Transgenerational adverse effects of valproate? A patient report from 90 affected families

Birth Defects Res. 2022 Jan 1;114(1):13-16. doi: 10.1002/bdr2.1967. Epub 2021 Dec 5.


Background: Valproate use during pregnancy increases risk in malformations and neurodevelopmental disorders. Data from the experimental setting in mice showed valproate is a direct inhibitor of histone deacetylase, inducing histone hyperacetylation, histone methylation, and DNA demethylation causing congenital malformations with an epigenetic inheritance. We investigated potential transgenerational adverse effects of valproate.

Methods: We questioned 108 individuals (from 90 families) suffering complications due to valproate exposure in utero who were parents themselves (85 women and 23 men) about the occurrence of malformations and neurodevelopmental disorders in their children. All were member of Aide aux Parents d'Enfants souffrants du Syndrome de l'AntiConvulsivant (APESAC), a charity created in 2011 to provide personal assistance and support to families suffering complications due to valproate exposure during pregnancy.

Results: Among their 187 children they reported 43 (23%) children with malformation(s) (26 hand or foot malformations; 15 dysmorphic facial features; 10 renal/urologic malformations; 6 spina bifida; 4 cardiac malformation; 2 craniosynostosis; 2 cleft lip and palate) and 82 (44%) children with neurodevelopmental disorders (63 problematic behaviors and autism; 41 psychomotor disorders; 16 language problems; 16 attention deficit; 5 mental retardation). Only 88 (47%) children had neither malformation nor developmental disorders.

Conclusion: These data add to the need for funding pharmacoepidemiological investigations of epigenetic inheritance caused by drugs causing malformations or neurodevelopmental disorders. Individuals exposed in utero to valproate must be informed about the risk, so they can consider fertility options, antenatal diagnosis, and adequate early surveillance.

Keywords: drug safety; epigenetic; epilepsy; neurodevelopmental disorders; teratogenicity.

MeSH terms

  • Abnormalities, Drug-Induced* / etiology
  • Animals
  • Anticonvulsants / therapeutic use
  • Cleft Lip* / chemically induced
  • Cleft Palate* / chemically induced
  • Drug-Related Side Effects and Adverse Reactions*
  • Epilepsy* / chemically induced
  • Epilepsy* / complications
  • Epilepsy* / drug therapy
  • Female
  • Histones / therapeutic use
  • Humans
  • Male
  • Mice
  • Pregnancy
  • Pregnancy Complications* / chemically induced
  • Valproic Acid / toxicity


  • Anticonvulsants
  • Histones
  • Valproic Acid