研究背景
自閉症譜系障礙自2008年至2018年，在東亞地區盛行率為0.51%。過去十年間，自閉症譜系障礙之全球盛行率劇增。截至2023年，台灣有19,790位自閉症譜系障礙患者。自閉症譜系障礙之明確病因仍未知，然目前已知其遺傳力約有80%，且基因表現可能受外在環境因素干擾。造成自閉症譜系障礙之風險因子包含懷孕期間母體因素、毒藥物及環境暴露、母體感染及父母高齡等多項原因。過去病理解剖發現，自閉症譜系障礙患者大腦中蕈毒鹼受體顯著減少；另有多項隨機對照試驗探討膽鹼脂酶抑制劑對於自閉症譜系障礙症狀之療效，顯示膽鹼系統不足與自閉症譜系障礙之關聯。先前已有探索性試驗發現孕期暴露膽鹼受體阻斷劑與自閉症譜系障礙之關聯，然目前未有孕期抗膽鹼負載與子代自閉症譜系障礙關聯性之研究。

研究目的
探討懷孕期間抗膽鹼負載與自閉症譜系障礙、廣泛性發展障礙、神經發展疾患及不良出生結果的風險之關聯。

研究方法
本研究進行全國性的回溯性世代研究。利用婦幼主題式資料庫、台灣健保資料庫、出生通報檔，納入於2004至2020年間單胞胎妊娠的孕婦及其子代，並排除妊娠年齡小於15歲或大於50歲的孕婦及性別登記異常之孕婦，亦排除缺乏胎兒妊娠周數及出生體重資訊的母子對，做為本研究族群。我們使用抗膽鹼負載量表 （Anticholinergic cognitive burden scale, ACB） 進行孕婦在第二妊娠期與第三妊娠期，用藥抗膽鹼負載之測量。研究結果是子代的神經發育障礙，從出生開始追踪，直到結果發生、子代年滿18歲、死亡或資料庫的時間終點，以先到者為準。我們應用傾向分數進行細項分組加權 （propensity score with fine stratification weighting） 控制可測量之干擾因子，以獲得了兩個協變量平衡的比較組。我們比較了在孕期間暴露於母親ACB分數為至少3分的兒童與暴露於ACB分數小於3分的兒童的風險差異。利用Cox比例風險迴歸 （Cox proportional hazards models） 進行神經發育障礙結果之風險比計算及其95%信賴區間，以評估妊娠期抗膽鹼負載與子代的神經發育障礙之間的關聯。此外我們由研究族群中選擇至少有兩個子代的母親，進行了手足對照分析，以檢驗潛在的遺傳或環境因素干擾效應。

研究結果與討論
本研究共納入2,939,670對母子，其中1,935,645對被用於手足對照分析。在主分析中我們發現母親的孕期ACB分數為至少3分與其子代患自閉症譜系障礙的風險增加顯著相關；與ACB得分小於3的母親相比，其校正後的風險比為1.11 （95% CI，1.09-1.12）。然而此關聯性在手足對照分析中並未觀察到，校正後的風險比為0.66 （95% CI，0.33-1.23），顯示主分析中觀察到的結果可能受基因與環境因素等干擾因子所影響。

結論
根據我們的研究結果，懷孕期間的抗膽鹼負載與子代自閉症譜系障礙的風險之間似乎沒有因果關係。儘管主分析最初表明母親孕期抗膽鹼負載較高的子代患自閉症譜系障礙的風險較高，但隨後的敏感性分析並不支持此關聯性。然而考慮到抗膽鹼負載較高的孕婦，其子代自閉症譜系障礙發病率仍相對較高，臨床醫師應更加關注並密切監測這群孕婦。

The prevalence of autism spectrum disorder (ASD) has significantly increased globally, including in Taiwan, over the last decade. Studies suggest a relationship between decreased cholinergic status in the brain and ASD, and an association between medications affecting the cholinergic system prenatally and ASD risk in children. Therefore, we conducted a population-based retrospective cohort study to investigate the association between anticholinergic burden during pregnancy and ASD risk in offspring using data from three health databases in Taiwan, including mothers with singleton pregnancies from 2004 to 2020. We assessed anticholinergic burden during the second and third trimesters using the Anticholinergic Cognitive Burden scale and followed adverse neurodevelopmental outcomes of children, including ASD. A propensity score with fine stratification weighting approach was used to control for covariates. Among 2,939,670 mother-child pairs, mothers with ACB scores of 3 or higher were associated with increased ASD risk in offspring (aHR 1.11, 95% CI 1.09-1.12). However, this association was not observed in the subsequent sibling control analysis (aHR 0.66, 95% CI 0.33-1.23). We concluded that anticholinergic burden during pregnancy is not causally linked to a higher ASD risk in offspring. The observed association is potentially influenced by genetic or environmental factors.

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