Association of reproductive factors with disease severity in women with relapsing-remitting multiple sclerosis

Background: While reproductive factors have been linked to multiple sclerosis (MS) onset and activity, their association with disability remains unclear. We investigated the relationship between reproductive variables and MS severity, measured by the Age-Related Multiple Sclerosis Severity Score (ARMSS). Methods: in 242 Italian women with relapsing-remitting MS, reproductive factors (age at menarche, oral contraceptive use, full-term pregnancies and pregnancy losses) were collected through a structured environmental questionnaire. Associations with ARMSS were assessed using linear regression models. Key findings on obstetric factors were replicated in an independent cohort (n = 465). Results: longer oral contraceptive use before MS onset was associated with lower ARMSS (β = -0.048; p-value = 3.6 × 10-3). Contrasting associations were observed for obstetric factors, with number of full-term pregnancies being associated with lower ARMSS (β = -0.35; p-value = 0.042), while pregnancy losses being associated with higher ARMSS (β = 0.61; p-value = 0.036). Consistently, women with full-term pregnancies only showed lower disability than those with pregnancy losses only (β = -0.72; p-value = 0.026). The association with full-term pregnancies was replicated in the validation cohort (β = -0.44; p-value = 6.55 × 10-3), as well as the lower ARMSS observed in women reporting full-term pregnancies only compared to those reporting pregnancy losses only (β = -0.49; p-value = 0.013). Conclusion: our results highlight how reproductive factors may contribute to individual variability in disease severity.