In this trial, 1202 infants between 500 and 999 grams birth weight were randomized to received either 0.1 mg/kg daily for three days, or equivalent volume of saline placebo. The primary outcome measures were the combined rate of death and neurosensory impairment at 18 months of age. Neurosensory impairment included cerebral palsy, cognitive delay, blindness or deafness. A number of secondary outcomes included pulmonary hemorrhage, PDA, chronic lung disease, cranial ultrasound abnormalities, NEC, and ROP. Infants with heart disease, renal disease, thrombocytopenia, or maternal indomethacin therapy were excluded. These infants were followed for 18 months or longer. Complete follow up data were available for 95% of all randomized infants. Demographic characteristics were not different between the two groups.

Results: 80% of infants in both groups received all three doses of indomethacin or placebo. As expected, the rate of PDA was substantially less in the indomethacin group (p=0.000005) The rates of severe IVH (Grades 3 & 4) were reduced significantly by indomethacin therapy. The other secondary outcomes were similar in both groups. Primary outcome measures of death and neurosensory impairment were not different.

Comment: The TIPP trial is certainly one of the best designed and controlled trials in our field. It is comforting to know that indomethacin does not increase any of the measured secondary outcomes, especially pulmonary hemorrhage and NEC. While indomethacin treatment apparently decreases the incidence of severe IVH, there does not seem to be an improved developmental outcome in the affected infants at least at 18 months corrected age. Given the plasticity of the developing human brain, perhaps we will see a difference as these children develop further and enter school. For the time being, a preference for as few severe cases of IVH as possible is understandable.