Abstract: We included three trials that involved a total of 431 participants which compared inhaled versus systemic corticosteroids to treat BPD. No new trials were included for the 2017 update. Although one study randomised infants at < 72 hours (N = 292), treatment started when infants were aged > 15 days. In this larger study, deaths were included from the point of randomisation and before treatment started. Two studies (N = 139) randomised and started treatment at 12 to 21 days. Two trials reported non-significant differences between groups for the primary outcome: incidence of death or BPD at 36 weeks' postmenstrual age among all randomised infants. Estimates for the largest trial were Relative risk (RR) 1.04 (95% Confidence interval (CI) 0.86 to 1.26), Risk difference (RD) 0.03 (95% CI -0.09 to 0.15); (moderate-quality evidence). Estimates for the other trial reporting the primary outcome were RR 0.94 (95% CI 0.83 to 1.05), RD -0.06 (95% CI -0.17 to 0.05); (low-quality evidence). Secondary outcomes that included data from all three trials showed no significant differences in the duration of mechanical ventilation or supplemental oxygen, length of hospital stay, or the incidence of hyperglycaemia, hypertension, necrotising enterocolitis, gastrointestinal bleed, retinopathy of prematurity or culture-proven sepsis moderate- to low-quality evidence). In a subset of 75 surviving infants who were enrolled from the United Kingdom and Ireland, there were no significant differences in developmental outcomes at seven years of age between groups (moderate-quality evidence). One study received grant support and the industry provided aerochambers and metered dose inhalers of budesonide and placebo for the same study. No conflict of interest was identified. We found no evidence that inhaled corticosteroids confer net advantages over systemic corticosteroids in the management of ventilator-dependent preterm infants. There was no evidence of difference in effectiveness or adverse event profiles for inhaled versus systemic steroids. A better delivery system guaranteeing selective delivery of inhaled steroids to the alveoli might result in beneficial clinical effects without increasing adverse events. To resolve this issue, studies are needed to identify the risk/benefit ratio of different delivery techniques and dosing schedules for administration of these medications. The long-term effects of inhaled steroids, with particular attention to neurodevelopmental outcomes, should be addressed in future studies.

Plain-language summary: All three included trials were randomised, but the blinding of intervention and outcome measurement varied. Data from two trials (enrolling 139 infants) were combined as they enrolled infants between 12 and 21 days of age, but data from one trial (enrolling 292 infants) were reported separately because researchers randomised infants aged less than 72 hours. The timing when the outcomes were measured varied among studies so it was not appropriate to combine some results. In one study all deaths that occurred were reported from the time babies were randomised not from when treatment started, hence there was a greater number of babies who died in that study. One study received grant support and the industry provided Aerochambers and metered dose inhalers of budesonide and placebo for the same study. No conflict of interest was identified. Evidence from two studies in 370 infants, who were randomised between 12 and 21 days of age and who contributed data to the primary outcome of this review, showed that inhaled steroids administered after 7 days of age compared with systemic steroids did not decrease the incidence of death or bronchopulmonary dysplasia (BPD) at 36 weeks' postmenstrual age. Evidence from the single study in which infants were randomised at less than 72 hours of age did not show difference the incidence of death or BPD. Evidence from three studies in 431 infants contributing to secondary outcomes showed that inhaled steroids administered after seven days of age compared with systemic steroids did not significantly alter the incidence of BPD at 36 weeks' postmenstrual age, hyperglycaemia, hypertension, duration of ventilation, duration of oxygen supplementation, length of hospital stay, intraventricular haemorrhage grade III-IV, periventricular leukomalacia, necrotising enterocolitis, gastrointestinal bleed, retinopathy of prematurity stage > 3, culture-proven sepsis or the incidence of adverse effects. Adverse event profiles did not differ for inhaled versus systemic steroids but some potential complications of steroid treatment have not been reported. More research is needed to show whether any form of routine use of steroids results in overall health improvements for babies at risk of bronchopulmonary dysplasia. Evidence quality (according to GRADE criteria) was moderate to low.