<p>Relapsing–remitting multiple sclerosis (RRMS) is the most common inflammatory demyelinating disease of the central nervous system, disproportionately affecting women of childbearing age. This systematic review evaluates the safety and efficacy of two disease-modifying therapies (DMTs), natalizumab and fingolimod, across the preconception, pregnancy, and postpartum periods. Following PRISMA guidelines, we analyzed four observational studies to assess relapse rates and maternal outcomes. Our findings reveal a distinct pattern in disease activity: a reduction in relapses during pregnancy, particularly in the third trimester, followed by a significant surge postpartum. This trend is likely attributable to an immunological shift, marked by a Th2-dominant response, reduced pro-inflammatory cytokines, and increased estrogen and progesterone levels. Notably, patients who had been treated with natalizumab or fingolimod exhibited higher relapse rates compared to those who had used other DMTs. This may reflect a potential selection bias, as these therapies are often prescribed for patients with more severe diseases, who may inherently present with higher relapse rates regardless of treatment discontinuation. Natalizumab continuation into the second trimester is associated with safety and a reduction in relapse risk, whereas fingolimod, due to its teratogenic risk, must be discontinued before conception. Given the inherent postpartum increase in disease activity, individualized care plans and close monitoring are essential. Randomized controlled trials and studies involving larger patient populations are necessary to improve our understanding of the topic and optimize therapeutic approaches, as our conclusions are based solely on observational study data.</p>