Kimford Meador, MD
Taking Precautions Before Pregnancy
“In keeping with the CDC recommendations to help prevent spina bifida and other birth defects, we should encourage women with epilepsy to start taking folate at menarche and to keep it up through menopause or until they have a hysterectomy or tubal ligation,” Dr. Meador said. He pointed out that half of pregnancies in the US are not planned, whether the woman is married or not. “So, if you wait for a woman to say, ‘I want to get pregnant,’ before you address AED pregnancy risks and the need for folate supplementation, you are going to miss half of the children who may be adversely affected.”
Among women with epilepsy, folate may confer additional benefits. In the Neurodevelopmental Effects of AEDs (NEAD) study, Dr. Meador and colleagues found that mean IQ was 6 points higher at age 6 in children whose mothers had taken periconceptional folate than in those whose mothers had not. Data from NEAD, a prospective, observational, multicenter study in the US and UK, have been used to assess various outcomes in children born to women with epilepsy taking carbamazepine, lamotrigine, phenytoin, or valproate monotherapy during pregnancy who were enrolled between October 1999 and February 2004.
For women who do not want to become pregnant, it is important to note that carbamazepine, phenobarbital, phenytoin, topiramate at doses greater than 200 mg, oxcarbazepine at doses greater than 1,200 mg, and other AEDs may lessen the effect of hormonal contraceptives. Some drugs, such as clonazepam, levetiracetam, and lamotrigine, do not significantly affect blood levels of hormonal contraceptive agents, Dr. Meador said. Estradiol has been shown to lower blood levels of lamotrigine, and while valproate does not appear to interact significantly with contraceptive agents, it can interact with other drugs.
Hormonal contraception may increase seizure rates significantly across all AED categories, compared with nonhormonal contraception, according to the preliminary findings of the Epilepsy Birth Control Registry. Compared with combined pills, both hormonal patch and progestin-only pills had greater risk ratios for seizure increase.
“My favorite reversible contraception for women with epilepsy is the intrauterine device, because it does not have systemic effects, and AEDs do not interfere with it,” Dr. Meador said.
AED Clearance During Pregnancy
Pregnancy appears to affect blood levels of AEDs. In a retrospective analysis of 115 pregnancies in 95 women with epilepsy, significant changes in clearance during pregnancy were observed for lamotrigine and levetiracetam, with average peak clearance increases of 191% and 207%, respectively. The investigators recommended the monitoring of serum AED concentrations in pregnant women who have epilepsy, with dosage adjustments as needed. “My approach is to assess blood levels either before pregnancy or early on, to draw blood monthly, and to maintain the blood level at the preconception level if they were seizure-free prior to pregnancy,” Dr. Meador said. “AED dosages should be adjusted within seven to 10 days after the baby is delivered to avoid toxicity, because the metabolism goes back to normal.”
Congenital Malformations
Although the majority of children born to women with epilepsy are healthy, congenital malformations associated with fetal exposure to AEDs can include heart defects, orofacial clefts, and skeletal, urologic, and neural tube defects, Dr. Meador pointed out. The European and International Registry of AEDs in Pregnancy showed an increase in malformation rates with increasing dose at the time of conception of monotherapy with carbamazepine, lamotrigine, valproic acid, and phenobarbital. Lamotrigine at doses lower than 300 mg/day and carbamazepine at doses lower than 400 mg/day had significantly lower risks of malformations than did valproic acid and phenobarbital at all investigated doses, and low-dose lamotrigine had lower risks than carbamazepine had at doses of 400 mg/day or greater.
A review of studies using the European Surveillance of Congenital Anomalies database showed a 2.6 odds ratio for spina bifida with fetal exposure to carbamazepine during the first trimester, compared with no use of an AED. The odds ratio for spina bifida after valproate exposure was 12.7, compared with no use of an AED. Fetal exposure to valproate also was associated with significantly increased odds for atrial septal defect, cleft palate, hypospadias, polydactyly, and craniosynostosis.
“We made many advances in the past 20 years in our knowledge of congenital malformations through these epilepsy registries around the world,” Dr. Meador said.
“I encourage physicians to urge women, especially those on new anticonvulsant drugs or who are on polytherapy, to join the North American AED Pregnancy Registry.”
Cognitive Defects
In the NEAD study, the mean IQ of 3-year-olds who had been exposed in utero to valproate was 9 points lower than that of children exposed in utero to lamotrigine, 7 points lower than that of children exposed in utero to phenytoin, and 6 points lower than that of children exposed in utero to carbamazepine. The association between valproate exposure and IQ was dose-dependent. “Verbal abilities were lower for valproate, compared with the other three drugs,” Dr. Meador said. “Children exposed to lamotrigine had better nonverbal abilities than those exposed to valproate, and the other two drugs had a trend in the same direction.”
At age 6, the same children who had been exposed to valproate did poorly on measures of verbal and memory abilities, compared with children exposed to the other AEDs, and on nonverbal and executive functions, compared with children exposed to lamotrigine (but not compared with children exposed to carbamazepine or phenytoin). High doses of valproate were negatively associated with IQ, verbal abilities, nonverbal abilities, memory, and executive function, but other AEDs were not. IQ at age 6 correlated with IQ at younger ages, and IQ improved with age for infants exposed to any AED.
Breastfeeding
Research has established that breastfeeding is beneficial for mother and child. “A concern has been raised that there is a risk that exposure to AEDs in breast milk might cause damage to the baby,” Dr. Meador remarked. To analyze that possibility, he and his colleagues examined data for the 42.9% of study children who were breastfed for a mean of 7.2 months. There were no differences in breastfeeding rates and duration between drugs. Although more study is needed to fully delineate the effects of all AEDs, the adjusted IQ was 4 points higher at age 6 for breastfed children than for children who were not breastfed, and verbal abilities were greater, as well.
—Adriene Marshall
