A sweeping analysis of more than 14,000 preterm infants across Canada has cast new light on one of neonatology’s most stubborn debates: whether a preemptive dose of hydrocortisone in the first days of life can protect the vulnerable lungs of babies born months too soon. The study, published today in the Journal of Perinatology, uses real-world data from 32 neonatal intensive care units participating in the Canadian Neonatal Network to weigh the promise of prophylactic hydrocortisone against the risk of death or moderate-to-severe bronchopulmonary dysplasia, a chronic lung disease that remains the most common serious complication of extreme prematurity.
Bronchopulmonary dysplasia arises when the unfinished lung, designed to develop bathed in amniotic fluid, is thrust into an oxygen-rich, mechanically ventilated environment. The resulting inflammation and arrested alveolarization trap infants in a cycle of prolonged respiratory support, recurrent infections, and lifelong pulmonary deficits. Corticosteroids, with their potent anti-inflammatory properties, have long been a logical therapeutic weapon. Postnatal dexamethasone, for instance, can reduce BPD rates but carries alarming neurodevelopmental risks. Hydrocortisone, the physiological stress hormone that the adrenal glands of extremely preterm infants often fail to produce in sufficient quantities, has emerged as a gentler alternative—at least in theory. Prior randomized trials hinted that early, low-dose hydrocortisone might improve survival without BPD, but small sample sizes, strict trial criteria, and conflicting results left clinicians without a clear mandate.
The new study, led by researchers from the University of Ottawa, leverages the power of observational data to see what happens when this therapy meets the messy reality of everyday practice. Between 2018 and 2022, 1,186 infants born before 28 weeks’ gestation and weighing less than 1,000 grams received prophylactic hydrocortisone, typically initiated within the first 36 hours of life at a dose of 1 mg per kilogram per day, continued for up to 10 to 15 days. These babies were compared to 13,043 infants who did not receive the drug, using advanced propensity score matching that balanced the two groups on 28 baseline characteristics including gestational age, sex, antenatal steroid exposure, chorioamnionitis, and severity of illness.
The headline finding is a cautiously optimistic one. In the primary analysis of well-matched cohorts, prophylactic hydrocortisone was associated with a statistically significant reduction in the composite outcome of death or moderate-to-severe BPD assessed at 36 weeks’ postmenstrual age. The adjusted odds ratio was 0.82, meaning the odds of the devastating outcome were 18 percent lower in the treated group. Digging deeper, the benefit appeared to be driven largely by a reduction in moderate-to-severe BPD among survivors, whereas mortality alone did not differ significantly between groups. Critically, the researchers also probed for signals of harm—necrotizing enterocolitis, spontaneous intestinal perforation, severe intraventricular hemorrhage, and late-onset sepsis—and found no excess risk that could be attributed to the hormone.
The mechanism behind this protective effect is biologically plausible and multilayered. Extremely preterm infants often exhibit relative adrenal insufficiency, with inappropriately low cortisol levels in the face of severe physiological stress. This deficiency impairs cardiovascular stability, forcing clinicians to rely on vasopressors and fluid boluses that can secondarily damage the lung endothelium. By restoring cortisol to levels that approximate those expected during critical illness, prophylactic hydrocortisone stabilizes blood pressure, reduces the need for mechanical ventilation, and dampens the systemic inflammatory cascade that drives alveolar simplification. The drug’s mineralocorticoid activity, often seen as a drawback, may actually be beneficial here by supporting sodium reabsorption and maintaining intravascular volume more physiologically.
Yet the study’s real-world nature also exposes its limitations. Despite meticulous propensity score methods, unmeasured confounding cannot be fully excluded—the very reason some units adopted the protocol while others did not might correlate with other care practices that influence BPD. Furthermore, the protocol varied slightly between sites, and adherence was not perfectly captured. The authors are careful not to claim causality, instead presenting their findings as “real-world effects” that complement randomized evidence. Indeed, the results align neatly with the largest randomized trial to date, the PREMILOC study, which demonstrated a survival-without-BPD benefit of early low-dose hydrocortisone in infants born below 25 weeks.
What makes this Canadian analysis particularly compelling is its ability to interrogate treatment effect heterogeneity. Subgroup analyses suggested that the youngest and smallest infants—those born between 23 and 25 weeks of gestation—derived the greatest absolute benefit, a pattern consistent with the biological gradient of adrenal immaturity. There was no interaction with sex, antenatal steroid exposure, or mode of delivery, reinforcing the notion that this intervention may be broadly applicable.
For neonatologists standing at the bedside of a 400-gram newborn fighting for each breath, these data shift the calculus. The fear of doing harm by administering a steroid has historically paralyzed practice; this study suggests that, in the right dose and the right window, hydrocortisone does not trade future neurodevelopment for immediate pulmonary gain. While long-term follow-up remains essential—the Canadian Neonatal Network cannot yet report school-age cognitive outcomes for these cohorts—the absence of a short-term safety signal is reassuring.
The public health implications are staggering. Bronchopulmonary dysplasia consumes enormous healthcare resources and devastates families; an intervention that cuts its incidence by nearly a fifth without increasing mortality or major morbidity could alter the trajectory of thousands of lives annually. The study’s authors call for implementation science approaches to understand why, despite mounting evidence, only a fraction of eligible infants nationwide actually receive the drug. As the global community of perinatology digests these findings, the balance may finally tip toward making prophylactic hydrocortisone a standard of care for the most fragile patients in the NICU.
Subject of Research: Prophylactic hydrocortisone and the odds of death or moderate to severe bronchopulmonary dysplasia in extremely preterm neonates
Article Title: Assessing the real-world effects of prophylactic hydrocortisone in the Canadian Neonatal Network: A cohort study
Article References: de Souza, M., Beltempo, M., Thébaud, B. et al. Assessing the real-world effects of prophylactic hydrocortisone in the Canadian Neonatal Network: A cohort study. J Perinatol (2026). https://doi.org/10.1038/s41372-026-02799-3
Image Credits: AI Generated
DOI: 10.1038/s41372-026-02799-3
Keywords: prophylactic hydrocortisone, bronchopulmonary dysplasia, preterm neonates, Canadian Neonatal Network, real-world evidence, propensity score matching, adrenal insufficiency, neonatal intensive care
