Indomethacin for asymptomatic patent ductus arteriosus in preterm infants

Abstract

Patent Ductus Arteriosus (PDA remains a significant cause of mortality and morbidity in premature infants. Indomethacin is an effective treatment to close a PDA, and has been used for many years with several treatment regimes, including prophylactic use in all at risk premature infants. There are however concerns regarding adverse side effects of indomethacin. By targeting a group of infants with an asymptomatic PDA, rather than treating all VLBW infants prophylactically, indomethacin use would be restricted, limiting the possibility of significant side effects to those with greater chance of benefit. To assess whether in premature neonates with asymptomatic PDA, treatment with indomethacin improves short and long term outcomes; in particular: incidence of symptomatic PDA, mortality, chronic neonatal lung disease (CLD), intraventricular haemorrhage (IVH), retinopathy of prematurity (ROP), neurodevelopmental outcome, length of ventilation. Standard strategies of the Cochrane Neonatal Review Group were used. Searches were made of the Oxford Database of Perinatal Trials, MEDLINE and EMBASE from 1966 to September 2002, CINAHL from 1982 to September 2002, and the Cochrane Controlled Trials Register (CENTRAL/CCTR) in The Cochrane Library, Issue 3, 2002. Searches were also made of previous reviews including cross‐referencing, abstracts, and conference and symposia proceedings published in Pediatric Research. All randomised controlled trials of indomethacin compared with placebo or no intervention for the treatment of asymptomatic PDA in premature infants were eligible. Standard methods of the Cochrane Neonatal Review Group were used. Trials identified by the search strategy were independently reviewed by each author and assessed for eligibility and trial quality. Data were then extracted independently by each author and compared, with any differences resolved following discussion. Any additional information required was requested from trial authors. Only published data was available for review. Results are expressed as typical relative risk and typical risk difference for dichotomous outcomes, and weighted mean difference for continuous variables. Three small trials involving a total of 97 infants were included. Meta analysis of combined data was possible for seven outcomes. Treatment of an asymptomatic PDA with indomethacin significantly reduced the incidence of symptomatic PDA (RR 0.36, 95% CI 0.19, 0.68) and duration of supplemental oxygen (WMD ‐12.5, 95% CI ‐23.8, ‐1.26). There was no evidence of effect on mortality (RR 1.32, 95% CI 0.45, 3.86), CLD (RR 0.91, 95% CI 0.62, 1.35), IVH (RR 1.21, 95% CI 0.62, 2.37), ROP (RR 0.68, 95% CI 0.26, 1.78), or length of ventilation (WMD ‐7.00 days, 95%CI ‐17.33, 3.34). Long term neurodevelopmental outcomes were not reported. One trial reported a significant reduction in the duration of supplemental oxygen following treatment with indomethacin in the subgroup of infants with birth weight less than 1000g. This review demonstrates a significant decrease in the incidence of symptomatic PDA following treatment of an asymptomatic PDA with indomethacin. There is also a small but statistically significant decrease in the duration of requirement for supplemental oxygen. There are no reported long term outcomes in the included trials, and so it is not possible to comment on possible long term effects. Further studies are required to determine the long term benefits or harms of closing a PDA prior to the onset of symptoms. 早產兒使用indomethacin治療無症狀開放性動脈導管 開放性動脈導管 (patent ductus arteriosus) 仍是早產兒罹病及死亡的重要原因。Indomethacin治療可以有效關閉開放性動脈導管，已採不同處方使用多年，包含高危險早產兒的預防使用；然而對於indomethacin的副作用也一直被關切。將使用對象限制於無症狀的開放性動脈導管的嬰兒，而非對極低體重早產兒全面的預防性使用，如此indomethacin的使用將被侷限，使得發生顯著副作用的可能性只限於有較大機會得到好處的族群。 評估早產兒無症狀開放性動脈導管以indomethacin治療，是否改善短期及長期後果，特別是有症狀開放性動脈導管的發生率、死亡率、慢性肺疾病、腦室內出血、早產兒視網膜病變、神經發展後果及呼吸器使用時間。 採用Cochrane Neonatal Review Group的標準策略，搜尋以下資料庫：Oxford Database of Perinatal Trials、MEDLINE and EMBASE (1966 – 2002九月) 、CINAHL (1982 – 2002九月) 、the Cochrane Controlled Trials Register (CENTRAL/CCTR) in The Cochrane Library, Issue 3, 2002。也搜尋之前的回顧文獻，包括相關參考資料、摘要、Pediatric Research的會議及摘要發表。 所有對於無症狀開放性動脈導管早產兒，比較使用indomethacin治療，及使用安慰劑或不治療的隨機試驗均納入。 使用Cochrane Neonatal Review Group的標準作法，搜尋出之試驗由作者獨立檢驗及評估試驗品質，以及是否適合納入。資料收集由每個作者各自做獨立分析及比較，任何歧異透過討論解決，任何額外需要的資訊均經由原試驗作者提供，只有發表過的資料被納入回顧。二分的結果以標準相對危險 (typical relative risk) 及危險差異 (risk difference) ，連續變數以加權的平均數差異 (weighted mean difference) 表示。 三個小試驗總共囊括97個嬰兒，綜合資料對七種結果作統合分析。以indomethacin治療無症狀開放性動脈導管顯著減少有症狀開放性動脈導管之發生率 (RR 0.36, 95% CI 0.19, 0.68) 及氧氣需求的時間 (WMD −12.5, 95% CI −23.8, −1.26) ，無明顯證據顯示可降低死亡率 (RR 1.32, 95% CI 0.45, 3.86) 、慢性肺疾病 (RR 0.91, 95% CI 0.62, 1.35) 、腦室內出血 (RR 1.21, 95% CI 0.62, 2.37) 、早產兒視網膜病變 (RR 0.68, 95% CI 0.26, 1.78)...