Prolonged versus short course of indomethacin for the treatment of patent ductus arteriosus in preterm infants

  • Review
  • Intervention




Indomethacin is a prostaglandin inhibitor used to treat patent ductus arteriosus (PDA) in preterm infants. Although indomethacin produces ductal closure in the majority of cases, it is ineffective in up to 40% of patients. Furthermore, the ductus will re-open in up to 35% of infants who initially respond to the drug. Prolonging the course of indomethacin has the potential to achieve higher rates of ductal closure.


To determine the effect of a prolonged course of indomethacin (compared to a short course) on the rate of treatment failure without unwanted side-effects in preterm infants with PDA.

Search methods

The search included review of personal files, abstracts of conferences, and the following electronic databases: MEDLINE (1966 to December 2006), EMBASE (1974 to December 2006), and Oxford Database of Perinatal Trials, Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 4, 2006). No language restrictions were applied.

Selection criteria

Randomized or quasi-randomized controlled trials including preterm infants with PDA, diagnosed on clinical and/or echocardiographic examination that evaluated indomethacin treatment by any route given as a long course (four or more doses) vs. a short course (three or fewer doses) were included in the review. Trials needed to report on at least one of the following outcomes: failure of PDA to close, need for re-treatment, PDA re-opening, PDA ligation, mortality, duration of assisted ventilation, chronic lung disease (CLD), duration of supplemental oxygen dependence, intraventricular hemorrhage (IVH) (all and severe), diminished urine output, increased serum creatinine, necrotizing enterocolitis (NEC), bleeding diathesis, retinopathy of prematurity (ROP), and duration of hospital stay.

Data collection and analysis

The three review authors independently abstracted data from each study. Relative risk (RR) and Risk Difference (RD) with 95% confidence intervals (CI) using the fixed effect model for meta-analysis are reported. When a statistically significant RD was found, the number needed to treat (NNT) or number needed to harm (NNH) was also calculated with 95% CIs. The I squared statistic was used to test for heterogeneity of results among included trials.

Main results

Five trials met inclusion criteria and included 431 infants. Prolonged indomethacin treatment when compared to the short course did not result in a statistically significant difference in PDA closure, re-treatment, re-opening, or ligation rates. The prolonged course was associated with an increased risk of NEC [typical RR 1.87 (95% CI 1.07, 3.27); typical RD 0.08 (95% CI 0.01, 0.15); NNH 13 (7, 100)] and a decreased incidence of renal function impairment, as evidenced by a lower proportion of infants having diminished urine output [typical RR 0.27 (95% CI 0.13, 0.6); typical RD -0.19 (95% CI -0.28, -0.09); NNT 5 (4, 11)] and increased serum creatinine level [typical RR 0.51 (95% CI 0.33, 0.77); typical RD -0.14 (95% CI -0.23, -0.06); NNT 7 (4, 16)].

Authors' conclusions

Implications for practice
Prolonged indomethacin course does not appear to have a significant effect on improving important outcomes, such as PDA treatment failure, CLD, IVH, or mortality. The reduction of transient renal impairment does not outweigh the increased risk of NEC associated with the prolonged course. Based on these results, a prolonged course of indomethacin cannot be recommended for the routine treatment of PDA in preterm infants.

Implications for research
There is a paucity of data on optimal dosing and duration of indomethacin therapy for the treatment of PDA, in particular for extremely low birth weight infants (ELBW) premature infants. It is likely that a single standard indomethacin regime is not the ideal for every premature infant. Therefore, individual patient response should be considered and evaluated, in particular in ELBW infants. Future randomized clinical trials should include this high risk population and investigate the effect of tailoring dose and duration of therapy to individual response in terms of echocardiographic findings and/or prostaglandin levels, focusing on clinically significant outcomes, including long-term neurodevelopmental outcomes. In addition, factors that may influence treatment effect, such as birth weight, gestational age, age at the time of randomization, total fluid intake, feeding practice, and severity of PDA, need to be taken into account when designing such studies.



對於有開放性動脈導管(ductus arteriosus)的早產兒,使用延長與短期indomethacin療程的比較

Indomethacin是一個前列腺素抑製劑(prostaglandin inhibitor),可用來治療早產兒之開放性動脈導管。雖然indomethacin使得大多數病兒的動脈導管關閉,但有多達百分之40的病人是無效的。此外,在一開始對藥物有反應的嬰兒,有多達百分之35的嬰兒動脈導管會重新開啟。延長indomethacin的療程,有可能會提高動脈導管的關閉率。




搜索包括審查作者個人檔案,會議的摘要,及以下的電子資料庫: MEDLINE (1966年到2006年12月), EMBASE (1974年到 2006年12月), 及Oxford Database of Perinatal Trials, Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 4, 2006年)等資料庫. 沒有語言上的限制。


臨床上或者心臟超音波檢查被診斷為開放性動脈導管的早產兒,任何路徑給予的indomethacin,延長(4次或更多次的劑量)與短期(3次或更少的劑量)的比較,其隨機或類隨機對照試驗(Randomized or quasirandomized controlled trials)都被涵蓋進來。這些試驗必須報告出至少以下一種結果: 開放性動脈導管無法關閉,需要再次治療,導管再次打開,導管結紮,死亡,輔助呼吸的時間,慢性肺疾病(chronic lung disease (CLD)),依賴氧氣使用的時間,腦室內出血(intraventricular hemorrhage (IVH))(全部及嚴重的),尿量減少,增加血清肌酐(serum creatinine),壞死性小腸結腸炎(necrotizing enterocolitis (NEC)),出血體質,早產兒視網膜病變(retinopathy of prematurity (ROP)),及住院的時間。


這三位審查的作者是獨立地摘取每個研究的資料。使用fixed effect model for metaanalysis,其 elative risk (RR) 和 Risk Difference (RD)與95% confidence intervals (CI) 被報告出來。當發現有統計上意義的RD,則number needed to treat (NNT)或者number needed to harm (NNH)的95% CIs也會被計算出來。I squared statistic 是用來測驗這些試驗中的非均質性結果。


五個試驗符合蒐集的條件且其中有431位的嬰兒。延長使用indomethacin的療程與短期使用相比時,並不能使動脈導管關閉、導管再次治療、導管重新打開或者導管結紮的比率有統計上的差異。而延長使用indomethacin的療程則有較高的風險會增加壞死性小腸結腸炎[typical RR 1.87 (95% CI 1.07, 3.27); typical RD 0.08 (95% CI 0.01, 0.15); NNH 13 (7, 100)]、減少發生腎功能損害(顯示於嬰兒有較低比例的尿量減少)[typical RR 0.27 (95% CI 0.13, 0.6); typical RD −0.19 (95% CI −0.28, −0.09); NNT 5 (4, 11)],及增加血清肌酐[typical RR 0.51 (95% CI 0.33, 0.77); typical RD −0.14 (95% CI −0.23, −0.06); NNT 7 (4, 16)]


此結果暗示著延長indomethacin的療程,對於改善開放性動脈導管治療失敗的情形、慢性肺疾病的發生、腦室內出血或者死亡率等重要預後,似乎沒有明顯的影響。延長療程所減少短暫腎功能受損的好處並沒有勝過增加壞死性小腸結腸炎的風險。基於這些結果,indomethacin的延長療程並不能例行性治療於有開放性動脈導管的早產兒。研究中顯示,對於治療開放性動脈導管的最佳劑量及使用時間長短上,尤其是在超低出生體重的早產兒(extremely low birth weight infants (ELBW))上,缺乏足夠的資料來作建議。有可能是因為單一標準的indomethacin療法是不適合每一個早產兒的。因此應該要考慮及評估個別病患的反應,尤其是超低體重早產兒。未來隨機對照試驗應該包含這些高危險族群,且應視心臟超音波結果及前列腺素濃度的個別反應來評估劑量修改及療程長短的效果。在臨床重要的預後部份,應著重在包括長期神經發育的結果。此外,在設計此類實驗時,如: 體重、妊娠週數、隨機試驗的年紀、總水分攝取、餵食技巧及開放動脈導管的嚴重度等可能會影響治療效果的因素都需要被考量進去。



此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。


有開放性動脈導管的早產兒使用延長與短期的indomethacin療程比較。 動脈導管是一條連接大動脈及肺動脈的血管。開放性動脈導管在胎兒上是正常的。它允許大部分的右心輸出血流繞過肺臟而供應到胎兒全身及子宮內的胎盤。在大部分的足月兒,其動脈導管在出生後的幾天內會關閉,起初是經由肌肉層的收縮來達到功能上的關閉,接著是經由血管內皮的重塑。如果動脈導管仍然存在,血液會從主動脈分流到肺循環,這可能會導致肺循環的超載,及腦、腸和腎臟血流的灌流減少。在早產兒,動脈導管可能會延遲或不關閉,部分是因為血液循環中的前列腺素有其血管擴張功能。Indomethacin可抑制前列腺素合成,因而被用來治療早產兒的開放性動脈導管。雖然indomethacin對於大部分的案例能成功的關閉動脈導管,但在一開始對藥物有反應的病人中,有百分之35的導管仍會重新開啟,而較為延長的indomethacin療程研究顯示有較高的導管關閉率。Indomethacin的重要副作用包括腎臟功能失常、降低血小板的凝集作用、壞死性小腸結腸炎。當indomethacin治療失敗,則會依臨床上需要,作手術結紮動脈導管。 在這次的檢閱中包含了五個隨機試驗。這些研究是在1988年到2000年被發表,共有431位早產兒及低體重兒。有四個實驗Indomethacin是由靜脈給予的,有一個是經口給予,在延長療程(6到8個劑量)給予總量為0.6到1.6mg/kg,而短期療程(2到3個劑量)給予總量為0.3到0.6mg/kg。延長的療程對於動脈導管的關閉失敗沒有重大的好處(4個研究,361位嬰兒)。延長的療程與短期療程相比,並沒有減少動脈導管在初次關閉後的重新打開比率(3個研究,322位嬰兒)、動脈導管的重新治療比率(5個研究,431位嬰兒)、與結紮比率(4個研究,310位嬰兒)。延長的療程與減少腎功能損傷的發生率有關(3個研究,318位嬰兒)。然而延長的療程與增加壞死性小腸結腸炎的風險有關(4個研究,310位嬰兒)。死亡的數字並無差別。

Plain language summary

Prolonged versus short course of indomethacin for the treatment of patent ductus arteriosus in preterm infants

The ductus arteriosus is a blood vessel that connects the aorta and pulmonary artery. The ductus arteriosus is normally present in the fetus. It allows the majority of the output of the right side of the heart to bypass the lungs and supply the body of the fetus and placenta in-utero. In most term infants the patent ductus arteriosus (PDA) closes within days of birth, first by contraction of a muscular layer to achieve functional closure and then by endothelial remodeling. If the ductus arteriosus persists, blood is shunted from the aorta to the pulmonary circulation, which can cause overloading of the pulmonary circulation and reduced perfusion of the brain, gut and kidneys. In preterm infants, closure may be delayed or fail to occur, due in part to circulating vasodilatory prostaglandins. Indomethacin inhibits prostaglandin synthesis and it is used to treat PDA in preterm infants. Although indomethacin is successful in closing the PDA in the majority of cases, the ductus will re-open in up to 35% of infants who initially respond to the drug and a more prolonged course of indomethacin has been studied to achieve higher rates of ductal closure. Important side effects of indomethacin include renal dysfunction, decreased platelet aggregation, and necrotizing enterocolitis (NEC). Where indomethacin fails, the ductus arteriosus may be surgically ligated if clinically indicated. Five randomized trials are included in this review. These studies were published between 1988 and 2000 and included a total of 431 preterm and low birth weight infants. Indomethacin was given intravenously in four trials and orally in one, in total amounts of 0.6 to 1.6 mg/kg for the prolonged course (six to eight doses) and 0.3 to 0.6 mg/kg for the short course (two to three doses). There was no significant benefit of prolonged indomethacin administration on failure of the PDA to close after completion of allocated treatment (four studies, 361 infants). Prolonged course of indomethacin compared to the short course did not reduce the rate of PDA re-opening after initial closure (three studies, 322 infants), rate of PDA re-treatment (five studies, 431 infants), or ligation rate (four studies, 310 infants). The prolonged course was associated with decreased incidence of renal function impairment (three studies, 318 infants). However, a prolonged indomethacin course increased the risk of NEC (four studies, 310 infants). The number of deaths was no different.