In the United States, three to five births out of every thousand are to women with epilepsy. When neurologist Page Pennell, M.D., first began seeing patients, she was astounded by the heart-wrenching stories told by female patients of childbearing age. Many of them had heard dire warnings from healthcare providers, Dr. Pennell recalls: “Warnings like, ‘There's no way you should have children. If you do, they'll be seriously harmed by your seizures or medications.’”
“That kind of advice can deeply impact a woman's goals and dreams,” says Dr. Pennell, associate professor at Harvard Medical School, director of research in the Division of Epilepsy at Harvard's Brigham and Women's Hospital, and member of the American Academy of Neurology (AAN). “Perhaps even worse, some women aren't talked to at all about this issue.”
In truth, some antiepileptic drugs (AEDs), also called anticonvulsants or anti-seizure medications, can cause birth defects. For example, valproate (brand name Depakote, Depakene) is known for causing both developmental malformations and cognitive impairment of newborns.
Studies also show that approximately 20 to 35 percent of women experience more seizures during pregnancy. This can be due to changing hormonal levels or the way AEDs are metabolized by the body. If drug levels decrease, the mother could be at risk of seizures, which could then adversely impact her developing child.
That's why data about the safety of AEDs for pregnant women is so important. At the 2013 Annual Meeting of the AAN, Dr. Pennell presented the results of a small study showing that concentrations of the widely prescribed AED carbamazepine (Tegretol) do not change much during pregnancy—and that's good. Steady concentrations of carbamazepine during pregnancy mean less risk for seizures.
“Data collected since 1998 by multiple registries gives us very valuable information about which medicines have a low or high risk for birth defects,” says Dr. Pennell, the study's senior author, “But what the registries don't tell is how to manage medications when women with epilepsy are pregnant.”
That left her thinking about what happens to changes in medication clearance (the elimination of a drug from the body via the liver and the kidneys). “I wondered, ‘How do we monitor and balance medications at a level that will control seizures and not overexpose the developing fetus?’” Dr. Pennell says.
She and her coauthors knew that the safest and most commonly prescribed AED, lamotrigine (Lamictal), has a higher clearance rate than most—meaning it is eliminated from the body more quickly—and requires continual adjustments in dosage to prevent seizures. Lamotrigine levels should be checked at least every four weeks. That may be a problem for women who cannot afford the blood tests because they have no insurance or limited coverage, she says—or for women who have difficulty getting to a lab.
So Dr. Pennell's team decided to study carbamazepine. The drug has a low risk of birth defects, and previous studies had not determined whether blood levels of carbamazepine remain stable during pregnancy.
“This is a very common clinical issue we face in neurology. We've been studying it as a community,” says Orrin Devinsky, M.D., Fellow of the AAN, professor of neurology, neurosurgery, and psychiatry at NYU School of Medicine, and director of the NYU and Saint Barnabas Epilepsy Centers.
“Most women who have active epilepsy need to be on medication—ideally only one. And we understand they're concerned about the potential of birth defects resulting from AEDS,” Dr. Devinsky says. “For many women on medications such as lamotrigine, we obtain and monitor levels regularly, typically once a month.”
The new study provides valuable data and supports prior studies, according to Dr. Devinsky. “It appears that over the course of pregnancy, carbamazepine levels don't decline much. Interestingly, the percentage of carbamazepine that's ‘free’—not bound to protein in the blood—actually rises a bit. That component, which gets into the brain by crossing the blood-brain barrier, is what stops seizures.”
“Dr. Pennell's research shows that the important components of carbamazepine and its metabolites [what the body produces when it breaks down a drug] didn't change significantly, nor was there an increase in seizures during these pregnancies,” says Cynthia L. Harden, M.D., AAN member and chief of the Division of Epilepsy and professor of neurology at Hofstra North Shore-LIJ School of Medicine's Cushing Neuroscience Institutes in New York. Dr. Harden was lead author of the 2009 AAN Practice Parameter addressing management of women with epilepsy. (Dr. Pennell was a coauthor.)
“A low risk of birth defects, lack of significant change in blood levels, and no increase in seizures makes carbamazepine reliable and generally safe to use,” Dr. Harden says.
“Carbamazepine may be a particularly good choice for patients who can't have really close monitoring or follow-up, whether here or in other countries,” adds Dr. Pennell.
This new study, which followed 16 pregnancies of 13 women, “is only one tiny part of the work going on in this field,” Dr. Pennell says. “We need more studies with enrollment from across the United States. We need to obtain new information and share it with people.”
As an example of such research, Dr. Pennell refers to a major new multicenter trial cosponsored by the National Institute of Neurological Disorders and Stroke (NINDS) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), both within the National Institutes of Health (NIH). Its title is Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD), a project that will include Dr. Pennell and Kimford Meador, M.D., of Emory University.
Researchers will study pregnant women with epilepsy to determine whether seizure frequency or severity worsens during pregnancy and post-partum; whether caesarean-section rates increase and why; and whether risk for depression increases during pregnancy and post-partum.
The team will examine the children of women with epilepsy to find out whether in utero AED exposure causes long-term effects on verbal and intellectual abilities and other neurobehavioral outcomes; whether adverse neonatal outcomes increase; and whether breastfeeding when taking AEDs impairs verbal, intellectual, and other cognitive abilities.
“In the last decade, we've discovered so much more about which medicines are safer,” Dr. Pennell says. “We know more about how to keep seizures controlled and keep babies healthy—improving outcomes for mothers and children.”
“When a mother has epilepsy, one of the most important predictors of a healthy outcome for the child is preparation for a pregnancy months to years before conception occurs,” says Page Pennell, M.D. “This often begins with the woman proactively talking to her doctors about how to plan for the safest pregnancy possible.”
Questions that a patient should ask her neurologist include:
* To avoid an unplanned pregnancy, what types of birth control are the most effective given the antiepileptic drugs (AEDs) I'm taking?
* Should I take any vitamins or supplements during my childbearing years? Which ones? Which ones should I take during pregnancy? Do the types or amounts change?
* For my types of seizures and epilepsy, what are the safest AEDs to take during pregnancy?
* What is the safest dose to keep my seizures controlled but not increase the risk for adverse effects on my developing baby?
* Should I get a blood test now to determine the level of AEDs? Should I get tested while pregnant—and if so, how often?
* Do I need to see a specialist obstetrician, such as a high-risk or maternal fetal medicine specialist, and will you actively communicate with that doctor?
To access all of Neurology Now's articles on epilepsy, go to http://bit.ly/xMSLvd .