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Adaptive functioning scores did not differ between children of women with and without epilepsy, but a significant decrease in functioning was seen with increasing third-trimester levels of anti-seizure medications (ASMs), the observational cohort study found.

No statistically significant difference emerged in adaptive functioning scores between 4.5-year-old children whose mothers had epilepsy and those whose mothers did not (parameter estimate [PE] 0.4, 95% CI -2.5 to 3.4, P=0.77), reported Morris Cohen, EdD, of Pediatric Neuropsychology International in Augusta, Georgia, and co-authors.

However, higher third-trimester ASM blood concentrations were associated with a significant decrease in adaptive functioning scores (adjusted PE −7.8, 95% CI −12.6 to −3.1, P=0.001), the researchers wrote in .

Fetal exposure to older ASMs like valproate (Depakote) has been linked to cognitive deficits, but cognitive and behavioral risks remain uncertain for many newer ASMs, Cohen and colleagues noted. Previous research from the MONEAD cohort showed that children with fetal exposure to newer ASMs showed no difference in verbal abilities at age 3 compared with unexposed children.

"The most important takeaway message is that the children of the persons with epilepsy on ASMs did not differ from the children of the control group with regard to any of these neurodevelopmental behavioral outcomes," co-author Page Pennell, MD, of the University of Pittsburgh in Pennsylvania, told 番茄社区 by email.

"These findings remind us to not increase doses carelessly beyond what is needed to maintain seizure control for the individual patient," Pennell pointed out.

"We know from our prior studies that active adjustment of ASM doses during pregnancy is needed to maintain seizure stability," she added. "The overall findings are extremely reassuring for adult persons with epilepsy who will need to continue their ASMs during pregnancy."

Adaptive functioning scores were based on the Adaptive Behavior Assessment System, Third Edition, General Adaptive Composite (ABAS-3 GAC), a rating assessment with higher scores indicating higher functioning.

Parents completed the assessment for their child at ages 3 and 4.5 years, and GAC scores at age 4.5 were used as the study's primary outcome. Parents also completed assessments of emotional or behavioral functioning, stress in the parent-child relationship, and autism spectrum disorder screening.

Participants were enrolled at U.S. epilepsy centers from 2012-2016. A total of 302 children of women with epilepsy (47.4% boys) and 84 children of women without epilepsy (53.6% boys) were included in the first primary analysis, which compared the groups' GAC scores. The second primary analysis, which looked at third-trimester ASM blood concentrations and GAC scores, included 271 children of women with epilepsy.

The association between increasing third-trimester ASM blood concentration and decreasing adaptive functioning scores was seen for levetiracetam (Keppra) (PE -18.9, 95% CI-26.8 to -10.9, P<0.001) and, to a lesser degree, lamotrigine (Lamictal) (PE -12.0, 95% CI -23.7 to -0.3, P=0.04), but sample sizes for other ASMs weren't big enough to assess.

Children in the maternal epilepsy and non-epilepsy groups had similar low proportions of neurodevelopmental disability, including intellectual disability and autism, the researchers added.

"The bottom line is that for the medications that we're studying, especially for levetiracetam and lamotrigine ... that these medications are relatively safe from both a birth defects standpoint and a neurodevelopmental standpoint, but with caveats -- and some of the caveats have to do with dose," noted Daniel Friedman, MD, of NYU Grossman School of Medicine, who wasn't involved in the analysis.

In principle, physicians use the lowest effective medication dose, but during pregnancy, doses may be increased because the body metabolizes ASMs more quickly, Friedman said.

"It may be another month before we recheck the level, and that may be appropriate for some women, but with other women, you may be at risk for overshooting," he said. "Making adjustments that are too high -- now you've increased their exposure to anti-seizure medications where you may not have had to."

The clinical significance of differences in children's GAC scores with increasing doses remains unclear, Friedman added. "How much this would impact their academic achievement, their social achievement? I don't have a good sense."

The MONEAD researchers acknowledged that study limitations included unknown potential confounders and small sample sizes for many ASMs. The distribution of ASMs in the study may not reflect the general population, they added. Another limitation was the subjectivity of assessments done by parents, Friedman said.

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