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FDA Drug Safety Communication: Children born to mothers who took Valproate products while pregnant may have impaired cognitive development

Safety Announcement
Additional Information for Patients
Additional Information for Healthcare Professionals
Data Summary
References  

Safety Announcement

[6-30-2011] The U.S. Food and Drug Administration (FDA) is informing 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.

Facts about Valproate

  • 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 unapproved uses) for other conditions, particularly for other psychiatric conditions.

  • Valproate products include: valproate sodium (Depacon), 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 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.  

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. A teratogen is anything known to cause birth defects during development of an embryo or fetus. Valproate products are assigned to Pregnancy Category D.  FDA released an Information for Healthcare Professionals communication in December 2009 on the risk of neural tube birth defects following exposure to valproate products during pregnancy. 

The benefits and the risks of valproate sodium and related products should be carefully weighed when prescribing these drugs to women of childbearing age, particularly for conditions not usually associated with permanent injury or death.  If the use of valproate is not essential, alternative medications that have a lower risk to the fetus of birth defects and adverse cognitive effects should be considered in pregnant women and women of childbearing age.  If the decision is made to use valproate in women of childbearing age, effective birth control should be used.
(See Data Summary).

Additional Information for Patients

  • Valproate should not be stopped without talking to a healthcare professional, even in pregnant women. Stopping valproate suddenly can cause serious problems. Not treating epilepsy or bipolar disorder (manic-depressive disorder) during pregnancy can be harmful to women and their developing babies.
  • If you take valproate during pregnancy, know that there is a higher risk that your child may have birth defects or may score lower on cognitive tests (tests that measure mental ability and capacity, such as IQ tests) in childhood than if you use another anti-seizure medicine during pregnancy.
  • Women of childbearing age who decide to take valproate should use effective birth control (contraception) while taking the drug. Women should talk to their healthcare professionals about the best kind of birth control to use while taking valproate.
  • Before you start valproate, you should tell your healthcare professional if you are pregnant or are planning to become pregnant. Healthcare professionals may discuss other treatment options with you.     
  • You should tell your healthcare professional right away if you become pregnant while taking valproate. You and your healthcare provider should decide if you should continue to take valproate while you are pregnant.
  • If you become pregnant while taking valproate, you should talk to your healthcare professional about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334.  The purpose of this registry is to collect additional information about the safety of antiepileptic drugs during pregnancy. Information about the North American Drug Pregnancy Registry can be found at North American Drug Pregnancy Registrydisclaimer icon.
  • If you took valproate while pregnant, let your child’s pediatrician know.
  • Valproate passes into breast milk, but its effects on developing babies remain unknown. You should talk to your healthcare professional about the best way to feed your baby if you take valproate.
  • You should report any side effects you experience to the FDA MedWatch program using the information in the “Contact Us” box at the bottom of the page.

 Additional Information for Healthcare Professionals  

  • 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 of 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 of 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 of 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.

Data Summary  

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 [95% confidence interval 88 to 97]) than children with prenatal exposure to the other evaluated antiepileptic drug monotherapy treatments: lamotrigine (101 [95% confidence interval 98 to 104]), carbamazepine (98 [95% confidence interval 95 to 102]) and phenytoin (99 [95% confidence interval 94 to 104]).1  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.

References  

  1. Meador KJ, Baker GA, Browning N, et al. Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Engl J Med 2009;360:1597-605.
  2. Gaily E, Kantola-Sorsa E, Hiilesmaa V, et al. Normal intelligence in children with prenatal exposure to carbamazepine.  Neurology 2004;62:28-32.
  3. Adab N, Jacoby AD, Chadwick D. Additional educational needs of children born to mothers with epilepsy.  J Neuro Neurosurg Psychiatry 2001;70:15-21.
  4. Adab N, Kini U, Vinten J, et al.  The longer term outcome of children born to mothers with epilepsy.  J Neurol Neurosurg Psychiatry 2004;75:1575–83.    

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