EBNEO Commentary: Does the effect of hydrocortisone in preterm infants depend on the baseline risk of BPD?

September 11, 2023

EBNEO Commentary: Does the effect of hydrocortisone in preterm infants depend on the baseline risk of BPD?

Manuscript Citation

Gentle SJ, Rysavy MA, Li L, et al. 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. JAMA Netw Open. 2023;6(5):e2315315. doi:10.1001/jamanetworkopen.2023.15315. PMID 37256621

Reviewed By

Timothy D. Nelin, MD
Children’s Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine
nelint@chop.edu

Nicolas A. Bamat, MD, MSCE
Children’s Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine
bamatn@chop.edu

Type of Investigation

Secondary post hoc analysis

Question

(P) Among preterm infants born at <30 weeks’ gestation, on mechanical ventilation at 14 to 28 postnatal days and having received mechanical ventilation for at least 7 days,

(I/C) Does an infant’s baseline predicted risk of grade 2 or 3 bronchopulmonary dysplasia (BPD),

(O) Modify the effect of hydrocortisone on the development of grade 2 or 3 BPD or death and moderate or severe neurodevelopmental impairment (NDI) or death

(T) by follow-up at 22 to 26 months corrected age?

Methods

Design: Secondary post hoc analysis of the NICHD NRN Hydrocortisone Trial (double-masked, placebo-controlled, randomized clinical trial of 800 preterm infants).

Participants: Preterm infants born at <30 weeks’ gestation, receiving mechanical ventilation at study entry between 14 and 28 postnatal days, and underwent mechanical ventilation for at least 7 days. Infants were randomized to either hydrocortisone or placebo treatment over a 10-day course.

Follow-up Period: Diagnosed with BPD by the 2019 NRN criteria at 36 weeks’ post-menstrual age (PMA). Assessed for moderate or severe NDI between 22 and 26 months of corrected age.

Setting: 19 academic NICUs in the United States.

Intervention and Comparison: Infants were randomized to 10 days of hydrocortisone or placebo treatment at time of study entry between 14 and 28 postnatal days. To define an interaction variable, baseline predicted risk of grade 2 or 3 BPD or death was calculated for each infant with the NICHD Neonatal BPD Outcome Estimator using baseline variables available on postnatal day 14. Infants were classified into quartiles of baseline risk for BPD or death based on this calculation.

Outcomes:

  • Primary composite outcome: Grade 2 or 3 BPD or death
  • Safety outcome: Moderate or severe NDI or death

Analysis:

  • Interactions between treatment group and quartiles of baseline predicted risk of grades 2 to 3 BPD or death were analyzed for both outcomes of grades 2 to 3 BPD or death and moderate or severe NDI or death.
  • Relative risk (RR) estimation and risk difference (RD) calculations were used to describe effect estimates across quartiles. Models accounted for variables used for stratification (center and gestational age).
  • Two-sided P < 0.05 indicated statistical significance.

Main Results:

Study Population: 799 preterm infants were included with a mean (SD) gestational age of 24.9 (1.5) weeks, mean (SD) birth weight of 715 (167) g, and mean estimated baseline risk for grades 2 to 3 BPD or death of 54% (range, 18-84%).

Primary Outcome: No significant interaction existed between treatment group and baseline predicted risk for grades 2 to 3 BPD or death on the efficacy outcome of grades 2 to 3 BPD or death. The relative risk (RR) ranged from 1.13 (95% CI, 0.82-1.55) in the quartile 1 to 0.94 (95% CI, 0.81-1.09) in quartile 4.

Safety Outcome: No significant interaction existed between treatment group and baseline estimated risk for grades 2 to 3 BPD or death and on the safety outcome of moderate or severe NDI or death. The RR ranged from 1.04 (95% CI, 0.80-1.36) in quartile 1 to 0.99 (95% CI, 0.80-1.22) in quartile 4.

 

Commentary (500 words):

BPD remains the most common chronic morbidity of preterm birth despite advances in the survival of preterm infants.1,2 Prior studies demonstrated postnatal corticosteroid effects vary with infants’ baseline BPD risk, motivating the current study to investigate if an infant’s baseline predicted risk for BPD or death modifies the effect of hydrocortisone.3,4 Unlike prior metaregression analyses comparing data between trials, Gentle et al. compared data among infants enrolled in the NICHD NRN Hydrocortisone Trial and did not identify statistically significant differences in the effects of hydrocortisone on death, BPD, or neurodevelopmental impairment when analyzed by infants’ baseline risk for BPD or death.

 

The findings published by Gentle et al. must be considered within the context of a subpopulation of extremely preterm infants with high baseline illness severity and may not generalize to broader preterm populations. The current data do not examine whether the baseline risk for BPD or death modifies the effect of hydrocortisone in all extremely preterm infants as infants in the NICHD NRN Hydrocortisone Trial carried a high risk for developing BPD based on the physiologic definition5 – 83.4% of infants in the hydrocortisone group and 86.4% of infants in the placebo group developed the composite outcome of death or BPD.6  Prior studies investigating postnatal hydrocortisone found that 49% and 71% of infants receiving placebo died or developed BPD, with lower rates of death or BPD among hydrocortisone exposed infants.7,8 Infants in those studies were exposed to hydrocortisone within 24 hours of birth and at a median of 10 days, respectively. Therefore, infants in the NICHD NRN Hydrocortisone Trial represent a subset of extremely preterm infants with higher overall risk for death or BPD and were exposed to hydrocortisone at an older age.

 

While no significant interaction of hydrocortisone treatment and baseline risk for BPD or death with the primary efficacy outcome was noted, close investigation suggests a trend towards a lower comparative relative risk for the development of grade 2 or 3 BPD in infants in the highest quartile of BPD or death risk (RR 0.94; 95% CI 0.81, 1.09) compared to infants in the lowest quartile of risk (RR 1.13; 95% CI 0.82, 1.55). The risk difference estimates for these quartiles highlight the clinical relevance of these trends: an estimate of a 5% higherabsolute risk for BPD or death among infants exposed to hydrocortisone in the lowest risk quartile and a 5% lower absolute risk among infants exposed to hydrocortisone in the highest risk quartile. These data suggest that infants with higher risks of BPD or death may comparatively benefit from postnatal hydrocortisone as administered in this trial, but with too much uncertainty.

 

In conclusion, among extremely preterm infants enrolled in the NICHD NRN Hydrocortisone Trial, the effect of hydrocortisone was not modified by baseline risk for developing grades 2 or 3 BPD or death. Further research, in larger and more representative cohorts of extremely preterm infants would aid in understanding potential differential effects of hydrocortisone exposure among infants with baseline differences in lung disease severity.

References

  1. Abman SH, Collaco JM, Shepherd EG, Keszler M, Cuevas-Guaman M, Welty SE et al. Interdisciplinary Care of Children with Severe Bronchopulmonary Dysplasia. Journal of Pediatrics 2017; 181: 12–28.
  2. Lee SM, Sie L, Liu J, Profit J, Lee HC. Evaluation of Trends in Bronchopulmonary Dysplasia and Respiratory Support Practice for Very Low Birth Weight Infants: A Population-Based Cohort Study. Journal of Pediatrics2022; 243. doi:10.1016/j.jpeds.2021.11.049.
  3. Doyle LW, Halliday HL, Ehrenkranz RA, Davis PG, Sinclair JC. An update on the impact of postnatal systemic corticosteroids on mortality and cerebral palsy in preterm infants: Effect modification by risk of bronchopulmonary dysplasia. Journal of Pediatrics 2014; 165. doi:10.1016/j.jpeds.2014.07.049.
  4. Doyle LW, Halliday HL, Ehrenkranz RA, Davis PG, Sinclair JC. Impact of postnatal systemic corticosteroids on mortality and cerebral palsy in preterm infants: Effect modification by risk for chronic lung disease. Pediatrics2005; 115. doi:10.1542/peds.2004-1238.
  5. Walsh MC, Yao Q, Gettner P, Hale E, Collins M, Hensman A et al. Impact of a physiologic definition on bronchopulmonary dysplasia rates. Pediatrics 2004; 114. doi:10.1542/peds.2004-0204.
  6. Watterberg KL, Walsh MC, Li L, Chawla S, D’Angio CT, Goldberg RN et al. Hydrocortisone to Improve Survival without Bronchopulmonary Dysplasia. New England Journal of Medicine 2022; 386. doi:10.1056/nejmoa2114897.
  7. Onland W, Cools F, Kroon A, Rademaker K, Merkus MP, Dijk PH et al. Effect of Hydrocortisone Therapy Initiated 7 to 14 Days after Birth on Mortality or Bronchopulmonary Dysplasia among Very Preterm Infants Receiving Mechanical Ventilation: A Randomized Clinical Trial. JAMA – Journal of the American Medical Association 2019; 321. doi:10.1001/jama.2018.21443.
  8. Baud O, Maury L, Lebail F, Ramful D, El Moussawi F, Nicaise C et al. Effect of early low-dose hydrocortisone on survival without bronchopulmonary dysplasia in extremely preterm infants (PREMILOC): A double-blind, placebo-controlled, multicentre, randomised trial. The Lancet 2016; 387. doi:10.1016/S0140-6736(16)00202-6.

 

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