Valproate Use During Spermatogenesis and Risk to Offspring

Area of Science:

• Reproductive toxicology
• Developmental neurobiology
• Pharmacoepidemiology

Background:

• Paternal valproate exposure during spermatogenesis raises concerns for teratogenic and neurodevelopmental outcomes in offspring.
• Existing data on paternal valproate exposure and offspring health is limited.

Purpose of the Study:

• To investigate the association between paternal valproate use during spermatogenesis and the risk of congenital malformations and neurodevelopmental disorders in offspring.

Main Methods:

• A nationwide cohort study in Denmark (1997-2017) included 1,235,353 children.
• Paternal valproate exposure was defined by fathers filling prescriptions within 3 months prior to conception.
• Log-binomial and Cox regression models were used to assess risks of malformations and neurodevelopmental disorders, respectively.

Main Results:

• Among 1,235,353 births, 1336 had fathers exposed to valproate during spermatogenesis.
• Paternal valproate exposure was not associated with an increased risk of major congenital malformations (ARR, 0.89; 95% CI, 0.67-1.18).
• No increased risk was observed for neurodevelopmental disorders (AHR, 1.10; 95% CI, 0.88-1.37) or autism spectrum disorder (AHR, 0.92; 95% CI, 0.65-1.30).

Conclusions:

• This large cohort study suggests paternal valproate exposure during spermatogenesis is not associated with increased offspring risk of congenital malformations or neurodevelopmental disorders.
• Robustness analyses, including dose-response and sibling comparisons, supported these findings.
• The findings contribute to understanding the safety profile of paternal valproate use.