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September 2009

Prenatal Valproate Lowers IQ
Valproate may adversely affect fetal cognitive development throughout pregnancy.

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In one study, amphetamine was not superior to caffeine as an augmentation strategy for patients with obsessive compulsive disorder.

Antipsychotics in Alzheimer's Patients: New Evidence on Metabolic Effects
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Contraception Use in Female Bipolar Patients Suboptimal; CBT Available over Internet for Insomnia

SSRIs and Gestational Hypertension
Use of a serotonin selective reuptake inhibitor beyond the first trimester of pregnancy is associated with an increased risk of hypertension and preeclampsia.

Prenatal Valproate Lowers IQ

September 2009

When a woman takes certain anticonvulsants early in pregnancy, she increases the risk that her baby will develop malformations (2008;31:22-23,45). Exposure of experimental animals to antiepileptic drugs at doses lower than what is teratogenic can produce adverse cognitive and behavioral effects in the offspring. Meador and collaborators assessed whether prenatal exposure to four antiepileptic agents in human babies could adversely affect neurodevelopmental outcomes.1

The authors enrolled 252 women treated with carbamazepine (Tegretol and others), lamotrigine (Lamictal), phenytoin (Dilantin and others), or valproate (Depakote and others) for epilepsy in a prospective, observational, multicenter study conducted in the United States and the United Kingdom and funded by the U.S. National Institutes of Health and a U.K. foundation. The current report is an interim analysis of cognitive outcomes in 309 children at 3 years of age.

On average, children exposed to valproate had IQ scores 9 points lower than those exposed to lamotrigine, 7 points lower than children exposed to phenytoin, and 6 points lower than those whose mothers took carbamazepine—all highly significant statistically. Moreover, the association between valproate use and decreased IQ was dose dependent. Children's IQs are usually closely related to their mothers' IQs. This was the case in children exposed to carbamazepine, lamotrigine, or phenytoin, but was not so in children exposed to valproate—suggesting that valproate disrupts this normally robust relationship. Valproate also increases the risk of congenital malformations in a dose-dependent fashion.

In an accompanying editorial, Tomson observes that the risk of major congenital malformations is two to four times higher when a pregnant woman takes valproate than with other antiepileptic drugs, such as carbamazepine or lamotrigine.2 However, the risk of anatomic birth defects occurs only during the first 2 to 3 months of gestation, while adverse effects on intellectual development may be caused by exposure throughout pregnancy.

Dr Meador's study was a naturalistic one. Mothers were not randomly assigned to which antiepileptic they took, which opens the possibility of confounding variables. From the standpoint of psychiatric practice, it is conceivable that factors related to epilepsy could contribute to these apparent adverse effects of valproate and might not be relevant for women being treated for psychiatric indications, such as bipolar disorder.

These observations and limitations notwithstanding, there is good reason to suspect that valproate itself has adverse effects on the fetus—possibly contributing to organ malformations when taken early in pregnancy and adversely affecting cognitive development throughout pregnancy. For these reasons, valproate should be used with caution, if at all, in pregnant women. And since approximately half of all pregnancies are unplanned, this caution should extend to all women of childbearing potential.

1Meador 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; the NEAD Study Group: Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Engl J Med 2009;360:1597–1605.

2Tomson T: Which drug for the pregnant woman with epilepsy? N Engl J Med 2009;360:1667-1669.