Early (< 7 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants

Abstract

Background: Bronchopulmonary dysplasia (BPD) remains a major problem for infants born extremely preterm. Persistent inflammation in the lungs is important in its pathogenesis. Systemic corticosteroids have been used to prevent or treat BPD because of their potent anti-inflammatory effects. Objectives: To examine the relative benefits and adverse effects of systemic postnatal corticosteroids commenced within the first six days after birth for preterm infants at risk of developing BPD. Search methods: We ran an updated search of the following databases on 25 September 2020: CENTRAL via CRS Web and MEDLINE via OVID. We also searched clinical trials databases and reference lists of retrieved articles for randomised controlled trials (RCTs). We did not include cluster randomised trials, cross-over trials, or quasi-RCTs. Selection criteria: For this review, we selected RCTs examining systemic (intravenous or oral) postnatal corticosteroid treatment started within the first six days after birth (early) in high-risk preterm infants. We included studies that evaluated the use of dexamethasone, as well as studies that assessed hydrocortisone, even when the latter was used primarily for management of hypotension, rather than for treatment of lung problems. We did not include trials of inhaled corticosteroids. Data collection and analysis: We used standard Cochrane methods. We extracted and analysed data regarding clinical outcomes that included mortality, BPD, mortality or BPD, failure to extubate, complications during the primary hospitalisation, and long-term health and neurodevelopmental outcomes. We used the GRADE approach to assess the certainty of evidence. Main results: Use of the GRADE approach revealed that the certainty of evidence was high for the major outcomes considered, except for BPD at 36 weeks for all studies combined, which was downgraded one level to moderate because of evidence of publication bias. We included 32 RCTs (4395 infants). The overall risk of bias of included studies was low; all were RCTs, and most trials used rigorous methods. Early systemic corticosteroids overall have little or no effect on mortality to the latest reported age (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.85 to 1.06; 31 studies, 4373 infants; high-certainty evidence), but hydrocortisone alone reduces mortality (RR 0.80, 95% CI 0.65 to 0.99; 11 studies, 1433 infants; high-certainty evidence). Early systemic corticosteroids overall probably reduce BPD at 36 weeks' postmenstrual age (PMA) (RR 0.80, 95% CI 0.73 to 0.88; 26 studies, 4167 infants; moderate-certainty evidence), as does dexamethasone (RR 0.72, 95% CI 0.63 to 0.82; 17 studies, 2791 infants; high-certainty evidence), but hydrocortisone has little to no effect (RR 0.92, 95% CI 0.81 to 1.06; 9 studies, 1376 infants; high-certainty evidence). Early systemic corticosteroids overall reduce the combined outcome of mortality or BPD at 36 weeks' PMA (RR 0.89, 95% CI 0.84 to 0.94; 26 studies, 4167 infants; high-certainty evidence), as do both dexamethasone (RR 0.88, 95% CI 0.81 to 0.95; 17 studies, 2791 infants; high-certainty evidence) and hydrocortisone (RR 0.90, 95% CI 0.82 to 0.99; 9 studies, 1376 infants; high-certainty evidence). Early systemic corticosteroids overall increase gastrointestinal perforation (RR 1.84, 95% CI 1.36 to 2.49; 16 studies, 3040 infants; high-certainty evidence), as do both dexamethasone (RR 1.73, 95% CI 1.20 to 2.51; 9 studies, 1936 infants; high-certainty evidence) and hydrocortisone (RR 2.05, 95% CI 1.21 to 3.47; 7 studies, 1104 infants; high-certainty evidence). Early systemic corticosteroids overall increase cerebral palsy (RR 1.43, 95% CI 1.07 to 1.92; 13 studies, 1973 infants; high-certainty evidence), as does dexamethasone (RR 1.77, 95% CI 1.21 to 2.58; 7 studies, 921 infants; high-certainty evidence) but not hydrocortisone (RR 1.05, 95% CI 0.66 to 1.66; 6 studies, 1052 infants; high-certainty evidence). Early systemic corticosteroids overall have little to no effect on the combined outcome of mortality or cerebral palsy (RR 1.03, 95% CI 0.91 to 1.16; 13 studies, 1973 infants; high-certainty evidence), nor does hydrocortisone (RR 0.86, 95% CI 0.71 to 1.05; 6 studies, 1052 infants; high-certainty evidence). However, early dexamethasone probably increases the combined outcome of mortality or cerebral palsy (RR 1.18, 95% CI 1.01 to 1.37; 7 studies, 921 infants; high-certainty evidence),. In sensitivity analyses by primary intention for treatment with hydrocortisone (lung problems versus hypotension), there was little evidence of differences in effects on major outcomes of mortality, BPD, or combined mortality or BPD, by indication for the drug. Authors' conclusions: Early systemic postnatal corticosteroid treatment (started during the first six days after birth) prevents BPD and the combined outcome of mortality or BPD. However, it increases risks of gastrointestinal perforation, cerebral palsy, and the combined outcome of mortality or cerebral palsy. Most beneficial and harmful effects are related to early treatment with dexamethasone, rather than to early treatment with hydrocortisone, but early hydrocortisone may prevent mortality, whereas early dexamethasone does not. Longer-term follow-up into late childhood is vital for assessment of important outcomes that cannot be assessed in early childhood, such as effects of early corticosteroid treatment on higher-order neurological functions, including cognitive function, executive function, academic performance, behaviour, mental health, motor function, and lung function. Further RCTs of early corticosteroids, particularly of hydrocortisone, should include longer-term survival free of neurodevelopmental disability as the primary outcome.