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Children Born to Women with Epilepsy Who Have Gene Variant More Likely to Have Poor Cognitive Outcomes

​Women with epilepsy who had gene variants associated with the risk of fetal alcohol syndrome (FAS) were more likely to have children with poorer cognitive outcomes, particularly in language domains, according to an abstract presented in December at the American Epilepsy Society conference in Nashville.

The findings could help doctors predict the likelihood of some cognitive outcomes in women with epilepsy who are pregnant or want to become pregnant, said lead author Yi Li, MD, PhD, a clinical assistant professor in the department of neurology and neurological sciences at Stanford University School of Medicine in California.

The analysis included 190 pregnant women with epilepsy who were enrolled in the prospective Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs study and who underwent whole genome sequencing. Their children were assessed at 2 years using the Bayley Scales of Infant and Toddler Development-3 (BSID-III); the language domain score was the primary outcome.

Total rare variant counts in FAS risk genes were significantly associated with language domains of the BSID-III (p= 0.02). Even when the analysis was adjusted to include the women's IQ and educational background, as well as the child's sex, exposure to alcohol, and post-birth average anxiety score, the rare genetic variant counts in the FAS risk genes emerged as an independent factor predicting the poorer language in BSID-III (p< 0.001).

The researchers focused on FAS variations because fetal ASM-associated behavioral teratogenicity and FAS share similar cognitive domains, including impaired intellectual function.

“The goal is to try and find a genetic biomarker from the mother and see if there's any connection or impact on the kids' neurocognitive outcomes," Dr. Li said. 

When she has a pregnant patient, Dr. Li mainly focuses on the medication dosage and ensuring they are treated with the medication known to have least teratogenicity. Less than half of the FDA-approved ASMs have solid data on pregnancy outcomes, she said, so one future step could involve dividing groups by fetal medication exposure to determine whether there's an interaction with the mother's genomic background, such as the FAS risk genes, she said.

“Then we could have an idea about how different medications might impact the genetic burden," Dr. Li said. “I'm imagining that, in the future, if we know what medication the patients are on, and we have this kind of information about the genetic background and medication dosing, we'd have a better picture if it's a high-risk or low-risk pregnancy regarding cognitive outcomes."

Dr. Li said the team is working on cognitive data from women with epilepsy whose children are now followed up to age 6 years. They hope to learn more about the mechanisms and unexplained variability seen in neurodevelopmental outcomes of children born to those women to provide better quality of care.

Jacqueline A. French, MD, FAAN, professor of neurology at the New York University Grossman School of Medicine and director of The Epilepsy Study Consortium, said she was not aware of other studies that had associated FAS outcomes with ASM issues in children of women with epilepsy. She said the results were surprising, and she encouraged further investigation, particularly into whether the genetic variation would impact the metabolism of the ASM in the baby in utero. If there was a correlation with impairment with one medication but not another, that could give neurologists and their patients more information about risk and pregnancy.

“My question is whether a similar correlation exists in women who do not have epilepsy and who do not drink but who have the FAS genetic variation," Dr. French said, adding that it could be very difficult to capture an accurate alcohol history.

Dr. Li had no disclosures.

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