Objectives To investigate the association between paternal use of antiepileptic drugs (AEDs) and adverse neurodevelopmental outcomes and major congenital malformations (MCM) in the offspring.
Methods Using nationwide Swedish registries, we included 1 144 795 births to 741 726 fathers without epilepsy and 4544 births to 2955 fathers with epilepsy. Of these, 2087 (45.9%) were born to fathers with epilepsy who had dispensed an AED during the conception period. Children who had both parents with epilepsy were excluded. The incidence rate of MCM, autism spectrum disorder, attention deficit hyperactivity disorder (ADHD) and intellectual disability in offspring was analysed.
Results Offspring of fathers exposed to AEDs did not show an increased risk of MCM (adjusted OR 0.9, 95% CI 0.7 to 1.2), autism (adjusted HR (aHR) 0.9, 95% CI 0.5 to 1.7), ADHD (aHR 1.1, 95% CI 0.7 to 1.9) or intellectual disability (aHR 1.3, 95% CI 0.6 to 2.8) compared with offspring of fathers with epilepsy not exposed to AEDs. Among offspring of fathers with epilepsy who used valproate in monotherapy during conception, rates of autism (2.9/1000 child-years) and intellectual disability (1.4/1000 child-years) were slightly higher compared with the offspring of fathers with epilepsy who did not use AEDs during conception (2.1/1000 child-years autism, 0.9/1000 child-years intellectual disability), but in the propensity-score adjusted analyses, no statistically significant increased risk of adverse outcomes was found.
Conclusions Paternal AED use during conception is not associated with adverse outcomes in the offspring.
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Contributors TT and NR were responsible for the planning and design of the work, NR for the statistical analyses and data acquisition. NR and TT were primarily responsible for the interpretation of data and for drafting the first manuscript. GM contributed with critical review of the interpretation and the manuscript and for revising the manuscript for intellectual content.
Funding The study was supported by grants from the Swedish Research Council for Health, Working Life and Welfare (grant No 2017–00134 and No 2019–00041). Dr Muraca is supported by a fellowship award from the Canadian Institutes of Health Research (CIHR).
Competing interests TT reports grants from Eisai, GSK, UCB, Bial, EU, Stockholm County Council, CURE, outside the submitted work and personal fees from Eisai, Sanofi, Sun Pharma, UCB, Sandoz.
Patient consent for publication Not required.
Ethics approval The study was approved by the Research Ethics Committee at Karolinska Institute, Stockholm, Sweden (No. 2017/1937-32, No. 2018/5:2).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement No data are available. Our data are derived from different administrative Swedish Health Care registers. Permission to use such data for research are associated with strict restrictions including that the data cannot be shared with others than those engaged in the specific research project.
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