背景
癲癇是一種慢性神經系統疾病，在已開發國家約有0.3%至1%的孕婦患有此疾病。患有癲癇的孕婦相較於一般孕婦還是有較高的死亡率和發生不良結果的風險，包括自發性流產和產後出血。懷孕期間的癲癇發作與產生胎兒併發症有關，如低出生體重、早產、胎齡過小和發育遲緩。因此會建議患有癲癇的孕婦在懷孕期間應繼續使用抗癲癇藥物。

然而，懷孕期間抗癲癇藥物的使用是否對胎兒有不良影響，如先天性畸形和神經發育障礙，可能導致懷孕的癲癇婦女停止使用抗癲癇藥物或減少劑量。過去的研究發現懷孕期間抗癲癇藥物處方率會下降，且因服藥依從性不佳而增加癲癇發作機率。然而瑞典的研究針對在懷孕前十年內曾有癲癇診斷，定義為患有active epilepsy的懷孕婦女 (WWAE)，並未發現懷孕期間不使用抗癲癇藥物會增加不良懷孕結果的風險。這不同的結果可能受到‶active epilepsy″定義，導致的confounding by indication影響。

我們曾以台灣健保資料庫分析2004年至2017年間抗癲癇藥物處方模式，也顯示WWAE在懷孕期間會減少抗癲癇藥物的使用。另外，使用抗癲癇藥品的比例明顯低於歐美國家。

對於懷孕期間抗癲癇藥物的使用與暴露的風險，在亞洲族群的證據仍有限。因此，需要進一步的研究針對WWAE族群評估其懷孕期間抗癲癇藥物的使用情況以及藥物暴露對母親和後代的影響。

研究目的
本研究旨在分析患有active epilepsy的懷孕婦女在懷孕期間抗癲癇藥物的使用情形，並評估在孕期使用抗癲癇藥物對此族群懷孕婦女和子代的短期及長期影響。

研究方法
本研究的資料來源包含台灣健保資料庫、出生通報檔、婦幼主題式資料庫、重大傷病檔和身心障礙檔。研究擷取自2009至2019年懷孕前被診斷為癲癇的15至55歲女性。利用產檢記錄來識別懷孕婦女，active epilepsy的定義為懷孕前兩年有兩次以上門診或一次住院癲癇就醫紀錄或曾開立抗癲癇藥品。利用出生通報檔與婦幼主題式資料庫串聯確認last menstrual period (LMP)。描述性分析包含懷孕前、懷孕期間和懷孕後的抗癲癇藥物使用情況。應用fixed time logistic regression model分析發生各種不良產前和產後結果之風險，並以Cox proportional hazard model分析孩童神經發育障礙之風險。研究也進行了多個敏感性分析，包括利用廣義估計式(Generalized estimating equations, GEE)統計懷孕期間不同暴露狀態的風險。

結果
本研究共納入2,492名患有active epilepsy的懷孕婦女。從2009年到2019年，第二代抗癲癇藥物的使用量逐年增加(從47-55%到60-80%)，而第一代抗癲癇藥物的使用量則逐年減少(從44-59%到17-33%)。研究結果顯示，懷孕期間有使用抗癲癇藥物的孕婦相較於未使用者在發生不良產前和產後結果上未達統計學上的顯著差異。然而，本研究觀察到未使用者有較高的不良產後結果發生率(event rate)，但使用者中先天性畸形的發生率較高。敏感性分析結果與主要分析結果皆相似。GEE分析結果顯示，懷孕期間使用多種抗癲癇藥物治療較單一治療有較高的不良產前結果的事件發生率，但仍未達統計上顯著差異。

結論
本研究評估二年內有癲癇就醫過的active epilepsy懷孕婦女，在懷孕期間抗癲癇藥物使用與停用之懷孕風險。在懷孕期間未使用抗癲癇藥物會有較高的不良結果的事件發生率，但未達統計學上差異。我們的研究結果，顯示國內臨床處置依循在懷孕期間繼續使用抗癲癇藥物的治療建議，尤其是對懷孕前六個月內尚有癲癇相關記錄的懷孕婦女。

BACKGROUND
Epilepsy is a chronic neurological disorder affecting 0.3% to 1% pregnant women in developed countries. Although most pregnant women with epilepsy (WWE) experience uncomplicated pregnancies, there is an increased risk of maternal mortality and adverse outcomes, including spontaneous miscarriage and postpartum hemorrhage. Seizures during pregnancy are associated with fetal complications such as low birth weight, preterm birth, small size for gestational age, and developmental delays. To mitigate risks, WWE are advised to continue their antiepileptic drugs (AEDs) therapy during pregnancy.

However, previous studies have raised concerns about the adverse effects of prenatal AEDs exposure on the offspring, including major congenital malformations (MCMs) and neurodevelopmental disorders (NDDs). Fears of these adverse effects may lead pregnant WWE to discontinue or reduce their AED dosage. Several studies have reported a decline in AED prescription rates during pregnancy and higher seizure rate was observed in non-compliant WWE. In contrast, a study in Sweden focused on women with active epilepsy (WWAE), defined as having an epilepsy diagnosis within ten years prior to conception, and found that AEDs non-exposure during pregnancy did not increase the risk of adverse pregnancy outcomes. These different outcomes may be influenced by confounding by indications due to the definition of active epilepsy.

Our analysis of pregnant WWAE between 2004 and 2017 using Taiwan National Health Insurance Databases (NHID) revealed a decreased AEDs prescription pattern during pregnancy. Furthermore, the analysis also indicated the AEDs prescription rate in WWAE is notably lower than that in Western countries.

Limited evidence exists on the risk of prenatal AEDs exposure and the AEDs utilization pattern in pregnant WWAE in Asia population. Thus, further research focusing on the WWAE population is necessary to evaluate AEDs use during pregnancy and the effects of prenatal AEDs exposure on mothers and offspring in Taiwan.

OBJECTIVE
The objectives of this study were to investigating the AEDs prescription pattern and to evaluate AEDs exposure during pregnancy and its impact on mothers and offspring among WWAE.

METHODS
Several databases, including the Taiwan NHID, Birth Certificate Database, Maternal and Child Health Database, Registry for Catastrophic Illness Database, and Disable Database were used in this study. Women aged 15 to 55 with epilepsy diagnosed prior to pregnancy from 2009 to 2019 were extracted. Pregnant women were identified through prenatal visit records, and active epilepsy was defined as with at least one diagnostic code for epilepsy on separate dates or at least one hospitalization of epilepsy or at least one prescription of AEDs within two years prior to conception. Birth Certificate Database and Maternal and Child Health Database were linked to establish the last menstrual period (LMP). AEDs exposure was analyzed before, during, and after pregnancy. Various prenatal and postnatal outcomes, as well as neurodevelopmental disorders, were evaluated. Fixed time logistic regression, and Cox proportional hazard models were used for data analysis. Sensitivity analyses were performed, including redefining the observational period of active epilepsy, propensity score matching, and stratified analysis based on comorbidities, etc. Generalized estimating equations (GEE) was used to adjust the dynamic AEDs exposure status in three trimesters.

RESULTS
2,492 WWAE were enrolled in this study. The utilization of 2nd generation AEDs increased over time (from 47-55% to 60-80%), while 1st generation AEDs declined (from 44-59% to 17-33%). The study found no statistically significant risk of prenatal and postnatal outcomes between women exposed to AEDs and those who were not. Increased event rate of adverse outcomes such as most of postnatal outcomes in the non-exposure group was observed in this study, while the incidence of congenital malformations was higher in the exposure group. Several sensitivity analyses showed similar results with primary analysis. The GEE analysis indicated that AEDs polytherapy was associated with marginal significant risk of prenatal outcomes.

CONCLUSION
This study evaluated pregnant WWAE who had sought medical care for epilepsy within two years before pregnancy. Among them, 42% discontinued the AEDs use during pregnancy. While there was a higher incidence of adverse outcomes in pregnant WWAE who did not use AEDs during pregnancy, this difference did not reach statistical significance. Our research findings indicated that clinical practice in Taiwan follows the guideline recommendations of continuing AEDs therapy during pregnancy, especially for pregnant women who have epilepsy-related records within the six months of pregnancy.

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