The prophylactic administration of indomethacin is known to reduce the frequency of patent ductus arteriosus and severe intraventricular hemorrhage in ELBW infants. This treatment is also known to be associated with drug-induced reductions on renal, intestinal and cerebral blood flow. This study was done to assess whether indomethacin prophylaxis in ELBW babies confers any long-term benefits. 1202 infants with birth weights of 500 – 999 grams were randomly assigned to receive either indomethacin (0.1 mg/kg) or placebo once daily for three days. The primary outcome was a composite of death, cerebral palsy, cognative delay, deafness and blindness at a corrected age of 18 months. Secondary long-term outcomes were hydrocephalus necessitating shunt placement, seizure disorder and microcephaly. Secondary short-term outcomes were patent ductus arteriosus (PDA), pulmonary hemorrhage, chronic lung disease, intracranial abnormalities by untrasound, necrotizing enterocolitis and retinopathy.

Results. Of the 574 infants who were received prophylaxis with indomethacin, 271 (47%) died or survived with impairments, as compared with 261 of 569 infants (46%) of infants in the placebo group (results not significantly different). Indomethacin reduced the incidence of PDA (24% vs 50% in the placebo group, p < 0.001) and of severe periventricular and intraventricular hemorrhage (9% vs 13% in the placebo group, p = 0.02). No other outcomes were altered by the prophylactic administration of indomethacin.

Comment. This was an excellent study that answers an important clinical question: Does prophylactic indomethacin improve survival without neurosensory impairment in ELBW babies. The answer is clearly "No". The study was a well-designed, multi-center, blinded, randomized controlled trial with a large sample size, and very few patients (<5%) were lost to follow up. The findings confirmed that indomethacin prophylaxis results in fewer ELBW babies with severe IVH, but this did not translate into a subsequent decrease in PVL or improvement in survival without long-term neurologic problems. Prophylactic indomethacin does result in a decreased need for PDA ligations, however approximately 20 infants must receive indomethacin prophylaxis to avert one operation. It was notable that no increase in serious adverse effects of indomethacin prophylaxis (such as NEC or retinopathy) was seen. It remains unclear whether it is safer or more effective to attempt to close the PDA early with the lower prophylactic dose of indomethacin, or later with the treatment dose regimen.