Valproic acid (VPA), marketed as Depakote, is commonly used for the treatment of epilepsy and bipolar disorder; however, this medication carries significant teratogenic risks during pregnancy, as well as increased risk for neurodevelopmental disorders, including autism spectrum disorder. Given the many risks and the fact that about half of all pregnancies are unplanned, we do not recommend using valproic acid in women of childbearing age.

Below is a summary of findings from major review articles and studies on this topic:

Risk of Major Malformations

Exposure to VPA during the first trimester is associated with a significant increase in major congenital malformations (MCMs) compared to the general population. 

• Absolute risk of MCMs: 10.93% (95% CI: 8.91–13.13), far exceeding the baseline risk of 2–3% in unexposed pregnancies.
• Specific malformations:
  • Neural tube defects (NTDs): 12.7-fold increased risk (e.g., spina bifida)
  • Cardiac anomalies: 2.5–5.7-fold increased risk (e.g., atrial septal defects, tetralogy of Fallot)
  • Cleft palate: 5.2-fold increased risk
  • Hypospadias: 4.8-fold increased risk
  • Limb/skeletal defects: Polydactyly (2.2-fold) and craniosynostosis (6.8-fold)

Dose Dependency and Polytherapy

• Higher doses (>1000 mg/day) correlate with elevated teratogenic risk. Doses <1000 mg/day may reduce but do not eliminate the risk of malformations.
• Polytherapy: Combining VPA with other antiepileptic drugs (AEDs) further increases MCM risk compared to monotherapy.

Neurodevelopmental and Behavioral Effects

Beyond congenital malformations, VPA is linked to:

• Increased risk of neurodevelopmental disorders: Autism spectrum disorder (ASD) and intellectual disability (ID).
• Cognitive deficits: Lower IQ scores, particularly with first-trimester exposure.

Folic Acid Supplementation

While the use of folic acid before and during pregnancy is recommended to reduce the risk of neural tube defects in the general population, evidence suggests that folic acid supplementation does not mitigate VPA-associated teratogenicity. However, it may modestly reduce the risk of neurodevelopmental disorders in VPA-exposed infants.

Clinical Recommendations

1. Avoid VPA in women of childbearing age whenever possible
2. Use effective contraception
3. Preconception counseling: Discuss risks and contraception with all women of reproductive age
4. Folic Acid: All women of childbearing age should take at least 400 mcg of supplemental folic acid daily. For those taking VPA, the recommended daily dose is 4-5 mg.
5. Lowest effective dose: If VPA is unavoidable, use <1000 mg/day in divided doses.
6. Monotherapy preferred: Minimize polytherapy to reduce additive risks.
7. Prenatal monitoring:
   • High-resolution ultrasound (weeks 16–18) to detect NTDs and cardiac defects
   • Maternal serum alpha-fetoprotein testing

Valproic acid’s teratogenic profile underscores the need for cautious prescribing. In women of childbearing age, clinicians should prioritize alternative treatment regimens that carry a lower risk. Shared decision-making, emphasizing both fetal risks and maternal health, is critical.

—Ruta Nonacs, MD PhD