A 2017 Cochrane review update analyzed whether inhaled corticosteroids, which theoretically offer localized lung benefits with fewer systemic side effects, are superior to systemic corticosteroids for preventing death or bronchopulmonary dysplasia (BPD) in ventilated, very low birth weight preterm infants. Based on two randomized controlled trials involving 294 infants, the analysis found no statistically significant difference between inhaled and systemic steroids for the primary outcomes of death or BPD at 36 weeks' postmenstrual age. However, key secondary outcomes revealed significant trade-offs: infants receiving inhaled steroids had a significantly longer duration of both mechanical ventilation and supplemental oxygen. On the other hand, they experienced a substantially lower incidence of hyperglycaemia but a higher rate of patent ductus arteriosus. A small long-term follow-up suggested a potential benefit of inhaled steroids in reducing later asthma diagnosis. The authors concluded that there is no evidence to recommend inhaled steroids over systemic steroids as a standard practice, as they did not demonstrate important advantages and had a mixed risk profile. They called for further trials to investigate different delivery methods, dosages, and long-term neurodevelopmental outcomes. [1]
Another 2017 Cochrane review update by the same authors also compared the effectiveness of inhaled versus systemic corticosteroids, administered after the first week of life, for preventing death or bronchopulmonary dysplasia (BPD) in ventilator-dependent, very low birth weight preterm infants. The review, which included three randomized controlled trials with 431 participants, found no evidence that inhaled corticosteroids provide a net advantage over systemic corticosteroids. The primary outcome of death or BPD at 36 weeks' postmenstrual age showed no significant difference between the two treatment groups. Furthermore, the analysis revealed no statistically significant differences in a range of important secondary outcomes, including the duration of mechanical ventilation and supplemental oxygen, length of hospital stay, and the incidence of common adverse effects like hyperglycaemia or sepsis. Long-term follow-up data on a subset of children also showed no significant differences in developmental outcomes at seven years of age. The authors concluded that there is currently no evidence to support the superiority of either treatment. They suggested that future research should focus on improved drug delivery systems to the lungs and must include long-term studies, particularly on neurodevelopmental outcomes, to fully resolve the issue. [2]
A 2022 narrative review extensively examined the use of inhaled corticosteroids, particularly in the context of neonatal respiratory care, focusing on managing conditions like bronchopulmonary dysplasia (BPD). The narrative underscored the therapeutic promise of budesonide, which has been associated with a reduction in the incidence of BPD. However, the NEuroSIS trial results introduced a conflicting perspective by revealing an increased mortality risk tied to early budesonide use, thereby amplifying the call for more focused research to definitively ascertain its safety profile and therapeutic efficacy in this vulnerable population. The narrative pinpointed a significant challenge in the widespread use of inhaled corticosteroids in neonates, noting that many existing therapies are utilized off-label due to a dearth of robust pediatric-specific trials. While inhaled corticosteroids offer the theoretical benefit of reducing systemic side effects compared to systemic corticosteroids, the current evidence supporting their use is not yet robust enough to fully endorse widespread clinical adoption without further study. This gap in conclusive evidence perpetuates a cautious approach among clinicians when considering inhaled corticosteroids as a frontline treatment for conditions like BPD, despite their potential benefits. With the increasing tendency to consider inhaled routes for local drug delivery in neonates who are vulnerable to significant systemic drug toxicity, these efforts are critical to transitioning these therapies from an off-label modality to a standard-of-care practice. [3]
A 2017 Cochrane systematic review evaluated the efficacy and safety of early administration of inhaled corticosteroids (ICS) for the prevention of chronic lung disease (CLD) in very low birth weight (VLBW) preterm neonates. The meta-analysis incorporated data from 10 randomized controlled trials (RCTs), totaling 1,644 neonates. Eligible trials enrolled infants with a birth weight ≤1500 grams who commenced ICS therapy within the first two weeks after birth. Pooled data from six trials (N = 1,285) indicated that early ICS significantly reduced the combined outcome of death or CLD at 36 weeks’ postmenstrual age (PMA; typical relative risk [RR] 0.86, 95% confidence interval [CI] 0.75 to 0.99; risk difference [RD] −0.06, 95% CI −0.11 to −0.00; number needed to treat for benefit [NNTB] 17). Among survivors only, a statistically significant reduction in CLD at 36 weeks’ PMA was also reported (typical RR 0.76, 95% CI 0.63 to 0.93; RD −0.07, 95% CI −0.13 to −0.02; NNTB 14). However, analysis of CLD at 36 weeks’ PMA among all randomized neonates revealed no significant difference (typical RR 0.97, 95% CI 0.62 to 1.52). No significant differences were observed in rates of serious adverse events, including sepsis, intraventricular haemorrhage (IVH), necrotizing enterocolitis (NEC), or adverse neurodevelopmental outcomes. The quality of evidence was rated as moderate, with limitations in sequence generation and incomplete reporting in several trials. Despite some statistically significant findings, the authors underscored that the clinical relevance remains uncertain due to wide confidence intervals and the long-term outcomes of included trials. [4]
A 2022 policy statement reviewed ICS in preterm infants, particularly focusing on their role in preventing CLD. A 2015 pivotal study within this review, the NEuroSIS trial, conducted a randomized controlled trial on 863 extremely low gestational age newborns (ELGANs) using early inhaled budesonide. While the trial showed no statistically significant difference in survival without CLD (60% vs 54%; relative benefit increase [RBI], 0.12; 95% CI, 0.01 to 0.26; p = 0.07), it did find a significant reduction in CLD incidence (relative risk [RR], 0.74; p = 0.004). However, concerns were raised as mortality was noted to be higher in the corticosteroid group (RR, 1.24; 95% CI, 0.91 to 1.69), highlighting potential safety issues. Systematic reviews and meta-analyses did not find ICS to confer an advantage over systemic corticosteroids, with inhaled steroids posing a potentially increased risk of mortality. Consequently, despite some promising results in reducing CLD incidence, the use of ICS did not demonstrate a clear benefit in overall outcomes, and individualized decisions are recommended. [5]
A 2018 non-randomized, open-label, dose-escalation trial evaluated the efficacy of inhaled hydrofluoralkane-beclomethasone dipropionate (HFA-BDP) in ventilator-dependent preterm infants at risk for BPD. Conducted across three Canadian NICUs, the study enrolled 41 neonates born at <32 weeks' gestational age or with birth weight <1,250 g who remained intubated and required a fractional inspired oxygen concentration (FiO₂) between 0.30 and 0.60 at 10 to 28 days of life. Participants were grouped into escalating doses of inhaled HFA-BDP (200, 400, 600, and 800 mcg administered twice daily) using a specially designed metered-dose inhaler (MDI) and valved delivery system. Each cohort received treatment over a 7-day period unless extubation was achieved earlier. Therapeutic efficacy, defined a priori as successful extubation or a >75% reduction in FiO₂ in at least 60% of participants within a dosing group, was not achieved at any dose level. However, infants receiving the highest dose of 800 mcg twice daily demonstrated a statistically significant reduction in mean post-treatment FiO₂ (0.30 ± 0.064, p = 0.02), despite comparable pretreatment oxygen requirements across all cohorts (mean FiO₂ ~0.39 to 0.40). No significant changes were observed in extubation rates or long-term neurodevelopmental outcomes across dosing groups, although a slight increase in severe cognitive delay was noted among infants in the 800 mcg cohort. Only one mild adverse event (transient hyperglycemia) was reported in this group. Long-term follow-up at 18–36 months corrected age revealed no dose-dependent trends in cerebral palsy (CP) incidence or severe neurocognitive impairment. This early-phase trial provides foundational dose-exploration data suggesting that higher-dose ICS may reduce oxygen dependency in this population but highlights the need for larger randomized studies with standardized neurodevelopmental assessments. [6]
A 2019 multicenter, prospective cohort study investigated the use of respiratory medications in extremely premature neonates, specifically targeting those born at less than 29 weeks of gestation. Conducted across 13 NICUs, the study prospectively collected daily data on respiratory medication exposure from birth until the infants reached 40 weeks postmenstrual age or were discharged earlier. The cohort comprised 832 newborns, providing a substantial dataset for analysis. The research highlighted that ICS were used in 16.5% of the population, with budesonide being the most commonly prescribed inhaled steroid. This utilization occurred despite limited data supporting the efficacy and safety of ICS in this demographically sensitive group. The study noted significant variability in medication practices between different centers, indicating a lack of standardized protocols and reflecting the current challenges faced in neonatal pharmacotherapy. This variability further underscores the need for controlled trials to determine safe and effective dosing regimens. The infants in the cohort were often exposed to medication dosages that exceeded published recommendations, raising concerns about potential adverse effects in such a vulnerable population. Overall, the findings emphasize the urgent requirement for rigorous clinical trials in neonatal populations to establish evidence-based guidelines for the use of ICS and other respiratory medications. Given the potential for both beneficial outcomes and significant side effects, including effects on pulmonary development and long-term respiratory health, careful evaluation of ICS in preterm infants is paramount. [7]
Several retrospective cohort analyses evaluated ICS prescribing patterns for infants across U.S. children’s hospitals. A 2024 analysis evaluated ICS prescribing practices for 74,123 premature infants across 308 NICUs who were born at <33 weeks' gestation and weighed <1,500 grams. According to analysis, 12.5% of eligible infants received ICS, with budesonide being the most prescribed agent (7.8%), followed by fluticasone (4.8%) and beclomethasone (1.7%). ICS administration began at a median of 35 days after birth (postmenstrual age [PMA]: 31 weeks) and lasted a median of 21 days, concluding at a median PMA of 36 weeks. Compared to non-recipients, ICS recipients were more likely to have received systemic steroids (49% vs. 10%), diuretics (75% vs. 24%), surfactant (82% vs. 53%), and bronchodilators (49% vs. 4%). They also had longer durations of mechanical ventilation (median: 3 vs. 0 weeks) and supplemental oxygen (median: 10 vs. 1 week). Likewise, a 2014 analysis reported that ICS was administered to 25% (n = 352) of the cohort, with beclomethasone being the most commonly prescribed (14%), followed by budesonide (9%) and fluticasone (6%). Infants born at ≤24 weeks' gestation and those with a birth weight of 500–999 grams demonstrated significantly higher adjusted odds of receiving ICS, as did those requiring prolonged respiratory support, with the odds increasing in a dose-dependent pattern based on duration of mechanical ventilation or CPAP. Timing analyses indicated increasing use over the first two months of hospitalization, peaking near hospital day 67. Among those treated with budesonide, the median therapy duration was 35 days (IQR: 10–57; range: 1–507), underscoring the extended exposure periods in routine clinical practice. Despite the off-label nature of ICS therapy in this population, its use remained persistent and heterogeneous across NICUs, underscoring a continued reliance on ICS as part of supportive care for premature infants with evolving or established chronic lung disease. [8], [9]
A 2013 narrative review provided a comprehensive overview of airway-administered pharmacotherapies in neonatal populations, specifically targeting conditions like BPD, pulmonary hypertension, transient tachypnea of the newborn (TTN), and persistent atelectasis. ICS such as budesonide, beclomethasone, fluticasone, and flunisolide were evaluated through multiple RCTs for their preventive and therapeutic roles in BPD. Seven RCTs conducted between 1998 and 2002 and encompassing 491 neonates did not demonstrate a statistically significant reduction in BPD incidence at 36 weeks postmenstrual age (PMA) or mortality. Likewise, eight late-treatment RCTs from 1993 to 2005, involving 232 neonates, failed to show clinical benefit in BPD prevention or survival, although they did note a statistically significant decrease in systemic corticosteroid use (RR 0.51, 95% CI 0.26 to 1.00). Additional comparisons between systemic and ICS, across five trials totaling 433 neonates, confirmed similar efficacy profiles with no significant differences in BPD or death outcomes. Moreover, a single-center randomized controlled trial investigated the intratracheal administration of budesonide via Survanta surfactant in 116 very low birth weight infants. This combined delivery method yielded a significantly higher rate of survival without BPD at 36 weeks PMA (82% vs. 58%, p = 0.025) and was associated with no long-term adverse effects in neurodevelopmental or physical growth assessments at 2–3 years of age. [10]