SEATTLE—Updated guidelines regarding the management of pregnancy issues in women with epilepsy, including the safety of antiepileptic drugs (AEDs), were presented at the 61st Annual Meeting of the American Academy of Neurology. Three separate practice parameters address the obstetric complications and changes in seizure frequency; teratogenesis and perinatal outcomes; and vitamin K, folic acid, blood levels, and breastfeeding. The guidelines, developed in collaboration with the American Epilepsy Society, were published in the April 27 online Neurology and the May Epilepsia.
The new guidelines are an update of the original version from 1998 and include data from the North American, European, United Kingdom, and Australian pregnancy registries. Cynthia Harden, MD, Gary Gronseth, MD, and Jennifer Hopp, MD, spoke about the recommendations for each practice parameter.
Obstetric Complications and Change in Seizure Frequency
A 20-member committee of neurologists, epileptologists, and doctors in pharmacy performed a literature search using MEDLINE, MEDLINE-In-Process, Current Contents, Biologic Abstracts, and BIOSIS for relevant articles published between 1985 and February 2008. Articles that determined the frequency of pregnancy- or epilepsy-related complications in a cohort of pregnant women with epilepsy were included in the analysis. Dr. Harden, who is the Director of the International Comprehensive Epilepsy Center at the University of Miami’s Miller School of Medicine, reported that women with epilepsy who are taking AEDs do not have a significantly increased risk of late-pregnancy bleeding or cesarean delivery, although a moderately increased risk (up to 1.5 times expected) was shown. A moderately increased risk for premature contractions, as well as premature labor and delivery, was not seen, although a substantial increase is possible for women who smoke.
“The findings strongly support that if a woman is seizure-free for a period of time—nine months to one year prior to becoming pregnant—it’s very likely that she will continue to remain seizure-free throughout the pregnancy (84% to 92%),” added Dr. Harden.
“Some of the most important findings of this practice parameter are what they do not demonstrate,” Dr. Harden and coauthors stated. “There was no conclusive evidence of an increased risk of many obstetrical complications often discussed as associated with women with epilepsy during pregnancy. This raises the possibility that there is no true difference in the rates of obstetrical complications in women with epilepsy compared to the general population.”
Teratogenesis and Perinatal Outcomes
To reevaluate management issues for the care of women with epilepsy during pregnancy, Dr. Harden and colleagues reviewed all relevant articles that were published between January 1985 and June 2007. Evidence suggests that if possible, valproate and AED polytherapy should be avoided during the first trimester to decrease the risk for major congenital malformations, as well as throughout the entire pregnancy. to prevent poor cognitive outcomes. The authors noted that valproic acid was associated with a 10-point decrease in verbal IQ.
Dr. Harden and colleagues reported that the risk for major congenital malformations is higher with valproate than with carbamazepine. Valproate has been associated with an increased risk for neural tube defects, facial clefts, hypospadias, and spina bifida. These associations were observed when valproate was used as either monotherapy or polytherapy.
The authors are unsure of why valproate is more dangerous than other AEDs; however, valproate is one of the only medications that causes neuronal apoptosis in neonatal rats. “I think that may be a key to the mechanism, but things are always more complicated in science than they initially seem to be, so I really think this is just a clue, maybe a hint, but there may be other mechanisms,” Dr. Harden said.
“One of the other findings to emphasize is that for a lot of the new antiepileptic medications, although evidence is being gathered, there’s not a lot of evidence to be able to tell us that they are safe or harmful, although hopefully we’ll have more evidence for that in the future,” commented Dr. Gronseth, Associate Professor and Vice Chairman at the University of Kansas Medical Center.
At this time, women who are taking valproate and planning to become pregnant should consider, with the guidance of their physician, changing to another antiseizure medication to avoid the risks of malformations and adverse cognitive outcomes. “This is a difficult clinical situation, but it can be navigated, and it should be undertaken at least six months before pregnancy to try to taper off valproate and onto another medicine,” said Dr. Harden.
“There is a lot of clinical judgment that has to go on for that decision, and for some women with epilepsy, there’s no choice if valproate is the only drug that really seems to work,” Dr. Gronseth added. “They will have to balance that risk with the potential risk of the patient’s seizures becoming uncontrolled.”