There have long been concerns regarding the use of the anticonvulsant valproate (Depakote) during pregnancy. First trimester use of valproate has been associated with a 3-5% risk of neural tube defects, as well as an increased risk of other malformations affecting the heart. In addition, recent reports have indicated that in utero exposure to valproate may also result in lower IQ.
Researchers from the United States and the United Kingdom are conducting the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study, a prospective, observational,multicenter study which has followed women with epilepsy who were taking a single antiepileptic agent (carbamazepine,lamotrigine, phenytoin, or valproate) during pregnancy.
In 2009, the first set of data from the NEAD study was published, including outcomes in a total of 309 children evaluated at 3 years of age. The authors reported that children who had been exposed to valproate in utero had significantly lower IQ scores than thosewho had been exposed to the other antiepileptic drugs. Lower IQ was a dose-dependent phenomenon, with the worse cognitive outcomes observed in children exposed to doses of valproate higher than 1000 mg/day.
Now, we have more data from the NEAD study. The children, now 4.5 years of age, were re-assessed, and the findings were basically the same as reported in the previous study. Children exposed to valproate had significantly lower IQ scores than thosewho had been exposed to carbamazepine, lamotrigine, and phenytoin.
- Adjusting for a variety of variables, including maternal IQ, maternal age, drug dosage, and gestationalage at birth, it was observed that on average childrenexposed to valproate had IQ scores 10 points lower than thescores of children exposed to the other antiepileptic agents
- The effect of valproate on IQ was dose-dependent.
- The frequency of marked intellectual impairment diminished with age except for valproate (10% with IQ <70 at 4.5 years).
- Age 4.5 outcomes significantly correlated with outcomes at 2 and 3 years of age; thus, it is possible to detect impairments early and to initiate appropriate interventions.
While the most significant effects were associated with exposure to valproate, exposure to the other antiepileptic drugs was also associated with cognitive deficits. In the previous report evaluating children at 3 years of age, it was shown that all 4 of the AEDs were associated with impaired verbal abilities compared to nonverbal abilities. The researchers found that the verbal deficits persist for all 4 AEDs at 4.5 years of age.
At the recent meeting of the American Academy of Neurology, more data from the NEAD study was presented, including outcomes from the children who are now 6 years of age. Again exposure to valproate was associated with lower IQs, as well as lower scores on tests of executive functioning, memory, verbal and nonverbal abilities. One interesting finding was that preconceptual supplementation with folate appeared to improve IQ in all children exposed to anticonvulsants in pregnancy.
The NEAD study has many strengths, including its prospective design, blinded cognitive assessments the use of standardized measures, and detailed monitoring of multiple potential confounding factors. While certain questions remain, it seems fairly clear that certain antiepileptic drugs, specifically valproate, may present a less desirable reproductive safety profile.
The bottom line? Not only does exposure to valproic acid during pregnancy carry a significant teratogenic risk, multiple studies have shown that there are long term effects on cognitive functioning.
Ruta Nonacs, MD PhD
Meador KJ, Baker GA, Browning N, Clayton-Smith J, Combs-Cantrell DT, Cohen M, Kalayjian LA, Kanner A, Liporace JD, Pennell PB, Privitera M, Loring DW; NEAD Study Group. Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Engl J Med 2009; 360(16):1597-605.
Meador KJ, Baker GA, Browning N, Cohen MJ, Bromley RL, Clayton-Smith J, Kalayjian LA, Kanner A, Liporace JD, Pennell PB, Privitera M, Loring DW, NEAD Study Group. Effects of fetal antiepileptic drug exposure: Outcomes at age 4.5 years. Neurology 2012; 78(16):1207-1214.