Background: There is concern about the increased risk of neurodevelopmental disorders (NDDs) among offspring of fathers taking valproate within 90 days before conception.
Methods: Using nationwide databases from Norway and Taiwan, this cohort study examined associations between exposure to paternal valproate monotherapy during the 90 days preceding conception and incidence of NDDs among offspring after at least 6 years of follow-up. Pooled logistic regression analyses compared risks of NDDs among offspring whose fathers were treated versus not treated with valproate in the overall cohort (population control); treated versus not treated with valproate among fathers with an indication for antiseizure medication (indication-restricted); and treated with valproate versus lamotrigine or levetiracetam (active-comparator). Adjusted hazard ratios and 95% confidence intervals (CIs) were generated with adjustment for confounding variables using propensity score fine stratification weighting (PS-FSW) in the indication-restricted and active-comparator analyses.
Results: Paternal valproate exposure in the 90 days before conception occurred in 319 of 339,500 (0.09%) offspring in Norway and 564 of 1,051,488 (0.05%) in Taiwan. In the population control analyses, the crude hazard ratios of NDDs among offspring exposed versus unexposed to valproate were 1.67 (95% CI, 1.10 to 2.54) in Norway and 1.35 (95% CI, 1.13 to 1.63) in Taiwan. In the indication-restricted PS-FSW analyses, the adjusted hazard ratios of NDDs among offspring exposed versus unexposed to valproate among fathers with an antiseizure medication indication were 1.20 (95% CI, 0.75 to 1.94) in Norway and 1.12 (95% CI, 0.92 to 1.35) in Taiwan. In the active-comparator PS-FSW analyses, the adjusted hazard ratios of NDDs in offspring with exposure to valproate versus lamotrigine or levetiracetam were 1.02 (95% CI, 0.57 to 1.82) in Norway and 1.22 (95% CI, 0.64 to 2.33) in Taiwan.
Conclusions: Paternal use of valproate within the 90 days before conception was not associated with an increased risk of NDDs in offspring after adjustment for confounding in Norwegian and Taiwanese cohorts. (Funded by the Research Council of Norway and the National Science and Technology Council of Taiwan.).