Indomethacin for asymptomatic patent ductus arteriosus in preterm infants

L Cooke, P Steer, P Woodgate
Cochrane Database of Systematic Reviews 2003, (2): CD003745

BACKGROUND: 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.

OBJECTIVES: 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.

SEARCH STRATEGY: 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.

SELECTION CRITERIA: All randomised controlled trials of indomethacin compared with placebo or no intervention for the treatment of asymptomatic PDA in premature infants were eligible.

DATA COLLECTION AND ANALYSIS: 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.

MAIN RESULTS: 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.

REVIEWER'S CONCLUSIONS: 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.

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