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Paternal Valproate Use and Neurodevelopmental Disorder and Congenital Malformation Risk in Offspring

Sandrine Colas1, Juliette Longin2, Ana Cristina Santos3

  • 1Patient Safety & Pharmacovigilance, Epidemiology & Benefit-Risk Evaluation, Sanofi, Gentilly, France.

JAMA Network Open
|November 10, 2025
PubMed

Insights

Paternal exposure to valproate, an antiseizure medication, was linked to a higher risk of neurodevelopmental disorders (NDD) in offspring compared to lamotrigine or levetiracetam. No increased risk of congenital malformations (CM) was observed between the groups.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Pediatrics

Background:

  • Limited data exists on the risks of neurodevelopmental disorders (NDD) and congenital malformations (CM) in offspring following paternal exposure to antiseizure medications.
  • Paternal exposure to certain antiseizure medications may influence offspring neurodevelopment and increase malformation risks.

Purpose of the Study:

  • To investigate the risk of NDD and CM in offspring paternally exposed to valproate versus lamotrigine or levetiracetam monotherapy.
  • To compare the incidence of NDD and CM in relation to paternal use of specific antiseizure medications prior to conception.

Main Methods:

  • An observational, population-based, nationwide cohort study utilizing Nordic registries with family linkage.
  • Offspring paternally exposed to valproate or lamotrigine/levetiracetam within 3 months prior to conception were identified and followed up to 12 years.
  • Propensity score weighting and Cox regression models were used for NDD analysis; logistic regression was used for CM analysis.

Main Results:

  • A significantly higher risk of NDD was observed in offspring paternally exposed to valproate compared to lamotrigine or levetiracetam (pooled adjusted HR, 1.50; 95% CI: 1.09-2.07).
  • No increased risk of congenital malformations (CM) was found between the valproate and lamotrigine/levetiracetam exposure groups (unadjusted pooled OR, 0.81; 95% CI, 0.48-1.36).
  • Study included over 5,700 offspring for NDD analysis and over 1,100 for CM analysis across Denmark, Norway, and Sweden.

Conclusions:

  • Paternal exposure to valproate is associated with an increased risk of NDD in offspring compared to lamotrigine or levetiracetam.
  • No association was found between paternal valproate exposure and the risk of congenital malformations.
  • Findings suggest careful consideration of antiseizure medication use in fathers planning conception, though heterogeneity in estimates warrants caution.
Abstract

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