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Identifying effect modifiers of systemic hydrocortisone treatment initiated 7–14 days after birth in ventilated very preterm infants on long-term outcome: secondary analysis of a randomised controlled trial


Objective To explore clinical effect modifiers of systemic hydrocortisone in ventilated very preterm infants for survival and neurodevelopmental outcome at 2 years’ corrected age (CA).

Design Secondary analysis of a randomised placebo-controlled trial.

Setting Dutch and Belgian neonatal intensive care units.

Patients Infants born <30 weeks’ gestational age (GA), ventilator-dependent in the second week of postnatal life.

Intervention Infants were randomly assigned to systemic hydrocortisone (cumulative dose 72.5 mg/kg; n=182) or placebo (n=190).

Main outcome measures The composite of death or neurodevelopmental impairment (NDI) at 2 years’ CA and its components. Candidate effect modifiers (GA, small for GA, respiratory index, sex, multiple births, risk of moderate/severe bronchopulmonary dysplasia or death) were analysed using regression models with interaction terms and subpopulation treatment effect pattern plots.

Results The composite outcome was available in 356 (96.0%) of 371 patients (one consent withdrawn). For this outcome, treatment effect heterogeneity was seen across GA subgroups (<27 weeks: hydrocortisone (n=141) vs placebo (n=156), 54.6% vs 66.2%; OR 0.61 (95% CI 0.38 to 0.98); ≥27 weeks: hydrocortisone (n=30) vs placebo (n=31), 66.7% vs 45.2%; OR 2.43 (95% CI 0.86 to 6.85); p=0.02 for interaction). This effect was also found for the component death (<27 weeks: 20.1% vs 32.1%; OR 0.53 (95% CI 0.32 to 0.90); ≥27 weeks: 28.1% vs 16.1%; OR 2.04 (95% CI 0.60 to 6.95); p=0.049 for interaction) but not for the component NDI. No differential treatment effects were observed across other subgroups.

Conclusion This secondary analysis suggests that in infants <27 weeks’ GA, systemic hydrocortisone may improve the outcome death or NDI, mainly driven by its component death. There was insufficient evidence for other selected candidate effect modifiers.

  • Neonatology
  • Infant Development
  • Respiratory Medicine

Data availability statement

Data are available upon reasonable request. Deidentified individual participant data (including data dictionaries) will be made available, in addition to study protocol, the statistical analysis plan and the analytical code. The data will be made available upon publication to researchers who provide a methodologically sound proposal for use in achieving the goals of the approved proposal. Proposals should be submitted to Professor Anton van Kaam (email:

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