Aarhus, Denmark—A new study bolsters the warning against the use of valproate in pregnant women with epilepsy. It also supports concerns about the use of topiramate and provides a preliminary indication for caution with the use of levetiracetam.

In the Danish study published in the Journal of the American Medical Association Neurology, Aarhus University researchers focused on 38,000 children of mothers with epilepsy. Among other issues, the researchers found a concerning link between the antiseizure medication valproate and the child’s risk of developing a range of psychiatric disorders.

“Our study shows that four out of 10 children born to mothers with epilepsy who had used valproate during pregnancy were diagnosed with a psychiatric disorder before the age of 18 and that the drug was particularly associated with an increased risk of diseases such as autism, ADHD [attention-deficit/hyperactivity disorder] and intellectual disability,” explained study researcher Jakob Christensen, MD, PhD, a professor at Aarhus University and a consultant at Aarhus University Hospital.

The authors emphasized that prenatal exposure to lamotrigine, carbamazepine, and oxcarbazepine was not associated with an increased risk of psychiatric disorders, unlike valproate. Associations were found, however, for prenatal exposure to topiramate and levetiracetam with ADHD.

The researchers pointed out that while prenatal antiseizure medication (ASM) exposure has been associated with adverse early neurodevelopment, associations with a wider range of psychiatric endpoints have not been studied.

In response, the study team used a prospective, population-based register study to assess approximately 4.5 million singleton children born alive in Denmark, Finland; Iceland, Norway; and Sweden from January 1, 1996, to December 31, 2017. Data analysis was performed from August 2021 to January 2023.

Of the 38,661 children of mothers with epilepsy, 42.6% were exposed to ASM and 51.3% were male. Their mean age at the end of the study was 7.5 years.

The results indicated that “prenatal valproate exposure was associated with an increased risk of the combined psychiatric end point (aHR, 1.80 [95% CI, 1.60-2.03]; cumulative risk at 18 years in ASM-exposed children, 42.1% [95% CI, 38.2%-45.8%]; cumulative risk at 18 years in unexposed children, 31.3% [95% CI, 28.9%-33.6%]), which was driven mainly by disorders within the neurodevelopmental spectrum,” according to the authors.

Associations were identified for prenatal exposure to topiramate with ADHD (adjusted hazard ratio [aHR] 2.38; 95% CI, 1.40-4.06) and exposure to levetiracetam with anxiety (aHR 2.17; 95% CI, 1.26-3.72) and ADHD (aHR 1.78; 95% CI, 1.03-3.07).

“Findings from this explorative study strengthen the evidence for the warning against the use of valproate in pregnancy and raise concern of risks of specific psychiatric disorders associated with topiramate and levetiracetam,” the researchers concluded. “This study provides reassuring evidence that lamotrigine, carbamazepine, and oxcarbazepine are not associated with long-term behavioral or developmental disorders but cannot rule out risks with higher doses.”

Background information in the study pointed out that the use of ASMs among pregnant women has increased during recent decades, estimating that between 0.5% and 2% of all children are born to women using ASMs during pregnancy. The study added that in expectant mothers, ASMs are used primarily for epilepsy but might be prescribed for other indications, such as mood disorders, migraine, and neuropathic pain.

Until now, the understanding of the potential link between ASMs and psychiatric disorders in childhood has been limited.

In the study, 42% of children of mothers who used valproate during pregnancy developed a psychiatric disorder before age 18 years. That can be compared with 31% of offspring of mothers with epilepsy who did not take antiseizure medication during pregnancy.

“Our research emphasizes the importance of understanding the potential harmful effects of epilepsy medicine during pregnancy and the continued lack of knowledge about how different types of medicine can affect the child's psychological development,” according to Dr. Christensen. “Our study shows that there is a need for more research and more accurate risk estimates to help pregnant women with epilepsy and their doctors make informed decisions about the use of medicine during pregnancy.”

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