Early administration of inhaled corticosteroids for preventing chronic lung disease in very low birth weight preterm neonates

Review question
Do inhaled corticosteroids administered to preterm infants with birth weight of up to 1500 grams beginning in the first two weeks after birth prevent chronic lung disease as reflected by the requirement for supplemental oxygen at 36 weeks' postmenstrual age?

Background
Preterm babies who require breathing support often develop chronic lung disease. It is thought that inflammation in the lungs may be part of the cause. Corticosteroid drugs when given orally or through a vein reduce this inflammation. However, the use of corticosteroids is associated with serious side effects including cerebral palsy (motor problem) and developmental delay. It is possible that inhaling steroids, so that the drug directly reaches the lung, may reduce the adverse effects. This review looked at trials that compared preterm babies who received steroids or placebo (inactive drug) by inhalation while they were receiving breathing support. There was no previous evidence that the early administration of inhaled steroids reduces chronic lung disease.

Study characteristics
From literature searches updated to 5 January 2016, 10 randomised controlled trials that enrolled 1644 infants were included.

Study funding sources
We are not aware of any financial support from the industry for the included studies.

Key results
In this update of the review there was no significant reduction in the rate of chronic lung disease at 36 weeks' postmenstrual age. A significant reduction in the combined outcome of death or chronic lung disease at 36 weeks' postmenstrual age among all randomised neonates and among survivors was noted. Even though the results were significant, the upper confidence interval was infinity (i.e. we would have to treat every baby with inhaled steroid to prevent one baby dying or developing chronic lung disease at 36 weeks' postmenstrual age). This would not be acceptable in clinical practice. A lower rate of reintubation (the need for the insertion of a tube into the airway) was noted in the steroid group compared with the control group in one large study. There were no statistically significant differences in short- and long-term complications between groups. The results of the long-term follow-up of one large study is awaited.

Quality of evidence
In general the quality of the studies was good.

Authors' conclusions: 

Based on this updated review, there is increasing evidence from the trials reviewed that early administration of inhaled steroids to VLBW neonates is effective in reducing the incidence of death or CLD at 36 weeks' PMA among either all randomised infants or among survivors. Even though there is statistical significance, the clinical relevance is of question as the upper CI limit for the outcome of death or CLD at 36 weeks' PMA is infinity. The long-term follow-up results of the Bassler 2015 study may affect the conclusions of this review. Further studies are needed to identify the risk/benefit ratio of different delivery techniques and dosing schedules for the administration of these medications. Studies need to address both the short- and long-term benefits and adverse effects of inhaled steroids with particular attention to neurodevelopmental outcome.

Read the full abstract...
Background: 

Chronic lung disease (CLD) remains a common complication among preterm infants. There is increasing evidence that inflammation plays an important role in the pathogenesis of CLD. Due to their strong anti-inflammatory properties, corticosteroids are an attractive intervention strategy. However, there are growing concerns regarding short- and long-term effects of systemic corticosteroids. Theoretically, administration of inhaled corticosteroids may allow for beneficial effects on the pulmonary system with a lower risk of undesirable systemic side effects.

Objectives: 

To determine the impact of inhaled corticosteroids administered to preterm infants with birth weight up to 1500 grams (VLBW) beginning in the first two weeks after birth for the prevention of CLD as reflected by the requirement for supplemental oxygen at 36 weeks' postmenstrual age (PMA).

Search strategy: 

Randomised and quasi-randomised trials were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 12) in the Cochrane Library (searched 5 January 2016), MEDLINE (1966 to 5 January 2016), Embase (1980 to 5 January 2016), CINAHL (1982 to 5 January 2016), reference lists of published trials and abstracts published in Pediatric Research or electronically on the Pediatric Academic Societies web-site (1990 to May 2016).

Selection criteria: 

We included in this review randomised controlled trials of inhaled corticosteroid therapy initiated within the first two weeks of life in VLBW preterm infants.

Data collection and analysis: 

We evaluated data regarding clinical outcomes, including: CLD at 28 days or 36 weeks' PMA; mortality; combined outcome of death or CLD at 28 days of age and at 36 weeks' PMA; the need for systemic corticosteroids; failure to extubate within 14 days; and adverse effects of corticosteroids. All data were analysed using Review Manager (RevMan) 5. Meta-analyses were performed using relative risk (RR) and risk difference (RD), along with their 95% confidence intervals (CI). If RD was significant, the number needed to treat for an additional beneficial outcome (NNTB) was calculated. We used the GRADE approach to assess the quality of evidence.

Main results: 

According to GRADE the quality of the studies was moderate. Three additional trials are included in this update. The present review includes data analyses based on 10 qualifying trials that enrolled 1644 neonates. There was no significant difference in the incidence of CLD at 36 weeks' PMA in the inhaled steroid versus the placebo group (5 trials, 429 neonates) among all randomised (typical RR 0.97, 95% CI 0.62 to 1.52; typical RD −0.00, 95% CI −0.07 to 0.06). There was no heterogeneity for this outcome (typical RR I² = 11%; typical RD I² = 0%). There was a significant reduction in the incidence of CLD at 36 weeks' PMA among survivors (6 trials, 1088 neonates) (typical RR 0.76, 95% CI 0.63 to 0.93; typical RD −0.07, 95% CI −0.13 to −0.02; NNTB 14, 95% CI 8 to 50). There was a significant reduction in the combined outcome of death or CLD at 36 weeks' PMA among all randomised neonates (6 trials, 1285 neonates) (typical RR 0.86, 95% CI 0.75 to 0.99; typical RD −0.06, 95% CI −0.11 to −0.00) (P = 0.04); NNTB 17, 95% CI 9 to infinity). There was no significant heterogeneity for any of these analyses (I² = 0%). A lower rate of reintubation was noted in the inhaled steroid group compared with the control group in one study. There were no statistically significant differences in short-term complications between groups and no differences in adverse events at long-term follow-up reported. Long-term follow-up of infants enrolled in the study by Bassler 2015 is ongoing.

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