Anatomical, behavioral, and cognitive teratogenicity associated with valproic acid: a systematic review.

Sabrina Wong, Angela T H Kwan, Kayla M Teopiz, Rodrigo B Mansur, Roger S McIntyre, Joshua D Rosenblat, Heidi K Y Lo, Gia Han Le, Kyle Valentino

Journal: CNS spectrums 2025;29(6):604-610

PMID: 39727238

Full Text on Ovid Technologies, Inc. View on PubMed

Abstract

BACKGROUND

Recent guidance from UK health authorities strongly cautions against the use of valproic acid (VPA) in persons under 55 because of reevaluated risk of teratogenicity.

OBJECTIVE

To summarize the extant literature documenting VPA-associated anatomical, behavioral, and cognitive teratogenicity.

METHOD

Pubmed, Medline, Cochrane Library, PsychInfo, Embase, Scopus, Web of Science, and Google Scholar were searched in accordance with PRISMA guidelines. Collected data covered study design, participant characteristics, anatomical, behavioral, or cognitive effects, and folic acid outcomes.

RESULTS

122 studies were identified meeting inclusion comprised of studies evaluating anatomical ( = 67), behavioral ( = 28), and cognitive ( = 47) teratogenicity. Twenty studies were identified reporting on the risk mitigation effects of folic acid supplementation. Prenatal VPA exposure is associated with anatomical teratogenicity including major congenital malformations (odds ratio [OR] 2.47-9.30; p < 0.005). Behavioral teratogenicity including autism (OR 1.70-4.38), impaired motor development (OR 7.0), and ADHD (OR 1.39) are also significantly associated with VPA exposure. VPA was associated with intellectual disability and low IQ (hazard ratio [HR] 2.4-4.48, verbal intelligence: Spearman's = -0.436, respectively). Teratogenic effects were dose-dependent across all domains and were significant when compared with controls and other antiepileptic drugs (eg, carbamazepine, lamotrigine, and levetiracetam). Folic acid supplementation does not significantly reduce the hazard associated with VPA.

CONCLUSIONS

VPA is significantly associated with anatomical, behavioral, and cognitive teratogenicity. Folic acid supplementation does not abrogate the risk of teratogenicity associated with VPA exposure. Available evidence supports recommendations to reduce VPA exposure in women of reproductive age.

Address: Brain and Cognition Discovery Foundation, Toronto, ON, Canada.; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.; Mood Disorder Psychopharmacology Unit, University Health Network, Toronto, ON, Canada.; Brain and Cognition Discovery Foundation, Toronto, ON, Canada.; Brain and Cognition Discovery Foundation, Toronto, ON, Canada.; Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.; Brain and Cognition Discovery Foundation, Toronto, ON, Canada.; Mood Disorder Psychopharmacology Unit, University Health Network, Toronto, ON, Canada.; Institute of Medical Science, University of Toronto, Toronto, ON, Canada.; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.; Department of Psychiatry, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong.; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.

DOI: 10.1017/S1092852924002311

Link outs

Free resources

Medical:

https://medlineplus.gov/pregnancyandmedicines.html

Subscription / membership required

Full Text Sources:

MeSH Terms: Humans, Valproic Acid, Pregnancy, Female, Abnormalities, Drug-Induced, Anticonvulsants, Folic Acid, Prenatal Exposure Delayed Effects