The Effect of Systemic Hydrocortisone Initiated 7 to 14 Days After Birth in Ventilated Preterm Infants on Mortality and Neurodevelopment at 2 Years’ Corrected Age: Follow-Up of a Double-Blind, Placebo-Controlled, Multicentre, Randomised Trial

Background: Our double-blind, placebo-controlled, randomised trial investigating systemic hydrocortisone in mechanically ventilated preterm infants (gestational age <30 weeks and/or birth weight <1250 grams) in the second week of life, reported no difference for the primary outcome death or bronchopulmonary dysplasia (BPD) at 36 weeks’ postmenstrual age. Here we report the results for death and neurodevelopmental impairment (NDI) at two years’ corrected age (CA). Methods: The infants were randomly assigned to a 22-day course of systemic hydrocortisone (cumulative dose 72∙5 mg/kg; n=182) or placebo (n=190) stratified by study centre and gestational age (<27, ≥27 weeks). Follow-up assessment was performed in the 16 neonatal trial centres at 2 years’ CA. Findings: Among 371 patients (mean gestational age 26 weeks) who completed the trial, 276 (74∙4%) survived till 2 years’ CA, and were assessed between April 18, 2014 and June, 27 2019; parents withdrew consent for one child treated with hydrocortisone. The composite outcome death or NDI was available in 356 (96∙0%) infants and occurred in 97 of 171 hydrocortisone treated infants (56∙7%), and in 116 of 185 infants (62∙7%) assigned to placebo (adjusted risk difference, -5∙2% [95% CI -15∙1 to 4∙6]; adjusted odds ratio, 0∙79 [95% CI 0∙51 to 1∙22], p=0∙28). Pre-specified subgroup analysis of infants <27 weeks gestation showed a significant reduction in death or NDI in the hydrocortisone group compared to the placebo group (54∙6% vs. 66∙2%; risk difference -11∙6% [95% CI -22∙4% to -0∙5%], p=0∙02 for interaction). Interpretation: The administration of hydrocortisone in the second week of life was not significantly associated with a difference in death or NDI in mechanically ventilated preterm infants. Future studies should confirm the observed increased intact survival in infants <27 weeks gestation treated with systemic hydrocortisone. Trial Registration: The SToP-BPD study was registered with The Netherlands Trial Register (NTR2768; registered on 17 February 2011) and the European Union Clinical Trials Register (EudraCT, 2010-023777-19; registered on 2 November 2010). Funding Statement: The Netherlands Organization for Health Research and Development ZonMW Priority Medicines for Children no. 11-32010-02. Declaration of Interests: Dr. van Kaam reports grants from The Netherlands Organization for Health Research and Development ZonMW during the conduct of the study. No other disclosures were reported. Ethics Approval Statement: The study-protocol was approved by the human research ethics committees at each participating centre. Written informed consent was obtained from both parents before randomisation.