Prophylactic indomethacin for preterm infants: a systematic review and meta-analysis

Background: Rates of long term morbidity remain unacceptably high in infants surviving after preterm birth. Prophylactic indomethacin has been shown to effectively reduce the rate of intraventricular haemorrhage in this group but there is the potential for unwanted side effects because of reduced organ perfusion. Objective: To examine the effect of prophylactic indomethacin on mortality and short and long term morbidity of preterm infants. Data sources: Medline (1966-2002), the Cochrane Controlled Trials Register and abstracts of the Society for Pediatric Research and the European Society for Pediatric Research were searched independently by both authors. Review methods: Trials were included if they used a randomised design, enrolled preterm infants given intravenous indomethacin within 24 hours of birth, and reported any of the prespecified outcome measures. Each author extracted data and assessed trial quality independently, according to the methods of the Cochrane Collaboration. Data were combined in a meta-analysis where appropriate. Results: Nineteen trials fulfilling the inclusion criteria were identified, of which four reported long term outcomes. Short term benefits of indomethacin were identified, including a reduction in the rate of severe intraventricular haemorrhage (relative risk (RR) 0.66 (95% confidence interval (Cl) 0.53 to 0.82)) and the need for surgical ligation of a patent ductus arteriosus (RR 0.51 (95% Cl 0.37 to 0.71)). No evidence of short term gastrointestinal or renal adverse effects was detected. There was no significant difference between indomethacin and control groups with respect to the important long term outcome of death or severe neurosensory impairment (RR 1.02 (95% Cl 0.90 to 1.15)). Conclusions: Prophylactic indomethacin has a number of short term benefits for the preterm infant but there is no evidence to suggest that it results in an improvement in the rate of survival free of disability.