幼兒時期全身麻醉與神經發展疾病的關聯性

The Association of Early Life General Anesthesia Exposure with Neurodevelopmental Disorders

柯玟如(Wen-Ru Ko)

指導教授 ： 林隆堯

中山醫學大學/醫學院/醫學研究所/博士(2014年)

https://doi.org/10.6834/CSMU.2014.00067

摘要

研究目的: 許多動物實驗發現全身麻醉劑會導致囓齒動物與哺乳動物的未成熟神經系統發生細胞凋亡和退化現象。有些研究也觀察到動物的新生兒時期暴露於全身麻醉藥物會造成長期的認知、學習及記憶功能缺損。人類嬰幼兒接受全身麻醉是否會導致神經系統後遺症，成為一個重要的議題。本研究以台灣全民健康保險研究資料庫為材料，設計全國性的縱向研究，探討嬰幼兒時期接受全身麻醉與注意力缺陷過動症(ADHD)及自閉症風險的關聯性。
材料與方法: 使用之資料來自台灣「全民健康保險研究資料庫」；採用兩組一百萬抽樣檔案的資料庫(2005年和2010年) ，並刪除重複抽樣者。研究一: 選取出生日期介於2001年1月1日和2005年12月31日者；排除三歲前已被診斷注意力缺陷/過動症者。三歲前出現全身麻醉申報碼者，即被歸類於暴露組；以性別及出生年月為根據，將每一個暴露的個體配對四個三歲前未接受過全身麻醉者，構成控制組。追蹤的標的設定為「三歲後出現注意力缺陷/過動症」。研究二: 選取出生日期介於2001年1月1日和2007年12月31日者；二歲前曾出現全身麻醉申報碼且全身麻醉之前未曾有自閉症診斷者，即被歸類於暴露組；以性別及出生年月為根據，將每一個暴露的個體配對四個二歲前未曾接受過全身麻醉且在指標日之前未有自閉症診斷者，構成控制組。追蹤的標的設定為「自閉症」。兩個研究的追蹤於2010年12月31日截止；以Cox氏比例危害模型加入潛在干擾因子調整，分析全身麻醉是否增加ADHD及自閉症的風險。
研究結果: 研究一: 此研究共包含暴露組3,293人；配對控制組 13,172人。對發生注意力缺陷/過動症而言，全身麻醉暴露之調整後危害比是1.06 (95%信賴區間: 0.86-1.31)； 單次暴露之調整後危害比1.11 (95%信賴區間: 0.88-1.41) ；多次暴露為0.96 (95%信賴區間: 0.71-1.31)；首次暴露的年齡與注意力缺陷/過動症風險之間也沒有關聯。研究二: 暴露組共5,197人，配對控制組共20,788人；兩組之自閉症發生率並無顯著差別(暴露組0.96%；控制組0.89%；P值= .62)。全身麻醉暴露之調整後危害比 0.93 (95% 信賴區間: 0.57- 1.53)；首次麻醉年齡和累計麻醉次數都與自閉症發生的風險無關。
結論與展望: 三歲前暴露於全身麻醉和注意力缺陷/過動症的風險無關聯；二歲前暴露於全身麻醉並不會增加自閉症的風險。未來展望為採用適當的研究對象和合適的研究設計，進一步研究全身麻醉和其他神經發展疾患的關聯性。

關鍵字

小兒麻醉 ； 全民健保研究資料庫 ； 自閉症 ； 注意力缺陷過動症 ； 神經發展

並列摘要

Background: Postnatal exposure to anesthetics causes neural apoptosis and degeneration in animals, but results from studies conducted on humans were discordant. Though some genes seem to contribute to susceptibility of neurodevelopmental disorders, other factors like perinatal insults and exposure to neurotoxic agents may also play important roles in gene-environmental interaction. Previous studies did not provide any information of the relationship between neurobehavioural disorders and anesthesia exposure in Asian children. We conducted two retrospective matched-cohort studies in Taiwan to investigate the association of early life anesthesia exposure with risk of attention deficit/hyperactivity disorder (ADHD) and autistic disorder.
Materials and Methods: Data were depicted from the National Health Insurance Research Database of Taiwan. Study I. Children born between 2001/01/01 and 2005/12/31 were included. Each child with general anesthesia exposure before three years of age was matched to four unexposed children. Proportional hazards regression was used to assess the association of anesthesia exposure with risk of ADHD. Study II. Children born between 2001/01/01 and 2007/12/31 were included. Each child with anesthesia exposure before two years of age was matched to four unexposed children. Proportional hazards regression was used to assess the association of anesthesia exposure with risk of developing autistic disorder. For both studies, the observation were concluded on 2010/12/31. Additional analyses were also made based on cumulative exposure number and age at the time of the first exposure.
Results: Study I. This matched-cohort comprised of 16,465 children, among which 3,293 were exposed to general anesthesia before three years of age. The adjusted hazard ratio of developing ADHD was 1.06 (95% CI: 0.86,1.31) for general anesthesia exposure. The adjusted hazard ratio of developing ADHD for single and multiple exposures was1.11 (95% CI: 0.88, 1.41) and 0.96 (95% CI: 0.71,1.31 ), respectively. No trend of increasing risk was noted based on age at the time of first exposure.
Study II. There were 5,197 children who were exposed to general anesthesia before the age of two. The 1:4 matched controls comprised 20,788 children. There were no differences in incidence of autistic disorder between the exposed group (0.96%) and the unexposed controls (0.89%). (P = .62) Cox proportional hazards regression showed that the hazard ratio of exposure to general anesthesia was 0.93 (95% confidence interval: 0.57, 1.53) after adjusting for potential confounders. Age at the first exposure did not influence the risk of autistic disorder. No relationship was noted between the total number of exposures and risk of autistic disorder.
Conclusions: Exposure to general anesthesia before three years of age did not increase the risk of ADHD. Exposure to general anesthesia before the age of two were not associated with development of autistic disorder.
No relationship could be identified between age at the first exposure or number of exposure and the risk of developing ADHD or autistic disorder.

並列關鍵字

attention deficit disorder with hyperactivity ； autistic disorder ； child ； general anesthesia ； cohort studies ； health insurance

參考文獻

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