GAINESVILLE, Fla. -- When it comes to antiepileptic drugs for pregnant women with epilepsy, Depakote (valproate) should be at the bottom of the list, researchers here reported.
GAINSESVILLE, Fla., Aug. 8 -- When it comes to antiepileptic drugs for pregnant women with epilepsy, Depakote (valproate) should be at the bottom of the list, according to the Neurodevelopmental Effects of Antiepileptic Drugs study group.
Major congenital malformations and fetal deaths were significantly more common in pregnancies of women taking Depakote compared with other antiepileptic drugs, and the effect of Depakote was dose-dependent, Kimford J. Meador, M.D., and colleagues, reported in the Aug, 8 issue of Neurology.
The findings come from a prospective observational study comparing Depakote monotherapy in pregnant women with Lamictal (lamotrigine), Tegretol (carbamazepine), and Dilantin (phenytoin).
The study was performed because pregnancy outcomes following in utero exposure to antiepileptic drugs are uncertain, leaving clinicians with no evidence-based approach to selection of these drugs for pregnant women.
"These results combined with several recent studies provide strong evidence that valproate poses the highest risk to the fetus," the investigators wrote. "For women who fail other antiepileptic drugs and require valproate, the dose should be limited if possible."
Of the agents studied, the four most commonly used antiepileptic drugs, Lamictal appeared to pose the lowest risk to the fetus, but this finding has not been seen in other studies, and needs to be confirmed through additional studies, the authors noted.
The report was part of an ongoing prospective observational study at 25 epilepsy centers in the United States and United Kingdom. The study was designed to determine whether there are differential long-term cognitive and behavioral neurodevelopmental effects for the offspring of pregnant women with epilepsy.
The investigators looked at a total of 333 mother and child pairs for in utero exposures to monotherapy with either Tegretol (110 pairs), Lamictal (98 pairs) Dilantin (56 pairs), or Depakote (69 pairs).
The outcomes of pregnancies for all women in the study were monitored, and the principal investigators at each of the centers reviewed and classified adverse events. A board-certified medical geneticist was consulted to determine whether major malformations in the fetuses or infants could be attributable to antiepileptic drugs.
The authors also controlled for a variety of potentially confounding factors, including maternal IQ, education, race, seizure type and frequency, antiepileptic drug dosages and compliance, and socioeconomic status.
They also controlled for use of folate prior to conception; use of tobacco, alcohol or other drugs during pregnancy; history of prior pregnancy abnormalities, complications during current pregnancy, gestational age at enrollment, and birth weight.
They found that 20.3% of women taking Depakote had pregnancies with serious adverse outcomes, compared with 10.7% of those taking Dilantin, 8.2% of those on Tegretol, and 1.0% of those on Lamictal.
The distribution of serious adverse outcomes differed significantly across the agents studied, and could only be explained by differences in in utero exposure, the investigators reported.
There were 12 serious adverse events in the Depakote group, including brachycephaly, coarctation of the aorta, hypoplastic right heart, atrial septal defects, hydronephrosis, undescended testes, hypospadias, cleft palate, dysplastic ribs, hand malformations, and pulmonary stenosis.
Tegretol was associated with five adverse vents, including absent kidney, duplicate renal pelvis, two cases of hypospadias, and an inguinal hernia. The hypospadias and hernia required surgical repair.
There were four adverse events in the Dilantin group, including agenesis of the corpus callosum, ventricular septal defect, hydronephrosis with extra renal pelvis, and undescended testicle requiring surgery.
The single event occurring in patients in the Lamictal group was a ventricular septal defect.
The investigators found that there was a dose-dependent effect of Depakote on total serious adverse outcomes.
"The rate of serious adverse outcomes was 24.2% for valproate when doses were at or above the median first trimester dose (i.e., 900 mg/day) and was 9.1% for doses below the median," they wrote. "The mean (range) dose for those with serious adverse outcomes was 1,268 mg/day (200 to 2,750 mg/day) and for those without malformations was 844 mg/day (200 to 2,000 mg/day)."
The findings suggest that pregnant women with epilepsy should be maintained whenever possible on antiepileptic drugs other than Depakote, or if their seizures are controlled only on Depakote, that they take the lowest possible effective dose, the investigators recommended.