Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants

Patent ductus arteriosus (PDA) occurs when an artery near the heart and lungs, which should close off soon after birth, stays open. Babies born preterm (premature) who have a PDA are at higher risk of severe illness and death. Indomethacin, a drug more commonly used for muscle and bone pain in adults, when given to preterm infants can help close a PDA. This review found evidence that giving all preterm infants (especially very preterm infants) indomethacin on the first day after birth reduced their risk of developing a PDA and the complications associated with PDA (including brain damage due to bleeding into the brain). However, despite these short term effects, the trials found evidence that indomethacin does not increase survival or reduce disability in the longer term.

Authors' conclusions: 

Prophylactic indomethacin has short-term benefits for preterm infants including a reduction in the incidence of symptomatic PDA, PDA surgical ligation, and severe intraventricular haemorrhage. However, there is no evidence of effect on mortality or neurodevelopment.

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Background: 

Persistent patent ductus arteriosus (PDA) is associated with mortality and morbidity in preterm infants. Prostaglandin synthetase inhibitors such as indomethacin promote PDA closure but also have potential side effects. The effect of the prophylactic use of indomethacin, where infants who may not have gone on to develop a symptomatic PDA would be exposed to indomethacin, warrants particular scrutiny.

Objectives: 

To determine the effect of prophylactic indomethacin on mortality and morbidity in preterm infants.

Search strategy: 

The standard search strategy of the Cochrane Neonatal Review Group was used. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 5, 2010), MEDLINE, EMBASE and CINAHL (until April 2010), conference proceedings, and previous reviews.

Selection criteria: 

Randomised or quasi-randomised controlled trials that compared prophylactic indomethacin versus placebo or no drug in preterm infants.

Data collection and analysis: 

The standard methods of the Cochrane Neonatal Review Group were used, with separate evaluation of trial quality and data extraction by two review authors.

Main results: 

Nineteen eligible trials in which 2872 infants participated were identified. Most participants were very low birth weight, but the largest single trial restricted participation to extremely low birth weight infants (N = 1202). The trials were generally of good quality.

The incidence of symptomatic PDA [typical relative risk (RR) 0.44, 95% confidence interval (CI) 0.38 to 0.50] and PDA surgical ligation (typical RR 0.51, 95% CI 0.37,0.71) was significantly lower in treated infants. Prophylactic indomethacin also significantly reduced the incidence of severe intraventricular haemorrhage (typical RR 0.66, 95% CI 0.53 to 0.82). Meta-analyses found no evidence of an effect on mortality (typical RR 0.96, 95% CI 0.81 to 1.12) or on a composite of death or severe neurodevelopmental disability assessed at 18 to 36 months old (typical RR 1.02, 95% CI 0.90, 1.15).

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