Seizure Drug Levels Plunge in Pregnancy, Chinese Study Warns

Women with epilepsy who take newer antiseizure medications during pregnancy may face a hidden risk: their blood levels of two widely prescribed drugs, levetiracetam and lamotrigine, fall sharply as gestation progresses, according to a prospective and retrospective study of Han Chinese women published in Acta Epileptologica. The research, led by Nanya Hao, Xiaoli Yi, Renjie Zhao, Xuechen Zhang, Jianxia Dong and Dong Zhou at West China Hospital of Sichuan University, tracked the apparent oral clearance of levetiracetam, oxcarbazepine and lamotrigine across every trimester and linked declining concentrations to worsening seizure control. The findings add ethnicity-specific pharmacokinetic data to a field long dominated by European and American cohorts, and they point toward earlier therapeutic drug monitoring for pregnant patients.

Epilepsy is one of the most prevalent neurological disorders, and managing it during pregnancy is clinically difficult. Uncontrolled seizures during gestation can lead to blunt trauma, hypoxemia, metabolic acidosis and spontaneous abortion, threatening both mother and fetus. At the same time, antenatal exposure to antiseizure medications carries teratogenic risk, and a dose-dependent increase in malformation rates has been observed across most investigated agents, including carbamazepine, lamotrigine and valproate. Treatment therefore demands a delicate balance: enough drug to protect the mother from seizures, but not so much that fetal exposure rises unnecessarily. That balance is complicated by the profound physiological changes of pregnancy, which include expanded serum volume, elevated renal blood flow, modified hepatic enzyme activity and dynamic fluctuations of reproductive hormones such as estrogen and progesterone, all of which alter how the body handles medication.

The study enrolled 52 pregnant women with epilepsy from West China Hospital of Sichuan University, of whom 16 were excluded for poor medication compliance or incomplete blood concentration data, leaving 36 participants with a mean age of 28.1 years and a mean body weight of 51.3 kilograms. Twenty-three received monotherapy with levetiracetam, oxcarbazepine or lamotrigine, while 13 took non-interacting polytherapy such as levetiracetam plus lamotrigine. Twenty of the women had focal epilepsy and 16 had generalized epilepsy. In total, 196 blood samples were analyzed: 92 levetiracetam samples from 23 pregnancies, 30 oxcarbazepine samples from 10 pregnancies and 64 lamotrigine samples from 16 pregnancies. During gestation, 16 of the participants, or 44.4 percent, experienced seizure deterioration.

Participants attended scheduled visits before conception and in each of the three trimesters, defined as conception to three months, three to six months and six to nine months. At each visit, peripheral venous blood was drawn before the morning dose to measure trough concentrations, which were determined by liquid chromatography-mass spectrometry. The team calculated apparent oral clearance as daily dose divided by 24 hours times serum concentration, using non-pregnant baseline values from preconception or postpartum measurements, and compared clearance across stages with a linear mixed-effects model. Seizure frequencies were recorded prospectively, with baseline frequencies drawn from a three-month preconception period in medical records. For each participant and trimester, the researchers computed the ratio of the trimester drug concentration to the preconception baseline concentration, abbreviated RTC, and compared RTC values between women whose seizures worsened and those whose seizures remained stable.

The clearance results were striking. Levetiracetam clearance rose by 30 percent in the first trimester, 40 percent in the second and 60 percent in the third compared with baseline, reaching 1.6 times the preconception value at its peak, a statistically significant increase. Lamotrigine showed the most dramatic change, with clearance peaking in the third trimester at roughly twice the baseline level, and the discussion section reports a peak of 2.11-fold. As a consequence, serum concentrations of both drugs fell significantly during pregnancy: by the third trimester, levetiracetam levels had dropped 38.2 percent and lamotrigine levels 47.8 percent relative to baseline, even though daily doses of both drugs were progressively increased across the second and third trimesters. Oxcarbazepine behaved differently, with no significant changes in clearance, serum concentration or daily dose throughout gestation.

The concentration ratios told a parallel story. RTC values for all three drugs declined progressively through pregnancy. Levetiracetam and oxcarbazepine ratios were lowest in the third trimester, down 27.1 percent and 22.3 percent respectively from pre-pregnancy levels, while lamotrigine showed a sharp decline in both the second trimester, down 42.5 percent, and the third, down 45.7 percent. When the researchers compared RTC values between women with and without increased seizure frequency, lower ratios were significantly associated with seizure worsening during the first trimester for all three drugs, although no significant associations emerged in the second or third trimesters.

Receiver operating characteristic analysis then identified preliminary thresholds. A decline in levetiracetam concentration to below 57 percent of the preconception baseline, meaning a drop of more than 43 percent, was associated with an increased risk of seizure worsening in the first trimester. For lamotrigine, concentrations below 74 percent of baseline, and for oxcarbazepine below 85 percent, were predictive of higher seizure frequency in the same period. The area under the curve was 0.84 for levetiracetam, 0.88 for oxcarbazepine and 0.92 for lamotrigine, though the confidence intervals for oxcarbazepine crossed the null and its result was not statistically significant. These thresholds differ from the previously reported Caucasian benchmark, in which a decline of more than 35 percent in levetiracetam or lamotrigine concentrations was linked to elevated risk of deterioration, and from guidance suggesting dose increases when serum concentrations deviate by more than 25 percent from the therapeutic reference range.

The authors argue that these discrepancies may reflect ethnic differences in the genes encoding drug-metabolizing enzymes and transporters, as well as individual variability. Prior studies in Caucasian populations reported 1.9-fold and 2.1-fold clearance increases for lamotrigine and levetiracetam respectively in a retrospective study of 135 pregnant women, and reductions in dose-normalized concentrations of 56.1 percent for lamotrigine and 36.8 percent for levetiracetam in a cohort of 430 participants, while a study of Israeli women found a 31.7 percent decrease in levetiracetam serum concentration and a 46.7 percent clearance increase. The mechanisms likely differ by drug: levetiracetam is mainly eliminated unchanged by the kidneys, so enhanced clearance in early pregnancy probably stems from increased renal blood flow and glomerular filtration rate, whereas lamotrigine, which is about 55 percent bound to serum proteins and metabolized by uridine diphosphate glucuronosyltransferases, may be cleared faster because estrogen enhances glucuronidation.

The study has important limitations that the authors acknowledge. Blood collection timing relative to the last dose was inconsistent and compliance was not formally monitored, which may have influenced concentration measurements. Confounding factors such as stress, sleep deprivation, hormonal fluctuations and preconception seizure history were not investigated, and medication adherence, sleep and psychological stress data were not collected, precluding causal inference. The small sample size constrains generalizability, the analysis of seizure exacerbation was restricted to univariate comparisons that should be regarded as exploratory, and the inclusion of both monotherapy and polytherapy patients may have introduced pharmacokinetic heterogeneity. No adjustments for multiple comparisons were made in the statistical testing.

Even so, the authors conclude that the findings support starting therapeutic drug monitoring of antiseizure medications early in pregnancy and adjusting doses to keep blood concentrations near the non-pregnant baseline. They caution that the results from this Han Chinese cohort may not directly apply to other ethnic groups and require external validation before clinical recommendations can be generalized, and that larger studies are needed to clarify whether monitoring-guided dose adjustments actually improve seizure control.

Subject of Research: Pharmacokinetic changes of second-generation antiseizure medications and seizure outcomes during pregnancy in Han Chinese women

Article Title: Pharmacokinetic changes and seizure outcomes in pregnant women taking second-generation antiseizure medications

Article References: Hao, N., Yi, X., Zhao, R., Zhang, X., Dong, J., & Zhou, D. (2026). Pharmacokinetic changes and seizure outcomes in pregnant women taking second-generation antiseizure medications. Acta Epileptologica, 8(1), Article 38. https://doi.org/10.1186/s42494-026-00275-1

Image Credits: AI Generated

DOI: 10.1186/s42494-026-00275-1

Keywords: epilepsy, pregnancy, levetiracetam, lamotrigine, oxcarbazepine, pharmacokinetics, therapeutic drug monitoring, seizure deterioration, Han Chinese, apparent oral clearance, RTC threshold, Acta Epileptologica