Prenatal Exposure to Antiseizure Medication may Increase Incidence of Psychiatric Disorders during childhood

A recent study published in JAMA Neurology may link prenatal exposure to antiepileptic medication to increased incisdence of psychiatric disorders in childhood and adolescence.

The use of antiseizure medication (ASM) among pregnant women has increased during recent decades, and today between 0.5% and 2% of all children are born to women using ASMs during pregnancy. In pregnancy, ASMs are used mainly for epilepsy but may be prescribed for other indications, such as mood disorders, migraine, and neuropathic pain.

There are increasing concerns of adverse effects in offspring after prenatal ASM exposure. The evidence of harm is most definitive for valproate and shows increased risk of congenital anomalies and adverse neurodevelopment, including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and impaired cognitive function. Other ASMs influence fetal growth and development, yet our understanding of the potential link with psychiatric disorders in childhood is limited.

In this study by Dreier et al, the authors studied a cohort of more than 38 000 children of mothers with epilepsy, and examined the association between prenatal exposure to common ASMs with a broad spectrum of psychiatric disorders in childhood and adolescence.

Our findings strengthen the evidence for the warning against the use of valproate in pregnancy, support concerns about the use of topiramate, and raise some concern about levetiracetam. For pregnant women with epilepsy, the results reassuringly indicate that prenatal exposure to lamotrigine, carbamazepine, and oxcarbazepine are associated with little or no long-term behavioral or developmental problems in their children.

The study found that children with prenatal valproate exposure faced an absolute risk of being diagnosed with a psychiatric disorder that exceeded 40% by the age of 18 years, mainly driven by a marked excess of neurodevelopmental disorders. These findings strengthen previous evidence of the association between prenatal valproate exposure and risk of ASD, ADHD, cognitive impairment, and developmental delay. The authors also report associations between prenatal valproate exposure with other psychiatric and behavioral disorders.

“We observed no increased risk of psychiatric disorders occurring mainly later in life (eg, schizophrenia or mood disorders). However, we found an increased risk of attachment disorder in children with prenatal valproate exposure, which has not been reported before. The potential mechanism is unclear, but insecure attachment has been reported to be more prevalent in children with neurodevelopmental disorders,26 which could explain the finding. It is also possible that women using valproate in pregnancy have more severe epilepsy and psychiatric comorbidity, which may in turn affect mother-child attachment during the child’s upbringing”, said the authors.

The studt also observed an increased risk of ADHD with prenatal topiramate exposure, which extends the potential behavioral risks identified in a recent SCAN-AED study based on the same cohort of children.

For lamotrigine, carbamazepine (with 1 exception), oxcarbazepine, clonazepam, pregabalin, and gabapentin, they found no association between prenatal exposure and psychiatric disorders. Evidence of cognitive and behavioral outcomes following prenatal exposure to these ASMs is most comprehensive for lamotrigine and carbamazepine.

The findings from this large multinational cohort study strengthen the evidence for the warning against the use of valproate in pregnancy, support concerns about the use of topiramate, raise preliminary indication for caution with use of levetiracetam, and provide reassuring evidence that lamotrigine, carbamazepine, and oxcarbazepine are not associated with long-term behavioral or developmental disorders. Long-term follow-up data are still needed for less frequently used ASMs to fully evaluate potential behavioral risks associated with prenatal exposure.

Reference

Dreier JW, Bjørk M, Alvestad S, et al. Prenatal Exposure to Antiseizure Medication and Incidence of Childhood- and Adolescence-Onset Psychiatric Disorders. JAMA Neurol. Published online April 17, 2023. doi:10.1001/jamaneurol.2023.0674