Birth Defects Linked to Valproic Acid

6 Birth Defects More Common in Pregnant Women Who Take Epilepsy Drug

By Denise Mann
WebMD Health News

Reviewed by Laura J. Martin, MD

June 9, 2010 -- Women with epilepsy who take valproic acid during the first trimester of pregnancy are more likely to have children with birth defects than women who took other epilepsy drugs or no medicine to control their seizures during pregnancy.

The findings appear in the June 10 issue of the New England Journal of Medicine.

Valproic acid is also used to treat other illnesses, including bipolar disorder and migraines. Brand names include Depakote, Depakene, Depacon, and Stavzor.

Almost 3 million people in the U.S. have some form of epilepsy, according to the Epilepsy Foundation.

"Our findings provide further support for the recommendation of the American Academy of Neurology to avoid the use of valproic acid, if possible, in pregnant women," conclude the researchers, who were led by Janneke Jentink, MSc, of the University of Groningen in Groningen, Netherlands. "Since switching drugs during or just before pregnancy is difficult, the risks associated with valproic acid use should be routinely considered in choosing therapy for women with childbearing potential."

The researchers reviewed data from eight studies that highlighted 14 birth defects that were more common among offspring of women who took this epilepsy drug during the first trimester. Next, they identified infants with these 14 birth defects from the European Surveillance of Congenital Anomalies (EUROCAT) antiepileptic-study database, and compared them to a group of infants with birth defects not previously connected to use of this drug and to a group of infants with chromosomal abnormalities.

6 Birth Defects Linked to Valproic Acid

The researchers found that six birth defects were more common among children of women who took valproic acid during first trimester than children of women who did not take antiseizure drugs:

  1. Spina bifida
  2. Atrial septal defect (a hole in the heart)
  3. Cleft palate
  4. Hypospadias (an abnormality in the opening of the urethra in boys)
  5. Polydactyly (extra fingers or toes)
  6. Craniosynostosis (one or more sutures on a baby's skull close prematurely)

When compared with other epilepsy drugs, valproic acid increased the risk for all of these birth defects except craniosynostosis, the study showed. It also showed an increased risk of ventricular septal defect (a hole in the heart) when compared to other epilepsy drugs.

"These findings support a relationship of these malformations with valproic acid specifically rather than to antiepileptic drugs generally or to underlying epilepsy," the researchers write. The use of this drug is not considered a marker for more severe epilepsy, but information on the type or severity of epilepsy was not available. The new study also did not include information on the doses of valproic acid that women used during pregnancy.

"It's a phenomenal drug for seizures and bipolar illness, but I won't use it during pregnancy if I can help it," says Catherine Birndorf, MD, a reproductive psychiatrist in New York City and the founding director of the Payne Whitney Women's Program at The New York Presbyterian Hospital-Weill Cornell Medical Center in New York. Birndorf typically counsels women who take this drug to treat bipolar disorder, not epilepsy.

It all comes down to a woman's personal risk and benefit profile, she says.

"The risk of untreated illnesses are great to both the woman and fetuses, and sometimes taking this medication may be the best choice," she says. "You need to look at it on a case-by-case basis, and look at reasonable alternatives. Sometimes there are no other choices because to stay well, you must be on this specific medication at high doses."

"If you are on [valproic acid] and it's working well, don't do anything rash like going off your medication," she says. "Go to your doctor and figure out if there are safer alternatives for treating your seizure or bipolar disorder during pregnancy."

Ideally this conversation should take place before you become pregnant. "Once you are pregnant, it's a different can of worms," she says.

Counseling Women Before Pregnancy

"The study provides further verification of our concerns of valproic acid standing out as high risk for birth defects during pregnancy and [conferring a] higher risk than other medications we can choose to prescribe for treatment of epilepsy, migraine, and bipolar disorder during pregnancy," says Page B. Pennell, MD, a neurologist and the director of research in the division of epilepsy at Brigham and Women's Hospital in Boston, and the chairwoman of the professional advisory board for the Epilepsy Foundation.

The study also provides information on the specific birth defects that are increased in the offspring of women with epilepsy who took the drug during their first trimester, she says.

"It is necessary to discuss these risks with women prior to pregnancy," she tells WebMD. "I tell all my patients to try and switch to a safer medication because these birth defects can have a huge impact on a child's life."


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"It is prudent and necessary for us to try and find another medication to control epilepsy or bipolar disorder among women of childbearing age," she says. "There are several medications that we can choose from, and almost any other medication will be a safer option for the developing fetus."

The good news is that more than 90% of women with epilepsy will have normal, healthy infants, according to the Epilepsy Foundation.

Fully half of all pregnancies are unplanned, Pennell says. This conversation needs to take place as soon as a woman hits puberty and continue through all of her childbearing years.

Depakote Manufacturer Responds

Depakote is manufactured by The Abbott Laboratories in Abbott Park, Ill.

"The risk of birth defects associated with valproic acid is well known and clearly stated in Depakote's medication labeling," says Abbott spokeswoman DeAnna DuBose.

"Because both the seizures themselves and the medications used to treat those seizures pose risks, it is crucial that women who are pregnant or may become pregnant work extensively with their physicians to balance the importance of seizure control with any potential effects of epilepsy therapy," she says.

Health Solutions From Our Sponsors

Epilepsy Foundation web site.
Catherine Birndorf, MD,founding director, Payne Whitney Women's Program, The New York Presbyterian Hospital-Weill Cornell Medical Center, New York.
Page B. Pennell, MD, director of research, division of epilepsy, Brigham and Women's Hospital, Boston; chair, professional advisory board, the Epilepsy Foundation.
DeAnna DuBose, spokeswoman, Abbott Laboratories, Abbott Park, Ill.
Jentink, J. New England Journal of Medicine, 2010; vol 362: pp 2185-2193.
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