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

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.