What are the fetal risks of valproate therapy during pregnancy?

Updated: Aug 20, 2019
  • Author: Carmel Armon, MD, MSc, MHS; Chief Editor: Stephen A Berman, MD, PhD, MBA  more...
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According to the AAN/AES guidelines, it is highly probable that intrauterine first-trimester valproate exposure carries a higher risk of major congenital malformations than carbamazepine exposure, and it is possible that it carries a higher risk than phenytoin or lamotrigine exposure. Valproate as part of polytherapy probably contributes to the development of major congenital malformations, and valproate as monotherapy possibly contributes. For monotherapy, intrauterine exposure to valproate probably reduces cognitive outcomes.

Meador et al reported that in utero exposure to valproate, compared with exposure to other AEDs, is associated with a lower intelligent quotient (IQ) in children. [23] This report derived from a prospective, observational, cohort study of pregnant women with epilepsy who took a single agent (carbamazepine, lamotrigine, phenytoin, or valproate) over a period of 5 years in 25 epilepsy centers in the United States and the United Kingdom.

The cohort study assessed the neurodevelopmental outcomes of children who were exposed in utero to several AEDs. [23] A planned interim analysis conducted when the children were aged 3 years found an increased risk of impaired cognitive function with valproate as compared with other commonly used antiepileptic drugs and determined that this association was dose-dependent. The investigators concluded that valproate should not be used as a first-line agent in women of childbearing potential.

A report based on analysis of data from the Neurodevelopmental Effects of Antiepileptic Medications (NEAD) study (Baker GA, World Congress of Neurology, 2009), indicated that the receptive and expressive language abilities of 3-year-olds who were exposed to sodium valproate in utero were lower than those of children who had been exposed to other AEDs.

In this report, the average score on measures of expressive language for 3-year-olds exposed to valproate in utero was 91, compared with 102 for those exposed to carbamazepine, 104 for those exposed to lamotrigine, and 101 for those exposed to phenytoin. On measures of receptive language, the average score for children exposed to valproate in utero was 89, compared with 97 for those exposed to carbamazepine and 101 for those exposed to lamotrigine or phenytoin.

A 2015 study from the United Kingdom extends these observations to school-aged children. It reports on outcomes of children born to women with epilepsy (n=243) and women without epilepsy (n=287) who were recruited during pregnancy and followed prospectively. Of the total cohort of children, 408 were blindly assessed at 6 years of age. Consistent with data from younger cohorts, school-aged children exposed in utero to valproate at maternal doses more than 800 mg daily continue to experience significantly poorer cognitive development than control children or children exposed to lamotrigine and carbamazepine.

The adjusted mean IQ was 9.7 points lower for children exposed to high-dose (>800 mg daily) valproate, with a similar significant effect observed for the verbal, nonverbal, and spatial subscales. These children also had an 8-fold increased need of educational intervention relative to control children. Valproate at doses < 800 mg daily was not associated with reduced IQ, but was associated with impaired verbal abilities (−5.6, 95% CI −11.1 to −0.1; p = 0.04) and a 6-fold increase in educational intervention (95% CI 1.4–18.0; p = 0.01). In utero exposure to carbamazepine or lamotrigine did not have a significant effect on IQ, but carbamazepine was associated with reduced verbal abilities (−4.2, 95% CI −0.6 to −7.8; p = 0.02) and increased frequency of IQ < 85. [24]

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