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, 2 (1), e186606

Association of Prenatal Exposure to Valproate and Other Antiepileptic Drugs With Risk for Attention-Deficit/Hyperactivity Disorder in Offspring


Association of Prenatal Exposure to Valproate and Other Antiepileptic Drugs With Risk for Attention-Deficit/Hyperactivity Disorder in Offspring

Jakob Christensen et al. JAMA Netw Open.

Erratum in

  • Error in Byline.
    JAMA Netw Open. 2019 Feb 1;2(2):e191243. doi: 10.1001/jamanetworkopen.2019.1243. JAMA Netw Open. 2019. PMID: 30794291 Free PMC article. No abstract available.


Importance: Valproate is an antiepileptic drug (AED) used in the treatment of epilepsy and many other neurological and psychiatric disorders. Its use in pregnancy is associated with increased risks of congenital malformations and adverse neurodevelopment in the offspring and may be associated with an increased risk of attention-deficit/hyperactivity disorder (ADHD).

Objective: To determine whether prenatal exposure to valproate and other AEDs is associated with an increased risk of ADHD in the offspring.

Design, setting, and participants: This was a population-based cohort study of all live-born singleton children in Denmark from January 1, 1997, to December 31, 2011 (N = 913 302). Information on prenatal exposure to AEDs, including valproate, was obtained from the Danish National Prescription Registry and all children with ADHD were identified (children with diagnosed ADHD in the Danish Psychiatric Central Research Register or children who redeemed a prescription for ADHD medication). The cohort was followed up from birth until the day of the ADHD diagnosis, death, emigration, or December 31, 2015, whichever came first. Data were analyzed in September 2018.

Exposures: Maternal use of valproate and other AEDs in pregnancy.

Main outcomes and measures: Cox regression estimates of the hazard ratio of ADHD. Estimates were adjusted for potential confounders.

Results: The cohort included 913 302 children (mean age at end of study, 10.1 years; median age, 9.4 years; interquartile range, 7.2-12.8 years; 468 708 [51.3%] male). A total of 580 were identified as having been exposed to valproate during pregnancy; of them, 49 (8.4%) had ADHD. Among the 912 722 children who were unexposed to valproate, 29 396 (3.2%) had ADHD. Children with prenatal valproate exposure had a 48% increased risk of ADHD (adjusted hazard ratio, 1.48; 95% CI, 1.09-2.00) compared with children with no valproate exposure. The absolute 15-year risk of ADHD was 4.6% (95% CI, 4.5%-4.6%) in children unexposed to valproate and 11.0% (95% CI, 8.2%-14.2%) in children who were exposed to valproate in pregnancy. No associations were found between other AEDs and ADHD.

Conclusions and relevance: Maternal use of valproate, but not other AEDs, during pregnancy was associated with an increased risk of ADHD in the offspring. These findings have important implications for the counseling of women of childbearing potential using valproate.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Christensen reported receiving honoraria from serving on the scientific advisory boards of and giving lectures for UCB Nordic and Eisai AB; and receiving travel funding from UCB Nordic. No other disclosures were reported.


Figure.. Adjusted Hazard Ratio of Attention-Deficit/Hyperactivity Disorder (ADHD) in the Offspring of Women Who Used Antiepileptic Drugs in Monotherapy During Pregnancy
Adjusted for maternal age at conception, maternal psychiatric history, maternal epilepsy, maternal diabetes, sex of the child, year of birth, and parity.

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    1. Samrén EB, van Duijn CM, Christiaens GC, Hofman A, Lindhout D. Antiepileptic drug regimens and major congenital abnormalities in the offspring. Ann Neurol. 1999;46(5):-. doi:10.1002/1531-8249(199911)46:5<739::AID-ANA9>3.0.CO;2-2 - DOI - PubMed
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