Heterogeneity of Treatment Effects of Hydrocortisone by Risk of Bronchopulmonary Dysplasia or Death Among Extremely Preterm Infants in the National Institute of Child Health and Human Development Neonatal Research Network Trial: A Secondary Analysis of a Randomized Clinical Trial

Abstract

Importance: Extremely preterm infants who develop bronchopulmonary dysplasia (BPD) are at a higher risk for adverse pulmonary and neurodevelopmental outcomes. In the National Institute of Child Health and Human Development Neonatal Research Network (NICHD NRN) Hydrocortisone Trial, hydrocortisone neither reduced rates of BPD or death nor increased rates of neurodevelopmental impairment (NDI) or death.

Objective: To determine whether estimated risk for grades 2 to 3 BPD or death is associated with the effect of hydrocortisone on the composite outcomes of (1) grades 2 to 3 BPD or death and (2) moderate or severe NDI or death.

Design, setting, and participants: This secondary post hoc analysis used data from the NICHD NRN Hydrocortisone Trial, which was a double-masked, placebo-controlled, randomized clinical trial conducted in 19 US academic centers. The NICHD HRN Hydrocortisone Trial enrolled infants born at a gestational age of less than 30 weeks who received mechanical ventilation for at least 7 days, including at the time of enrollment, and who were aged 14 to 28 postnatal days. Infants were enrolled between August 22, 2011, and February 4, 2018, with follow-up between 22 and 26 months of corrected age completed on March 29, 2020. Data were analyzed from September 13, 2021, to March 25, 2023.

Intervention: Infants were randomized to 10 days of hydrocortisone or placebo treatment.

Main outcomes and measures: Infants' baseline risk of grades 2 to 3 BPD or death was estimated using the NICHD Neonatal BPD Outcome Estimator. Differences in absolute and relative treatment effects by baseline risk were evaluated using interaction terms in models fitted to the efficacy outcome of grades 2 to 3 BPD or death and the safety outcome of moderate or severe NDI or death by follow-up.

Results: Among the 799 infants included in the analysis (421 boys [52.7%]), the mean (SD) gestational age was 24.9 (1.5) weeks, and the mean (SD) birth weight was 715 (167) g. The mean estimated baseline risk for grades 2 to 3 BPD or death was 54% (range, 18%-84%) in the study population. The interaction between treatment group and baseline risk was not statistically significant on a relative or absolute scale for grades 2 to 3 BPD or death; the size of the effect ranged from a relative risk of 1.13 (95% CI, 0.82-1.55) in quartile 1 to 0.94 (95% CI, 0.81-1.09) in quartile 4. Similarly, the interaction between treatment group and baseline risk was not significant on a relative or absolute scale for moderate or severe NDI or death; the size of the effect ranged from a relative risk of 1.04 (95% CI, 0.80-1.36) in quartile 1 to 0.99 (95% CI, 0.80-1.22) in quartile 4.

Conclusions and relevance: In this secondary analysis of a randomized clinical trial, the effect of hydrocortisone vs placebo was not appreciably modified by baseline risk for grades 2 to 3 BPD or death.

Trial registration: ClinicalTrials.gov Identifier: NCT01353313.

Figure 1.. Efficacy Outcome

The observed frequency (A), relative risk (B), and risk reduction (C) of grades 2 to 3 bronchopulmonary dysplasia (BPD) or death in the hydrocortisone vs placebo treatment groups are shown by quartile (Q) of baseline estimated risk of grades 2 to 3 BPD or death. Symbols (circles, squares, and triangles) represent estimated values by quartile of baseline risk; error bars indicate 95% CIs. The horizontal orange lines indicate the model estimated results; the horizontal blue lines and dashed lines indicate the overall trial result and 95% CIs, respectively. Grades 2 to 3 BPD or death did not differ by interaction between treatment group and baseline risk for grades 2 to 3 BPD or death.

Figure 2.. Safety Outcome

The observed frequency (A), relative risk (B), and risk reduction (C) of moderate or severe neurodevelopmental impairment (NDI) or death in the hydrocortisone vs placebo treatment groups by quartile (Q) of baseline estimated risk of grades 2 to 3 bronchopulmonary dysplasia (BPD) or death. Symbols (circles, squares, and triangles) represent estimated values by quartile of baseline risk; error bars indicate 95% CIs. The horizontal orange lines indicate the model estimated results; the horizontal blue lines and dashed lines indicate the overall trial result and 95% CIs, respectively. Moderate or severe NDI or death did not differ by interaction between treatment group and baseline risk for grades 2 to 3 BPD or death.