Long-Term Effects of Indomethacin Prophylaxis in Extremely-Low-Birth-Weight Infants
Barbara Schmidt, M.D., Peter Davis, M.D., Diane Moddemann, M.D., Arne Ohlsson, M.D., Robin S. Roberts, M.Sc., Saroj Saigal, M.D., Alfonso Solimano, M.D., Michael Vincer, M.D., Linda L. Wright, M.D., for the Trial of Indomethacin Prophylaxis in Preterms Investigators
Background The prophylactic administration of indomethacin reducesthe frequency of patent ductus arteriosus and severe intraventricularhemorrhage in very-low-birth-weight infants (those with birthweights below 1500 g). Whether prophylaxis with indomethacinconfers any long-term benefits that outweigh the risks of drug-inducedreductions in renal, intestinal, and cerebral blood flow isnot known.
Methods Soon after they were born, we randomly assigned 1202infants with birth weights of 500 to 999 g (extremely low birthweight) to receive either indomethacin (0.1 mg per kilogramof body weight) or placebo intravenously once daily for threedays. The primary outcome was a composite of death, cerebralpalsy, cognitive delay, deafness, and blindness at a correctedage of 18 months. Secondary long-term outcomes were hydrocephalusnecessitating the placement of a shunt, seizure disorder, andmicrocephaly within the same time frame. Secondary short-termoutcomes were patent ductus arteriosus, pulmonary hemorrhage,chronic lung disease, ultrasonographic evidence of intracranialabnormalities, necrotizing enterocolitis, and retinopathy.
Results Of the 574 infants with data on the primary outcomewho were assigned to prophylaxis with indomethacin, 271 (47percent) died or survived with impairments, as compared with261 of the 569 infants (46 percent) assigned to placebo (oddsratio, 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 intraventricularhemorrhage (9 percent, vs. 13 percent in the placebo group;odds ratio, 0.6; P=0.02). No other outcomes were altered bythe prophylactic administration of indomethacin.
Conclusions In extremely-low-birth-weight infants, prophylaxiswith indomethacin does not improve the rate of survival withoutneurosensory impairment at 18 months, despite the fact thatit reduces the frequency of patent ductus arteriosus and severeperiventricular 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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