The study published in the Journal of the American Medical Association Network Open sought to determine if paternal use of valproate during spermatogenesis was associated with risk of congenital malformations and neurodevelopmental disorders among offspring.
To determine that, the Aarhus University researchers conducted a nationwide cohort study in Denmark involving about 1.2 million children, including 1,336 children born to fathers who filled prescriptions for valproate during spermatogenesis.
The article noted that concerns have been raised about teratogenic and long-term neurodevelopmental outcomes of paternal use of valproate during spermatogenesis.
Included in the study were singletons born in Denmark between January 1, 1997, and December 31, 2017, identified in the Medical Birth Register. The researchers identified congenital malformations in the first year of life, while neurodevelopmental disorders were identified from age 1 year until December 31, 2018. Statistical analysis was performed March 2024.
For purposes of the study, paternal valproate exposure was defined as fathers who filled one or more prescriptions for valproate immediately before or during the time of spermatogenesis (i.e., 3 months prior to conception). In addition to its primary usage to treat epilepsy, valproate is prescribed for bipolar disorder management and migraine prophylaxis.
Median follow-up in the study was 10.1 years (interquartile range [IQR], 5.1-14.8 years) for valproate-exposed children and 10.3 years (IQR, 5.2-15.6 years) for valproate-unexposed children. In the first year of life, 43,903 children (3.6%) received a diagnosis of major congenital malformations, while 51,633 children (4.2%) received a diagnosis of neurodevelopmental disorders during follow-up.
“When comparing the risk among valproate-exposed children with that among unexposed children, the [adjusted relative risk] of major congenital malformations was 0.89 (95% CI, 0.67-1.18), the AHR of neurodevelopmental disorders was 1.10 (95% CI, 0.88-1.37), and the AHR of autism spectrum disorder was 0.92 (95% CI, 0.65-1.30),” according to the researchers. “In analyses addressing the robustness of the findings (i.e., dose-response analyses, sibling analyses, analyses restricted to children of fathers with epilepsy, analyses that used children with paternal lamotrigine exposure as active comparator, and analyses that used children with paternal exposure to valproate only before spermatogenesis as a negative control exposure), there still was no increased risk of any of the included endpoints.”
Background information in the article advises that epilepsy is one of the most prevalent neurologic disorders among males of fertile age, and the antiseizure medication valproate is commonly used for epilepsy in males of fertile age.
“The teratogenic potential of valproate is widely recognized and use by mothers in pregnancy has been associated with an increased risk of congenital malformations and neurodevelopmental disorders, including, and perhaps most notably, autism among the offspring,” the authors wrote. “Despite the well-known risks associated with maternal exposure to valproate in pregnancy, the risk of congenital malformations and neurodevelopmental disorders associated with paternal exposure in relation to conception is still uncertain. However, recently, the UK Medicines and Healthcare Products Regulatory Agency issued a warning against the use of valproate among males younger than 55 years due to concerns related to male fertility and risk of neurodevelopmental disorders among the offspring.”
They added, however, that in the study of more than 1 million births identified in Danish healthcare registers, they were unable to identify an increased risk of congenital malformations and neurodevelopmental disorders among children who were born to fathers who filled prescriptions for valproate during spermatogenesis.
“The findings were robust and persisted when we compared the risk among children with paternal valproate exposure with the risk in the overall population, when assessing the risk in dose response and sibling analyses, when restricting the analyses to fathers with epilepsy and epilepsy with unknown underlying cause, when comparing with the children of fathers with lamotrigine exposure, when taking time trends into account, and when comparing with children born of fathers who discontinued valproate use,” the researchers added.
The researchers noted that they were unable to replicate the recent findings by the European Medicines Agency’s Pharmacovigilance Risk Assessment Committee, which reported results from a study based on register data from Denmark, Norway, and Sweden that found paternal valproate exposure to be associated with increased risk of neurodevelopmental disorders (adjusted hazard ratio, 1.50 [95% CI, 1.09-2.07]) but not congenital malformations (crude odds ratio, 0.81 [95% CI, 0.48-1.36]) among their offspring.
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