New Antiepileptic Drugs May Not Increase Birth Defect Risk

Allison Gandey

May 17, 2011 — Registry data of more than 800,000 births suggest new antiepileptic drugs do not increase the risk for major birth defects.

"Our study is not definitive in any sense concerning the safety of newer-generation antiepileptics," lead study author Ditte Mølgaard-Nielsen, MSc, from the Statens Serum Institut in Copenhagen, Denmark, told Medscape Medical News, "but it adds to the knowledge available where more knowledge is very much needed."

The Danish nationwide study suggests that first-trimester exposure to lamotrigine, oxcarbazepine, topiramate, gabapentin, or levetiracetam compared favorably with no exposure.

Antiepileptic drugs.

The results are published in the May 18 issue of the Journal of the American Medical Association.

The researchers report the prevalence of antiepileptic drug use in pregnant women is 0.2% to 0.5%. Although most take these medications for epilepsy, others have prescriptions for the treatment of bipolar mood disorders, migraine, and neuropathic pain syndrome.

Older-generation antiepileptic drugs, such as valproate, phenobarbital, phenytoin, and carbamazepine, have been associated with an approximately 3-fold increased risk for birth defects.

In this study, investigators identified 1532 pregnant women exposed to new antiepileptic drugs. Of these, 3.2% of infants were born with birth defects compared with 2.4% with no antiepileptic drug exposure.

Unadjusted estimates showed a significant association between most new antiepileptic drugs and birth defects, the study authors point out. However, after adjusting for previous use of older-generation antiepileptic drug use and epilepsy, no association remained.

Table. Prevalence Odds Ratio of Major Birth Defects

The investigators report that risk estimates could not be calculated for levetiracetam due to a lack of cases.

Lamotrigine was the most commonly prescribed antiepileptic drug. Investigators found the risk with high-dose lamotrigine was greater than with low-dose treatment.

Pregnant women taking 250 mg per day or more had a 1.73 odds ratio of having an infant with a major birth defect. The 95% confidence interval was 1.21 to 2.48. The adjusted ratio was 1.29 with a confidence interval of 0.88 to 1.90. Patients taking lower doses of lamotrigine had an adjusted odds ratio of 0.84 with a confidence interval of 0.39 to 1.82.

Asked by Medscape Medical News to comment on the findings, Kimford Meador, MD, lead investigator of the ongoing Neurodevelopmental Effects of Antiepileptic Drugs study, complimented the national registry analysis that adjusted for confounding factors and had a large sample size for lamotrigine.

"The percentage of birth defects listed for lamotrigine is likely higher than it would be for monotherapy as both polytherapy and monotherapy appear to be included in their estimate," he said.

Dr. Meador, from Emory University in Atlanta, Georgia, was less enthusiastic about the numbers for the other antiepileptic drugs. "The information is encouraging, but the sample sizes are too small to be definitive. It is not clear that the association of maternal epilepsy with birth defects is not confounded by antiepileptic drug dose since the treatment of epilepsy usually employs higher doses overall than migraine, pain, and psychiatric indications."

Like all previous studies, Dr. Meador pointed out, no blood levels were taken. "The marked individual variability in metabolic changes during pregnancy could obscure teratogenic dose effects."

Still, he said, "the findings add to our knowledge base."

This study was funded by the Danish Medical Research Council and the Lundbeck Foundation. The researchers have disclosed no relevant financial relationships.

JAMA. 2011;305:1996-2002. Abstract