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Previous Volume 344:1966-1972 June 28, 2001 Number 26 Next

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ABSTRACT

Background The prophylactic administration of indomethacin reduces the frequency of patent ductus arteriosus and severe intraventricular hemorrhage in very-low-birth-weight infants (those with birth weights below 1500 g). Whether prophylaxis with indomethacin confers any long-term benefits that outweigh the risks of drug-induced reductions in renal, intestinal, and cerebral blood flow is not known.

Methods Soon after they were born, we randomly assigned 1202 infants with birth weights of 500 to 999 g (extremely low birth weight) to receive either indomethacin (0.1 mg per kilogram of body weight) or placebo intravenously once daily for three days. The primary outcome was a composite of death, cerebral palsy, cognitive delay, deafness, and blindness at a corrected age of 18 months. Secondary long-term outcomes were hydrocephalus necessitating the placement of a shunt, seizure disorder, and microcephaly within the same time frame. Secondary short-term outcomes were patent ductus arteriosus, pulmonary hemorrhage, chronic lung disease, ultrasonographic evidence of intracranial abnormalities, necrotizing enterocolitis, and retinopathy.

Results Of the 574 infants with data on the primary outcome who were assigned to prophylaxis with indomethacin, 271 (47 percent) died or survived with impairments, as compared with 261 of the 569 infants (46 percent) assigned to placebo (odds ratio, 1.1; 95 percent confidence interval, 0.8 to 1.4; P=0.61). Indomethacin reduced the incidence of patent ductus arteriosus (24 percent, vs. 50 percent in the placebo group; odds ratio, 0.3; P<0.001) and of severe periventricular and intraventricular hemorrhage (9 percent, vs. 13 percent in the placebo group; odds ratio, 0.6; P=0.02). No other outcomes were altered by the prophylactic administration of indomethacin.

Conclusions In extremely-low-birth-weight infants, prophylaxis with indomethacin does not improve the rate of survival without neurosensory impairment at 18 months, despite the fact that it reduces the frequency of patent ductus arteriosus and severe periventricular and intraventricular hemorrhage.

Source Information

From the Departments of Pediatrics (B.S., S.S.) and Clinical Epidemiology and Biostatistics (B.S., A.O., R.S.R.), McMaster University, Hamilton, Ont., Canada; the Royal Women's Hospital, Melbourne, Australia (P.D.); the Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Canada (D.M.); the Departments of Pediatrics, Obstetrics and Gynecology, and Health Administration, University of Toronto, Toronto (A.O.); the Department of Pediatrics, University of British Columbia, Vancouver, Canada (A.S.); the Department of Pediatrics, Dalhousie University, Halifax, N.S., Canada (M.V.); and the Neonatal Research Network, National Institute of Child Health and Human Development, Bethesda, Md. (L.L.W.).

Address reprint requests to Dr. Schmidt at the Department of Pediatrics, McMaster University, HSC 3N11E, 1200 Main St. W., Hamilton, ON, L8N 3Z5, Canada, or at schmidt{at}mcmaster.ca.

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