Project Details

Neurodevelopment at 2 years of extremely preterm infants who received early intratracheal budesonide

Brett Manley, MBBS, PhD

Summary

BACKGROUND Intratracheal budesonide mixed with surfactant has been a promising intervention to increase survival free of bronchopulmonary dysplasia (BPD) in extremely preterm infants. The international PLUSS trial (Manley et al, JAMA 2014) enrolled 1059 extremely preterm infants and found no significant difference in survival free of BPD between infants who received intratracheal budesonide mixed with surfactant and those who received surfactant alone. Recently, the NICHD “BiB” primary trial results were published (Ambalavanan, JAMA et al 2025) and were very similar. Children enrolled in PLUSS were followed up at 24 months’ corrected age to assess longer-term health and neurodevelopmental outcomes. These results are the first large-scale, longer-term outcome data from trials of intratracheal budesonide. Registration: Australian New Zealand Clinical Trials Registry, ACTRN12617000322336. OBJECTIVE To determine any differences between the PLUSS trial groups at 24 months’ corrected age for the primary outcome of survival without moderate-severe neuro-developmental disability. DESIGN/METHODS Assessments at 24 months included: 1) a physical examination and health assessment (including hearing, vision, growth, and respiratory health); 2) Bayley Scales of Infant and Toddler Development (3rd or 4th ed.) for cognitive, language, and motor development; 3) Gross Motor Function Classification System to determine the severity of any cerebral palsy; 4) Infant-Toddler Social and Emotional Assessment (ITSEA); and 5) the Predicting Asthma Risk in Children (PARC) questionnaire. The Primary outcome at 24 months is survival without moderate-severe neurodevelopmental disability, defined as any one or more of moderate or severe developmental delay, moderate or severe cerebral palsy, deafness, or blindness. Secondary outcomes include: death; age-standardized developmental scores for cognition, language, and motor function; developmental delay; cerebral palsy; moderate or severe neurosensory disabilities; sex- and age-standardized emotional-behavioral scores; body size; and asthma risk score. Funding for these longer-term assessments was from the Thrasher Research Fund (USA) and Cure Kids (New Zealand). RESULTS The primary outcome was available for 974 (92% of all enrolled) infants. They were assessed at a median of 26 months’ corrected gestational age. There was no statistically significant difference in the rate of the primary outcome between the groups: 52.3% in the surfactant + budesonide group vs. 49.2% in the surfactant only group: risk difference 3.1% (95% CI -3.2, 9.4). There was also no difference in any of the components of the primary outcome, or in the severity of any cerebral palsy. There was no difference in mean PARC scores, or in the rate of a score of 5 or more that is predictive of school age asthma. The ITSEA is still to be analysed. CONCLUSIONS In this international, randomized trial in extremely preterm infants, early intratracheal budesonide mixed with surfactant, compared with surfactant alone, did not increase survival free of moderate-severe neurodisability at 2 years, or improve the rate of asthma symptoms. This is the first large trial to report longer-term outcomes of intratracheal budesonide mixed with surfactant for extremely preterm infants. PLANS The remaining secondary results are being analysed and a report will be prepared for submission to a high-ranking journal for publication in the coming months. The results have been presented as an oral plenary at PSANZ (Perth, Australia) and as a poster at PAS (Boston, USA). They will be presented at additional conferences during 2026. Parents who requested the results will be sent these by email in due course, when finalized and published.