"During pregnancy in women with epilepsy, lower blood concentrations of antiseizure medications can have adverse clinical consequences," they write in JAMA Neurology.
"We found that, during pregnancy, the concentrations of almost all anti-seizure medications (ASMs) will drop significantly if no dose adjustments are made," Dr. Page B. Pennell of the University of Pittsburgh School of Medicine, in Pennsylvania, told Reuters Health by email.
Dr. Pennell and her colleagues conducted the prospective, observational MONEAD study over slightly more than three years at 20 U.S. sites to investigate pregnancy-associated concentration changes for several antiseizure medications in women with epilepsy.
They enrolled pregnant women with epilepsy and nonpregnant women with epilepsy as controls. Participants were between 14 and 45 years of age with an intelligence quotient over 70, and, for the pregnant women, a fetal gestational age of less than 20 weeks. The median age among the 326 pregnant women and the 104 controls was 29 years.
The women had their blood drawn during four pregnancy study visits and three postpartum visits for the pregnant women, and seven visits over 18 months for control participants. The researchers calculated dose-normalized concentrations as total or unbound plasma medication concentrations divided by total daily dose.
They monitored medication plasma concentrations in women taking monotherapy or in combination with noninteracting medications. The pregnant women were monitored through nine months after delivery, with similar time points for the controls.
Women with epilepsy taking lamotrigine, levetiracetam, lacosamide, oxcarbazepine, and zonisamide experienced significant decreases in dose-normalized concentrations during pregnancy.
Compared with postpartum values, dose-normalized concentrations during pregnancy were decreased by up to 56% for lamotrigine (P<0.001), 37% for levetiracetam (P<0.001), 40% for lacosamide (P<0.001), 33% for oxcarbazepine (P<0.001), and 30% for zonisamide (P<0.001), 31% for unbound oxcarbazepine (P<0.001), and 17% for carbamazepine (P=0.03).
No significant changes were detected for topiramate or unbound carbamazepine (or the metabolite carbamazepine-10,11- epoxide). However, a "markedly lower median value in the third trimester compared with the nonpregnant postpartum period" for topiramate "suggests potential clinical relevance and should be examined further," the researchers say.
Compared with dose-normalized concentrations in controls, pregnancy dose-normalized median concentrations dropped markedly by week of gestational age.
"Epilepsy is one of the few disorders in which it is imperative to maintain an individualized target serum concentration to prevent seizure worsening, while avoiding unnecessary over-exposure to the fetus during development," Dr. Pennell said. "Findings from this study provide support for performing therapeutic-drug monitoring for most ASMs and for beginning it early in pregnancy prior to marked weight gain."
"Because MONEAD enrollment could occur up to 20 weeks gestational age, we were not able to optimally characterize first trimester changes in dose-normalized concentrations, especially for the ASMs without large sample sizes," she noted.
Dr. Patrick S. Ramsey, a professor obstetrics and gynecology and chief of the Division of Maternal-Fetal Medicine at the University of Texas Health Science Center at San Antonio, told Reuters Health by email, "The literature has limited data on the pharmacokinetics of commonly used medications in pregnancy. This study provided important information related to pharmacology and pharmacokinetics of anti-seizure medications to inform care for women with seizure disorders in pregnancy."
"Strengths of the study are the large number of women on anti-seizure medications evaluated in a very systematic way with repetitive evaluation of drug levels throughout pregnancy and postpartum, and the comparison to non-pregnant women," said Dr. Ramsey, who was not involved in the study. "The main weakness of the study is that they looked only at levels of anti-seizure medications and did not correlate that with seizure control, which ultimately is the goal of therapy."
Dr. Jacob Pellinen, an assistant professor of neurology and the co-director of Continuous EEG at University of Colorado Medicine in Aurora, said, "This is the largest study of its kind and provides extensive information on the pharmacokinetics of antiseizure drugs during pregnancy. It provides valuable data on a broader range of medications than prior studies, which is crucial information for clinicians who may be managing a variety of medications and need to balance seizure risk and medication safety."
"It's important for clinicians who are caring for women with epilepsy to be aware that pregnancy can have a large impact on the blood levels of antiseizure medications, even in the first trimester," Dr. Pellinen, who also was not involved in the study, told Reuters Health by email. "Seizures pose a significant danger during pregnancy, and antiseizure medications are associated with potential risks, so it is important to have information to guide clinical decision-making and optimize maternal and child health."
The authors are planning further related research.
The study did not receive commercial funding.
SOURCE: https://bit.ly/3gNRnq3 JAMA Neurology, online February 14, 2022.
By Lorraine L. Janeczko
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