Importance Limited clinical evidence is available about the risk of neurodevelopmental disorders (NDD), including autism spectrum disorders and congenital malformations (CM), in offspring following paternal exposure to antiseizure medications. Objective To investigate the risk of NDD (any subtype) and CM (major and/or minor) in offspring paternally exposed to valproate vs lamotrigine or levetiracetam monotherapy within 3 months prior to conception. Design, Setting, and Participants This observational, population-based, nationwide cohort study used Nordic registries data with family linkage (offspring born between 1997-2018 Denmark, 2010-2019 Norway, and 2007-2019 Sweden). Offspring born within the study period and paternally exposed to either (1) valproate or (2) lamotrigine or levetiracetam were identified and followed-up until 12 years or the end of the study period, whichever came first. Data were obtained from October 2020 (Denmark), June 2021 (Norway), and March 2021 in Sweden)and analyzed from October 2020 to July 2023. Exposures Paternal exposure to (1) valproate or (2) lamotrigine or levetiracetam during the spermatogenic risk window (derived from each National Prescription Registry). Main Outcomes and Measures The primary and secondary outcomes were NDD and CM, respectively, in offspring aged 12 years or younger. Country-specific hazard ratios (HRs) for NDD were estimated using Cox regression models and propensity score weighting (PSW), subsequently pooled via meta-analysis. Odds ratios (ORs) for CM were estimated using unadjusted logistic regression models for Denmark and Norway, but were not estimated for Sweden due to database constraints. Results NDD analysis included 5721 offspring, with 1950 in Denmark (valproate: 793 offspring; lamotrigine or levetiracetam: 1157 offspring), 1416 in Norway (valproate: 398 offspring; lamotrigine or levetiracetam: 1018 offspring), and 2355 in Sweden (valproate: 930 offspring; lamotrigine or levetiracetam: 1425 offspring). After excluding offspring with outlier weights and/or incomplete observation in the PSW-adjusted analyses, NDD occurrence was observed in 38 of 678 offspring (5.6%) vs 36 of 1118 offspring (3.2%), 13 of 325 offspring (4.0%) vs 21 of 910 offspring (2.3%), and 47 of 841 offspring (5.6%) vs 34 of 1334 offspring (2.5%) exposed to valproate vs lamotrigine or levetiracetam in Denmark, Norway, and Sweden, respectively. PSW-adjusted analyses showed significantly higher risk in the valproate vs lamotrigine or levetiracetam group (pooled adjusted HR, 1.50; 95% CI: 1.09-2.07; P = .01). CM analysis included 1161 offspring, with 648 in Denmark (valproate: 259 offspring; lamotrigine or levetiracetam: 389 offspring) and 513 in Norway (valproate: 169 offspring; lamotrigine or levetiracetam: 344 offspring), and found no increased risk (unadjusted pooled OR, 0.81; 95% CI, 0.48-1.36). Conclusions and Relevance In this cohort study, higher NDD risk was observed in offspring paternally exposed to valproate vs lamotrigine or levetiracetam, but no difference in CM risk was observed between the 2 exposure groups. However, these findings should be interpreted with caution due to the heterogeneity in the unadjusted estimates.
Colas et al. (Mon,) studied this question.