PICO Summary: Does prophylactic indomethacin reduce mortality and morbidity in preterm infants?

BackgroundPatent ductus arteriosus (PDA) and intraventricular haemorrhage (IVH) are both associated with increased mortality and morbidity in preterm infants. Indomethacin has been used successfully to treat symptomatic PDA and may also prevent or limit IVH in the neonatal period. However, there are potential unwanted side effects of indomethacin, in particular a potential for reduced organ perfusion that might outweigh any clinical benefits.
ParticipantsPreterm newborn infants (<37 weeks gestation).
InterventionProphylactic indomethacin within 24 h of birth. No dosage regimen was prespecified.
ComparisonPlacebo or no prophylactic indomethacin within 24 h of birth.
Outcome(s)Primary outcomes:
 • Neonatal mortality;
 • Intraventricular hemorrhage;
 • Neurodevelopmental outcome;
 • Patent ductus arteriosus.
StudiesRandomized controlled trials.
Study description and settingNineteen randomized controlled trials with a total of 2872 infants were included in the review of Fowlie and coworkers (Fowlie 2002). Twelve were carried out in the USA., the others in both middle and high income countries, and one international collaboration. Dosage schedules for indomethacin varied from a single dose of 0.2 mg/kg at 24 h of age to a daily dose of 0.1 mg/kg given for 6 days. Long-term follow up: 18–54 months of age. Relatively few data were available examining long-term neurodevelopmental outcome.
ResultsThere was no evidence of a difference in overall mortality between infants receiving prophylactic indomethacin and control infants (typical RR 0.96, 95% CI 0.81, 1.12; 18 trials, 2769 infants). There was no evidence of effect of prophylactic indomethacin on long-term neurosensory impairment, i.e. no significant difference in rates of cognitive delay, cerebral palsy, blindness or deafness (3 trials, 1388 infants). The incidence of symptomatic patent ductus arteriosus was significantly reduced in treated infants (typical RR 0.44, 95% CI 0.38, 0.50; NNT 4; 14 trials, 3193 infants). Prophylactic indomethacin reduced the need for surgical PDA ligation (typical RR 0.51, 95% CI 0.37, 0.71; NNT 20; eight trials, 1791 infants). Prophylactic indomethacin significantly reduced the incidence of Grade 3 and 4 intraventricular hemorrhage (typical RR 0.66, 95% CI 0.53, 0.82; NNT 20; 14 trials, 2588 infants). There is no evidence that treatment affects respiratory outcomes, rates of necrotizing enterocolitis, excessive clinical bleeding or sepsis. Transient oliguria is seen more often with prophylactic indomethacin (typical RR 1.90, 95% CI 1.45, 2.47, NNH 5(3–12), 8 trials, 2115 infants) but this is not associated with major renal impairment.
Confidence in resultsOne out of three trials had unclear allocation concealment. High quality of evidence concerning most outcomes reported, e.g. symptomatic PDA, surgical PDA ligation, IVH grades 3–4, side effects. Moderate quality evidence concerning long-term outcomes, since follow-up is curtailed at 18 months of age and loss to follow-up as high as 25% of children.
Key figure(s)Thumbnail image of
Figure captionProphylactic indomethacin vs. control: Effect on severe intraventricular hemorrhage
Search for eligible studiesInitial literature search (English only): October 1994 included :MEDLINE; EMBASE; and the Oxford Database of Perinatal Trials (ODPT). A search by first author of any abstracts was done in the Science Citation Index to try and identify any corresponding full manuscripts published. None were identified. The search was last updated in 2009.
ConclusionProphylactic use of indomethacin in very low birth weight infants results in a reduction in the incidence of symptomatic PDA, the need for surgical PDA ligation, and the incidence of IVH including grade 3 and 4 IVH. There is no evidence of a difference in long-term mortality rates or short-term adverse effects such as necrotizing enterocolitis. There is a temporary reduction in urine output in babies given indomethacin. There is no evidence to suggest either benefit or harm in longer term outcomes including neurodevelopment.
CitationFowlie PW, Davis PG. Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants. Cochrane Database of Systematic Reviews 2002, Issue 3. Art. No.: CD000174. DOI: 10.1002/14 651 858.CD000174.
Date completed18 February 2010
People who helped prepare this Cochrane PICO:Irene Schiering, MD, Fellow Neonatology, Emma Children's Hospital AMC, Amsterdam, the Netherlands)