Pharmacokinetic Changes and Seizure Outcomes in Pregnant Women Taking Second-Generation Antiepileptic Drugs

Pharmacokinetic Changes and Seizure Outcomes in Pregnant Women Taking Second-Generation Antiepileptic Drugs | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Pharmacokinetic Changes and Seizure Outcomes in Pregnant Women Taking Second-Generation Antiepileptic Drugs Nan ya Hao, Xiaoli Yi, Jianxia Dong, Dong Zhou This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8245797/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose The study aims to investigate pharmacokinetic alterations in second-generation antiepileptic drugs (AEDs) and evaluate the relationship between drug blood concentration fluctuations and the seizure control deterioration in pregnant women. Methods A prospective study was conducted in 52 pregnancies with epilepsy. Clinical data of participants including oral daily doses and seizure frequency were acquired from the patients’ routine clinical practice. Blood AEDs concentrations obtained via therapeutic drug monitoring(TDM) were used to calculate apparent oral clearance at preconception and each trimester during pregnancy. Clearane changes were assessed between non-pregnant baseline and gestational trimesters. The ratio of AEDs concentration to the individual preconception baseline concentration (RTC) in each trimester was compared between patients experiencing seizure deterioration and those maintaining stability. Moreover, receiver operating characteristic (ROC) curve predicted the threshold RTC for increased seizure frequency. Results The apparent oral clearance of levetiracetam (LEV) and lamotrigine (LTG) showed a significant increase across all trimesters versus nonpregnant baseline. Peak clearance occurred in the third trimester for LTG with a 2.0-fold relative clearance (p < 0.05).Similarly, LEV displayed maximum apparent oral clearance(Cl) increase during the third trimester, reaching 1.6 times baseline values (p < 0.05). As a result, serum concentrations of LEV and LTG significantly decreased during pregnancy compared to non-pregnant baseline levels (p < 0.05). However, apparent oral clearance and blood level of oxcarbazepine (OXC) remained stable throughout gestation compared to preconception baseline. Moreover, RTC values significantly differed between participants with and without seizure deterioration for all three AEDs, indicating lower RTCs were associated with seizure worsening. Conclusion Significant pharmacokinetic fluctuations in LEV and LTG were observed in Chinese pregnant women. Our study validated the necessity of early therapeutic drug monitoring of newer AEDs and dose adjustments to maintain blood concentrations near non-pregnant baselines for pregnant women with epilepsy. Antiepileptic drugs therapeutic drug monitoring (TDM) pharmacokinetic changes seizure frequency Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 1. Introduction Epilepsy represents one of the most prevalent neurological disorders, and effective seizure management for pregnant women poses significant clinical challenges[1,2]. During gestation period, epileptic seizures may lead to severe complications including blunt trauma, hypoxemia, metabolic acidosis, and spontaneous abortion, endangering both maternal and fetal health[3,4]. Concurrently, antenatal exposure to antiepileptic drugs (AEDs) carries teratogenic risks for fetal development[5]. A dose-dependent increase in malformation rates is observed across most investigated antiepileptic agents, such as carbamazepine (CBZ), lamotrigine (LTG) and valproate (VPA)[6]. Consequently, therapeutic strategies for pregnant women with epilepsy require meticulous balancing between effective maternal seizure control and minimization fetal AEDs exposure. First-generation antiepileptic drugs (AEDs), including phenobarbital, sodium valproate, and carbamazepine, have been associated with significant adverse outcomes such as congenital malformations and neurocognitive impairments in offspring[7,8]. In contrast, newer-generation AEDs have emerged as preferred therapeutic options for controlling seizures during pregnancy, owing to their improved safety, lower teratogenic risk and enhanced efficacy in seizure management. Recent clinical evidence has demonstrated that second-generation antiepileptic drugs (AEDs), particularly levetiracetam (LEV), oxcarbazepine (OXC), and lamotrigine (LTG), are increasingly prescribed for pregnancy women with epilepsy[9]. Approximately one-third of the administered dose of LEV is hydrolyzed in the systemic circulation, and the remainder is eliminated unchanged via renal excretion[10]. After oral administration, OXC undergoes hepatic metabolism to its active metabolite, 10-monohydroxy derivative (MHD), which subsequently traverses the blood-brain barrier to exert antiepileptic effects[11]. Lamotrigine exhibits approximately 55% plasma protein binding and is metabolized primarily by uridine diphosphate glucose glucuronosyltransferases. The maternal physiological alteration during pregnancy, including expanded plasma volume, elevated renal blood flow, modified hepatic enzyme activity and dynamic fluctuations in reproductive hormones (particularly estrogen and progesterone), collectively alter the pharmacokinetic profiles of antiepileptic drugs (AEDs)[12,13]. Studies have reported a nearly three-fold increase in the oral apparent clearance of LTG during pregnancy compared to pre-pregnancy levels[14]. Elevated clearance during pregnancy also resulted in subtherapeutic serum concentrations of LEV[15,16]. The blood concentrations of these AEDs declined as pregnancy progress with notable individual difference. This pharmacokinetic alteration of AEDs potentially elevate two critical risks: increased seizure recurrence due to subtherapeutic levels and fetal teratogenic exposure from sustained AEDs concentrations. Consequently, therapeutic drug monitoring (TDM) of AEDs may be assisted in optimizing dosing regimens throughout gestation. Previous work recommend monitoring of AEDs concentrations twice before pregnancy and monthly monitoring of AED levels during pregnancy. It has reported that epileptic pregnancies carrying over 35% reduction in serum concentrations of LEV and LTG experienced significantly elevated risks of seizure deterirataion[17]. Some studies advise dose increase to maintain optimal therapeutic efficacy when serum concentrations of antiepileptic drugs deviate by more than 25% from the established therapeutic reference range[18–20]. Currently, evidence remains limited regarding pharmacokinetic alterations of newer AEDs and dosage adjustment guided by TDM during pregnancy, especially for Asian populations. Our study investigated fluctuations in clearance rates and serum concentrations of these three AEDs, while evaluating impact of these pharmacokinetic variations on eizure control in a Chinese population. 2. Methods 2.1 Study population This is a prospective study conducted in West China Hospital of Sichuan University.We enrolled pregnant women taking newer antiepileptic drugs in this study. All patients met the following inclusion criteria: (1) age ≥ 16 years; (2) diagnosis of epilepsy according to International League Against Epilepsy in 2017[ 21 ]; (3) gestational age < 14 weeks and (4) monotherapy or non-interacting polytherapy with levetiracetam, oxcarbazepine or lamotrigine. Excluded criteria comprised: (1)concurrent cardiopulmonary, renal or hepatic dysfunction; (2)sever thyroid disorders, anemia, progressive neurological diseases or other severe medications known to affect the outcome of pregnancy. Furthermore, patients with poor medication compliance or inability to provide detailed information for AED doses and seizure frequency were excluded from the trial. Our study was approved by Ethics Committee of Sichuan University and all participants were provided written informed consent prior to enrollment. 2.2 Study design and data collection Upon enrollment in this study, participants underwent scheduled clinical visits during preconception, first trimester (conception-3 months), second trimester (3–6 months) and third trimester (6–9 months), respectively (Fig. 1 ).At each visit, research staff collected peripheral venous blood collection preceding morning medication administration to measure valley concentrations. Then, plasma concentrations of levetiracetam, oxcarbazepine, 10-monohydroxy derivate of oxcarbazepine and lamotrigine were determined using liquid chromatography-mass spectrometry(AB SCIEX Triple QuadTM 4500MD) in Hangzhou Duan Medical Laboratory. Clinicians intensified therapeutic drug monitoring when seizures deteriorated and adjusted AEDs regimens based on blood levels of AEDs, seizuring frequency and maternal adverse effects.. Clinical data including daily oral dose, drug administration administration timing, drug leakage and seizure frequency were extracted from the patients’ medical records. 2.3 Study evaluations 2.3.1Alterations in AEDs clearance during pregnancy Blood samples were collected from participants at each clinical visit and absolute serum concentrations of AEDs were measured. Total daily dose and maternal weight were acquired from the medical records. To investigate the alterations in AEDs clearance during pregnancy, we calculated apparent oral clearance (Cl) using the following formula:Cl = daily dose (mg/kg) / serum concentration (mg/L)[ 22 ].Non-pregnant baseline C values were derived from measurements before conception or postpartum.A linear mixed model was used to analyze Cl variations between baseline values and each trimester of pregnancy 2.3.2 Alterations in seizure frequency during pregnancy To investigate potential seizure exacerbation during pregnancy, we prospectively recorded seizure frequency of each participant throughout gestational trimesters. Non-pregnant baseline seizure frequency was derived from medical records from the three-month preconception period..Concurrently, we calculated relative seizure frequencies for each trimester to evaluate potential epileptic deterioration We recorded relative frequencies of epilepsy using a binary classification system (1 = exceeding preconception baseline; 0 = equal to or below baseline). Due to the reported correlations between AEDs blood levels and seizure control, we calculated trimester concentration ratios (RTC = trimester concentration/preconception baseline) for each participant. Then, comparative analysis of RTC values between participants with and without seizure exacerbation was conducted to examine correlation between AEDs serum concentrations and seizure frequencies. Furthermore, we identify potential threshold RTC values predictive of seizure exacerbation for each AED using receiver operating characteristic (ROC) curve analysis[ 23 ]. 2.4 Statistical analysis SPSS Statistics version 19.0 (SPSS, Chicago, IL, USA) was used for statistical analyses. Longitudinal changes in antiepileptic drug (AED) clearance rates and plasma concentrations were examined using a linear mixed-effects model. Student's t-test comparisons of RTC values between patients who experiencing seizure deterioration and who did not revealed significant differences. A p < 0.05 was considered statistically significant. 3. Results 3.1 Clinical characteristics of participants As depicted in table 1 and figure 2, a total of 52 pregnancies with epilepsy were initially enrolled in this study. However, 16 participants were excluded due to poor medication compliance or incomplete blood concentration data. Finally, 36 participants completed the whole follow-up survey. Among them, 23 pregnancies received monotherapy (LEV, OXC or LTG) and 13 pregnancies were treated with non-interacting polytherapy on LEV+LTG, LEV+OXC or LEV+CBZ, respectively. Researchers collected 196 blood samples from these participants to monitor serum concentration of AEDs, including 92 LEV samples from 23 pregnancies, 30 OXC samples from 10 pregnancies, and 74 samples from 16 pregnancies. The participants had a mean age of 28.1 ± 4.1 years (range: 22-38) and average body weight of 51.3 kg (range: 44-61). 55.6% (20) of the pregnant women had focal epilepsy and 44.4% (16) were suffered from generalized epilepsy. During gestination, 44.4% (16) of the participants experienced seizure deterioration. Table 1. Clinical characteristics of participants in this study Participants’ characteristics Total number of participants LEV OXC LTG LExV+OXC LEV+LTG OXC+LTG samples 36 12 3 8 5 6 2 Seizure type no. (% of total participants) FE 20(55.6) 7(58.3) 3(100) 1(12.5) 5(100) 2(33.3) 2(100) GF 16(44.4) 5(41.6) 0(0) 7（87.5） 0(0) 4(66.7) 0(0) Seizure worsening no. (% of total participants) 16(44.4) 8(75.0) 1(33.3) 2(25) 2(40) 4(66.7) 0(0) Average age, y(range) 28.1 (22-38) 29.3 (23-38) 29.3 (25-33) 28.4 (22-33) 27.6 (20-36) 25.5 (23-31) 28 (27-29) Average weight, kg（range） 51.3 (46-61) 50.1 (46-55) 54.7 (53-55) 49.9 (45-56) 54.8 (48-61) 50.3 (46-57) 53.5 (53-54) Abbreviations: LEV, levetiracetam; OXC, oxcarbazepine;LTG, lamotrigine; FE, focal originated epilepsy; GF generalized originated epilepsy. 3.2 Doses and plasma cncentration variations during pregnancy The total daily dosages and serum drug concentrations of AEDs in gestational trimesters are presented in Table 2. Mean daily doses of LEV, OXC and LTG were 951.1 ± 384.7 mg (range, 125-1500), 731.3 ± 272.1 mg (range, 300-1500) and 134.4 ± 67.3 mg (range, 25-250), respectively. As shown in Figure 3, daily doses of LEV and LTG progressively increased during gestation while their serum concentrations exhibited trimester-dependent reductions compared to preconception baselines levels. The third trimester manifested maximal concentration decreases for both LEV (38.2% reduction relative to baseline, p < 0.05; Figure 3A) and LTG (47.8% reduction, p < 0.05; Figure 3C). In contrast, OXC maintained stable serum concentrations (Figure 3B) without significant dosage adjustments throughout gestational periods (Table 2). Table 2 Daily dosages of AEDs during pregnancy AEDs Mean daily dose,mg (range) Non-pregnant Baseline 1st trimester 2nd trimester 3rd trimester LEV 907.6 (125-1500) 907.6 (125-1500) 972.8 (125-1500) 1016.3 (125-1500) OXC 810.0 (300-1500) 705.0 (300-1200) 705.0 (300-1200) 705.0 (300-1200) LTG 135.9 (25-250) 131.3 (25-250) 132.8 (25-250) 137.5 (25-250) 3.3 Clearance changes of AEDs during pregnancy This study evaluated changes in apparent oral clearance (Cl) of AEDs in every trimester during pregnancy. As shown in figure 4, both LEV and LTG showed progressive increases in Cl throughout gestation. Though inter-trimester comparisons represented no significant differences, Cl of LEV increased by 30%, 40%, and 60% above baseline values in the first, second and third trimesters, respectively (p < 0.05,Figure 4A). Also, LTG displayed peak Cl increase during the third trimester, reaching 2.0 times baseline values (p < 0.05,Figure 4C). In contrast, Cl of OXC during pregnancy showed no significant difference comparable to non-pregnant baseline level throughout all gestational stages (Figure 4B). 3.4 Correlation between serum concentration and seizure frequency during pregnancy We calculated the ratio of AED concentration to the individual non-pregnant baseline concentration (RTC) in each trimester. Generally, RTC values for all three AEDs declined progressively throughout pregnancy (Figure 5). The minimum RTC values for LEV and OXC occurred in the third trimester, representing decreases of 27.1% and 22.3% compared to the pre-pregnancy levels, respectively (Figure 5). Notably, a sharp decline in RTC was observed for LTG during both the second (42.5% decrease) and third (45.7% decrease) trimester in comparison to the nonpregnant baseline (Figure 5). An overview of the changes in epileptic frequency during pregnancy were presented in Table 3. Among participants receiving LEV, OXC, or LTG monotherapy, seizure frequency increased in all trimesters. Of 36 total pregnancies, 20 (55.6%) experienced worsened seizures at any gestational stage (Table 3) This included 8 on LEV monotherapy, 3 on LTG, 1 on OXC, 2 on LEV+OXC polytherapy, and 4 on LEV+LTG polytherapy. For the 23 pregnancies on LEV monotherapy, seizure frequency increased in 6 (26.1%), 9 (39.1%), and 11 (47.8%) during the first, second, and third trimesters, respectively (Table 3). Among 16 pregnancies receiving LTG, 7 (43.8%) suffered increased seizures frequency in the third trimester (Table 3). Seizure deterioration progressively increased with gestational advancement for pregnancies on LEV and LTG. In contrast, the number of pregnancies experienced seizure exacerbation remained relatively stable in frequency among patients treated with OXC (Table 3). To clarify the relationship between seizure frequency and AEDs blood level changes, we compared RTC values in pregnancies with increased seizure frequency versus those without per trimester(Table 3). The results revealed that lower RTCs were significantly associated with higher risk of seizure worsening during the first trimester for all three AED (p < 0.05). In contrast, no significant differences emerged in the second or third trimesters. Furthermore, a receiver operating characteristic (ROC) curve evaluated RTC thresholds predicting seizure deterioration risk (Figure 6). RTC reductions exceeding these thresholds indicated increased risk of seizure worsening. For LEV, an RTC decline >43% correlated with higher seizure worsening risk during the first trimester (Figure 6). In addition, serum concentration below 74% (LTG) and 85% (OXC) of the target levels might be predictors of increased seizure frequency in the first trimester (Figure 6). Table 3 . Seizure frequency changes during pregnancy and relation of seizure frequency to RTC of AEDs. Stages of pregnancy 1st trimester 2nd trimester 3rd trimester Changes in epileptic frequency Yes No Yes No Yes No LEV Samples (% of total participants) 6 (26.1) 17 (73.9) 9 (39.1) 14 (60.9) 11 (47.8) 12 (52.2) Ratio to target concentration 0.56 ± 0.12 0.84 ± 0.22 0.65 ± 0.27 0.81 ± 0.16 0.68 ± 0.41 0.77 ± 0.18 p* 0.002 0.09 0.5 OXC Samples (% of total participants) 2 (20) 8 (80) 3 (30) 7 (70) 2 (20) 8 (80) Ratio to target concentration 0.47 ± 0.51 0.92 ± 0.10 0.61 ± 0.45 0.90 ± 0.07 0.76 ± 0.28 0.84 ± 0.07 p* 0.02 0.11 0.7 LTG Samples (% of total participants) 3 (18.8) 13 (81.2) 5 (31.2) 11 (68.8) 7 (43.8) 9 (56.2) Ratio to target concentration 0.52 ± 0.22 0.82 ± 0.09 0.55 ± 0.24 0.63 ± 0.36 0.52 ± 0.17 0.57 ± 0.32 p* 0.02 0.6 0.7 * T-tests were used to compare RTC values between pregnancies exhibiting increased seizure frequency versus those without in each trimester. A p-value < 0.05 indicated statistical significance.. *p < 0.05 indicated statistical significance. 4. Discussion Previous reports on changes in AEDS clearance during pregnancy were predominantly involved Caucasian populations. Evidence regarding pharmacokinetic alterations of newer AEDs and dosage adjustments for pregnant women, particularly for Asian populations, remains limited. Our study provides valuable pharmacokinetic data on second-generation AEDs, oxcarbazepine, and lamotrigine—during pregnancy in Chinese population. Our results confirmed that alterations in AED pharmacokinetics were common for pregnant woman. Using Cl as a dose- and weight-corrected metric for plasma AED concentrations, we found significant increases in Cl. These increases would resulted in decreased AED blood levles without compensatory dose adjustments, particularly in LTG and LEV monotherapy participates. We also observed progressive increases in seizure frequency throughout gestation in pregnancies treated with LEV and LTG. LEV and LTG have become frequently prescribed antiepileptic drugs for women with epilepsy due to their high oral bioavailability and low teratogenic risk[24,25]. Our prospective study corroborates prior evidence demonstrating markedly increased Cl of LEV and LTG during pregnancy compared to non-pregnant baseline values[26,27]. We observed elevated Cl of LEV as early as the first trimester, with peak Cl increasing 1.6-fold (p < 0.05, Fig. 4A) and concomitant serum concentrations decreasing by 38.2% (p < 0.05,Fig. 3A). Since LEV undergoes predominantly renal excretion in unchanged form[28,29], this enhanced Cl during early pregnancy probably results from increased renal blood flow and glomerular filtration rate[30,31]. Similarly, LTG exhibited substantial pharmacokinetic alterations: peak Cl reached 2.11 times the non-pregnant level (p < 0.05, Fig. 4C) and serum concentrations declined by up to 45.7% versus preconception values during the third trimester(Figures 3C). As LTG undergoes extensive hepatic metabolism via uridine-diphosphate glucuronosyltransferases[32,33], this pharmacokinetic changes may be partially ascribed to estrogen-induced augmentation of enhanced glucuronidation would increase OXC clearance, our study detected only minor alterations in OXC Cl and blood levels (p>0.05, Fig.3B and Fig.4B). A recent cohort study also reported no statistically significant changes in OXC pharmacokinetics during pregnancy, aligning with previous evidence indicating stable OXC clearance throughout gestation. Previous studies have verified that reduced plasma concentrations of AEDs, specifically LEV, LTG, and OXC, correlate with increased seizure frequency during gestination[34]. Our results further confirmed that lower RTCs associated with higher seizure exacerbation rates(Fig.4). To clarify the relationship between seizure frequency and AED concentrations, we compared RTC values per trimester in pregnancies with increased seizure frequency versus those maintaining stable frequency. Our analysis revealed that LEV concentration reductions exceeding 43% predicted worsened seizure control in the first trimester. Similarly, serum concentrations below 74% (LTG) and 85% (OXC) of individual non-pregnant baseline concentrations during the first trimester may predict elevated epilepsy exacerbation risk. These findings underscore the clinical significance of RTC reduction. Our finding that blood concentrations of OXC showed no significant change during pregnancy was consistent with previous studies reporting stable OXC levels in pregnant women. However, the extent of fluctuation in blood concentrations, clearance and RTC differed from previous researches. In a retrospective study of 135 pregnant woman with epilepsy, the results reported 1.9-fold and 2.1-fold increases in baseline clearance for LTG and LEV, respectively, in Caucasian patients [ 35]. Also, a cohort study of 430 participants revealed 56.1% and 36.8% reductions in dose-normalized concentrations for LTG and LEV during pregnancy in Caucasian women[27]. Similarly, a previous study demonstrated a 31.7% decrease in serum concentration and 46.7% increase in clearance for LEV among Israeli women compared to preconception baselines[36]. Furthermore, RTC thresholds in our study differed from established Caucasian thresholds that >35% decrease in AED levels correlating with seizure worsening. It has been recognized that seizure deterioration during pregnancy may stem not only from declining AED levels but also hormonal fluctuations, maternal age, metabolic enzyme polymorphisms, sleep disorders, and stress. We therefore attribute discrepancies between our results and prior studies to individual variability and racial differences. Therefore, we consider the discrepancy between our results and previous studies probably owing to individual variability and racial differences. There are several limitations of this research. First, inconsistent timing of blood draws relative to the last AED dose and unmonitored patient compliance may have influenced measured AED blood concentrations. Second, the effects of confounding factors including stress, sleep deprivation, hormonal fluctuations, and pre-conception seizure history on AED levels and seizure frequency during pregnancy were not investigated. Additionally, the small sample size, particularly the limited subgroup of women taking OXC, constrains generalizability. Nevertheless, our study contributes available pharmacokinetic data on AED variation in Han Chinese population. Our findings suggest that lower blood concentrations of AEDs correlate with increased seizure frequency, underscoring the clinical value of beginning TDM of AEDs early in pregnancy. Future studies with larger sample size are needed to clarify the the impact of TDM-guided dose adjustments on on seizure control and risks for epilepsy deterioration during pregnancy. 5. Conclusion Our prospective study revealed a significant increase in Cl of LEV and LTG in a Chinese population. Furthermore, the results demonstrated that lower RTC values correlated with increased seizure frequency during pregnancy among all three AEDs. This investigation suggests that TMD of AEDs should begin early in pregnancy with dose adjustments to maintain blood concentration near non-pregnant baselines. Declarations Acknowledgements We gratefully acknowledge the patients included in our research. Authors’ contributions Nan ya Hao: Investigation, Data collection, Writing-original draft. Xiaoli Yi:Methodology, Data curation, and Writing-original draft. Jianxia Dong:Data curation, Writing-review&editing. Dong Zhou:Supervision, Writing-review&editing, Project administration. Funding This study was supported by the National Natural Science Foundation of China (82204297), Natural Science Foundation of Sichuan Province (2025ZNSFSC1734), Young Scientists Fund of Sichuan Provincial Natural Science Foundation (2025ZNSFSC1643), Qimingxing Research Fund for Young Talents of West China hospital (HXOMX0093). Data availability All data are available from the corresponding author upon reasonable request. Ethics approval and consent to participate This research received approval from the ethics committee of Sichuan University (2022-1847). All participants provided written informed consent allowing the utilization of their anonymized medical data for analysis and publication in this research. Consent for publication Not applicable. Competing interests All authors declare that they have no competing financial interests in this paper. References Arfman IJ, Wammes-van der Heijden EA, Ter Horst PGJ, Lambrechts DA, Wegner I, Touw DJ. Therapeutic Drug Monitoring of Antiepileptic Drugs in Women with Epilepsy Before, During, and After Pregnancy. Clin Pharmacokinet. 2020;59(4):427-445. Neri S, Mastroianni G, Gardella E, Aguglia U, Rubboli G. Epilepsy in neurodegenerative diseases. Epileptic Disord. 2022;24(2):249-273. Meador KJ, Cohen MJ, Loring DW, May RC, Brown C, Robalino CP, et al. Two-Year-Old Cognitive Outcomes in Children of Pregnant Women With Epilepsy in the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs Study. JAMA Neurol. 2021 ;78(8):927-936. Pa B, G SS, Thomas G, Kp A. Dosage Optimization of Lamotrigine in Pregnancy: A Pharmacometric Approach Using Modeling and Simulation. J Clin Pharmacol. 2022 ;62(12):1557-1565. Andrade C. Epilepsy, Antiepileptic Drugs, and Adverse Pregnancy Outcomes, 2: Major Congenital Malformations With Antiepileptic Drug Monotherapy. J Clin Psychiat. 2024 ;85(3):24f15432. Shi X, Wang Y, Zhang Y, Song C, Jiang Y, Zhao J, et al.. Effects of antiepileptic drugs polytherapy on pregnancy outcomes in women with epilepsy: An observation study in northwest China. Epilepsy Behav. 2022 ;135:108904. Thigpen J, Owens HD. The Use of Antiepileptic Drugs During Pregnancy and Fetal Outcomes. Neonatal Netw. 2022 ;41(4):226-231. Birnbaum AK, Meador KJ, Karanam A, Brown C, May RC, Gerard EE, et al. Antiepileptic Drug Exposure in Infants of Breastfeeding Mothers With Epilepsy. JAMA Neurol. 2020 ;77(4):441-450. Lagae L. The importance of assessing behaviour and cognition in antiepileptic drug trials in children and adolescents. Acta Neurol Belg. 2017 ;117(2):425-432. Schelhaas M, Wegner I, Edens M, Wammes-Van Der Heijden E, Touw D, Ter Horst P. Association of Levetiracetam Concentration With Seizure Frequency in Pregnant Women With Epilepsy. Neurology. 2023;100(2):e172-e181. Yuan Y, Zhang S, Yuan Y, Yan X, Zhang L, Ran YW. Pharmacogenomics of oxcarbazepine in the treatment of epilepsy. Pharmacogenomics. 2023 ;24(6):335-343. Kacirova I, Grundmann M, Brozmanova H. Monitoring of lamotrigine concentrations in mothers, colostrum, and breastfed newborns during the early postpartum period. Biomed Pharmacother. 2022 ;151:113167. Karanam A, Pennell PB, French JA, Harden CL, Allien S, Lau C, et al. Lamotrigine clearance increases by 5 weeks gestational age: Relationship to estradiol concentrations and gestational age. Ann Neurol. 2018 ;84(4):556-563. Wang ML, Tao YY, Sun XY, Guo Y, Wang ZY, Cao YF, et al. Estrogen profile and pharmacogenetics-based lamotrigine dosing regimen optimization: Recommendations for pregnant women with epilepsy. Pharmacol Res. 2021 ;169:105610. Voinescu PE, Park S, Chen LQ, Stowe ZN, Newport DJ, Ritchie JC, et al. Antiepileptic drug clearances during pregnancy and clinical implications for women with epilepsy.Neurology. 2018 ;91(13):e1228-e1236. Freund B, Chen B, Kaplan PW, Johnson EL. Managing Antiseizure Medications in Pregnancy: Is Earlier and More Frequent Monitoring Better? Neurol Clin Pract. 2023;13(4):e200169. Reisinger TL, Newman M, Loring DW, Pennell PB, Meador KJ. Antiepileptic drug clearance and seizure frequency during pregnancy in women with epilepsy. Epilepsy Behav. 2013;29(1):13-8. Harden CL, Hopp J, Ting TY, Pennell PB, French JA, Allen Hauser W, et al. Management issues for women with epilepsy-Focus on pregnancy (an evidence-based review): I. Obstetrical complications and change in seizure frequency: Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Epilepsia. 2009 May;50(5):1229-36. Kumaravel J, Sarma P, Suri V, Singh P, Prakash A, Medhi B. Therapeutic Drug Monitoring of Levetiracetam in Different Trimesters of Pregnant Women with Epilepsy in a Tertiary Care Center: A Prospective Study. Neurol India. 2024 ;72(2):358-363. Jiménez M, Grau-López L, Ciurans J, García-Esperón C, Fumanal A, Barambio S, et al. Epilepsy and pregnancy. Factors associated with epileptic seizures during pregnancy.Neurologia. 2023;38(2):106-113. Specchio N, Wirrell EC, Scheffer IE, Nabbout R, Riney K, Samia P, et al. International League Against Epilepsy classification and definition of epilepsy syndromes with onset in childhood: Position paper by the ILAE Task Force on Nosology and Definitions. Epilepsia. 2022;63(6):1398-1442. Johnson EL, Stowe ZN, Ritchie JC, Newport DJ, Newman ML, Knight B, et al. Carbamazepine clearance and seizure stability during pregnancy. Epilepsy Behav. 2014;33:49-53. Karanam A, Pennell PB, Meador KJ, Long Y, Birnbaum AK. Characterization of lamotrigine disposition changes during and after pregnancy in women with epilepsy.Pharmacotherapy. 2025;45(1):33-42. Mari L, Placidi F, Romigi A, Tombini M, Del Bianco C, Ulivi M, et al. Levetiracetam, lamotrigine and carbamazepine: which monotherapy during pregnancy? Neurol Sci. 2022;43(3):1993-2001. Stjerna S, Huber-Mollema Y, Tomson T, Perucca E, Battino D, Craig J, et al. Cognitive outcomes after fetal exposure to carbamazepine, lamotrigine, valproate or levetiracetam monotherapy: Data from the EURAP neurocognitive extension protocol. Epilepsy Behav. 2024 ;159:110024. Pennell PB, Karanam A, Meador KJ, Gerard E, Kalayjian L, Penovich P, et al. Antiseizure Medication Concentrations During Pregnancy: Results From the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) Study. JAMA Neurol. 2022;79(4):370-379. Larcin L, Ngwasiri C, Neven A, Damase-Michel C, Kirakoya-Samadoulougou F. Real-World Assessment of Psychotropic and Antiepileptic Drug Use During Pregnancy in Belgium: Trends, Predictors, and Comparative Risk of Congenital Anomalies (2010-2016). Pharmacoepidem Dr S. 2024;33(10):e70021. Chappell K, Kimmons LA, Haller JT, Canada RB, He H, Hudson JQ. Levetiracetam pharmacokinetics in critically ill patients undergoing renal replacement therapy. J Crit Care. 2021;61:216-220. Kalaria SN, Armahizer M, McCarthy P, Badjatia N, Gobburu JV, Gopalakrishnan M. A Practice-Based, Clinical Pharmacokinetic Study to Inform Levetiracetam Dosing in Critically Ill Patients Undergoing Continuous Venovenous Hemofiltration (PADRE-01). J Clin Transl Sci.2020;13(5):950-959. Hochbaum M, Kienitz R, Rosenow F, Schulz J, Habermehl L, Langenbruch L, et al. Trends in antiseizure medication prescription patterns among all adults, women, and older adults with epilepsy: A German longitudinal analysis from 2008 to 2020. Epilepsy Behav. 2022;130:108666. Reimers A, Brodtkorb E. Second-generation antiepileptic drugs and pregnancy: a guide for clinicians. Expert Rev Neurother. 2012;12(6):707-17. Lee ZN, van Nuland M, Bognàr T, Leijten FSS, van der Elst KCM. Association of Lamotrigine Plasma Concentrations With Efficacy and Toxicity in Patients With Epilepsy: A Retrospective Study. Ther Drug Monit. 2024;46(5):642-648. Wang W, Battini V, Carnovale C, Noordam R, van Dijk KW, Kragholm KH, et al. A novel approach for pharmacological substantiation of safety signals using plasma concentrations of medication and administrative/healthcare databases: A case study using Danish registries for an FDA warning on lamotrigine. Pharmacol Res.2023;193:106811. Yin X, Liu Y, Guo Y, Zhao L, Li G, Tan X. Pharmacokinetic changes for newer antiepileptic drugs and seizure control during pregnancy.Cns Neurosci Ther. 2022;28(5):658-666. Hao N, Abdulaziz AT, Lu L, Chen Y, Li T, Liu J, et al. Seizure control and pregnancy outcomes in Chinese women with epilepsy: A prospective multicenter cohort study. Epilepsia.2025 ;66(5):1573-1584. Yin X, Liu Y, Guo Y, Zhao L, Li G, Tan X. Pharmacokinetic changes for newer antiepileptic drugs and seizure control during pregnancy. CNS Neurosci Ther. 2022;28(5):658-666. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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1","display":"","copyAsset":false,"role":"figure","size":371028,"visible":true,"origin":"","legend":"\u003cp\u003eStudy design of this study. This study enrolled pregnant women diagnosed with epilepsy. Participants underwent a total of 4 visits, one during the preconception period, followed by trimestral evaluations at first trimester ((1-13 weeks of gestation), second trimester (13-26 weeks of gestation) and third trimester (27-40 weeks of gestation), respectively. Visits were conducted more frequently when participants exhibited increased seizure activity.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8245797/v1/2c80911a3c968abc52d78798.png"},{"id":98427636,"identity":"b61310cb-68ff-4657-823c-4b4a0a7bc90d","added_by":"auto","created_at":"2025-12-17 16:40:54","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":640950,"visible":true,"origin":"","legend":"\u003cp\u003eThe study flowchart of participants recruitment and data evaluation procedures. ANOVA, Single-factor analysis of variance; LEV, levetiracetam; LTG, lamotrigine;OXC, oxcarbazepine.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8245797/v1/f4da0ff19db2e3fec6735c83.png"},{"id":98427578,"identity":"b6bf2149-2c7f-4ec8-923d-413fab6793a6","added_by":"auto","created_at":"2025-12-17 16:40:45","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":805497,"visible":true,"origin":"","legend":"\u003cp\u003eSerum concentrations of AEDs during pregnancy. Results indicated means ± SD. *p \u0026lt; 0.05 denote statistically significant variations versus non-pregnant baseline levels\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-8245797/v1/65399d8e40816c2e67016c42.png"},{"id":98048529,"identity":"feb74f3d-c079-4ad3-a6e0-4690ae677942","added_by":"auto","created_at":"2025-12-12 08:34:00","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":866831,"visible":true,"origin":"","legend":"\u003cp\u003eClearance changes of AEDs during pregnancy. Results indicated means ± SD. Statistical analyses revealed significant clearance variations during pregnancy compared to preconception baseline levels (*p \u0026lt; 0.05).\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-8245797/v1/f97aaeeac3d6f614904c2b48.png"},{"id":98428449,"identity":"372071f5-42df-4b1b-a98e-5681f7815dfe","added_by":"auto","created_at":"2025-12-17 16:42:02","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":358603,"visible":true,"origin":"","legend":"\u003cp\u003eThe ratio of AED concentration to the individual non-pregnant baseline concentration during each trimester of pregnancy. Results indicated means ± SD.\u003c/p\u003e","description":"","filename":"Figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-8245797/v1/b377dd0331afee968aac4ce8.png"},{"id":98048528,"identity":"8b8802cd-8453-467a-b61d-2a00ec275f9d","added_by":"auto","created_at":"2025-12-12 08:34:00","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":729459,"visible":true,"origin":"","legend":"\u003cp\u003eReceiver operating characteristic (ROC) curve were used to assess the RTC thresholds of AEDs predicting increased seizure frequency. The area under the curve (AUC) values were as follows: LEV, AUC = 0.84 (95% CI: 0.67-1.01, p value: 0.01). OXC, AUC = 0.88 (95% CI: 0.62-1.12, p value: 0.12). and LTG, AUC = 0.92 (95% CI: 0.76-1.08, p value: 0.03).\u003c/p\u003e","description":"","filename":"Figure6.png","url":"https://assets-eu.researchsquare.com/files/rs-8245797/v1/a23785c79526d5aeaf45a9bf.png"},{"id":98623013,"identity":"497f205d-1f10-4fd4-a1be-1914188a2a91","added_by":"auto","created_at":"2025-12-19 17:04:02","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4343981,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8245797/v1/7b0ecbef-614f-433d-90a9-8ead4064e331.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Pharmacokinetic Changes and Seizure Outcomes in Pregnant Women Taking Second-Generation Antiepileptic Drugs","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eEpilepsy represents one of the most prevalent neurological disorders, and effective seizure management for pregnant women poses significant clinical challenges[1,2]. During gestation period, epileptic seizures may lead to severe complications including blunt trauma, hypoxemia, metabolic acidosis, and spontaneous abortion, endangering both maternal and fetal health[3,4]. Concurrently, antenatal exposure to antiepileptic drugs (AEDs) carries teratogenic risks for fetal development[5]. A dose-dependent increase in malformation rates is observed across most investigated antiepileptic agents, such as carbamazepine (CBZ), lamotrigine (LTG) and valproate (VPA)[6]. Consequently, therapeutic strategies for pregnant women with epilepsy require meticulous balancing between effective maternal seizure control and minimization fetal AEDs exposure.\u003c/p\u003e\n\u003cp\u003eFirst-generation antiepileptic drugs (AEDs), including phenobarbital, sodium valproate, and carbamazepine, have been associated with significant adverse outcomes such as congenital malformations and neurocognitive impairments in offspring[7,8]. In contrast, newer-generation AEDs have emerged as preferred therapeutic options for controlling seizures during pregnancy, owing to their improved safety, lower teratogenic risk and enhanced efficacy in seizure management. Recent clinical evidence has demonstrated that second-generation antiepileptic drugs (AEDs), particularly levetiracetam (LEV), oxcarbazepine (OXC), and lamotrigine (LTG), are increasingly prescribed for pregnancy women with epilepsy[9].\u003c/p\u003e\n\u003cp\u003eApproximately one-third of the administered dose of LEV is hydrolyzed in the systemic circulation, and the remainder is eliminated unchanged via renal excretion[10]. After oral administration, OXC undergoes hepatic metabolism to its active metabolite, 10-monohydroxy derivative (MHD), which subsequently traverses the blood-brain barrier to exert antiepileptic effects[11]. Lamotrigine exhibits approximately 55% plasma protein binding and is metabolized primarily by uridine diphosphate glucose glucuronosyltransferases. The maternal physiological alteration during pregnancy, including expanded plasma volume, elevated renal blood flow, modified hepatic enzyme activity and dynamic fluctuations in reproductive hormones (particularly estrogen and progesterone), collectively alter the pharmacokinetic profiles of antiepileptic drugs (AEDs)[12,13].\u003c/p\u003e\n\u003cp\u003eStudies have reported a nearly three-fold increase in the oral apparent clearance of LTG during pregnancy compared to pre-pregnancy levels[14]. Elevated clearance during pregnancy also resulted in subtherapeutic serum concentrations of LEV[15,16]. The blood concentrations of these AEDs declined as pregnancy progress with notable individual difference. This pharmacokinetic alteration of AEDs potentially elevate two critical risks: increased seizure recurrence due to subtherapeutic levels and fetal teratogenic exposure from sustained AEDs concentrations. Consequently, therapeutic drug monitoring (TDM) of AEDs may be assisted in optimizing dosing regimens throughout gestation. Previous work recommend monitoring of AEDs concentrations twice before pregnancy and monthly monitoring of AED levels during pregnancy.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIt has reported that epileptic pregnancies carrying over 35% reduction in serum concentrations of LEV and LTG experienced significantly elevated risks of seizure deterirataion[17]. Some studies advise dose increase to maintain optimal therapeutic efficacy when serum concentrations of antiepileptic drugs deviate by more than 25% from the established therapeutic reference range[18–20]. Currently, evidence remains limited regarding pharmacokinetic alterations of newer AEDs and dosage adjustment guided by TDM during pregnancy, especially for Asian populations. Our study investigated fluctuations in clearance rates and serum concentrations of these three AEDs, while evaluating impact of these pharmacokinetic variations on eizure control in a Chinese population.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Study population\u003c/h2\u003e\u003cp\u003eThis is a prospective study conducted in West China Hospital of Sichuan University.We enrolled pregnant women taking newer antiepileptic drugs in this study. All patients met the following inclusion criteria: (1) age\u0026thinsp;\u0026ge;\u0026thinsp;16 years; (2) diagnosis of epilepsy according to International League Against Epilepsy in 2017[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]; (3) gestational age\u0026thinsp;\u0026lt;\u0026thinsp;14 weeks and (4) monotherapy or non-interacting polytherapy with levetiracetam, oxcarbazepine or lamotrigine. Excluded criteria comprised: (1)concurrent cardiopulmonary, renal or hepatic dysfunction; (2)sever thyroid disorders, anemia, progressive neurological diseases or other severe medications known to affect the outcome of pregnancy. Furthermore, patients with poor medication compliance or inability to provide detailed information for AED doses and seizure frequency were excluded from the trial. Our study was approved by Ethics Committee of Sichuan University and all participants were provided written informed consent prior to enrollment.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Study design and data collection\u003c/h2\u003e\u003cp\u003eUpon enrollment in this study, participants underwent scheduled clinical visits during preconception, first trimester (conception-3 months), second trimester (3\u0026ndash;6 months) and third trimester (6\u0026ndash;9 months), respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).At each visit, research staff collected peripheral venous blood collection preceding morning medication administration to measure valley concentrations. Then, plasma concentrations of levetiracetam, oxcarbazepine, 10-monohydroxy derivate of oxcarbazepine and lamotrigine were determined using liquid chromatography-mass spectrometry(AB SCIEX Triple QuadTM 4500MD) in Hangzhou Duan Medical Laboratory. Clinicians intensified therapeutic drug monitoring when seizures deteriorated and adjusted AEDs regimens based on blood levels of AEDs, seizuring frequency and maternal adverse effects.. Clinical data including daily oral dose, drug administration administration timing, drug leakage and seizure frequency were extracted from the patients\u0026rsquo; medical records.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Study evaluations\u003c/h2\u003e\u003cdiv id=\"Sec6\" class=\"Section3\"\u003e\u003ch2\u003e2.3.1Alterations in AEDs clearance during pregnancy\u003c/h2\u003e\u003cp\u003eBlood samples were collected from participants at each clinical visit and absolute serum concentrations of AEDs were measured. Total daily dose and maternal weight were acquired from the medical records. To investigate the alterations in AEDs clearance during pregnancy, we calculated apparent oral clearance (Cl) using the following formula:Cl\u0026thinsp;=\u0026thinsp;daily dose (mg/kg) / serum concentration (mg/L)[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].Non-pregnant baseline C values were derived from measurements before conception or postpartum.A linear mixed model was used to analyze Cl variations between baseline values and each trimester of pregnancy\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section3\"\u003e\u003ch2\u003e2.3.2 Alterations in seizure frequency during pregnancy\u003c/h2\u003e\u003cp\u003eTo investigate potential seizure exacerbation during pregnancy, we prospectively recorded seizure frequency of each participant throughout gestational trimesters. Non-pregnant baseline seizure frequency was derived from medical records from the three-month preconception period..Concurrently, we calculated relative seizure frequencies for each trimester to evaluate potential epileptic deterioration We recorded relative frequencies of epilepsy using a binary classification system (1\u0026thinsp;=\u0026thinsp;exceeding preconception baseline; 0\u0026thinsp;=\u0026thinsp;equal to or below baseline). Due to the reported correlations between AEDs blood levels and seizure control, we calculated trimester concentration ratios (RTC\u0026thinsp;=\u0026thinsp;trimester concentration/preconception baseline) for each participant. Then, comparative analysis of RTC values between participants with and without seizure exacerbation was conducted to examine correlation between AEDs serum concentrations and seizure frequencies. Furthermore, we identify potential threshold RTC values predictive of seizure exacerbation for each AED using receiver operating characteristic (ROC) curve analysis[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003e2.4 Statistical analysis\u003c/h2\u003e\u003cp\u003eSPSS Statistics version 19.0 (SPSS, Chicago, IL, USA) was used for statistical analyses. Longitudinal changes in antiepileptic drug (AED) clearance rates and plasma concentrations were examined using a linear mixed-effects model. Student's t-test comparisons of RTC values between patients who experiencing seizure deterioration and who did not revealed significant differences. A p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e\u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003e3.1 Clinical characteristics of participants\u003c/p\u003e\n\u003cp\u003eAs depicted in table 1 and figure 2, a total of 52 pregnancies with epilepsy were initially enrolled in this study. However, 16 participants were excluded due to poor medication compliance or incomplete blood concentration data. Finally, 36 participants completed the whole follow-up survey. Among them, 23 pregnancies received monotherapy (LEV, OXC or LTG) and 13 pregnancies were treated with non-interacting polytherapy on LEV+LTG, LEV+OXC or LEV+CBZ, respectively. Researchers collected 196 blood samples from these participants to monitor serum concentration of AEDs, including 92 LEV samples from 23 pregnancies, 30 OXC samples from 10 pregnancies, and 74 samples from 16 pregnancies. The participants had a mean age of 28.1 \u0026plusmn; 4.1 years (range: 22-38) and average body weight of 51.3 kg (range: 44-61). 55.6% (20) of the pregnant women had focal epilepsy and 44.4% (16) were suffered from generalized epilepsy. During gestination, 44.4% (16) of the participants experienced seizure deterioration.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1.\u0026nbsp;\u003c/strong\u003eClinical characteristics of participants in this study\u003c/p\u003e\n\u003cdiv align=\"Left\"\u003e\n \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"553\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 84px;\"\u003e\n \u003cp\u003eParticipants\u0026rsquo;\u003c/p\u003e\n \u003cp\u003echaracteristics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003eTotal number of participants\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003eLEV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003eOXC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003eLTG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003eLExV+OXC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003eLEV+LTG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003eOXC+LTG\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 84px;\"\u003e\n \u003cp\u003esamples\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" style=\"width: 553px;\"\u003e\n \u003cp\u003eSeizure type no.\u003c/p\u003e\n \u003cp\u003e(% of total participants)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 84px;\"\u003e\n \u003cp\u003eFE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e20(55.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e7(58.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e3(100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e1(12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e5(100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e2(33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e2(100)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 84px;\"\u003e\n \u003cp\u003eGF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e16(44.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e5(41.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e7（87.5）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e4(66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 84px;\"\u003e\n \u003cp\u003eSeizure worsening no. (% of total participants)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e16(44.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e8(75.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e1(33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e2(25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e2(40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e4(66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 84px;\"\u003e\n \u003cp\u003eAverage age, y(range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e28.1\u003c/p\u003e\n \u003cp\u003e(22-38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e29.3\u003c/p\u003e\n \u003cp\u003e(23-38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e29.3 (25-33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e28.4 (22-33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e27.6\u003c/p\u003e\n \u003cp\u003e(20-36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e25.5\u003c/p\u003e\n \u003cp\u003e(23-31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003cp\u003e(27-29)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 84px;\"\u003e\n \u003cp\u003eAverage weight, kg（range）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e51.3\u003c/p\u003e\n \u003cp\u003e(46-61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e50.1\u003c/p\u003e\n \u003cp\u003e(46-55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e54.7\u003c/p\u003e\n \u003cp\u003e(53-55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e49.9\u003c/p\u003e\n \u003cp\u003e(45-56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e54.8\u003c/p\u003e\n \u003cp\u003e(48-61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e50.3\u003c/p\u003e\n \u003cp\u003e(46-57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e53.5\u003c/p\u003e\n \u003cp\u003e(53-54)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eAbbreviations: LEV, levetiracetam; OXC, oxcarbazepine;LTG, lamotrigine; FE, focal originated epilepsy; GF generalized originated epilepsy.\u003c/p\u003e\n\u003cp\u003e3.2 Doses and plasma cncentration variations during pregnancy\u003c/p\u003e\n\u003cp\u003eThe total daily dosages and serum drug concentrations of AEDs in gestational trimesters are presented in Table 2. Mean daily doses of LEV, OXC and LTG were 951.1 \u0026plusmn; 384.7 mg (range, 125-1500), 731.3 \u0026plusmn; 272.1 mg (range, 300-1500) and 134.4 \u0026plusmn; 67.3 mg (range, 25-250), respectively. As shown in Figure 3, daily doses of LEV and LTG progressively increased during gestation while their serum concentrations exhibited trimester-dependent reductions compared to preconception baselines levels. The third trimester manifested maximal concentration decreases for both LEV (38.2% reduction relative to baseline, p \u0026lt; 0.05; Figure 3A) and LTG (47.8% reduction, p \u0026lt; 0.05; Figure 3C). In contrast, OXC maintained stable serum concentrations (Figure 3B) without significant dosage adjustments throughout gestational periods (Table 2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2 Daily dosages of AEDs during pregnancy\u003c/p\u003e\n\u003cdiv align=\"Left\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 55px;\"\u003e\n \u003cp\u003eAEDs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" style=\"width: 469px;\"\u003e\n \u003cp\u003eMean daily dose,mg (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003eNon-pregnant Baseline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003e1st trimester\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003e2nd trimester\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e3rd trimester\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 55px;\"\u003e\n \u003cp\u003eLEV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003e907.6 (125-1500)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003e907.6 (125-1500)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003e972.8 (125-1500)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e1016.3 (125-1500)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 55px;\"\u003e\n \u003cp\u003eOXC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003e810.0 (300-1500)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003e705.0 (300-1200)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003e705.0 (300-1200)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e705.0 (300-1200)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 55px;\"\u003e\n \u003cp\u003eLTG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003e135.9 (25-250)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003e131.3 (25-250)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003e132.8 (25-250)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e137.5 (25-250)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e3.3 Clearance changes of AEDs during pregnancy\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study evaluated changes in apparent oral clearance (Cl) of AEDs in every trimester during pregnancy. As shown in figure 4, both LEV and LTG showed progressive increases in Cl throughout gestation. Though inter-trimester comparisons represented no significant differences, Cl of LEV increased by 30%, 40%, and 60% above baseline values in the first, second and third trimesters, respectively (p \u0026lt; 0.05,Figure 4A). Also, LTG displayed peak Cl increase during the third trimester, reaching 2.0 times baseline values (p \u0026lt; 0.05,Figure 4C). In contrast, Cl of OXC during pregnancy showed no significant difference comparable to non-pregnant baseline level throughout all gestational stages (Figure 4B).\u003c/p\u003e\n\u003cp\u003e3.4 Correlation between serum concentration and seizure frequency during pregnancy\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe calculated the\u0026nbsp;ratio of AED concentration to the individual non-pregnant baseline concentration (RTC) in each trimester. Generally, RTC values for all three AEDs declined progressively throughout pregnancy (Figure 5). The minimum RTC values for LEV and OXC occurred in the third trimester, representing decreases of 27.1% and 22.3% compared to the pre-pregnancy levels, respectively (Figure 5). Notably, a sharp decline in RTC was observed for LTG during both the second (42.5% decrease) and third (45.7% decrease) trimester in comparison to the nonpregnant baseline (Figure 5).\u003c/p\u003e\n\u003cp\u003eAn overview of the changes in epileptic frequency during pregnancy were presented in Table 3. Among participants receiving LEV, OXC, or LTG monotherapy, seizure frequency increased in all trimesters. Of 36 total pregnancies, 20 (55.6%) experienced worsened seizures at any gestational stage (Table 3) This included 8 on LEV monotherapy, 3 on LTG, 1 on OXC, 2 on LEV+OXC polytherapy, and 4 on LEV+LTG polytherapy. For the 23 pregnancies on LEV monotherapy, seizure frequency increased in 6 (26.1%), 9 (39.1%), and 11 (47.8%) during the first, second, and third trimesters, respectively (Table 3). Among 16 pregnancies receiving LTG, 7 (43.8%) suffered increased seizures frequency in the third trimester (Table 3). Seizure deterioration progressively increased with gestational advancement for pregnancies on LEV and LTG. In contrast, the number of pregnancies experienced seizure exacerbation remained relatively stable in frequency among patients treated with OXC (Table 3).\u003c/p\u003e\n\u003cp\u003eTo clarify the relationship between seizure frequency and AEDs blood level changes, we compared RTC values in pregnancies with increased seizure frequency versus those without per trimester(Table 3). The results revealed that lower RTCs were significantly associated with higher risk of seizure worsening during the first trimester for all three AED (p \u0026lt; 0.05). In contrast, no significant differences emerged in the second or third trimesters. Furthermore, a receiver operating characteristic (ROC) curve evaluated RTC thresholds predicting seizure deterioration risk (Figure 6). RTC reductions exceeding these thresholds indicated increased risk of seizure worsening. For LEV, an RTC decline \u0026gt;43% correlated with higher seizure worsening risk during the first trimester (Figure 6). In addition, serum concentration below 74% (LTG) and 85% (OXC) of the target levels might be predictors of increased seizure frequency in the first trimester (Figure 6).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3\u003c/strong\u003e. Seizure frequency changes during pregnancy and relation of seizure frequency to RTC of AEDs.\u003c/p\u003e\n\u003cdiv align=\"Left\"\u003e\n \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"568\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 140px;\"\u003e\n \u003cp\u003eStages of pregnancy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 144px;\"\u003e\n \u003cp\u003e1st trimester\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 144px;\"\u003e\n \u003cp\u003e2nd trimester\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 140px;\"\u003e\n \u003cp\u003e3rd trimester\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 140px;\"\u003e\n \u003cp\u003eChanges in epileptic frequency\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 41px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eLEV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003eSamples (% of total participants)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e6 (26.1)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e17 (73.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e9 (39.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e14 (60.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e11 (47.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e12 (52.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003eRatio to target concentration\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.56 \u0026plusmn; 0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.84 \u0026plusmn; 0.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e0.65 \u0026plusmn; 0.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e0.81 \u0026plusmn; 0.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e0.68 \u0026plusmn; 0.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e0.77 \u0026plusmn; 0.18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003ep*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 144px;\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 144px;\"\u003e\n \u003cp\u003e0.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 140px;\"\u003e\n \u003cp\u003e0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 41px;\"\u003e\n \u003cp\u003eOXC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003eSamples (% of total participants)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e2 (20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e8 (80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e3 (30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e7 (70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e2 (20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e8 (80)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003eRatio to target concentration\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.47 \u0026plusmn; 0.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.92 \u0026plusmn; 0.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e0.61 \u0026plusmn; 0.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e0.90 \u0026plusmn; 0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e0.76 \u0026plusmn; 0.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e0.84 \u0026plusmn; 0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003ep*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 144px;\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 144px;\"\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 140px;\"\u003e\n \u003cp\u003e0.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 41px;\"\u003e\n \u003cp\u003eLTG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003eSamples (% of total participants)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e3 (18.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e13 (81.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e5 (31.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e11 (68.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e7 (43.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e9 (56.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003eRatio to target concentration\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.52 \u0026plusmn; 0.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.82 \u0026plusmn; 0.09\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e0.55 \u0026plusmn; 0.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e0.63 \u0026plusmn; 0.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e0.52 \u0026plusmn; 0.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e0.57 \u0026plusmn; 0.32\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003ep*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 144px;\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 144px;\"\u003e\n \u003cp\u003e0.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 140px;\"\u003e\n \u003cp\u003e0.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e* T-tests were used to compare RTC values between pregnancies exhibiting increased seizure frequency versus those without in each trimester. A p-value \u0026lt; 0.05 indicated statistical significance.. *p \u0026lt; 0.05 indicated statistical significance.\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003ePrevious reports on changes in AEDS clearance during pregnancy were predominantly involved Caucasian populations. Evidence regarding pharmacokinetic alterations of newer AEDs and dosage adjustments for pregnant women, particularly for Asian populations, remains limited. Our study provides valuable pharmacokinetic data on second-generation AEDs, oxcarbazepine, and lamotrigine—during pregnancy in Chinese population. Our results confirmed that alterations in AED pharmacokinetics were common for pregnant woman. Using Cl as a dose- and weight-corrected metric for plasma AED concentrations, we found significant increases in Cl. These increases would resulted in decreased AED blood levles without compensatory dose adjustments, particularly in LTG and LEV monotherapy participates. We also observed progressive increases in seizure frequency throughout gestation in pregnancies treated with LEV and LTG.\u003c/p\u003e\n\u003cp\u003eLEV and LTG have become frequently prescribed antiepileptic drugs for women with epilepsy due to their high oral bioavailability and low teratogenic risk[24,25]. Our prospective study corroborates prior evidence demonstrating markedly increased Cl of LEV and LTG during pregnancy compared to non-pregnant baseline values[26,27]. We observed elevated Cl of LEV as early as the first trimester, with peak Cl increasing 1.6-fold (p \u0026lt; 0.05, Fig. 4A) and concomitant serum concentrations decreasing by 38.2% (p \u0026lt; 0.05,Fig. 3A). Since LEV undergoes predominantly renal excretion in unchanged form[28,29], this enhanced Cl during early pregnancy probably results from increased renal blood flow and glomerular filtration rate[30,31]. Similarly, LTG exhibited substantial pharmacokinetic alterations: peak Cl reached 2.11 times the non-pregnant level (p \u0026lt; 0.05, Fig. 4C) and serum concentrations declined by up to 45.7% versus preconception values during the third trimester(Figures 3C). As LTG undergoes extensive hepatic metabolism via uridine-diphosphate glucuronosyltransferases[32,33], this pharmacokinetic changes may be partially ascribed to estrogen-induced augmentation of enhanced glucuronidation would increase OXC clearance, our study detected only minor alterations in OXC Cl and blood levels (p\u0026gt;0.05, Fig.3B and Fig.4B). A recent cohort study also reported no statistically significant changes in OXC pharmacokinetics during pregnancy, aligning with previous evidence indicating stable OXC clearance throughout gestation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePrevious studies have verified that reduced plasma concentrations of AEDs, specifically LEV, LTG, and OXC, correlate with increased seizure frequency during gestination[34]. Our results further confirmed that lower RTCs associated with higher seizure exacerbation rates(Fig.4). To clarify the relationship between seizure frequency and AED concentrations, we compared RTC values per trimester in pregnancies with increased seizure frequency versus those maintaining stable frequency. Our analysis revealed that LEV concentration reductions exceeding 43% predicted worsened seizure control in the first trimester. Similarly, serum concentrations below 74% (LTG) and 85% (OXC) of individual non-pregnant baseline concentrations during the first trimester may predict elevated epilepsy exacerbation risk. These findings underscore the clinical significance of RTC reduction.\u003c/p\u003e\n\u003cp\u003eOur finding that blood concentrations of OXC showed no significant change during pregnancy was consistent with previous studies reporting stable OXC levels in pregnant women. However, the extent of fluctuation in blood concentrations, clearance and RTC differed from previous researches. In a retrospective study of 135 pregnant woman with epilepsy, the results reported 1.9-fold and 2.1-fold increases in baseline clearance for LTG and LEV, respectively, in Caucasian patients\u003csup\u003e[\u003c/sup\u003e35]. Also, a cohort study of 430 participants revealed 56.1% and 36.8% reductions in dose-normalized concentrations for LTG and LEV during pregnancy in Caucasian women[27]. Similarly, a previous study demonstrated a 31.7% decrease in serum concentration and 46.7% increase in clearance for LEV among Israeli women compared to preconception baselines[36]. Furthermore, RTC thresholds in our study differed from established Caucasian thresholds that \u0026gt;35% decrease in AED levels correlating with seizure worsening. It has been recognized that seizure deterioration during pregnancy may stem not only from declining AED levels but also hormonal fluctuations, maternal age, metabolic enzyme polymorphisms, sleep disorders, and stress. We therefore attribute discrepancies between our results and prior studies to individual variability and racial differences. Therefore, we consider the discrepancy between our results and previous studies probably owing to individual variability and racial differences.\u003c/p\u003e\n\u003cp\u003eThere are several limitations of this research. First, inconsistent timing of blood draws relative to the last AED dose and unmonitored patient compliance may have influenced measured AED blood concentrations. Second, the effects of confounding factors including stress, sleep deprivation, hormonal fluctuations, and pre-conception seizure history on AED levels and seizure frequency during pregnancy were not investigated. Additionally, the small sample size, particularly the limited subgroup of women taking OXC, constrains generalizability. Nevertheless, our study contributes available pharmacokinetic data on AED variation in Han Chinese population. Our findings suggest that lower blood concentrations of AEDs correlate with increased seizure frequency, underscoring the clinical value of beginning TDM of AEDs early in pregnancy. Future studies with larger sample size are needed to clarify the the impact of TDM-guided dose adjustments on on seizure control and risks for epilepsy deterioration during pregnancy.\u003c/p\u003e"},{"header":"5.\tConclusion","content":"\u003cp\u003eOur prospective study revealed a significant increase in Cl of LEV and LTG in a Chinese population. Furthermore, the results demonstrated that lower RTC values correlated with increased seizure frequency during pregnancy among all three AEDs. This investigation suggests that TMD of AEDs should begin early in pregnancy with dose adjustments to maintain blood concentration near non-pregnant baselines.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAcknowledgements\u003c/p\u003e\n\u003cp\u003eWe gratefully acknowledge the patients included in our research.\u003c/p\u003e\n\u003cp\u003eAuthors\u0026rsquo;\u0026nbsp;contributions\u003c/p\u003e\n\u003cp\u003eNan ya Hao: Investigation, Data collection, Writing-original draft.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eXiaoli Yi:Methodology, Data curation, and Writing-original draft. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eJianxia Dong:Data curation, Writing-review\u0026amp;editing.\u003c/p\u003e\n\u003cp\u003eDong Zhou:Supervision, Writing-review\u0026amp;editing, Project administration.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThis study was supported by the National Natural Science Foundation of China (82204297), Natural Science Foundation of Sichuan Province (2025ZNSFSC1734), Young Scientists Fund of Sichuan Provincial Natural Science Foundation (2025ZNSFSC1643), Qimingxing Research Fund for Young Talents of West China hospital (HXOMX0093).\u003c/p\u003e\n\u003cp\u003eData availability\u003c/p\u003e\n\u003cp\u003eAll data are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research received approval from the ethics committee of Sichuan University (2022-1847). All participants provided written informed consent allowing the utilization of their anonymized medical data for analysis and publication in this research.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare that they have no competing financial interests in this paper.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eArfman IJ, Wammes-van der Heijden EA, Ter Horst PGJ, Lambrechts DA, Wegner I, Touw DJ. Therapeutic Drug Monitoring of Antiepileptic Drugs in Women with Epilepsy Before, During, and After Pregnancy. Clin Pharmacokinet. 2020;59(4):427-445. \u003c/li\u003e\n\u003cli\u003eNeri S, Mastroianni G, Gardella E, Aguglia U, Rubboli G. Epilepsy in neurodegenerative diseases. Epileptic Disord. 2022;24(2):249-273. \u003c/li\u003e\n\u003cli\u003eMeador KJ, Cohen MJ, Loring DW, May RC, Brown C, Robalino CP, et al. Two-Year-Old Cognitive Outcomes in Children of Pregnant Women With Epilepsy in the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs Study. JAMA Neurol. 2021 ;78(8):927-936.\u003c/li\u003e\n\u003cli\u003ePa B, G SS, Thomas G, Kp A. Dosage Optimization of Lamotrigine in Pregnancy: A Pharmacometric Approach Using Modeling and Simulation. J Clin Pharmacol. 2022 ;62(12):1557-1565.\u003c/li\u003e\n\u003cli\u003eAndrade C. Epilepsy, Antiepileptic Drugs, and Adverse Pregnancy Outcomes, 2: Major Congenital Malformations With Antiepileptic Drug Monotherapy. J Clin Psychiat. 2024 ;85(3):24f15432. \u003c/li\u003e\n\u003cli\u003eShi X, Wang Y, Zhang Y, Song C, Jiang Y, Zhao J, et al.. Effects of antiepileptic drugs polytherapy on pregnancy outcomes in women with epilepsy: An observation study in northwest China. Epilepsy Behav. 2022 ;135:108904. \u003c/li\u003e\n\u003cli\u003eThigpen J, Owens HD. The Use of Antiepileptic Drugs During Pregnancy and Fetal Outcomes. Neonatal Netw. 2022 ;41(4):226-231.\u003c/li\u003e\n\u003cli\u003eBirnbaum AK, Meador KJ, Karanam A, Brown C, May RC, Gerard EE, et al. Antiepileptic Drug Exposure in Infants of Breastfeeding Mothers With Epilepsy. JAMA Neurol. 2020 ;77(4):441-450. \u003c/li\u003e\n\u003cli\u003eLagae L. The importance of assessing behaviour and cognition in antiepileptic drug trials in children and adolescents. Acta Neurol Belg. 2017 ;117(2):425-432. \u003c/li\u003e\n\u003cli\u003eSchelhaas M, Wegner I, Edens M, Wammes-Van Der Heijden E, Touw D, Ter Horst P. Association of Levetiracetam Concentration With Seizure Frequency in Pregnant Women With Epilepsy. Neurology. 2023;100(2):e172-e181. \u003c/li\u003e\n\u003cli\u003eYuan Y, Zhang S, Yuan Y, Yan X, Zhang L, Ran YW. Pharmacogenomics of oxcarbazepine in the treatment of epilepsy. Pharmacogenomics. 2023 ;24(6):335-343. \u003c/li\u003e\n\u003cli\u003eKacirova I, Grundmann M, Brozmanova H. Monitoring of lamotrigine concentrations in mothers, colostrum, and breastfed newborns during the early postpartum period. Biomed Pharmacother. 2022 ;151:113167.\u003c/li\u003e\n\u003cli\u003eKaranam A, Pennell PB, French JA, Harden CL, Allien S, Lau C, et al. Lamotrigine clearance increases by 5 weeks gestational age: Relationship to estradiol concentrations and gestational age. Ann Neurol. 2018 ;84(4):556-563.\u003c/li\u003e\n\u003cli\u003eWang ML, Tao YY, Sun XY, Guo Y, Wang ZY, Cao YF, et al. Estrogen profile and pharmacogenetics-based lamotrigine dosing regimen optimization: Recommendations for pregnant women with epilepsy. Pharmacol Res. 2021 ;169:105610. \u003c/li\u003e\n\u003cli\u003eVoinescu PE, Park S, Chen LQ, Stowe ZN, Newport DJ, Ritchie JC, et al. Antiepileptic drug clearances during pregnancy and clinical implications for women with epilepsy.Neurology. 2018 ;91(13):e1228-e1236. \u003c/li\u003e\n\u003cli\u003eFreund B, Chen B, Kaplan PW, Johnson EL. Managing Antiseizure Medications in Pregnancy: Is Earlier and More Frequent Monitoring Better? Neurol Clin Pract. 2023;13(4):e200169.\u003c/li\u003e\n\u003cli\u003eReisinger TL, Newman M, Loring DW, Pennell PB, Meador KJ. Antiepileptic drug clearance and seizure frequency during pregnancy in women with epilepsy. Epilepsy Behav. 2013;29(1):13-8. \u003c/li\u003e\n\u003cli\u003eHarden CL, Hopp J, Ting TY, Pennell PB, French JA, Allen Hauser W, et al. Management issues for women with epilepsy-Focus on pregnancy (an evidence-based review): I. Obstetrical complications and change in seizure frequency: Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Epilepsia. 2009 May;50(5):1229-36. \u003c/li\u003e\n\u003cli\u003eKumaravel J, Sarma P, Suri V, Singh P, Prakash A, Medhi B. Therapeutic Drug Monitoring of Levetiracetam in Different Trimesters of Pregnant Women with Epilepsy in a Tertiary Care Center: A Prospective Study. Neurol India. 2024 ;72(2):358-363. \u003c/li\u003e\n\u003cli\u003eJim\u0026eacute;nez M, Grau-L\u0026oacute;pez L, Ciurans J, Garc\u0026iacute;a-Esper\u0026oacute;n C, Fumanal A, Barambio S, et al. Epilepsy and pregnancy. Factors associated with epileptic seizures during pregnancy.Neurologia. 2023;38(2):106-113. \u003c/li\u003e\n\u003cli\u003eSpecchio N, Wirrell EC, Scheffer IE, Nabbout R, Riney K, Samia P, et al. International League Against Epilepsy classification and definition of epilepsy syndromes with onset in childhood: Position paper by the ILAE Task Force on Nosology and Definitions. Epilepsia. 2022;63(6):1398-1442. \u003c/li\u003e\n\u003cli\u003eJohnson EL, Stowe ZN, Ritchie JC, Newport DJ, Newman ML, Knight B, et al. Carbamazepine clearance and seizure stability during pregnancy. Epilepsy Behav. 2014;33:49-53. \u003c/li\u003e\n\u003cli\u003eKaranam A, Pennell PB, Meador KJ, Long Y, Birnbaum AK. Characterization of lamotrigine disposition changes during and after pregnancy in women with epilepsy.Pharmacotherapy. 2025;45(1):33-42. \u003c/li\u003e\n\u003cli\u003eMari L, Placidi F, Romigi A, Tombini M, Del Bianco C, Ulivi M, et al. Levetiracetam, lamotrigine and carbamazepine: which monotherapy during pregnancy? Neurol Sci. 2022;43(3):1993-2001.\u003c/li\u003e\n\u003cli\u003eStjerna S, Huber-Mollema Y, Tomson T, Perucca E, Battino D, Craig J, et al. Cognitive outcomes after fetal exposure to carbamazepine, lamotrigine, valproate or levetiracetam monotherapy: Data from the EURAP neurocognitive extension protocol. Epilepsy Behav. 2024 ;159:110024. \u003c/li\u003e\n\u003cli\u003ePennell PB, Karanam A, Meador KJ, Gerard E, Kalayjian L, Penovich P, et al. Antiseizure Medication Concentrations During Pregnancy: Results From the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) Study. JAMA Neurol. 2022;79(4):370-379. \u003c/li\u003e\n\u003cli\u003eLarcin L, Ngwasiri C, Neven A, Damase-Michel C, Kirakoya-Samadoulougou F. Real-World Assessment of Psychotropic and Antiepileptic Drug Use During Pregnancy in Belgium: Trends, Predictors, and Comparative Risk of Congenital Anomalies (2010-2016). Pharmacoepidem Dr S. 2024;33(10):e70021.\u003c/li\u003e\n\u003cli\u003eChappell K, Kimmons LA, Haller JT, Canada RB, He H, Hudson JQ. Levetiracetam pharmacokinetics in critically ill patients undergoing renal replacement therapy. J Crit Care. 2021;61:216-220. \u003c/li\u003e\n\u003cli\u003eKalaria SN, Armahizer M, McCarthy P, Badjatia N, Gobburu JV, Gopalakrishnan M. A Practice-Based, Clinical Pharmacokinetic Study to Inform Levetiracetam Dosing in Critically Ill Patients Undergoing Continuous Venovenous Hemofiltration (PADRE-01). J Clin Transl Sci.2020;13(5):950-959. \u003c/li\u003e\n\u003cli\u003eHochbaum M, Kienitz R, Rosenow F, Schulz J, Habermehl L, Langenbruch L, et al. Trends in antiseizure medication prescription patterns among all adults, women, and older adults with epilepsy: A German longitudinal analysis from 2008 to 2020. Epilepsy Behav. 2022;130:108666. \u003c/li\u003e\n\u003cli\u003eReimers A, Brodtkorb E. Second-generation antiepileptic drugs and pregnancy: a guide for clinicians. Expert Rev Neurother. 2012;12(6):707-17. \u003c/li\u003e\n\u003cli\u003eLee ZN, van Nuland M, Bogn\u0026agrave;r T, Leijten FSS, van der Elst KCM. Association of Lamotrigine Plasma Concentrations With Efficacy and Toxicity in Patients With Epilepsy: A Retrospective Study. Ther Drug Monit. 2024;46(5):642-648. \u003c/li\u003e\n\u003cli\u003eWang W, Battini V, Carnovale C, Noordam R, van Dijk KW, Kragholm KH, et al. A novel approach for pharmacological substantiation of safety signals using plasma concentrations of medication and administrative/healthcare databases: A case study using Danish registries for an FDA warning on lamotrigine. Pharmacol Res.2023;193:106811. \u003c/li\u003e\n\u003cli\u003eYin X, Liu Y, Guo Y, Zhao L, Li G, Tan X. Pharmacokinetic changes for newer antiepileptic drugs and seizure control during pregnancy.Cns Neurosci Ther. 2022;28(5):658-666. \u003c/li\u003e\n\u003cli\u003eHao N, Abdulaziz AT, Lu L, Chen Y, Li T, Liu J, et al. Seizure control and pregnancy outcomes in Chinese women with epilepsy: A prospective multicenter cohort study. Epilepsia.2025 ;66(5):1573-1584. \u003c/li\u003e\n\u003cli\u003eYin X, Liu Y, Guo Y, Zhao L, Li G, Tan X. Pharmacokinetic changes for newer antiepileptic drugs and seizure control during pregnancy. CNS Neurosci Ther. 2022;28(5):658-666.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Antiepileptic drugs, therapeutic drug monitoring (TDM), pharmacokinetic changes, seizure frequency","lastPublishedDoi":"10.21203/rs.3.rs-8245797/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8245797/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e\u003cp\u003eThe study aims to investigate pharmacokinetic alterations in second-generation antiepileptic drugs (AEDs) and evaluate the relationship between drug blood concentration fluctuations and the seizure control deterioration in pregnant women.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eA prospective study was conducted in 52 pregnancies with epilepsy. Clinical data of participants including oral daily doses and seizure frequency were acquired from the patients\u0026rsquo; routine clinical practice. Blood AEDs concentrations obtained via therapeutic drug monitoring(TDM) were used to calculate apparent oral clearance at preconception and each trimester during pregnancy. Clearane changes were assessed between non-pregnant baseline and gestational trimesters. The ratio of AEDs concentration to the individual preconception baseline concentration (RTC) in each trimester was compared between patients experiencing seizure deterioration and those maintaining stability. Moreover, receiver operating characteristic (ROC) curve predicted the threshold RTC for increased seizure frequency.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eThe apparent oral clearance of levetiracetam (LEV) and lamotrigine (LTG) showed a significant increase across all trimesters versus nonpregnant baseline. Peak clearance occurred in the third trimester for LTG with a 2.0-fold relative clearance (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05).Similarly, LEV displayed maximum apparent oral clearance(Cl) increase during the third trimester, reaching 1.6 times baseline values (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). As a result, serum concentrations of LEV and LTG significantly decreased during pregnancy compared to non-pregnant baseline levels (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). However, apparent oral clearance and blood level of oxcarbazepine (OXC) remained stable throughout gestation compared to preconception baseline. Moreover, RTC values significantly differed between participants with and without seizure deterioration for all three AEDs, indicating lower RTCs were associated with seizure worsening.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eSignificant pharmacokinetic fluctuations in LEV and LTG were observed in Chinese pregnant women. Our study validated the necessity of early therapeutic drug monitoring of newer AEDs and dose adjustments to maintain blood concentrations near non-pregnant baselines for pregnant women with epilepsy.\u003c/p\u003e","manuscriptTitle":"Pharmacokinetic Changes and Seizure Outcomes in Pregnant Women Taking Second-Generation Antiepileptic Drugs","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-12 08:33:55","doi":"10.21203/rs.3.rs-8245797/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9f3e2264-076c-4565-84a2-10f87cc73731","owner":[],"postedDate":"December 12th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-29T02:24:52+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-12 08:33:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8245797","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8245797","identity":"rs-8245797","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}