In Utero Exposure to Antiseizure Medications Tied to Neurodevelopmental Effects

The use of some prenatal antiseizure medications (ASMs) during pregnancy may result in adverse postnatal neurodevelopmental outcomes, according to study findings published in Neurology.

Researchers conducted a systemic review of relevant prospective and retrospective studies published in English between 1990 and 2023 to characterize the neurodevelopmental effects of ASM use during pregnancy. Social, emotional, behavioral, adaptive, and neurodevelopmental outcome data were extracted from the studies. Quality assessments of all included studies in the review were conducted using the Newcastle-Ottawa scale and extracted data were synthesized into a narrative review.

A total of 43 studies (prospective cohort studies, 19; population-based studies, 10; retrospective cohort studies, 9; cross-sectional observational studies, 5) were included in the final review.

Compared with offspring exposed to other ASMs and/or unexposed control individuals, offspring exposed to valproate were found to have poorer adaptive functioning and social skills and the following:

• 1.5-fold greater risk for being diagnosed with attention-deficit/hyperactivity disorder (ADHD),
• 2- to 4-fold increased risk for autism spectrum disorder (ASD),
• 2- to 4-fold increased risk for emotional and behavioral disorders, and
• 2- to 5-fold higher risk for intellectual disability.

The effects of valproate on neurodevelopmental outcomes were dose dependent and typically observed in pregnancies during which more than 900 mg of valproate was used daily.

Compared with no exposure to topiramate, exposure to the ASM was associated with an increased risk for poor adaptive functioning and the following:

• 2-fold increased risk for ASD,
• 2.38-fold higher risk for ADHD, and a
• 3.5-fold increased risk for intellectual disability.

One study that investigated dosing reported that effects were dose dependent.

Exposure to carbamazepine vs a history of no exposure was associated with a higher prevalence of behavioral regulation problems, a 1.8-fold increased risk for tic disorder, and a potential 3.2-fold increased risk for behavioral and emotional disorders.

Data about risk for intellectual disability were conflicting. Most studies did not find a dose-dependent relationship between carbamazepine exposure and neurodevelopmental outcomes.

One study reported that exposure to phenobarbital monotherapy was associated with an increased risk for learning disabilities and another reported a 7.6-fold increased risk for behavioral and emotional disorders. However, both studies were based on small numbers of cases.

Most studies found that polypharmacy with valproate was associated with increased risk for ASD, ADHD, intellectual disability, and developmental delay among exposed offspring. Polypharmacy with valproate and lamotrigine vs ASM monotherapy was associated with a 3- to 4-fold increased risk for abnormal behavior and emotional development. Conversely, 5 studies did not find associations between antiseizure polypharmacy and an increased risk for worse neurodevelopmental outcomes.

No clear evidence about the relationship between exposure to phenytoin, lamotrigine, levetiracetam, oxcarbazepine, clonazepam, gabapentin, or pregabalin in utero and neurodevelopmental outcomes were found.

Study limitations included heterogeneity in outcome measures and small samples of monotherapy exposures.

“Future research into the neurodevelopmental effects of prenatal exposure to ASMs, including most newer agents, is much needed,” the researchers concluded.

Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.