(19-07-11) Antiepileptic Drugs and Risk for Major Birth Defects: Three Studies, Varied Findings

Despite methodological distinctions, results suggest that low-dose monotherapy is an ideal goal during pregnancy.
Major congenital malformations (MCMs) are of concern to clinicians who prescribe antiepileptic drugs to women of reproductive age. Three recent studies of antiepileptic drug therapy during pregnancy have yielded varying results about the risks and benefits of these agents.
In the manufacturer-sponsored International Lamotrigine Pregnancy Registry study (recruitment, 1992?2009), women (65% from the U.S.) voluntarily enrolled ? preferably early during pregnancy ? through their clinicians, who provided information about pregnancy outcomes. Earliest exposure occurred during the first trimester in most pregnancies. MCMs were reported in 2.2% of infants born to women who received lamotrigine monotherapy, 10.7% of offspring of women who received lamotrigine plus valproic acid, and 2.8% of children born to women who received lamotrigine plus an antiepileptic drug other than valproic acid. No dose-response was found for lamotrigine monotherapy.
The industry-supported European and International Registry of Antiepileptic Drugs in Pregnancy (EURAP; recruitment, 1999?present) includes patients who receive antiepileptic drugs for any indication within 16 weeks' gestational age. Researchers assessed prevalence of MCMs within 12 months after birth in offspring of women who received various doses of carbamazepine, lamotrigine, valproic acid, or phenobarbital monotherapy. The association with MCMs was dose-dependent for each antiepileptic drug. For <300-mg lamotrigine daily, the MCM rate was 2.0% (similar to that in the general population); for doses 300 mg daily, the MCM rate was 4.5%. For the lowest and highest doses of other antiepileptic drugs, MCM rates were 5.6% vs. 24.2% (valproic acid), 3.4% vs. 8.7% (carbamazepine), and 5.4% vs. 13.7% (phenobarbital).
In the third study, researchers evaluated outcomes of all live births in Denmark from January 1996 through September 2008 to determine whether first-trimester monotherapy with one of five newer antiepileptic drugs (lamotrigine, oxcarbazepine, topiramate, gabapentin, and levetiracetam) was associated with excess risk for MCMs. Major malformations were identified in 2.4% of the general population and in 3.2% of offspring exposed to any of these antiepileptic drugs, yielding an unadjusted odds ratio of 1.35. In analysis that accounted for maternal epilepsy and use of older antiepileptic drugs, the adjusted OR was 0.99. Rates of major birth defects were 4.6% with topiramate, 3.7% with lamotrigine, 2.8% with oxcarbazepine, 1.7% with gabapentin, and 0% with levetiracetam.
Comment: Studies of major congenital malformations associated with drug therapy must be interpreted cautiously because participant recruitment, inclusion, and exclusion can create bias. These three studies differed in recruitment (voluntary or population-based), maternal confounders (e.g., comorbid medical conditions, other medications), duration of follow-up, and presence of appropriate controls. Loss to follow-up was substantial in the lamotrigine study (28.5%), and EURAP excluded 15.4% of patients for reasons such as use of other teratogenic drugs. Maternal folate intake was not studied in the lamotrigine or Danish studies. Lastly, although the EURAP study included information on seizures during pregnancy, types of seizure activity were not specified. Despite these methodological distinctions, the studies collectively suggest that low-dose monotherapy is an ideal goal for antiepileptic therapy during pregnancy. Lamotrigine (studied in the largest number of pregnant women) is consistently associated with MCM rates of 2% to 4%. Higher MCM rates result from use of valproic acid, which now carries an FDA safety alert about cognitive effects in offspring; therefore, this agent should be avoided in women of reproductive age without concomitant highly effective contraception.
? Autumn Klein, MD, PhD
Dr. Klein is an Assistant Professor of Neurology and Obstetrics/Gynecology and Chief, Division of Women's Neurology, University of Pittsburgh Medical Center-Presbyterian and Magee Women's Hospital.

Source: Published in Journal Watch Women's Health July 14, 2011

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