FDA Issues Warning about More Depakote Birth Defect Risk

After a new study linked Depakote and other valproate medications taken during pregnancy to an increased risk of autism and autism spectrum disorders, the FDA has decided to put its strongest warning for pregnancy associated complications on the drug, designating it pregnancy class X for migraine prevention, which means that the drug’s dangers outweigh its benefits for pregnant women. The new study adds to other work showing the drug increases risk for birth defects when taken by pregnant women.

What Is Depakote?

Depakote is a commercial name for a valproate product, specifically divalproex sodium. It comes in three different variations, including Depakote CP and Depakote ER. Other variations on the drug include:

• Valproate sodium (Depacon, an injectable formulation)
• Valproic acid (Depakene and Stavzor)

As well as generic formulations.

Valproate products are approved for migraine prevention, epilepsy, and bipolar disorder.

Study Shows Depakote Increases Risk of Autism

A study published in the Journal of the American Medical Association in April showed that women who took Depakote or similar drugs during pregnancy were more likely to give birth to children with autism or autism spectrum disorders. The study looked at birth and pediatric records for children in the Danish health registry from 1996 to 2006. The study compared children of women given Depakote during pregnancy with women who did not take the drug during pregnancy and found the drug was associated with:

• A 3X increase in risk for autism spectrum disorders (1.53% vs. 4.44%)
• A 5X increase in risk for childhood autism (0.48% vs. 2.56%)

In an attempt to remove a potential confounder, the study also compared children born to mothers with epilepsy and found that even in this limited group Depakote was associated with elevated risk of:

• 1.7X increase in risk for autism spectrum disorders (2.44% vs. 4.15%)
• 3X increase in risk for childhood autism (1.02% vs. 2.95%)

The current study is a follow-up of work previously reported in 2011, about which the FDA had also issued a warning.

Autism spectrum disorder is a broad class of conditions that includes autism, Asperger syndrome, Rett syndrome, and others.

Depakote Already Associated with Birth Defects

The troubled drug Depakote has already been associated with birth defect risks. A 2010 review of studies linked the drug to an increased risk of birth defects when taken by mothers in their first trimester. The risks increased significantly for six different types of birth defects:

• Spina bifida (12.7X increased risk)—in which the neural tube fails to close around the brain and spinal cord
• Craniosynostosis (6.8X)—in which one or more of the cranial sutures on the baby’s skull closes prematurely
• Cleft palate (5.2X)
• Hypospadias (4.8X)—in which the urethra opening in the penis is in the bottom rather than the end
• Atrial septal defect (2.5X)
• Polydactyly (2.2X)

Although the study noted that the risks for Depakote were similar to those for other antiepileptic drugs, which probably contributed to the FDA’s decision to continue to allow the drug for pregnant women, although a black box warning describing the risks was added in 2009.

FDA Action

However, since the current research seems to indicate that the risks for Depakote and similar drugs outweigh the benefits for migraine prevention, the FDA has decided it is time to change the classification of the drug, from the current pregnancy class D (positive evidence of human fetal risk) to pregnancy class X (risks of use clearly outweigh benefits).

The drug will remain in pregnancy class D for control of manic episodes and epilepsy.

The change will not take place immediately, since new labeling must be written, but all patients and doctors should be aware of the new classification and consider alternate treatment for migraine prevention in pregnant women. Women of childbearing age are encouraged to use effective birth control if they are taking Depakote or other types of valproic acid.

There are already numerous lawsuits in progress for birth defects associated with valproic acid. It is likely that more will be filed after this labeling change.