Primary and secondary outcome measures Outcomes included neurodevelopmental disorders (NDD), defined by International Classification of Diseases, 10th Revision codes F70-F98—pervasive developmental disorders (PDD, F84) and mental retardation (MR, F70-F79) were studied separately—and visits to speech therapists. The reference group comprised children prenatally exposed to lamotrigine. Children were followed until outcome, loss to follow-up, death or 31 December 2016. We performed inverse probability of treatment weighting analyses using the propensity score, which included maternal and infant characteristics. Hazard ratios (HRs) were calculated using Cox models.

Results The cohort comprised 9034 children, 2916 of which were exposed to lamotrigine, 1627 to pregabalin, 1246 to clonazepam, 991 to valproic acid (VPA), 621 to levetiracetam, 502 to carbamazepine, 477 to topiramate, 378 to gabapentin and 143 to oxcarbazepine. None of these AEDs, except VPA, was associated with an increased risk of any of the four neurodevelopmental outcomes investigated. Exposure to VPA was associated with increased risks of NDDs (HR=2.7, 95% CI (1.8 to 4.0)), PDD (HR=4.4 (2.1 to 9.3)), MR (HR=3.1 (1.5 to 6.2)) and visits to speech therapists (HR=1.5 (1.1 to 1.9)), with a dose-response relationship.

Conclusions No increased risk of any of the neurodevelopmental outcomes investigated in this study was observed with prenatal exposure to levetiracetam, pregabalin, oxcarbazepine, topiramate, gabapentin, clonazepam or carbamazepine, compared with lamotrigine. However, this study corroborates the well-known association between maternal use of VPA during pregnancy and the risk of neurodevelopmental disorders in the offspring. Longer follow-up is necessary to confirm these findings.