Antiepileptic drugs, including valproic acid, lamotrigine, and gabapentin, are used to treat mood and anxiety symptoms in various psychiatric disorders. We have data indicating that prenatal exposure to some AEDs, especially valproic acid, not only increases the risk for major malformations, but is associated with an increased risk for adverse neurodevelopmental outcomes. ONE systematic review published in Neurology reviews studies evaluating neurodevelopmental outcomes in children prenatally exposed to valproic acid and other AEDs. In this analysis, data from a set 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 increased risk of diagnosis of emotional and behavioral disturbances and poor adaptive functioning compared to offspring exposed to other AEDs and unexposed controls.
The risk of adverse neurodevelopmental outcomes appears to be dose-related, with worse outcomes observed at doses of 900 mg per day or greater. However, some studies have reported worse neurodevelopmental outcomes with average daily doses as low as 600 to 750 mg.
Carbamazepine (Tegretol)
In three cohort studies, carbamazepine-exposed offspring had a higher prevalence (12%–14%) of behavioral problems compared to unexposed children, characterized by aggression and hyperactivity. Findings of intellectual disability were inconsistent.
Topiramate (Topamax)
Less information is available on neurodevelopmental outcomes in children with prenatal exposure to topiramate. Of the 10 studies included in this review, 5 contained samples of fewer than 10 offspring exposed to topiramate.
That said, there is a growing body of evidence showing that prenatal exposure to topiramate may be associated with worse neurodevelopmental outcomes. A population-based study of 247 topiramate-exposed children found a two-fold increased risk of ASD diagnoses and a 3.5-fold increased risk of ID among topiramate-exposed offspring compared to unexposed offspring, particularly in children exposed to doses greater than 100 mg daily.
Another recent population-based study of 290 topiramate-exposed offspring found a 2.38-fold increased risk of ADHD compared to unexposed offspring.
Lamotrigine (Lamictal)
Compared to unexposed offspring, lamotrigine-exposed offspring demonstrate comparable neurodevelopmental function. Prospective cohort and population-based studies have found no increased risk of ASD diagnoses in samples including more than 15,000 reports.
None of the 13 included studies found evidence of a dose-response relationship between lamotrigine and adverse neurodevelopmental outcomes.
Other antiepileptic drugs
There are no data for the remaining AEDs, including gabapentin, pregabalin, lacosamide, zonisamide, clobazam, perabanel, ethosuximide, or brivaracetam.
Clinical Implications
The current systematic review confirms previous studies indicating worse neurodevelopmental outcomes associated with 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 increased risk of emotional and behavioral disorders. This finding, combined with the high risk of major malformations associated with valproic acid, suggests 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 childbearing age.
Currently, there is insufficient information on long-term neurodevelopmental outcomes in children exposed to other AEDs, such as gabapentin and pregabalin. There is, however, a growing body of literature showing that topiramate exposure may be associated with worse neurodevelopmental outcomes, with one study showing a 2-fold increased risk of ASD and a 3.5-fold increased risk of intellectual disability. These studies suggest that topiramate may have similar long-term risks to valproic acid. Furthermore, it is concerning that adverse effects have been observed at a relatively low dose of topiramate (100 mg).
This systematic review supports the reproductive safety of lamotrigine, indicating no increased risk of adverse neurodevelopmental outcomes in children exposed to this AED during pregnancy.
Ruta Nonacs, MD PhD
bibliographical references
Honybun E, Cockle E, Malpas CB, O’Brien TJ, Vajda FJ, Perucca P, Rayner G. Neurodevelopmental and functional outcomes following in utero exposure to anticonvulsant drugs: A systematic review. Neurology. 2024 Apr 23; 102(8):e209175.
