The FDA ( Food and Drug Administration ) has informed the public that children born to mothers who take the anti-seizure medication Valproate sodium or related products ( Valproic acid and Divalproex sodium ) during pregnancy have an increased risk of lower cognitive test scores than children exposed to other anti-seizure medications during pregnancy. This conclusion is based on the results of epidemiologic studies that show that children born to mothers who took Valproate sodium or related products throughout their pregnancy tend to score lower on cognitive tests ( IQ and other tests ) than children born to mothers who took other anti-seizure medications during pregnancy.

Valproate products are FDA-approved drugs to treat seizures, and manic or mixed episodes associated with bipolar disorder ( manic-depressive disorder ), and to prevent migraine headaches. They are also used off-label for other conditions, particularly for other psychiatric conditions.

Valproate products include: Valproate sodium ( Depacon; in Italy: Depakin ), Divalproex sodium ( Depakote, Depakote CP, and Depakote ER ), Valproic acid ( Depakene and Stavzor ), and their generics.

In the primary epidemiologic study upon which FDA’s conclusion is based, cognitive tests were performed at age three. In supportive studies, cognitive tests were performed at ages five to 16. Cognitive tests are commonly used to assess development in a variety of areas, including intelligence, abstract reasoning, and problem solving.

The long-term effects on cognitive development from exposure to Valproate sodium or related products during pregnancy are unknown. It is also not known whether these effects occur when fetal exposure is limited to less than the full duration of pregnancy, such as the first trimester.

FDA previously warned pregnant women and women of childbearing age about Valproate use during pregnancy due to the known risk of birth defects ( teratogenic effects ) of these products.
Valproate products are assigned to Pregnancy Category D.

Several published epidemiological studies have indicated that children exposed to Valproate in utero have lower cognitive test scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero.
The largest of these studies is a prospective cohort study conducted in the United States and United Kingdom that found children with prenatal exposure to Valproate throughout pregnancy had lower Differential Ability Scale ( D.A.S ) scores at age 3 ( 92 ) than children with prenatal exposure to the other evaluated antiepileptic drug monotherapy treatments: Lamotrigine ( 101 ), Carbamazepine ( 98 ) and Phenytoin ( 99 ).

The D.A.S., which has a mean score of 100 ( SD = 15 ), is a battery of cognitive tests designed for children 2.5 to 17 years of age. The D.A.S. is a measure of cognitive development performed in children who are too young to undergo IQ testing, and generally correlates with IQ scores later in childhood.

Although all of the available studies have methodological limitations, the weight of the evidence supports the conclusion that Valproate exposure in utero causes subsequent adverse effects on cognitive development in offspring.

Source: FDA, 2011

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