| 摘要: | 研究背景
在早產兒中，動脈導管未閉合的併發症十分常見，超過三成的極低出生體重嬰兒會發生。動脈導管未閉合可能導致肺部過度灌注和全身灌注不足，引起肺水腫、肺出血、支氣管肺發育不良、腦室內出血和壞死性腸炎等併發症，威脅到嬰兒的健康。
目前動脈導管未閉合的治療原則基於三個治療階段。第一階段是限制水分攝入，等待自行閉合，此為保守療法。在第二階段，使用藥物輔助動脈導管閉合。最後，當之前的兩階段治療無效時，將考慮更侵入性的動脈導管結紮手術。然而手術可能導致住院時間延長和嬰兒死亡風險增加。因此，成功的藥物治療可以避免動脈導管結紮手術帶來的不良後果。
非類固醇消炎藥物通常用於治療動脈導管未閉合，其機轉為抑制前列腺素的合成及血管擴張作用。嬰兒在服用非類固醇消炎藥物時可能會出現尿量減少等副作用。為了預防此副作用的產生，醫師會同時處方利尿劑。然而，利尿劑的使用可能通過刺激腎臟前列腺素的分泌，促使動脈導管保持通暢，卻因此可能導致動脈導管未能閉合。
過去的研究結果對於在動脈導管藥物治療中添加利尿劑的效果並未提供明確的實證。為了填補這一研究空白，本研究旨在調查台灣嬰兒中利尿劑與非類固醇消炎藥物聯合使用與需使用動脈導管結紮手術之間的關聯性。
研究目的
本研究有三個研究目的：（1）呈現於2008年至2017年期間台灣接受安胎治療的孕婦及動脈導管未閉合之嬰兒中，分娩前孕婦使用影響動脈導管的產前藥物使用情況及動脈導管的患病率和治療趨勢。（2）評估懷孕期間給予影響動脈導管閉合的藥物與嬰兒發生動脈導管未閉合的風險之間的相關性。（3）評估利尿劑的聯合使用與動脈導管未閉合之嬰兒需要進行動脈導管結紮手術的風險之間的相關性。
研究方法
本研究為回溯性的世代研究。資料來源為台灣衛生福利部之衛生福利資料科學中心的全人口檔。研究族群為2008年1月1日至2017年12月31日的一歲以下之動脈導管未閉合的嬰兒及18歲到49歲之間的孕婦。
第一個研究目的，為觀察與計算呈現於2008年至2017年期間各年度動脈導管未閉合之盛行率，以及分析藥物的年平均百分比變化，包含動脈導管治療藥物與影響動脈導管的產前藥物使用情況。
第二個研究目的之研究族群為18歲以上(含) 49歲以下(含)，於懷孕期間曾接受過安胎處置紀錄之懷孕婦女，並依據影響動脈導管的產前藥物使用狀況分為暴露組與對照組：暴露組定義為在2008年至2017年有影響動脈導管藥物的住院用藥紀錄，且用藥期間為第三孕期或生產前90天，將影響動脈導管藥物分為五大類後與對照組進行比較。對照組則為沒有使用影響動脈導管的產前藥物之曾接受過安胎處置紀錄之懷孕婦女。懷孕日為研究起始日期生產後一年間，追蹤所誕下之嬰兒是否被診斷出動脈導管未閉合或接受過動脈導管結紮手術。
第三個研究目的之研究族群為一歲以下(含)罹患動脈導管未閉合之嬰兒，並依據是否聯合使用利尿劑分為暴露組與對照組：暴露組定義為在出生當天至出生後一個月至少服用一種口服或注射利尿劑並聯合非類固醇消炎藥物治療。對照組則為單獨使用非類固醇消炎藥物治療動脈導管未閉合之嬰兒。出生日為研究起始日期，追蹤從出生後一個月後至一歲期間是否接受過動脈導管結紮手術。
另外，將使用1：1傾向配對分數來平衡暴露組和對照組之間的可測量的干擾因子。將使用多變量羅吉斯迴歸分析模型來評估影響動脈導管的產前藥物暴露與嬰兒罹患動脈導管未閉合與動脈導管結紮手術風險之間的相關性，以及利尿劑的聯合使用與動脈導管結紮手術風險之間的相關性。
研究結果
在第一個研究目的中觀察到，足月出生的嬰兒中，動脈導管未閉合的患病率為0.2%，早產兒和極低出生體重的嬰兒則分別為2.5%和20.4%。常用於動脈導管治療的藥物中，對乙?氨基酚使用率最高，佔34%，其次是布洛芬（21.2%），而??美辛較少使用（3.6%）。利尿劑的使用率高達77.3%，且呈現逐年增加。在孕晚期住院期間，最常使用的藥物是非類固醇消炎藥物，其中對乙?氨基酚最常用，其次是利尿劑、鈣通道阻滯劑、類固醇和硫酸鎂。從2008年到2017年，孕婦住院期間藥物使用百分比無明顯波動。
第二個研究目的中，共納入15,498位懷孕期間曾接受過安胎處置紀錄之懷孕婦女，於五大類影響動脈導管的產前藥物中，僅孕婦於產前使用利尿劑對於嬰兒罹患動脈導管未閉合（aOR=0.71, 95% CI= 0.52-0.98）及接受動脈導管結紮手術（aOR=0.37, 95% CI= 0.18-0.75）的風險被發現與對照組具有顯著差異。
第三個研究目的中，共納入1,153位有接受非類固醇消炎藥物治療之動脈導管未閉合的嬰兒，動脈導管未閉合的嬰兒在接受利尿劑和非類固醇消炎藥物的聯合治療時，與僅接受非類固醇消炎藥物治療的嬰兒相比，接受動脈導管結紮手術的風險顯著增加（aOR=3.45, 95% CI= 1.93-6.15）。
結論
本研究發現台灣罹患動脈導管未閉合的嬰兒，於動脈導管未閉合的藥物治療期間，聯合使用利尿劑和非類固醇消炎藥物會增加嬰兒需要進一步進行動脈導管結紮手術的風險。因此在接受非類固醇消炎藥物治療動脈導管未閉合的期間，在沒有必要的情況下，盡量避免同時使用利尿劑，以減少降低療效的潛在風險。
Background
The complication of patent ductus arteriosus (PDA) was very common in premature newborns, occurring in approximately 30% of very low birth weight (VLBW) infants (BW <1500 g). Failure of the closure of the ductus arteriosus (DA) could result in PDA, which often threatened the infants' survival. PDA could cause hyperperfusion of the pulmonary and systemic hypoperfusion, causing complications such as pulmonary edema, pulmonary hemorrhage, bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), and necrotizing enterocolitis (NEC).
The current PDA treatment principle was based on three-stage treatment. The first stage was to restrict water intake to wait for the PDA closure as a conservative approach. In the second stage, pharmacological agents were used to assist the PDA closure. Finally, more invasive PDA-ligation surgery would be considered when previous treatments were ineffective. However, surgery could prolong hospitalization and increase the risk of infant mortality. Therefore, successful pharmacological treatment could avoid the adverse outcomes associated with PDA-ligation.
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) such as indomethacin and ibuprofen were often prescribed to treat PDA due to the mechanism of inhibiting the synthesis of prostaglandin and the vasodilatory effects. Infants may experience side effects like decreasing in urine output when taking NSAIDs. To prevent it, furosemide, a diuretic, was a preferred combined medicine to improve the infant’s urination situation. However, the use of furosemide can contribute to the patency of the PDA through renal stimulation of renal PGE2, which could potentially result in the failure of PDA closure.
Previous research did not provide conclusive results regarding the addition of diuretics in pharmacological treatment of PDA. To address this research gap, this study aimed to investigate the association between the combined use of diuretics and NSAIDs and the risk of requiring PDA-ligation among Taiwanese infants.
Objectives
The aims of this study were as follows: (1) To give a comprehensive report about the prevalence and trends of patent ductus arteriosus and the PDA-affecting medication use before delivery among pregnant women who underwent tocolysis treatment and the PDA treatment among infants from 2008 to 2017 in Taiwan. (2) To assess the association between the administration of PDA-affecting medication during pregnancy and the risk of PDA in infants among pregnant women who underwent tocolysis treatment. (3) To evaluate the association between the combination use of diuretics and the risk of PDA-ligation among PDA infants.
Method
This study was a retrospective cohort study. The data source was the National Health Insurance Research Database (NHIRD) provided by the Health and Welfare Data Science Center of the Ministry of Health and Welfare in Taiwan. The study population included infants under one year of age with PDA and pregnant women aged 18 to 49 years between January 1, 2008, and December 31, 2017.
The first research objective was to observe and calculate the annual prevalence of PDA from 2008 to 2017 and analyze the annual average percentage change of medication use, including PDA treatment medications and PDA-affecting medications.
The second research objective focused on pregnant women aged 18 to 49 years who have records of tocolysis treatment during pregnancy. They were divided into exposed and control groups based on the use of PDA-affecting medication: the exposed group was defined as having hospitalization records of PDA-affecting medication between 2008 and 2017 during the third trimester or 90 days before delivery, and the PDA-affecting medication was categorized into five classes for comparison with the control group. The control group consisted of pregnant women who did not use PDA-affecting medication. The index date of the study was the date of pregnancy, and the infants born within one year were followed up to determine if they were diagnosed with PDA or underwent PDA-ligation.
The third research objective focused on infants under one year of age diagnosed with PDA. They were divided into exposed and control groups based on whether diuretics were used in combination: the exposed group was defined as infants who received at least one oral or intravenous diuretic within one month from birth and received combination treatment with NSAIDs. The control group consisted of infants treated solely with NSAIDs for PDA. The date of birth served as the index date of the study, and the infants were followed up from one month after birth until the age of one year to determine if they underwent PDA-ligation surgery.
Propensity score matching was utilized in a 1:1 ratio to address potential confounding factors between the exposed and control groups. Multivariate logistic regression analysis was performed to evaluate the association between exposure to PDA-affecting medication and the risk of infants developing PDA and requiring PDA-ligation. Similarly, multivariate logistic regression analysis was conducted to evaluate the association between the combined use of diuretics and the risk of PDA-ligation.
Results
In the first research objective, it was observed that among full-term infants, the prevalence of PDA was 0.2%. For premature infants and very low birth weight infants, the prevalence was 2.5% and 20.4%, respectively. Among the commonly used drugs for ductus arteriosus treatment, the highest usage rate was for acetaminophen, accounting for 34.0%. This was followed by ibuprofen (21.2%), while indomethacin was less frequently used (3.6%). The usage rate of diuretics was high, reaching 77.3%, and it increased annually. During the late stages of pregnancy hospitalization, the most commonly used drugs were NSAIDs, with acetaminophen being the most frequently used, followed by diuretics, calcium channel blockers, steroids, and magnesium sulfate. From 2008 to 2017, there were no significant fluctuations in the percentage of medication use during hospitalization for pregnant women.
In the second research objective, a total of 15,498 pregnant women who had records of tocolysis treatment during pregnancy were included. Among the five categories of PDA-affecting medication, only the use of diuretics by pregnant women was found to have a significant difference compared to the control group in terms of reducing the risk of infants developing PDA (aOR=0.71, 95% CI= 0.52-0.98) and requiring PDA-ligation surgery (aOR=0.37, 95% CI= 0.18-0.75).
In the third research objective, a total of 1,153 infants with PDA were included. Infants receiving combined treatment with furosemide and NSAIDs had a significantly increased risk of requiring PDA-ligation surgery compared to infants receiving only NSAIDs treatment (aOR=3.45, 95% CI= 1.93-6.15).
Conclusion
This study discovered that the combined administration of furosemide and NSAIDs for the treatment of PDA in infants in Taiwan raised the likelihood of infants requiring PDA-ligation surgery. Therefore, it is recommended to avoid combining furosemide with NSAIDs during PDA treatment unless necessary, to minimize the potential risk of decreased effectiveness. |
