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Published on: November 20, 2015
Long-term effects of indomethacin prophylaxis in extremely-low-birth-weight infants
B Schmidt1, P Davis, D Moddemann
1Department of Pediatrics, McMaster University, Hamilton, Ont, Canada. schmidt@mcmaster.ca
Insights
Prophylactic indomethacin in extremely-low-birth-weight infants did not improve survival without neurosensory impairment. While it reduced patent ductus arteriosus and intraventricular hemorrhage, these benefits did not translate to better long-term outcomes.
Area of Science:
- Neonatalogy
- Pediatric Pharmacology
- Clinical Trials
Background:
- Prophylactic indomethacin is known to decrease patent ductus arteriosus and intraventricular hemorrhage in very-low-birth-weight infants.
- The long-term benefits versus risks of indomethacin, considering its effects on organ blood flow, remain unclear.
Purpose of the Study:
- To investigate the long-term efficacy of prophylactic indomethacin in extremely-low-birth-weight infants.
- To determine if indomethacin improves survival without neurosensory impairment at 18 months corrected age.
Main Methods:
- A randomized trial involving 1202 infants (500-999 g birth weight) assigned to receive indomethacin or placebo for three days.
- The primary outcome was a composite of death or neurosensory impairment (cerebral palsy, cognitive delay, deafness, blindness) at 18 months corrected age.
Main Results:
- No significant difference in the primary outcome between indomethacin and placebo groups (47% vs. 46%, P=0.61).
- Indomethacin significantly reduced patent ductus arteriosus (24% vs. 50%, P<0.001) and severe intraventricular hemorrhage (9% vs. 13%, P=0.02).
- No other short-term or long-term outcomes were significantly altered.
Conclusions:
- Prophylactic indomethacin does not improve survival without neurosensory impairment in extremely-low-birth-weight infants at 18 months corrected age.
- Despite reducing specific morbidities like PDA and IVH, indomethacin does not confer overall long-term developmental benefits.
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.
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