June 30, 2011 — The US Food and Drug Administration (FDA) has issued a safety announcement to underline the increased risk for lower cognitive test scores among children born to mothers taking the antiseizure medication valproate sodium or the related products valproic acid and divalproex sodium during pregnancy, relative to other antiepileptic medications.
Valproate products are approved to treat seizures and manic or mixed episodes associated with bipolar disorder (manic-depressive disorder), and to prevent migraine headaches, a MedWatch alert notes. They are also used off-label for other conditions, particularly other psychiatric conditions.
"FDA has evaluated all available evidence to date, and will be adding information about the risk of lower cognitive test scores to the valproate product labels in the Warnings and Precautions section, the Use in Specific Populations: Pregnancy section, and to the Medication Guides that are being developed for the valproate drug products," the alert notes.
The FDA previously warned pregnant women and women of childbearing age about valproate use during pregnancy because of known teratogenic effects, and valproate products are assigned to Pregnancy Category D. The FDA also released an Information for Healthcare Professionals communication in December 2009 on the risk for neural tube birth defects after exposure to valproate products during pregnancy.
Their conclusion is based on epidemiologic studies showing that children exposed to valproate in utero tend to score lower on cognitive testing than children exposed to other agents.
The primary study supporting the conclusion is based on the well-known work of Kimford Meador, MD, from Emory University in Atlanta, Georgia, and investigators in the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study. The FDA has used the data from testing performed when the children were age 3; these resultswere published in the New England Journal of Medicine in 2009.
The NEAD results showed that children exposed to valproate in utero throughout pregnancy had lower Differential Ability Scale (DAS) scores at age 3 years (92; 95% confidence interval [CI], 88 - 97) than those with prenatal exposure to other evaluated monotherapies, including lamotrigine (101; 95% CI, 98 - 104), carbamazepine (98; 95% CI, 95 - 102), and phenytoin (99; 95% CI, 94 - 104).
At the American Academy of Neurology's recent annual meeting, Dr. Meador and colleagues presented further data from follow-up to 4.5 years of age in the NEAD study, with essentially the same conclusions. (See theMedscape Medical News report here.) Guidelines on pregnancy in epilepsy developed by the American Academy of Neurology and the American Epilepsy Society released in 2009 already suggest that valproate should be avoided during pregnancy if possible.
The FDA warning also cites several additional supportive studies, where cognitive tests were performed at ages 5 to 16 years.
The long-term effects on cognitive development from exposure to valproate sodium or related products during pregnancy are unknown, the MedWatch statement notes, nor is it known whether these effects occur when fetal exposure is limited to less than the full duration of pregnancy, such as the first trimester.
"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," the FDA announcement concludes.
For healthcare professionals, the statement gives the following guidance; they should:
- Inform women of childbearing age of the increased risk for adverse effects on cognitive development with prenatal valproate exposure.
- Continue to counsel women of childbearing potential taking valproate about the increased risk for major malformations, including neural tube defects, when valproate is used during pregnancy.
- Weigh the benefits and risks of valproate when prescribing this drug to women of childbearing age, particularly when treating a condition not usually associated with permanent injury or death. Alternative medications that have a lower risk for adverse birth outcomes should be considered. Healthcare professionals should discuss the relative risks and benefits of appropriate alternative therapies.
- Untreated or inadequately treated epilepsy or bipolar disorder during pregnancy increases the risk for complications in both the pregnant mother and her developing baby.
- If the decision is made to prescribe valproate to women of childbearing age, healthcare professionals should recommend use of effective contraception for women who are not planning a pregnancy.
- Inform patients of the North American Antiepileptic Drug (NAAED) Pregnancy Registry and encourage patients who become pregnant to enroll by calling 1-888-233-2334.
- Report adverse events involving valproate to the FDA MedWatch program, using the information in the "Contact Us" box at the bottom of the page.
Valproate products include valproate sodium (Depacon), divalproex sodium (Depakote, Depakote CP, andDepakote ER), valproic acid (Depakene and Stavzor), and their generics.
Adverse effects related to valproate products should be reported to MedWatch, the FDA's safety information and adverse event reporting program, by telephone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online athttps://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm, or by mail to MedWatch, FDA, 5600 Fishers Lane, Rockville, Maryland 20852-9787.