Source: Colas S, Longin J, Santos AC, et al. Paternal valproate use and neurodevelopmental disorder and congenital malformation risk in offspring. JAMA Netw Open. 2025;8(11):e2542581; doi: 10.1001/jamanetworkopen.2025.42581.Investigators from multiple institutions conducted a retrospective study to assess the association between valproate use in fathers near the time of conception and risk of neurodevelopmental disorders (NDD) and congenital malformations (CM) in their children. For the study, data from multiple national registries in Denmark, Norway, and Sweden were reviewed. Eligible participants were infants born in Denmark between 1997 and 2018, 2010–2019 in Norway, and 2007–2019 in Sweden. Infants born to fathers who were exposed to valproate monotherapy within 3 months of conception, defined as ≥1 more prescription fills during that period, were included in the analyses. The control group included infants with paternal exposure to lamotrigine or levetiracetam monotherapy within 3 months of conception also were identified. Study participants were followed up to 12 years after birth. The primary outcome was a diagnosis of an NDD based on ICD-10 diagnostic code. The rate of NDD in children with paternal exposure to valproate and those in the control group was compared separately in each country using propensity weighted (PSW), adjusted Cox regression. The results from the three countries were pooled using meta-analysis. The secondary outcome was a CM, based on ICD-10 codes, and included live and stillborn infants from Denmark and Norway. Separate logistic regression models were used to assess the risk of CM associated with paternal valproate use in each of the 2 countries, and the results were combined.For the NDD analyses, data were analyzed on 5,721 children, including 2,121 with paternal valproate exposure and 3,600 controls. Rates of NDD in the valproate exposure groups in Denmark, Norway, and Sweden were 5.6%, 4.0%, and 5.6%, respectively, and 3.2%, 2.3%, and 2.5%, respectively, for children in the control groups. In the PSW-adjusted models, the risk of NDD was not significantly higher in children exposed to valproate vs those exposed to lamotrigine or levetiracetam in any of the 3 countries, assessed individually. However, when the data from the 3 countries were pooled, valproate exposure was associated with an increased risk of NDD (PSW-adjusted hazard ratio, 1.50; 95% CI, 1.09, 2.07). The CM included 428 offspring with paternal valproate exposure and 733 controls. There was no significant increase in risk of CM for those with paternal valproate exposure in either country when analyzed separately, or in the pooled analysis (odds ratio, 0.81; 95% CI, 0.48, 1.36).The authors conclude that, compared to children whose fathers were exposed to lamotrigine or levetiracetam near the time of conception, paternal exposure to valproate was associated with an increased risk of NDD, but not CM.Dr Badawi has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.The Neurodevelopmental Effects of Antiepileptic Drugs study conducted at the turn of the century identified the long-term developmental risks for children of mothers taking valproate.1 Prenatal paternal factors influencing child development have been investigated only more recently. Advanced paternal age has been associated with increased prevalence of autism, and both extremes of paternal age have been associated with impairments in child social development.2 Animal studies have demonstrated transmission of epigenetic CNS changes to offspring of fathers exposed to the equivalent of binge drinking long before conception.3A recent review of studies examining the outcomes of pregnancies in which the father was taking antiseizure medication at conception revealed no significant increase in developmental concerns in their children.4 However, these studies did not examine the impact of individual medications and may have considered only medications taken at the time of conception rather than accounting for the 3-month period of spermatogenesis. The current researchers took advantage of available health care data for fathers, mothers, and child outcomes. Their weighted analysis also accounts for a myriad of prenatal, perinatal, and postnatal factors that could impact neurodevelopment. Although a significant difference in the prevalence of NDD for children of fathers exposed to valproate was found only in the pooled analysis, this important finding warrants additional prospective study. The authors acknowledge the factors that may have influenced child outcomes, including paternal diagnoses warranting valproate treatment vs lamictal/lamotrigine, and the fact that more fathers were exposed to valproate in the early years of the study period allowing longer follow-up and opportunity for NDD diagnosis.Future prospective studies will ideally have a non-medication exposed control group, given the overall low rate of NDD diagnosis in this study population. Developmental assessments at comparable ages will allow for direct comparisons and evaluation of different streams of development.Influences on child neurodevelopment are extremely complex, involving genetic, epigenetic, and environmental influences. The significance of paternal factors (eg, valproate exposure) historically have been studied, and in recent decades the significance of paternal factors is now being acknowledged.
A 2026 study studied this question.