Risk Factors for Relapses in Multiple Sclerosis Beyond Disease-Modifying Therapy: An Umbrella Review of Systematic Reviews and Meta-Analyses

Background/Objectives: People with MS continue to experience relapses despite the use of disease-modifying therapies. This has motivated growing interest in the potential of non-pharmacological factors to reduce relapse risk. However, previous studies have been heterogeneous, and current clinical guidelines lack clarity on which measures should be incorporated into routine care. We aim to conduct an umbrella review of systematic reviews with meta-analyses to determine the current evidence on non-pharmacological exposures associated with relapse risk in MS. Methods: We searched PubMed, Embase and Cochrane to identify systematic reviews with meta-analyses that evaluated the association between non-pharmacological exposures and relapse risk. We included observational studies that reported on relapses as an outcome. The effect sizes (relative risk [RR] or standardized mean difference [SMD]) and certainty of evidence were assessed using components of the GRADE framework. Results: We screened 3366 articles and identified 11 systematic reviews for inclusion. Protective factors were breastfeeding (RR 0.63, high certainty), pregnancy (SMD −0.52, moderate certainty), menopause (SMD −0.5, low certainty), autumn months (RR 0.97, moderate certainty) and increasing levels of vitamin D (RR 0.9, low certainty). Risk factors were early postpartum period (RR 1.87, moderate certainty) and stress (d = 0.53, moderate certainty). Influenza vaccination (low certainty), COVID-19 infection (low certainty), and vitamin D levels above 50 nmol/L (low certainty) were not statistically associated with relapse risk. Conclusions: Our umbrella review highlights the need for more robust studies to strengthen the certainty of evidence on non-pharmacological exposures and relapse risk in people with MS. Current findings support promoting breastfeeding, careful disease management throughout the pregnancy–postpartum period, and the implementation of stress mitigation strategies.