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Children of mothers who took certain anti-seizure medications while pregnant do not have worse neurodevelopmental outcomes at age 6, according to a long-running study funded by the National Institutes of Health (NIH). The study was published in JAMA Neurology.
“Controlling seizures during pregnancy is an important part of prenatal care for women with epilepsy, but for years, the effects of newer anti-seizure medications on their children was unknown,” said Adam Hartman, M.D., program director at NIH’s National Institute of Neurological Disorders and Stroke (NINDS). “One major component of this study was correlating the cognitive abilities of children with maternal blood levels of the drugs. This opens the door to future work and might inform better dosing strategies.”
Treating epilepsy during pregnancy is challenging, as some anti-seizure medications, primarily older drugs such as valproate, are known to cause serious birth defects and cognitive problems in children, including lower IQ and autism spectrum disorders. Newer anti-seizure drugs that are widely used today are generally considered safe, but little is known about whether they affect cognition in children after fetal exposure.
In the study, researchers assessed language abilities in 387 children at age 6 (298 were born to women with epilepsy who took anti-seizure medications). Children were tested on a variety of verbal abilities, including vocabulary and matching spoken words to pictures. There were no differences in language scores between children of women who took the medications and those who didn’t. Most women were taking lamotrigine, levetiracetam, or a combination of both drugs during and after pregnancy.
“What makes this study meaningful is that when you assess a child at 6, the tests are a lot more sensitive than at earlier ages, especially 2-year-olds. There’s measurable impact on school performance and results are more predictive of adult cognitive ability,” said Kimford Meador, M.D., co-lead investigator of the study and professor of neurology at Stanford University.
Finding the most effective and safest doses during pregnancy is also a challenge, and risks tend to vary between anti-seizure drugs. Prior studies from the same research team have shown that high doses of levetiracetam could lead to poorer cognitive outcomes at age 2 and 3, and worse adaptive functioning at age 4 and a half, but the overall outcomes for all ages were positive.
“We need to balance making sure there is enough medicine on board to protect the mother and her developing fetus from seizures, but not too much where we’re creating risk for the child,” said Dr. Meador.
The study also found that folate use during the first 12 weeks of pregnancy was associated with better cognitive and behavioral outcomes, even at higher doses. Folate is an essential nutrient that can help prevent birth defects in the brain and spine of a developing fetus. This held true for children of women with and without epilepsy. High doses at or above 4 mg per day did not have adverse effects, which contrasts with prior studies that found long-term risks associated with high doses of folic acid.
This report is part of the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study, a prospective, long-term study that looked at how anti-seizure medications affect pregnant women with epilepsy and their children from birth up to 6 years of age. Led by Dr. Meador and Page Pennell, M.D., chair of neurology at the University of Pittsburgh, the study took place at 20 medical centers across the United States.
Additional analyses revealed no adverse effects of anti-seizure medications on breastfeeding. Researchers point out that more studies need to be done to understand the risks of high doses of folate and less common anti-seizure medications, including newer drugs on the market.
This study was supported by the NINDS and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (U01NS038455 and U01NS050659), and was part of the MONEAD study (NCT01730170).