Background: It is widely accepted that relapses of multiple sclerosis (MS) decrease during pregnancy; however, studies show an increased risk of relapse in the first months postpartum. Objectives: As part of a systematic review, we described postpartum relapse in women with relapsing MS and evaluated the effect of disease-modifying drugs (DMDs), including treatment decisions. Methods: Searches of EMBASE and MEDLINE databases were undertaken to identify relevant studies published from November 20092019. Twenty studies were identified, and 17 reporting postpartum relapses included. Results: Across these studies, 2522 patients and 2803 pregnancies were included; 1611 pregnancies were exposed to DMDs during preconception, 451 during pregnancy, and 540 during postpartum. Postpartum relapses were mainly reported as relapse rate (RR; n=6 [range 0.1-0.6]) and annualized RR (n=5 [range 0.2-1.1]). DMD-exposure during early pregnancy was associated with fewer postpartum relapses (DMD: platform therapy, n=2; intravenous infusion, n=1) compared with no DMD in 3 of 4 identified studies; the remaining study found no difference between groups (patients with relapses exposed to various DMDs, 23%; unexposed, 27%). DMD-exposure preconception generally had no effect on postpartum relapses (DMD: various, n=3) compared with no DMD; however, one study found high-efficacy DMD use (intravenous infusion or oral) preconception was associated with postpartum relapse with an odds ratio of 2.11 (95% CI: 1.32-3.27) versus no high-efficacy DMD. Some studies suggested early postpartum restarting of DMDs reduced number of relapses compared with delayed restart (DMD: various, n=3; intravenous infusion, n=2); however, others noted no significant effect on relapse risk (DMD: various, n=3). Conclusions: Findings regarding postpartum relapses in women with MS exposed to DMDs were varied. Limited evidence suggested high-efficacy DMDs preconception increases risk of postpartum relapse, likely due to higher disease activity in these patients. Thus, in terms of clinical disease activity, decision-making concerning benefit-risk of DMD use before, during and after pregnancy remains difficult.