fees, travel grants, and unconditional research support from Biogen, Novartis, Roche, Sanofi-Genzyme, and Teva. Dr Ruet reported funding for travel or speaker honoraria from Biogen, Merck, Alexion, Novartis, and Sanofi-Genzyme; served as consultant for Horizon; and received research support from Biogen, Bristol Myers Squibb, Sanofi-Genzyme, Roche, and Merck. Dr Maillart reported consulting and lecturing fees from Alexion, Biogen, Horizon, Janssen, Merck, Novartis, Roche, Sandoz, Sanofi-Genzyme, and Teva Pharmaceuticals and research support from Biogen. Dr Labauge reported fees and grants from Biogen, Sanofi-Genzyme, Novartis, Alexion, and Merck. Dr Zephir repoted consulting or lecture fees 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, Ligue Française contre la Sclérose en Plaques, Fédérations hospitalo-universitaires, Imminent, and Fondation Association pour la Recherche sur la Sclérose en Plaques. Dr Kwiatkowski reported consulting or lecture fees and invitations for national and international congresses from Biogen, Janssen, Merck, Sandoz, Sanofi-Genzyme, Novartis, and Roche. Dr Papeix reported lecturing fees, travel grants, and research support from Biogen, Janssen, Novartis, Roche, Sanofi-Genzyme, Alexion, and Amgen. Dr Defer reported consulting and lecturing fees from Biogen, Novartis, Merck, Roche, and Teva; funding for travel from Merck, Biogen, Sanofi-Genzyme, Novartis, and Teva; and research supporting from Merck, Biogen, and Novartis. Dr Moreau reported advisory fees from Biogen, MedDay, Novartis, and Sanofi-Genzyme. Dr Laplaud reported serving on scientific advisory boards for Alexion, Bristol Myers Squibb, Roche, Sanofi-Genzyme, Novartis, Merck, Janssen, and Biogen; received conference travel support or speaker honoraria from Alexion, Novartis, Biogen, Roche, Sanofi-Genzyme, Bristol Myers Squibb and Merck; and received research support from Fondation Association pour la Recherche sur la Sclérose en Plaques, Fondation European Database for Multipin Sclerosis, and Agence Nationale de la Recherche. Dr Berger reported honoraria and consulting fees from Novartis, Sanofi-Genzyme, Biogen, Merck, Roche, and Teva. Dr Dubessy reported consulting fees and travel grants from Horizon Therapeutics and Novartis Pharma. Dr Clavelou reported consulting and lecturing fees, travel grants, and unconditional research support from Biogen, Janssen, MedDay, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva. Dr Thouvenot reported consulting and lecturing fees, travel grants, or unconditional research support from Actelion, Biogen, Janssen, Merck, Novartis, Roche, and Sanofi-Genzyme. Dr Heinzlef reported consulting and lecturing fees from Bayer Schering, Merck, Teva, Sanofi-Genzyme, Novartis, Almirall, and Biogen; travel grants from Novartis, Teva, Sanofi-Genzyme, Merck, and Biogen; and research support from Roche, Merck, and Novartis. Dr Al-Khedr reported consulting or lecture fees and invitations for national and international congresses from Biogen, Merck, Sandoz, Sanofi-Genzyme, Alexion, Novartis, and Roche. Olivier Casez reported consulting fees and travelling or congress fees from Biogen, Roche, Merck, Novartis, Janssen, and Sanofi-Genzyme. Dr Bourre reported serving on scientific advisory board for Alexion, Bristol Myers Squibb, Biogen, Sanofi-Genzyme, Janssen, Merck, Horizon, Novartis, Roche, and Sandoz and received funding for travel and honoraria from Alexion, Merck, Novartis, Sanofi-Genzyme, Roche, and Janssen. Dr Wahab reported consulting fees and travelling or congress fees from Roche, Merck, Novartis, and Janssen. Dr Magy reported consulting fees and traveling fees from Biogen, Merck, Novartis, Roche, and Sanofi-Genzyme. Dr Camdessanche reported consulting and lecturing fees from Akcea, Alexion, Alnylam, Argenx, Biogen, Bristol Myers Squibb, CSL-Behring, Sanofi-Genzyme, GSK, Grifols, Laboratoire Français des Biotechnologies, Merck, Natus, Novartis, Pfizer, Pharmalliance, UCB Pharma, Teva, and SNF-Floerger and travel grants from Akcea, Alexion, Alnylam, Argenx, Biogen, CSL-Behring, Sanofi-Genzyme, Grifols, Laboratoire Français des Biotechnologies, Merck, Natus, Novartis, Pfizer, Teva, and SNF-Floerger. Dr Doghri reported consulting fees, lecturing fees, travel grants, or unconditional research support from Merck, Sanofi-Genzyme, Sandoz, Novartis, Alexion, and Horizon. Dr Vukusic reported lecturing fees, travel grants, and research support from Biogen, Bristol Myers Squibb–Celgene, Janssen, Merck, Novartis, Roche, Sandoz, and Sanofi-Genzyme. No other disclosures were reported.

Comment in

  • doi: 10.1001/jamaneurol.2025.2559

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