Early prophylactic hydrocortisone fails to prevent lung disease in extremely preterm infants

A new systematic review and meta-analysis, published in Frontiers in Pediatrics, pooled data from 14 studies covering 3,416 extremely preterm infants and found that early low-dose hydrocortisone, started within the first 24 to 48 hours after birth, did not significantly improve survival free of bronchopulmonary dysplasia, did not significantly reduce the lung disease itself, and did not lower mortality before hospital discharge. Worse, the treatment carried a measurable cost: a statistically significant increase in late-onset sepsis. Bronchopulmonary dysplasia remains the defining chronic complication of extreme prematurity.

Among very preterm or very low birth weight infants, its prevalence is approximately 35 percent at 28 days of life and 21 percent at 36 weeks' postmenstrual age, the standard clinical benchmark. In extremely low gestational age infants, it can exceed 40 percent. The disease arises when alveolar and pulmonary vascular development is arrested under the combined assault of antenatal inflammation, postnatal infection, oxygen exposure, and mechanical ventilation.

Immature antioxidant defenses and underdeveloped endocrine responses compound the injury, making the first postnatal days a window in which the trajectory of lung development can be altered. The biological rationale for hydrocortisone is elegant. Many extremely preterm infants experience a state of relative adrenal insufficiency, meaning their adrenal glands cannot mount an adequate cortisol response to the cardiovascular and inflammatory stress of birth and intensive care.

This deficit may worsen hemodynamic instability and fuel pulmonary inflammation. Corticosteroids suppress inflammation and support circulatory adaptation, and hydrocortisone, unlike the far more potent dexamethasone, mimics the body's own hormone profile with mineralocorticoid activity and a gentler biologic footprint. Early high-dose dexamethasone had already been linked to gastrointestinal, infectious, metabolic, and neurodevelopmental harms, so low-dose hydrocortisone emerged as a seemingly safer prophylactic strategy, designed to compensate for adrenal immaturity rather than to rescue established disease.

Hope for the approach was anchored in the French PREMILOC trial, which randomized 523 infants born at 24 to 27 plus 6 weeks' gestation within 24 hours of birth to hydrocortisone or placebo. Survival without bronchopulmonary dysplasia at 36 weeks' postmenstrual age was 60 percent with hydrocortisone versus 51 percent with placebo, a result that electrified the field. But PREMILOC also sounded an alarm: among infants born at 24 to 25 weeks, late-onset sepsis occurred in 40 percent of hydrocortisone-treated infants versus 23 percent of placebo recipients, even though sepsis rates did not differ significantly in the trial population as a whole.

Uncertainty deepened around spontaneous gastrointestinal perforation, particularly when hydrocortisone was combined with indomethacin for patent ductus arteriosus treatment. The new review, conducted under PRISMA 2020 guidance with a prospectively registered protocol, searched PubMed, Cochrane CENTRAL, Scopus, and Web of Science from inception to May 2026. Eligible studies enrolled infants born before 30 weeks' gestation who received prophylactic systemic hydrocortisone at a starting dose of no more than 2.0 mg/kg/day, begun within 24 to 48 hours of birth, with a total course including tapering not exceeding 15 days.

Comparators were placebo or no hydrocortisone. The review accepted randomized and quasi-randomized trials, their follow-up reports, and comparative observational studies, reflecting how limited the randomized evidence for this indication remains. Fourteen studies from France, Italy, Finland, the United States, Sweden, China, and the United Kingdom made the final cut, with sample sizes ranging from 34 to 1,106 infants.

The pooled verdict was sobering. Survival without bronchopulmonary dysplasia at 36 weeks' postmenstrual age, reported across ten studies with 2,703 infants, showed a risk ratio of 1.07 with a 95 percent confidence interval of 0.97 to 1.19 and a p-value of 0.18, numerically favorable but statistically null. Bronchopulmonary dysplasia at 36 weeks itself yielded a risk ratio of 0.94 (95 percent CI 0.85 to 1.04, p = 0.25).

All-cause mortality before discharge showed a risk ratio of 1.07 (95 percent CI 0.77 to 1.49, p = 0.69), and death before 36 weeks was essentially identical between groups. Heterogeneity was minimal, with an I-squared of 0 percent for the primary composite outcome, and leave-one-out sensitivity analyses confirmed that no single study drove the pooled estimate, which ranged only from 1.06 to 1.09. Respiratory support outcomes were similarly flat.

The pooled mean difference for duration of mechanical ventilation was minus 1.11 days (95 percent CI minus 4.67 to 2.46), and for oxygen therapy minus 5.81 days (95 percent CI minus 14.55 to 2.93), neither significant. The need for oxygen at discharge was comparable between groups. The authors note that the included studies span nearly three decades of neonatal practice, from trials recruiting in the late 1990s to cohorts from the 2020s, during which antenatal corticosteroid coverage, surfactant strategy, non-invasive ventilation, oxygen saturation targets, and infection control all changed substantially.

A therapy whose effect depends on baseline inflammatory and respiratory risk may therefore differ between earlier and later eras, and pooling across the whole period may dilute an effect present in only part of it. Beneath the neutral headline, subgroup analyses whispered a more nuanced story. Among infants exposed to chorioamnionitis, the risk ratio for survival without bronchopulmonary dysplasia favored hydrocortisone at 1.26 (95 percent CI 1.01 to 1.56), while among those without exposure the estimate was smaller and non-significant.

Among infants born before 26 weeks' gestation, the risk ratio was 1.39 (95 percent CI 1.02 to 1.90), a significant signal in the group with the greatest developmental immaturity and highest baseline risk. The authors stress these findings are exploratory. Chorioamnionitis was diagnosed histologically in some studies and clinically in others, none applied the modern Triple I criteria, and study-level subgroup estimates can be distorted by differences in case mix and trial conduct.

A prior meta-analysis of roughly a quarter of a million preterm infants found chorioamnionitis significantly associated with bronchopulmonary dysplasia, lending biological plausibility to an inflammation-targeted benefit. Safety outcomes sharpened the clinical calculus. Late-onset sepsis was significantly more frequent with hydrocortisone, with a risk ratio of 1.19 (95 percent CI 1.05 to 1.35, p = 0.01), a clinically important signal given the immature immune defenses, prolonged hospitalization, and invasive device exposure that already burden these infants.

Gastrointestinal perforation was not significantly increased (risk ratio 1.34, 95 percent CI 0.93 to 1.93), but the point estimate sat above unity and the confidence interval cannot exclude a substantial harm, particularly near indomethacin exposure. Necrotizing enterocolitis, severe intraventricular hemorrhage, retinopathy of prematurity, pulmonary hemorrhage, and treated hypertension or insulin requirement showed no significant differences. Neurodevelopmental impairment at 2 years (risk ratio 0.93) and cerebral palsy showed no significant associations, though the 5-to-7-year estimates came from the follow-up of a single trial with small event counts and strikingly wide confidence intervals, leaving long-term safety genuinely unresolved.

The review's conclusion is unambiguous: current evidence does not support routine prophylactic hydrocortisone for all extremely preterm infants solely to prevent bronchopulmonary dysplasia. Clinical decisions should remain individualized, aligned with local protocols, gestational age, hemodynamic status, infection risk, and patent ductus arteriosus treatment strategy, with particular caution in units with high baseline sepsis rates. Notably, the observational studies, which roughly doubled the evidence base and added contemporary real-world data from Swedish national and other cohorts, produced estimates consistent with the randomized trials when analyzed as a prespecified design subgroup, so the main conclusion does not hinge on confounding-prone data.

The authors call for adequately powered trials and individual patient data meta-analyses to identify which infants, if any, derive a favorable balance of benefit and harm, with standardized disease definitions, prespecified sepsis and perforation endpoints, and follow-up to school age.

Subject of Research: Early prophylactic low-dose hydrocortisone for bronchopulmonary dysplasia prevention in extremely preterm infants

Article Title: Early prophylactic low-dose hydrocortisone for bronchopulmonary dysplasia prevention in extremely preterm infants: a systematic review and meta-analysis

Article References: Abu Shehadeh, L., Al Ghamdi, T. A., Alzahrani, R. A., Mushari, B. Y., Alotaibi, L. A., Sadik, L., Kheder, O. M., Hagr, T., & Alnawfal, B. M. (2026). Early prophylactic low-dose hydrocortisone for bronchopulmonary dysplasia prevention in extremely preterm infants: a systematic review and meta-analysis. Frontiers in Pediatrics, 14, Article 1934115. https://doi.org/10.3389/fped.2026.1934115

Image Credits: AI Generated

DOI: 10.3389/fped.2026.1934115

Keywords: bronchopulmonary dysplasia, hydrocortisone, extremely preterm infants, systematic review, meta-analysis, neonatology, late-onset sepsis, chorioamnionitis, corticosteroids, neonatal outcomes, prematurity, respiratory support