Evaluation of Moderate-Course Hydrocortisone for the Prevention of Bronchopulmonary Dysplasia in Premature Infants: A Pilot Study

Bronchopulmonary dysplasia (BPD) is a chronic lung disease that commonly affects preterm infants and is secondary to a range of insults, including infection, inflammation, and ventilator- and oxygen-induced injury, which contribute to the compromised development of premature lungs.^1–3

Postnatal corticosteroids, such as dexamethasone or hydrocortisone, are frequently used for the prevention and management of BPD. Hydrocortisone has both mineralocorticoid and glucocorticoid activity, closely mimicking endogenous cortisol, while dexamethasone does not substantially bind to mineralocorticoid receptors, and can eventually lead to neuronal apoptosis due to prolonged receptor inactivity.^4,5 Postnatal corticosteroid use has been associated with adverse neurodevelopmental outcomes, such as cerebral palsy, particularly with prolonged courses of high-dose dexamethasone (≥0.5 mg/kg daily).^6,7 Because of this concern, the American Academy of Pediatrics released a policy statement in 2002 recommending against the routine use of systemic dexamethasone for the prevention or treatment of chronic lung disease in very low birth weight infants.⁵ Several prospective randomized trials have been published since the release of this statement, including trials exploring the use of hydrocortisone as an alternative corticosteroid given the adverse effects associated with dexamethasone and the physiologic differences between dexamethasone and hydrocortisone.^3,8–10 The most recent revision in 2022 concluded that routine use of postnatal corticosteroids cannot be recommended; however, if the decision is made to administer postnatal corticosteroids, it recommends that a low dose be provided for a short, predefined duration, such as 7 to 10 days, or during mechanical ventilation weaning through successful extubation.⁵

At our institution, a 9-day, 18-mg/kg cumulative hydrocortisone course (3 mg/kg/day for 3 days, followed by 2 mg/kg/day for 3 days, followed by 1 mg/kg/day for 3 days, divided every 8 hours) is often used to facilitate weaning of respiratory support for infants with evolving BPD. This regimen has not been reported in the published literature and represents a “moderate” course in terms of both cumulative dose and duration compared with previously studied regimens. This pilot study aimed to characterize hydrocortisone use for the prevention of BPD in premature infants at a single center and contribute to data that are lacking in the literature pertaining to the safety and efficacy of the hydrocortisone regimen used.

Preterm infants born at less than 36 weeks’ gestation admitted to the neonatal intensive care unit between October 1, 2019, and October 1, 2024, who completed our hydrocortisone course for any respiratory indication before 36 weeks’ postmenstrual age (PMA) were eligible for inclusion. The primary outcome was survival without moderate or severe BPD at 36 weeks’ PMA, defined by the National Institute of Child Health and Development consensus.¹¹ Secondary outcomes included death, hospital length of stay, successful extubation (defined as remaining extubated for at least 7 days) during the corticosteroid course or during hospital stay, re-intubation rates, total days of intubation and/or supplemental oxygen, the need for repeat corticosteroid courses, and the need for BPD treatment and supplemental oxygen at discharge.

Results

Ninety-one patients were identified in the electronic medical record, of whom 17 met the inclusion criteria (Supplemental Table). Maternal and infant demographic data are presented in Table 1. The median PMA at initiation of the hydrocortisone course was 30 weeks, with a median postnatal age of 23 days and a median dosing weight of 1100 g. Fifteen mothers (88%) received antenatal corticosteroids. All patients were invasively mechanically ventilated before initiation of hydrocortisone, with a median fraction of inspired oxygen requirement of 0.50, and the majority (65%) required high-frequency mechanical ventilation.

Table 1.

Baseline Demographics (N = 17)*

Maternal
Age at delivery, median (IQR), yr	29 (23–31)
Chorioamnionitis requiring antibiotics	0 (0)
Cesarean delivery	14 (82)
Antenatal steroids	15 (88)
PPROM	15 (88)
Infant
Gestational age, median (IQR), wk, days	25 wk 2 days (24wk 4 days–27wk 2 days)
Birth weight, median (IQR), g	700 (660–800)
Male	9 (53)
Race
White	7 (41)
African American	8 (47)
Other	2 (12)
Hispanic or Latino	4 (24)
Multiple birth	3 (18)
Surfactant administration	16 (94)
Number of doses, median (IQR)	2 (2–3)

* All numbers are n (%) unless otherwise specified.

At 36 weeks’ PMA, no infants survived without moderate or severe BPD (Table 2). Most patients (71%) were categorized as severe BPD, but no infant deaths were observed. At the conclusion of the hydrocortisone course, 6 patients (35%) remained on high-frequency mechanical ventilation, 5 (30%) either remained on or were de-escalated to conventional mechanical ventilation, and 6 patients (35%) were extubated to continuous positive airway pressure (Figure). Successful extubation throughout hospital stay was observed in 13 patients (76%) at a median PMA of 32 weeks.

Table 2.

Infant Outcomes (N = 17)*

Primary Outcome Assessed at 36 Weeks’ PMA
Survival without BPD	0 (0)
Moderate BPD†	5 (29)
Severe BPD‡	12 (71)
Secondary Outcomes
Mode of ventilation at end of corticosteroid course
Continuous positive airway pressure	6 (35)
Conventional mechanical ventilation	5 (30)
High frequency mechanical ventilation	6 (35)
FiO2, median (IQR), %	32 (28–36)
Death	0 (0)
Survival without BPD at discharge	6 (35)
Hospital length of stay, median (IQR), days	156 (124–199)
Total days of intubation, median (IQR), days	58 (36–114)
Total days of supplemental oxygen, median (IQR), days	141 (101–199)
Successful extubation during corticosteroid course	6 (35)
Reintubation required	1 (17)
Successful extubation during hospital stay	13 (76)
PMA at time of extubation, median (IQR), wk, days	32 wk 4 days (31 wk 1 day–34 wk 0 days)
Repeat steroid courses required	8 (42)
Number of repeat courses, median (IQR)	2 (1–3)

BPD, bronchopulmonary dysplasia; FiO₂, fraction of inspired oxygen; PMA, postmenstrual age

* All numbers are n (%) unless otherwise specified.

† Moderate BPD was defined as requiring supplemental oxygen for at least 28 days and an FiO₂ requirement of <0.30.

‡ Severe BPD was defined as requiring supplemental oxygen for at least 28 days and an FiO₂ requirement of at least 0.30.

Figure.

Respiratory requirements upon initiation and discontinuation of hydrocortisone.

The most observed complications during the hospital stay were patent ductus arteriosus requiring intervention (71%) and late-onset sepsis (65%). Seven patients (41%) were discharged without supplemental oxygen, 6 patients (35%) were discharged on nasal cannula, and 4 patients (24%) were discharged with a tracheostomy. Adverse effects observed throughout the hydrocortisone course are displayed in Table 3. Growth was not affected during hydrocortisone therapy, with a median weight gain of 17 g/kg/day and a median length gain of 0.9 cm over 9 days.

Table 3.

Rates of Other Complications After Intervention (N = 17)*

During Corticosteroid Course
Hyperglycemia requiring insulin	1 (6)
Hypertension requiring antihypertensive agents	0 (0)
Throughout Hospital Stay
Intestinal perforation	1 (6)
Necrotizing enterocolitis	1 (6)
PDA requiring intervention	12 (71)
Medical management	11 (92)
Surgical intervention	3 (25)
Late-onset sepsis	11 (65)
Severe IVH or cystic PVL	3 (18)
Severe ROP	1 (6)
Additional Outcomes
Need for BPD treatment at discharge	12 (71)
Respiratory requirement at discharge
None (room air)	7 (41)
Nasal cannula	6 (35)
Tracheostomy	4 (24)
Steroids prescribed for the indication of adrenal insufficiency at discharge	4 (24)

BPD, bronchopulmonary dysplasia; IVH, intraventricular hemorrhage; PDA, patent ductus arteriosus; PVL, periventricular leukomalacia; ROP, retinopathy of prematurity

* All numbers are n (%) unless otherwise specified.

In conclusion, our hydrocortisone regimen did not prevent the development of moderate to severe BPD in this cohort, consistent with findings from 2 randomized controlled trials evaluating hydrocortisone use.^3,10 However, we found that late use (>7 days postnatal age) of our “moderate” hydrocortisone course in premature, very low birth weight infants around 30 weeks’ PMA may have helped facilitate extubation with minimal adverse effects. Of note, the receipt of antenatal corticosteroids in the majority (88%) of our cohort may have contributed to the rates of BPD and successful extubations, despite conflicting data on the association between antenatal corticosteroids and BPD in premature infants.^12,13 Limitations of our study include its small sample size and retrospective design, lack of long-term neurodevelopmental outcomes assessment, and the absence of a comparison with another corticosteroid regimen. The findings of this pilot study warrant continued investigation into hydrocortisone use in premature infants, with larger prospective studies needed to better define the potential impact of our moderate hydrocortisone course on BPD severity, successful liberation from mechanical ventilation, and long-term neurodevelopmental outcomes.

ABBREVIATIONS

BPD

bronchopulmonary dysplasia;

PMA

postmenstrual age;

ROP

retinopathy of prematurity