What is the available literature on the risk of inhaled corticosteroid (ICS)-induced adrenal insufficiency in preterm infants with bronchopulmonary dysplasia (BPD)?

Background
Bronchopulmonary dysplasia (BPD), also referred to as neonatal chronic lung disease (CLD), is the most common chronic pulmonary condition in preterm infants, particularly those born extremely preterm (<28 weeks of gestation).1,2 It develops as a result of multiple factors including lung immaturity, surfactant deficiency, oxygen toxicity, ventilator-induced barotrauma, and inflammation. Management is multifaceted and typically includes supplemental oxygen, mechanical ventilation, nutritional support, fluid restriction, and pharmacologic therapy such as diuretics, bronchodilators, and corticosteroids.1-3 While systemic corticosteroids such as dexamethasone can improve lung function, their use is limited by significant short- and long-term adverse effects.2 Of particular concern is the suppression of the hypothalamic-pituitary-adrenal (HPA) axis, a critical endocrine feedback loop that regulates cortisol production.4 Chronic exposure to exogenous corticosteroids, can impair this axis, leading to secondary adrenal insufficiency due to reduced adrenocorticotropic hormone (ACTH) stimulation.5 In infants, adrenal insufficiency may present subtly with symptoms such as poor growth or weight loss, lethargy, vomiting, or hypotension, and can progress to adrenal crisis during physiologic stress.6

The function of the HPA axis in neonates, particularly preterm infants, is not completely understood and differs significantly from that of older children and adults. Term infants typically have a relatively intact HPA axis at birth, and cortisol production increases appropriately in response to stress such as illness or delivery.7 However, in preterm infants, especially those born before 30 weeks’ gestation, adrenal immaturity may impair the ability to mount an adequate cortisol response, a phenomenon referred to as transient or relative adrenal insufficiency of prematurity.8,9 Basal cortisol concentrations in preterm neonates are often low, and the cortisol response to stress or stimulation may be blunted, though there is significant individual variability.10 Consequently, interpreting adrenal function in neonates, and particularly the effects of exogenous corticosteroids on HPA axis suppression, remains challenging.

The American Academy of Pediatrics (AAP) recommends a restrictive approach to postnatal systemic glucocorticoid therapy for BPD prevention in extremely preterm infants.2,3 Routine prophylactic use is discouraged, as it could unnecessarily expose many infants who will not develop BPD to potential harms. Instead, systemic corticosteroids are reserved for high-risk infants—those who remain ventilator-dependent at 1 to 4 weeks of age and cannot be weaned, or who require more than 50% oxygen supplementation.2,3

To minimize systemic adverse effects, inhaled delivery of corticosteroids has been suggested as an alternative to systemic administration.11 The theoretical benefits of inhaled corticosteroids (ICS) include targeted drug delivery, lower total corticosteroid exposure, and a reduced risk of systemic side effects such as impaired growth or neurodevelopmental delay.12 Data evaluating the extent to which ICS contribute to secondary AI in neonates and infants remains unclear.

This review aims to evaluate the available evidence on the risk of secondary adrenal insufficiency associated with ICS use in infants, focusing on randomized and prospective studies. A relevant case report is also summarized to highlight clinically significant outcomes that may not be captured in trials. Efficacy of ICS in this population is not evaluated in this review.

Literature Review

Budesonide
In a 2009 non-randomized trial by Bauer et al., growth effects of inhaled budesonide in preterm infants with BPD was investigated.13 In this prospective, controlled study, 30 premature infants (gestational age 26–31 weeks) were divided into 3 groups: 10 with BPD received inhaled budesonide 100 mcg/kg/day (divided into 2 doses) for 4 weeks, 10 with BPD received no budesonide, and 10 healthy controls. Energy expenditure and growth were primary outcomes. Salivary cortisol concentration, used to assess HPA axis function, was a secondary outcome of this trial.

Energy expenditure increased in infants with BPD compared to healthy controls. Marked suppression of endogenous cortisol production was observed in the budesonide-treated group. Median salivary cortisol levels in these infants fell significantly below age-expected norms and were consistently lower than healthy infants (budesonide-treated group: 0.9 nmol/L vs. control group 5.4 nmol/L; p<0.001). Salivary cortisol concentrations in the control groups remained within the normal range throughout the study period and no difference was observed between the untreated infants with BPD and the control group. Budesonide-treated infants maintained similar rates of weight gain and linear growth as the other groups, suggesting there was no adverse effects on somatic growth over the 4-week period.

Beclomethasone
In a large, multicenter, randomized, placebo-controlled trial, Cole et al. evaluated whether early inhaled beclomethasone therapy suppressed adrenal function in preterm infants.14 A total of 253 ventilated infants born at <33 weeks’ gestation and ≤1250 g were enrolled between 3 and 14 days of life and randomized to receive inhaled beclomethasone at 40 mcg/kg/day for 1 week followed by a dose taper over the next 4 weeks or placebo via metered-dose inhaler and spacer for 28 days. Adrenal function was assessed on study day 21 using low-dose cosyntropin stimulation.

The study found that while infants receiving beclomethasone had slightly lower median basal cortisol levels compared to placebo (5 vs. 6 µg/dL, P = 0.04), there was no evidence of adrenal suppression based on stimulated cortisol levels. Cortisol responses to cosyntropin were similar between groups (median peak 22 µg/dL vs. 27 µg/dL; P = 0.42), and the majority of infants in both groups achieved a cortisol rise indicative of preserved adrenal reserve (≥20 µg/dL or ≥2-fold increase).

A double-blind, placebo-controlled trial evaluated beclomethasone dipropionate delivered via metered-dose inhaler with an in-line spacer in 19 ventilated preterm infants (2 weeks old) with early BPD.15 Infants received either placebo (n=9) or beclomethasone ~1 mg/kg/day in three divided doses (n=10) for 7 days or until extubated.

Compared with placebo, beclomethasone showed no adverse effects on growth, glucose, hemodynamics, or infection risk, and importantly, no evidence of adrenal suppression was observed based on serum cortisol levels and adrenal stimulation testing.15 In the beclomethasone-treated group, mean serum cortisol levels (ug/dL) at study entry, day 3, day 7, and 2 weeks after study completion were 7.8, 8.9, 7.6, and 7.3, respectively. In the beclomethasone-treated group, mean serum cortisol levels after the ACTH stimulation test at study entry and 2 weeks after study completion were 30.3 and 28.8 ug/dL, respectively. In the placebo group, cortisol levels remained stable from baseline and throughout the study. Mean plasma ACTH levels (pg/mL) in the beclomethasone-treated group at study entry and 2 weeks after study completion was 16.2 and 23, respectively and in the placebo-treated group was 15 and 29.6, respectively. While more infants in the beclomethasone group were successfully extubated during the study, the trial was small and primarily demonstrates that short-term ICS exposure did not produce clinically significant adrenal insufficiency in this population.

Fluticasone
A 1998 randomized controlled pilot study by Ng et al. assessed the impact of high-dose inhaled fluticasone propionate in very low birthweight infants.16 Twenty-five infants born at less than 32 weeks’ gestation and weighing less than 1500 g were randomized to receive either fluticasone propionate 1000 mcg/day (n=13) or placebo (n=12) for 14 days. Adrenal function was evaluated using human corticotropin-releasing hormone (hCRH) stimulation.

Infants in the fluticasone group had significantly suppressed plasma ACTH and serum cortisol at baseline and after hCRH stimulation compared to placebo (e.g., 30-min cortisol: 298 vs. 753 nmol/L; P < 0.001).16 These findings provide evidence that high-dose inhaled fluticasone can cause moderate to severe suppression of the HPA axis in this population, likely due to pulmonary vascular absorption bypassing first-pass hepatic metabolism. The degree of pituitary suppression was similar to that reported with systemic dexamethasone. The authors reported that infants who received fluticasone did not demonstrate signs or symptoms of adrenal insufficiency.

Case report
In a case report by Smith et al. a female infant weighing 820 g born at 25 weeks’ gestation developed severe adrenal suppression as a consequence of ICS therapy for BPD.17 The infant experienced typical complications of extreme prematurity, including respiratory distress syndrome, and was started on inhaled budesonide 500 mcg twice daily on day 9 of life to manage her respiratory condition. On day 59, when she was transferred to a secondary NICU and the budesonide was being weaned, she became acutely unwell with respiratory distress and suspected urosepsis. Laboratory investigation revealed the underlying diagnosis of neonatal hypothalamic-pituitary-adrenal suppression, with undetectable morning cortisol levels that were well below the normal reference range. The infant was successfully treated with stress-dose hydrocortisone during her acute illness, and her cortisol levels normalized by 3 months of age, confirming that the suppression was temporary and reversible.

Discussion
It is important to note that dosing in several of these trials does not align with current neonatal recommendations. For budesonide, the recommended dose is 0.25–0.5 mg every 12–24 hours,18 which is higher than the dose used in the Bauer trial. In contrast, the Ng trial used 1000 mcg/day of fluticasone, a dose substantially higher than current recommendations of 250 mcg/day for infants weighing 0.5–1.2 kg and 500 mcg/day for weight >1.2 kg.18

Evidence on the risk of adrenal insufficiency from ICS in preterm infants with BPD is limited and inconclusive. Most available studies are small, use different agents, doses, delivery methods, and treatment duration, making results difficult to compare. Outcomes are often based on biochemical markers rather than clinical markers of adrenal insufficiency, and interpretation is complicated by the developmental immaturity of the neonatal HPA axis as well as unclear optimal timing of testing in relation to drug administration and discontinuation. Data from older children with asthma are sometimes extrapolated, but these findings may not apply to preterm infants due to differences in disease state, drug absorption, and metabolism. In addition, follow-up has generally been short, with little information on long-term growth or neurodevelopment. Together, these weaknesses highlight why a clear answer is lacking. These mixed findings suggest that adrenal suppression risk may be dose- and agent-dependent, requiring careful consideration of individual patient factors and close monitoring when using ICS in preterm infants with immature HPA axis function.

Risk Factors for Adrenal Suppression
In older pediatric populations with asthma, several factors have been associated with increased risk of adrenal suppression from inhaled corticosteroids (ICS). Higher daily doses—particularly above 291 µg/day of fluticasone propionate (FP) or ≥22 µg/kg/day—significantly raise the odds of HPA axis suppression, even when moderate dosing is used over several months.19 Delivery method influences absorption, with dry powder inhalers (DPI) linked to greater systemic exposure than metered-dose inhalers (MDI) used with a spacer.20 Potent CYP3A4 inhibitors (e.g., ritonavir, fluconazole) can markedly increase ICS systemic levels, leading to adrenal insufficiency or iatrogenic Cushing syndrome.21 Additional factors include low body weight, high adherence, and possible genetic predispositions affecting steroid metabolism.22 These studies did not include infants with BPD, and therefore the findings may not be directly generalizable, however, the insights may help guide safer prescribing and monitoring practices in children and are particularly relevant when evaluating risk in infants, who may be even more susceptible due to their immature drug metabolism and baseline adrenal vulnerability.

Conclusion
The potential for secondary adrenal insufficiency with ICS in neonates, especially those born preterm, is a of concern. While not all ICS appear to exert the same level of systemic absorption, high doses (particularly of potent agents like fluticasone) have been shown to significantly suppress the HPA axis. Conversely, beclomethasone and budesonide, when used at lower or moderate doses, may pose a lesser risk, although biochemical suppression cannot be fully ruled out. Interpretation of adrenal function in neonates remains complex due to developmental

variability in cortisol production and the limitations of available testing. Given that ICS are not currently recommended by the AAP for the routine management of BPD, these findings underscore the importance of recognizing and monitoring potential adverse endocrine effects in infants who are exposed to ICS in select clinical circumstances. In such situations, clinicians should carefully weigh the potential benefits against the risk of adrenal suppression, opt for the lowest effective dose and safest delivery method, and consider screening in high-risk infants.

References

  1. Stark AR, Eichenwald EC. Bronchopulmonary dysplasia (BPD): Management and outcome. In: Martin RJ, Tehrani N, eds. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com. Updated January 6, 2025. Accessed August 15, 2025.
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  10. Ng PC, Lee CH, Lam CW, et al. Transient adrenocortical insufficiency of prematurity and systemic hypotension in very low birthweight newborns. Arch Dis Child Fetal Neonatal Ed. 2002;86(2):F119-F122. doi:10.1136/fn.86.2.F119
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Prepared by:
Travis Hanson, PharmD
PGY2 Pediatric Pharmacy Resident
University of Illinois Chicago Retzky College of Pharmacy

Edited by:
Rita Soni, PharmD
Clinical Assistant Professor, Drug Information Pharmacist
University of Illinois Chicago Retzky College of Pharmacy

October 2025

The information presented is current as of July 22, 2025. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.