Late (≥ 7 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants

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.

Plain language summary

Late (from the age of seven days) systemic postnatal corticosteroids for preventing bronchopulmonary dysplasia in preterm infants

Review question: to determine the benefits and harms associated with treatment consisting of drugs that suppress inflammation, called corticosteroids, given starting seven days of age or later to prevent or treat lung injury, known as bronchopulmonary dysplasia (sometimes also called chronic lung disease), in babies born too early (preterm).

Background: corticosteroids can reduce lung inflammation in newborns with bronchopulmonary dysplasia but may cause harm. Bronchopulmonary dysplasia is a major problem for newborn babies in neonatal intensive care units, and is associated with both a higher death rate and worse longer‐term outcomes among survivors. Persistent inflammation of the lungs is the most likely cause of bronchopulmonary dysplasia. Corticosteroid drugs have strong anti‐inflammatory effects and so have been used to prevent or to treat bronchopulmonary dysplasia, particularly in babies who cannot be weaned from mechanical ventilation.

Study characteristics: we reviewed all clinical trials in preterm babies that gave corticosteroids systemically, that is, either as an injection or as a medicine, starting from the first seven days of age, and provided data on rates of bronchopulmonary dysplasia later in the newborn period. We included 23 studies (1817 infants). Search is up‐to‐date as of 25 September 2020.

Key results: this review indicates that giving systemic corticosteroids to babies starting at seven days or later after birth reduce the risks of death and bronchopulmonary dysplasia, without increasing rates of cerebral palsy (a disorder affecting movement ability) in later childhood. However, the longer‐term outcomes have not been well studied. It seems wise to limit late use of systemic corticosteroids to babies who cannot be weaned from mechanical ventilation, and to minimise the dose and duration of any course of treatment.

Results for two ongoing studies are awaited.

Certainty of evidence: overall the certainty of evidence supporting our conclusions for major outcomes is high.

Summary of findings

Summary of findings 1. Systemic corticosteroids (dexamethasone or hydrocortisone) compared with control (placebo or nothing) for chronic lung disease in preterm infants.

Systemic corticosteroids (dexamethasone or hydrocortisone) compared with control (placebo or nothing) for chronic lung disease in preterm infants
Patient or population: preterm infants with chronic lung disease Setting: multiple neonatal intensive care units from high‐income countries Intervention: systemic corticosteroids (dexamethasone or hydrocortisone) Comparison: control (placebo or nothing)
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with control (placebo or nothing)	Risk with systemic corticosteroids (dexamethasone or hydrocortisone)
Mortality at latest reported age	Study population (studies treating with dexamethasone or hydrocortisone)		RR 0.81 (0.66 to 0.99)	1428 (21 RCTs)	⊕⊕⊕⊕ HIGH	Critical outcome
	228 per 1000	185 per 1000 (151 to 226)
	Study population (subgroup of studies treating with dexamethasone)		RR 0.85 (0.66 to 1.11)	993 (19 RCTs)	⊕⊕⊕⊕ HIGH	Critical outcome
	193 per 1000	164 per 1000 (128 to 215)
	Study population (subgroup of studies treating with hydrocortisone)		RR 0.74 (0.54 to 1.02)	435 (2 RCTs)	⊕⊕⊕⊕ HIGH	Critical outcome
	305 per 1000	226 per 1000 (165 to 311)
BPD at 36 weeks' PMA	Study population (studies treating with dexamethasone or hydrocortisone)		RR 0.89 (0.80 to 0.99)	988 (14 RCTs)	⊕⊕⊕⊝ MODERATEa	Strong evidence for subgroup differences (interaction P < 0.001)
	594 per 1000	529 per 1000 (475 to 588)
	Study population (subgroup of studies treating with dexamethasone)		RR 0.76 (0.66 to 0.87)	553 (12 RCTs)	⊕⊕⊕⊝ MODERATEa
	659 per 1000	501 per 1000 (435 to 573)
	Study population (subgroup of studies treating with hydrocortisone)		RR 1.10 (0.92 to 1.31)	435 (2 RCTs)	⊕⊕⊕⊕ HIGH
	516 per 1000	567 per 1000 (474 to 676)
Mortality or BPD at 36 weeks' PMA	Study population (studies treating with dexamethasone or hydrocortisone)		RR 0.85 (0.79 to 0.92)	988 (14 RCTs)	⊕⊕⊕⊝ MODERATEb	Strong evidence for subgroup differences (interaction P < 0.001)
	771 per 1000	656 per 1000 (609  to 710)
	Study population (subgroup of studies treating with dexamethasone)		RR 0.75 (0.67 to 0.84)	553 (12 RCTs)	⊕⊕⊕⊝ MODERATEb
	787 per 1000	590 per 1000 (527to 661)
	Study population (subgroup of studies treating with hydrocortisone)		RR 0.98 (0.88 to 1.09)	435 (2 RCTs)	⊕⊕⊕⊕ HIGH
	753 per 1000	738 per 1000 (663 to 832)
Cerebral palsy ‐ at latest reported age	Study population (studies treating with dexamethasone or hydrocortisone)		RR 1.17 (0.84 to 1.61)	1290 (17 RCTs)	⊕⊕⊕⊕ HIGH	Critical outcome.
	93 per 1000	109 per 1000 (78 to 150)
	Study population (subgroup of studies treating with dexamethasone)		RR 1.17 (0.84 to 1.61	1290 (17 RCTs)	⊕⊕⊕⊕ HIGH	Critical outcome
	121 per 1000	135 per 1000 (95 to 193)
	Study population (subgroup of studies treating with hydrocortisone)		RR 1.40 (0.60 to 3.26)	435 (2 RCTs)	⊕⊕⊕⊕ HIGH	Critical outcome
	40 per 1000	57 per 1000
Mortality or cerebral palsy ‐ at latest reported age	Study population (studies treating with dexamethasone or hydrocortisone)		RR 0.90 (0.76 to 1.06)	1290 (17 RCTs)	⊕⊕⊕⊕ HIGH	Critical outcome.
	324 per 1000	291 per 1000 (246 to 343)
	Study population (subgroup of studies treating with dexamethasone)		RR 0.95 (0.77 to 1.16)	855 (15 RCTs)	⊕⊕⊕⊕ HIGH	Critical outcome
	312 per 1000	296 per 1000 (240 to 362)
	Study population (subgroup of studies treating with hydrocortisone)		RR 0.82 (0.62 to 1.08)	435 (2 RCTs)	⊕⊕⊕⊕ HIGH	Critical outcome
	345 per 1000	283 per 1000
*The risk in the intervention group (and its 95% confidence interval) is based on assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). BPD: bronchopulmonary dysplasia; CI: confidence interval; PMA: postmenstrual age; RCT: randomised controlled trial; RR: risk ratio.
GRADE Working Group grades of evidence. High certainty: further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low certainty: we are very uncertain about the estimate.

^aDowngraded one level because publication bias was suspected.

^bDowngraded one level for moderate heterogeneity.

Background

Description of the condition

Surfactant therapy has improved outcomes for preterm infants with respiratory distress syndrome but has only modestly reduced the risk of bronchopulmonary dysplasia (BPD) (Egberts 1997). Recent data suggest approximately 50% of infants born at < 28 weeks' gestation who survive to 36 weeks' gestation have BPD, with rates remaining stubbornly high, even since exogenous surfactant and more non‐invasive ventilation have been introduced into clinical care over the past 30 years (Cheong 2020). Management BPD in infants is both time‐consuming and costly. The term 'bronchopulmonary dysplasia' describes injury with maldevelopment of the lung that follows preterm birth and is a major problem in neonatal intensive care units. Persistent lung inflammation is the most likely underlying pathogenesis.

Description of the intervention

Postnatal corticosteroid treatment has been shown to have some acute effects on lung function in infants with established BPD, especially among those who are ventilator‐dependent (CDTG 1991; Mammel 1983). Corticosteroids may be given parenterally or enterally. Investigators have expressed concern that the benefits of corticosteroids might not outweigh their adverse effects, which include hypertension, hyperglycaemia, intestinal perforation, and extreme catabolism (Anonymous 1991; Ng 1993). Animal studies have also raised concerns about adverse effects on the central nervous system of corticosteroids given perinatally to immature offspring (Flagel 2002; Gramsbergen 1998).

How the intervention might work

Corticosteroids might prevent or treat BPD through their potent anti‐inflammatory effects.

Why it is important to do this review

Multiple published systematic reviews have examined the use of systemic postnatal corticosteroids in infants with or at risk of BPD (Arias‐Camison 1999; Bhuta 1998; Doyle 2000; Doyle 2010a; Doyle 2010b; Doyle 2010c; Doyle 2014a; Doyle 2014b; Doyle 2017b; Halliday 1997; Halliday 1999; Tarnow‐Mordi 1999). Other systematic reviews have addressed early versus late use of inhaled corticosteroids for preventing BPD (Shah 2017a), or for treating BPD (Onland 2017a), as well as use of systemic versus inhaled corticosteroids for preventing BPD (Shah 2017b), or for treating BPD (Shah 2017c). Another review compared different systemic corticosteroid regimens (Onland 2017b).

Two existing Cochrane Reviews have explored trials in which systemic postnatal corticosteroids were started within seven days of birth (Doyle 2017a), or were started more than seven days after birth (Doyle 2017b). The present systematic review updates the review of systemic corticosteroids started seven days or more after birth.

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.

Methods

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials (RCTs) of late (seven days or more) systemic postnatal corticosteroid treatment for preterm infants with evolving or established BPD that reported clinically important outcome variables. We did not include cluster randomised, cross‐over, or quasi‐randomised controlled trials.

Types of participants

We included preterm infants with evolving or established BPD, defined as oxygen‐dependent, ventilator‐dependent, or both, with or without radiographic changes of BPD.

Types of interventions

Treatment with systemic corticosteroids (dexamethasone or hydrocortisone) versus control (placebo or nothing).

Types of outcome measures

These are divided into primary and secondary outcomes.

Primary outcomes

• Mortality at various ages (including at 28 days after birth, at 36 weeks' postmenstrual age, at discharge home after primary hospitalisation, and at latest age reported)

• BPD (including at 28 days after birth, at 36 weeks' postmenstrual age, and at 36 weeks' postmenstrual age among survivors)

• Mortality or BPD (at 28 days after birth and at 36 weeks' postmenstrual age)

• Longer‐term outcomes into childhood (including blindness, deafness, cerebral palsy, and major neurosensory disability)

Secondary outcomes

• Failure to extubate

• Late rescue with corticosteroids

• Need for home oxygen therapy

• Complications during primary hospitalisation (including infection, hyperglycaemia, hypertension, pulmonary air leak, patent ductus arteriosus, severe intraventricular haemorrhage, periventricular leukomalacia, necrotising enterocolitis, sepsis, gastrointestinal bleeding, intestinal perforation, and severe retinopathy of prematurity)

• Later childhood outcomes, including respiratory function, blood pressure, and growth

Search methods for identification of studies

Electronic searches

We conducted a comprehensive updated search in September 2020 including Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 9), in the Cochrane Library; and OVID MEDLINE(R) and Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Daily and Versions(R) (1 January 2016 to 25 September 2020). We have included the search strategies for each database in Appendix 1. We did not apply language restrictions.

We searched clinical trial registries for ongoing and recently completed trials. We searched the World Health Organization’s International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en/) and the US National Library of Medicine’s ClinicalTrials.gov (clinicaltrials.gov), via Cochrane CENTRAL. Additionally, we searched the International Standard Randomized Controlled Trials Number (ISRCTN) Registry (http://www.isrctn.com/) for any unique trials not found through the Cochrane CENTRAL search.

This is the fifth update of this review. Our previous search details are listed in Appendix 2 and Appendix 3.

Searching other resources

We also searched the reference lists of all identified publications for additional references not identified by the electronic literature search.

Data collection and analysis

We used the methods of Cochrane Neonatal for data collection and analysis.

Selection of studies

We included all RCTS that fulfilled the selection criteria presented in the previous section. Two review authors (LWD and JC) independently reviewed results of the updated search and selected studies for inclusion. We resolved disagreements by discussion.

Data extraction and management

For each included trial, we sought information regarding methods of randomisation, blinding, and stratification, and whether the trial was single‐ or multi‐centred. Information on trial participants included birth weight, gestational age, and sex. We analysed information on the following clinical outcomes: mortality, BPD (including BPD at 28 days after birth, BPD at 36 weeks' postmenstrual age, BPD at 36 weeks' postmenstrual age in survivors, late rescue with corticosteroids (among all infants and survivors), and need for home oxygen therapy), mortality or BPD (at 28 days after birth and at 36 weeks' postmenstrual age), and long‐term outcomes (including blindness, deafness, cerebral palsy, and major neurosensory disability). Secondary outcomes included failure to extubate, complications during primary hospitalisation (including infection, hyperglycaemia, glycosuria, hypertension, echodensities on ultrasound scan of brain, necrotising enterocolitis, gastrointestinal bleeding, gastrointestinal perforation, and severe retinopathy of prematurity), and longer‐term outcomes of cognitive delay, respiratory health and function, blood pressure, and growth during childhood.

For each study, one review author (LWD) entered final data into Review Manager (RevMan) 5 (Review Manager 2020); a second review author (SH) then checked the data for accuracy. We resolved discrepancies through discussion or through consultation with a third assessor (HLH).

We attempted to contact the authors of original reports to request further details when information regarding any of the above was unclear.

Assessment of risk of bias in included studies

Two review authors (LWD and JC) independently assessed risk of bias (low, high, or unclear) of all included trials using the Cochrane ‘Risk of bias’ tool for the following domains (Higgins 2011).

• Sequence generation (selection bias).

• Allocation concealment (selection bias).

• Blinding of participants and personnel (performance bias).

• Blinding of outcome assessment (detection bias).

• Incomplete outcome data (attrition bias).

• Selective reporting (reporting bias).

• Any other bias.

We resolved disagreements by discussion or by consultation with a third assessor. See Appendix 4 for a more detailed description of risk of bias for each domain. 

Measures of treatment effect

We used the standard methods of Cochrane Neonatal to analyse data.

We performed statistical analyses using Review Manager (RevMan) 5 (Review Manager 2020). We analysed dichotomous data using risk ratio (RR), risk difference (RD), and the number needed to treat for an additional beneficial outcome (NNTB), or the number needed to treat for an additional harmful outcome (NNTH). We reported the 95% confidence interval (CI) for all estimates.

We analysed continuous data using mean difference (MD), or standardised mean difference (SMD) to combine trials that measured the same outcome using different methods.

Unit of analysis issues

For clinical outcomes such as episodes of sepsis, we analysed the data as proportions of neonates having one or more episodes.

Dealing with missing data

For included studies, we noted levels of attrition. When we had concern regarding the impact of including studies with high levels of missing data in the overall assessment of treatment effect, we planned to explore this concern using sensitivity analysis.

We performed all outcome analyses on an intention‐to‐treat basis (i.e. we included in the analyses all participants randomised to each group). The denominator for each outcome in each trial was the number randomised minus any participants whose outcomes were known to be missing.

Assessment of heterogeneity

We examined heterogeneity between trials by inspecting forest plots and quantifying the impact of heterogeneity using the I² statistic. If noted, we planned to explore possible causes of statistical heterogeneity using prespecified subgroup analysis (e.g. differences in study quality, participants, intervention regimens, outcome assessments).

Assessment of reporting biases

We assessed possible publication bias and other biases by examining symmetry/asymmetry on funnel plots. In addition, we computed Egger's statistic on funnel plots to assess the strength of the evidence for publication bias.

For included trials that were recently performed (and therefore prospectively registered), we used the websites www.clinicaltrials.gov and www.controlled-trials.com to explore possible selective reporting of study outcomes by comparing primary and secondary outcomes for reports in which primary and secondary outcomes were proposed at trial registration. If we found such discrepancies, we planned to contact the primary investigators to request missing data on outcomes prespecified at trial registration.

Data synthesis

When we judged meta‐analysis to be appropriate, we carried out the analysis using Review Manager (RevMan) 5, supplied by Cochrane (Review Manager 2020). We used the Mantel‐Haenszel method for estimates of typical RR and RD. We analysed continuous measures using the inverse variance method, and we computed MDs or SMDs. 

We used the fixed‐effect model for all meta‐analyses.

Subgroup analysis and investigation of heterogeneity

We included subgroup analyses by type of corticosteroid used (dexamethasone or hydrocortisone) if we identified a sufficient number of trials to make such subgroup analyses meaningful.

Sensitivity analysis

We planned to perform sensitivity analyses for situations where this might affect interpretation of significant results (e.g. when risk of bias was associated with the quality of some of included trials).

Summary of findings and assessment of the certainty of the evidence

We used the GRADE approach, as outlined in the GRADE Handbook (Schünemann 2013), to assess the certainty of evidence for the following (clinically relevant) outcomes: mortality, BPD (including BPD at 28 days after birth, BPD at 36 weeks' postmenstrual age, BPD at 36 weeks' postmenstrual age in survivors, late rescue with corticosteroids (among all infants and survivors), and need for home oxygen therapy), mortality or BPD (at 28 days after birth and at 36 weeks' postmenstrual age), and long‐term outcomes (including blindness, deafness, cerebral palsy, and major neurosensory disability).

Two review authors (LWD and JC) independently assessed the certainty of evidence for each of the outcomes above. We considered evidence from RCTs as high certainty but downgraded the evidence one level for serious (or two levels for very serious) limitations based upon the following: design (risk of bias), consistency across studies, directness of evidence, precision of estimates, and presence of publication bias. We used the GRADEpro GDT Guideline Development Tool to create Table 1 to report the certainty of evidence.

The GRADE approach results in an assessment of the certainty of a body of evidence as one of four grades.

• High certainty: further research is very unlikely to change our confidence in the estimate of effect.

• Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

• Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

• Very low certainty: we are very uncertain about the estimate.

Results

Description of studies

Up to the 2014 update of this review, 21 studies had been included.

For the 2017 update of this review, database searches for the calendar years 2013‐2017 identified 4930 references; other search sources identified 102 additional references. After removing 852 duplicate records, 4180 title abstracts were screened, 4166 full texts were excluded, 14 full text articles were assessed for eligibility, and no new studies were included at that time.

Results of the search

For the current update of this review, database searches for the calendar years 2016‐2020 identified 3760 references; other search sources identified no additional references. After removing 404 duplicate records, 3356 title abstracts were screened, 3351 full texts were excluded, five full text articles were assessed for eligibility, and two new studies were included. See Figure 1.

1.

Study flow diagram: review update.

 With addition of the two new RCTs, we have included in this updated review 23 RCTs, in total, that have recruited 1817 infants. These trials enrolled preterm infants who were oxygen‐ or ventilator‐dependent (or both) beyond six days of age. Investigators typically used dexamethasone at an initial dose of 0.5 to 1.0 mg/kg/d, with initial duration of therapy ranging from three days to six weeks. In two studies, the corticosteroid was hydrocortisone (Onland 2019; Parikh 2013). Details are given below and in the Characteristics of included studies table.

We discuss the excluded trials below and in the Characteristics of excluded studies table.

We identified two ongoing RCTs of hydrocortisone to prevent or treat BPD (He 2020; NCT01353313). See Characteristics of ongoing studies.

Included studies

We included 23 RCTs (1817 infants) in this updated review.

Ariagno 1987 was updated with more data provided by investigators in September 2000. Investigators randomised 34 preterm infants of less than 1501 grams birth weight who were ventilator‐dependent and were not weaning from mechanical ventilation at three weeks of age to parenteral dexamethasone (n = 17) or placebo (n = 17) groups. Treated babies received one of two regimens: a 10‐day course of 1.0 mg/kg/d for four days and 0.5 mg/kg/d for six days ((total dose 7 mg/kg dexamethasone over 10 days), or a seven‐day course of 1.0 mg/kg/d for three days followed by 0.5 mg/kg/d for four days (total dose 8.5 mg/kg dexamethasone over 10 days). Researchers calculated total respiratory system compliance from a pneumotachometer and made airway pressure measurements during mechanical inflation before and after seven days of treatment. Outcomes included mortality, duration of ventilation and oxygen therapy, and complications of prematurity and treatment. Country: USA.

Avery 1985 enrolled 16 infants with birth weight less than 1500 grams, a clinical and radiographic diagnosis of respiratory distress syndrome, inability to be weaned from the ventilator after two weeks, and radiological evidence of stage II or III BPD (Northway 1967). Researchers excluded babies if they had patent ductus arteriosus, congenital heart disease, sepsis, or pneumonia; had received intravenous lipids for at least 24 hours; and were over six weeks of age. To those randomised to receive dexamethasone (n = 8), investigators gave 0.5 mg/kg/d intravenously in two divided doses for three days, followed by 0.3 mg/kg/d for a further three days, thereafter decreased by 10% of the current dose every three days until a dose of 0.1 mg/kg/d was reached. At that point, they gave the drug on alternate days for one week, then discontinued (total dose approximately 8 mg/kg dexamethasone over 42 days). Control infants (n = 8) did not receive a placebo. Country: USA.

Brozanski 1995 was a prospective randomised double‐blind trial conducted to assess the efficacy and safety of pulse doses of dexamethasone for survival without supplemental oxygen given to very low birth weight infants at high risk of BPD. Trial authors randomly assigned 78 infants with birth weight less than 1501 grams, who were ventilator‐dependent at seven days, to receive pulse doses of dexamethasone 0.5 mg/kg/d 12‐hourly or an equivalent volume of a saline placebo for three days at 10‐day intervals, until they no longer required supplemental oxygen or mechanical ventilation, or had reached 36 weeks' postmenstrual age (total minimum dose 3 mg/kg dexamethasone over three days). Infants were excluded from the study if they had complex congenital anomalies, pulmonary hypoplasia, or haemodynamic instability. Country: USA. Participants were recruited between March 1991 and April 1993. Supported by grants from the Magee‐Women's Health Foundation Research Fund and the GCRC/National Institutes of Health 5M0 IRR00084.

CDTG 1991 (Collaborative Dexamethasone Trial Group 1991) was a multi‐centre trial conducted at 31 centres in six countries (UK, Ireland, Belgium, Germany, Canada, and USA) over a period of two and a half years from August 1986 to January 1989. A total of 287 infants who were oxygen‐dependent and had been in a static or deteriorating condition over the preceding week were eligible for trial entry from around three weeks of age. Study authors excluded infants with major malformations (n = 2), and they delayed trial entry to allow treatment of any intercurrent infection or heart failure. Infants did not have to require mechanical ventilation ‐ at the time of entry approximately two‐thirds of infants were intubated and one‐third were not. Those allocated to the dexamethasone group (n = 143) received 0.6 mg/kg/d intravenously (or orally if there was no intravenous line) for one week (total dose 4.2 mg/kg dexamethasone over seven days). There was an option to give a second tapering nine‐day course (0.6, 0.4, and 0.2 mg/kg/d for three days each) if, after initial improvement, relapse occurred. Control infants (n = 142) received an equivalent volume of saline placebo. Supported by Action Research for Crippled Children.

Cummings 1989 randomised 36 preterm infants with birth weight less than 1251 grams and gestational age less than 31 weeks, who were dependent on oxygen (> 29%) and mechanical ventilation (rate > 14 per minute with no evidence of weaning during the previous 72 hours) at two weeks of age, to receive a 42‐day course of dexamethasone or an 18‐day course of dexamethasone or saline placebo. They did not include infants with symptomatic patent ductus arteriosus, renal failure, or sepsis. To infants in the 42‐day group (n = 13), researchers administered dexamethasone at a dose of 0.5 mg/kg/d for three days and 0.3 mg/kg/d for the next three days. They then reduced the dose by 10% every three days until a dose of 0.1 mg/kg was reached on Day 34. After three days at this dose, the drug was given on alternate days for one week and then was stopped (total dose 7.9 mg/kg dexamethasone over 42 days). Infants in the 18‐day dexamethasone group (n = 12) received the same initial dose of 0.5 mg/kg/d for three days, but their dose was then decreased more rapidly by 50% every three days until a dose of 0.06 mg/kg was reached on Day 10. After three days at this dose, study authors gave the drug on alternate days for one week and then stopped (total dose 3 mg/kg dexamethasone over 18 days). For the remaining four treatment days, those infants received saline placebo. Infants in the control group (n = 11) received saline placebo for 42 days. Researchers combined the two treatment groups for the purposes of this meta‐analysis and provided additional data on some short‐term and long‐term outcomes for inclusion in this review. Country: USA. Participants were recruited between January 1986 and June 1987.

Doyle 2006 included a total of 70 infants of less than 1000 grams birth weight or born at less than 28 weeks' gestation, who were at least seven days of age and were ventilator‐dependent and considered eligible for postnatal corticosteroids. Exclusions were few and comprised only those with congenital anomalies likely to adversely affect long‐term neurological outcomes. Trialists worked at 11 collaborating centres within Australia, New Zealand, and Canada and performed stratification by centre. They randomly allocated infants to twice‐daily doses of a 10‐day tapering course of dexamethasone sodium phosphate (0.15 mg/kg/d for three days, 0.10 mg/kg/d for three days, 0.05 mg/kg/d for two days, 0.02 mg/kg/d for two days (total dose 0.89 mg/kg dexamethasone over 10 days) (n = 35 infants)) or to an equivalent volume of 0.9% saline placebo (n = 35 infants). A repeat course of the same blinded drug was a therapeutic option for attending physicians. The dexamethasone preparation did not contain bisulphite preservative. Researchers based the sample size calculation for the original trial on detecting improvement in survival free of major neurosensory disability from 50% to 60%, with a two‐sided type I error rate of 5% and 80% power, and required that a total of 814 infants be recruited. This study was stopped early at 70 infants, not only because less than 10% of the initial sample had been recruited after 2.5 years (March 2000 to October 2002), making it unlikely that the total sample size of 814 would be achieved within a reasonable time, but also because the rate of recruitment had fallen ‐ not increased ‐ even though more centres had entered the study from the time of its inception. Countries: Australia, New Zealand, Canada. Supported by the National Health ad Medical Research Council of Australia (Project Grant 108700).

Durand 1995 was a prospective randomised trial of 44 infants of birth weight 501 grams to 1500 grams and gestational age between 24 and 32 weeks who failed to be weaned from the ventilator at 7 to 14 days; one infant was excluded after randomisation because of birth weight < 500 grams, and hence data were reported for 43 infants. Their oxygen requirement was > 29% and ventilator rate > 14 per minute. Investigators excluded infants with documented sepsis, evidence of systemic hypertension, congenital heart disease, renal failure, intraventricular haemorrhage (grade IV), and multiple congenital anomalies. Infants in the treatment group (n = 23) received dexamethasone 0.5 mg/kg/d 12‐hourly intravenously for the first three days, 0.25 mg/kg/d for the next three days, and 0.10 mg/kg/d on the seventh day of treatment (total dose 2.35 mg/kg dexamethasone over seven days). Controls (n = 20) received no placebo and no dexamethasone during the seven‐day study period. At the end of the study week, the attending clinician could start dexamethasone treatment for controls. Country: USA. Participants were recruited between December 1990 and November 1992.

Harkavy 1989 randomised 21 preterm infants who were ventilator‐ and oxygen‐dependent at 30 days of age to receive dexamethasone or placebo. They gave dexamethasone 0.5 mg/kg/d in two or more doses either intravenously or by mouth (total dose 1 mg/kg dexamethasone or more over 2 days), and they gave an equivalent volume of saline to controls. Country: USA. Participants were recruited between April 1983 and July 1987. Supported by a grant from the Columbia Hospital for Women Research Foundation.

Kari 1993 was a randomised double‐blind placebo‐controlled trial that enrolled 41 infants with birth weight less than 1501 grams, gestational age greater than 23 weeks, dependence on mechanical ventilation at 10 days, and no signs of patent ductus arteriosus, sepsis, gastrointestinal bleeding, or major malformations. Infants in the dexamethasone group (n = 17) received 0.5 mg/kg/d intravenously in two doses for seven days (total dose 3.5 mg/kg dexamethasone over seven days), whereas the placebo group (n = 24) received normal saline. Country: Finland. Participants were recruited between January 1989 and February 1991. Supported by The Foundation for Pediatric Research, The Academy of Finland, and The Sigfrid Juselius Foundation.

In Kazzi 1990, 23 preterm infants with birth weight less than 1500 grams and radiological findings consistent with a diagnosis of BPD who were ventilator‐dependent at three to four weeks of age were eligible for study entry provided they needed more than 34% oxygen and had a ventilator rate greater than 14 per minute or peak inspiratory pressure > 17 cmH₂O. Infants had to show lack of improvement in ventilator dependency during the preceding five days. Infants in the treatment group (n = 12) received dexamethasone 0.50 mg/kg/d for three days, given as a single daily dose by nasogastric tube. The dose was tapered to 0.40 mg/kg/d for two days, then to 0.25 mg/kg/d for two days (total dose 2.8 mg/kg dexamethasone over seven days). Thereafter, infants received hydrocortisone administered in four divided doses every six hours, beginning with 8 mg/kg/d for two days and tapered by 50% of the dose every other day until 0.5 mg/kg/d was reached (total dose 31 mg/kg hydrocortisone over 10 days). After a total of 17 days, treatment was discontinued. Infants in the control group (n = 11) received equal volumes of saline. In subgroup analysis by type of corticosteroid, this study is included in the dexamethasone subgroup because the dose of corticosteroid received comprised more dexamethasone than it did hydrocortisone. Country: USA. Participants were recruited between August 1986 and February 1989.

Kothadia 1999 randomly allocated 118 preterm infants (birth weight < 1501 grams) between 15 and 25 days of age who were ventilator‐dependent to receive a 42‐day tapering course of dexamethasone (n = 57) or saline placebo (n = 61). The dosage schedule was 0.25 mg/kg 12‐hourly for three days and 0.15 mg/kg 12‐hourly for three days, followed by a 10% reduction in dose every three days until a dose of 0.1 mg/kg had been received for three days, from which time they received 0.1 mg/kg every other day until 42 days after entry (total dose 7.9 mg/kg dexamethasone over 42 days). Study authors provided additional data on some short‐term outcomes for inclusion in this review. Country: USA. Participants were recruited between April 1992 and May 1995. Supported by the Brenner Children's Hospital, Winston‐Salem, North Carolina.

Kovacs 1998 was a double‐blind RCT conducted to assess the efficacy of a combination of prophylactic systemic dexamethasone and nebulised budesonide in reducing the incidence and severity of BPD in infants at less than 30 weeks' gestation and weighing less than 1501 grams who were ventilator‐dependent at the age of seven days. Thirty infants received dexamethasone 0.25 mg/kg twice daily for three days (total dose 1.5 mg/kg dexamethasone over three days), followed by nebulised budesonide 500 µg twice daily for 18 days. Thirty control infants received systemic and inhaled saline. Study authors provided additional data on some short‐term and long‐term outcomes for inclusion in this review. Country: Canada. Participants were recruited between March 1993 and October 1995.

Noble‐Jamieson 1989 enrolled 18 infants over four weeks of age who required more than 30% oxygen delivered by a headbox (oxyhood). Congenital infection, gastric erosion, and necrotising enterocolitis were absolute contraindications to trial entry; investigators excluded one infant because of necrotising enterocolitis. Entry was postponed if an infant had a central venous catheter, active infection, untreated patent ductus arteriosus, glucose intolerance, or major segmental pulmonary collapse. Trial entry was postponed for 11 infants, mainly because of suspected sepsis. Researchers randomly allocated infants to receive either dexamethasone (n = 9) or saline (n = 9). They gave dexamethasone orally or intravenously at a dose of 0.25 mg/kg twice daily for the first week, 0.125 mg/kg twice daily for the second week, and 0.10 mg/kg daily for the third week (total dose 3.325 mg/kg dexamethasone over 21 days). Twice‐weekly cranial ultrasound scans were performed on all infants, with scans analysed blinded to treatment allocation after completion of the study. Country: England.

Ohlsson 1992 enrolled 25 infants with birth weight less than 1501 grams after receiving parental informed consent, if the following criteria were met: postnatal age 21 to 35 days, inspired oxygen greater than 29%, chest radiograph consistent with BPD, and treatment with diuretics resulting in no signs of improvement in ventilator requirements during the previous 72 hours. Researchers excluded infants if they had a diagnosis of suspected or proven infection, significant congenital malformation, or clinical evidence of patent ductus arteriosus, necrotising enterocolitis, and gastrointestinal haemorrhage or perforation. The treatment group (n = 12) received dexamethasone 0.50 mg/kg 12‐hourly for three days, 0.25 mg/kg 12‐hourly for three days, 0.125 mg/kg 12‐hourly for three days, and 0.125 mg/kg daily for three days (total dose 5.625 mg/kg dexamethasone over 12 days). Investigators gave dexamethasone intravenously at a standard volume of 1 mL. The Research Ethical Committee did not permit use of an intravenous placebo, so a physician not involved in subsequent care of the infant gave a sham injection of 1 mL of normal saline into the bed in the control group (n = 13). Study authors provided additional data for some short‐term outcomes for inclusion in this review. Country: Canada. Participants were recruited between April 1986 and June 1988. Supported by a grant from the Dean's Fund of the University of Toronto.

Onland 2019 was a double‐blind RCT conducted to compare hydrocortisone with placebo in infants < 1250 grams birth weight or < 30 weeks' gestational age who were ventilator‐dependent between 7 and 14 days of age and at high risk of developing BPD. Infants were ineligible if they had chromosomal defects or major congenital malformations or had received corticosteroids for improving lung function in the first week of life. A total of 181 infants received a total dose of 72.5 mg/kg of hydrocortisone over 22 days, and 190 infants received placebo. The primary endpoint was mortality or BPD at 36 weeks' postmenstrual age. Countries: Netherlands and Belgium. Participants were recruited from 15 November 2011 to 23 December 2016. Supported by a project grant from The Netherlands Organization for Health Research and Development (priority medicines for children grant 11‐32010‐02).

Papile 1998 was a double‐blind RCT conducted to compare the benefits and hazards of initiating dexamethasone therapy at two weeks of age versus four weeks of age to 371 ventilator‐dependent very low birth weight (501 grams to 1500 grams) infants who had respiratory index scores (mean airway pressure (MAP) × fraction of inspired oxygen) ≥ 2.4 at 13 to 15 days of age that had been increasing or minimally decreasing during the previous 48 hours, or a score of 4.0, even if there had been improvement during the preceding 48 hours; had received no glucocorticoid treatment after birth; had no evidence or suspicious signs of sepsis as judged by the treating physician; and had no major congenital anomaly of the cardiovascular, pulmonary, or central nervous system. A total of 182 infants received dexamethasone for two weeks followed by placebo for two weeks, and 189 infants received placebo for two weeks followed by either dexamethasone (those with a respiratory index score ≥ 2.4 on treatment Day 14) or additional placebo for two weeks. The dexamethasone dose was 0.5 mg/kg/d intravenously or orally for five days, then 0.3 mg/kg for three days, 0.14 mg/kg for three days, and 0.06 mg/kg for three days (total dose 4.0 mg/kg dexamethasone over 14 days). Only outcome data at 28 days were eligible for inclusion in this review (see below). Country: USA. Participants were recruited from September 1992 to July 1995. Supported by cooperative agreements (U10 HD27881, U10 HD21373, U10 HD27851, U10 HD27853, U10 HD21397, U10 HD19897, U10 HD21415, U10 HD27856, U10 HD21364, U10 HD27880, U10 HD27904, U10 HD27871, and U10 HD21385) with the National Institute of Child Health and Human Development and by General Clinical Research Center grants MO1 RR 00997, MO1 RR 08084, MO1 RR 00750, MO1 RR 00070, and MO1 RR 06022. Dexamethasone was provided by Merck Sharp & Dohme.

Parikh 2013 was a double‐blind RCT of hydrocortisone versus saline placebo given to 64 infants with birth weight ≤ 1000 grams who were ventilator‐dependent between 10 and 21 days of age and at high risk of developing BPD, with the primary outcome of differences in brain tissue volumes on magnetic resonance imaging (MRI) at term‐equivalent age. Infants were excluded if they were at < 23 weeks' gestation at birth, were previously treated with corticosteroids, were receiving indomethacin treatment or were likely to receive it within seven days, had presumed sepsis or necrotising enterocolitis, or had a major congenital anomaly of the cardiopulmonary or central nervous system. Thirty‐one infants received a total of 17 mg/kg of hydrocortisone over seven days, and 33 infants received an identical volume of saline placebo. This trial included follow‐up at 18 to 22 months of age, corrected for prematurity. Country: USA. Participants were recruited between 11 October 2005 and 8 September 2008. Supported by National Institutes of Neurological Disorders and Stroke (K23‐NS048152) and National Center for Research Resources (UL1RR024148 to University of Texas Health Science Center at Houston Center for Clinical and Translational Sciences).

Romagnoli 1997 was a randomised trial of 30 preterm infants who were ventilator‐ and oxygen‐dependent at 10 days and were at 90% risk of developing BPD based on the trial authors' own scoring system. Fifteen infants received dexamethasone 0.5 mg/kg/d for six days, 0.25 mg/kg/d for six days, and 0.125 mg/kg/d for two days (total dose 4.75 mg/kg dexamethasone over 14 days). Control infants (n = 15) did not receive any steroid. Study authors provided additional data on some short‐term outcomes for inclusion in this review. Country: Italy. Participants were recruited between April 1996 and June 1997.

Scott 1997 was a double‐blind RCT of dexamethasone versus saline placebo given to 15 infants who were ventilator‐dependent between 11 and 14 days of age with an inspired oxygen requirement greater than 60%. The primary outcome was cortisol response to adrenocorticotrophic hormone (ACTH). Infants with lethal anomalies were excluded. Ten infants received a total of 1.9 mg/kg of dexamethasone over five days, and five infants received an identical volume of saline placebo. Country: USA. Participants were recruited between 11 October 2005 and 8 September 2008. Supported by a Bristol‐Myers Research Grant and the General Clinical Research Center of the University of New Mexico, Program DRR (NIH 5M01RR00997‐14‐18).

Vento 2004 was a randomised trial of 20 neonates with birth weight < 1251 grams and gestation < 33 weeks who were oxygen‐ and ventilator‐dependent on the 10th day of life. Infants received dexamethasone 0.5 mg/kg/d for three days, 0.25 mg/kg/d for three days, and 0.125 mg/kg/d for one day (total dose 2.375 mg/kg dexamethasone over seven days) (n = 10), or they received no steroid treatment (n = 10). Country: Italy. Participants were recruited between August 1998 and July 2000.

In Vincer 1998, researchers randomly assigned 20 very low birth weight infants who were ventilator‐dependent at 28 days to receive either a six‐day course of intravenous dexamethasone 0.5 mg/kg/d for three days followed by 0.3 mg/kg/d for the final three days (total dose 2.4 mg/kg dexamethasone over six days) (n = 11), or an equal volume of saline placebo (n = 9). This trial included a two‐year follow‐up. Study authors provided additional data on some short‐term outcomes for inclusion in this review. Country: Canada.

Walther 2003 was a double‐blind randomised clinical trial involving 36 preterm infants with birth weight > 599 grams, gestation of 24 to 32 weeks, and respiratory distress syndrome requiring mechanical ventilation with oxygen > 29% or respiratory index > 1.7 between 7 and 14 days of life. Exclusion criteria were sepsis or other documented infection, congenital heart disease, systemic hypertension, unstable clinical status (renal failure, grade IV intraventricular haemorrhage), or multiple congenital anomalies. Eligible infants received dexamethasone 0.2 mg/kg/d for four days, 0.15 mg/kg/d for four days, 0.1 mg/kg for four days, and 0.05 mg/kg for two days (total dose 1.9 mg/kg over 14 days) (n = 19 infants), or saline placebo (n = 17 infants). Country: USA. Participants were recruited between December 1996 and November 1999. Supported by NIH grant P20 RR11145 and GCRC grant M01 RR00425.

Yates 2019 was a multi‐centre randomised blinded parallel‐group placebo‐controlled feasibility study, designed to be the forerunner of a larger RCT. Eligible infants were at < 30 weeks’ gestational age with postnatal age from 10 to 24 days, were ventilator‐dependent and receiving at least 30% inspired oxygen, and were at high risk of developing BPD. Excluded were infants who had received previous courses of postnatal steroids for respiratory disease; and those who had a severe congenital anomaly affecting the lungs, heart, or central nervous system; who had a surgical abdominal procedure or patent ductus arteriosus ligation; or who had an illness or medication for which postnatal corticosteroid would be contraindicated. Eligible infants were randomised to very low‐dose dexamethasone (0.05 mg/kg daily for 10 days, then every second day on Days 12, 14, and 16 after trial entry (total dose 0.65 mg/kg dexamethasone over 16 days) (n = 12 infants)), or saline placebo (n = 10 infants). Country: England. Participants were recruited between 21 July 2017 and 14 April 2018. Supported by the Efficacy and Mechanism Evaluation (EME) programme ‐ a Medical Research Council and National Institute for Health Research (NIHR) partnership.

Excluded studies

In total, we excluded 46 studies. Vento 2004 was listed as excluded and provided data for two separate cohorts of infants ‐ the first cohort randomised at 10 days of age (those data are included in this "Late" review), and the second cohort randomised at four days of age (hence these data are included in the "Early" review (Doyle 2021)).

We excluded 32 studies that were included in Doyle 2021. That Cochrane Review addressed the use of postnatal corticosteroids commenced in the first six days after birth to prevent BPD in preterm infants (Anttila 2005; Baden 1972; Batton 2012; Baud 2016; Biswas 2003; Bonsante 2007; Efird 2005; Garland 1999; Halac 1990; Hochwald 2014; Kopelman 1999; Lauterbach 2006; Lin 1999; Mukhopadhyay 1998; Ng 2006; Peltoniemi 2005; Rastogi 1996; Romagnoli 1999; Sanders 1994; Shinwell 1996; Sinkin 2000; Soll 1999; Stark 2001; Subhedar 1997; Suske 1996; Tapia 1998; Vento 2004a; Wang 1996; Watterberg 1999; Watterberg 2004; Yeh 1990; Yeh 1997).

We excluded an additional study because it compared two different dosages of dexamethasone only (Marr 2019). We excluded other studies for a variety of reasons. See Characteristics of excluded studies.

Risk of bias in included studies

Overall most studies had low risk of bias (Figure 2; Figure 3). All were RCTs, although the method of random allocation was not always clear. Allocation concealment applied to most studies. Blinding of investigators and others was achieved most often with the use of placebo, usually saline solution. Follow‐up reporting for short‐term outcomes during primary hospitalisation most often was complete but was more variable for long‐term outcomes beyond discharge and later into childhood.

2.

3.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Ariagno 1987 was a double‐blind trial in which the pharmacist performed randomisation. Trialists provided outcomes for all enrolled infants. Follow‐up consisted of the following: investigators assessed surviving children at 12, 24, and 36 months of age, corrected for prematurity, in the High‐Risk Follow‐Up Clinic. Data included cerebral palsy and auditory status, but criteria were not defined. Personnel involved and blinding of assessors to treatment groups were unclear. The follow‐up rate of survival was 96% (23/24) (Ariagno 2000).

Avery 1985 paired and compared treatment and control infants for success in weaning. Investigators stratified infants at entry by weight into three categories: less than 1000 grams, 1000 grams to 1250 grams, and 1251 grams to 1500 grams. Within each weight group, equal numbers of treatment cards and control cards were placed into envelopes for random selection. The first treated infant and the first control infant within a given weight category made the first pair, and researchers considered in the sequential analysis only infants who were paired for weaning success. If both infants in a pair were successful or had treatment failure, the result was a tie and the pair was discarded. If one infant weaned and the other did not, the pair was scored as favouring treatment or control. The study was stopped when significance was reached from weaning from the ventilator in the sequential analysis of untied pairs. At that time, 16 infants had been studied and 14 had been matched to form seven pairs. Study authors reported no follow‐up component.

In Brozanski 1995, researchers achieved randomisation by using a random numbers table and stratified infants according to sex and birth weight (< 1000 grams versus > 999 grams). They reported treatment allocation on cards inside sequentially numbered envelopes that were kept in the pharmacy where randomisation took place. Investigators enrolled 88 infants but provided outcome data, apart from survival without supplemental oxygen at 36 weeks' postmenstrual age, for only 78 infants. They withdrew 10 infants during the study because of pharmacy error (dexamethasone group two infants, placebo group one infant), parental choice (placebo group two infants), or attending physician request (dexamethasone group one infant, placebo group four infants). All five infants withdrawn from the study by the attending physician subsequently received an extended course of dexamethasone. Follow‐up consisted of the following (Hofkosh 1995): unknown observer(s) blinded to treatment group allocation saw survivors at 12 months of age, corrected for prematurity. The follow‐up rate of survivors was 68% (44/65). Study authors did not specify criteria for the diagnosis of cerebral palsy. Psychological assessment included the Mental Developmental Index (MDI) of the Bayley Scales of Infant Development (BSID). Study authors provided no data on major neurodevelopmental disability.

CDTG 1991 assigned groups by telephone call to the Clinical Trial Service Unit in Oxford. Investigators stratified infants by clinical centre and by whether or not they were ventilator‐dependent. After completion of the trial, clinicians could give open steroids if this was clinically indicated because of life‐threatening deterioration. Researchers retained infants in the group to which they had been allocated for the purpose of analysis. They enrolled 287 infants in the trial; two were ineligible because of major malformations (Fallot's tetralogy, oesophageal atresia), leaving 285 infants included in the analysis. Follow‐up consisted of the following (Jones 1995): researchers provided data on survivors at 36 months of age, not corrected for prematurity. Primary sources of data, obtained in the UK and in Ireland, were healthcare provider visitors, who provided data on major neurosensory diagnoses or other chronic problems, and general practitioners, who provided data on health and hospitalisations. Parents completed questionnaires, including the Minnesota Child Development Inventory (CDI). Parents, healthcare visitors, and general practitioners (GPs) were unaware of treatment group allocation. In some countries, investigators sought data from paediatricians only (< 10% cases). The follow‐up rate of survivors was 94% (209/223). Trialists did not specify criteria for the diagnosis of cerebral palsy or blindness, but they defined severe hearing loss (deafness) as hearing loss requiring either hearing aids or special schooling. Major disability comprised any types of non‐ambulant cerebral palsy at three years of age, < 50% of age level on the CDI, or predicted special schooling for sensory or other impairment. Further follow‐up at 13 to 17 years of age consisted of the following (Jones 2005a; Jones 2005b): assessors who were blinded to treatment group allocation assessed surviving children from the 25 individual British and Irish study centres at 13 to 17 years of age. Families completed a questionnaire on functional status, diagnoses of potentially disabling conditions (visual or hearing impairment, learning disabilities, cerebral palsy, and epilepsy), and the child's schooling. Study authors asked GPs to complete a questionnaire to report known functional problems, diagnoses, and hospital admissions. The paediatrician responsible for each child's care made the diagnosis of cerebral palsy. One of three research nurses blinded to the children's original treatment allocation visited surviving children at home. They administered a non‐verbal reasoning test and the British Picture Vocabulary Scale and averaged these scores as a proxy for IQ. Investigators defined moderate disability as consisting of one or two of the following: IQ 2 to 3 standard deviations (SD) below the mean, ambulatory cerebral palsy, hearing deficits corrected with hearing aids, impaired vision, or a behaviour disorder with a major impact on schooling. They defined severe disability as any of the following: IQ > 3 SDs below the mean, wheelchair‐dependent cerebral palsy, uncorrectable hearing loss, blindness (perception of light only), or three moderate disabilities. Respiratory function included spirometry to measure forced expiratory volume in one second (FEV₁), forced vital capacity (FVC), the FEV₁/FVC ratio, and forced expired flow from 25% to 75% (FEF)_25%-75%; study authors expressed results and growth measurements as standardised scores (z‐scores). They assessed other outcomes, but we did not include them in the review. These included data on types of schooling, teacher questionnaires on a child's ability, and the Strengths and Difficulties Questionnaire. The follow‐up rate of eligible survivors at 13 to 17 years was 77% (150/195), including data from five severely disabled children at three years of age who were not contacted as teenagers.

In Cummings 1989, investigators achieved randomisation by sequential assignment from a table of random numbers known only to a pharmacist who had no knowledge of the clinical status of infants. Study authors present outcome data for all 36 infants enrolled in the study. This trial included two experimental groups: one treated for 18 days, and the other treated for 42 days, compared with a single control group. For these analyses, we combined treatment groups (n = 25) and compared the combined data with data from the control group (n = 11). Follow‐up consisted of the following: a paediatrician and an occupational therapist saw survivors at 15 months of age, corrected for prematurity. Observers were blinded to treatment group allocation. The follow‐up rate of survivors was 100% (23/23). Researchers specified criteria for the diagnosis of cerebral palsy but did not specify criteria for blindness or deafness. Psychological assessment included the MDI and the Psychomotor Developmental Index (PDI) of the BSID. Major disability comprised any of the following: cerebral palsy or MDI or PDI < 1 SD. Investigators later assessed survivors at four years of age and confirmed neurological status for all participants (Cummings 2002 (personal communication follow‐up of Cummings 1989)). Researchers provided further follow‐up at 15 years of age (Gross 2005). Assessors were blinded to treatment group allocation. Outcomes included growth (body size converted to z‐scores), general health, respiratory morbidity, and respiratory function testing. Cognition was assessed by the Wechsler Intelligence Scale for Children ‐ Third Edition (WISC‐III). Teachers completed data on class repetition, performance, and behaviour. Pulmonary function testing included spirometry to measure FEV₁, FVC, and FEF_25%-75%, along with measurement of lung volumes (total lung capacity (TLC) and residual volume (RV)) by nitrogen washout; study authors expressed results as % predicted for age, height, and sex. Trial authors reported numbers of surviving children with ongoing respiratory symptoms of wheezing or congestion and interpreted these as a diagnosis of asthma for meta‐analysis. They defined intact survival as a normal neurological examination, IQ > 70, and receiving education in a normal classroom. For the meta‐analysis, investigators defined major neurological disability as any of an abnormal neurological examination (i.e. cerebral palsy), cognitive delay (IQ < 71), or not in a regular classroom (with or without additional help). They did not measure blood pressure.

Doyle 2006 was a double‐blind trial with randomisation performed centrally by non‐clinical staff independent of the chief investigators, with random variation in block sizes of two to eight for each centre. Syringes were prepared and labelled identically within the pharmacy department at the centre, concealing treatment allocation from study site investigators and the infant's caregivers. They discouraged but did not prohibit open‐label corticosteroids after randomisation; some infants may have received both a second course of their initially allocated study drug and open‐label corticosteroids. No one apart from the pharmacists at individual study sites had access to the treatment code. Trial authors reported short‐term outcomes for all enrolled infants. Follow‐up included the following (Doyle 2007 (follow‐up publication of Doyle 2006)): paediatricians and psychologists who were blinded to treatment group allocation assessed surviving children at 24 months of age, corrected for prematurity, at individual study sites. They considered children to have a neurosensory impairment if they had cerebral palsy (criteria included abnormalities of tone and motor dysfunction), blindness (bilateral vision worse than 6/60), deafness requiring hearing aids or worse, or developmental delay (defined as a MDI on the BSID < 85 (< ‐1 SD) (Bayley 1993). Researchers graded severity of the neurosensory disability imposed by the impairment as follows: severe ‐ bilateral blindness, cerebral palsy with the child unlikely ever to walk, or MDI < 55 (< ‐3 SD); moderate ‐ deafness, cerebral palsy in children not walking at two years but expected to walk, or MDI from 55 to < 70 (‐3 SD to < ‐2 SD); mild ‐ cerebral palsy but walking at two years with only minimal limitation of movement or MDI 70 to < 85 (< ‐2 SD to ‐1 SD). They considered the remaining children to have no neurosensory disability. Major neurosensory disability comprised moderate or severe disability. The follow‐up rate of survivors at two years was 98% (58/59).

In Durand 1995, investigators performed randomisation via blind drawing of random cards contained in sealed envelopes. Clinical personnel were not aware of the group assignment of any infant. Study authors present outcome data for 43 of the 44 enrolled infants. They excluded one infant in the control group from all analyses as the result of birth weight < 500 grams. Follow‐up consisted of the following (Durand 2012 (personal communication follow‐up of Durand 1995)): a developmental paediatrician, a paediatric neurologist, and other specialised personnel (including a psychologist) assessed surviving children at 12 months of age, corrected for prematurity. A paediatric ophthalmologist performed all eye examinations. All staff were blinded to treatment group allocation. Children were considered to have a neurosensory impairment if they had cerebral palsy (defined as non‐progressive motor impairment with abnormal muscle tone and decreased range of movement), blindness (bilateral vision worse than 6/60), deafness requiring hearing aids or worse, or developmental delay (defined as MDI < 70 on the BSID). The follow‐up rate of survivors at 12 months was 78% (29/37).

Harkavy 1989 achieved randomisation by using random numbers held in the pharmacy. Clinicians and investigators were unaware of treatment assignments. Study authors provided outcome data for 21 of the 22 enrolled infants. One infant died after consent but before random assignment to a treatment group. Follow‐up consisted of the following (Harkavy 2002 (personal communication follow‐up of Harkavy 1989)): a neonatologist and an occupational therapist saw survivors at ages ranging from 6 to 24 months, corrected for prematurity. Observers were blinded to treatment group allocation. The follow‐up rate of survivors was 32% (6/19). Trialists did not specify criteria for the diagnosis of cerebral palsy, blindness, or deafness. Psychological assessment included the MDI of the BSID. Study authors did not define major disability.

In Kari 1993, researchers performed randomisation in blocks of 10 for each participating hospital. Clinicians and investigators were unaware of treatment assignments. Study authors present outcomes for all 41 infants enrolled in the trial. The number of infants recruited was only 25% of the estimate required for the sample size. Therefore, the study was discontinued after 26 months. Follow‐up consisted of the following (Mieskonen 2003): only one of four centres in this multi‐centre study provided follow‐up; this centre contributed 23 of the 41 participants to the original study. Three infants died before discharge (one dexamethasone; two placebo). No late deaths in childhood are known. Survivors were followed in the hospital's outpatient clinic. One child in the dexamethasone group had deafness requiring a hearing aid, seizures treated with anticonvulsants, and attention deficit hyperactivity disorder, and required assistance with schooling but did not have cerebral palsy at 7.8 years of age. This child would not co‐operate with the respiratory component of the study. Another child in the dexamethasone group had no confirmed cerebral palsy at 2.6 years of age and was not traced at school age but was said to be attending normal school. One child in the placebo group had multiple difficulties in speech and cognitive function at five years of age and was expected to require extra help at school but refused further follow‐up. Another child in the placebo group had minor difficulties in comprehension at five years of age but was lost to further follow‐up. In total, 16 children participated in the follow‐up study at seven to nine years of age. Neurological status at five years of age was obtained from hospital records, including assessments for cerebral palsy (abnormal muscle tone, increased tendon reflexes and positive Babinski sign, or persistent or exaggerated primitive reflexes, dyskinesia, or ataxia), visual or hearing deficits, and school maturity (details of testing not given). Severe disability comprised any of more than mild cerebral palsy, severe global delay (not defined), or sensory or other impairment requiring special schooling; moderate disability comprised any of mild cerebral palsy, severe deafness, moderate global delay (extra help needed at school, assessment of global retardation or language problems), or home oxygen beyond three years of age. For this meta‐analysis, we have extracted data for major neurological disability for those with more than mild cerebral palsy, blindness, or deafness, or needing extra help with schooling. One investigator blinded to neonatal details then assessed children at 7.8 to 9.2 years of age, including presumably treatment group allocation. Age was not corrected for prematurity. Study authors measured children for height and weight and performed lung function tests, electrocardiography (ECG), and echocardiography.

In Kazzi 1990, randomisation was assigned by drawing a pre‐coded card prepared from a table of random numbers. Infants were stratified by birth weight into three groups: less than 1000 grams, 1000 grams to 1250 grams, and 1251 grams to 1500 grams. The pharmacist drew the card from the appropriate group, and neither investigators nor nursery staff were aware of the treatment group. Study authors provided outcome data for all 23 enrolled infants and reported no follow‐up component.

In Kothadia 1999, researchers randomised infants within six strata, defined in terms of birth weight (500 grams to 800 grams, 801 grams to 1100 grams, and 1101 grams to 1500 grams) and sex, with a block size of eight. They did not describe the exact method of randomisation. Control infants were given an equal volume of normal saline. Investigators assessed outcome data in a blinded fashion. Study authors initially described zero cross‐over in this trial, but review of data at age 19 years revealed that one child who was randomised to placebo received a 42‐day tapering course of placebo, then subsequently a 12‐day tapering course of dexamethasone. In addition, three of the children randomised to placebo received 24‐hour courses of dexamethasone for upper airway oedema. Follow‐up consisted of the following: a developmental paediatrician or one of two neonatologists and a physical therapist saw survivors at 12 months of age, corrected for prematurity, if any neurological abnormality was detected. Observers were blind to treatment group allocation. The follow‐up rate of survivors at 12 months of age was 98% (93/95). Trialists specified criteria for the diagnosis of cerebral palsy. Paediatric ophthalmologists diagnosed blindness. Study authors did not define deafness. Psychological assessment included the MDI of the BSID; investigators assessed the first 10 infants using the original Bayley Scales, and the remainder using BSID‐II. Major disability comprised any of cerebral palsy, blindness, or an MDI < ‐2 SD. Children were assessed again at 4 to 6 years of age and at 8 to 11 years of age (Nixon 2007; O'Shea 2007; Washburn 2006). Parents, children, and follow‐up examiners were not aware of children's randomisation assignment. Investigators diagnosed cerebral palsy at four to six years if the child had a neuromotor abnormality detected on neurological examination by a nurse with specialised training in neurodevelopmental follow‐up, and if the parent reported that the child was receiving treatment for cerebral palsy. A parent was interviewed again at the 8‐ to 11‐year visit as to whether a diagnosis of cerebral palsy had ever been made. For intelligence and academic achievement, at the four‐ to six‐year visit, a child psychologist assessed the child using the Differential Abilities Scales (DAS), the Kaufman Survey of Early Academic and Language Skills (K‐SEALS), and the Vineland Adaptive Behavioral Scales (VABS). At the 8‐ to 11‐year visit, a child psychologist assessed the child using the Wechsler Individual Achievement Tests (WIAT), the Wechsler Intelligence Scale for Children ‐ Third Edition (WISC‐III), and the Vineland Adaptive Behavior Scale (VABS). Investigators defined a major neurodevelopmental impairment at 4 to 6 years and/or at 8 to 11 years as cerebral palsy, and at 4 to 6 years of age as mental retardation (IQ < 70 on either the DAS (n = 11 participants) or the WISC‐III (n = 71 participants) and a VABS composite score < 70) at last follow‐up. For five dexamethasone‐treated and eight placebo‐treated children who did not undergo intelligence testing at 4 to 6 years or at 8 to 11 years of age, they defined major neurodevelopmental impairment as blindness, cerebral palsy (at the most recent visit), or a Bayley MDI < 70 for adjusted age. All survivors were assessed at least once at or beyond one year of age. The follow‐up rate at 4 to 11 years of age was 88% (84/95). Respiratory data were collected at 8 to 11 years of age via pulmonary function testing. Researchers obtained forced expiratory flow rates and volumes (FVC, FEV₁, FEV₁/FVC ratio, and FEF_{25% -75%}) expressed as % of predicted as appropriate, and considered abnormal if below the fifth percentile. They determined TLC and RV from body plethysmography and expressed these as a ratio (RV/TLC), as well as pulmonary diffusing capacity (diffusing capacity of the lungs for carbon monoxide (DLCO)) via the single‐breath carbon monoxide technique. However, most children could not cope with plethysmography and the single‐breath diffusion manoeuvre, hence study authors did not analyse TLC, RV, and diffusing capacity data. Investigators also assessed asthma diagnosis and airway reactivity. They categorised children as having asthma if the parent or guardian reported that the child had asthma, had used medications for asthma treatment, or both. A sub‐sample of children underwent maximal progressive exercise testing on a cycle ergometer as part of the larger study. Researchers repeated spirometry immediately and five minutes post exercise, as well as 20 minutes following three puffs of albuterol delivered with a spacer. They used a 15% decrease in FEV₁ from pre‐exercise values as the criterion to define exercise‐induced bronchoconstriction, and they considered a 12% increase in FEV₁ from pre‐exercise levels to be a positive bronchodilator response. The follow‐up rate at 8 to 11 years of age for respiratory data was 72% (68/95) but was 66% (63/95) for respiratory function testing. 

Kovacs 1998 assigned eligible infants using a "blocked" randomisation procedure, and only the designated pharmacist who prepared all study medications was aware of group assignments. Researchers stratified infants before randomisation into two categories according to gestational age (22 to 26 weeks versus 27 to 29 weeks). Follow‐up consisted of the following (Kovacs 2002 (personal communication follow‐up of Kovacs 1998)): study authors obtained data from the regular follow‐up clinic at ages up to 90 months in 70% (33/47) of survivors and did not specify personnel involved, blinding of assessors to treatment group, and criteria for various diagnoses, including cerebral palsy and major disability.

Noble‐Jamieson 1989 did not describe the method of randomisation. Medical and nursing staff were unaware of the drug given. Study authors provided outcome data for all 18 enrolled infants and reported no follow‐up component.

Ohlsson 1992 performed randomisation by using computer‐generated random numbers and wrote down allocation groups on cards enclosed in opaque envelopes and kept under lock in the pharmacy. Envelopes were available only to the pharmacist who drew the appropriate card and distributed the study drug. We have described under Description of studies the problem of administering placebo. Trialists discontinued treatment for suspected infection in one infant in each group and treatment for blood transfusion‐derived cytomegalovirus in one infant in the study group. They provided outcome data for all enrolled infants. Follow‐up consisted of the following (Ohlsson 1990 (additional publication of Ohlsson 1992)): researchers saw survivors in the regular follow‐up clinic up to at least 18 months of age in 96% (23/24) of cases; the remaining survivor was developing normally when last seen at 12 months of age. Age was probably not corrected for prematurity. Study authors did not specify personnel involved nor blinding of observers, neither did they specify criteria for the diagnoses of cerebral palsy and blindness. Psychological assessment included the MDI of the BSID.

In Onland 2019, the randomisation schedule was computer‐generated, with stratification for study centre and gestational age in two groups (< 27 weeks and > 26 weeks), The allocation ratio was 1:1 with block randomisation using variable block sizes. Multiple birth infants were randomised independently, unless parents or caretakers explicitly demanded that siblings should be in the same treatment arm. Infants’ parents and all members of the child's medical team and investigators were blinded to group allocation throughout the study. Survivors were assessed at two years' corrected age. Neurodevelopmental impairment was defined as presence of one or more of the following: cognitive and/or motor composite score less than 85 on the Bayley Scales of Infant and Toddler Development Third Edition (Dutch version), cerebral palsy greater than level II in the Gross Motor Function Classification System, or hearing or visual impairment. Additional data were obtained from the authors on the rates of cerebral palsy (personal communication, September 2021).

In Papile 1998, random assignment took place at each centre's pharmacy via the urn method ‐ a procedure that promotes equal distribution of participants among treatment groups. To blind clinical staff to treatment group assignment, investigators prepared different volumes of placebo (saline) to match the various doses of dexamethasone. They reported no follow‐up component.

In Parikh 2013, an individual not involved in the study generated the randomisation sequence, but study authors did not specify the precise method. They described two strata ‐ one for birth weight (< 751 grams versus 751 to 1000 grams) and one for respiratory index score (2 to 4 versus > 4). Access to the randomisation assignment was limited to two study pharmacists, and blinding was maintained by using an identical volume of saline placebo. Follow‐up consisted of the following (Parikh 2013; Parikh 2015): certified examiners assessed survivors at 18 to 22 months' corrected age and were blinded to group allocation. Certified examiners diagnosed cerebral palsy and specified the criteria for diagnosis. Study authors defined bilateral deafness as bilateral hearing loss requiring amplification, and bilateral blindness as bilateral vision loss with only form or shadow vision or no useful vision. Psychological assessment included the Bayley Scales of Infant and Toddler Development ‐ Third Edition (Bayley III). Investigators defined any neurodevelopmental impairment as any of cerebral palsy, cognitive delay, language delay, blindness, or deafness.

Romagnoli 1997 achieved random allocation by opening numbered, sealed envelopes. Researchers did not give placebo to control infants. They reported outcome measures for all 30 infants included in the study. Follow‐up consisted of the following (Romagnoli 2002): one paediatrician and one neurologist saw survivors at 36 to 42 months of age, corrected for prematurity, with observers blinded to treatment group allocation. The follow‐up rate of survivors was 100% (30/30). The neurologist made the diagnosis of cerebral palsy, but study authors did not specify the criteria used and reported no specific criteria for blindness and deafness. Psychological assessment included the Stanford Binet Test ‐ Third Revision. Study authors provided no data on major disability.

Scott 1997 achieved randomisation using a random numbers table. Blinding was maintained by using an identical volume of saline placebo. There was no follow‐up component.

Vento 2004 did not state the method of randomisation. It is not clear whether clinicians caring for infants or those assessing outcomes were blinded to treatment group assignment. The control group did not receive a placebo. Follow‐up consisted of the following (Vento 2012 (personal communication follow‐up of Vento 2004)): a paediatric neurologist who was blinded to treatment group allocation assessed surviving children between one and four years of age, corrected for prematurity up to two years. They considered children to have a major neurosensory impairment if they had non‐ambulant cerebral palsy, blindness (bilateral vision worse than 6/60), deafness requiring hearing aids or worse, or severe cognitive delay (defined as IQ < 55). The follow‐up rate of survivors at a mean age of 26 months was 100% (18/18).

Vincer 1998 achieved random allocation but did not describe in the abstract the method used. Control infants were given equal volumes of saline placebo, which concealed treatment allocation. Follow‐up consisted of the following (Vincer 2002 (personal communication follow‐up of Vincer 1998)): one of two neonatologists saw survivors at 24 months of age, corrected for prematurity. They referred children with a developmental abnormality to a neurologist. Observers were blind to treatment group allocation. The follow‐up rate of survivors was 100% (17/17). Study authors specified criteria for the diagnosis of cerebral palsy, but not for blindness or deafness. Psychological assessment included the MDI of the BSID. Major disability comprised any of moderate or severe cerebral palsy, bilateral blindness, deafness, or MDI < 2 SD.

In Walther 2003, a staff pharmacist was in charge of randomisation and drug preparation. Investigators and clinical caregivers were unaware of treatment allocation. Infants in the control group received a saline placebo. Open‐label steroid therapy was used only if it became essential for management of ventilator dependency, ideally seven days after completion of therapy and at the discretion of the attending neonatologist. Follow‐up consisted of the following (Walther 2012 (personal communication follow‐up of Walther 2003)): surviving children were assessed at between one and four years of age with no details provided about correction for prematurity and personnel involved; however, trial personnel were blinded to knowledge of treatment group allocation. They defined developmental delay as MDI < 70 on the BSID. The follow‐up rate of survivors was 78% (25/32).

In Yates 2019, randomisation was managed via a secure web‐based randomisation facility hosted centrally, with continuous telephone backup available. The randomisation programme used a minimisation algorithm to ensure balance between trial groups, with respect to collaborating hospital, sex, multiple births, gestational age at birth, and existing diuretic therapy for the 24 hours before randomisation. Multiple births from the same family were randomised individually. Dexamethasone and saline placebo were supplied in identical vials, and hence staff were unaware of treatment allocation. Open‐label treatment was allowed after the 16‐day intervention period had elapsed; however open‐label could start earlier at clinician discretion. There was no long‐term follow‐up component.

Allocation

We found little evidence of allocation bias overall; most studies had no evidence of allocation bias, and in a small minority the risk was unclear.

Blinding

We found little evidence of blinding bias overall; most studies had no evidence of blinding bias, but small minorities had unclear or high risk of blinding bias.

Incomplete outcome data

We found little evidence of attrition bias overall; most studies had no evidence of attrition bias, and a small minority had unclear risk.

Selective reporting

Just over one‐half of studies had no evidence of selective reporting bias, and the remainder had unclear risk of selective reporting bias.

Other potential sources of bias

A majority of studies used a valid method of random sequence generation, but in approximately 40% of studies, the methods used for randomisation were unclear.

Effects of interventions

See: Table 1

Results of meta‐analysis

Meta‐analysis of these 23 studies yielded the following results.

Mortality

Evidence indicates that late systemic corticosteroid treatment was associated with reduced mortality at all ages: 28 days (typical risk ratio (RR) 0.60, 95% confidence interval (CI) 0.40 to 0.89; typical risk difference (RD) ‐0.04, 95% CI ‐0.09 to ‐0.00; 7 studies, 970 infants; Analysis 1.1), 36 weeks' postmenstrual age (typical RR 0.70, 95% CI 0.52 to 0.94; typical RD ‐0.05, 95% CI ‐0.10 to ‐0.01; 15 studies, 1029 infants; Analysis 1.2), before hospital discharge (typical RR 0.79, 95% CI 0.63 to 0.98; typical RD ‐0.04, 95% CI ‐0.08 to ‐0.00; 20 studies, 1406 infants; Analysis 1.3), and at latest reported age (RR 0.81, 95% CI 0.66 to 0.99; RD ‐0.05, 95% CI ‐0.09 to ‐0.00; 21 studies, 1428 infants; Analysis 1.4).

1.1. Analysis.

Comparison 1: Mortality at different ages, Outcome 1: Neonatal mortality before 28 days after birth

1.2. Analysis.

Comparison 1: Mortality at different ages, Outcome 2: Mortality at 36 weeks' postmenstrual age

1.3. Analysis.

Comparison 1: Mortality at different ages, Outcome 3: Mortality to hospital discharge

1.4. Analysis.

Comparison 1: Mortality at different ages, Outcome 4: Mortality at latest reported age

No evidence suggests publication bias for mortality at latest reported age upon examination of a funnel plot (Egger test, P = 0.78) (Figure 4).

4.

Funnel plot of comparison: 1 Mortality, outcome: 1.4 Mortality at latest reported age.

Bronchopulmonary dysplasia

The incidence of BPD was significantly decreased at 28 days of life (typical RR 0.90, 95% CI 0.84 to 0.95; typical RD ‐0.11, 95% CI ‐0.17 to ‐0.05; 7 studies, 994 infants; Analysis 2.1), and at 36 weeks' postmenstrual age (typical RR 0.89, 95% CI 80 to 0.99; typical RD ‐0.07, 95% CI ‐0.13 to ‐0.01; 14 studies, 988 infants; Analysis 2.2), but the evidence was not as strong at 36 weeks' postmenstrual age among survivors (typical RR 0.91, 95% CI 0.82 to 1.01; typical RD ‐0.06, 95% CI ‐0.13 to 0.01; 9 studies, 624 infants; Analysis 2.3). We noted strong evidence of publication bias upon examining a funnel plot for BPD at 36 weeks (Egger test, P < 0.001) (Figure 5). Data show reduced need for late rescue with corticosteroids (typical RR 0.48, 95% CI 0.41 to 0.57; typical RD ‐0.20, 95% CI ‐0.24 to ‐0.16; 15 studies, 1489 infants; Analysis 2.4) and reduced need for home oxygen both overall (typical RR 0.71, 95% CI 0.54 to 0.94; typical RD ‐0.08, 95% CI ‐0.14 to ‐0.01; 7 studies, 611 infants; Analysis 2.5) and for survivors only (typical RR 0.69, 95% CI 0.51 to 0.94; typical RD ‐0.13, 95% CI ‐0.24 to ‐0.03; 6 studies, 277 infants; Analysis 2.6).

2.1. Analysis.

Comparison 2: Bronchopulmonary dysplasia (BPD), Outcome 1: BPD at 28 days after birth

2.2. Analysis.

Comparison 2: Bronchopulmonary dysplasia (BPD), Outcome 2: BPD at 36 weeks' postmenstrual age

2.3. Analysis.

Comparison 2: Bronchopulmonary dysplasia (BPD), Outcome 3: BPD at 36 weeks in survivors

5.

Funnel plot of comparison: 2 Bronchopulmonary dysplasia (BPD), outcome: 2.2 BPD at 36 weeks' postmenstrual age.

2.4. Analysis.

Comparison 2: Bronchopulmonary dysplasia (BPD), Outcome 4: Late rescue with corticosteroids

2.5. Analysis.

Comparison 2: Bronchopulmonary dysplasia (BPD), Outcome 5: Home on oxygen

2.6. Analysis.

Comparison 2: Bronchopulmonary dysplasia (BPD), Outcome 6: Survivors discharged home on oxygen

Mortality or bronchopulmonary dysplasia

Strong evidence indicates that the combined outcome of mortality or BPD was decreased both at 28 days of life (typical RR 0.87, 95% CI 0.83 to 0.91; typical RD ‐0.12 to 95% CI ‐0.16 to ‐0.08; 6 studies, 934 infants; Analysis 3.1) and at 36 weeks' postmenstrual age (RR 0.85, 95% CI 0.79 to 0.92; RD ‐0.12, 95% CI ‐0.17 to ‐0.07; 14 studies, 988 infants; Analysis 3.2). We found little evidence of publication bias upon examining a funnel plot for mortality or BPD at 36 weeks (Egger test, P = 0.33) (Figure 6).

3.1. Analysis.

Comparison 3: Mortality or BPD, Outcome 1: Mortality or BPD at 28 days after birth

3.2. Analysis.

Comparison 3: Mortality or BPD, Outcome 2: Mortality or BPD at 36 weeks' postmenstrual age

6.

Funnel plot of comparison: 3 Mortality or BPD, outcome: 3.2 Mortality or BPD at 36 weeks' postmenstrual age.

Failure to extubate

Failure to extubate was significantly decreased at three days (typical RR 0.83, 95% CI 0.78 to 0.88; typical RD ‐0.16, 95% CI ‐0.21 to ‐0.11; 10 studies, 764 infants; Analysis 4.1), at seven days (typical RR 0.67, 95% CI 0.62 to 0.73; typical RD ‐0.27, 95% CI ‐0.32 to ‐0.22; 17 studies, 1130 infants; Analysis 4.2), at 14 days (typical RR 0.65, 95% CI 0.53 to 0.80; typical RD ‐0.19, 95% CI ‐0.28 to ‐0.10; 5 studies, 458 infants; Analysis 4.3), and at 28 days (typical RR 0.57, 95% CI 0.37 to 0.89; typical RD ‐0.14, 95% CI ‐0.25 to ‐0.03; 3 studies, 236 infants; Analysis 4.4).

4.1. Analysis.

Comparison 4: Failure to extubate, Outcome 1: Failure to extubate by 3rd day after treatment

4.2. Analysis.

Comparison 4: Failure to extubate, Outcome 2: Failure to extubate by 7th day after treatment

4.3. Analysis.

Comparison 4: Failure to extubate, Outcome 3: Failure to extubate by 14th day after treatment

4.4. Analysis.

Comparison 4: Failure to extubate, Outcome 4: Failure to extubate by 28th day after treatment

Complications during primary hospitalisation

Metabolic complications

Results show increased risks of hyperglycaemia (typical RR 1.59, 95% CI 1.34 to 1.89; typical RD 0.10, 95% CI 0.07 to 0.14; 19 studies, 1684 infants; Analysis 5.2) and glycosuria (typical RR 8.03, 95% CI 2.43 to 26.5; typical RD 0.72, 95% CI 0.52 to 0.91; 2 studies, 48 infants; Analysis 5.3), as well as increased risk of hypertension (typical RR 1.67, 95% CI 1.19 to 2.33; typical RD 0.04, 95% CI 0.01 to 0.06; 17 studies, 1628 infants; Analysis 5.4).

5.2. Analysis.

Comparison 5: Complications during primary hospitalisation, Outcome 2: Hyperglycaemia

5.3. Analysis.

Comparison 5: Complications during primary hospitalisation, Outcome 3: Glycosuria

5.4. Analysis.

Comparison 5: Complications during primary hospitalisation, Outcome 4: Hypertension

Gastrointestinal complications

We found little evidence for differences in gastrointestinal complications: necrotising enterocolitis (typical RR 0.92, 95% CI 0.62 to 1.38; 11 studies, 1409 infants; Analysis 5.6), gastrointestinal bleeding (typical RR 1.33, 95% CI 0.97 to 1.83; 9 studies, 1385 infants; Analysis 5.7), or gastrointestinal perforation (RR 0.67, 95% CI 0.26 to 1.70; 5 studies, 552 infants; Analysis 5.8).

5.6. Analysis.

Comparison 5: Complications during primary hospitalisation, Outcome 6: Necrotising enterocolitis (NEC)

5.7. Analysis.

Comparison 5: Complications during primary hospitalisation, Outcome 7: Gastrointestinal bleeding

5.8. Analysis.

Comparison 5: Complications during primary hospitalisation, Outcome 8: Gastrointestinal perforation

Other complications

No evidence suggests that infection rates were different between groups (typical RR 1.03, 95% CI 0.91 to 1.16; 20 studies, 1742 infants; Analysis 5.1). Evidence indicates an increase in severe retinopathy of prematurity overall (typical RR 1.27, 95% CI 1.03 to 1.58; typical RD 0.06, 95% CI 0.01 to 0.12; 13 studies, 929 infants; Analysis 5.9), but not among survivors (typical RR 1.17, 95% CI 0.94 to 1.45; 10 studies, 697 infants; Analysis 5.10). Evidence shows an increase in hypertrophic cardiomyopathy (typical RR 2.76, 95% CI 1.33 to 5.74; typical RD 0.13, 95% CI 0.05 to 0.20; 4 studies, 238 infants; Analysis 5.11). We found little evidence for real reductions in pneumothorax (typical RR 0.89, 95% CI 0.53 to 1.49; 3 studies, 157 infants; Analysis 5.12) or in severe intraventricular haemorrhage (typical RR 0.54, 95% CI 0.26 to 1.11; 7 studies, 639 infants; Analysis 5.13).

5.1. Analysis.

Comparison 5: Complications during primary hospitalisation, Outcome 1: Infection

5.9. Analysis.

Comparison 5: Complications during primary hospitalisation, Outcome 9: Severe retinopathy of prematurity (ROP)

5.10. Analysis.

Comparison 5: Complications during primary hospitalisation, Outcome 10: Severe ROP in survivors

5.11. Analysis.

Comparison 5: Complications during primary hospitalisation, Outcome 11: Hypertrophic cardiomyopathy

5.12. Analysis.

Comparison 5: Complications during primary hospitalisation, Outcome 12: Pneumothorax

5.13. Analysis.

Comparison 5: Complications during primary hospitalisation, Outcome 13: Severe intraventricular haemorrhage (IVH)

Follow‐up data

• Rates of children with low cut‐off scores for the Mental Developmental Index on the Bayley Scales were little affected overall (typical RR 0.81, 95% CI 0.47 to 1.38; 7 studies, 333 infants; Analysis 6.1) or among survivors assessed (typical RR 0.74, 95% CI 0.45 to 1.22; 7 studies, 232 infants; Analysis 6.2). Rates of children with low cut‐off scores for the Psychomotor Developmental Index on the Bayley Scales were little affected overall (typical RR 0.78, 95% CI 0.34 to 1.80; 1 study, 118 infants; Analysis 6.3) or among survivors assessed (typical RR 0.67, 95% CI 0.30 to 1.50; 1 study, 90 infants; Analysis 6.4)

• The increase in retinopathy of prematurity did not translate into a significant increase in blindness overall (typical RR 0.78, 95% CI 0.35 to 1.73; 13 studies, 784 infants; Analysis 6.5) or among survivors assessed (typical RR 0.77, 95% CI 0.35 to 1.67; 13 studies, 539 infants; Analysis 6.6)

• We found little evidence for a difference in rates of deafness overall (typical RR 0.56, 95% CI 0.26 to 1.27; 9 studies, 936 infants; Analysis 6.7) or among survivors assessed (typical RR 0.62, 95% CI 0.29 to 1.36; 9 studies, 616 infants; Analysis 6.8)

• We found little evidence for a difference in rates of cerebral palsy at the latest reported age overall (typical RR 1.17, 95% CI 0.84 to 1.61; 17 studies, 1290 infants; Analysis 6.10) or among survivors assessed at the latest reported age (typical RR 1.15, 95% CI 0.81 to 1.61; 16 studies, 628 infants; Analysis 6.16). A funnel plot for the outcome of cerebral palsy at latest reported age provided little evidence of publication bias (Egger test, P = 0.13) (Figure 7). Cerebral palsy was not significantly increased in studies limited to the first three years after birth (typical RR 1.11, 95% CI 0.81 to 1.51; 16 studies, 1311 infants; Analysis 6.9), or among survivors assessed at 1‐3 years of age (typical RR 1.08, 95% CI 0.79 to 1.47; 16 studies, 923 infants; Analysis 6.15. The combined rate of mortality or cerebral palsy was little affected in studies limited to the first three years after birth (typical RR 0.89, 95% CI 0.76 to 1.04; 16 studies, 1311 infants; Analysis 6.13). The combined rate of either mortality or cerebral palsy at latest reported age was not significantly different (typical RR 0.90, 95% CI 0.76 to 1.06; 16 studies, 1290 infants; Analysis 6.14). A funnel plot for the outcome mortality or cerebral palsy at latest reported age provided little evidence of publication bias (Egger test, P = 0.99) (Figure 8)

• Major neurosensory disability was not significantly different overall (typical RR 1.09, 95% CI 0.88 to 1.34; 10 studies, 1090 infants; Analysis 6.17) or among survivors assessed (typical RR 1.01, 95% CI 0.83 to 1.22; 10 studies, 778 infants; Analysis 6.20). The combined rate of mortality or major neurosensory disability was not significantly different (typical RR 0.96, 95% CI 0.85 to 1.08; 10 studies, 1090 infants; Analysis 6.19)

• The rate of abnormal neurological examination overall was increased (typical RR 1.81, 95% CI 1.05 to 3.11; typical RD 0.13, 95% CI 0.02 to 0.24; 4 studies, 200 infants; Analysis 6.21), but the clinical importance of this finding is unclear in the absence of important increases in cerebral palsy or major neurosensory disability. Rates of the combined outcome of mortality or abnormal neurological examination were not significantly different between groups (typical RR 0.96, 95% CI 0.71 to 1.31; 4 studies, 200 infants; Analysis 6.23)

• The only study reporting re‐hospitalisation rates over the first five years noted little evidence of a difference between groups (Analysis 6.25; Analysis 6.26). The same study with follow‐up of survivors to five years noted little evidence for increased maternal reports of wheezing (RR 1.47, 95% CI 0.82 to 2.64; 1 study, 74 infants; Analysis 7.1), need for corrective lenses (RR 1.61, 95% CI 0.82 to 3.13; 1 study, 74 infants; Analysis 7.2), and need for physical therapy (RR 1.49, 95% CI 0.71 to 3.11; 1 study, 74 infants; Analysis 7.3), and a non‐significant decrease in the need for speech therapy (RR 0.46, 95% CI 0.21 to 1.02; 1 study, 74 infants; Analysis 7.4)

• Data show no substantial differences between groups for other outcomes in later childhood, including IQ, respiratory health or function, blood pressure, and growth, with the exceptions of a significant reduction in rates of children with FEV₁ < ‐2 SD (typical RR 0.58, 95% CI 0.36 to 0.94; 2 studies, 187 infants; Analysis 8.2), increased standardised mean difference for FEV₁ (standardised mean difference (SMD) 0.28, 95% CI 0.01 to 0.55; 4 studies, 222 participants; Analysis 8.5), and increased mean difference for forced vital capacity (MD 7.68% predicted, 95% CI 1.69 to 13.68; 3 studies, 98 participants; Analysis 8.7).

6.1. Analysis.

Comparison 6: Long‐term follow‐up, Outcome 1: Bayley Mental Developmental Index (MDI) < ‐2 SD

6.2. Analysis.

Comparison 6: Long‐term follow‐up, Outcome 2: Bayley MDI < ‐2 SD in survivors tested

6.3. Analysis.

Comparison 6: Long‐term follow‐up, Outcome 3: Bayley Psychomotor Developmental Index (PDI) < ‐2 SD

6.4. Analysis.

Comparison 6: Long‐term follow‐up, Outcome 4: Bayley PDI < ‐2 SD in survivors tested

6.5. Analysis.

Comparison 6: Long‐term follow‐up, Outcome 5: Blindness

6.6. Analysis.

Comparison 6: Long‐term follow‐up, Outcome 6: Blindness in survivors assessed

6.7. Analysis.

Comparison 6: Long‐term follow‐up, Outcome 7: Deafness

6.8. Analysis.

Comparison 6: Long‐term follow‐up, Outcome 8: Deafness in survivors assessed

6.10. Analysis.

Comparison 6: Long‐term follow‐up, Outcome 10: Cerebral palsy at latest reported age

6.16. Analysis.

Comparison 6: Long‐term follow‐up, Outcome 16: Cerebral palsy in survivors assessed at latest age

7.

Funnel plot of comparison: 6 Long‐term follow‐up, outcome: 6.10 Cerebral palsy at latest reported age.

6.9. Analysis.

Comparison 6: Long‐term follow‐up, Outcome 9: Cerebral palsy at 1 to 3 years of age

6.15. Analysis.

Comparison 6: Long‐term follow‐up, Outcome 15: Cerebral palsy in survivors assessed at 1‐3 years of age

6.13. Analysis.

Comparison 6: Long‐term follow‐up, Outcome 13: Mortality or cerebral palsy at 1 to 3 years

6.14. Analysis.

Comparison 6: Long‐term follow‐up, Outcome 14: Mortality or cerebral palsy at latest reported age

8.

Funnel plot of comparison: 6 Long‐term follow‐up, outcome: 6.14 Mortality or cerebral palsy at latest reported age.

6.17. Analysis.

Comparison 6: Long‐term follow‐up, Outcome 17: Major neurosensory disability (variable criteria ‐ see individual studies)

6.20. Analysis.

Comparison 6: Long‐term follow‐up, Outcome 20: Major neurosensory disability (variable criteria) in survivors assessed

6.19. Analysis.

Comparison 6: Long‐term follow‐up, Outcome 19: Mortality or major neurosensory disability (variable criteria)

6.21. Analysis.

Comparison 6: Long‐term follow‐up, Outcome 21: Abnormal neurological exam (variable criteria ‐ see individual studies)

6.23. Analysis.

Comparison 6: Long‐term follow‐up, Outcome 23: Mortality or abnormal neurological exam (variable criteria)

6.25. Analysis.

Comparison 6: Long‐term follow‐up, Outcome 25: Re‐hospitalisation

6.26. Analysis.

Comparison 6: Long‐term follow‐up, Outcome 26: Re‐hospitalisation in survivors seen at follow‐up

7.1. Analysis.

Comparison 7: Later childhood outcomes, Outcome 1: Recurrent wheezing in survivors examined at 5 years

7.2. Analysis.

Comparison 7: Later childhood outcomes, Outcome 2: Use of corrective lenses in survivors examined at 5 years

7.3. Analysis.

Comparison 7: Later childhood outcomes, Outcome 3: Use of physical therapy in survivors examined at 5 years

7.4. Analysis.

Comparison 7: Later childhood outcomes, Outcome 4: Use of speech therapy in survivors examined at 5 years

8.2. Analysis.

Comparison 8: Respiratory outcomes in childhood ‐ after 5 years, Outcome 2: Forced expired volume in 1 second < ‐2 SD

8.5. Analysis.

Comparison 8: Respiratory outcomes in childhood ‐ after 5 years, Outcome 5: Forced expired volume in 1 second ‐ standardised mean difference

8.7. Analysis.

Comparison 8: Respiratory outcomes in childhood ‐ after 5 years, Outcome 7: Forced vital capacity ‐ % predicted

Differences by type of corticosteroid used

When such comparisons were possible, there were few outcomes for which evidence shows differences in treatment effects between RCTs involving dexamethasone and those involving only hydrocortisone. Notable exceptions were that effects of corticosteroids in reducing BPD at 36 weeks (Analysis 2.2), in reducing mortality or BPD at 36 weeks (Analysis 3.2), and in increasing the rate of hypertension (Analysis 5.4) all arose from treatment with dexamethasone ‐ not with hydrocortisone. 

Sensitivity analysis, excluding studies with higher risk of bias

Two studies had higher risk of bias largely because they included no control groups, and hence blinding to knowledge of treatment allocation was not possible (Durand 1995; Romagnoli 1997). Both studies involved dexamethasone only. Excluding these two studies from major outcomes of mortality at latest age, BPD at 36 weeks, combined mortality or BPD at 36 weeks, cerebral palsy, or mortality or cerebral palsy had little effect on most odds ratios or on any CIs, and altered no conclusions, with one exception; for outcomes of BPD at 36 weeks for all studies combined, the typical RR was 0.89 (95% CI 0.80 to 0.99) with all studies included (Analysis 2.2), but was changed slightly to typical RR 0.93 (95% CI 0.83 to 1.03) when the two studies were excluded.

Results of individual trials

Ariagno 1987: total respiratory system compliance improved in the dexamethasone group (P < 0.05). Time from initiation of treatment to first extubation was shorter for the dexamethasone group (6 versus 45 days; P = 0.0006), but time to final extubation was not significantly different (30 versus 48 days). Data show 10 deaths ‐ five in the dexamethasone group and five in the control group ‐ all occurring after the treatment period. Proportionate weight gain was greater among control infants (P < 0.003) during treatment. Five dexamethasone‐treated infants had infection, as did two in the control group. Hyperglycaemia and hypertension were similar between groups. At follow‐up, cerebral palsy was detected in one child in the dexamethasone group at 36 months of age and in three controls at 12 months of age.

Avery 1985: sequential analysis exceeded the criterion (P < 0.005) when seven consecutive untied pairs showed weaning with dexamethasone and failure to wean in control infants. Pulmonary compliance improved by 64% in the treated group and by 5% in the control group (P < 0.01). Results show no significant intergroup differences in mortality, length of hospital stay, sepsis, hypertension, hyperglycaemia, or electrolyte abnormalities.

Brozanski 1995: at 36 weeks' postmenstrual age, results show a significant increase in survival rates without oxygen supplementation (17/39 versus 7/39; P = 0.03) and a significant decrease in the incidence of BPD (46% versus 23%; P = 0.047) in the group that received pulse dexamethasone therapy. Supplemental oxygen requirements were less throughout the study period in the dexamethasone group (P = 0.013). Mortality and durations of supplemental oxygen, ventilator support, and hospital stay did not differ significantly between groups. The need for insulin therapy for hyperglycaemia was increased in the dexamethasone group (P < 0.05). At follow‐up, data show no significant differences between groups in rate of cerebral palsy among survivors assessed (20% versus 21%). Rate of death or survival among randomised children with cerebral palsy was lower in the dexamethasone group (23% versus 33%), but this difference was not statistically significant. The mean Mental Developmental Index (MDI) was 89.5 (SD 23.7) in the dexamethasone group and 80.8 (SD 26.0) in the control group ‐ a non‐significant difference.

CDTG 1991: dexamethasone treatment significantly reduced the duration of mechanical ventilation among infants who were ventilator‐dependent at entry (median days for survivors, 11 versus 17.5). Data show no statistically significant differences between total groups of survivors in time receiving supplemental oxygen and length of stay in hospital, although trends favoured the dexamethasone group. Twenty‐five infants in each group died before hospital discharge; most were ventilator‐dependent at trial entry. Open treatment with steroids was later given to 18% of the dexamethasone group and 43% of the placebo group (P < 0.001). We found little evidence of serious side effects and noted that infection rates in particular were similar in the two groups. At follow‐up, results show no clear differences between randomised groups in the original study for outcomes at three years. This conclusion held when data for cerebral palsy, blindness, and deafness were updated on the basis of results obtained at 13 to 17 years of age. Rates of intellectual impairment and moderate and severe disability at 13 to 17 years of age were similar in both groups, and data reveal no substantial differences in lung function or growth z‐scores, nor in proportions with high blood pressure.

Cummings 1989: infants in the 42‐day dexamethasone group, but not those in the 18‐day group, were weaned from mechanical ventilation significantly faster than controls (median 29, 73, and 84 days, respectively; P < 0.05) and from supplemental oxygen (medians 65, 190, and 136 days, respectively; P < 0.05). No clinical complications of steroid administration were noted. At follow‐up, combining both dexamethasone groups revealed no significant differences between dexamethasone‐treated and control children for rates of cerebral palsy, blindness, deafness, developmental delay, or major neurosensory disability among survivors, or for death or survival with cerebral palsy, or for death or survival with major disability among those randomised. Neurological status was confirmed at four years of age for all children (Cummings 2002 (personal communication follow‐up of Cummings 1989)). Data show no significant differences in psychometric test scores at 15 months or 4 years of age. Between 4 and 15 years, one child in the 18‐day group had died, leaving 22 survivors, all of whom (100%) were assessed at 15 years of age. There were no significant differences between dexamethasone groups combined and the placebo group for any of the major neurological outcomes, nor for growth or respiratory function.

Doyle 2006: substantially more infants were extubated successfully by 10 days in the dexamethasone group than in the control group (odds ratio (OR) 11.2, 95% confidence interval (CI) 3.2 to 39.0; P < 0.001). Twelve of 21 dexamethasone‐treated infants were re‐intubated after initial extubation compared with one of four placebo‐treated infants. Mortality was reduced but not significantly in the dexamethasone group (OR 0.52, 95% CI 0.14 to 1.95; P = 0.33), and the same was true for BPD among survivors (OR 0.58, 95% CI 0.08 to 3.32; P = 0.71). Combined rates of death or BPD (86% versus 91%; P = 0.45) and death or severe BPD (34% versus 46%; P = 0.33) were not different between groups. During the first 10 days, mean airway pressure (MAP), peak inspiratory pressure, and inspired oxygen concentration all decreased significantly in the dexamethasone group compared with the placebo group. Data show no differences between groups in rates of high blood glucose levels or high blood pressure. Open‐label use of corticosteroids, sepsis, necrotising enterocolitis, patent ductus arteriosus, and severe retinopathy of prematurity were similar for the two groups. No infant had gastrointestinal perforation or bleeding. One infant in the placebo group had cardiac hypertrophy, but none in the dexamethasone group. At follow‐up, rates of cerebral palsy, blindness, and deafness, of Bayley MDI or PDI < ‐1 SD, or of major neurological disability were similar in the two groups, as were combined rates of death or cerebral palsy, or death or major disability.

Durand 1995: data show significant differences in compliance and tidal volume in the dexamethasone group compared with the control group (P < 0.001). Dexamethasone also significantly decreased inspired oxygen concentration and MAP (both P < 0.001) and facilitated successful weaning from mechanical ventilation. BPD (supplemental oxygen at 36 weeks' postmenstrual age, chest radiograph changes) was significantly decreased in the dexamethasone group (2/21 versus 8/17; P < 0.01). Survival with BPD was also better in the dexamethasone group (19/23 versus 9/20; P < 0.02). Except for transient increases in blood pressure and plasma glucose, we found no evidence of adverse effects of treatment and no significant differences in rates of infection, intraventricular haemorrhage, and retinopathy of prematurity. Thirteen infants in the control group subsequently received dexamethasone.

Harkavy 1989: dexamethasone treatment reduced age at extubation (39.4 days versus 57.2 days) compared with placebo. Average oxygen requirements for the steroid‐treated group were significantly lower during the first 10 days of treatment, but data show no significant differences between groups in age of weaning to room air (74.9 days versus 95.5 days), age at discharge (111 days versus 119 days), or number of deaths (1 (11%) versus 2 (17%)). Dexamethasone therapy was associated with a significantly increased incidence of hyperglycaemia (89% versus 8%; P = 0.01) but did not influence significantly the incidence of hypertension, intraventricular haemorrhage, infection, or retinopathy of prematurity. Steroid‐treated infants had a significant delay in weight gain (P < 0.02) during the first three weeks of treatment. Among the small number of children followed up, cerebral palsy was diagnosed in one of three in the dexamethasone group and in two of three controls.

Kari 1993: at 28 days of life, pulmonary outcome was significantly better among girls treated with dexamethasone but not in all infants. Data show no significant differences between groups in long‐term outcomes, except a shorter duration of supplemental oxygen among dexamethasone‐treated female infants. After one week of dexamethasone treatment, results show significant but short‐lived suppression of basal cortisol concentrations and of the adrenal response to ACTH. Investigators observed no serious side effects. At follow‐up, the only hospital providing follow‐up data reported no significant differences between dexamethasone and control children in rates of mortality, cerebral palsy, blindness, deafness, or major neurological disability, nor of death or survival with cerebral palsy or death or survival with major neurological disability, among those randomised. At seven to nine years of age, data show some improvement in lung function among eight steroid‐treated children compared with seven controls, and no substantial differences in height or weight between steroid and placebo groups, but data were not reported in a form that would allow meta‐analysis. No children had hypertrophic cardiomyopathy.

Kazzi 1990: infants who received dexamethasone required less oxygen on Days 8 and 17 (P < 0.005) and were more likely to be extubated eight days after therapy (8/12 versus 3/11; P < 0.05, P = 0.12 after Yates correction) compared with infants in the control group. Dexamethasone significantly shortened the duration of mechanical ventilation (median 4 versus 22 days; P < 0.05), but we found no evidence of effects on duration of oxygen therapy, hospitalisation, or home oxygen therapy, nor on the occurrence and severity of retinopathy of prematurity, rate of growth, or mortality.

Kothadia 1999: infants treated with dexamethasone were on mechanical ventilation and supplemental oxygen for fewer days after study entry (median days on ventilator: 5th and 95th centiles, 13 (1 to 64) versus 25 (6 to 104); days on oxygen: 59 (6 to 247) versus 100 (11 to 346)). Fewer infants in the dexamethasone group had failed to be extubated by the third day (82% versus 97%) or the seventh day (63% versus 90%). Data show no significant differences in rates of death, infection, or severe retinopathy of prematurity. At one‐year follow‐up, more surviving dexamethasone‐treated infants had cerebral palsy (24% versus 7%) and abnormal findings on neurological examination (42% versus 18%). However, deaths before one year were more frequent in the placebo group (26%) than in the dexamethasone group (12%); thus, rates of the combined outcome, death or cerebral palsy at one year, were not significantly different (dexamethasone 33% versus placebo 31%). An additional child in the placebo group was reported to have cerebral palsy at age four to six years. Risk of cerebral palsy was higher among surviving dexamethasone‐treated children at four to six years of age, although cognitive, functional, and medical outcomes were not significantly different between treated and non‐treated survivors. The combined outcome, death or cerebral palsy, was also similar at four‐ to six‐year follow‐up. Results show no substantial differences in rates of asthma, nor in blood pressure or growth. Fewer participants in the dexamethasone group had a low value for FEV₁ at between 8 and 11 years (dexamethasone 40% versus placebo 68%).

Kovacs 1998: mortality in hospital was not significantly different in the two groups (27% dexamethasone versus 17% controls). It is not possible to determine precisely when infants died, and hence this study cannot contribute to mortality at 28 days or at 36 weeks. Steroid‐treated infants required less ventilatory support between 9 and 17 days of age, and less supplemental oxygen between 8 and 10 days of age. Fewer infants in the dexamethasone group had failed to be extubated by the seventh day (73% versus 93%). Infants in this group also had better pulmonary compliance at 10 days, but comparison with controls revealed that all improvements were not maintained over ensuing weeks. Incidences of BPD at 28 days of life and at 36 weeks' postmenstrual age among survivors were not significantly different between groups (80% versus 87% at 28 days of life; 45% versus 56% at 36 weeks' postmenstrual age). We found no evidence of steroid‐related adverse effects, other than transient glycosuria. At follow‐up, data show no significant differences between dexamethasone‐treated and control children in rates of cerebral palsy, blindness, deafness, developmental delay, or major neurosensory disability among survivors assessed, nor in death or survival with cerebral palsy or death or survival with major disability among those randomised.

Noble‐Jamieson 1989: dexamethasone‐treated infants showed more rapid improvement in ventilation requirements during the first week of treatment, although the overall duration of oxygen therapy was similar in both groups. Cranial ultrasound examination revealed new periventricular abnormalities in three out of five dexamethasone‐treated infants with previous normal scans, compared with none of four placebo‐treated infants.

Ohlsson 1992: dexamethasone facilitated weaning from mechanical ventilation (P = 0.015). The incidence of infection was not significantly increased, although glycosuria (P = 0.0002) and systolic blood pressure (P = 0.003) were increased and heart rate (P = 0.0001) and weight gain (P = 0.0002) were decreased in the dexamethasone‐treated group. At follow‐up among survivors, cerebral palsy was diagnosed in one of 11 children in the dexamethasone group, and in three of 13 controls.

Onland 2019: hydrocortisone was associated with reduction in mortality at 36 weeks' postmenstrual age (15% versus 24%; P = 0.048) but a higher rate of BPD (55% versus 50%; P = 0.31) and no substantial effect on the primary endpoint of death or BPD (71% versus 74%; P = 0.54). Short‐term benefits included higher rates of successful extubation over the first 14 days of treatment and a reduction in treatment with open‐label steroids (28% versus 57%; P < 0.001), but adverse effects included more hyperglycaemia requiring insulin treatment (18% versus 8%; P = 0.004). At follow‐up, rates of neurodevelopmental impairment, cerebral palsy, and visual and hearing impairment were similar in the two groups, as were combined rates of death or cerebral palsy, or death or neurodevelopmental impairment.

Papile 1998: as infants in the early group were given dexamethasone from 14 days, they can be considered as having been treated late by our definition (> 7 days of age). Upon examination of only 28‐day outcomes, babies in this study's late group can be considered as controls, as they did not receive dexamethasone until after 28 days. Mortality at 28 days was 7/182 in the early group (treated) compared with 16/189 in the late group (controls). Oxygen was required on Day 28 in 141/182 versus 168/189, and the combination of 28‐day mortality or oxygen requirement was evident in 147/182 versus 184/189; the latter was significant (P < 0.001). It is not possible to use long‐term follow‐up data in this meta‐analysis, as all infants were eligible for dexamethasone after 28 days.

Parikh 2013: data show no substantial differences in brain tissue volume between groups. Low‐dose hydrocortisone had little effect on any other reported outcomes, including mortality, BPD, and acute complications. The follow‐up rate of survivors was 86% overall (37/43). Cerebral palsy was diagnosed in 15% (3/20) of survivors in the steroid group and in 6% (1/17) of those in the placebo group. Rates of cognitive and language delay, defined as < 80 on the Bayley III, were 21% versus 47% and 50% versus 59% in steroid and placebo groups, respectively. Rates of cognitive and language delay could not be pooled with others in the meta‐analysis that used earlier versions of the Bayley Scales, because tests and definitions were different. Rates of any neurodevelopmental impairment were similar between the two groups.

Romagnoli 1997: treated infants showed an increase in dynamic respiratory compliance and a decreased incidence of BPD at 28 days of life and at 36 weeks' postmenstrual age. Fewer infants in the dexamethasone group had failed to be extubated by the seventh day (40% versus 87%). Dexamethasone‐treated infants had lower weight gain during treatment and a significantly higher incidence of hypertrophic cardiomyopathy compared with controls. Data show no significant differences between groups regarding incidence of hypertension, sepsis, necrotising enterocolitis, or hyperglycaemia. At follow‐up, data show no significant differences between dexamethasone‐treated and control children for rates of cerebral palsy, blindness, deafness, or intellectual impairment among survivors assessed, or for death or survival with cerebral palsy among those randomised.

Scott 1997: cortisol responses to ACTH were lower in the dexamethasone group than in the placebo group. On Day 28 of life, eight of 10 infants in the dexamethasone group no longer required mechanical ventilation, compared with none of five infants in the placebo group (P = 0.04, as reported by trial authors).

Vento 2004: six dexamethasone‐treated infants and five control infants were extubated within seven days. Data show no significant differences between groups regarding respiratory distress syndrome, patent ductus arteriosus, or severe intraventricular haemorrhage (grade 3 or 4), as well as lower absolute cell counts (P ≤ 0.05) and proportions of polymorphonuclear cells (P < 0.001) in tracheal aspirate fluid in the treated group on Day 7. Treated infants also had an increase in dynamic pulmonary compliance, which was significant compared with the control group at seven days (P < 0.05). We noted no significant differences between groups regarding inspired oxygen concentration but found that infants in the dexamethasone group had significantly lower MAP on Day 7 (P < 0.05).

Vincer 1998: two of 11 dexamethasone‐treated infants died before hospital discharge compared with one of nine control infants. The number of days when infants had apnoeic spells (14 versus 2; P = 0.005) was greater in the dexamethasone‐treated group. Fewer infants in the dexamethasone group had failed to be extubated by the third day (27% versus 100%) or the seventh day (27% versus 100%). Data show a trend towards more retinopathy of prematurity in the dexamethasone group (64% versus 22%; P = 0.064) but similarities in all other outcome variables between groups. At follow‐up among survivors, cerebral palsy was diagnosed in four of nine children in the dexamethasone group and in two of eight controls.

Walther 2003: MAP on the first day of life was higher in the control group than in the dexamethasone group (9.1 versus 7.5 cm H₂O; P < 0.05). More infants in the dexamethasone group were successfully extubated within 7 to 14 days than in the placebo group (P < 0.05). Hyperglycaemia occurred more frequently in the dexamethasone group (P < 0.05), and infants in the control group more often received open‐label dexamethasone (P < 0.05). Incidences of hypertension, sepsis, necrotising enterocolitis, spontaneous gastrointestinal perforation, gastrointestinal bleeding, intraventricular haemorrhage, or periventricular leukomalacia were not significantly different between groups. Similarly, data show no significant differences in duration of ventilation or oxygen, BPD, nor mortality or survival without BPD between groups. Two infants in the control group were discharged home while on oxygen.

Yates 2019: two of the 12 infants in the dexamethasone group had received hydrocortisone prior to study entry, compared with none of 10 infants in the placebo group. In infants who remained in the study seven days after trial entry, five of eight dexamethasone‐treated infants were extubated by Day 7, compared with four of six control infants. Two of 12 dexamethasone‐treated infants died before 36 weeks' postmenstrual age compared with one of 10 control infants; 100% of survivors in both groups had BPD at 36 weeks' postmenstrual age or at discharge (if sooner) (dexamethasone 10/10; placebo 9/9).

Discussion

In this review, we found reductions in mortality at all ages (to 28 days after birth, to 36 weeks' corrected age, to hospital discharge, and at latest reported age) when systemic corticosteroids were started after seven days of age. Both dexamethasone and hydrocortisone contributed to the reduction in mortality, but evidence for either of them alone in reducing mortality was weaker than when they were combined. Systemic corticosteroids show other clear benefits after seven days of age in reducing rates of BPD at 28 days after birth and at 36 weeks' postmenstrual age, and in reducing the combined outcome of mortality or BPD at both time points; these benefits were attributable to dexamethasone ‐ not to hydrocortisone. Systemic corticosteroids also facilitated extubation at multiple time points. These benefits of corticosteroids came at the cost of higher rates of short‐term complications of hypertension, hyperglycaemia, glycosuria, and hypertrophic cardiomyopathy. An increase in severe retinopathy of prematurity was not accompanied by significant increases in blindness or in the need for corrective lenses at follow‐up.

Corticosteroids may have other significant effects. They can cause weight loss or poor weight gain (Ariagno 1987; Harkavy 1989; Ohlsson 1992). Although catchup growth after corticosteroid therapy has been reported (Gibson 1993), worries about reduced brain growth have been noted in animal studies (Gramsbergen 1998; Weichsel 1977), as well as in human studies (Papile 1998). Animal studies have shown abnormal lung growth (Tschanz 1995).

For this review, data on long‐term neurosensory follow‐up were available from 17 studies comprising 1348 randomised infants, but these studies were of varying methodological quality. The significant increase in abnormal neurological examination among those randomised is of potential concern; however, this is tempered by data showing that cerebral palsy and major neurosensory disability, both overall and among survivors, were not significantly increased, and that abnormal neurological examination findings were reported in only four of the 17 follow‐up studies, and among only 200 randomised participants. It should also be noted that some of the studies reporting cerebral palsy as an outcome did so when children were aged less than five years, an age when a diagnosis of cerebral palsy is not certain in all cases (Stanley 1982). Moreover, only one study was designed primarily to test effects of postnatal corticosteroids on adverse long‐term neurosensory outcomes; that study was terminated for futility with < 10% of the projected sample size recruited (Doyle 2006). All studies were underpowered to detect clinically important differences in long‐term neurosensory outcomes. Researchers performing animal studies have expressed concern about possible adverse effects of corticosteroids used at these doses during early postnatal life on the neurodevelopment of very immature infants (Weichsel 1977). Clearly, more information on long‐term outcomes of survivors is needed.

Clinicians must weigh the benefits of acute improvement in respiratory function and increased chances of extubation, along with improved survival, against potential detrimental effects, both metabolic and neurological. Dexamethasone may be a harmful drug for the immature brain, and clinicians must consider limiting its use to situations in which it is essential to achieve weaning from the ventilator. Lower doses and shorter courses should be considered for these infants; the DART study (an RCT of low‐dose, short‐course dexamethasone in ventilator‐dependent infants), which provided a total dose of only 0.89 mg/kg over 10 days, reported short‐term benefits of extubation and reduced respiratory support (Doyle 2006). Additional studies of low‐dose systemic corticosteroids for infants at high risk of developing BPD beyond the first week of life are warranted.

Summary of main results

In this review, we found evidence for reductions in mortality, BPD, and the combined outcome of mortality or BPD, without evidence for an effect on cerebral palsy, or the combined outcome of mortality or cerebral palsy. Whether systemic corticosteroids given starting from seven days of age improve survival free of long‐term neurodevelopmental disability among infants with evolving BPD remains to be confirmed.

Overall completeness and applicability of evidence

Data on in‐hospital outcomes were relatively complete, but data on longer‐term outcomes were incomplete. Results are applicable to ventilator‐dependent infants at high risk of developing BPD.

Quality of the evidence

Review authors assessed the certainty of evidence for five major outcomes: mortality at latest reported age, BPD at 36 weeks, mortality or BPD at 36 weeks, cerebral palsy at latest reported age, and mortality or cerebral palsy at latest reported age (Table 1). We assessed the certainty of evidence for most outcomes as high, except for BPD at 36 weeks, which we downgraded to moderate quality because we noted risk of publication bias in these studies, and for the combined outcome of mortality or BPD at 36 weeks because of moderate heterogeneity, particularly among those treated with dexamethasone. Excluding two studies at higher risk of bias from a sensitivity analysis altered no conclusions.

Potential biases in the review process

Although Embase records are indexed in CENTRAL, we acknowledge that the omission of a search of Embase in 2020 may have reduced the sensitivity of our search.

Agreements and disagreements with other studies or reviews

Evidence showing benefit from systemic corticosteroids started from the age of seven days of age for reducing the rate of mortality among infants with evolving BPD is stronger than in earlier versions of this review (Doyle 2017b). Other main conclusions concerning BPD, extubation, and short‐term complications are consistent with earlier reviews.

Authors' conclusions

Implications for practice.

The condition of the ventilator‐dependent infant with evolving BPD from the age of seven days or later may be at least transiently improved by a course of systemic corticosteroids. High‐quality or moderate‐quality evidence shows that such treatment reduces rates of mortality, BPD, and the combined outcome of mortality or BPD, without evidence of increasing rates of cerebral palsy. However, the methodological quality of studies determining long‐term outcomes is limited: in most reports, surviving children have been assessed predominantly before school age, and no study has been sufficiently powered to detect important adverse long‐term neurodevelopmental outcomes. Given evidence of both benefits and harms of treatment, and limitations of the evidence for long‐term outcomes at present, it appears prudent to reserve the use of late systemic corticosteroids for infants who cannot be weaned from mechanical ventilation via an endotracheal tube from the age of seven days of age, and to minimise the dose and duration of any course of treatment.

Evidence is insufficient to guide the use of late systemic corticosteroids to prevent BPD among infants who are not intubated.

Implications for research.

Studies are needed to examine the lowest safe dose of corticosteroid. One large ongoing placebo‐controlled trial of systemic hydrocortisone in ventilator‐dependent infants beyond the first week after birth may help to establish the role of hydrocortisone, if any, in intubated infants (NCT01353313). Hydrocortisone at more physiological doses should be compared with dexamethasone at lower doses for ventilator‐dependent infants. Studies of other corticosteroids, such as betamethasone or methylprednisolone, might be worthwhile. Review authors have noted a compelling need for long‐term follow‐up studies among all children who have been enrolled in randomised controlled trials of postnatal corticosteroids. Investigators must examine a broad range of adverse neurodevelopmental outcomes, which include major neurosensory (including cerebral palsy, visual and auditory function) as well as cognitive and behavioural outcomes that may be more evident at older ages. New studies should be designed to assess overall risks and benefits of corticosteroids and should be sufficiently powered to detect important adverse long‐term neurodevelopmental sequelae.

Despite increasing use of non‐invasive ventilation, infants still become oxygen‐dependent and may develop BPD. Outcomes of systemic corticosteroids given to infants on non‐invasive ventilation remain to be investigated.

What's new

Date	Event	Description
25 September 2020	New search has been performed	This review updates the existing review "Late (> 7 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants". We have added data from a large study investigating hydrocortisone in ventilator‐dependent infants > 7 days of age (Onland 2019). We have also corrected some minor errors in the previous review. We added data from Yates 2019 as well
25 September 2020	New citation required and conclusions have changed	More available evidence shows a reduction in mortality at all ages from treatment with late systemic corticosteroids

History

Protocol first published: Issue 3, 1998
Review first published: Issue 3, 1998

Date	Event	Description
10 July 2017	New search has been performed	This review updates the existing review "Late (> 7 days) postnatal corticosteroids for chronic lung disease in preterm infants". We have added follow‐up data on early childhood from one Parikh 2016 The short‐term benefits and side effects of postnatal corticosteroids are confirmed. Data from long‐term neurodevelopmental follow‐up are now available for 16 studies; small, non‐significant increases in cerebral palsy or major neurosensory disability were offset by small, non‐significant reductions in mortality. Hence data show little effect of postnatal corticosteroids on the combined outcomes of death with either cerebral palsy or major neurosensory disability
10 July 2017	New citation required but conclusions have not changed	Conclusions remain unchanged
8 January 2014	New citation required but conclusions have not changed	We added a reference for an ongoing randomised controlled trial of hydrocortisone in infants with postnatal age of 7 to 14 days
6 September 2013	New search has been performed	We updated searches on 22 August 2013
7 August 2013	New search has been performed	This review updates the existing review "Late (> 7 days) postnatal corticosteroids for chronic lung disease in preterm infants". The short‐term benefits and side effects of postnatal corticosteroids are confirmed. Data from long‐term neurodevelopmental follow‐up are now available for 15 studies; small, non‐significant increases in cerebral palsy or major neurosensory disability were offset by small, non‐significant reductions in mortality. Hence data show little effect of postnatal corticosteroids on the combined outcomes of death with either cerebral palsy or major neurosensory disability
7 October 2008	New citation required but conclusions have not changed	We prepared substantive updates
7 October 2008	Amended	This review combines and updates the existing reviews "Delayed (> 3 weeks) postnatal corticosteroids for chronic lung disease in preterm infants" and "Moderately early (7‐14 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants", published in the Cochrane Library, Issue 3, 2003 The short‐term benefits and side effects of postnatal corticosteroids are confirmed. Data on long‐term neurodevelopmental follow‐up are now available for 12 studies; small, non‐significant increases in cerebral palsy or major neurosensory disability were offset by small, non‐significant reductions in mortality. Hence data show little effect of postnatal corticosteroids on the combined outcomes of death with either cerebral palsy or major neurosensory disability
1 April 2008	Amended	We have converted this review to the new review format
11 November 2002	New citation required and conclusions have changed	We have made substantive amendments
11 November 2002	New search has been performed	This review updates the existing review "Delayed (> 3 weeks) postnatal corticosteroids for chronic lung disease in preterm infants", published in the Cochrane Library, Issue 2, 2001 We have included additional long‐term neurodevelopmental follow‐up data for Harkavy 1989 (unpublished data provided by investigators) and Ohlsson 1992 (data obtained from Masters of Science thesis). With the addition of these follow‐up data, the previously reported non‐significant trend associating delayed steroid treatment with increased risk of cerebral palsy is somewhat less marked

Appendices

Appendix 1. 2020 search methods

The RCT filters have been created using Cochrane's highly sensitive search strategies for identifying randomised trials (Higgins 2020). The neonatal filters were created and tested by the Cochrane Neonatal Information Specialist.

CENTRAL via CRS Web

Date ranges: 01 January 2016 to 25 September 2020
Terms:
1 MESH DESCRIPTOR Adrenal Cortex Hormones EXPLODE ALL AND CENTRAL:TARGET
2 MESH DESCRIPTOR Steroids EXPLODE ALL AND CENTRAL:TARGET
3 MESH DESCRIPTOR Glucocorticoids EXPLODE ALL AND CENTRAL:TARGET
4 adrenal cortex hormone* OR dexamethasone OR betamethasone OR hydrocortisone OR steroid OR steroids OR corticosteroid* OR prednisolone OR methylprednisolone OR glucocorticoid* AND CENTRAL:TARGET
5 #1 OR #2 OR #3 OR #4
6 MESH DESCRIPTOR Infant, Newborn EXPLODE ALL AND CENTRAL:TARGET
7 infant or infants or infant's or "infant s" or infantile or infancy or newborn* or "new born" or "new borns" or "newly born" or neonat* or baby* or babies or premature or prematures or prematurity or preterm or preterms or "pre term" or premies or "low birth weight" or "low birthweight" or VLBW or LBW or ELBW or NICU AND CENTRAL:TARGET
8 #7 OR #6 AND CENTRAL:TARGET
9 #5 AND #8
10 2016 TO 2020:YR AND CENTRAL:TARGET
11 #10 AND #9

MEDLINE via OVID

Date ranges: 01 January 2016 to 25 September 2020
Terms:
1. exp Adrenal Cortex Hormones/
2. exp Steroids/
3. exp Glucocorticoids/
4. (adrenal cortex hormone* or dexamethasone or betamethasone or hydrocortisone or steroid or steroids or corticosteroid* or prednisolone or methylprednisolone or glucocorticoid*).mp.
5. 1 or 2 or 3 or 4
6. exp infant, newborn/
7. (newborn* or new born or new borns or newly born or baby* or babies or premature or prematurity or preterm or pre term or low birth weight or low birthweight or VLBW or LBW or infant or infants or 'infant s' or infant's or infantile or infancy or neonat*).ti,ab.
8. 6 or 7
9. randomized controlled trial.pt.
10. controlled clinical trial.pt.
11. randomized.ab.
12. placebo.ab.
13. drug therapy.fs.
14. randomly.ab.
15. trial.ab.
16. groups.ab.
17. or/9‐16
18. exp animals/ not humans.sh.
19. 17 not 18
20. 8 and 19
21. randomi?ed.ti,ab.
22. randomly.ti,ab.
23. trial.ti,ab.
24. groups.ti,ab.
25. ((single or doubl* or tripl* or treb*) and (blind* or mask*)).ti,ab.
26. placebo*.ti,ab.
27. 21 or 22 or 23 or 24 or 25 or 26
28. 7 and 27
29. limit 28 to yr="2019 ‐Current"
30. 20 or 29
31. 5 and 30
32. limit 31 to yr="2016 ‐Current"

ISRCTN

Date ranges: 2016 to 2020
Terms:
corticosteroid* within Participant age range: Neonate
"Adrenal Cortex Hormones AND ( Participant age range: Neonate )"
"Glucocorticoid* AND ( Participant age range: Neonate )"
Steroids within Participant age range: Neonate

Appendix 2. 2017 search methods

We used the criteria and standard methods of Cochrane and Cochrane Neonatal.

We conducted a comprehensive search that included the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 1), in the Cochrane Library; MEDLINE via PubMed (January 2013 to 21 February 2017); Embase (January 2013 to 21 February 2017); and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (January 2013 to 21 February 2017), using the following search terms: (adrenal cortex hormones OR dexamethasone OR betamethasone OR hydrocortisone OR steroid OR corticosteroid), plus database‐specific limiters for RCTs and neonates (see below for full search strategies for each database). We did not apply language restrictions.

We searched clinical trials registries for ongoing and recently completed trials (clinicaltrials.gov; World Health Organization International Trial Registry and Platform (www.whoint/ictrp/search/en/); the ISRCTN Registry).

PubMed: ((infant, newborn[MeSH] OR newborn OR neonate OR neonatal OR premature OR low birth weight OR VLBW OR LBW or infan* or neonat*) AND (randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized [tiab] OR placebo [tiab] OR drug therapy [sh] OR randomly [tiab] OR trial [tiab] OR groups [tiab]) NOT (animals [mh] NOT humans [mh]))

Embase: (infant, newborn or newborn or neonate or neonatal or premature or very low birth weight or low birth weight or VLBW or LBW or Newborn or infan* or neonat*) AND (human not animal) AND (randomized controlled trial or controlled clinical trial or randomized or placebo or clinical trials as topic or randomly or trial or clinical trial)

CINAHL: (infant, newborn OR newborn OR neonate OR neonatal OR premature OR low birth weight OR VLBW OR LBW or Newborn or infan* or neonat*) AND (randomized controlled trial OR controlled clinical trial OR randomized OR placebo OR clinical trials as topic OR randomly OR trial OR PT clinical trial)

The Cochrane Library: (infant or newborn or neonate or neonatal or premature or preterm or very low birth weight or low birth weight or VLBW or LBW)

Results Database Searches:

PubMed: 2446
Cinahl: 145
Embase: 1846
Cochrane: 493

Gross: 4930
Duplicates: 852
Net screened: 4078

Results Trial Registry Searches:

clinicaltrials.gov: (21)+(17)+(51)= 89
controlled‐trials.com: (3)+(1 duplicate)+ (0)= 3
WHO: 10Total:  102

Total screened:  4180 (2017 search)

Appendix 3. 2013 search methods

For previous versions of this review, we sought randomised controlled trials of postnatal corticosteroid therapy from the Cochrane Central Register of Controlled Trials (CENTRAL; 2013, Issue 8), MEDLINE (1966 to August 2013), handsearching of paediatric and perinatal journals, and examination of previous review articles and information received from practising neonatologists. We searched MEDLINE using the terms: adrenal cortex hormones or dexamethasone or betamethasone or hydrocortisone or steroids or corticosteroids, limits randomised controlled trials, human, all infant: birth to 23 months. We contacted the authors of all studies, when possible, to confirm details of reported follow‐up studies, or to obtain any information about long‐term follow‐up when none had been reported.

Appendix 4. Risk of bias tool

Sequence generation (checking for possible selection bias). Was the allocation sequence adequately generated?

For each included study, we categorised the method used to generate the allocation sequence as:

• low risk (any truly random process, e.g. random number table; computer random number generator);

• high risk (any non‐random process, e.g. odd or even date of birth; hospital or clinic record number); or

• unclear risk.

Allocation concealment (checking for possible selection bias). Was allocation adequately concealed?

For each included study, we categorised the method used to conceal the allocation sequence as:

• low risk (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);

• high risk (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth); or

• unclear risk.

Blinding of participants and personnel (checking for possible performance bias). Was knowledge of the allocated intervention adequately prevented during the study?

For each included study, we categorised the methods used to blind study participants and personnel from knowledge of which intervention a participant received. We assessed blinding separately for different outcomes or classes of outcomes. We categorised methods as:

• low risk, high risk, or unclear risk for participants; and

• low risk, high risk, or unclear risk for personnel.

Blinding of outcome assessment (checking for possible detection bias). Was knowledge of the allocated intervention adequately prevented at the time of outcome assessment?

For each included study, we categorised the methods used to blind outcome assessment. We assessed blinding separately for different outcomes or classes of outcomes. We categorised the methods as:

• low risk for outcome assessors;

• high risk for outcome assessors; or

• unclear risk for outcome assessors.

Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations). Were incomplete outcome data adequately addressed?

For each included study and for each outcome, we described completeness of data including attrition and exclusions from analysis. We noted whether attrition and exclusions were reported, numbers included in the analysis at each stage (compared with total randomised participants), reasons for attrition or exclusion when reported, and whether missing data were balanced across groups or were related to outcomes. When trial authors reported or supplied sufficient information, we re‐included missing data in the analyses. We categorised methods as:

• low risk (< 20% missing data);

• high risk (≥ 20% missing data); or

• unclear risk.

Selective reporting bias. Are reports of the study free of the suggestion of selective outcome reporting?

For each included study, we described how we investigated the possibility of selective outcome reporting bias and what we found. We assessed the methods as:

• low risk (when it is clear that all of the study's prespecified outcomes and all expected outcomes of interest to the review have been reported);

• high risk (when not all of the study's prespecified outcomes have been reported; one or more reported primary outcomes were not prespecified outcomes of interest and are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported); or

• unclear risk.

Other sources of bias. Was the study apparently free of other problems that could put it at high risk of bias?

For each included study, we described any important concerns we had about other possible sources of bias (e.g. whether there was a potential source of bias related to the specific study design, whether the trial was stopped early owing to some data‐dependent process). We assessed whether each study was free of other problems that could put it at risk of bias as:

• low risk;

• high risk; or

• unclear risk.

If needed, we explored the impact of the level of bias by undertaking sensitivity analyses.

Data and analyses

Comparison 1. Mortality at different ages.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Neonatal mortality before 28 days after birth	7	970	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.39, 0.92]
1.1.1 Dexamethasone	6	599	Risk Ratio (M‐H, Fixed, 95% CI)	0.46 [0.24, 0.86]
1.1.2 Hydrocortisone	1	371	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.43, 1.40]
1.2 Mortality at 36 weeks' postmenstrual age	15	1029	Risk Ratio (M‐H, Fixed, 95% CI)	0.70 [0.52, 0.94]
1.2.1 Dexamethasone	13	594	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.43, 1.08]
1.2.2 Hydrocortisone	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.49, 1.04]
1.3 Mortality to hospital discharge	20	1406	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.63, 0.98]
1.3.1 Dexamethasone	18	971	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.62, 1.10]
1.3.2 Hydrocortisone	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.53, 1.03]
1.4 Mortality at latest reported age	21	1428	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.66, 0.99]
1.4.1 Dexamethasone	19	993	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.66, 1.11]
1.4.2 Hydrocortisone	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.54, 1.02]

Comparison 2. Bronchopulmonary dysplasia (BPD).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 BPD at 28 days after birth	7	994	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.84, 0.95]
2.1.1 Dexamethasone	6	623	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.81, 0.94]
2.1.2 Hydrocortisone	1	371	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.83, 1.04]
2.2 BPD at 36 weeks' postmenstrual age	14	988	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.80, 0.99]
2.2.1 Dexamethasone	12	553	Risk Ratio (M‐H, Fixed, 95% CI)	0.76 [0.66, 0.87]
2.2.2 Hydrocortisone	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.92, 1.31]
2.3 BPD at 36 weeks in survivors	9	624	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.82, 1.01]
2.3.1 Dexamethasone	7	278	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.69, 0.93]
2.3.2 Hydrocortisone	2	346	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.88, 1.17]
2.4 Late rescue with corticosteroids	15	1489	Risk Ratio (M‐H, Fixed, 95% CI)	0.48 [0.41, 0.57]
2.4.1 Dexamethasone	13	1054	Risk Ratio (M‐H, Fixed, 95% CI)	0.46 [0.37, 0.57]
2.4.2 Hydrocortisone	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	0.52 [0.40, 0.67]
2.5 Home on oxygen	7	611	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.54, 0.94]
2.6 Survivors discharged home on oxygen	6	277	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.51, 0.94]

Comparison 3. Mortality or BPD.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Mortality or BPD at 28 days after birth	6	934	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.83, 0.91]
3.1.1 Dexamethasone	5	563	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.79, 0.90]
3.1.2 Hydrocortisone	1	371	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.84, 0.98]
3.2 Mortality or BPD at 36 weeks' postmenstrual age	14	988	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.79, 0.92]
3.2.1 Dexamethasone	12	553	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.67, 0.84]
3.2.2 Hydrocortisone	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.88, 1.09]

Comparison 4. Failure to extubate.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Failure to extubate by 3rd day after treatment	10	764	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.78, 0.88]
4.1.1 Dexamethasone	9	408	Risk Ratio (M‐H, Fixed, 95% CI)	0.76 [0.69, 0.84]
4.1.2 Hydrocortisone	1	356	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.84, 0.98]
4.2 Failure to extubate by 7th day after treatment	17	1130	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.62, 0.73]
4.2.1 Dexamethasone	16	783	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.60, 0.73]
4.2.2 Hydrocortisone	1	347	Risk Ratio (M‐H, Fixed, 95% CI)	0.70 [0.60, 0.82]
4.3 Failure to extubate by 14th day after treatment	5	458	Risk Ratio (M‐H, Fixed, 95% CI)	0.65 [0.53, 0.80]
4.3.1 Dexamethasone	4	124	Risk Ratio (M‐H, Fixed, 95% CI)	0.63 [0.45, 0.90]
4.3.2 Hydrocortisone	1	334	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.51, 0.85]
4.4 Failure to extubate by 28th day after treatment	3	236	Risk Ratio (M‐H, Fixed, 95% CI)	0.58 [0.37, 0.89]

Comparison 5. Complications during primary hospitalisation.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Infection	20	1742	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.91, 1.16]
5.1.1 Dexamethasone	18	1307	Risk Ratio (M‐H, Fixed, 95% CI)	1.14 [0.96, 1.35]
5.1.2 Hydrocortisone	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.73, 1.04]
5.2 Hyperglycaemia	19	1684	Risk Ratio (M‐H, Fixed, 95% CI)	1.59 [1.34, 1.89]
5.2.1 Dexamethasone	17	1249	Risk Ratio (M‐H, Fixed, 95% CI)	1.53 [1.26, 1.85]
5.2.2 Hydrocortisone	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	1.85 [1.23, 2.77]
5.3 Glycosuria	2	48	Risk Ratio (M‐H, Fixed, 95% CI)	8.03 [2.43, 26.52]
5.4 Hypertension	17	1628	Risk Ratio (M‐H, Fixed, 95% CI)	1.67 [1.19, 2.33]
5.4.1 Dexamethasone	15	1193	Risk Ratio (M‐H, Fixed, 95% CI)	2.45 [1.48, 4.06]
5.4.2 Hydrocortisone	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.70, 1.73]
5.5 New cranial echodensities	1	18	Risk Ratio (M‐H, Fixed, 95% CI)	7.00 [0.41, 118.69]
5.6 Necrotising enterocolitis (NEC)	11	1409	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.62, 1.38]
5.6.1 Dexamethasone	9	974	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.54, 1.63]
5.6.2 Hydrocortisone	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.51, 1.63]
5.7 Gastrointestinal bleeding	9	1385	Risk Ratio (M‐H, Fixed, 95% CI)	1.33 [0.97, 1.83]
5.7.1 Dexamethasone	8	1014	Risk Ratio (M‐H, Fixed, 95% CI)	1.38 [0.99, 1.93]
5.7.2 Hydrocortisone	1	371	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.40, 2.74]
5.8 Gastrointestinal perforation	5	552	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.26, 1.70]
5.8.1 Dexamethasone	3	117	Risk Ratio (M‐H, Fixed, 95% CI)	0.36 [0.02, 8.05]
5.8.2 Hydrocortisone	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.27, 1.92]
5.9 Severe retinopathy of prematurity (ROP)	13	929	Risk Ratio (M‐H, Fixed, 95% CI)	1.27 [1.03, 1.58]
5.9.1 Dexamethasone	12	558	Risk Ratio (M‐H, Fixed, 95% CI)	1.38 [1.07, 1.79]
5.9.2 Hydrocortisone	1	371	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.76, 1.59]
5.10 Severe ROP in survivors	10	697	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.94, 1.45]
5.10.1 Dexamethasone	9	416	Risk Ratio (M‐H, Fixed, 95% CI)	1.31 [0.99, 1.74]
5.10.2 Hydrocortisone	1	281	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.69, 1.40]
5.11 Hypertrophic cardiomyopathy	4	238	Risk Ratio (M‐H, Fixed, 95% CI)	2.76 [1.33, 5.74]
5.12 Pneumothorax	3	157	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.53, 1.49]
5.13 Severe intraventricular haemorrhage (IVH)	7	639	Risk Ratio (M‐H, Fixed, 95% CI)	0.54 [0.26, 1.11]
5.13.1 Dexamethasone	6	268	Risk Ratio (M‐H, Fixed, 95% CI)	0.51 [0.23, 1.13]
5.13.2 Hydrocortisone	1	371	Risk Ratio (M‐H, Fixed, 95% CI)	0.70 [0.12, 4.14]
5.14 Cystic periventricular leukomalacia	2	392	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.30, 1.84]
5.14.1 Dexamethasone	1	21	Risk Ratio (M‐H, Fixed, 95% CI)	0.31 [0.01, 6.74]
5.14.2 Hydrocortisone	1	371	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.31, 2.15]

5.5. Analysis.

Comparison 5: Complications during primary hospitalisation, Outcome 5: New cranial echodensities

5.14. Analysis.

Comparison 5: Complications during primary hospitalisation, Outcome 14: Cystic periventricular leukomalacia

Comparison 6. Long‐term follow‐up.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Bayley Mental Developmental Index (MDI) < ‐2 SD	7	333	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.47, 1.38]
6.2 Bayley MDI < ‐2 SD in survivors tested	7	232	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.45, 1.22]
6.3 Bayley Psychomotor Developmental Index (PDI) < ‐2 SD	1	118	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.34, 1.80]
6.4 Bayley PDI < ‐2 SD in survivors tested	1	90	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.30, 1.50]
6.5 Blindness	13	784	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.35, 1.73]
6.5.1 Dexamethasone	12	720	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.35, 1.73]
6.5.2 Hydrocortisone	1	64	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
6.6 Blindness in survivors assessed	13	539	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.35, 1.67]
6.6.1 Dexamethasone	12	502	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.35, 1.67]
6.6.2 Hydrocortisone	1	37	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
6.7 Deafness	9	936	Risk Ratio (M‐H, Fixed, 95% CI)	0.57 [0.26, 1.27]
6.7.1 Dexamethasone	7	501	Risk Ratio (M‐H, Fixed, 95% CI)	0.56 [0.22, 1.44]
6.7.2 Hydrocortisone	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	0.59 [0.13, 2.71]
6.8 Deafness in survivors assessed	9	616	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.29, 1.36]
6.8.1 Dexamethasonep	7	325	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.27, 1.66]
6.8.2 Hydrocortisone	2	291	Risk Ratio (M‐H, Fixed, 95% CI)	0.52 [0.11, 2.36]
6.9 Cerebral palsy at 1 to 3 years of age	16	1311	Risk Ratio (M‐H, Fixed, 95% CI)	1.11 [0.81, 1.52]
6.9.1 Dexamethasone	14	876	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.76, 1.50]
6.9.2 Hydrocortisone	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	1.40 [0.60, 3.26]
6.10 Cerebral palsy at latest reported age	17	1290	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.84, 1.61]
6.10.1 Dexamethasone	15	855	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.79, 1.60]
6.10.2 Hydrocortisone	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	1.40 [0.60, 3.26]
6.11 Mortality before follow‐up in trials assessing cerebral palsy at 1‐3 years of age	16	1746	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.66, 0.93]
6.11.1 Dexamethasone	16	1311	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.65, 0.99]
6.11.2 Hydrocortisone	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.54, 1.02]
6.12 Mortality before follow‐up in trials assessing cerebral palsy at latest reported age	17	1290	Odds Ratio (M‐H, Fixed, 95% CI)	0.73 [0.56, 0.97]
6.12.1 Dexamethasone	15	855	Odds Ratio (M‐H, Fixed, 95% CI)	0.79 [0.55, 1.12]
6.12.2 Hydrocortisone	2	435	Odds Ratio (M‐H, Fixed, 95% CI)	0.67 [0.43, 1.03]
6.13 Mortality or cerebral palsy at 1 to 3 years	16	1311	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.76, 1.04]
6.13.1 Dexamethasone	14	876	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.76, 1.12]
6.13.2 Hydrocortisone	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.62, 1.08]
6.14 Mortality or cerebral palsy at latest reported age	17	1290	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.76, 1.06]
6.14.1 Dexamethasone	15	855	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.77, 1.16]
6.14.2 Hydrocortisone	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.62, 1.08]
6.15 Cerebral palsy in survivors assessed at 1‐3 years of age	16	923	Risk Ratio (M‐H, Fixed, 95% CI)	1.08 [0.79, 1.47]
6.15.1 Dexamethasone	14	631	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.75, 1.47]
6.15.2 Hydrocortisone	2	292	Risk Ratio (M‐H, Fixed, 95% CI)	1.27 [0.55, 2.93]
6.16 Cerebral palsy in survivors assessed at latest age	17	883	Odds Ratio (M‐H, Fixed, 95% CI)	1.17 [0.80, 1.71]
6.16.1 Dexamethasone	15	591	Odds Ratio (M‐H, Fixed, 95% CI)	1.14 [0.75, 1.74]
6.16.2 Hydrocortisone	2	292	Odds Ratio (M‐H, Fixed, 95% CI)	1.29 [0.53, 3.17]
6.17 Major neurosensory disability (variable criteria ‐ see individual studies)	10	1090	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.88, 1.34]
6.17.1 Dexamethasone	8	655	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.85, 1.60]
6.17.2 Hydrocortisone	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.78, 1.35]
6.18 Mortality before follow‐up in trials assessing major neurosensory disability (variable criteria)	10	1090	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.64, 1.00]
6.18.1 Dexamethasone	8	655	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.63, 1.15]
6.18.2 Hydrocortisone	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.54, 1.02]
6.19 Mortality or major neurosensory disability (variable criteria)	10	1090	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.85, 1.08]
6.19.1 Dexamethasone	8	655	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.86, 1.26]
6.19.2 Hydrocortisone	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.75, 1.04]
6.20 Major neurosensory disability (variable criteria) in survivors assessed	10	778	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.83, 1.22]
6.20.1 Dexamethasone	8	480	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.81, 1.50]
6.20.2 Hydrocortisone	2	298	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.73, 1.19]
6.21 Abnormal neurological exam (variable criteria ‐ see individual studies)	4	200	Risk Ratio (M‐H, Fixed, 95% CI)	1.81 [1.05, 3.11]
6.22 Mortality before follow‐up in trials assessing abnormal neurological exam (variable criteria)	4	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.57 [0.33, 0.99]
6.23 Mortality or abnormal neurological exam (variable criteria)	4	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.71, 1.31]
6.24 Abnormal neurological exam (variable criteria) in survivors assessed	4	145	Risk Ratio (M‐H, Fixed, 95% CI)	1.62 [0.96, 2.73]
6.25 Re‐hospitalisation	1	118	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.79, 1.66]
6.26 Re‐hospitalisation in survivors seen at follow‐up	1	92	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.72, 1.34]

6.11. Analysis.

Comparison 6: Long‐term follow‐up, Outcome 11: Mortality before follow‐up in trials assessing cerebral palsy at 1‐3 years of age

6.12. Analysis.

Comparison 6: Long‐term follow‐up, Outcome 12: Mortality before follow‐up in trials assessing cerebral palsy at latest reported age

6.18. Analysis.

Comparison 6: Long‐term follow‐up, Outcome 18: Mortality before follow‐up in trials assessing major neurosensory disability (variable criteria)

6.22. Analysis.

Comparison 6: Long‐term follow‐up, Outcome 22: Mortality before follow‐up in trials assessing abnormal neurological exam (variable criteria)

6.24. Analysis.

Comparison 6: Long‐term follow‐up, Outcome 24: Abnormal neurological exam (variable criteria) in survivors assessed

Comparison 7. Later childhood outcomes.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Recurrent wheezing in survivors examined at 5 years	1	74	Risk Ratio (M‐H, Fixed, 95% CI)	1.47 [0.82, 2.64]
7.2 Use of corrective lenses in survivors examined at 5 years	1	74	Risk Ratio (M‐H, Fixed, 95% CI)	1.61 [0.82, 3.13]
7.3 Use of physical therapy in survivors examined at 5 years	1	74	Risk Ratio (M‐H, Fixed, 95% CI)	1.49 [0.71, 3.11]
7.4 Use of speech therapy in survivors examined at 5 years	1	74	Risk Ratio (M‐H, Fixed, 95% CI)	0.46 [0.21, 1.02]
7.5 Intellectual impairment in survivors tested at 5 or more years	3	254	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.71, 1.52]
7.6 IQ	2	92	Std. Mean Difference (IV, Fixed, 95% CI)	0.08 [‐0.35, 0.51]

7.5. Analysis.

Comparison 7: Later childhood outcomes, Outcome 5: Intellectual impairment in survivors tested at 5 or more years

7.6. Analysis.

Comparison 7: Later childhood outcomes, Outcome 6: IQ

Comparison 8. Respiratory outcomes in childhood ‐ after 5 years.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
8.1 Asthma in survivors assessed	2	213	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.44, 1.16]
8.2 Forced expired volume in 1 second < ‐2 SD	2	187	Risk Ratio (M‐H, Fixed, 95% CI)	0.58 [0.36, 0.94]
8.3 Forced expired volume in 1 second ‐ z‐score	1	124	Mean Difference (IV, Fixed, 95% CI)	0.28 [‐0.14, 0.70]
8.4 Forced expired volume in 1 second ‐ % predicted	3	98	Mean Difference (IV, Fixed, 95% CI)	5.87 [‐1.26, 13.00]
8.5 Forced expired volume in 1 second ‐ standardised mean difference	4	222	Std. Mean Difference (IV, Fixed, 95% CI)	0.29 [0.02, 0.56]
8.6 Forced vital capacity ‐ z‐score	1	120	Mean Difference (IV, Fixed, 95% CI)	0.09 [‐0.31, 0.49]
8.7 Forced vital capacity ‐ % predicted	3	98	Mean Difference (IV, Fixed, 95% CI)	7.77 [1.79, 13.74]
8.8 Forced vital capacity ‐ standardised mean difference	4	218	Std. Mean Difference (IV, Fixed, 95% CI)	0.25 [‐0.02, 0.52]
8.9 FEV₁/FVC %	1	63	Mean Difference (IV, Fixed, 95% CI)	1.00 [‐3.70, 5.70]
8.10 FEV₁/FVC < ‐2 SD	1	63	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.44, 1.77]
8.11 FEF25% -75% ‐ % predicted	1	63	Mean Difference (IV, Fixed, 95% CI)	7.00 [‐5.40, 19.40]
8.12 Positive bronchodilator response	1	55	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.42, 3.23]
8.13 Forced vital capacity < ‐2 SD	2	183	Risk Ratio (M‐H, Fixed, 95% CI)	0.57 [0.24, 1.34]
8.14 Exercise‐induced bronchoconstriction	1	56	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.13, 5.73]

8.1. Analysis.

Comparison 8: Respiratory outcomes in childhood ‐ after 5 years, Outcome 1: Asthma in survivors assessed

8.3. Analysis.

Comparison 8: Respiratory outcomes in childhood ‐ after 5 years, Outcome 3: Forced expired volume in 1 second ‐ z‐score

8.4. Analysis.

Comparison 8: Respiratory outcomes in childhood ‐ after 5 years, Outcome 4: Forced expired volume in 1 second ‐ % predicted

8.6. Analysis.

Comparison 8: Respiratory outcomes in childhood ‐ after 5 years, Outcome 6: Forced vital capacity ‐ z‐score

8.8. Analysis.

Comparison 8: Respiratory outcomes in childhood ‐ after 5 years, Outcome 8: Forced vital capacity ‐ standardised mean difference

8.9. Analysis.

Comparison 8: Respiratory outcomes in childhood ‐ after 5 years, Outcome 9: FEV₁/FVC %

8.10. Analysis.

Comparison 8: Respiratory outcomes in childhood ‐ after 5 years, Outcome 10: FEV₁/FVC < ‐2 SD

8.11. Analysis.

Comparison 8: Respiratory outcomes in childhood ‐ after 5 years, Outcome 11: FEF_{25% -75%} ‐ % predicted

8.12. Analysis.

Comparison 8: Respiratory outcomes in childhood ‐ after 5 years, Outcome 12: Positive bronchodilator response

8.13. Analysis.

Comparison 8: Respiratory outcomes in childhood ‐ after 5 years, Outcome 13: Forced vital capacity < ‐2 SD

8.14. Analysis.

Comparison 8: Respiratory outcomes in childhood ‐ after 5 years, Outcome 14: Exercise‐induced bronchoconstriction

Comparison 9. Growth in childhood.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
9.1 Height ‐ z‐score	2	208	Mean Difference (IV, Fixed, 95% CI)	0.14 [‐0.18, 0.46]
9.2 Height < ‐2 SD	3	229	Risk Ratio (M‐H, Fixed, 95% CI)	0.76 [0.36, 1.60]
9.3 Weight ‐ z‐score	2	207	Mean Difference (IV, Fixed, 95% CI)	0.03 [‐0.35, 0.40]
9.4 Weight < ‐2 SD	2	90	Risk Ratio (M‐H, Fixed, 95% CI)	0.64 [0.17, 2.37]
9.5 Body mass index (BMI) ‐ z‐score	2	205	Mean Difference (IV, Fixed, 95% CI)	0.02 [‐0.34, 0.38]
9.6 BMI < ‐2 SD	1	67	Risk Ratio (M‐H, Fixed, 95% CI)	0.49 [0.13, 1.87]

9.1. Analysis.

Comparison 9: Growth in childhood, Outcome 1: Height ‐ z‐score

9.2. Analysis.

Comparison 9: Growth in childhood, Outcome 2: Height < ‐2 SD

9.3. Analysis.

Comparison 9: Growth in childhood, Outcome 3: Weight ‐ z‐score

9.4. Analysis.

Comparison 9: Growth in childhood, Outcome 4: Weight < ‐2 SD

9.5. Analysis.

Comparison 9: Growth in childhood, Outcome 5: Body mass index (BMI) ‐ z‐score

9.6. Analysis.

Comparison 9: Growth in childhood, Outcome 6: BMI < ‐2 SD

Comparison 10. Blood pressure in childhood.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
10.1 Systolic blood pressure > 95th centile	2	207	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.49, 1.45]
10.2 Systolic blood pressure z‐score	1	67	Mean Difference (IV, Fixed, 95% CI)	0.04 [‐0.43, 0.52]
10.3 Diastolic blood pressure > 95th centile	2	206	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.23, 4.60]
10.4 Diastolic blood pressure z‐score	1	67	Mean Difference (IV, Fixed, 95% CI)	0.01 [‐0.32, 0.34]

10.1. Analysis.

Comparison 10: Blood pressure in childhood, Outcome 1: Systolic blood pressure > 95th centile

10.2. Analysis.

Comparison 10: Blood pressure in childhood, Outcome 2: Systolic blood pressure z‐score

10.3. Analysis.

Comparison 10: Blood pressure in childhood, Outcome 3: Diastolic blood pressure > 95th centile

10.4. Analysis.

Comparison 10: Blood pressure in childhood, Outcome 4: Diastolic blood pressure z‐score

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Ariagno 1987.

Study characteristics
Methods	Double‐blind randomised controlled trial
Participants	34 preterm infants < 1501 grams birth weight, ventilator‐dependent, no weaning from mechanical ventilation at 3 weeks. CXR changes
Interventions	2 regimens were used in this study: 10‐day and 7‐day 10‐day: intravenous dexamethasone 1 mg/kg/d for 4 days followed by 0.5 mg/kg/d for 6 days 7‐day: 1 mg/kg/d for 3 days followed by 0.5 mg/kg/d for 4 days Of 17 dexamethasone‐treated infants, 4 received the 10‐day protocol, and 13 the 7‐day protocol Saline placebos were used during respective treatment periods
Outcomes	Pulmonary function tests Failure to extubate Mortality Hyperglycaemia Hypertension Infection GI bleeding NEC Mortality Time to extubation Rates of weight gain and head growth Need for home oxygen Duration of oxygen ROP CP
Notes	Results in the abstract were updated with complete data provided by investigators in September 2000
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random allocation by pharmacist
Allocation concealment (selection bias)	Low risk	Blinding of randomisation: yes Random allocation by pharmacist
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Use of placebo
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinding of outcome assessment: yes
Incomplete outcome data (attrition bias) All outcomes	Low risk	Complete follow‐up: yes for outcomes measured within the first year; no for later outcomes
Selective reporting (reporting bias)	Unclear risk	Insufficent information
Other bias	Low risk	None

Avery 1985.

Study characteristics
Methods	Randomised controlled trial
Participants	Inclusion: 16 infants < 1500 grams birth weight, age 2 to 6 weeks, with respiratory distress syndrome but at entry radiological signs of BPD of stage 2 or 3 by Northway Classification Exclusions: PDA, congenital heart disease, pneumonia, IV lipids within 24 hours
Interventions	Intravenous dexamethasone 0.5 mg/kg/d every 12 hours intravenously for 3 days, 0.3 mg/kg/d for 3 days decreased by 10% every 3 days Placebo not administered
Outcomes	Pulmonary function tests Extubation within 3 days Mortality Sepsis Hypertension Hyperglycaemia Duration of hospital stay
Notes	—
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Random allocation by opening sealed envelopes. Stratification by birth weight and sequential analysis
Allocation concealment (selection bias)	Low risk	Random allocation by opening sealed envelopes. Stratification by birth weight and sequential analysis Blinding of randomisation: yes
Blinding of participants and personnel (performance bias) All outcomes	High risk	Blinding of intervention: no placebo was used
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Blinding of outcome: uncertain
Incomplete outcome data (attrition bias) All outcomes	Low risk	Complete follow‐up: yes
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported
Other bias	Low risk	None

Brozanski 1995.

Study characteristics
Methods	Double‐blind randomised controlled trial
Participants	Inclusion: 78 infants < 1501 grams who were ventilator‐dependent at 7 days Exclusions: complex congenital anomalies, pulmonary hypoplasia, haemodynamic instability
Interventions	Dexamethasone 0.25 mg/kg/d 12‐hourly for 2 days, repeated every 10 days until 36 weeks' PMA or until ventilator support or supplemental oxygen no longer needed. An occasional dose of study drug was administered as an intramuscular injection when intravenous access was not possible Control infants were given an equivalent volume of saline intravenously twice daily for 3 days
Outcomes	Inspired oxygen concentration Duration of supplemental oxygen Survival without oxygen at 30 days and 34 weeks CLD GI bleeding IVH Death NEC ROP (> stage II) Hyperglycaemia Pulmonary air leak Sepsis Worsening IVH (grade > II)
Notes	—
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random allocation via sealed envelopes kept in the pharmacy. Stratification by sex and birth weight (< 1000 grams vs > 999 grams)
Allocation concealment (selection bias)	Low risk	Random allocation via sealed envelopes kept in the pharmacy. Stratification by sex and birth weight (< 1000 grams vs > 999 grams) Blinding of randomisation: yes
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Blinding of intervention: yes
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinding of outcome: yes
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Complete follow‐up: no; results given for 78 out of 88 enrolled infants
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported
Other bias	Low risk	None

CDTG 1991.

Study characteristics
Methods	Multi‐centre double‐blind randomised controlled trial
Participants	Inclusion: 285 preterm infants from 3 weeks of age with oxygen dependency, with or without mechanical ventilation, whose condition was static or deteriorating over the preceding week Exclusion: major malformation (n = 2)
Interventions	Dexamethasone 0.6 mg/kg/d for 1 week intravenously or orally, with an option to give a second tapering 9‐day course (0.6, 0.4, and 0.2 mg/kg/d for 3 days each) if, after initial improvement, relapse occurred. Matching saline placebo was given intravenously (or orally if no intravenous line) for 1 week
Outcomes	Duration of mechanical ventilation Death, sepsis NEC Pneumothorax Blood pressure Plasma glucose GI bleeding O₂ Hospital stay Cerebral palsy and blindness in survivors as assessed by questionnaires from general practitioners, healthcare visitors, and parents
Notes	Babies could be enrolled if breathing spontaneously
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random allocation via unmarked vials and telephone randomisation. Stratification by clinical centre and by whether or not babies were ventilator‐dependent
Allocation concealment (selection bias)	Low risk	Random allocation via unmarked vials and telephone randomisation. Stratification by clinical centre and by whether or not babies were ventilator‐dependent Blinding of randomisation: yes
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Blinding of intervention: yes
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinding of outcome measurement: yes
Incomplete outcome data (attrition bias) All outcomes	Low risk	Survivors at 3 years were followed up. 14 infants died after discharge, and follow‐up information was available for 209 of the 223 infants (94% follow‐up)
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported
Other bias	Low risk	None

Cummings 1989.

Study characteristics
Methods	Double‐blind randomised controlled trial
Participants	Incluson: 36 2‐week‐old infants < 1251 grams birth weight, < 31 weeks, needing mechanical ventilation and > 29% oxygen at entry Exclusions: PDA, renal failure, sepsis Infants in control group received a saline placebo
Interventions	Dexamethasone 0.5 mg/kg/d for 3 days, 0.3 mg/kg/d for 3 days, then reduced by 10% every 3 days to 0.1 mg/kg/d for 3 days, then alternate days for 2 days or 0.5 mg/kg/d for 3 days, reduced by 50% every 3 days to 0.06 mg/kg/d for 3 days, then alternate days for 7 days
Outcomes	Duration of IPPV Duration of oxygen Duration of hospital stay Rates of pneumothorax Rates of hyperglycaemia Rates of sepsis Rates of GI bleeding Rates of transfusions Rates of ROP Rates of mortality Growth and development
Notes	—
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomised allocation to 1 of 3 groups via a table of random numbers kept in the pharmacy
Allocation concealment (selection bias)	Low risk	Randomised allocation to 1 of 3 groups via a table of random numbers kept in the pharmacy Blinding of randomisation: yes
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Blinding of intervention: yes
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinding of outcome measurement: yes
Incomplete outcome data (attrition bias) All outcomes	Low risk	Complete follow‐up: yes Blinding of outcome measurement: yes
Selective reporting (reporting bias)	Unclear risk	All prespecified outcomes reported
Other bias	Low risk	None

Doyle 2006.

Study characteristics
Methods	Multi‐centre double‐blind randomised controlled trial
Participants	Inclusion: 70 infants at < 28 weeks' gestation or < 1000 grams birth weight, ventilator‐dependent after 7 days Exclusions: congenital neurological defects, chromosomal anomalies, other disorders likely to cause long‐term neurological deficits
Interventions	A 10‐day tapering course of dexamethasone (0.15 mg/kg/d for 3 days, 0.10 mg/kg/d for 3 days, 0.05 mg/kg/d for 2 days, and 0.02 mg/kg/d for 2 days). Total dose of dexamethasone 0.89 mg/kg over 10 days Control infants were given equivalent volumes of normal saline placebo A repeat course of the same blinded drug was allowed at the discretion of attending clinicians
Outcomes	Ventilator settings Oxygen requirements Hyperglycaemia Hypertension Growth BPD (any oxygen at 36 weeks) Severe BPD (> 30% oxygen at 36 weeks' PMA) Mortality Infection NEC GI bleeding PDA ROP Cardiac hypertrophy Cranial ultrasound abnormalities Long‐term follow‐up at 2 years of age for neurological impairments and disabilities, including cerebral palsy, by staff blinded to treatment allocation
Notes	Sample size estimate was 814, but study was stopped early because of slow recruitment
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random allocation was computer‐generated centrally, independent of investigators, except the statistician, and was stratified by centre, with randomly permuted blocks of 2 to 8 infants
Allocation concealment (selection bias)	Low risk	Blinding of randomisation: yes
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Blinding of intervention: yes
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinding of outcome measurement: yes
Incomplete outcome data (attrition bias) All outcomes	Low risk	Complete follow‐up: yes
Selective reporting (reporting bias)	Unclear risk	All prespecified outcomes reported
Other bias	Unclear risk	Early stopping of trial may or may not introduce bias

Durand 1995.

Study characteristics
Methods	Randomised controlled trial
Participants	Inclusion: 43 preterm babies 7 to 14 days old with birth weight 501 grams to 1500 grams, gestational age 24 to 32 weeks, needing mechanical ventilation with < 30% oxygen Exclusions: congenital heart disease, IVH (grade IV), multiple anomalies
Interventions	Intravenous dexamethasone 0.5 mg/kg/d for 3 days, then 0.25 mg/kg/d for 3 days and 0.10 mg/kg for 1 day Control infants were not given a placebo
Outcomes	Pulmonary function tests Inspired oxygen concentration Ventilator settings BPD (36 weeks' PMA) Infection ROP IVH
Notes	—
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Blind drawing of random cards in sealed envelopes
Allocation concealment (selection bias)	Low risk	Yes
Blinding of participants and personnel (performance bias) All outcomes	High risk	Blinding of intervention: no
Blinding of outcome assessment (detection bias) All outcomes	High risk	Blinding of outcome measurement: only for respiratory mechanics
Incomplete outcome data (attrition bias) All outcomes	Low risk	Complete follow‐up
Selective reporting (reporting bias)	Unclear risk	All prespecified outcomes reported
Other bias	Low risk	None

Harkavy 1989.

Study characteristics
Methods	Double‐blind randomised controlled trial
Participants	21 preterm infants with ventilator and O₂ dependency at 30 days
Interventions	Dexamethasone 0.5 mg/kg/d every 12 hours for 2 weeks intravenously or orally Saline placebo given to controls
Outcomes	Inspired oxygen concentration Duration of oxygen Mortality Hypertension Hyperglycaemia Infection ROP
Notes	—
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random allocation in the pharmacy via cards of random numbers
Allocation concealment (selection bias)	Low risk	Allocation concealment: yes
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Blinding of intervention: yes
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinding of outcome: yes
Incomplete outcome data (attrition bias) All outcomes	Low risk	Complete follow‐up: yes
Selective reporting (reporting bias)	Unclear risk	All prespecified outcomes reported
Other bias	Low risk	None

Kari 1993.

Study characteristics
Methods	Multi‐centre double‐blind randomised controlled trial
Participants	Inclusion: 41 preterm infants 10 days old, weighing < 1501 grams with gestational age > 23 weeks, and ventilator‐dependent Exclusions: PDA, sepsis, GI bleeding, major malformation
Interventions	Dexamethasone 0.5 mg/kg/d given intravenously 12‐hourly for 7 days Infants in the control group received normal saline as a placebo
Outcomes	BPD Duration of IPPV Hypertension Hyperglycaemia Sepsis Perforated colon Cryotherapy for ROP
Notes	—
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Random allocation: method not stated
Allocation concealment (selection bias)	Low risk	Allocation concealment: yes
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Blinding of intervention: yes
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinding of outcome measurement: yes
Incomplete outcome data (attrition bias) All outcomes	Low risk	Complete follow‐up: yes
Selective reporting (reporting bias)	Unclear risk	All prespecified outcomes reported
Other bias	Low risk	None

Kazzi 1990.

Study characteristics
Methods	Double‐blind randomised controlled trial
Participants	Inclusion: 23 preterm infants, 3 to 4 weeks old, who weighed < 1500 grams at birth, with radiological findings of BPD and needing mechanical ventilation in > 34% oxygen; failure of medical treatment Exclusions: PDA, pneumonia, sepsis, hypertension
Interventions	Dexamethasone 0.5 mg/kg/d for 3 days, 0.4 mg/kg/d for 2 days, 0.25 mg/kg/d for 2 days, given by nasogastric tube as a single daily dose, then hydrocortisone every 6 hours for 10 days Infants in the control group received equal volumes of saline
Outcomes	Inspired oxygen concentration Ventilator settings Extubation < 9 days Hyperglycaemia Sepsis Hypertension ROP Duration of oxygen Mechanical ventilation Hospital stay
Notes	—
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random allocation achieved by drawing a card prepared from random numbers tables in the pharmacy; stratification for birth weight (< 1000 grams, 1000 grams to 1250 grams, and 1251 grams to 1500 grams)
Allocation concealment (selection bias)	Low risk	Allocation concealment: yes
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Blinding of intervention: yes
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinding of outcome: yes
Incomplete outcome data (attrition bias) All outcomes	Low risk	Complete follow‐up: yes
Selective reporting (reporting bias)	Unclear risk	All prespecified outcomes reported
Other bias	Low risk	None

Kothadia 1999.

Study characteristics
Methods	Double‐blind randomised controlled trial
Participants	118 preterm infants, < 1501 grams, age 15 to 25 days, ventilator‐dependent over 30% oxygen; no PDA, major malformation, HIV, or hepatitis B virus infection
Interventions	42‐day tapering course of dexamethasone or equal volume of normal saline. Dexamethasone 0.25 mg/kg 12‐hourly for 3 days, 0.15 mg/kg 12‐hourly for 3 days, then 10% reduction in dose every 3 days until dose of 0.1 mg/kg had been given for 3 days, from which time 0.1 mg/kg every other day until 42 days after entry
Outcomes	Duration of ventilation Oxygen Hospital stay Death Oxygen at 36 weeks' PMA ROP (stage 3) Infection Hypertension Hyperglycaemia Follow‐up: Bayley MDI and PDI, cerebral palsy, abnormal neurological examination findings
Notes	—
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random allocation within 6 strata according to birth weight (500 grams to 800 grams, 801 grams to 1100 grams, and 1101 grams to 1500 grams) and sex. Method not stated
Allocation concealment (selection bias)	Low risk	Random allocation within 6 strata according to birth weight (500 grams to 800 grams, 801 grams to 1100 grams, and 1101 grams to 1500 grams) and sex. Method not stated Blinding of randomisation: yes
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Blinding of intervention: yes
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinding of outcome: yes
Incomplete outcome data (attrition bias) All outcomes	Low risk	Complete follow‐up: yes for outcomes measured within first year; no for outcomes measured at 5 or more years
Selective reporting (reporting bias)	Unclear risk	All prespecified outcomes reported
Other bias	Low risk	None

Kovacs 1998.

Study characteristics
Methods	Double‐blind randomised controlled trial
Participants	60 ventilator‐dependent infants at < 30 weeks' gestation and < 1501 grams birth weight
Interventions	Dexamethasone given systemically at a dose of 0.25 mg/kg twice daily for 3 days followed by nebulised budesonide 500 µg twice daily for 18 days Control infants received systemic and inhaled saline placebos
Outcomes	Survival to discharge Ventilatory support between 9 and 17 days Supplemental oxygen between 8 and 10 days Pulmonary compliance at 10 days Elastase/albumin ratios in tracheal aspirates Need for rescue dexamethasone Time to extubation Duration of oxygen in survivors BPD at 36 weeks' PMA in survivors Duration of hospital stay
Notes	—
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random allocation in pharmacy, with stratification by gestational age (22 to 26 weeks vs 27 to 29 weeks)
Allocation concealment (selection bias)	Low risk	Allocation concealment: yes
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Blinding of intervention: yes
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinding of outcome measurement: yes
Incomplete outcome data (attrition bias) All outcomes	Low risk	Complete follow‐up: yes
Selective reporting (reporting bias)	Unclear risk	All prespecified outcomes reported
Other bias	Low risk	None

Noble‐Jamieson 1989.

Study characteristics
Methods	Double‐blind randomised controlled trial
Participants	Inclusion: 18 preterm infants over 4 weeks old and needing > 30% oxygen Exclusions: congenital anomalies, infection, gastric erosion, NEC
Interventions	Dexamethasone 0.5 mg/kg/d for 7 days orally or intravenously, 0.25 mg/kg/d for 7 days, 0.1 mg/kg/d for 7 days. Saline placebo given to controls
Outcomes	Inspired oxygen concentration Duration of oxygen Leukocytosis Cranial ultrasound scan
Notes	Spontaneously breathing infants could be enrolled
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Random allocation: method not stated
Allocation concealment (selection bias)	Unclear risk	Blinding of randomisation: not clear
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Blinding of intervention: yes
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinding of outcome measurement: yes
Incomplete outcome data (attrition bias) All outcomes	Low risk	Complete follow‐up: yes
Selective reporting (reporting bias)	Unclear risk	Primary outcome not clearly specified
Other bias	Low risk	None

Ohlsson 1992.

Study characteristics
Methods	Double‐blind randomised controlled trial
Participants	Inclusion: 25 preterm infants, 21 to 35 days old, < 1501 grams birth weight, needing mechanical ventilation > 29% O₂. Chest radiograph consistent with BPD Exclusions: infection, congenital anomaly, PDA, NEC, GI bleeding or perforation
Interventions	Dexamethasone 0.5 mg/kg twice daily for 3 days, followed by 0.25 mg/kg twice daily for 3 days, 0.125 mg/kg twice daily for 3 days, and 0.125 mg/kg once daily for 3 days intravenously Intravenous placebo was not permitted by Ethics Committee. Sham injection of saline was given into the bed in the control group by a physician not involved in respiratory care of the infant or not involved in the study. A band‐aid was affixed to a possible site for intravenous infusion
Outcomes	Extubation < 7 days Change in chest radiograph Blood pressure Full blood picture Perforation of stomach Severe ROP Death
Notes	—
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Random allocation in pharmacy via sealed envelopes
Allocation concealment (selection bias)	Low risk	Allocation concealment: yes
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Blinding of intervention: probably
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinding of outcome: yes
Incomplete outcome data (attrition bias) All outcomes	Low risk	Complete follow‐up: yes
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported
Other bias	Low risk	None

Onland 2019.

Study characteristics
Methods	SToP‐BPD trial is a randomised double‐blind placebo‐controlled multi‐centre study This trial aimed to determine the efficacy and safety of postnatal hydrocortisone administration at moderately early postnatal onset vs placebo in reducing the combined outcome of mortality or BPD at 36 weeks' postmenstrual age in ventilator‐dependent preterm infants
Participants	371 very low birth weight infants (gestational age < 30 weeks and/or birth weight < 1250 grams) who were ventilator‐dependent at postnatal age of 7 to 14 days
Interventions	Hydrocortisone (cumulative dose 72.5 mg/kg) or placebo administered during a 22‐day tapering schedule
Outcomes	Primary outcome Combined outcome mortality or BPD at 36 weeks' postmenstrual age Secondary outcomes Short‐term effects on the pulmonary condition Adverse effects during hospitalisation Long‐term neurodevelopmental sequelae wereassessed at 2 years' corrected gestational age ‐ and are included in the current report Analysis was performed on an intention‐to‐treat basis
Notes	Trial registration number Netherlands Trial Register (NTR): NTR2768 This trial is funded by a Project Grant from the The Netherlands Organisation for Health Research and Development ZonMW Priority Medicines for Children, No. 11‐32010‐02
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated random allocation
Allocation concealment (selection bias)	Low risk	Allocation concealment: yes
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Blinding of intervention: yes
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinding of outcome measurement: yes
Incomplete outcome data (attrition bias) All outcomes	Low risk	Complete follow‐up: yes
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported
Other bias	Low risk	None

Papile 1998.

Study characteristics
Methods	Multi‐centre double‐blind randomised controlled trial
Participants	Inclusion: 371 very low birth weight (501 grams to 1500 grams) infants who were ventilator‐dependent at 2 weeks of age and had respiratory index scores (MAP × FiO₂) ≥ 2.4, which had been increasing or minimally decreasing over the previous 48 hours, or score ≥ 4.0 even if there had been improvement in the preceding 48 hours Exclusions: received steroid treatment after birth, signs of sepsis as judged by treating physician, major congenital anomaly of cardiovascular, pulmonary, or central nervous system
Interventions	Dexamethasone 0.50 mg/kg/d intravenously or orally for 5 days, followed by 0.30 mg/kg/d for 3 days, then 0.14 mg/kg/d for 3 days, and finally 0.06 mg/kg/d for 3 days, making a total period of 2 weeks followed by placebo for 2 weeks Control group did not receive dexamethasone until after 4 weeks. From 2 to 4 weeks, they received a saline placebo
Outcomes	28‐day mortality Need for oxygen at 28 days 28‐day mortality Oxygen at 28 days
Notes	This was described as an early (2 weeks) vs late (4 weeks) dexamethasone study. Infants in the "early" group were considered to have received late steroid treatment according to our definition (> 7 days), whereas infants in the "late" group served as controls for 28‐day outcomes before dexamethasone treatment was started
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random allocation at each centre's pharmacy by the urn method to promote equal distribution of participants between treatment groups
Allocation concealment (selection bias)	Low risk	Allocation concealment: yes
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Blinding of intervention: yes
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinding of outcome measurements: yes
Incomplete outcome data (attrition bias) All outcomes	Low risk	Complete follow‐up: yes
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported
Other bias	Low risk	None

Parikh 2013.

Study characteristics
Methods	Double‐blind randomised controlled trial
Participants	64 infants with birth weight < 1001 grams, ventilator‐dependent between 10 and 21 days of age, with respiratory index ≥ 2 and estimated 75% risk of developing CLD
Interventions	Hydrocortisone total of 17 mg/kg over 7 days (3 mg/kg/d for 4 days, 2 mg/kg/d for 2 days, and 1 mg/kg/d for 1 day). Identical volume saline placebo
Outcomes	Primary outcome Brain tissue volume on MRI at term‐equivalent age Secondary outcomes Mortality BPD Acute complications Outcomes at 18 to 22 months of age, corrected for prematurity, were also reported
Notes	—
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Random allocation by an individual not involved in the study. Exact method of randomisation not described. Birth weight (≤ 750 grams vs 751 grams to 1000 grams) and respiratory index score (2 to 4 vs > 4) strata
Allocation concealment (selection bias)	Low risk	Allocation concealment: yes
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Blinding of intervention: yes
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinding of outcome measurement: yes
Incomplete outcome data (attrition bias) All outcomes	Low risk	Complete follow‐up: yes
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported
Other bias	Low risk	None

Romagnoli 1997.

Study characteristics
Methods	Randomised controlled trial
Participants	30 preterm infants, oxygen‐ and ventilator‐dependent on 10th day, at high risk of BPD by authors' own scoring system (90% risk)
Interventions	Dexamethasone 0.50 mg/kg/d for 6 days, 0.25 mg/kg/d for 6 days, and 0.125 mg/kg/d for 2 days (total dose 4.75 mg/kg) from 10th day intravenously. Control group received no placebo
Outcomes	Failure to extubate at 28 days BPD (28 days of life and 36 weeks' PMA) Infection Hyperglycaemia Hypertension PDA Severe IVH NEC Received late steroids Severe ROP Left ventricular hypertrophy
Notes	—
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Random allocation via numbered sealed envelopes
Allocation concealment (selection bias)	Low risk	Alloocation concealment: yes
Blinding of participants and personnel (performance bias) All outcomes	High risk	Blinding of intervention: no
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinding of outcome measurement: yes
Incomplete outcome data (attrition bias) All outcomes	Low risk	Complete follow‐up: yes
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported
Other bias	Low risk	None

Scott 1997.

Study characteristics
Methods	Double‐blind randomised controlled trial
Participants	15 infants ventilator‐dependent between 11 and 14 days of age with FiO₂ > 0.60
Interventions	Dexamethasone 0.5 mg/kg/d for 2 days, then 0.3 mg/kg/d for 3 days (total dose 1.9 mg/kg) Identical volume saline placebo
Outcomes	Primary outcome Cortisol response to ACTH Secondary outcomes Mortality Acute complications
Notes	—
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random allocation via a random numbers table
Allocation concealment (selection bias)	Unclear risk	Allocation concealment: yes
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Blinding of intervention: yes
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinding of outcome measurement: yes
Incomplete outcome data (attrition bias) All outcomes	Low risk	Complete follow‐up: yes
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported
Other bias	Low risk	None

Vento 2004.

Study characteristics
Methods	Randomised controlled trial
Participants	Inclusion: 20 infants < 1251 grams birth weight and < 33 weeks' gestational age who were oxygen‐dependent on 10th day of life Exclusions: not specified
Interventions	Intravenous dexamethasone 0.50 mg/kg/d for 3 days, 0.25 mg/kg/d for 3 days, and 0.125 mg/kg/d for 1 day (total dose 2.375 mg/kg) Control group received no steroid treatment
Outcomes	Tracheal aspirate fluid cell counts Pulmonary mechanics Extubation during the study PDA IVH (> grade II)
Notes	—
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Random allocation: method not specified
Allocation concealment (selection bias)	Unclear risk	Allocation concealment: unclear
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Blinding of intervention: not clear
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinding of outcome measurements: yes
Incomplete outcome data (attrition bias) All outcomes	Low risk	Complete follow‐up: yes
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported
Other bias	Low risk	None

Vincer 1998.

Study characteristics
Methods	Double‐blind randomised controlled trial
Participants	20 very low birth weight infants who were ventilator‐dependent at 28 days' postnatal age
Interventions	6‐day course of intravenous dexamethasone 0.50 mg/kg/d for 3 days followed by 0.30 mg/kg/d for final 3 days Equal volume of saline placebo
Outcomes	Mortality Median number of days ventilated after treatment Days of apnoeic spells Length of hospital stay Weight and head circumference at 2 years Corrected MDI ROP Cerebral palsy in survivors Blindness in survivors
Notes	Published as an abstract only
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Random assignment: method not stated
Allocation concealment (selection bias)	Low risk	Allocation concealment: yes
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Blinding of intervention: probably
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinding of outcome measurements: yes
Incomplete outcome data (attrition bias) All outcomes	Low risk	Complete follow‐up: yes
Selective reporting (reporting bias)	Unclear risk	Outcomes not clearly specified
Other bias	Low risk	None

Walther 2003.

Study characteristics
Methods	Double‐blind randomised controlled trial
Participants	Inclusion: 36 infants of gestation 24 to 32 weeks and birth weight > 599 grams with respiratory distress syndrome requiring mechanical ventilation with > 29% oxygen or respiratory index (MAP × inspired oxygen) > 1.9 and ventilator rate > 16/min on Days 7 to 14 after birth Exclusions: sepsis, congenital heart disease, hypertension, unstable clinical status (renal failure, grade IV IVH), multiple congenital anomalies
Interventions	14‐day course of dexamethasone (0.20 mg/kg/d for 4 days, 0.15 mg/kg/d for 4 days, 0.10 mg/kg/d for 4 days, and 0.05 mg/kg/d for 2 days). Total dose of dexamethasone 1.9 mg/kg over 14 days Control infants received equivalent amounts of normal saline placebo
Outcomes	Ventilator settings MAP Inspired oxygen concentration Extubation within 7 to 14 days Hyperglycaemia Hypertension Serum cortisol Received late dexamethasone BPD (oxygen at 36 weeks' PMA) Survival without BPD
Notes	—
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random allocation by staff pharmacist, with investigators and clinicians unaware of treatment assignment
Allocation concealment (selection bias)	Low risk	Allocation concealment: yes
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Blinding of intervention: yes
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinding of outcome measurements: yes
Incomplete outcome data (attrition bias) All outcomes	Low risk	Complete follow‐up: yes
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported
Other bias	Low risk	None

Yates 2019.

Study characteristics
Methods	Double‐blind randomised controlled trial
Participants	Inclusion: 22 infants at gestational age < 30 weeks between 10 and 24 days after birth at high risk of BPD (receiving mechanical ventilation via an endotracheal tube with > 29% oxygen and positive end‐expiratory pressure at least 4 cm H₂O), unlikely to be extubated within 48 hours (in clinician's opinion) Exclusions: unlikely to survive, on steroids for lung disease, major malformation, previous abdominal surgery, surgery for PDA, contraindication to corticosteroids
Interventions	Dexamethasone 0.05 mg/kg once daily on Days 1 to 10 after randomisation, then on alternate days (i.e. on Days 12, 14, and 16), Total of 13 doses (total dose of dexamethasone 0.65 mg/kg) Control infants received equivalent amounts of normal saline placebo
Outcomes	Primary outcome Time to extubation for at least 24 hours Secondary outcomes Time to first extubation after first IMP dose (whether or not > 24 hours) Extubation by Day 7 (when the baby remained extubated for at least 24 hours) Extubation by Day 7 (whether or not the baby remained extubated for at least 24 hours) Survival to 36 weeks’ PMA
Notes	Trial stopped due to slow recruitment and lack of funding
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation was managed centrally, with telephone backup available all at times. Randomisation used a minimisation algorithm to ensure balance between trial groups in collaborating hospital, sex, multiple births, gestational age at birth, and existing diuretic therapy for the 24 hours before randomisation. Babies from multiple births were randomised individually
Allocation concealment (selection bias)	Low risk	Allocation concealment: yes
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Blinding of intervention: yes
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinding of outcome measurements: yes
Incomplete outcome data (attrition bias) All outcomes	Low risk	Major endpoint of time to extubation was heavily censored by dropouts for sepsis or for open‐label corticosteroids. Less than 50% contributed to the primary endpoint of time to extubation. However, outcome data were 100% for important outcomes such as mortality or oxygen dependency at 36 weeks' postmenstrual age
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported
Other bias	Low risk	None

ACTH: adrenocorticotropic hormone; BPD: bronchopulmonary dysplasia; CLD: chronic lung disease;CP: cerebral palsy; CXR: chest X‐ray;FiO₂: fraction of inspired oxygen;GI: gastrointestinal; HIV: human immunodeficiency virus; IMP: investigational medical product; IPPV: intermittent positive‐pressure ventilation;IVH: intraventricular haemorrhage;IV: intravenous; MAP: mean airway pressure;MDI: Mental Developmental Index; MRI: magnetic resonance imaging; NEC: necrotising enterocolitis; NTR: Netherlands Trial Register; PDA: patent ductus arteriosus; PDI: Psychomotor Developmental Index; PMA: postmenstrual age; ROP: retinopathy of prematurity.

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Anttila 2005	Early neonatal dexamethasone treatment for prevention of BPD ‐ in "Early (< 7 days) systemic postnatal corticosteroids for preventing bronchopulmonary dysplasia in preterm infants" review (Doyle 2021)
Armstrong 2002	Follow‐up study of 2 different dexamethasone regimens without an untreated control group
Ashton 1994	No clinical outcomes assessed
Baden 1972	Controlled trial of hydrocortisone therapy in infants with respiratory distress syndrome ‐ in "Early (< 7 days) systemic postnatal corticosteroids for preventing bronchopulmonary dysplasia in preterm infants" review (Doyle 2021)
Batton 2012	Feasibility study of early blood pressure management in extremely preterm infants ‐ in "Early (< 7 days) systemic postnatal corticosteroids for preventing bronchopulmonary dysplasia in preterm infants" review (Doyle 2021)
Baud 2016	Included in "Early (< 7 days) systemic postnatal corticosteroids for preventing bronchopulmonary dysplasia in preterm infants" review (Doyle 2021)
Biswas 2003	Pulmonary effects of triiodothyronine (T3) and hydrocortisone (HC) supplementation in preterm infants at less than 30 weeks' gestation ‐ in "Early (< 7 days) systemic postnatal corticosteroids for preventing bronchopulmonary dysplasia in preterm infants" review (Doyle 2021)
Bloomfield 1998	2 different courses of dexamethasone compared; no placebo control group
Bonsante 2007	Randomised placebo‐controlled trial of early low‐dose hydrocortisone in very preterm infants ‐ in "Early (< 7 days) systemic postnatal corticosteroids for preventing bronchopulmonary dysplasia in preterm infants" review (Doyle 2021)
Couser 1992	Dexamethasone given only to facilitate extubation; no long‐term data reported
Cranefield 2004	2 dexamethasone regimens compared without an untreated control group
Durand 2002	2 different courses of dexamethasone compared without a placebo control group
Efird 2005	Randomised controlled trial of prophylactic hydrocortisone supplementation for prevention of hypotension in extremely low birth weight infants ‐ in "Early (< 7 days) systemic postnatal corticosteroids for preventing bronchopulmonary dysplasia in preterm infants" review (Doyle 2021)
Ferrara 1990	Single dose of intravenous dexamethasone given before extubation; no long‐term outcome data reported
Garland 1999	Randomised controlled trial of a 3‐day course of dexamethasone therapy to prevent BPD in ventilated neonates ‐ in "Early (< 7 days) systemic postnatal corticosteroids for preventing bronchopulmonary dysplasia in preterm infants" review (Doyle 2021)
Groneck 1993	No clinical outcomes reported
Halac 1990	Controlled trial of prenatal and postnatal corticosteroid therapy to prevent neonatal necrotising enterocolitis ‐ in "Early (< 7 days) systemic postnatal corticosteroids for preventing bronchopulmonary dysplasia in preterm infants" review (Doyle 2021)
Hochwald 2014	Included in "Early (< 7 days) systemic postnatal corticosteroids for preventing bronchopulmonary dysplasia in preterm infants" review (Doyle 2021)
Kopelman 1999	Single very early dexamethasone dose improves respiratory and cardiovascular adaptation in preterm infants ‐ in "Early (< 7 days) systemic postnatal corticosteroids for preventing bronchopulmonary dysplasia in preterm infants" review (Doyle 2021)
Lauterbach 2006	Included in "Early (< 7 days) systemic postnatal corticosteroids for preventing bronchopulmonary dysplasia in preterm infants" review (Doyle 2021)
Lin 1999	Prevention of BPD in preterm infants by early postnatal dexamethasone therapy ‐ in "Early (< 7 days) systemic postnatal corticosteroids for preventing bronchopulmonary dysplasia in preterm infants" review (Doyle 2021)
Mammel 1983	Randomised trial with a cross‐over design, so that all infants were treated at some time with dexamethasone
Marr 2019	Comparison of 9‐day course of dexamethasone with 42‐day course of dexamethasone ‐ no placebo group
Merz 1999	Dexamethasone started at 7 or 14 days with no placebo control group
Mukhopadhyay 1998	Role of early postnatal dexamethasone in respiratory distress syndrome ‐ in "Early (< 7 days) systemic postnatal corticosteroids for preventing bronchopulmonary dysplasia in preterm infants" review (Doyle 2021)
Ng 2006	Double‐blind randomised controlled study of a stress dose of hydrocortisone for rescue treatment of refractory hypotension in preterm infants ‐ in "Early (< 7 days) systemic postnatal corticosteroids for preventing bronchopulmonary dysplasia in preterm infants" review (Doyle 2021)
Odd 2004	2 dexamethasone regimens compared without an untreated control group
Peltoniemi 2005	Trial of early neonatal hydrocortisone administration for prevention of BPD in high‐risk infants ‐ in "Early (< 7 days) systemic postnatal corticosteroids for preventing bronchopulmonary dysplasia in preterm infants" review (Doyle 2021)
Rastogi 1996	Randomised controlled trial of dexamethasone to prevent BPD in surfactant‐treated infants ‐ in "Early (< 7 days) systemic postnatal corticosteroids for preventing bronchopulmonary dysplasia in preterm infants" review (Doyle 2021)
Romagnoli 1999	Controlled trial of early dexamethasone treatment for prevention of BPD in preterm infants ‐ in "Early (< 7 days) systemic postnatal corticosteroids for preventing bronchopulmonary dysplasia in preterm infants" review (Doyle 2021)
Sanders 1994	2 doses of early intravenous dexamethasone for prevention of BPD in babies with respiratory distress syndrome ‐ in "Early (< 7 days) systemic postnatal corticosteroids for preventing bronchopulmonary dysplasia in preterm infants" review (Doyle 2021)
Shinwell 1996	Early postnatal dexamethasone treatment to prevent BPD in infants with respiratory distress syndrome ‐ in "Early (< 7 days) systemic postnatal corticosteroids for preventing bronchopulmonary dysplasia in preterm infants" review (Doyle 2021)
Sinkin 2000	Early dexamethasone ‐ attempting to prevent BPD ‐ in "Early (< 7 days) systemic postnatal corticosteroids for preventing bronchopulmonary dysplasia in preterm infants" review (Doyle 2021)
Soll 1999	Early postnatal dexamethasone therapy for prevention of BPD ‐ in "Early (< 7 days) systemic postnatal corticosteroids for preventing bronchopulmonary dysplasia in preterm infants" review (Doyle 2021)
Stark 2001	Randomised trial of early dexamethasone to prevent death or BPD in extremely low birth weight infants ‐ in "Early (< 7 days) systemic postnatal corticosteroids for preventing bronchopulmonary dysplasia in preterm infants" review (Doyle 2021)
Subhedar 1997	Open randomised controlled trial of inhaled nitric oxide and early dexamethasone in high‐risk preterm infants ‐ in "Early (< 7 days) systemic postnatal corticosteroids for preventing bronchopulmonary dysplasia in preterm infants" review (Doyle 2021)
Suske 1996	Effects of early postnatal dexamethasone therapy on ventilator dependency in surfactant‐substituted preterm infants ‐ in "Early (< 7 days) systemic postnatal corticosteroids for preventing bronchopulmonary dysplasia in preterm infants" review (Doyle 2021)
Tapia 1998	Early dexamethasone administration for BPD in preterm infants with respiratory distress syndrome ‐ in "Early (< 7 days) systemic postnatal corticosteroids for preventing bronchopulmonary dysplasia in preterm infants" review (Doyle 2021)
Vento 2004a	Early dexamethasone administration to prevent BPD. Study has 2 groups ‐ 1 group started treatment on Day 4 and results are included in "Early (< 7 days) systemic postnatal corticosteroids for preventing bronchopulmonary dysplasia in preterm infants" review (Doyle 2021). The other group started treatment on Day 10 and results are included in the current "Late" review
Wang 1996	Measurement of pulmonary status and surfactant protein levels during dexamethasone treatment for neonatal respiratory distress syndrome ‐ in "Early (< 7 days) systemic postnatal corticosteroids for preventing bronchopulmonary dysplasia in preterm infants" review (Doyle 2021)
Watterberg 1999	Prophylaxis of early adrenal insufficiency to prevent BPD: a multi‐centre trial ‐ in "Early (< 7 days) systemic postnatal corticosteroids for preventing bronchopulmonary dysplasia in preterm infants" review (Doyle 2021)
Watterberg 2004	Prophylaxis of early adrenal insufficiency to prevent BPD: a multi‐centre trial ‐ in "Early (< 7 days) systemic postnatal corticosteroids for preventing bronchopulmonary dysplasia in preterm infants" review (Doyle 2021)
Wilson 1988	Reported only short‐term hormonal changes; no long‐term outcome data
Yeh 1990	Early postnatal dexamethasone therapy for preterm infants with severe respiratory distress syndrome: a double‐blind, controlled study ‐ in "Early (< 7 days) systemic postnatal corticosteroids for preventing bronchopulmonary dysplasia in preterm infants" review (Doyle 2021)
Yeh 1997	Early postnatal dexamethasone therapy for prevention of BPD in preterm infants with respiratory distress syndrome: a multi‐centre clinical trial. ‐ in "Early (< 7 days) systemic postnatal corticosteroids for preventing bronchopulmonary dysplasia in preterm infants" review (Doyle 2021)
Yoder 1991	No clinical outcomes assessed

BPD: bronchopulmonary dysplasia; HC: hydrocortisone; T3: triiodothyronine.

Characteristics of ongoing studies [ordered by study ID]

He 2020.

Study name	Hydrocortisone to treat early bronchopulmonary dysplasia in very preterm infants: study protocol for a randomised controlled trial
Methods	Randomised controlled trial comparing hydrocortisone vs placebo
Participants	Infants between 26 and 30 weeks and 6 days' gestational age with birth weight < 1500 grams who are NOT receiving invasive ventilation at 28 days after birth but who have an oxygen dependency > 30% or are on non‐invasive ventilation support or nasal cannula oxygen > 21%
Interventions	Hydrocortisone 0.5 mg/kg twice a day for 7 days, then 0.5 mg/kg once a day for 3 days (total dose of hydrocortisone 8.5 mg/kg), or equal volume saline placebo
Outcomes	Survival without moderate or severe BPD at 36 weeks' postmenstrual age
Starting date	Listed to start 1 August 2019
Contact information	Christian Wieg, Sichaun, China
Notes	China Clinical Trial Registration Center ChiCTR1900021854. Registered on 13 March 2019

NCT01353313.

Study name	A randomised controlled trial of the effect of hydrocortisone on survival without bronchopulmonary dysplasia and on neurodevelopmental outcomes at 22 to 26 months of age in intubated infants < 30 weeks' gestation age
Methods	Randomised controlled trial comparing hydrocortisone vs placebo
Participants	Infants < 30 weeks' gestational age intubated between 14 and 28 days after birth with high risk of developing BPD
Interventions	Hydrocortisone: 4 mg/kg/d every 6 hours × 2 days, then 2 mg/kg/d every 6 hours × 3 days, then 1 mg/kg/d every 12 hours × 3 days, then 0.5 mg/kg/d as a single dose × 2 days (total dose 18 mg/kg) Equal volume saline placebo
Outcomes	Improvement in survival without physiologically defined moderate to severe BPD Survival without moderate or severe neurodevelopmental impairment at 18 to 22 months' corrected age
Starting date	September 2011. Trial has finished recruitment and follow‐up phase. Results awaited
Contact information	Kristi Watterberg, New Mexico
Notes	clinicaltrials.gov/ct2/show/NCT01353313?term=watterberg+AND+hydrocortisone&rank=1

BPD: bronchopulmonary dysplasia.

Differences between protocol and review

• For the 2021 review we changed the title of the review to "Late (≥ 7 days) systemic postnatal corticosteroids for prevention of BPD in preterm infants" because we realised that two studies that had always been included started treatment at seven days of age precisely

• We added methods, plans for Summary of findings tables, and GRADE recommendations, which were not included in the original protocol. For the 2017 update, we changed the title of the review to "Late (> 7 days) systemic postnatal corticosteroids for prevention of BPD in preterm infants"

• As of July 2019, Cochrane Neonatal no longer searches Embase for its reviews. RCTs and controlled clinical trials (CCTs) from Embase are added to the Cochrane Central Register of Controlled Trials (CENTRAL) via a robust process (see How CENTRAL is created). Cochrane Neonatal has validated its searches to ensure that relevant Embase records are found when CENTRAL is searched (Ovelman 2020)

• Also starting in July 2019, Cochrane Neonatal no longer searches for RCTs and CCTs on the following platforms: ClinicalTrials.gov and World Health Organization’s International Clinical Trials Registry Platform (ICTRP), as records from both platforms are added to CENTRAL on a monthly basis (see How CENTRAL is created). Comprehensive search strategies are executed in CENTRAL to retrieve relevant records. The International Standard Randomized Controlled Trials Number (ISRCTN Registry) (at www.isrctn.com/; formerly Controlled‐trials.com) is searched separately

• Starting in September 2020, Cochrane Neonatal no longer searches for RCTs and quasi‐RCTs from the Cumulative Index to Nursing and Allied Health Literature (CINAHL), as records are identified and added to CENTRAL on a monthly basis through Cochrane's Centralised Search Service project (see How CENTRAL is created at https://www.cochranelibrary.com/central/central-creation#CINAHL%20section)

• For the 2020 update, we ran searches of the following databases: CENTRAL via CRS Web and MEDLINE via OVID. Search strategies are available in Appendix 1. Previous search methods are available in Appendix 2 and Appendix 3

Contributions of authors

Lex Doyle collated data on long‐term neurosensory outcomes. For earlier reviews, he assisted Henry Halliday, Richard Ehrenkranz, and Jeanie Cheong in identifying relevant studies, synthesising data, and writing some of the earlier versions of the review. He identified new studies for the current review.

Jeanie Cheong identified studies in the previous version of the review and has assisted in identifying studies in the most recent literature search, synthesising data, and writing the current version of this review.

Susanne Hay assisted in identifying studies in the most recent literature search, double‐checking and synthesising data, and writing the current version of this review.

Brett Manley assisted in identifying studies in the most recent literature search, double‐checking and synthesising data, and writing the current version of this review.

Henry Halliday identified all studies, synthesised data, wrote earlier versions of this review, and assisted in identifying studies in the most recent literature search, interpreting data, and writing the current version of this review.

Sources of support

Internal sources

• Action Research (UK) Grant to study effects of postnatal steroids, UK

  Action Research (UK) Grant to study effects of postnatal steroids

External sources

• National Health and Medical Research Council, Australia

  Research grant support from National Health and Medical Research Council of Australia

• Vermont Oxford Network, USA

  Cochrane Neonatal Reviews are produced with support from Vermont Oxford Network, a worldwide collaboration of health professionals dedicated to providing evidence‐based care of the highest quality for newborn infants and their families

Declarations of interest

Lex Doyle's institution received Centre of Research Excellence grant funding from the National Health and Medical Research Council (NHMRC) of Australia. He was Chief Investigator of the DART study, a randomised controlled trial of low‐dose, short‐course dexamethasone in ventilator‐dependent infants (Doyle 2006). This study was funded by the NHMRC of Australia.

Jeanie Cheong received a Career Development Fellowship, for salary support, from the Australian Medical Research Future Fund.

Susanne Hay was the PI on a network meta‐analysis of systemic corticosteroids for bronchopulmonary dysplasia, for which her institution received a grant from the Deborah Munroe Noonan Memorial Research Fund. She works as a neonatologist at Beth Israel Deaconess Medical Center.

Brett Manley's institution received funding for a Career Development Fellowship from the Australian Medical Research Future Fund. His institution also received project grant funding from the NHMRC of Australia. He has published articles and review articles on the topic of postnatal steroids in peer‐reviewed journals, and has commented on social media. He works as a Consultant Neonatologist at The Royal Women's Hospital, in Parkville, Victoria, Australia.

Henry Halliday is Joint Editor of Neonatology.

Data from Doyle 2006 were extracted by HLH and Richard Ehrenkranz (deceased).

New search for studies and content updated (conclusions changed)