OBJECTIVE: To assess the risk of disease reactivation during pregnancy after natalizumab suspension in women with multiple sclerosis (MS).METHODS: Data of all pregnancies occurring between 2009 and 2015 in patients with MS treated with natalizumab and referring to 19 participating sites were collected and compared with those of pregnancies in untreated patients and patients treated with injectable immunomodulatory agents through a 2-factor repeated measures analysis. Predictors of disease activity were assessed through stepwise multivariable logistic regression models.RESULTS: A total of 92 pregnancies were tracked in 83 women receiving natalizumab. Among these pregnancies, 74 in 70 women resulted in live births, with a postpartum follow-up of at least 1 year, and were compared with 350 previously published pregnancies. Relapse rate during and after pregnancy was higher in women treated with natalizumab (p<0.001). In multivariable analysis, longer natalizumab washout period was the only predictor of relapse occurrence during pregnancy (p= 0.001). Relapses in the postpartum year were related to relapses during pregnancy (p= 0.019) and early reintroduction of disease-modifying drugs (DMD;p= 0.021). Disability progression occurred in 16.2% of patients and was reduced by early reintroduction of DMD (p= 0.024).CONCLUSIONS: Taken as a whole, our findings indicate that the combination of avoiding natalizumab washout and the early resumption of DMD after delivery could be the best option in the perspective of maternal risk. This approach must take into account possible fetal risks that need to be discussed with the mother and require further investigation.CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in women with MS, the risk of relapses during pregnancy is higher in those who had been using natalizumab as compared to those who had been using interferon-β or no treatment.