Friday, September 2, 2016

Cognitive effects of prenatal antiepileptic drug exposure

Bromley RL, Calderbank R, Cheyne CP, Rooney C, Trayner P, Clayton-Smith J,
García-Fiñana M, Irwin B, Morrow JI, Shallcross R, Baker GA; UK Epilepsy and
Pregnancy Register. Cognition in school-age children exposed to levetiracetam,
topiramate, or sodium valproate. Neurology. 2016 Aug 31. pii:
10.1212/WNL.0000000000003157. [Epub ahead of print]

To investigate the effects of prenatal exposure to monotherapy levetiracetam, topiramate, and valproate on child cognitive functioning.
This was a cross-sectional observational study. Children exposed to monotherapy levetiracetam (n = 42), topiramate (n = 27), or valproate (n = 47) and a group of children born to women who had untreated epilepsy (n = 55) were enrolled retrospectively from the UK Epilepsy and Pregnancy Register. Assessor-blinded neuropsychological assessments were conducted between 5 and 9 years of age. Information was collected on demographic and health variables and adjusted for in multiple regression analyses.
In the adjusted analyses, prenatal exposure to levetiracetam and topiramate were not found to be associated with reductions in child cognitive abilities, and adverse outcomes were not associated with increasing dose. Increasing dose of valproate, however, was associated with poorer full-scale IQ (-10.6, 95% confidence interval [CI] -16.3 to -5.0, p < 0.001), verbal abilities (-11.2, 95% CI -16.8 to -5.5, p < 0.001), nonverbal abilities (-11.1, 95% CI -17.3 to -4.9, p < 0.001), and expressive language ability (-2.3, 95% CI -3.4 to -1.6, p < 0.001). Comparisons across medications revealed poorer performance for children exposed to higher doses of valproate in comparison to children exposed to higher doses of levetiracetam or topiramate.
Preconception counseling should include discussion of neurodevelopmental outcomes for specific treatments and their doses and women should be made aware of the limited nature of the evidence base for newer antiepileptic drugs.

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Teens whose moms took valproate and other antiepileptic drugs (AEDs) during pregnancy lag behind their classmates in math and reading skills, according to preliminary results of a new study.

Previous studies looked at the cognitive effect of being exposed to these drugs prenatally but only up to about preschool age.

The new results were reported here by Lars S. Elkjær, research year student, Department of Neurology, Aarhus University Hospital, Aarhus, Denmark,at the 2nd Congress of the European Academy of Neurology…

The researchers adjusted the results for many possible confounders, including family income and the educational level of the mother, which, according to Elkjær, is one of the most important factors influencing how well kids perform in the school setting. They also adjusted for calendar year and the child's gender.

At the meeting here, Elkjær reported only the results from the sixth grade testing.

"Overall, the AED-exposed children performed significantly worse, especially the children exposed to valproate," compared with an unexposed reference group of children (who after standardization, performed at the mean of 0), said Elkjær.

For valproate, the adjusted mean z-score was –0.28 (95% confidence interval [CI], –0.41 to –0.14).

Interestingly, children exposed to clonazepam also performed significantly worse on these school tests than did unexposed kids.

However, lamotrigine-exposed children "are performing almost identically to the unexposed children," said Elkjær. The adjusted mean z-score for lamotrigine was 0.01 (95% CI, –0.01 to 0.04).

The children whose mothers took an AED during pregnancy did worse than unexposed children, whether or not the mother took the drug because of epilepsy. Elkjær later told delegates that it would be "a good idea" to learn what other diagnoses these women might have had…
Session co-chair Reeta Kälviäinen, MD, PhD, professor of clinical epileptology, University of Eastern Finland, Kuopio, Finland, commented that it's because of the Danish registries that such a study could be carried out. She also emphasized the importance of investigating the effect of prenatal valproate exposure in the teenage years.

"That is very important because, at the moment, we only know the effect of valproate at the preschool age, and there might be some catching up going on" among exposed children, she said.

Asked if a high dose of valproate had an even larger effect on cognitive skills in exposed children, Elkjær noted that not many children in the cohort were exposed to a high level of valproate. His research group has not yet done such an analysis but hopes to do so, he said.

2nd Congress of the European Academy of Neurology. Abstract O1109. Presented May 28, 2016.

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