IMPORTANCE: Understanding the association between pregnancy and clinical outcomes in women with moderate to severe multiple sclerosis (MS) disability is crucial for guiding family planning and management strategies. OBJECTIVE: To assess peripregnancy relapse activity and disability progression in women with a preconception Expanded Disability Status Scale (EDSS) score of 3 or higher. DESIGN, SETTING, AND PARTICIPANTS: This multicenter retrospective cohort study used data from the MSBase Registry, with clinical observations spanning 1984 through 2024. Study cohorts included pregnant women with MS with a preconception EDSS score of 3 or higher (range: 3-10, with higher scores indicating more severe MS-related disability) and propensity score-matched nonpregnant women with MS (controls). MAIN OUTCOMES AND MEASURES: The main outcomes were peripregnancy annualized relapse rates (ARRs) and time to 6-month confirmed disability worsening (CDW). RESULTS: A total of 1631 women with MS were included, of whom 575 were in the pregnant cohort (median [IQR] age at pregnancy, 32.5 [29.1-36.1] years) and 1056 were in the nonpregnant cohort (median [IQR] age, 32.6 [27.5-37.2] years). The median (range) preconception EDSS score was 3.5 (3.0-7.5). Relapse activity decreased during pregnancy, with a 75% reduction in ARR during the first trimester (rate ratio [RR], 0.25; 95% CI, 0.15-0.43), and increased to 36% above preconception levels in the first 3 months post partum (RR, 1.36; 95% CI, 1.06-1.75). Relapse during pregnancy was associated with a higher preconception ARR (odds ratio [OR], 1.56; 95% CI, 1.10-2.20) and preconception use of natalizumab (OR, 4.42; 95% CI, 1.24-23.57) or fingolimod (OR, 14.07; 95% CI, 2.81-91.30). Older age (OR, 0.92; 95% CI, 0.85-0.99) and continuation of disease-modifying therapy into pregnancy (OR, 0.42; 95% CI, 0.19-1.00) were associated with reduced risk. Disease-modifying therapy reinitiation within 1 month post partum was associated with lower odds of early postpartum relapse (OR, 0.45; 95% CI, 0.23-0.86). There was no significant difference in time to CDW between the pregnant and nonpregnant groups (hazard ratio [HR], 1.15; 95% CI, 0.96-1.38). However, ARR during pregnancy (HR, 1.37; 95% CI, 1.13-1.65) and postpartum EDSS score higher than 4 (HR, 2.69; 95% CI, 1.80-4.03) were associated with shorter time to CDW. CONCLUSIONS AND RELEVANCE: In this cohort study, women with moderate to severe MS disability exhibited a pattern of peripregnancy relapse activity similar to that reported in women with less disability. Pregnancy was not associated with worse long-term disability outcomes, although optimizing disease control in the peripregnancy period remained critical.

Academic MS Center Zuyd Department of Neurology Zuyderland Medical Center Sittard Geleen Netherlands

Austin Health Melbourne Victoria Australia

Azienda Ospedaliera di Rilievo Nazionale San Giuseppe Moscati Avellino Avellino Italy

Brain and Mind Centre The University of Sydney Sydney New South Wales Australia

Centre for Rehabilitation Disability and Sport Medicine Department of Neurosciences Imaging and Clinical Sciences Gabriele d'Annunzio University of Chieti and Pescara Chieti Italy

Centre Hospitalier de l'Université de Montréal and Universite de Montreal Montreal Quebec Canada

Centro Sclerosi Multipla Unità Operativa Complessa di Neurologia Azienda Ospedaliera per l'Emergenza Cannizzaro Catania Italy

Clinical Neuroimmunology and MS Unit Koşuyolu Hospital Istanbul Turkey

Clinical Outcomes Research Unit Department of Medicine University of Melbourne Melbourne Victoria Australia

Department of Biotechnological and Applied Clinical Sciences University of L'Aquila L'Aquila Italy

Department of Medicine School of Clinical Sciences Monash University Clayton Victoria Australia

Department of Neurological Sciences Faculty of Medicine Yeditepe University Istanbul Turkey

Department of Neurology Alfred Health Melbourne Victoria Australia

Department of Neurology and Center of Clinical Neuroscience 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Department of Neurology Box Hill Hospital Melbourne Victoria Australia

Department of Neurology Centro Hospitalar Universitario de São João Porto Portugal

Department of Neurology Clinical Investigation Centre for Neurosciences and Mental Health Razi University Hospital Tunis Tunisia

Department of Neurology Faculty of Medicine and University Hospital Hradec Králové Charles University Prague Czech Republic

Department of Neurology Faculty of Medicine and University Hospital in Pilsen Charles University Prague Czech Republic

Department of Neurology Faculty of Medicine Palacký University and University Hospital Olomouc Olomouc Czech Republic

Department of Neurology Faculty of Medicine University of Ostrava Ostrava Czech Republic

Department of Neurology Masaryk University Brno and University Hospital Brno Czech Republic

Department of Neurology Monash Health Clayton Victoria Australia

Department of Neurology Waikato Hospital Hamilton New Zealand

Department of Neuroscience MS Center Neurology Unit Santa Maria delle Croci Hospital Azienda Unità Sanitaria Locale Romagna Ravenna Italy

Department of Neuroscience School of Translational Medicine Monash University Melbourne Victoria Australia

Department of Neurosciences Eastern Health Clinical School Monash University Melbourne Victoria Australia

Dipartimento di Scienze Biomediche e Neuromotorie Università di Bologna Bologna Italia

Division of Neurology Department of Medicine Amiri Hospital Sharq Kuwait

Faculty of Medicine of Tunis University of Tunis El Manar Tunis Tunisia

Hunter Medical Research Institute University of Newcastle Newcastle New South Wales Australia

Hunter New England Health John Hunter Hospital Newcastle New South Wales Australia

Immune Tolerance Laboratory Ingham Institute and Department of Medicine University of New South Wales Sydney New South Wales Australia

Institute for Advanced Biomedical Technologies Department of Neurosciences Imaging and Clinical Sciences Gabriele d'Annunzio University of Chieti and Pescara Chieti Italy

Istituto di Ricovero e Cura a Carattere Scientifico Istituto delle Scienze Neurologiche di Bologna Bologna Italia

Izmir University of Economics Medical Point Hospital Izmir Turkey

MS Centre Clinical Neurology Santissima Annunziata University Hospital Chieti Italy

Multiple Sclerosis Centro Servicio y Unidad de Referencia Murcia Spain

Multiple Sclerosis Research Association Izmir Turkey

Neuroimmunology Centre Department of Neurology Royal Melbourne Hospital Melbourne Victoria Australia

Neuroinmunología Clínica y Esclerosis Múltiple San Antonio Catholic University Murcia Spain

School for Mental Health and Neuroscience Department of Neurology Maastricht University Medical Center Maastricht Netherlands

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