Prophylactic hydrocortisone and the risk of sepsis in neonates born extremely preterm

Baud O, Lehert P, PREMILOC study group. Eur J Pediatr. 2025 Jun 14;184(7):419. doi:10.1007/s00431-025-06248-9.

Introduction

Extremely preterm neonates face significant risks of morbidity and mortality, with bronchopulmonary dysplasia (BPD) and late-onset sepsis (LOS) among the most serious complications. Prophylactic low-dose hydrocortisone (HC) has emerged as a promising intervention to improve survival without BPD, yet concerns about its potential to increase LOS risk have tempered enthusiasm. This study re-analyzes data from the PREMILOC trial to clarify the relationship between prophylactic HC and LOS risk, adjusting for key perinatal risk factors and competing risks.

Understanding this balance is critical for neonatal clinicians aiming to optimize outcomes in this vulnerable population, as the benefits of HC in reducing mortality must be weighed against any potential infectious risks.

Study Overview

The study employed three statistical models—Poisson regression, Cox regression, and Fine and Gray competing risks analysis—to evaluate the association between HC and LOS, adjusting for perinatal covariates such as gestational age, delivery mode, and supplemental corticosteroid use.

Key Findings

• LOS incidence was 24% (64/264) in placebo group and 30% (77/255) in HC group; difference not statistically significant (P = 0.12)
• Higher gestational age at birth and vaginal delivery independently associated with lower LOS risk (P < 0.001 and P = 0.005 respectively)
• Supplemental corticosteroids administered after day 10 but before LOS onset were linked to reduced LOS risk (P < 0.001)
• Perinatal asphyxia showed a trend toward increased LOS risk (P = 0.065)
• Adjusted relative risk for LOS with prophylactic HC was 1.041 (95% CI, 0.738 to 1.471; P = 0.817), indicating no significant effect
• Competing risk analysis confirmed no significant effect of HC on LOS (hazard risk ratio 1.105; 95% CI, 0.787 to 1.552; P = 0.560)
• Prophylactic HC significantly reduced risk of death (hazard risk ratio 0.427; 95% CI, 0.259 to 0.707; P < 0.001)

Evidence Synthesis

The findings align with the original PREMILOC trial (¹), which demonstrated improved survival without BPD with prophylactic HC. This benefit is further supported by a high-quality individual patient data meta-analysis (²) and a comprehensive Cochrane review on early systemic corticosteroids (³), both confirming efficacy and safety.

Secondary analyses of the PREMILOC cohort have refined the understanding of HC’s benefits and risks, adjusting for baseline characteristics (⁴) and exploring predictors of treatment response (⁷). Long-term follow-up studies at 2 and 5 years post-intervention show reassuring neurodevelopmental outcomes, supporting the intervention’s safety profile (^5,6).

Real-world observational data from a UK neonatal unit corroborate the tolerance and safety of prophylactic HC outside trial settings (⁸). Collectively, this evidence clarifies that while HC reduces mortality and BPD, it does not significantly increase LOS risk after appropriate statistical adjustment.

Summary Table of Key Related Research

Clinical Implications

• Prophylactic low-dose hydrocortisone reduces mortality and BPD without significantly increasing late-onset sepsis risk in extremely preterm neonates.
• Adjustment for perinatal risk factors is essential to accurately assess infection risk associated with HC.
• Long-term neurodevelopmental safety supports the use of HC as a standard prophylactic intervention in this population.
• Clinicians should consider supplemental corticosteroid timing and perinatal factors when managing these infants.

Strengths & Limitations

Future Directions

Further research is needed to identify neonatal subgroups that may derive differential benefit or harm from prophylactic hydrocortisone, including exploration of baseline cortisol levels and other biomarkers. Long-term neurodevelopmental outcomes beyond 5 years and direct comparisons of different low-dose corticosteroid regimens or durations remain important areas for future study.

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