Just the Right Dose: Antiepileptic Drug Clearance Changes Early in Pregnancy

Young pregnant woman with doctor in ambulance.New research from Brigham and Women’s experts in women’s epilepsy provides guidance on whether and when effectiveness of antiepileptic drugs (AEDs) may be altered by the metabolic changes of pregnancy. The results suggest a need for therapeutic drug monitoring as soon as pregnancy is known.

This research reflects the work of the  Women’s Epilepsy Program  at Brigham and Women’s Hospital, one of the largest such programs in the United States. Its clinical care and research focus on the impact of female hormones on epilepsy and on helping women achieve healthy pregnancies.

The study investigated drug clearance of five commonly used AEDs. Results showed that for levetiracetam (one of the two most commonly-used AEDs during pregnancy), clearance significantly changes by the first trimester and remains elevated during the second and third trimesters. For oxcarbazepine and topiramate, clearance was elevated by the second trimester. The study was published in Neurology.

“For clinicians who manage women on levetiracetam, this is important information, as they may opt to begin therapeutic drug monitoring as early as possible in pregnancy,” said lead author P. Emanuela Voinescu, MD, PhD, associate neurologist in the Brigham’s Department of Neurology. “We demonstrate clearance changes early in the first trimester, with an estimated increase to 1.42 to 2.02-fold baseline clearance.”

In recent decades, the practice of discouraging pregnancy for women with epilepsy has shifted as researchers zeroed in on the therapeutic index of AEDs that could control seizures without endangering the developing fetus. Early work on managing AEDs through pregnancy, including that of  Page Pennell, MD, director of research for the Brigham’s Division of Epilepsy, resulted in 2009 guidelines from the American Academy of Neurology and the American Epilepsy Society.

“Now that we have a number of medications being used more in pregnancy, we still have questions of how to manage these medications in pregnancy,” said Dr. Pennell, senior author of the new study, which she began while at Emory University. “And it’s clear from this recent paper that changes in drug clearance start right away in pregnancy.” Pennell is a member of the committee that will soon update the 2009 guidelines.

Integrating Care at the Women’s Epilepsy Program

Drs. Voinescu and Pennell see patients at the Women’s Epilepsy Program. Care includes contraceptive needs and preparing for pregnancy with optimal medication and vitamin regimens. Once pregnant, women receive closely integrated epilepsy and obstetrical care. Neurologists and high-risk obstetricians have coordinated their Epilepsy-Pregnancy Clinics so women can see both specialists in one day, sometimes together with ultrasound and genetic counseling appointments.

AED dosage levels are measured via the monthly blood draw at the OB visit. The neurologists receive the results and recommend dosage changes. With the new data from the recent study, “we want those results very early in pregnancy,” said Dr. Voinescu. “It’s too late if you adjust meds only when the woman starts gaining weight.”

Any new, pregnant patient in the program is seen within a week, to gain the earliest advantage in adjusting medications and addressing nutrition and other needs.

An Epilepsy-Pregnancy clinic follows patients through six postpartum weeks, providing newborn medicine expertise on breast feeding and other care. Then patients return to their community neurologist. Over the past five years, the Program has cared for 198 patients through 248 pregnancies.

Other ongoing pregnancy-related research at the Women’s Epilepsy Program includes:

  • The Brigham is one 3 leading lead sites in the 10-year, 20-site MONEAD study that is measuring maternal outcomes and neurodevelopment effects of antiepileptic drugs. Now in its 6th year, the study is intended to help women and their clinicians make well-informed choices about medications and dosages during pregnancy to keep the mother’s seizures controlled without adversely effecting on the fetal neurodevelopment.
  • Recent work showing dramatic drug clearance during pregnancy has led to the question of whether a genetic driver is responsible, which Dr. Voinescu is now studying through an award from the Women’s Brain Initiative at the Brigham.

Brigham and Women’s Hospital is affiliated with the North American Antiepileptic Drug Pregnancy Registry, the largest US research program to date aimed at identifying the safest drugs for pregnant women with epilepsy and their unborn babies.

To refer a patient for an appointment with one of our specialists at the Women’s Epilepsy Program, please contact us at 617-732-7432.

 

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