Lex W Doyle1,2,3,4, Jeanie L Cheong1,2,4, Susanne Hay5, Brett J Manley1,4, Henry L Halliday6. 1. Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Australia. 2. Clinical Sciences, Murdoch Children's Research Institute, Parkville, Australia. 3. Department of Paediatrics, University of Melbourne, Parkville, Australia. 4. Newborn Research, The Royal Women's Hospital, Parkville, Australia. 5. Department of Neonatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. 6. Retired Honorary Professor of Child Health, Queen's University Belfast, Belfast, UK.
Abstract
BACKGROUND: Many infants born preterm develop bronchopulmonary dysplasia (BPD), with lung inflammation playing a role. Corticosteroids have powerful anti-inflammatory effects and have been used to treat individuals with established BPD. However, it is unclear whether any beneficial effects outweigh the adverse effects of these drugs. OBJECTIVES: To examine the relative benefits and adverse effects of late (starting at seven or more days after birth) systemic postnatal corticosteroid treatment for preterm infants with evolving or established BPD. SEARCH METHODS: We ran an updated search on 25 September 2020 of the following databases: 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 quasi-RCTs. SELECTION CRITERIA: We selected for inclusion in this review RCTs comparing systemic (intravenous or oral) postnatal corticosteroid treatment versus placebo or no treatment started at seven or more days after birth for preterm infants with evolving or established BPD. 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, and cerebral palsy. 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 most of the major outcomes considered, except for BPD at 36 weeks for all studies combined and for the dexamethasone subgroup, which were downgraded one level to moderate because of evidence of publication bias, and for the combined outcome of mortality or BPD at 36 weeks for all studies combined and for the dexamethasone subgroup, which were downgraded one level to moderate because of evidence of substantial heterogeneity. We included 23 RCTs (1817 infants); 21 RCTS (1382 infants) involved dexamethasone (one also included hydrocortisone) and two RCTs (435 infants) involved hydrocortisone only. The overall risk of bias of included studies was low; all were RCTs and most trials used rigorous methods. Late systemic corticosteroids overall reduce mortality to the latest reported age (risk ratio (RR) 0.81, 95% confidence interval (CI) 0.66 to 0.99; 21 studies, 1428 infants; high-certainty evidence). Within the subgroups by drug, neither dexamethasone (RR 0.85, 95% CI 0.66 to 1.11; 19 studies, 993 infants; high-certainty evidence) nor hydrocortisone (RR 0.74, 95% CI 0.54 to 1.02; 2 studies, 435 infants; high-certainty evidence) alone clearly reduce mortality to the latest reported age. We found little evidence for statistical heterogeneity between the dexamethasone and hydrocortisone subgroups (P = 0.51 for subgroup interaction). Late systemic corticosteroids overall probably reduce BPD at 36 weeks' postmenstrual age (PMA) (RR 0.89, 95% CI 0.80 to 0.99; 14 studies, 988 infants; moderate-certainty evidence). Dexamethasone probably reduces BPD at 36 weeks' PMA (RR 0.76, 95% CI 0.66 to 0.87; 12 studies, 553 infants; moderate-certainty evidence), but hydrocortisone does not (RR 1.10, 95% CI 0.92 to 1.31; 2 studies, 435 infants; high-certainty evidence) (P < 0.001 for subgroup interaction). Late systemic corticosteroids overall probably reduce the combined outcome of mortality or BPD at 36 weeks' PMA (RR 0.85, 95% CI 0.79 to 0.92; 14 studies, 988 infants; moderate-certainty evidence). Dexamethasone probably reduces the combined outcome of mortality or BPD at 36 weeks' PMA (RR 0.75, 95% CI 0.67 to 0.84; 12 studies, 553 infants; moderate-certainty evidence), but hydrocortisone does not (RR 0.98, 95% CI 0.88 to 1.09; 2 studies, 435 infants; high-certainty evidence) (P < 0.001 for subgroup interaction). Late systemic corticosteroids overall have little to no effect on cerebral palsy (RR 1.17, 95% CI 0.84 to 1.61; 17 studies, 1290 infants; high-certainty evidence). We found little evidence for statistical heterogeneity between the dexamethasone and hydrocortisone subgroups (P = 0.63 for subgroup interaction). Late systemic corticosteroids overall have little to no effect on the combined outcome of mortality or cerebral palsy (RR 0.90, 95% CI 0.76 to 1.06; 17 studies, 1290 infants; high-certainty evidence). We found little evidence for statistical heterogeneity between the dexamethasone and hydrocortisone subgroups (P = 0.42 for subgroup interaction). Studies had few participants who were not intubated at enrolment; hence, it is not possible to make any meaningful comments on the effectiveness of late corticosteroids in preventing BPD in non-intubated infants, including those who might in the present day be supported by non-invasive techniques such as nasal continuous positive airway pressure or high-flow nasal cannula oxygen/air mixture, but who might still be at high risk of later BPD. Results of two ongoing studies are awaited. AUTHORS' CONCLUSIONS: Late systemic postnatal corticosteroid treatment (started at seven days or more after birth) reduces the risks of mortality and BPD, and the combined outcome of mortality or BPD, without evidence of increased cerebral palsy. However, the methodological quality of studies determining long-term outcomes is limited, and no studies were powered to detect increased rates of important adverse long-term neurodevelopmental outcomes. This review supports the use of late systemic corticosteroids for infants who cannot be weaned from mechanical ventilation. The role of late systemic corticosteroids for infants who are not intubated is unclear and needs further investigation. 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 late systemic 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 late systemic corticosteroids should include longer-term survival free of neurodevelopmental disability as the primary outcome.
BACKGROUND: Many infants born preterm develop bronchopulmonary dysplasia (BPD), with lung inflammation playing a role. Corticosteroids have powerful anti-inflammatory effects and have been used to treat individuals with established BPD. However, it is unclear whether any beneficial effects outweigh the adverse effects of these drugs. OBJECTIVES: To examine the relative benefits and adverse effects of late (starting at seven or more days after birth) systemic postnatal corticosteroid treatment for preterm infants with evolving or established BPD. SEARCH METHODS: We ran an updated search on 25 September 2020 of the following databases: 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 quasi-RCTs. SELECTION CRITERIA: We selected for inclusion in this review RCTs comparing systemic (intravenous or oral) postnatal corticosteroid treatment versus placebo or no treatment started at seven or more days after birth for preterm infants with evolving or established BPD. 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, and cerebral palsy. 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 most of the major outcomes considered, except for BPD at 36 weeks for all studies combined and for the dexamethasone subgroup, which were downgraded one level to moderate because of evidence of publication bias, and for the combined outcome of mortality or BPD at 36 weeks for all studies combined and for the dexamethasone subgroup, which were downgraded one level to moderate because of evidence of substantial heterogeneity. We included 23 RCTs (1817 infants); 21 RCTS (1382 infants) involved dexamethasone (one also included hydrocortisone) and two RCTs (435 infants) involved hydrocortisone only. The overall risk of bias of included studies was low; all were RCTs and most trials used rigorous methods. Late systemic corticosteroids overall reduce mortality to the latest reported age (risk ratio (RR) 0.81, 95% confidence interval (CI) 0.66 to 0.99; 21 studies, 1428 infants; high-certainty evidence). Within the subgroups by drug, neither dexamethasone (RR 0.85, 95% CI 0.66 to 1.11; 19 studies, 993 infants; high-certainty evidence) nor hydrocortisone (RR 0.74, 95% CI 0.54 to 1.02; 2 studies, 435 infants; high-certainty evidence) alone clearly reduce mortality to the latest reported age. We found little evidence for statistical heterogeneity between the dexamethasone and hydrocortisone subgroups (P = 0.51 for subgroup interaction). Late systemic corticosteroids overall probably reduce BPD at 36 weeks' postmenstrual age (PMA) (RR 0.89, 95% CI 0.80 to 0.99; 14 studies, 988 infants; moderate-certainty evidence). Dexamethasone probably reduces BPD at 36 weeks' PMA (RR 0.76, 95% CI 0.66 to 0.87; 12 studies, 553 infants; moderate-certainty evidence), but hydrocortisone does not (RR 1.10, 95% CI 0.92 to 1.31; 2 studies, 435 infants; high-certainty evidence) (P < 0.001 for subgroup interaction). Late systemic corticosteroids overall probably reduce the combined outcome of mortality or BPD at 36 weeks' PMA (RR 0.85, 95% CI 0.79 to 0.92; 14 studies, 988 infants; moderate-certainty evidence). Dexamethasone probably reduces the combined outcome of mortality or BPD at 36 weeks' PMA (RR 0.75, 95% CI 0.67 to 0.84; 12 studies, 553 infants; moderate-certainty evidence), but hydrocortisone does not (RR 0.98, 95% CI 0.88 to 1.09; 2 studies, 435 infants; high-certainty evidence) (P < 0.001 for subgroup interaction). Late systemic corticosteroids overall have little to no effect on cerebral palsy (RR 1.17, 95% CI 0.84 to 1.61; 17 studies, 1290 infants; high-certainty evidence). We found little evidence for statistical heterogeneity between the dexamethasone and hydrocortisone subgroups (P = 0.63 for subgroup interaction). Late systemic corticosteroids overall have little to no effect on the combined outcome of mortality or cerebral palsy (RR 0.90, 95% CI 0.76 to 1.06; 17 studies, 1290 infants; high-certainty evidence). We found little evidence for statistical heterogeneity between the dexamethasone and hydrocortisone subgroups (P = 0.42 for subgroup interaction). Studies had few participants who were not intubated at enrolment; hence, it is not possible to make any meaningful comments on the effectiveness of late corticosteroids in preventing BPD in non-intubated infants, including those who might in the present day be supported by non-invasive techniques such as nasal continuous positive airway pressure or high-flow nasal cannula oxygen/air mixture, but who might still be at high risk of later BPD. Results of two ongoing studies are awaited. AUTHORS' CONCLUSIONS: Late systemic postnatal corticosteroid treatment (started at seven days or more after birth) reduces the risks of mortality and BPD, and the combined outcome of mortality or BPD, without evidence of increased cerebral palsy. However, the methodological quality of studies determining long-term outcomes is limited, and no studies were powered to detect increased rates of important adverse long-term neurodevelopmental outcomes. This review supports the use of late systemic corticosteroids for infants who cannot be weaned from mechanical ventilation. The role of late systemic corticosteroids for infants who are not intubated is unclear and needs further investigation. 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 late systemic 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 late systemic corticosteroids should include longer-term survival free of neurodevelopmental disability as the primary outcome.
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