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Observational Study
. 2025 Nov 3;8(11):e2542581.
doi: 10.1001/jamanetworkopen.2025.42581.

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

Sandrine Colas  1 , Juliette Longin  2 , Ana Cristina Santos  3 , Sigal Kaplan  4 , Romina di Giuseppe  5 , David Bigat  6 , Alessandra Venerus  7 , Marte-Helene Bjørk  8   9 , Marie-Laure Kürzinger  1 , Maria Roberta Cilio  10 , Florent Richy  11   12
Affiliations
Observational Study

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

Sandrine Colas et al. JAMA Netw Open. .

Abstract

Importance: Limited clinical evidence is available about the risk of neurodevelopmental disorders (NDD), including autism spectrum disorders and congenital malformations (CM), in offspring following paternal exposure to antiseizure medications.

Objective: To investigate the risk of NDD (any subtype) and CM (major and/or minor) in offspring paternally exposed to valproate vs lamotrigine or levetiracetam monotherapy within 3 months prior to conception.

Design, setting, and participants: This observational, population-based, nationwide cohort study used Nordic registries data with family linkage (offspring born between 1997-2018 [Denmark], 2010-2019 [Norway], and 2007-2019 [Sweden]). Offspring born within the study period and paternally exposed to either (1) valproate or (2) lamotrigine or levetiracetam were identified and followed-up until 12 years or the end of the study period, whichever came first. Data were obtained from October 2020 (Denmark), June 2021 (Norway), and March 2021 in Sweden)and analyzed from October 2020 to July 2023.

Exposures: Paternal exposure to (1) valproate or (2) lamotrigine or levetiracetam during the spermatogenic risk window (derived from each National Prescription Registry).

Main outcomes and measures: The primary and secondary outcomes were NDD and CM, respectively, in offspring aged 12 years or younger. Country-specific hazard ratios (HRs) for NDD were estimated using Cox regression models and propensity score weighting (PSW), subsequently pooled via meta-analysis. Odds ratios (ORs) for CM were estimated using unadjusted logistic regression models for Denmark and Norway, but were not estimated for Sweden due to database constraints.

Results: NDD analysis included 5721 offspring, with 1950 in Denmark (valproate: 793 offspring; lamotrigine or levetiracetam: 1157 offspring), 1416 in Norway (valproate: 398 offspring; lamotrigine or levetiracetam: 1018 offspring), and 2355 in Sweden (valproate: 930 offspring; lamotrigine or levetiracetam: 1425 offspring). After excluding offspring with outlier weights and/or incomplete observation in the PSW-adjusted analyses, NDD occurrence was observed in 38 of 678 offspring (5.6%) vs 36 of 1118 offspring (3.2%), 13 of 325 offspring (4.0%) vs 21 of 910 offspring (2.3%), and 47 of 841 offspring (5.6%) vs 34 of 1334 offspring (2.5%) exposed to valproate vs lamotrigine or levetiracetam in Denmark, Norway, and Sweden, respectively. PSW-adjusted analyses showed significantly higher risk in the valproate vs lamotrigine or levetiracetam group (pooled adjusted HR, 1.50; 95% CI: 1.09-2.07; P = .01). CM analysis included 1161 offspring, with 648 in Denmark (valproate: 259 offspring; lamotrigine or levetiracetam: 389 offspring) and 513 in Norway (valproate: 169 offspring; lamotrigine or levetiracetam: 344 offspring), and found no increased risk (unadjusted pooled OR, 0.81; 95% CI, 0.48-1.36).

Conclusions and relevance: In this cohort study, higher NDD risk was observed in offspring paternally exposed to valproate vs lamotrigine or levetiracetam, but no difference in CM risk was observed between the 2 exposure groups. However, these findings should be interpreted with caution due to the heterogeneity in the unadjusted estimates.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Colas reported receiving personal fees from Sanofi as an employee outside the submitted work. Dr Longin reported receiving personal fees from Sanofi (consulting fees), Pfizer (consulting fees), Novo Nordisk (consulting fees), Amgen (consulting fees), Association Française du Vitiligo (consulting fees), Stane (consulting fees), Docaposte (consulting fees), Sesam Consulting (consulting fees), Helsia (consulting fees), and Hemosquid (consulting fees) outside the submitted work. Dr Kaplan reported receiving personal fees from Teva Pharmaceutical as an employee outside the submitted work. Dr Bigat reported personal fees from Sanofi as employee outside the submitted work. Dr Bjørk reported being a marked authorization holder of valproate (fees paid to institution for data extraction and analyses); receiving personal fees from Novartis (speaking honoraria and consulting fees), Eisai (speaking honoraria), Pfizer (speaking honoraria and consulting fees), Lundbeck (speaking honoraria and consulting fees), Angelini Pharma (speaking honoraria and consulting fees), Organon (speaking honoraria), Jazz Pharmaceuticals (advisory board honoraria), and AbbVie (speaking honoraria); grants from The Norwegian Epilepsy Foundation (2 grants for unrelated work), The Research Council of Norway (grants for migraine research), Trond Mohn Research Foundation (grants for research into antiseizure medication teratogenecity), Klinbeforsk (clinical treatment research of Norway), and The Research Council of the Nordics (Norforsk; grants for research into antiseizure medication teratogenecity) outside the submitted work. Dr Kürzinger receiving personal fees from Sanofi as an employee outside the submitted work. Dr Cilio reported receiving research funding from the Clinical Research Fund of Cliniques Universitaires Saint-Luc and the European Joint Program on Rare Diseases (Innovative Rare Diseases Challenge); royalties from Elsevier as a coeditor of a book; honorarium from Springer Nature for her role as associate editor of Pediatric Research; and serving as a paid consultant for UCB, Sanofi Pharma, Eisai, and Jazz Pharmaceuticals outside the submitted work. Dr Richy reported being an IQVIA employee at the time the original study was performed. No other disclosures were reported.

Figures

Figure.
Figure.. Study Population of the Primary Outcome Cohorts From Denmark, Norway, and Sweden
Study population of the primary outcome cohort for descriptive and comparative analysis in Denmark, Norway, and Sweden. ASM indicates antiseizure medication; CM, congenital malformation; LMP2, last menstrual period plus 2 weeks; NDD, neurodevelopment disorders. aThe exclusion criteria are not mutually exclusive. The same child can be counted in different exclusion categories, explaining why numbers do not necessarily add up.
See this image and copyright information in PMC

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