Large Taiwan study finds no increased risk of autism, ADHD, intellectual disability, tic disorders or congenital malformations following paternal valproate exposure during sperm development
Use of the antiseizure medication valproate by fathers during the three months before conception was not associated with an increased risk of neurodevelopmental disorders or congenital malformations in their children, according to a large nationwide study published in Neurology.
The study analyzed health data from more than 2.5 million children in Taiwan and found no increased risk of autism spectrum disorder, attention-deficit/hyperactivity disorder (ADHD), tic disorders, intellectual disability, or congenital malformations among children whose fathers used valproate during the period of sperm development.
The findings provide additional data on paternal exposure to valproate, an area that has received considerably less research than maternal exposure. However, the researchers emphasized that further studies with longer follow-up are needed before conclusions are drawn about changes to current prescribing practices.
Study Analyzed More Than 2.5 Million Children
Researchers used data from the Taiwan National Health Insurance Research Database and identified 2,583,503 children born between 2001 and 2016.
Paternal valproate exposure was defined as use of the medication during the three months before conception, corresponding to the period of sperm development. A total of 1,701 children were exposed to paternal valproate during this period.
The children were followed through 2021, with an average follow-up of approximately 12 years. Researchers assessed diagnoses of autism spectrum disorder, ADHD, tic disorders, intellectual disability, and congenital malformations using medical records.
No Increased Risk of Neurodevelopmental Disorders
In the overall study population, 1.6% of children were diagnosed with autism, 7.7% with ADHD, 1.5% with tic disorders, and 1.1% with intellectual disability.
Among children whose fathers had taken valproate before conception, the corresponding figures were 1.9% for autism, 10.2% for ADHD, 1.4% for tic disorders, and 1.5% for intellectual disability.
After statistical adjustment, paternal valproate exposure was not associated with an increased risk of any of these neurodevelopmental disorders.
The adjusted hazard ratios were 0.86 for autism spectrum disorder, 1.02 for ADHD, 0.80 for tic disorders, and 0.81 for intellectual disability, with confidence intervals that included no increased risk.
No Significant Association With Congenital Malformations
The study also examined congenital malformations.
Overall, 3.7% of children in the study population had a recorded congenital malformation, compared with 3.9% among children whose fathers had used valproate.
After adjustment for relevant factors, paternal valproate exposure was not associated with an increased risk of congenital malformations. The adjusted odds ratio was 1.07 (95% CI, 0.83–1.37).
Sibling Analysis Supports the Main Findings
To further account for factors that may be shared between siblings, researchers conducted a sibling-comparison analysis.
The study identified 548 exposure-discordant sibling sets, in which one child was exposed to paternal valproate during the three months before conception while a sibling was not exposed because the father was not taking the medication during that period.
The sibling analysis did not show an increased risk of neurodevelopmental disorders or congenital malformations associated with paternal valproate exposure.
Findings Also Examined Other Antiseizure Medications
Researchers additionally assessed other commonly prescribed antiseizure medications.
A few associations were observed at nominal statistical significance in the population-based analyses, but these did not remain significant in the sibling-comparison analyses.
The authors therefore reported no increased risk of neurodevelopmental disorders among offspring following paternal exposure to valproate or other antiseizure medications in the study.
Findings Differ From Concerns About Maternal Valproate Exposure
Valproate has established concerns regarding fetal development when used during pregnancy. Previous research has linked maternal exposure to increased risks of congenital malformations and certain neurodevelopmental outcomes.
The current study addresses a different exposure pathway: paternal use before conception. Because paternal medication exposure does not occur through direct fetal exposure during pregnancy, researchers have been investigating whether medication exposure during sperm development could influence offspring outcomes.
The present findings did not identify an increased risk associated with paternal valproate exposure, but they do not establish that the medication has no possible reproductive effects in every population or circumstance.
Longer Follow-Up Studies Still Needed
The researchers noted that some children had shorter follow-up periods, with the minimum follow-up being approximately five years. This could mean that some neurodevelopmental diagnoses emerging later in childhood were not captured.
The study was also conducted using health records from Taiwan, so additional research in other populations may help determine whether the findings are consistent across different ethnic and healthcare settings.
The authors concluded that more evidence is needed before the findings are used to guide changes in prescribing practices for men taking valproate or other antiseizure medications.
Important Highlights
- A nationwide study analyzed 2,583,503 children in Taiwan to examine paternal antiseizure medication exposure.
- 1,701 children had fathers who used valproate during the three months before conception.
- Paternal valproate exposure was not associated with increased risks of autism, ADHD, tic disorders or intellectual disability.
- No significant association was found between paternal valproate exposure and congenital malformations.
- A sibling-comparison analysis involving 548 exposure-discordant sibling sets supported the main findings.
- Researchers emphasized that longer-term and additional studies are needed before drawing conclusions about changes to current prescribing practices.
