Prenatal Valproate Exposure and Risk of Autism Spectrum Disorders and Childhood Autism
Open accessAbstract
IMPORTANCE: Valproate is used for the treatment of epilepsy and other neuropsychological disorders and may be the only treatment option for women of childbearing potential. However, prenatal exposure to valproate may increase the risk of autism. OBJECTIVE: To determine whether prenatal exposure to valproate is associated with an increased risk of autism in offspring. DESIGN, SETTING, AND PARTICIPANTS: Population-based study of all children born alive in Denmark from 1996 to 2006. National registers were used to identify children exposed to valproate during pregnancy and diagnosed with autism spectrum disorders (childhood autism [autistic disorder], Asperger syndrome, atypical autism, and other or unspecified pervasive developmental disorders). We analyzed the risks associated with all autism spectrum disorders as well as childhood autism. Data were analyzed by Cox regression adjusting for potential confounders (maternal age at conception, paternal age at conception, parental psychiatric history, gestational age, birth weight, sex, congenital malformations, and parity). Children were followed up from birth until the day of autism spectrum disorder diagnosis, death, emigration, or December 31, 2010, whichever came first. MAIN OUTCOMES AND MEASURES: Absolute risk (cumulative incidence) and the hazard ratio (HR) of autism spectrum disorder and childhood autism in children after exposure to valproate in pregnancy. RESULTS: Of 655,615 children born from 1996 through 2006, 5437 were identified with autism spectrum disorder, including 2067 with childhood autism. The mean age of the children at end of follow-up was 8.84 years (range, 4-14; median, 8.85). The estimated absolute risk after 14 years of follow-up was 1.53% (95% CI, 1.47%-1.58%) for autism spectrum disorder and 0.48% (95% CI, 0.46%-0.51%) for childhood autism. Overall, the 508 children exposed to valproate had an absolute risk of 4.42% (95% CI, 2.59%-7.46%) for autism spectrum disorder (adjusted HR, 2.9 [95% CI, 1.7-4.9]) and an absolute risk of 2.50% (95% CI, 1.30%-4.81%) for childhood autism (adjusted HR, 5.2 [95% CI, 2.7-10.0]). When restricting the cohort to the 6584 children born to women with epilepsy, the absolute risk of autism spectrum disorder among 432 children exposed to valproate was 4.15% (95% CI, 2.20%-7.81%) (adjusted HR, 1.7 [95% CI, 0.9-3.2]), and the absolute risk of childhood autism was 2.95% (95% CI, 1.42%-6.11%) (adjusted HR, 2.9 [95% CI, 1.4-6.0]) vs 2.44% (95% CI, 1.88%-3.16%) for autism spectrum disorder and 1.02% (95% CI, 0.70%-1.49%) for childhood autism among 6152 children not exposed to valproate. CONCLUSIONS AND RELEVANCE: Maternal use of valproate during pregnancy was associated with a significantly increased risk of autism spectrum disorder and childhood autism in the offspring, even after adjusting for maternal epilepsy. For women of childbearing potential who use antiepileptic medications, these findings must be balanced against the treatment benefits for women who require valproate for epilepsy control.
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No significant associations were found between neurodevelopment and exposure to other AEDs such as carbamazepine, lamotrigine or phenytoin.
“No significant associations were found between neurodevelopment and exposure to other AEDs such as carbamazepine, lamotrigine or phenytoin.5–8”
Exposure of pregnant women to VPA, but not other anti-epileptic treatments, nearly triples their risk for having a child with ASD, and ASD-like behavioral phenotypes have been replicated in rodent models of prenatal VPA exposure.
“Exposure of pregnant women to VPA, but not other anti-epileptic treatments, nearly triples their risk for having a child with ASD [44, 69] and ASD-like behavioral phenotypes have been replicated in rodent models of prenatal VPA exposure (see Supplementary Table 3).”
From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [69]
Maternal exposure to VPA is associated with increased risk of ASD incidence in offspring.
“More specifically, clinical studies have shown that maternal exposure to VPA, a branched short-chain fatty acid used as an antiepileptic drug, is associated with increased risk of ASD incidence in offspring (Christensen et al., 2013; Ornoy, 2009).”
From Mechanisms underlying microbial-mediated changes in social behavior in mouse models of autism spectrum disorder (2019) · cites this paper as Christensen et al., 2013
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- Authors
- Christensen, J., Grønborg, T. K., Sørensen, M. J., Schendel, D., Parner, E. T., Pedersen, L. H., & Vestergaard, M.
- Affiliations
- Aarhus University Hospital (DK)
- Corresponding author
- Christensen, Jakob
- ORCID
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2013-04-24
- Volume
- 309
- Issue
- 16
- Pages
- 1696
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- PMC
- PMC4511955
- OpenAlex
- W2117487291
- Cited by
- 1,357
- References
- 3
- Citations by year
- 2026: 68 · 2025: 99 · 2024: 130 · 2023: 105 · 2022: 127 · 2021: 119 · 2020: 146 · 2019: 110 · 2018: 99 · 2017: 87 · 2016: 81 · 2015: 94 · 2014: 55 · 2013: 33 · 2012: 1
- FWCI
- 81.83
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- JAMA (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (CC999999)
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Pregnancy and Medication Impact
- Keywords
- valproic acid, prenatal drug exposure, autism spectrum disorder, childhood autism, autism risk, Asperger syndrome, atypical autism, pervasive developmental disorders
- MeSH terms
- Adolescent, Adult, Anticonvulsants, Autistic Disorder, Mental Disorders, Child, Child Development Disorders, Pervasive, Child, Preschool, Denmark, Epilepsy, Female, Follow-Up Studies, Humans, Male, Maternal Age, Pregnancy, Pregnancy Complications, Prenatal Exposure Delayed Effects, Registries, Risk, Valproic Acid, Incidence, Young Adult
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