June 10, 2010 -- Using the antiseizure medication valproic acid (Depakote) in the first trimester of pregnancy significantly increased the risk of six types of birth defect, European researchers found.
In an analysis of more than 98,000 pregnancies, the risk of the serious spinal defect known as spina bifida was increased more than 12 times for children of mothers on the drug, according to Lolkje T.W. de Jong-van den Berg, of the University of Groningen in the Netherlands and colleagues.
The risks of another five defects were increased between two and seven times, the researchers reported in the June 10 issue of the New England Journal of Medicine.
Those findings support recommendations by the American Academy of Neurology to avoid the use of the drug in pregnancy, the researchers wrote. In the clinic, they continued, the risks of birth defects associated with valproic acid should be routinely considered in women of childbearing age.
Looking at past studies and comparing them against an antiepileptic-study database set up by the European Surveillance of Congenital Anomalies (EUROCAT), the researchers found that six malformations were significantly linked to a woman's valproic acid use in her first trimester of pregnancy. In addition to spina bifida, the children of these women faced a more than doubled risk of a heart condition known as an atrial septal defect and a five-fold risk of cleft palate.
The risk of hypospadias -- a condition in which the opening of the urethra in boys is on the underside of the penis rather than the end -- went up nearly five times with a mother's use of the drug. Craniosynostosis, a condition in which the bones of the skull close too early, was nearly seven times as common in these children, and polydactyly, a condition in which a child has more than five fingers per hand, was more than twice as common.
On the other hand, the researchers found, absolute risks of malformations remained low, ranging from 0.1 percent for craniosynostosis to 0.7 percent for hypospadias. The absolute risk for spina bifida associated with valproic acid was 0.6 percent, they found.
The researchers also cautioned that the study was observational, so it could not indicate anything about cause and effect. They were also unable to say anything about possible confounding by indication, since the drug is used for several clinical indications, or the effects of varying dosages.