Literature Review

Valproate Exposure in Utero Significantly Decreases Educational Attainment in Children

Children of mothers prescribed multiple AEDs during pregnancy appear to be less likely to achieve the national minimum standard test scores.


In utero exposure to antiepileptic drugs (AEDs) in combination, or sodium valproate alone, significantly decreases educational attainment in children age 7, compared with both a matched control group and the all-Wales national average, according to a report published online ahead of print March 27 in the Journal of Neurology, Neurosurgery and Psychiatry. “These results give further support to the cognitive and developmental effects of in utero exposure to sodium valproate as well as multiple AEDs, which should be balanced against the need for effective seizure control for women during pregnancy,” said lead author Arron S. Lacey, Prudent Healthcare Intelligence Unit Research Data Analyst at Swansea University in the UK, and colleagues.

Arron S. Lacey

Although valproate is considered the most effective drug for treating genetic generalized epilepsy, recent prospective psychometric studies revealed cognitive impairment and neurodevelopmental disorders in 30% to 40% of children exposed to valproate in utero, as well as a significant decrease in IQ. According to Mr. Lacey and colleagues, to adequately counsel women about the risks of uncontrolled seizures during pregnancy and cognitive outcomes for their children, “it is important to know whether the psychometric differences seen in research conditions translate to children in the community.”

To identify whether children exposed to AEDs in utero have poorer school performance, Mr. Lacey and colleagues used the Secure Anonymous Information Linkage databank to access routinely collected health care records and identify children born to mothers with epilepsy. They then linked the identified children to their national attainment Key Stage 1 (KS1) tests in mathematics, language, and science at age 7, and compared them with matched controls (children born to mothers without epilepsy), and with the national KS1 results. As outcome measures, the investigators used the core subject indicator (CSI), which is the proportion of children achieving a minimum standard in all subjects, and the results in individual subjects.

The researchers identified 440 children born to mothers with epilepsy with available KS1 results. Compared with a matched control group, fewer children with mothers prescribed sodium valproate during pregnancy achieved the national minimum standard in CSI (12.7% less than the control group), mathematics (12.1%), language (10.4%) and science (12.2%). Even fewer children with mothers prescribed multiple AEDs during pregnancy achieved the national minimum standard in CSI (20.7% less than the control group), mathematics (21.9%), language (19.3%), and science (19.4%). Researchers did not observe significant differences in children whose mothers were prescribed carbamazepine or women taking an AED, when compared with the control group.

According to the researchers, the main strength of the study is the ability to select a large cohort of 440 children with national test results without major recruitment bias and compare it with a large control group. One main study limitation “was not being able to use the maternal IQ, as well as other maternal factors, such as maternal weight or alcohol consumption during pregnancy, as covariates,” said the authors. In addition, researchers were unable to account for how parental style, or ability, may have influenced educational attainment.

“Our results add to the growing evidence that in utero exposure to certain AEDs can cause developmental problems in children. Women with epilepsy should be informed of this risk, and alternative treatment regimens should be discussed before their pregnancy with a physician that specializes in epilepsy,” the researchers concluded.

—Erica Tricarico

Suggested Reading

Lacey AS, Pickrell WO, Thomas RH, et al. Educational attainment of children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry. 2018 March 27 [Epub ahead of print].

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