Drops in Use of Valproate Linked To Fewer Australian Birth Defects


WASHINGTON — Decreased use of valproate to manage epilepsy during pregnancy in Australia has produced a corresponding drop in fetal malformations associated with the drug, Dr. Frank Vajda said at the joint annual meeting of the American Epilepsy Society and the American Clinical Neurophysiology Society.

Dr. Vajda, a neurologist at the Victorian Epilepsy Centre in Victoria, Australia, presented the most recent data from the Australian Pregnancy Registry for Women on Antiepileptic Medication. The registry, established in 1999, has enrolled 810 women—77% of all Australian women who had taken antiepilepsy drugs (AEDs) for any reason. The 64-month data contained outcome information on 715 births.

Of the women in the registry, most who were currently taking AEDs (692) were taking the drugs for epilepsy. Other indications were bipolar disorder (11), pain (4), sleep (1), and unspecified (14). The majority of the women (504) were on AED monotherapy.

Most of the births (640) were of live infants without congenital malformations. There were 44 births with fetal malformations: 27 live births with defects, 9 live births with defects that emerged by 1 year, and 8 induced abortions of malformed fetuses. The malformations included spina bifida, anencephaly, holoprosencephaly, Dandy-Walker syndrome, and a variety of cardiac defects.

There were also 23 spontaneous abortions, one induced abortion for maternal indications, and seven stillbirths; no malformations were noted in these fetuses.

The only significant drug/defect associations occurred in women taking high doses of valproate, either as monotherapy or polytherapy. Women taking more than 1,100 mg/day of valproate as monotherapy had a 13-fold increased risk of fetal malformations, compared with women not taking any AEDs. Women taking similar doses of the drug as polytherapy had a sixfold increased risk of fetal malformations.

The rate of malformation among women taking less than 1,100 mg/day was higher than the 2%–3% that occurs in the general population, but the difference was not statistically significant.

Australian physicians appear to be heeding the data linking valproate to birth defects, Dr. Vajda said. The rate of valproate prescribing and dosages prescribed has decreased over the length of the registry, as have the rates of fetal malformation. In 1999, 26% of women on the registry were on the drug. The rate increased to 33% by 2001 and has since dropped to 21%. The average daily dose has decreased from 1,780 mg in 1999 to 936 mg in 2004.

The rate of malformation associated with valproate monotherapy was 16% before 2004, compared with 7% in 2004; the rate associated with polytherapy was 10% before 2004 and 0% in 2004.

However, he noted, the rates of malformation among women on carbamazepine or lamotrigine monotherapy have increased. For carbamazepine, the pre-2004 rate was 4.8%; it rose to 6.5% in 2004. The rate associated with lamotrigine monotherapy was 4.5% before 2004 and rose to 8.6% in 2004. The average dosages of these drugs increased from 1999–2004 as well.

“These are not regarded as significant as the numbers are,” Dr. Vajda said in an interview. “It's possible that the increases in dosing may play a part, but there are no significant data available as yet.”

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