Background: Planning pregnancy in patients with active multiple sclerosis (MS) is highly challenging because treatment withdrawn may be associated with dramatic disease reactivation. Objective: To compare two strategies for women with active MS who were planning pregnancy: stopping natalizumab (1) at the end of the first trimester and (2) at conception. Methods: Standardized strategy for women with active MS was initiated in our department. Maintenance of natalizumab until the end of first trimester was recommended (“secured first trimester” (SFT)). When patients refused, they were advised to continue until conception (“secured conception” (SC)). Predictors of disease activity during pregnancy were assessed. Results: Forty-six pregnancies were prospectively followed (30 with SFT and 16 with SC). One congenital anomaly occurred in the SC group. The proportions of patients with relapse and disability progression during pregnancy were lower in the SFT than in the SC group (3.6% vs 38.5%, p < 0.005 and 3.6% vs 30.8%, p < 0.05, respectively). Predictors of relapse and disability progression during pregnancy were the time when natalizumab was stopped (conception vs end of first trimester) and the number of relapses during the year before natalizumab. Conclusion: Maintaining natalizumab during the first trimester may reduce the risk of disease reactivation during pregnancy in patients with active MS.