Intellectual functioning in clinically confirmed fetal valproate syndrome

Neurotoxicol Teratol. Jan-Feb 2019;71:16-21. doi: 10.1016/ Epub 2018 Nov 16.


Background: An increased risk of impaired intelligence (IQ) has been documented in valproate-exposed children, but investigations have not previously focused on those with a clinical diagnosis of Fetal Valproate Syndrome (FVS).

Methods: This cross sectional observational study recruited individuals with a diagnosis of FVS and completed standardized assessments of intellectual abilities making comparisons to a normative comparison group. Both mean difference (MD) and prevalence of scores below the lower average range were analyzed.

Results: The mean full-scale IQ in 31 individuals with FVS (mean age 14.97; range 6-27 years) was 19 points lower (19.55, 95% CI -24.94 to 14.15), and IQ scores <70 were present in 26%. The mean differences for verbal comprehension (21.07, 95% CI -25.84 to -16.29), working memory (19.77, 95% CI -25.00 to -14.55) and processing speed (16.87, 95% CI -22.24 to -11.50) performances were poorer than expected with the mean differences over one standard deviation from the comparison group. Sixty one percent of cases demonstrated disproportionately lower verbal comprehension ability. There were no significant group differences for IQ in high vs. moderate dose valproate or mono vs. polytherapy. There were no differences in IQ between those with and those without a major congenital malformation. The requirement for educational intervention was high at 74%.

Conclusion: Intellectual difficulties are a central feature of FVS and are more severe in their presentation in individuals with a diagnosis of valproate embryopathy. Individuals with FVS who present with the characteristic facial presentation should be considered at high risk of cognitive difficulties regardless of the dose of valproate exposure or the presence of a major congenital malformation.

Keywords: Epilepsy; Fetal anticonvulsant syndrome; Fetal valproate syndrome; Intelligence; Pregnancy; Sodium valproate; Teratology.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Drug-Induced*
  • Adolescent
  • Adult
  • Child
  • Comprehension / drug effects*
  • Cross-Sectional Studies
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Intellectual Disability / chemically induced*
  • Intellectual Disability / psychology
  • Male
  • Memory, Short-Term / drug effects*
  • Valproic Acid / adverse effects*
  • Wechsler Scales
  • Young Adult


  • Valproic Acid

Supplementary concepts

  • Valproic acid antenatal infection