Authors' objectives: In extremely preterm babies, born before 28 weeks’ gestation, a large (≥ 1.5 mm in diameter) patent ductus arteriosus present beyond 3 days of age is associated with higher mortality and morbidity than infants without a patent ductus arteriosus. The cyclooxygenase inhibitor ibuprofen may be used to treat patent ductus arteriosus. Whether selective early treatment of a large patent ductus arteriosus with ibuprofen improves health and developmental outcomes is not known.

Authors' results and conclusions: A total of 326 infants were randomised to ibuprofen and 327 to placebo. The primary outcome occurred in 220/318 infants (69.2%) in the ibuprofen group and in 202/318 infants (63.5%) in the placebo group (adjusted risk ratio 1.09, 95% confidence interval 0.98 to 1.20; p = 0.10). A total of 44 of 323 infants (13.6%) in the ibuprofen group and 33 of 321 infants (10.3%) in the placebo group died by 36 weeks of gestation (adjusted risk ratio 1.32, 95% confidence interval 0.92 to 1.90). Two unforeseeable serious adverse events occurred that were possibly related to ibuprofen. At 24 months of corrected age, outcome data were available for 263 and 274 children in the ibuprofen and placebo groups, respectively. Survival without moderate to severe neurodevelopmental impairment in the ibuprofen and placebo groups was 131/248 (53.0%) and 134/259 (51.9%), respectively; adjusted risk ratio 1.01 (95% confidence interval 0.86 to 1.18); p = 0.901. Survival without respiratory morbidity was 66/210 (31.4%) and 74/220 (33.6%), respectively; adjusted risk ratio 0.92 (95% confidence interval 0.70 to 1.20); p = 0.536. Median duration of oxygen supplementation was 76.0 and 78.0 days, respectively. The risk of death or moderate or severe bronchopulmonary dysplasia at 36 weeks of post menstrual age was not statistically significantly lower for extremely preterm infants randomised to early treatment with ibuprofen compared to placebo. There was no evidence of an improvement in survival without moderate to severe neurodevelopmental impairment or survival without respiratory morbidity at 24 months’ corrected age, after selective early treatment of a large patent ductus arteriosus with ibuprofen in children born extremely preterm.

Authors' methods: We conducted a multicentre, randomised, double-blind, placebo-controlled trial evaluating early treatment (≤ 72 hours after birth) with ibuprofen for a large patent ductus arteriosus in extremely preterm infants. The primary outcome was a composite of death or moderate or severe bronchopulmonary dysplasia at 36 weeks’ of post menstrual age. The short-term secondary outcomes included complications of prematurity, patent ductus arteriosus closure and side effects of treatment. The main long-term outcome was survival without moderate or severe neurodevelopmental impairment, using parent report or classified by blinded end-point review committee at 24 months of corrected age. Other secondary outcomes included survival without respiratory morbidity and duration of oxygen supplementation. A health economic evaluation was undertaken. Open-label therapy was received by 29.8% of infants in the placebo group, potentially increasing the percentage of infants with patent ductus arteriosus closure in this group. The first dose of trial treatment was administered at a median of 61 hours after birth, later than in other trials.

Project Status: Completed

URL for project: https://www.journalslibrary.nihr.ac.uk/programmes/hta/NIHR135850

Year Published: 2026

URL for published report: https://www.journalslibrary.nihr.ac.uk/hta/GJSG2422

URL for additional information: English

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: England, United Kingdom

DOI: 10.3310/GJSG2422

Organisation Name: NIHR Health Technology Assessment programme

Contact Address: NIHR Journals Library, National Institute for Health and Care Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK

Contact Name: journals.library@nihr.ac.uk

Contact Email: journals.library@nihr.ac.uk