Hydrocortisone in Preterm Infants and School-Age Functional Outcomes: Comprehensive Review of Evidence from Randomized Clinical Trials

Highlights

• Neonatal hydrocortisone administered at 14 to 28 postnatal days in very preterm infants at high risk for bronchopulmonary dysplasia (BPD) does not reduce functional impairment at early school-age.
• Functional impairment, primarily motor delay and reduced exercise capacity, remains prevalent in approximately three-quarters of children born extremely preterm regardless of hydrocortisone treatment.
• Long-term neurodevelopmental safety of hydrocortisone is supported, with no significant increase in adverse cognitive or academic outcomes.
• Risk stratification and timing of therapy are critical; hydrocortisone’s effects do not appear modified by baseline BPD risk across gestational age groups.

Background

Bronchopulmonary dysplasia (BPD) is the most prevalent chronic morbidity associated with premature birth, especially in infants born before 30 weeks’ gestation. It results from complex interactions among immaturity, mechanical ventilation, oxygen toxicity, and inflammation. BPD not only increases inpatient morbidity and resource use but also contributes to long-lasting respiratory dysfunction and neurodevelopmental impairment (NDI). Postnatal corticosteroids have been used to prevent or treat BPD, with dexamethasone demonstrating efficacy in reducing BPD incidence but raising significant concerns about adverse long-term neurodevelopmental effects. Hydrocortisone has been proposed as a potentially safer alternative due to its different glucocorticoid and mineralocorticoid receptor activity and a better safety profile in early life. However, evidence regarding its impact on both respiratory outcomes and long-term functional outcomes remains limited and mixed.

Key Content

Chronological Development of Evidence on Hydrocortisone in Preterm Infants

Early-phase clinical trials and observational studies have investigated hydrocortisone’s role in preventing BPD and its safety profile. The PREMILOC trial (2008–2014) evaluated early low-dose hydrocortisone and reported improved survival without BPD and no significant increase in neurodevelopmental impairment at 2 years of age (PMID: 28384828). Follow-up at 5 years suggested some improvement in neurocognitive domains like working memory without affecting full-scale IQ significantly (PMID: 36417367).

The National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN) conducted a pivotal Hydrocortisone for BPD Trial (NCT01353313), enrolling 800 preterm infants (<30 weeks’ gestational age) mechanically ventilated at 14 to 28 postnatal days. Participants received a 10-day tapering course of hydrocortisone (4 mg/kg/day initially) or placebo. The primary neonatal efficacy outcome was survival without moderate or severe BPD at 36 weeks postmenstrual age, and the primary safety outcome was survival without moderate or severe neurodevelopmental impairment at 22–26 months corrected age (PMID: 35320643).

Findings from this trial and subsequent secondary analyses revealed that hydrocortisone treatment did not significantly reduce BPD or death rates compared with placebo. Furthermore, no statistically significant difference in neurodevelopmental impairment or death was observed in the primary safety outcome. Importantly, hypertension occurred more frequently in the hydrocortisone group, underscoring the need for cautious monitoring (PMID: 35320643).

In a recent extended prospective follow-up of this cohort into early school-age (corrected age 5 to 70%), underscoring the persistent developmental challenges in this vulnerable population (PMID: 41359352).

Evidence by Outcomes and Therapeutic Parameters

Study/Trial	Population	Intervention	Primary Outcomes	Key Results	Follow-up Duration
PREMILOC (PMID: 28384828, 36417367)	Extremely preterm infants (<28 wk GA)	Early low-dose hydrocortisone (0.5 mg/kg bid x7 days, then once daily x3 days)	Survival without BPD Neurodevelopment at 2 years and 5 years	Improved survival without BPD No significant difference in overall NDI at 2 years At 5 years, better working memory retention with HC	5 years
NICHD NRN Hydrocortisone Trial (PMID: 35320643, 41359352)	Very preterm infants (<30 wk GA), ventilated ≥7 days at 14-28 days	10-day tapering course hydrocortisone (starting 14–28 days)	Survival without moderate/severe BPD Survival without NDI School-age functional impairment (motor, cognitive, academic, exercise)	No significant improvement in survival without BPD No significant difference in NDI or school-age functional impairment More hypertension in HC group	Up to school age (5-7 yrs)

Safety Profile

Hydrocortisone generally demonstrated a favorable neurodevelopmental safety profile compared to dexamethasone but was associated with an increased incidence of hypertension requiring treatment during hospitalization. Long-term follow-up has not demonstrated increased neurocognitive or motor impairments attributable directly to hydrocortisone exposure. However, persistent high rates of functional impairment indicate multifactorial influences beyond corticosteroid use.

Insights from Secondary and Subgroup Analyses

Secondary analyses by the NICHD NRN trial investigators (PMID: 40090543, 37722765) did not find that hydrocortisone modified the relationship between patent ductus arteriosus and respiratory or neurodevelopmental outcomes. Subgroup analyses pointed to possible treatment heterogeneity by gestational age, with improved mortality outcomes in infants <27 weeks, though neurodevelopmental impact remains unclear.

Other Corticosteroid Interventions and Comparative Evidence

Contrastingly, dexamethasone postnatal corticosteroid use for BPD prevention or treatment has been confirmed to reduce BPD but increase risk of adverse neurodevelopmental outcomes, shifting clinical preference towards hydrocortisone or limiting steroid use. Inhaled steroids like budesonide showed no significant neurodevelopmental benefit with increased mortality concerns (PMID: 29320647). Low-dose, carefully timed systemic hydrocortisone remains a candidate with better balance of efficacy and safety.

Expert Commentary

Corticosteroid therapy for BPD prevention in preterm infants continues to pose a clinical challenge balancing efficacy against neurodevelopmental safety. The NICHD NRN Hydrocortisone Trial and extended follow-up findings substantially contribute to our understanding by demonstrating that late hydrocortisone, though safe in neurodevelopmental terms, does not reduce the high burden of functional impairment prevalent in survivors.

Despite hydrocortisone’s potential to mitigate lung inflammation, the lack of significant improvement in survival without BPD or functional outcomes suggests that multi-factorial drivers of neurodevelopmental impairment persist beyond neonatal respiratory morbidities. The timing, dosing, and patient selection for corticosteroid interventions require further refinement, integrating biomarkers and risk stratification models.

Current guidelines and expert panels cautiously endorse hydrocortisone use in ventilator-dependent preterm infants after the first week of life to facilitate extubation but emphasize the necessity of minimizing dosing and duration to reduce potential harm. This review underscores the imperative for ongoing rigorous long-term follow-up in randomized trials assessing neonatal therapeutics, with robust multidimensional functional assessments extending into school-age years.

Conclusion

Hydrocortisone administered between 14 to 28 days of life in very preterm infants at high risk of BPD does not significantly alter long-term functional motor, cognitive, academic, or pulmonary outcomes at early school age, despite being neurodevelopmentally safe. High rates of persistent functional impairment at school age highlight the enduring vulnerability of this population beyond neonatal intensive care interventions. Future research must focus on integrated therapeutic approaches addressing inflammation, injury, and neurodevelopmental support, along with personalized medicine strategies based on risk and biological phenotypes. Extended follow-up and comprehensive outcome measures remain essential to inform clinical decision-making and health policy.

References

• DeMauro SB, Kirpalani H, Hintz S, et al. Hydrocortisone in Preterm Infants and School-Age Functional Outcomes: Follow-Up of a Randomized Clinical Trial. JAMA Pediatr. 2025 Dec 8. doi:10.1001/jamapediatrics.2025.4801. PMID: 41359352.
• Watterberg KL, Kallapur S, et al. Hydrocortisone to Improve Survival without Bronchopulmonary Dysplasia. N Engl J Med. 2022;386(12):1121-1131. doi:10.1056/NEJMoa2114897. PMID: 35320643.
• Baud O, Laguerre B, et al. Association Between Early Low-Dose Hydrocortisone Therapy in Extremely Preterm Neonates and Neurodevelopmental Outcomes at 2 Years of Age. JAMA. 2017;317(13):1329-1337. doi:10.1001/jama.2017.2692. PMID: 28384828.
• Loureiro B, Fournet JC, et al. Neurocognitive outcomes at age 5 years after prophylactic hydrocortisone in infants born extremely preterm. Dev Med Child Neurol. 2023;65(7):926-932. doi:10.1111/dmcn.15470. PMID: 36417367.
• Jobe AH. Postnatal corticosteroids for chronic lung disease: evidence and hopes. Semin Perinatol. 2014;38(2):98-105. doi:10.1053/j.semperi.2013.11.003. PMID: 24560267.