AAN 2009: New Guidelines Released on Pregnancy with Epilepsy

Allison Gandey

April 28, 2009

April 28, 2009 (Seattle, Washington) — New guidelines confirm that pregnancy is relatively safe for women with epilepsy, but panelists say the antiepileptic valproate should be avoided if possible.

The 3 practice-parameter documents, each focusing on a different aspect of pregnancy in women with epilepsy, were developed by the American Academy of Neurology (AAN) and the American Epilepsy Society. Unveiled Monday at the AAN's 61st Annual Meeting, the work is also published online in Neurology. A 20-member committee including general neurologists, epileptologists, and doctors in pharmacy evaluated available evidence.

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Drs. Cynthia L Harden, Gary S Gronseth, and Jennifer L Hopp at a press briefing

"Overall, what we found should be very reassuring," said lead author Cynthia Harden, MD, from the University of Miami's Miller School of Medicine, in Florida, told reporters attending a press briefing. "Counter to previous dogma, women with epilepsy are not at a substantially increased risk for cesarean section, late pregnancy bleeding, or premature contractions or delivery. Also, if a woman is seizure-free 9 months before she becomes pregnant, it's very likely that she will continue to remain seizure-free throughout the pregnancy."

However, their review of the effects of various antiepileptic drugs on pregnancy outcomes, particularly valproate, reached conclusions similar to other data recently reported. In the April 16 issue of the New England Journal of Medicine, investigators showed new 3-year cognitive-outcome results (Meador KJ et al. N Engl J Med. 2009;360:1597-605). The work is part of the ongoing Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study. Led by Kimford Meador, MD, from Emory University, in Atlanta, researchers concluded that valproate should not be used first line in women who may become pregnant.

Dr. Harden praised the work, calling it, "great science." She says the literature review that provided the basis of the new practice parameters did not include these latest findings, but their committee came to a similar conclusion.

"Valproate increases the risk of birth defects and may impair cognitive development," panelist Gary Gronseth, MD, from the Kansas University Medical Center, in Kansas City, told Medscape Neurology & Neurosurgery. He says the evidence suggests that valproate should be avoided if possible. "But for some patients it may not be possible," he noted, "so it's hard to make an absolute recommendation, and things really have to be individualized based on how the patient responds."

The guidelines also suggest that, if possible, women with epilepsy should not take more than 1 drug at a time during pregnancy. Panelists report that taking multiple antiepileptics may also increase the risk for birth defects and impair cognitive development.

A relationship between treatment dose and the risk of complications may also exist, and the guidelines suggest that limiting doses may help.

Teratogenicity of Antiepileptic Drugs

Antiepileptic Major Congenital Malformations Cognitive Impairment Birth Defects
Valproate Substantial risk Likely Neural tube, facial clefts, and possibly hypospadias
Carbamazepine Likely no substantial risk Probably not Posterior cleft palate
Lamotrigine Possibly no substantial risk Probably not Not mentioned
Phenobarbital Not mentioned Possibly Possible cardiac malformations
Phenytoin Possibly no substantial risk Possibly Cleft palate

For many antiepileptic drugs — especially newer products — Dr. Gronseth said there were too few patients in the studies to make conclusions and the teratogenicity of these drugs remains unknown.

Once a patient is pregnant, the committee suggests that changing from valproate several weeks into gestation will not avoid the risk for major congenital malformations, since this phenomenon occurs very early in pregnancy. This may also apply to cognitive impairment, since the timing of exposure related to this adverse outcome is unknown. Instead, women should plan pregnancies if possible and try to adjust their medications prior to becoming pregnant.

Many antiepileptic drugs cross through the placenta or into breast milk in measurable concentrations. The panel reports that the clinical consequences for the newborn of ingesting medication through breast milk "remain sorely underexplored."

Pregnancy may change the level of medication or increase clearance. The guidelines suggest that physicians consider monitoring patients on all antiepileptic drugs, but especially those on lamotrigine, carbamazepine, or phenytoin.

Drugs That Cross Through the Placenta or Into Breast Milk

Antiepileptic Crosses the Placenta Transfers to Breast Milk Pregnancy Changes Level of Medication
Valproate Probably Not significant Unknown
Carbamazepine Probably Not significant Somewhat
Lamotrigine Maybe Yes Yes
Phenobarbital Probably Not significant Unknown
Phenytoin Probably Not significant Yes
Primidone Probably Yes Unknown
Levetiracetam Probably Yes Possibly
Gabapentin Maybe Yes Not mentioned
Oxcarbazepine Maybe Not mentioned Possibly
Topiramate Maybe Yes Not mentioned
Ethosuximide Insufficient data Not mentioned Unknown

During the press briefing, Dr. Harden emphasized that patients should not abruptly discontinue medication. Most women with epilepsy need to continue taking medication during pregnancy because uncontrolled seizures can be harmful.

Women on antiepileptic drugs have an increased risk of having babies who are small for gestational age. The babies also have an increased risk of having a 1-minute Apgar score greater than 7.

Perinatal Outcomes of Women on Antiepileptics

Outcome Risk
Small for gestational age About double
1-min Apgar score < 7 About double
Perinatal death Not substantial

The guidelines do not include information on other perinatal outcomes such as respiratory distress, intrauterine growth retardation, and neonatal intensive-care-unit admission because of inadequate data.

"Preconceptional folic-acid supplementation may be effective in preventing major congenital malformations," said Jennifer Hopp, MD, from the University of Maryland, in Baltimore.

The guidelines suggest supplementing women with epilepsy with at least 0.4 mg of folic acid before they become pregnant.

It is estimated that about half a million women with epilepsy in the United States are of childbearing age and that about 4 out of every 1000 births are to women with epilepsy.

"For too long, women living with epilepsy have feared the added risk of premature birth and other consequences of both their epilepsy and their medications," Howard Soule, PhD, chief science officer for the Milken Family Foundation, in Santa Monica, California, said in a news release. "The results of this project will help relieve the worries of these women and their families."

The guidelines were funded in part by the Milken Family Foundation. Dr. Harden reports having financial ties to Cyberonics, GlaxoSmithKline, UCB Pharma, Valeant, SK Pharmaceuticals, Abbott, Forest, and Ortho McNeil. Dr. Gronseth is on the speakers' bureau of Boehringer-Ingelheim. Dr. Jennifer Hopp has given testimony in a medicolegal case.

Neurology. Published online before print April 27, 2009.