Low-dose indomethacin and prevention of intraventricular hemorrhage: a multicenter randomized trial
L R Ment1, W Oh, R A Ehrenkranz
1Dept of Pediatrics, Yale University School of Medicine, New Haven, CT 06510.
Insights
Low-dose indomethacin significantly reduces the incidence and severity of intraventricular hemorrhage (IVH) in very low birth weight neonates. This treatment also aids in closing the patent ductus arteriosus without notable adverse effects.
Area of Science:
- Neonatal Medicine
- Pediatric Neurology
- Pharmacology
Background:
- Intraventricular hemorrhage (IVH) is a significant risk factor for neurodevelopmental impairments in very low birth weight neonates.
- Previous research suggested indomethacin may reduce IVH incidence and severity.
Purpose of the Study:
- To evaluate the efficacy of low-dose prophylactic indomethacin in lowering the incidence and severity of IVH in very low birth weight neonates.
- To assess the impact of indomethacin on patent ductus arteriosus and adverse events.
Main Methods:
- A prospective, randomized, placebo-controlled trial involving 431 neonates (600-1250g birth weight) with no initial signs of IVH.
- Low-dose indomethacin (0.1 mg/kg) administered intravenously for three doses starting at 6-12 postnatal hours.
- Serial cranial ultrasound and echocardiography used for monitoring.
Main Results:
- A statistically significant reduction in IVH incidence (12% vs. 18%) and severe IVH (grade 4) was observed in the indomethacin group.
- Indomethacin treatment was associated with significant closure of the patent ductus arteriosus by day five.
- No significant differences in adverse events were noted between the indomethacin and placebo groups.
Conclusions:
- Low-dose prophylactic indomethacin is effective in reducing the incidence and severity of IVH, particularly severe forms, in very low birth weight neonates.
- Indomethacin demonstrates efficacy in closing the patent ductus arteriosus.
- The treatment is well-tolerated, with no significant adverse drug events reported.
Objectives:
Parenchymal involvement of intraventricular hemorrhage (IVH) is a major risk factor for neurodevelopmental handicap in very low birth weight neonates. Previous trials have suggested that indomethacin would lower the incidence and severity of IVH in very low birth weight neonates.
Methods:
We enrolled 431 neonates of 600- to 1250-g birth weight with no evidence for IVH at 6 to 11 hours of age in a prospective, randomized, placebo-controlled trial to test the hypothesis that low-dose indomethacin (0.1 mg/kg intravenously at 6 to 12 postnatal hours and every 24 hours for two more doses) would lower the incidence and severity of IVH. Serial cranial ultrasound examinations and echocardiographs were performed.
Results:
There were no differences in the birth weight, gestational age, sex, Apgar scores, and percent of neonates treated with surfactant between the indomethacin and placebo groups. Within the first 5 days, 25 (12%) indomethacin-treated and 40 (18%) placebo-treated neonates developed IVH (P = .03, trend test). Only one indomethacin-treated patient experienced grade 4 IVH compared with 10 placebo-treated neonates (P = .01). Sixteen indomethacin-treated neonates and 29 control neonates died (P = .08); there was a difference favoring indomethacin with respect to survival time (P = .06). Eighty-six percent of all neonates had a patent ductus arteriosus on the first postnatal day; indomethacin was associated with significant ductal closure by the fifth day of life (P < .001). There were no differences in adverse events attributed to indomethacin between the two treatment groups.
Conclusions:
Low-dose prophylactic indomethacin significantly lowers the incidence and severity of IVH, particularly the severe form (grade 4 IVH). In addition, indomethacin closes the patent ductus arteriosus and is not associated with significant adverse drug events in very low birth weight neonates.
