Association Between Prenatal Valproate Exposure and Performance on Standardized Language and Mathematics Tests in School-aged Children

JAMA Neurol. 2018 Jun 1;75(6):663-671. doi: 10.1001/jamaneurol.2017.5035.


Importance: Valproate sodium is used for the treatment of epilepsy and other neuropsychiatric disorders in women of childbearing potential. However, there are concerns about impaired cognitive development in children who have been exposed to valproate during pregnancy.

Objective: To estimate the association between long-term school performance and prenatal exposure to valproate and a number of other antiepileptic drugs (AEDs).

Design, setting, and participants: In a prospective, population-based cohort study conducted from August 1, 2015, to May 31, 2017, data used in the study were provided by Statistics Denmark on April 15, 2016. All children born alive in Denmark between 1997 and 2006 (n = 656 496) were identified. From this cohort, children who did not participate in the national tests, with presumed coding errors in gestational age and children missing information on their mother's educational level or household income were excluded (n = 177 469) leaving 479 027 children for the analyses. Children were identified and linked across national registers that had information on exposure, covariates, and outcome. The primary outcome was performance in national tests, an academic test taken by students in Danish primary and lower secondary state schools. We assessed performance in Danish and mathematics at different grades among valproate-exposed children and compared their performance with that of unexposed children and children exposed to another AED (lamotrigine). Test scores were standardized to z scores and adjusted for risk factors.

Main outcome and measures: Difference in standardized z scores in Danish and mathematics tests among valproate-exposed children compared with unexposed and lamotrigine-exposed children.

Results: Of the 656 496 children identified, 479 027 children who participated in the national tests were evaluated, including children exposed to the following AEDs in monotherapy: valproate, 253; phenobarbital, 86; oxcarbazepine, 236; lamotrigine, 396; clonazepam, 188; and carbamazepine, 294. The mean (SD) age of the 244 095 children completing the sixth-grade Danish test was 12.9 (0.39) years; 122 774 (50.3%; 95% CI, 50.1% to 50.5%) were boys and 121 321 (49.7%; 95% CI, 49.5% to 49.9%) were girls. Valproate-exposed children scored worse on the sixth-grade Danish tests (adjusted difference, -0.27 SD; 95% CI, -0.42 to -0.12) and sixth-grade mathematics tests (adjusted difference, -0.33 SD; (95% CI, -0.47 to -0.19) compared with unexposed children and children exposed to lamotrigine (adjusted difference, -0.33 SD; 95% CI, -0.60 to -0.06). Also, children exposed to clonazepam scored worse in the sixth-grade Danish tests (adjusted difference, -0.07 SD; 95% CI, -0.12 to -0.02). Carbamazepine, lamotrigine, phenobarbital, and oxcarbazepine were not linked to poor school performance compared with unexposed children.

Conclusions and relevance: Maternal use of valproate was associated with a significant decrease in school performance in offspring compared with children unexposed to AEDs and children exposed to lamotrigine. Findings of this study further caution against the use of valproate among women of childbearing potential.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Academic Performance / trends*
  • Anticonvulsants / adverse effects*
  • Child
  • Cohort Studies
  • Denmark / epidemiology
  • Female
  • Humans
  • Language*
  • Male
  • Mathematics* / education
  • Pregnancy
  • Prenatal Exposure Delayed Effects / chemically induced*
  • Prenatal Exposure Delayed Effects / diagnosis
  • Prenatal Exposure Delayed Effects / epidemiology
  • Prospective Studies
  • Schools / trends
  • Students / psychology
  • Valproic Acid / adverse effects*


  • Anticonvulsants
  • Valproic Acid