Antiepileptic drugs, including valproic acid, lamotrigine, and gabapentin, are used for the treatment of mood and anxiety symptoms across different psychiatric disorders. We have data to indicate that prenatal exposure to some AEDs, specifically valproic acid, not only increases risk for major malformations but is associated with an increased risk for adverse neurodevelopmental outcomes. A systematic review published in Neurology examines studies assessing neurodevelopmental outcomes in children prenatally exposed to valproic acid and other AEDs. In this analysis, data from a total of 43 studies were included. 

Valproic Acid (Depakote)

Prenatal exposure to valproic acid was associated with a 2- to 4-fold increased risk of autism spectrum disorder (ASD), a 2- to 5-fold increased risk of intellectual disability (ID), a 1.5-fold increased risk of ADHD, a 2- to 4-fold higher risk of diagnosis of emotional and behavioral disorders, and poor adaptive functioning compared to offspring exposed to other AEDs and unexposed controls. 

The risk of adverse neurodevelopmental outcomes appears to be dose-dependent, with worse outcomes seen at doses of 900 mg per day or greater; however, some studies have reported worse neurodevelopmental outcomes with mean daily doses as low as 600 to 750 mg.

Carbamazepine (Tegretol)

Across three cohort studies, carbamazepine-exposed offspring had a higher prevalence (12%–14%) of behavioral regulation problems compared with unexposed children, characterized by aggression and hyperactivity. Findings of intellectual disability have been inconsistent.

Topiramate (Topamax)

Less information is available regarding neurodevelopmental outcomes in children with prenatal exposure to topiramate. Of the 10 studies that included in this review, 5 contained samples of less than 10 topiramate-exposed offspring.

That said, there is a growing body of evidence indicating that prenatal exposure to topiramate may be associated with worse neurodevelopmental outcomes. A population-based study including 247 topiramate-exposed children found a 2-fold increased risk of ASD diagnoses and a 3.5-fold increased risk of ID among topiramate-exposed offspring compared with unexposed offspring, particularly in children exposed to doses above 100 mg daily. 

Another recent population-based study of 290 topiramate-exposed offspring found a 2.38-fold increased risk of ADHD compared with unexposed offspring.

Lamotrigine (Lamictal)

Compared to unexposed offspring, lamotrigine-exposed offspring demonstrate comparable neurodevelopmental functioning. Prospective cohort and population-based studies have found no increased risk of ASD diagnoses across samples including over 15,000 exposures. 

None of the 13 included studies found evidence of a dose-response relationship between lamotrigine and adverse neurodevelopmental outcomes. 

Other Antiepileptic Drugs

Evidence for the remaining AEDs, including gabapentin, pregabalin, lacosamide, zonisamide, clobazam, perampanel, ethosuximide, or brivaracetam, is lacking. 

Clinical Implications

The current systematic review confirms previous studies indicating worse neurodevelopmental outcomes related to prenatal exposure to valproic acid, including a 2- to 4-fold increased risk of ASD, a 2- to 5-fold increased risk of intellectual disability (ID), and a 2- to 4-fold higher risk of emotional and behavioral disorders. This finding, paired with the high risk of major malformations associated with valproic acid, indicates that valproic acid should be avoided in women during pregnancy. And because half of all pregnancies are unplanned, these findings support the avoidance of valproic acid in all women of reproductive age.

There is currently inadequate information on long-term neurodevelopmental outcomes in children exposed to other AEDs, such as gabapentin and pregabalin. There is, however, a growing literature to indicate that exposure to topiramate may be associated with worse neurodevelopmental outcomes, with one study showing a 2-fold increased risk of ASD and and a 3.5-fold increased risk of intellectual disability. These studies indicate that topiramate may carry similar long-term risks to valproic acid. In addition, it is concerning that adverse outcomes have been observed at a relatively low dose of topiramate (100 mg).

This systematic review supports the reproductive safety of lamotrigine, indicating no increase in risk of adverse neurodevelopmental outcomes in children exposed to this AED during pregnancy.

Ruta Nonacs, MD PhD


Honybun E, Cockle E, Malpas CB, O’Brien TJ, Vajda FJ, Perucca P, Rayner G. Neurodevelopmental and Functional Outcomes Following In Utero Exposure to Antiseizure Medication: A Systematic Review. Neurology. 2024 Apr 23;102(8):e209175. 

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