WEDNESDAY, June 9 (HealthDay News) -- The offspring of women who took the epilepsy drug valproic acid during the first trimester of pregnancy are much more likely to have serious births defects affecting the brain, heart and limbs, a new study finds.

Babies whose mothers took valproic acid during the first trimester were 12.7 times more likely to have spina bifida, in which the spinal cord and backbone fail to develop or close properly, compared to babies whose mothers did not take the drug.

Babies whose mothers took valproic acid were also 2.5 times more likely to have an atrial septal defect (a heart defect); about five times as likely to have a cleft palate (a defect of the upper lip and roof of the mouth) or hypospadias (a penis abnormality); more than twice as likely to be born with an extra digit on the hand (polydactyly); and nearly seven times more likely to have craniosynostosis (premature fusion of the skull during fetal development that restricts skull and brain growth).

While valproic acid (brand names include Depakene and Depakote) was associated with a higher relative risk of the six birth defects, the absolute risk of having a baby with any of the defects remains small, the researchers noted. For example, the risk of having a baby with spina bifida was 0.6 percent, or six in 1,000, among women who took the drug compared to five in 1,000 of babies born to mothers who didn't take any epilepsy medication.

Yet given mounting evidence of the risks of valproic acid to fetuses, researchers urged women of childbearing age to try other drugs to control their seizures.

"These findings provide further evidence to avoid valproic acid, if possible, in pregnant women and [for doctors] to discuss with girls and women of childbearing potential the risk of the drug for the unborn child," said senior study author Lolkje T.W. de Jong-van den Berg, of the University of Groningen in the Netherlands.

Dr. Kimford Meador, a professor of neurology at Emory University in Atlanta, echoed that warning.

"This drug should not be used as a first-line drug for epilepsy in women of childbearing age," Meador said. "There are multiple types of malformations that can be associated with valproic acid."

The review is published in the June 10 issue of the New England Journal of Medicine.

In the review, researchers first looked at eight studies that included nearly 1,600 births and identified some 14 birth defects that seemed to be much more common among the children of women who took valproic acid early in pregnancy.

Researchers then took that information and analyzed data from a large European study that included nearly 4 million births and 98,000 birth defects. They found women who took valproic acid in early pregnancy had two to 12 times the risk of having a baby with one of six specific birth defects compared to women who took no epilepsy drugs. The findings were similar when birth defect rates among those taking valproic acid were compared to the rates for women who took other epilepsy drugs, leading researchers to conclude it was the valproic acid, not some other epilepsy drug, that was to blame.

Among those who took valproic acid during early pregnancy, the chances of having a baby with any of the defects was less than 1 percent -- cleft palate (0.3 percent), hypospadias (0.7 percent), polydactyly (0.2 percent), craniosynostosis (0.1 percent).

Previous research has also linked valproic acid to spina bifida, other birth defects and cognitive problems in children, Meador noted. In April 2009, Meador was the lead author of a study that appeared in the New England Journal of Medicine that linked exposure to valproic acid in the womb to lower IQ scores in children at age 3.

The American Academy of Neurology recommends avoiding the use of valproic acid in pregnant women, according to background information in the article. Yet since up to half of pregnancies are unplanned, according to the study, all women of childbearing age should be warned about the dangers, researchers said.

Despite such concerns, valproic acid is often still prescribed, Meador said. In 2006, valproic acid was the second most commonly prescribed epilepsy drug, he noted.

Valproic acid is also prescribed to prevent migraines and for bipolar disorder, he added.

Despite the risks, valproic acid can be a very effective drug and may be the best choice for some patients whose seizures are not well-controlled by other medications, Meador said.

More information

The National Institute of Neurological Disorders and Stroke has more on epilepsy.