Background <p>Natalizumab (NTZ) is a monoclonal antibody used in treating relapsing forms of multiple sclerosis (MS). However, there is still insufficient information about its long-term safety during pregnancy and lactation. This study aims to provide further insights into the short- and long-term effects of NTZ on mothers with MS and their children exposed to the drug during pregnancy and breastfeeding.</p> Materials and methods <p>We recruited prospectively and retrospectively 14 women with MS, treated with NTZ, and their 15 children. All women continued NTZ treatment throughout pregnancy, and 10 of them also during breastfeeding. The follow-up period ranged from 1 to 5 years post-delivery, in the group exposed to NTZ both during pregnancy and breastfeeding; from 2 to 10 years post-delivery in the group exposed to NTZ exclusively during pregnancy.</p> Results <p>During pregnancy, no relapses were reported, suggesting persistent efficacy of NTZ therapy. However, 1 out of 14 mothers experienced postpartum clinical events, without concomitant MRI activity MRI findings, and 2 other patients presented an isolated increase in lesion load, on MRI performed within 1 month after delivery, without clinical relapses. Neonatal outcomes were favorable, with normal birth parameters and absence of infections or developmental delays, with no differences between those exposed or not to NTZ during breastfeeding.</p> Conclusions <p>NTZ therapy during pregnancy and breastfeeding is associated with favorable maternal and neonatal outcomes up to 10 years follow-up.</p>