A new cohort study has some answers.
The report in the Journal of the American Medical Association Neurology notes that adaptive functioning did not appear to differ between children of women with epilepsy and children of women without epilepsy. On the other hand, report authors from Pediatric Neuropsychology International, LLC in Augusta, Georgia, and a range of U.S. universities noted that a significant decrease in functioning was seen with increasing third trimester ASM blood concentrations.
The researchers advised that their secondary analysis revealed the association was clearest for levetiracetam and lamotrigine, which were the ASMs with sample sizes large enough for analysis.
“This study suggests that these exposure-dependent associations warrant psychiatric or psychological screening and referral of women with epilepsy and their offspring when appropriate,” according to the authors.
The investigators sought to examine the association of fetal ASM exposure with subsequent adaptive, behavioral, emotional, and neurodevelopmental disorder outcomes at ages 2, 3, and 4.5 years.
The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs study is a prospective, observational cohort study that was conducted at 20 epilepsy centers in the U.S. It enrolled 456 pregnant women with epilepsy or without epilepsy from December 19, 2012, to January 13, 2016, and included 302 children of women with epilepsy (143 boys [47.4%]) and 84 children of women without epilepsy (45 boys [53.6%]). The offspring of participants were followed up with formal assessments at ages 2, 3, 4.5, and 6 years, and statistical analysis took place from August 2022 to May 2023.
In the study, exposures included the mother’s epilepsy status, as well as her ASM blood concentration in the third trimester (for children of women with epilepsy). ASM regimen did not determine which women with epilepsy were enrolled.
The primary outcome was defined as the Adaptive Behavior Assessment System, Third Edition (ABAS-3) General Adaptive Composite (GAC) score among children aged 4.5 years. The researchers compared children of women with epilepsy and children of women without epilepsy, while assessing the associations of ASM exposures with outcomes among exposed children.
The results indicated that overall adaptive functioning (ABAS-3 GAC score at 4.5 years) did not significantly differ between children of women with epilepsy and children of women without epilepsy (parameter estimate [PE], 0.4; 95% CI, –2.5 to 3.4; P = .77).
In adjusted analyses, the significant decrease in functioning was identified with increasing third trimester maximum ASM blood concentrations (PE, –7.8; 95% CI, –12.6 to –3.1; P = .001).
“This decrease in functioning was evident for levetiracetam (PE, –18.9 [95% CI, –26.8 to –10.9]; P < .001) and lamotrigine (PE, –12.0 [95% CI, –23.7 to –0.3]; P = .04), the ASMs with sample sizes large enough for analysis,” the researchers advised. “Results were similar with third trimester maximum daily dose.”
Because of that, the authors recommended “psychiatric or psychological screening and referral of women with epilepsy and their offspring are recommended when appropriate,” adding, “Additional research is needed to confirm these findings.”
Background information in the study noted that while knowledge of ASM-related teratogenesis has increased over the past 2 decades, the risks of fetal exposure are known for only a few ASMs.
The authors pointed out that previous research has reported a greater cognitive neurodevelopmental risk for valproate compared with carbamazepine, lamotrigine, or phenytoin, with decreased adaptive functioning and a greater risk of attention-deficit/hyperactivity disorder.
“However, ASM prescription practices have changed,” the authors added, “and the cognitive and behavioral risks remain uncertain for most ASMs except for levetiracetam, which appears to have less risks than valproate.”
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