Effect of Early Targeted Treatment of Ductus Arteriosus with Ibuprofen on Survival Without Cerebral Palsy at 2 Years in Infants with Extreme Prematurity: A Randomized Clinical Trial

J Pediatr. 2021 Jun;233:33-42.e2. doi: 10.1016/j.jpeds.2020.12.008. Epub 2020 Dec 9.

Abstract

Objective: To examine the effects of early echocardiography-targeted ibuprofen treatment of large patent ductus arteriosus (PDA) on survival without cerebral palsy at 24 months of corrected age.

Study design: We enrolled infants born at <28 weeks of gestation with a large PDA on echocardiography at 6-12 hours after birth to ibuprofen or placebo by 12 hours of age in a multicenter, double blind, randomized-controlled trial. Open-label ibuprofen was allowed for prespecified criteria of a hemodynamically significant PDA. The primary outcome was survival without cerebral palsy at 24 months of corrected age.

Results: Among 337 enrolled infants, 109 had a small or closed ductus and constituted a reference group; 228 had a large PDA and were randomized. The primary outcome was assessed at 2 years in 108 of 114 (94.7%) and 102 of 114 (89.5%) patients allocated to ibuprofen or placebo, respectively. Survival without cerebral palsy occurred in 77 of 108 (71.3%) after ibuprofen, 73 of 102 (71.6%) after placebo (adjusted relative risk 0.98, 95% CI 0.83-1.16, P = .83), and 77 of 101 (76.2%) in reference group. Infants treated with ibuprofen had a lower incidence of PDA at day 3. Severe pulmonary hemorrhage during the first 3 days occurred in 2 of 114 (1.8%) infants treated with ibuprofen and 9 of 114 (7.9%) infants treated with placebo (adjusted relative risk 0.22, 95% CI 0.05-1.00, P = .05). Open-label rescue treatment with ibuprofen occurred in 62.3% of infants treated with placebo and 17.5% of infants treated with ibuprofen (P < .001), at a median (IQR) age of 4 (3, 5) and 4 (4, 12) days, respectively.

Conclusions: Early echocardiography-targeted ibuprofen treatment of a large PDA did not change the rate of survival without cerebral palsy.

Trial registration: Eudract 2011-003063-30 and ClinicalTrials.gov: NCT01630278.

Keywords: bronchopulmonary dysplasia; cerebral palsy; patent ductus arteriosus; premature birth.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cerebral Palsy / epidemiology*
  • Child, Preschool
  • Cyclooxygenase Inhibitors / therapeutic use*
  • Double-Blind Method
  • Ductus Arteriosus, Patent / drug therapy*
  • Ductus Arteriosus, Patent / mortality
  • Humans
  • Ibuprofen / therapeutic use*
  • Infant
  • Infant, Extremely Premature*
  • Infant, Newborn

Substances

  • Cyclooxygenase Inhibitors
  • Ibuprofen

Associated data

  • ClinicalTrials.gov/NCT01630278
  • EudraCT/2011-003063-30