Systemic corticosteroids for the prevention of bronchopulmonary dysplasia, a network meta‐analysis

Abstract

Background

Despite considerable improvement in outcomes for preterm infants, rates of bronchopulmonary dysplasia (BPD) remain high, affecting an estimated 33% of very low birthweight infants, with corresponding long‐term respiratory and neurosensory issues. Systemic corticosteroids can address the inflammation underlying BPD, but the optimal regimen for prevention of this disease, balancing of the benefits with the potentially meaningful risks of systemic corticosteroids, continues to be a medical quandary.

Numerous studies have shown that systemic corticosteroids, particularly dexamethasone and hydrocortisone, effectively treat or prevent BPD. However, concerning short and long‐term side effects have been reported and the optimal approach to corticosteroid treatment remains unclear.

Objectives

To determine whether differences in efficacy and safety exist between high‐dose dexamethasone, moderate‐dose dexamethasone, low‐dose dexamethasone, hydrocortisone, and placebo in the prevention of BPD, death, the composite outcome of death or BPD, and other relevant morbidities, in preterm infants through a network meta‐analysis, generating both pairwise comparisons between all treatments and rankings of the treatments.

Search methods

We searched the Cochrane Library for all systematic reviews of systemic corticosteroids for the prevention of BPD and searched for completed and ongoing studies in the following databases in January 2023: Cochrane Central Register of Controlled Trials, MEDLINE, Embase, and clinical trial databases.

Selection criteria

We included randomized controlled trials (RCTs) in preterm infants (< 37 weeks’ gestation) at risk for BPD that evaluated systemic corticosteroids (high‐dose [≥ 4 mg/kg cumulative dose] dexamethasone, moderate‐dose [≥ 2 to < 4 mg/kg] dexamethasone, low‐dose [< 2 mg/kg] dexamethasone, or hydrocortisone) versus control or another systemic corticosteroid.

Data collection and analysis

Our main information sources were the systematic reviews, with reference to the original manuscript only for data not included in these reviews. Teams of two paired review authors independently performed data extraction, with disagreements resolved by discussion. Data were entered into Review Manager 5 and exported to R software for network meta‐analysis (NMA). NMA was performed using a frequentist model with random‐effects. Two separate networks were constructed, one for early (< seven days) initiation of treatment and one for late (≥ seven days) treatment initiation, to reflect the different patient populations evaluated. We assessed the certainty of evidence derived from the NMA for our primary outcomes using principles of the GRADE framework modified for application to NMA.

Main results

We included 59 studies, involving 6441 infants, in our analyses.

Only six of the included studies provided direct comparisons between any of the treatment (dexamethasone or hydrocortisone) groups, forcing network comparisons between treatments to rely heavily on indirect evidence through comparisons with placebo/no treatment groups. Thirty‐one studies evaluated early corticosteroid treatment, 27 evaluated late corticosteroid treatment, and one study evaluated both early and late corticosteroid treatments.

Early treatment (prior to seven days after birth):

Benefits:NMA for early treatment showed only moderate‐dose dexamethasone to decrease the risk of BPD at 36 weeks' postmenstrual age (PMA) compared with control (RR 0.56, 95% CI 0.39 to 0.80; moderate‐certainty evidence), although the other dexamethasone dosing regimens may have similar effects compared with control (high‐dose dexamethasone, RR 0.71, 95% CI 0.50 to 1.01; low‐certainty evidence; low‐dose dexamethasone, RR 0.83, 95% CI 0.67 to 1.03; low‐certainty evidence). Other early treatment regimens may have little or no effect on the risk of death at 36 weeks' PMA. Only moderate‐dose dexamethasone decreased the composite outcome of death or BPD at 36 weeks' PMA compared with control (RR 0.77, 95% CI 0.60 to 0.98; moderate‐certainty evidence).

Harms: Low‐dose dexamethasone increased the risk for cerebral palsy (RR 1.92, 95% CI 1.12 to 3.28; moderate‐certainty evidence) compared with control. Hydrocortisone may decrease the risk of major neurosensory disability versus low‐dose dexamethasone (RR 0.65, 95% CI 0.41 to 1.01; low‐certainty evidence).

Late treatment (at seven days or later after birth):

Benefits: NMA for late treatment showed high‐dose dexamethasone to decrease the risk of BPD both versus hydrocortisone (RR 0.66, 95% CI 0.51 to 0.85; low‐certainty evidence) and versus control (RR 0.72, CI 0.59 to 0.87; moderate‐certainty evidence). The late treatment regimens evaluated may have little or no effect on the risk of death at 36 weeks' PMA. High‐dose dexamethasone decreased risk for the composite outcome of death or BPD compared with all other treatments (control, RR 0.69, 95% CI 0.59 to 0.80, high‐certainty evidence; hydrocortisone, RR 0.69, 95% CI 0.58 to 0.84, low‐certainty evidence; low‐dose dexamethasone, RR 0.73, 95% CI 0.60 to 0.88, low‐certainty evidence; moderate‐dose dexamethasone, RR 0.76, 95% CI 0.62 to 0.93, low‐certainty evidence).

Harms: No effect was observed for the outcomes of major neurosensory disability or cerebral palsy.

The evidence for the primary outcomes was of overall low certainty, with notable deductions for imprecision and heterogeneity across the networks.

Authors' conclusions

While early treatment with moderate‐dose dexamethasone or late treatment with high‐dose dexamethasone may lead to the best effects for survival without BPD, the certainty of the evidence is low. There is insufficient evidence to guide this therapy with regard to plausible adverse long‐term outcomes. Further RCTs with direct comparisons between systemic corticosteroid treatments are needed to determine the optimal treatment approach, and these studies should be adequately powered to evaluate survival without major neurosensory disability.

Plain language summary

What are the benefits and risks of different corticosteroid treatments delivered intravenously for the prevention of bronchopulmonary dysplasia in infants born prematurely?

Key messages

· In this review, we used network meta‐analysis (NMA), a relatively new tool that allows comparisons between all relevant treatment options, including those that have not been directly compared with each other in previous clinical trials.

· NMA was able to add a small amount of information to the existing data, most notably with comparisons between the effects of different corticosteroid doses for the prevention of bronchopulmonary dysplasia (BPD) in infants born prematurely.

· The optimal way to deliver corticosteroids remains unknown, as there is not enough evidence on harmful long‐term outcomes to fully guide decision‐making.

What is BPD?

Infants born very prematurely can develop lung injury know as bronchopulmonary dysplasia (BPD), which can have serious and lasting harmful effects.

How can BPD be prevented?

Anti‐inflammatory drugs known as corticosteroids can decrease the development of BPD through their anti‐inflammatory properties, but they also have their own potential risks. The optimal corticosteroid treatment plan to balance these benefits and risks is unknown, including which type of corticosteroid (options include dexamethasone and hydrocortisone), what dose of corticosteroid, and at what age to start treatment.

What did we want to find out?

In this review, we wanted to compare the benefits and risks of different corticosteroid treatment regimens (the type of corticosteroid, dose, and timing) delivered to premature infants systemically, that is through the vein.

What did we do?

We included trials that evaluated corticosteroid treatment in infants born preterm with risk for the development of BPD, and we reported on any of our predefined outcome measures. We included 59 studies, involving 6441 infants, in our analyses. We chose to compare early (before seven days after birth) and late (seven days or more after birth) corticosteroid treatments separately, as these treatments likely address different patient populations.

What did we find?

Of the many different corticosteroid treatment regimens we compared for treating infants born preterm, two different regimens seem to be most beneficial in helping infants survive without developing BPD:

· treatment beginning late, after 7 days of life, with a higher dose of dexamethasone (at or above 4 mg/kg of body weight);

· treatment beginning early, before 7 days of life, with a moderate dose of dexamethasone (at or above 2 mg/kg but below 4 mg/kg of body weight).

More studies are needed comparing these different treatments and considering their long‐term effects.

What are the limitations of the evidence?

Our certainty in the evidence was generally low.

How up to date is this evidence?

We searched for evidence through February 2022.

Background

Description of the condition

Although outcomes for infants born preterm have improved considerably over the years, bronchopulmonary dysplasia (BPD) remains a major cause of neonatal morbidity, affecting approximately one in three very low birthweight infants (Horbar 2012). Affected infants suffer from long‐term pulmonary and neurosensory problems (Anderson 2006; Bhandari 2003; Bhandari 2006).

First described by Northway in 1967, BPD was initially thought to be mainly iatrogenic in nature, secondary to oxygen toxicity and barotrauma from the crude techniques of respiratory support in use at that time (Northway 1967). Today, it is seen in more complex terms. This 'new' BPD is thought to result from limited development of the immature alveolar and vascular systems of preterm lungs (Bhandari 2007; Jobe 2009), and the resultant inflammation as these structures take on the stresses of ex‐utero life, including oxygen exposure and distending pressures to achieve ventilation.

Description of the intervention

Corticosteroids have been a mainstay in the prevention of BPD, as they address the mediating inflammation. Numerous studies have shown that systemic corticosteroids, particularly dexamethasone and hydrocortisone, effectively prevent BPD (Doyle 2021a; Doyle 2021b; Onland 2017). Extremely concerning side effects have been reported, however, including short‐term complications (hypertension, hyperglycemia, gastrointestinal bleeding, gastrointestinal perforation, and sepsis), poor somatic growth, poor brain growth, and serious neurosensory sequelae (Doyle 2021a; Doyle 2021b; Jobe 2009; Onland 2017). This led to recommendations from the American Academy of Pediatrics (AAP) Committee on Fetus and Newborn, strongly cautioning against routine use of corticosteroids in this population (Watterberg 2010).

How the intervention might work

Dexamethasone and hydrocortisone are thought to prevent BPD via potent anti‐inflammatory effects.

Dexamethasone, a corticosteroid with exclusive glucocorticoid action, was the first systemic corticosteroid to be widely adopted for the management of BPD. Once heralded as the 'cure' for BPD, trials demonstrated improvement in respiratory function and successful extubation after treatment (Avery 1985; Cummings 1989; Garland 1999; Rastogi 1996b; Yeh 1990; Yeh 1997). Subsequent evidence demonstrated serious adverse effects of dexamethasone treatment, however, including spontaneous intestinal perforation and cerebral palsy (CP) (Stark 2001). Long‐term risks include chronic suppression of the hypothalamic‐pituitary‐adrenal axis (Karemaker 2008; Rizvi 1992), and long‐term neurosensory impairments (Yeh 1998; Yeh 2004).

Hydrocortisone, a corticosteroid produced by the adrenal glands with near equal glucocorticoid and mineralocorticoid effect, is a less potent and shorter‐acting alternative to dexamethasone for the management of BPD. It is 25 to 50 times less potent, with a half‐life of eight hours, as opposed to the 36 to 54 hour half‐life of dexamethasone (Gupta 2012). It has been studied for replacement in the setting of the immature hypothalamic‐pituitary‐adrenal axis of preterm infants, with early (< 48 hours) use demonstrating that risk of patent ductus arteriosus (PDA) decreased, but survival only increased for infants born in the context of chorioamnionitis or with initially low cortisol levels (Baud 1999; Gupta 2012; Peltoniemi 2005; Watterberg 1995; Watterberg 1999). Concerning side effects have also been reported for hydrocortisone, including short‐term complications (hypertension, hyperglycemia, gastrointestinal bleeding, sepsis), poor somatic and brain growth, and serious neurosensory sequelae (Patra 2015; Peltoniemi 2016).

Why it is important to do this review

Reviews of the extant literature by traditional methods have found insufficient evidence to make a recommendation for any particular systemic corticosteroid for the prevention of BPD, prompting the American Academy of Pediatrics (AAP) to state that “additional RCTs of postnatal glucocorticoids are warranted to optimize therapy and improve outcomes for these infants” (Watterberg 2010).

Aspects of current trial knowledge of the different systemic corticosteroid treatments for BPD are as follows. Earlier management strategies with dexamethasone initiated in the first week after birth are effective in reducing the incidence of BPD, but present risks for significant short‐ and long‐term adverse outcomes (Doyle 2021a). Treatment with systemic corticosteroids after the first week after birth has shown promise for fewer adverse outcomes, but sufficient trial evidence to suggest an optimal dosage regimen (high dose versus low dose, short versus long duration of therapy) to optimize this benefit‐to‐risk ratio is lacking (Doyle 2021b; Onland 2017). Low‐dose dexamethasone therapy (generally < 0.2 mg/kg per day) could be useful in facilitating extubation with fewer short‐term adverse effects than higher doses of dexamethasone (Doyle 2006), but differences in long‐term outcomes remain unclear. Early hydrocortisone therapy (1 mg/kg daily for the first 14 days), especially in cases of perinatal inflammation (such as exposure to chorioamnionitis), may decrease the incidence of BPD with fewer adverse neurosensory effects (Watterberg 2004). A few studies have evaluated hydrocortisone therapy beyond the first week after birth for BPD, with limited benefit observed. There are minimal trial data providing head‐to‐head comparisons between systemic corticosteroid treatment regimens.

While awaiting definitive RCTs, which would require considerable resources and extremely large sample sizes, the tool of network meta‐analysis (NMA) presents an attractive avenue for a greater understanding of the optimal therapy, by building indirect comparisons from existing trial data. Indeed, to our knowledge, two prior groups have recently pursued this approach (Ramaswamy 2021; Zeng 2018). Both groups found superiority of high‐dose dexamethasone for survival without BPD, although these networks combined both early and late treatments. This combination threatens network transitivity, as patients receiving corticosteroids for ventilator dependence beyond the first week after birth are arguably sicker and a distinct population from those receiving treatment in the first days after birth. We attempted to address this issue by building two separate networks for analysis, one for early treatment and one for late treatment.

Objectives

To determine whether differences in efficacy and safety exist between high‐dose dexamethasone, moderate‐dose dexamethasone, low‐dose dexamethasone, hydrocortisone, and placebo in the prevention of BPD, death, the composite outcome of death or BPD, and other relevant morbidities, in preterm infants through a network meta‐analysis, generating both pairwise comparisons between all treatments and rankings of the treatments.

Methods

Criteria for considering studies for this review

Types of studies

We included RCTs, irrespective of language or year of publication. Quasi‐randomized trials were considered, but none were identified. Cluster‐randomized trials and cross‐over trials were not eligible for inclusion.

Types of participants

We included preterm infants (< 37 weeks' gestation) with BPD risk, as determined by individual trials’ inclusion criteria. We assumed that these infants would be equally eligible to be randomized to any of the treatments below.

Types of interventions

We included treatment with systemic corticosteroids (high‐dose dexamethasone, moderate‐dose dexamethasone, low‐dose dexamethasone, or hydrocortisone) versus control (placebo or no treatment) or other corticosteroid preparation (specifically high‐dose dexamethasone, moderate‐dose dexamethasone, low‐dose dexamethasone, or hydrocortisone).

We considered early (initiated prior to seven days after birth) versus late (initiated at seven days after birth or later) treatment separately. We defined high‐dose versus moderate‐dose versus low‐dose dexamethasone relative to 2.0 mg/kg and 4.0 mg/kg cumulative dose cut‐points, as per previous analyses (Onland 2009). We evaluated the included hydrocortisone studies for potential for separation into similar high‐, moderate‐, and low‐dose nodes; however, we decided that such partitioning was not appropriate, given uncertainty for an accurate dose conversion for pulmonary corticosteroids and that the conventional (0.75 mg dexamethasone:20 mg hydrocortisone) dose conversion of hydrocortisone studies would have placed all but one study in the “low‐dose” range of corticosteroid exposure. We determined the threshold of high versus low contamination, or the extent to which infants received corticosteroids outside the RCT parameters, to be at the median (35% in prior literature; Doyle 2005).

Analyses were based on the intended dosing for the trial, which, given the high contamination rates, varied from the doses received. We attempted to account for this study characteristic as well, with the addition of subgroup analysis by dose contamination.

In the network meta‐analysis, nodes were defined by each of the treatments (specifically, high‐dose dexamethasone, moderate‐dose dexamethasone, low‐dose dexamethasone, hydrocortisone, and placebo/no treatment). We did not split or lump nodes in any analysis.

Types of outcome measures

The following outcomes were chosen based on anticipated clinical relevance around the decision for corticosteroid treatment.

Primary outcomes

1. BPD (defined as oxygen supplementation or respiratory support with positive pressure at 36 weeks’ postmenstrual age)

2. Mortality (at 36 weeks' postmenstrual age)

3. Composite outcome of death, from any cause, or BPD (at 36 weeks’ postmenstrual age)

Secondary outcomes

1. Failure to extubate (within seven days of treatment initiation)

2. Cerebral palsy (at latest reported age)

3. Major neurosensory disability (as defined by study authors)

Serious adverse effects

1. Gastrointestinal (GI) perforation

2. Necrotizing enterocolitis

3. Hypertension

4. Growth failure (as defined by the study authors)

5. Infection

Search methods for identification of studies

Electronic searches

Searches were conducted at a number of points between 2016 and February 2022. Searches were limited from 2016 forward based on the rationale that the authors had screened results from three related Cochrane Reviews (Doyle 2021a; Doyle 2021b; Onland 2017). We did not limit searches by language or publication type. The following sources were searched:

• Ovid MEDLINE(R) and Epub Ahead of Print, In‐Process, In‐Data‐Review & Other Non‐Indexed Citations, Daily and Versions 1946 to February 2022;

• Embase (Ovid) 1974 to 2022;

• Cochrane CENTRAL via CRS, January 2022.

Trial registration records were identified using the following:

• US National Library of Medicine, ClinicalTrials.gov;

• World Health Organization International Clinical Trials Registry Platform (apps.who.int/trialsearch);

• ISRCTN Registry.

Search strategies are available in: Appendix 1; Appendix 2; Appendix 3.; Appendix 4.

We considered adverse effects described in included studies only, and therefore did not run separate searches to look for adverse effects.

Searching other resources

We reviewed the reference lists of all identified articles for relevant articles not located in the primary search.

Data collection and analysis

Our main information sources were the systematic reviews, with updates assisted by our team of review authors.

Selection of studies

Two review authors performed study selection (SH, CO). We independently evaluated studies for inclusion in agreement with the inclusion and exclusion criteria. Studies that did not satisfy the criteria were systematically and sequentially excluded. We recorded the reason for exclusion. We resolved disagreements between the reviewers by team consensus.

Data extraction and management

Our study paid attention to meaningful clinical groupings by building separate networks for studies evaluating early (prior to the seventh day after birth) treatment of corticosteroids and for studies evaluating later (at seven days after birth or later), more targeted, application of corticosteroids. Teams of two paired review authors independently performed data extraction for each study (SH, RFS, JZ, MK; when relevant, study authors were never involved in extracting data from their own study). This was performed at the review level, with reference to the original manuscript when items were missing. We included details on intended corticosteroid dosing, the day after birth that corticosteroids were initiated, duration of therapy, and exposure to antenatal corticosteroids, in addition to the assigned trial intervention. We resolved disagreements between the review authors at any stage by discussion and, where we could not reach a decision, a third review author mediated (RFS, JZ) and, when necessary, made the final decision on inclusion. We entered data into Review Manager 5 (Review Manager 2020), exported to R software (R Core Team 2013), and checked it for accuracy.

Outcome data

From each included study, we extracted data on the interventions being compared, and their respective primary and secondary outcomes. All relevant arm‐level data were extracted (e.g. number of events and number of patients for binary outcomes).

Data on potential effect modifiers

From each included study, we extracted the following study interventions and population characteristics that may act as effect modifiers:

1. corticosteroid dosing (intended dose for the trial, including cumulative dose and duration of therapy);

2. the day after birth that corticosteroids were initiated;

3. inclusion of rescue therapy with systemic corticosteroids;

4. respiratory status at time of corticosteroid initiation (whether or not on mechanical ventilation);

5. exposure to antenatal corticosteroids;

6. gestational age;

7. birthweight.

Other data

From each included study, we extracted the following additional information:

1. country or countries in which the study was performed;

2. date of publication and dates of recruitment;

3. type of publication (full‐text publication, abstract publication, unpublished data);

4. trial registration reference.

Assessment of risk of bias in included studies

Risk of bias, or the extent to which a study's results may have deviated from the truth secondary to a systemic flaw in design or execution, had already been determined and published for most included studies by Cochrane Neonatal authors (Doyle 2021a; Doyle 2021b; Onland 2017). Since we evaluated the same or similar outcomes for which this risk of bias was assessed, we incorporated these assessments into our analysis. The only deviations from these original risk of bias assessments were in the rare cases where the Risk of bias tool was found to have been applied inconsistently between the contributing systematic reviews. In these instances, adjustments were made by consensus of four review authors (SH, RS, MK, JZ). For new studies identified and included in this review, we followed the same process of risk of bias assessment, in accordance with the criteria outlined in the Cochrane Handbook for Systematic Reviewsof Interventions (Higgins 2017). This was based on domains anticipated to affect RCT outcomes; specifically, randomization process, deviations from intended interventions, missing outcome data, outcome measurement, and selection of the reported result.

For these new included studies, two review authors (SH, RS) independently assessed the risk of bias (low, high, or unclear) of all included trials using the Cochrane Risk of Bias tool for the following domains (Higgins 2017).

1. Sequence generation (selection bias);

2. Allocation concealment (selection bias);

3. Blinding of participants and personnel (performance bias);

4. Blinding of outcome assessment (detection bias);

5. Incomplete outcome data (attrition bias);

6. Selective reporting (reporting bias);

7. Any other bias.

We resolved any disagreements by discussion. See Appendix 5 for a more detailed description of risk of bias for each domain.

Measures of treatment effect

Relative treatment effects

Each of the outcomes in this review is a dichotomous outcome. As such, for each of our outcomes, we expressed summary estimates for binary endpoints as risk ratios (RRs). We did not evaluate any continuous outcomes. We expressed all pairwise comparisons between interventions with 95% confidence intervals (CI). We summarized these in forest plots, displaying the results from pairwise, indirect, and network (combining direct and indirect) analyses for the comparisons of treatment with systemic corticosteroids (high‐dose dexamethasone, moderate‐dose dexamethasone, low‐dose dexamethasone, or hydrocortisone) versus control (placebo or no treatment) or other corticosteroid preparation.

Relative treatment ranking

We built an overall ranking from these risk ratios (RRs), and calculated corresponding P‐Scores, an index reflecting the degree to which an intervention is superior or inferior to the others, with values ranging from 1 (the best intervention) to 0 (the worst intervention), to explore potential orderings of treatment hierarchy (Salanti 2011).

Unit of analysis issues

Multi‐arm trials

We included multi‐arm trials and accounted for the correlation between the effect estimates in the network meta‐analysis. We treated multi‐arm studies as multiple independent comparisons in pairwise meta‐analyses and these were not combined in any analysis.

Cluster‐randomized trials

Cluster‐randomized trials were not eligible for this review.

Cross‐over trials

Cross‐over trials were not eligible for this review.

Dealing with missing data

For included studies, we noted the levels of attrition. We planned to employ sensitivity analysis to explore the impact of including studies with high levels of missing data in the overall assessment of treatment effect. We defined a high level of missing data as 20% or greater. For all outcomes, we carried out analyses on an intention‐to‐treat basis: that is, we included all participants randomized to each group in the analyses, and all participants were analyzed in the group to which they were allocated, regardless of whether or not they received the allocated intervention. We planned to use the number randomized minus any participants whose outcomes were known to be missing as the denominator for each outcome in each trial.

Assessment of heterogeneity

Assessment of clinical and methodological heterogeneity within treatment comparisons

Our review explored pairwise and network comparisons, with a focus on potential new information available through network comparisons. The heterogeneity for pairwise comparisons was presented visually on forest plots and the percentage of variation that can be attributed to heterogeneity rather than chance using the I² statistic. Heterogeneity for network comparisons was estimated following the random‐effects model. This was reported in CINeMA as part of the credibility evaluation (CINeMA 2017; see Summary of Findings and assessment of the certainty of the evidence section).

Assessment of transitivity across treatment comparisons

We assessed transitivity by comparing the distributions of the potential effect modifiers across different pairwise comparisons. These effect modifiers included corticosteroid dosing (intended dose for the trial, including cumulative dose and duration of therapy), the day after birth that steroids were initiated, inclusion of rescue therapy with systemic corticosteroids, respiratory status at time of corticosteroid initiation (whether or not on mechanical ventilation), exposure to antenatal corticosteroids, gestational age, and birthweight.

Assessment of statistical inconsistency

To assess the global consistency of the network, we applied the design‐by‐treatment interaction model (Higgins 2012; Jackson 2014).

If potential indications of inconsistency were encountered, we explored study characteristics which explained their appearance and undertook sensitivity analyses to address the issue. To assess the impact of covariates on our findings, we planned to explore subgroup analyses or meta‐regression adjustments (or both) (Dias 2012; Salanti 2009). We used comparison‐adjusted funnel plots to explore for the presence of publication bias (Chaimani 2013).

Assessment of reporting biases

We used comparison‐adjusted funnel plots to explore for the presence of publication bias in the primary outcomes (Salanti 2009).

Data synthesis

Methods for direct comparisons

We conducted a standard pairwise meta‐analysis with a random‐effects model using Review Manager 5 to calculate the pooled RR and corresponding 95% CI (Review Manager 2020).

Methods for indirect and network comparisons

We performed the network meta‐analysis within a frequentist framework, using a random‐effects model. We performed all analyses using R statistical software, using the netmeta package (R Core Team 2013).

Subgroup analysis and investigation of heterogeneity

Subgroup analysis

As gestational age and birthweight are known to modify the risk of adverse outcomes, we planned to perform subgroup analyses per these predetermined stratifications to elucidate the impact of baseline risk on treatment effect. For the primary outcomes, we planned the following prespecified subgroup analyses, repeating the above statistical approach for each analysis.

1. Course duration (< 14 days versus ≥ 14 days)

2. Gestational age (< 28 weeks versus ≥ 28 weeks)

3. Birthweight (< 1000 grams versus ≥ 1000 grams)

4. Use of rescue therapy (as above, cut‐point determined around the median)

We planned to assess subgroup differences by first comparing the network diagram for each subgroup, followed by a pairwise and network meta‐analysis for each subgroup, to compare their relative treatment effects and their relative treatment ranking.

Sensitivity analysis

For the primary outcomes, we planned sensitivity analyses for the following.

1. Risk of bias (restricted to low risk of bias studies only).

2. Trial size (restricted to large studies, in recognition of the greater likelihood for small studies than large or multicenter studies to suffer publication bias). The cut‐off for defining a small study can vary between research topics, and we determined the specific cut‐off for this sensitivity analysis based upon the median study size of the included studies.

3. Removing trials with more than 20% missing data for any relevant outcome.

We assessed differences by evaluating the relative effects and assessment of model fit.

Summary of findings and assessment of the certainty of the evidence

The Summary of findings tables present evidence comparing treatment with systemic corticosteroids (high‐dose dexamethasone, moderate‐dose dexamethasone, low‐dose dexamethasone, or hydrocortisone) versus control (placebo or no treatment) or other corticosteroid preparation (specifically high‐dose dexamethasone, moderate‐dose dexamethasone, low‐dose dexamethasone, or hydrocortisone). We defined high‐dose versus moderate‐dose versus low‐dose dexamethasone cut‐points relative to the precedent in previous literature of 2.0 mg/kg and 4.0 mg/kg cumulative dose (Onland 2009).

We separately considered early (prior to the first seven days after birth) versus late (at seven days or later after birth) corticosteroid treatment.

We created Summary of findings tables (Table 1; Table 2) for each primary outcome and the balancing secondary outcome of cerebral palsy. Outcomes in the Summary of findings table included:

1. Summary of findings: early treatment.

Outcome	Effects and confidence in the estimate of effects
	High‐dose dexamethasone		Moderate‐dose dexamethasone		Low‐dose dexamethasone		Hydrocortisone
BPD (at 36 weeks’ PMA)
Placebo/no treatment comparator 308/1000a (31%)	RR 0.71 (0.50 to 1.01)	89 fewer/1000 (154 fewer to 3 more)	RR 0.56 (0.39 to 0.80)	136 fewer/1000 (189 fewer to 62 fewer)	RR 0.83 (0.67 to 1.03)	52 fewer/1000 (102 fewer to 9 more)	RR 0.92 (0.76 to 1.10)	25 fewer/1000 (74 fewer to 31 more)
	Low Confidence in estimateb,c		Moderate Confidence in estimateb		Low Confidence in estimateb,c		Low Confidence in estimateb,c
Rank 5	Rank 2 Based on 592 participants (4 RCTs)		Rank 1 Based on 787 participants (5 RCTs)		Rank 3 Based on 1412 participants (8 RCTs)		Rank 4 Based on 1376 participants (9 RCTs)
Mortality (at 36 weeks’ PMA)
Placebo/no treatment comparator 208/1000a (21%)	RR 1.02 (0.79 to 1.33)	4 more/1000 (44 fewer to 69 more)	RR 1.12 (0.88 to 1.42)	25 more/1000 (25 fewer to 87 more)	RR 1.06 (0.86 to 1.31)	12 more/1000 (29 fewer to 64 more)	RR 0.86 (0.68 to 1.08)	29 fewer/1000 (67 fewer to 17 more)
	Moderate Confidence in estimatec		Moderate Confidence in estimatec		Moderate Confidence in estimatec		Moderate Confidence in estimatec
Rank 2	Rank 3 Based on 592 participants (4 RCTs)		Rank 5 Based on 787 participants (5 RCTs)		Rank 4 Based on 1412 participants (8 RCTs)		Rank 1 Based on 1385 participants (10 RCTs)
Death or BPD (at 36 weeks’ PMA)
Placebo/no treatment comparator 515/1000a (52%)	RR 0.87 (0.71 to 1.05)	67 fewer/1000 (149 fewer to 26 more)	RR 0.77 (0.60 to 0.98)	118 fewer/1000 (206 fewer to 10 fewer)	RR 0.92 (0.78 to 1.08)	41 fewer/1000 (113 fewer to 41 more)	RR 0.89 (0.76 to 1.04)	57 fewer/1000 (124 fewer to 21 more)
	Moderate Confidence in estimatec		Moderate Confidence in estimated		Moderate Confidence in estimatec		Moderate Confidence in estimatec
Rank 5	Rank 2 Based on 662 participants (5 RCTs)		Rank 1 Based on 717 participants (4 RCTs)		Rank 4 Based on 1412 participants (8 RCTs)		Rank 3 Based on 1376 participants (9 RCTs)
Cerebral palsy (at latest reported age)
Placebo/no treatment comparator 74/1000a (7%)	RR 1.56 (0.66 to 3.65)	288 more/1000 (175 fewer to 1365 more)	RR 0.67 (0.11 to 3.87)	170 fewer/1000 (458 fewer to 1478 more)	RR 1.92 (1.12 to 3.28)	62 more/1000 (1174 more to 36 more)	RR 1.07 (0.63 to 1.82)	36 more/1000 (191 fewer to 422 more)
	Moderate Confidence in estimatec		Low Confidence in estimateb,c		Moderate Confidence in estimatec		Moderate Confidence in estimatec
Rank 2	Rank 4 Based on 304 participants (2 RCTs)		Rank 1 Based on 50 participants (1 RCT)		Rank 5 Based on 567 participants (4 RCTs)		Rank 3 Based on 1052 participants (6 RCTs)

Summary of findings table: early

Estimates of effects, credible intervals, and certainty of the evidence for systemic corticosteroids for the treatment of BPD

Population: preterm infants at risk for BPD

Interventions: high‐dose dexamethasone, moderate‐dose dexamethasone, low‐dose dexamethasone, hydrocortisone

Comparison: placebo/no treatment

Settings: NICU

The basis for the assumed risk is provided in the footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% confidence interval).

Confidence rating is based on CINeMA (Nikolakopoulou 2020; Papakonstantinou 2020). However, for the above comparisons, confidence was not downgraded for inability to determine incoherence, as estimates were based on direct evidence.

Rank based on P value

^aBaseline risks obtained from mean baseline risk from included studies.
^bDowngraded by original review authors for suspicion of publication bias.
^cDowngraded for imprecision.
^dDowngraded for heterogeneity.

BPD: bronchopulmonary dysplasia; NICU: neonatal intensive care unit; PMA: postmenstrual age; RCT: randomized controlled trial; RR: risk ratio

2. Summary of findings: late treatment.

Outcome	Effects and confidence in the estimate of effects
	High‐dose dexamethasone		Moderate‐dose dexamethasone		Low‐dose dexamethasone		Hydrocortisone
BPD (at 36 weeks’ PMA)
Placebo/no treatment comparator 594/1000a (59%)	RR 0.72 (0.59 to 0.87)	166 fewer/1000 (244 fewer to 77 fewer)	RR 0.86 (0.67 to 1.10)	83 fewer/1000 (196 fewer to 59 more)	RR 0.91 (0.77 to 1.07)	43 fewer/1000 (137 fewer to 42 more)	RR 1.10 (0.92 to 1.30)	59 more/1000 (48 fewer to 178 more)
	Moderate Confidence in estimateb		Low Confidence in estimateb,c		Low Confidence in estimateb,c		Low Confidence in estimateb,c
Rank 4	Rank 1 Based on 287 participants (5 RCTs)		Rank 2 Based on 240 participants (7 RCTs)		Rank 3 Based on 314 participants (7 RCTs)		Rank 5 Based on 435 participants (2 RCTs)
Mortality (at 36 weeks’ PMA)
Placebo/no treatment comparator 175/1000a (18%)	RR 0.69 (0.34 to 1.39)	54 fewer/1000 (116 fewer to 68 more)	RR 0.80 (0.39 to 1.63)	35 fewer/1000 (107 fewer to 110 more)	RR 1.05 (0.53 to 2.08)	9 more/1000 (82 fewer to 189 more)	RR 0.69 (0.27 to 1.33)	54 fewer/1000 (128 fewer to 58 more)
	Moderate Confidence in estimatec		Moderate Confidence in estimatec		Moderate Confidence in estimatec		Moderate Confidence in estimatec
Rank 5	Rank 2 Based on 287 participants (6 RCTs)		Rank 3 Based on 281 participants (8 RCTs)		Rank 4 Based on 314 participants (7 RCTs)		Rank 1 Based on 435 participants (2 RCTs)
Death or BPD (at 36 weeks’ PMA)
Placebo/no treatment comparator 771/1000a (77%)	RR 0.69 (0.59 to 0.80)	239 fewer/1000 (316 fewer to 154 fewer)	RR 0.91 (0.78 to 1.05)	69 fewer/1000 (170 fewer to 39 more)	RR 0.94 (0.85 to 1.05)	46 fewer/1000 (116 fewer to 39 more)	RR 0.99 (0.89 to 1.10)	8 fewer/1000 (85 fewer to 77 more)
	High Confidence in estimate		Moderate Confidence in estimatec		Moderate Confidence in estimatec		Moderate Confidence in estimatec
Rank 5	Rank 1 Based on 287 participants (5 RCTs)		Rank 2 Based on 240 participants (7 RCTs)		Rank 3 Based on 314 participants (7 RCTs)		Rank 4 Based on 435 participants (2 RCTs)
Cerebral palsy (at latest reported age)
Placebo/no treatment comparator 100/1000a (10%)	RR 1.06 (0.69 to 1.63)	6 more/1000 (32 fewer to 63 more)	RR 1.36 (0.66 to 2.80)	36 more/1000 (34 fewer to 180 more)	RR 0.79 (0.35 to 1.80)	21 fewer/1000 (65 fewer to 80 more)	RR 0.52 (0.10 to 2.83)	48 fewer/1000 (90 fewer to 183 more)
	Moderate Confidence in estimatec		Low Confidence in estimatec,d		Moderate Confidence in estimatec		Moderate Confidence in estimatec
Rank 3	Rank 4 Based on 627 participants (8 RCTs)		Rank 5 Based on 228 participants (7 RCTs)		Rank 2 Based on 275 participants (5 RCTs)		Rank 1 Based on 371 participants (1 RCT)

Summary of findings table: late

Estimates of effects, credible intervals, and certainty of the evidence for systemic corticosteroids for the treatment of BPD

Population: preterm infants at risk for BPD

Interventions: high‐dose dexamethasone, moderate‐dose dexamethasone, low‐dose dexamethasone, hydrocortisone

Comparison: placebo/no treatment

Settings: NICU

The basis for the assumed risk is provided in the footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% confidence interval).

Confidence rating was based on CINeMA [Nikolakopoulou 2020; Papakonstantinou 2020]. However, for the above comparisons, confidence was not downgraded for inability to determine incoherence, as estimates were predominantly based on direct evidence.

Rank based on P values

^aBaseline risks obtained from mean baseline risk from included studies.
^bDowngraded by original review authors for suspicion of publication bias.
^cDowngraded for imprecision.
^dDowngraded for within‐study bias.

BPD: bronchopulmonary dysplasia; NICU: neonatal intensive care unit; PMA: postmenstrual age; RCT: randomized controlled trial; RR: risk ratio.

1. death, from any cause, or bronchopulmonary dysplasia (at 36 weeks' postmenstrual age);

2. bronchopulmonary dysplasia (at 36 weeks' postmenstrual age);

3. mortality (at 36 weeks' postmenstrual age);

4. cerebral palsy (at latest reported age).

GRADE (Guyatt 2008), a standardized and systematic tool to rate the certainty in the evidence and strength of recommendations, was employed by the contributing review authors for the above outcomes. In accordance with the GRADE approach (Higgins 2020), prior review authors (Doyle 2021a; Doyle 2021b; Onland 2017), evaluated the risk of bias. They then assessed the certainty of available direct evidence for each outcome and rated the evidence using the standard GRADE approach. The assessment was conducted based on consideration of:

1. study design limitations (risk of bias);

2. inconsistency;

3. imprecision;

4. indirectness;

5. publication bias.

As GRADE assessments were designed for application to direct evidence, we utilized relatively new methods to apply the above GRADE framework to our network meta‐analysis, to optimize clinical applicability and interpretation (Khalifah 2018). To do so, we used CINeMA (Confidence in Network Meta‐Analysis)—a web tool developed to compute the percentage contribution of each direct contrast to each of the network estimates (CINeMA 2017). We used the CINeMA tool to rate the evidence from each study based on six criteria (Salanti 2014).

1. Within‐study bias;

2. Across‐studies bias;

3. Indirectness;

4. Imprecision;

5. Heterogeneity;

6. Incoherence.

The results of the assessments for each of the six criteria were then mapped to a final rating following the usual GRADE scale as: 'high', 'moderate', 'low', and 'very low.'

Our team of review authors evaluated the certainty rating for the evidence (direct and indirect), and arrived at consensus for each assignment.

For ease of comparison when interpreting the relative effects of all systemic corticosteroids, the Summary of findings tables include the relative effect estimates, absolute effect estimates, certainty judgments, and treatment rankings. Given the ultimate goal of informing medical decision‐making, we chose to present a composite Summary of findings table for each network, instead of presenting each outcome in its own table. This allowed us to display together the top interventions for beneficial and harmful outcomes. These tables were structured based on recent recommendations (Yepes‐Nuñez 2019).

Results

Description of studies

We included 59 studies. Thirty‐one studies evaluated early corticosteroid treatment, 27 evaluated late corticosteroid treatment, and one study evaluated both early and late corticosteroid treatments. Most studies explicitly evaluated infants in the very to extremely low birthweight range (< 1500 grams) or in the very or extremely preterm gestational age range (< 32 weeks), or both. Additionally, most studies included mechanical ventilation as an entry criterion (Table 3; Table 4). One study from our search is awaiting classification, as it was published after our analysis was performed (Watterberg 2022; Characteristics of studies awaiting classification), and one study from our search is ongoing (He 2020; Ongoing studies).

3. Early treatment: included studies.

Study	Comparison	GA range (weeks)	BW range (g)	MV on entry	Time steroids initiated	Initial dosing (mg/kg/d)	Duration (d)	Cumulative dosing (mg/kg)
Anttila 2005	LDD vs Ctrl	≤ 32	500 to 999	Y	< 6 h	0.5	2	1
Baden 1972	Hc vs Ctrl	n/a	n/a	N	< 24 h	25	1	50
Batton 2012	Hc vs Ctrl	23 to 26	n/a	N	< 24 h	1	4	4
Baud 2016	Hc vs Ctrl	24 to 27	n/a	N	< 24 h	1	10	8.5
Biswas 2003	Hc vs Ctrl	≤ 30	n/a	Y	< 9 h	1	7	6
Bonsante 2007	Hc vs Ctrl	24 to 30	500 to 1249	Y	< 48 h	0.5	12	10.5
Efird 2005	Hc vs Ctrl	23 to 29	500 to 1000	N	< 2 h	1	5	5.8
Garland 1999	LDD vs Ctrl	≥ 24	500 to 1500	Y	24 h to 48 h	0.4	3	1.35
Halac 1990	HDD vs Ctrl	≤ 34	≤ 1500	N	< 1 h	2	7	14
Hochwald 2014	Hc vs Ctrl	≤ 30	≤ 1250	N	< 48 h	2	2	7
Kopelman 1999	LDD vs Ctrl	≤ 28	n/a	Y	< 2 h	0.2	1	0.2
Lauterbach 2006	LDD vs Ctrl	n/a	≤ 1500	N	4 d	0.5	3	1.5
Lin 1999	HDD vs Ctrl	n/a	500 to 1999	Y	< 6 h	0.5	28	6.16
Mukhopadhyay 1998	MDD vs Ctrl	≤ 34	≤ 2000	Y	< 6 h	1	3	3
Ng 2006	Hc vs Ctrl	≤ 32	≤ 1500	N	< 7 d	1	5	15
Peltoniemi 2005	Hc vs Ctrl	23 to 30	501 to 1250	Y	< 36 h	2	10	11.5
Rastogi 1996	MDD vs Ctrl	n/a	700 to 1500	Y	< 12 h	0.5	12	3.3
Romagnoli 1999	MDD vs Ctrl	≤ 33	≤ 1251	Y	4 d	0.5	7	2.375
Sanders 1994	LDD vs Ctrl	≤ 30	n/a	Y	12 h to 18 h	1	1	1
Shinwell 1996	LDD vs Ctrl	n/a	500 to 2000	Y	< 12 h	0.5	3	1.5
Sinkin 2000	LDD vs Ctrl	≤ 30	n/a	Y	12 h to 18 h	1	1	1
Soll 1999	MDD vs Ctrl	n/a	501 to 1000	Y	12 h	0.5	12	2.7
Stark 2001	LDD vs Ctrl	n/a	501 to 1000	Y	12 h	0.15	10	0.89
Subhedar 1997	HDD vs Ctrl	≤ 32	n/a	Y	96 h	1	6	4.5
Suske 1996	MDD vs Ctrl	24 to 34	≤ 1500	Y	6 h	0.5	5	2.5
Tapia 1998	MDD vs Ctrl	n/a	700 to 1600	Y	< 36 h	0.5	12	2.79
Vento 2004	MDD vs Ctrl	≤ 33	≤ 1251	Y	4 d	0.5	7	2.375
Wang 1996	HDD vs Ctrl	n/a	1000 to 1999	Y	< 12 h	0.5	21	5.95
Watterberg 1999	Hc vs Ctrl	n/a	500 to 999	Y	< 48 h	1	12	10.5
Watterberg 2004	Hc vs Ctrl	n/a	500 to 999	Y	12 h to 48 h	1	15	13.5
Yeh 1990	HDD vs Ctrl	n/a	700 to 1999	Y	4	1	12	5.52
Yeh 1997	HDD vs Ctrl	n/a	≤ 2000	Y	< 12 h	0.25	28	6.16

BW: birth weight; Ctrl: control; GA: gestational age; Hc: hydrocortisone; HDD: high‐dose dexamethasone; LDD: low‐dose dexamethasone; MDD: moderate‐dose dexamethasone; MV: mechanical ventilation; N: no; n/a: not applicable; Y: yes

4. Late treatment: included studies.

Study	Comparison	GA range (weeks)	BW range (g)	MV on entry	DAB steroids initiated	Initial dosing (mg/kg/d)	Duration (d)	Cumulative dosing (mg/kg)
Ariagno 1987	HDD vs Ctrl	n/a	≤ 1500	Y	21	1	10; 7	7; 5
Avery 1985	HDD vs Ctrl	n/a	≤ 1500	Y	14 to 42	0.5	30	6.21
Brozanski 1995	HDD vs Ctrl	n/a	≤ 1500	Y	7	0.5	3‐day pulse	Varies (1.5/pulse)
CDTG 1991	HDD vs Ctrl	n/a	n/a	N	21	0.6	7	4.2
Cummings 1989a [moderate‐dose vs placebo]	MDD vs Ctrl	≤ 30	≤ 1250	Y	14	0.5	18	3
Cummings 1989b [high‐dose vs placebo]	HDD vs Ctrl	≤ 30	≤ 1250	Y	14	0.5	42	7.9
Cummings 1989c [moderate‐dose vs high‐dose]	MDD vs HDD	≤ 30	≤ 1250	Y	14	0.5	18 or 42	3 or 7.9
Da Silva 2002	LDD vs MDD	n/a	n/a	n/a	7 to 21	0.1 or 0.5	7	0.7 or ∼2.35
Doyle 2006	LDD vs Ctrl	≤ 28	≤ 1000	Y	> 7	0.15	10	0.89
Durand 1995	MDD vs Ctrl	24 to 32	501 to 1500	Y	7 to 14	0.5	7	2.35
Durand 2002	LDD vs MDD	24 to 32	501 to 1500	Y	7 to 14	0.2 or 0.5	7	1 or 2.4
Harkavy 1989	HDD vs Ctrl	n/a	n/a	Y	30	0.5	14	7
Kari 1993	MDD vs Ctrl	≥ 23	≤ 1500	Y	10	0.5	7	7
Kazzi 1990	MDD vs Ctrl	n/a	≤ 1500	Y	21 to 28	0.5	7 d and 10 h	≅ 3.96
Kothadia 1999	HDD vs Ctrl	n/a	≤ 1500	Y	15 to 25	0.5	42	6.91
Kovacs 1998	LDD vs Ctrl	22 to 30	≤ 1500	Y	7	0.5	3	1.5
Malloy 2005	LDD vs MDD	≤ 34	≤ 1500	Y	28	0.08 or 0.5	7	0.56 or 2.7
McEvoy 2004	LDD vs MDD	24 to 32	501 to 1500	Y	7 to 21	0.2 or 0.5	7	1 or 2.4
Noble‐Jamieson 1989	HDD vs Ctrl	n/a	n/a	N	> 28	0.5	21	5.95
Odd 2004	MDD vs HDD	n/a	≤ 1250	Y	7 to 28	0.5	Varies or 42	Varies (median 3.8) or 6.6
Ohlsson 1992	HDD vs Ctrl	n/a	≤ 1500	Y	21 to 35	1	12	5.625
Onland 2019	Hc vs Ctrl	≤ 30	≤ 1250	Y	7 to 14	5	22	72.5
Papile 1998	MDD vs Ctrl	n/a	501 to 1500	Y	13 to 15	0.5	14	3.25
Parikh 2013	Hc vs Ctrl	n/a	≤ 1000	Y	10 to 21	3	7	17
Romagnoli 1997	HDD vs Ctrl	n/a	n/a	Y	10	0.5	14	4.75
Scott 1997	MDD vs Ctrl	n/a	n/a	Y	11 to 14	0.5	5	1.9
Vento 2004	MDD vs Ctrl	≤ 33	≤ 1250	Y	10	0.5	7	2.375
Vincer 1998	MDD vs Ctrl	n/a	< 1500	Y	28	0.5	6	2.4
Walther 2003	LDD vs Ctrl	24 to 32	≥ 600	Y	7 to 14	0.2	14	1.9
Yates 2019	LDD vs Ctrl	≤ 30	n/a	Y	10 to 21	0.05	13	0.65

BW: birth weight; Ctrl: control; DAB: day after birth; GA: gestational age; Hc: hydrocortisone; HDD: high‐dose dexamethasone; LDD: low‐dose dexamethasone; MDD: moderate‐dose dexamethasone; MV: mechanical ventilation; N: no; n/a: not applicable; Y: yes

Importantly, only six of the included studies provided direct comparisons between any of the treatment (dexamethasone or hydrocortisone) groups, forcing network comparisons between treatments to rely heavily on indirect evidence through comparisons with placebo/no treatment groups (Figure 1; Figure 2; Figure 3; Figure 4; Figure 5; Figure 6).

1.

Network plot for early systemic steroid treatment with the outcome of BPD. Nodes represent different interventions, and node‐size is proportional to the number of studies included in the analysis. Edge width (the thickness of the lines connecting the nodes) is proportional to the number of comparisons.

2.

Network plot for early systemic steroid treatment with the outcome of death

3.

Network plot for early systemic steroid treatment with the composite outcome of death or BPD

4.

Network plot for late systemic steroid treatment with the outcome of BPD

5.

Network plot for late systemic steroid treatment with the outcome of death

6.

Network plot for late systemic steroid treatment with the composite outcome of death or BPD

Results of the search

Searches identified 5615 references (5548 from database searching; 67 via other methods) (Figure 7). After removing 1250 duplicates, 4365 were available for screening. We excluded 4228 based on title/abstract and reviewed 137 full‐text articles. We included 59 studies (reported in 124 publications) (Characteristics of included studies). We excluded seven full‐text articles (reported in 10 publications) (Characteristics of excluded studies); placed one in awaiting classification (reported in two publications) (Studies awaiting classification); and identified one ongoing study (Characteristics of ongoing studies).

7.

Study flow diagram

Included studies

Ultimately, 59 studies (involving 6441 infants) were included in the final network meta‐analyses (see Characteristics of included studies tables). One study was a multi‐arm trial which included infants randomly assigned to one of three dosage regimens; this was split into three comparisons for the purposes of our analysis (Cummings 1989; Cummings 1989a [moderate‐dose vs placebo]; Cummings 1989b [high‐dose vs placebo]; Cummings 1989c [moderate‐dose vs high‐dose]). Studies were conducted in hospital settings across multiple continents, although mostly in North America and Europe. Most studies evaluated infants < 32 weeks' gestational age or infants < 1500 grams birthweight and were restricted to infants on mechanical ventilation.

Excluded studies

We excluded seven studies for not providing relevant comparisons for our predetermined networks and cut‐points (for example, comparing high‐dose dexamethasone to high‐dose dexamethasone when the high‐dose cut‐point of 4.0 mg/kg cumulative dosing was applied) (for details see Characteristics of excluded studies).

Risk of bias in included studies

No studies were judged as having high risk of bias, and 12 studies were determined to have an overall moderate risk of bias (Avery 1985; Durand 1995; Hochwald 2014; Lauterbach 2006; Mukhopadhyay 1998; Odd 2004; Romagnoli 1997; Romagnoli 1999; Subhedar 1997; Suske 1996; Vento 2004; Vincer 1998; Figure 8; Figure 9). The most frequent bias risk encountered was lack of blinding (Figure 10; Figure 11; Figure 12; Figure 13; Figure 14; Figure 15; Figure 16; Figure 17).

8.

Risk of bias graph: review authors' judgments about each risk of bias item presented as percentages across all included studies

9.

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

10.

Risk of bias contributions, BPD with early treatment.

Figure produced via CINeMA webtool to depict risk of bias contributions by network comparison. Green indicates low risk of bias; yellow indicates unclear risk of bias; and red indicates high risk of bias.

11.

Risk of bias contributions, death with early treatment.

Figure produced via CINeMA webtool to depict risk of bias contributions by network comparison. Green indicates low risk of bias; yellow indicates unclear risk of bias; and red indicates high risk of bias.

12.

Risk of bias contributions, death or BPD with early treatment.

Figure produced via CINeMA webtool to depict risk of bias contributions by network comparison. Green indicates low risk of bias; yellow indicates unclear risk of bias; and red indicates high risk of bias.

13.

Risk of bias contributions, CP with early treatment.

Figure produced via CINeMA webtool to depict risk of bias contributions by network comparison. Green indicates low risk of bias; yellow indicates unclear risk of bias; and red indicates high risk of bias.

14.

Risk of bias contributions, BPD with late treatment.

Figure produced via CINeMA webtool to depict risk of bias contributions by network comparison. Green indicates low risk of bias; yellow indicates unclear risk of bias; and red indicates high risk of bias.

15.

Risk of bias contributions, death with late treatment.

Figure produced via CINeMA webtool to depict risk of bias contributions by network comparison. Green indicates low risk of bias; yellow indicates unclear risk of bias; and red indicates high risk of bias.

16.

Risk of bias contributions, death or BPD with late treatment.

Figure produced via CINeMA webtool to depict risk of bias contributions by network comparison. Green indicates low risk of bias; yellow indicates unclear risk of bias; and red indicates high risk of bias.

17.

Risk of bias contributions, CP with late treatment.

Figure produced via CINeMA webtool to depict risk of bias contributions by network comparison. Green indicates low risk of bias; yellow indicates unclear risk of bias; and red indicates high risk of bias.

Allocation

We judged the following studies as having unclear random sequence generation: Anttila 2005; Avery 1985; CDTG 1991; Da Silva 2002; Durand 1995; Kari 1993; Kopelman 1999; Lin 1999; Ohlsson 1992; Parikh 2013; Peltoniemi 2005; Romagnoli 1997; Sanders 1994; Sinkin 2000; Soll 1999; Suske 1996; Tapia 1998; Vincer 1998; Wang 1996; Yeh 1990; Yeh 1997.

We judged the following studies as having unclear allocation concealment: Lauterbach 2006; Papile 1998.

We judged following studies as having both unclear random sequence generation and unclear allocation concealment: Da Silva 2002; Durand 2002; Hochwald 2014; Mukhopadhyay 1998; Noble‐Jamieson 1989; Vento 2004.

We judged all other studies as having a low risk of bias in this domain.

Blinding

We judged the following studies as having a high risk of bias for blinding either of participants and personnel or outcome assessment or both: Avery 1985; Durand 1995; Durand 2002; Lauterbach 2006; Mukhopadhyay 1998; Odd 2004; Romagnoli 1997; Romagnoli 1999; Subhedar 1997; Suske 1996.

We judged the following studies as having an unclear risk of bias for blinding of either partipants and personnel or outcome assessment or both: Hochwald 2014; Ohlsson 1992; Vento 2004; Vincer 1998.

We judged all other studies as having a low risk of bias in this domain.

Incomplete outcome data

We judged the following studies as having a high risk of bias for incomplete outcome reporting: Malloy 2005; McEvoy 2004.

We judged the following studies as having an unclear risk of bias for incomplete outcome reporting: Brozanski 1995; Da Silva 2002; Durand 2002.

We judged all other studies as having a low risk of bias in this domain.

Selective reporting

We judged the following studies as having an unclear risk of bias for selective reporting: Ariagno 1987; Batton 2012; Da Silva 2002; Hochwald 2014; Noble‐Jamieson 1989; Vincer 1998.

We judged all other studies as having a low risk of bias in this domain.

Other potential sources of bias

We have rated some studies as having an unclear risk of other bias: Baud 2016 (stopped early due to lack of funding); Doyle 2006 (stopped early due to slow recruitment); Stark 2001 (stopped early due to unanticipated adverse events); Watterberg 2004 (stopped early due to increased incidence of apparently spontaneous GI perforation in the hydrocortisone group); Malloy 2005 (no report of funding source); Soll 1999 (published as an extended abstract and presented at a clinical meeting, not as a journal article).

We judged all other studies as having a low risk of bias in this domain.

Effects of interventions

Forest plots of evaluated data (largely represented in contributing Cochrane Neonatal reviews) are included here, with subgroups retained even if no data were available for analysis. Data for our network meta‐analyses are presented below.

Early (< seven days) treatment

Primary outcomes

BPD at 36 weeks' PMA

Twenty‐six studies, representing 4167 infants, provided information on the primary outcome of BPD (Anttila 2005; 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; Tapia 1998; Watterberg 1999; Watterberg 2004; Yeh 1997). Only moderate‐dose dexamethasone decreased the risk of BPD compared with placebo (RR 0.56, 95% CI 0.39 to 0.80; I² = 41.40%, 95% CI 3.70% to 64.40%; moderate‐certainty evidence; Figure 18). The two other dosing regimens for dexamethasone may decrease the risk of BPD compared with placebo (high‐dose dexamethasone, RR 0.71, 95% CI 0.50 to 1.01, low‐certainty evidence; low‐dose dexamethasone, RR 0.83, 95% CI 0.67 to 1.03, low‐certainty evidence). Ranking by P‐Scores showed moderate‐dose dexamethasone to be preferable for prevention of BPD (P‐Score 0.95), followed by high‐dose dexamethasone (P‐Score 0.70). However, consistency of the underlying network could not be evaluated due to an insufficient number of direct comparisons.

18.

Effect of early corticosteroids on BPD at 36 weeks' PMA

Death at 36 weeks' PMA

For the primary outcome of death, 27 studies were included, representing 4176 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; Peltoniemi 2005; Rastogi 1996; Romagnoli 1999; Sanders 1994; Shinwell 1996; Sinkin 2000; Soll 1999; Stark 2001; Subhedar 1997; Tapia 1998; Watterberg 1999; Watterberg 2004; Yeh 1997). The evaluated treatments may have little or no effect on the risk of death (Figure 19). Hydrocortisone was found to be the preferable treatment for the prevention of mortality (P‐Score 0.8999), followed by placebo (P‐Score 0.55). However, consistency of the underlying network could not be evaluated due to an insufficient number of direct comparisons.

19.

Effect of early corticosteroids on death at 36 weeks' PMA

Death or BPD at 36 weeks' PMA

Twenty‐six studies, representing 4167 infants, provided information on the composite outcome of death or BPD in the early treatment network (Anttila 2005; 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; Tapia 1998; Watterberg 1999; Watterberg 2004; Yeh 1997). Only moderate‐dose dexamethasone decreased the risk of this composite outcome compared with placebo (RR 0.77, 95% CI 0.60 to 0.98; I² = 0%, 95% CI 0% to 44.60%; moderate‐certainty evidence; Figure 20). Ranking by P‐Scores showed moderate‐dose dexamethasone to be the preferred treatment (P‐Score 0.87), followed by high‐dose dexamethasone (P‐Score 0.61). However, consistency of the underlying network could not be evaluated due to an insufficient number of direct comparisons.

20.

Effect of early corticosteroids on death or BPD at 36 weeks' PMA

Secondary outcomes

Forest plots for the secondary outcome comparisons are available in our data repository.

Low‐dose dexamethasone increased the risk for CP (RR 1.92, 95% CI 1.12 to 3.28) compared with placebo, and no intervention demonstrated an effect on major neurosensory disability. Low‐dose dexamethasone additionally increased the risk for hypertension (RR 2.93, 95% CI 1.53 to 5.61) compared with placebo. High‐dose dexamethasone, moderate‐dose dexamethasone, and hydrocortisone all decreased the risk for failure to extubate compared with control (RR 0.75, 95% CI 0.62 to 0.91; RR 0.45, 95% CI 0.28 to 0.72; RR 0.8, 95% CI 0.69 to 0.94; respectively). Moderate‐dose dexamethasone was more effective in decreasing this risk than the other interventions (RR 1.68, 95% CI 1.00 to 2.82 versus high‐dose dexamethasone; RR 2.11, 95% CI 1.20 to 3.70 versus low‐dose dexamethasone; RR 1.80, 95% CI 1.08 to 2.99 versus hydrocortisone). Both hydrocortisone and low‐dose dexamethasone increased the risk of gastrointestinal (GI) perforation compared with placebo (RR 1.86, 95% CI 1.06 to 3.24; RR 1.93, 95% CI 1.12 to 3.33; respectively). No effect was observed for the secondary outcomes of sepsis or NEC. There were insufficient data to evaluate the secondary outcome of growth failure, with only one included study evaluating this outcome.

P‐Scores showed placebo/no treatment to be preferable in reducing the risk of most adverse secondary outcomes—sepsis (P‐Score 0.6556), GI perforation (P‐Score 0.90), and hypertension (P‐Score 0.78). Moderate‐dose dexamethasone was the best treatment for reducing the risk of failure to extubate (P‐Score 0.99) and cerebral palsy (0.76; ranking above control at 0.69); there were no available data for moderate‐dose dexamethasone on major neurosensory disability. Hydrocortisone was the best treatment for reducing the risk of major neurosensory disability (P‐Score 0.93), ranking above control (P‐Score 0.69). High‐dose dexamethasone was the best treatment for reducing NEC (P‐Score 0.84) (Table 5).

5. Early treatment: P values.

Outcome	High‐dose dexamethasone	Moderate‐dose dexamethasone	Low‐dose dexamethasone	Hydrocortisone	Placebo/no treatment
BPD	0.701	0.948	0.493	0.296	0.063
Death	0.463	0.232	0.356	0.900	0.549
Death or BPD	0.607	0.868	0.417	0.528	0.079
Failure to extubate	0.657	0.989	0.232	0.534	0.088
Sepsis	0.507	0.583	0.447	0.308	0.656
GI perforation	0.510	0.492	0.284	0.318	0.897
NEC	0.839	0.644	0.230	0.432	0.356
Hypertension	0.612	0.562	0.223	0.318	0.785
Major neurosensory disability	0.153	n/a	0.241	0.926	0.681
CP	0.311	0.760	0.136	0.603	0.690

BPD: bronchopulmonary dysplasia; CP: cerebral palsy; GI: gastrointestinal; n/a: not applicable; NEC: necrotizing enterocolitis

Late (≥ seven days) treatment

Primary outcomes

BPD at 36 weeks' PMA

Seventeen studies, including 1114 infants, provided information on the primary outcome of BPD in the late treatment network (Brozanski 1995; Cummings 1989a [moderate‐dose vs placebo]; Cummings 1989b [high‐dose vs placebo]; Cummings 1989c [moderate‐dose vs high‐dose]; Doyle 2006; Durand 1995; Durand 2002; Kothadia 1999; Kovacs 1998; Malloy 2005; McEvoy 2004; Ohlsson 1992; Onland 2019; Parikh 2013; Romagnoli 1997; Scott 1997; Vincer 1998; Walther 2003; Yates 2019). High‐dose dexamethasone lowered the risk of BPD both versus hydrocortisone (RR 0.66, 95% CI 0.51 to 0.85; low‐certainty evidence. I² = 0%, 95% CI 0% to 52.30%) and versus placebo (RR 0.72, CI 0.59 to 0.87; moderate‐certainty evidence; Figure 21). P‐Scores ranked high‐dose dexamethasone as the most beneficial treatment to prevent BPD (P‐Score 0.96). Moderate‐dose dexamethasone was the next most beneficial treatment (P‐Score 0.65). Evidence suggests that the consistency assumption of the underlying network was likely satisfied (Q: 1.9, df: 2, P: 0.39).

21.

Effect of late corticosteroids on BPD at 36 weeks' PMA

Death at 36 weeks' PMA

For the primary outcome of death, 18 studies were included, representing 1155 infants (Brozanski 1995; Cummings 1989a [moderate‐dose vs placebo]; Cummings 1989b [high‐dose vs placebo]; Cummings 1989c [moderate‐dose vs high‐dose]; Doyle 2006; Durand 1995; Durand 2002; Kari 1993; Kothadia 1999; Kovacs 1998; Malloy 2005; McEvoy 2004; Ohlsson 1992; Onland 2019; Parikh 2013; Romagnoli 1997; Scott 1997; Vincer 1998; Walther 2003; Yates 2019). The evaluated treatments may have little or no effect on the risk of death at 36 weeks' PMA (Figure 22). P‐Scores ranked hydrocortisone as the most beneficial treatment to prevent death (P‐Score 0.71), closely followed by high‐dose dexamethasone (P‐Score 0.71). Evidence suggests that the consistency assumption of the underlying network was likely satisfied (Q: 2.41, df: 2, P: 0.30).

22.

Effect of late corticosteroids on death at 36 weeks' PMA

Death or BPD at 36 weeks' PMA

Seventeen studies, including 1114 infants, provided information on the composite outcome of death or BPD (Brozanski 1995; Cummings 1989a [moderate‐dose vs placebo]; Cummings 1989b [high‐dose vs placebo]; Cummings 1989c [moderate‐dose vs high‐dose]; Doyle 2006; Durand 1995; Durand 2002; Kothadia 1999; Kovacs 1998; Malloy 2005; McEvoy 2004; Ohlsson 1992; Onland 2019; Parikh 2013; Romagnoli 1997; Scott 1997; Vincer 1998; Walther 2003; Yates 2019). High‐dose dexamethasone lowered the risk of death or BPD compared with all other treatments (placebo, RR 0.69, 95% CI 0.59 to 0.80, high‐certainty evidence; hydrocortisone, RR 0.69, 95% CI 0.58 to 0.84, low‐certainty evidence; low‐dose dexamethasone, RR 0.73, 95% CI 0.60 to 0.88, low‐certainty evidence; moderate‐dose dexamethasone, RR 0.76, 95% CI 0.62 to 0.93, low‐certainty evidence; I² = 0%, 95% CI 0% to 51.10%; Figure 23). Low‐dose dexamethasone may decrease the risk of death or BPD compared with placebo (RR 0.93, 95% CI 0.83 to 1.03, moderate‐certainty evidence). P‐Scores ranked high‐dose dexamethasone as the most beneficial treatment to prevent composite death or BPD (P‐Score 1.00). Moderate‐dose dexamethasone was the next most beneficial treatment for preventing the combination outcome of death or BPD (P‐Score 0.61). Evidence suggests that the consistency assumption of the underlying network was likely satisfied (Q: 2.08, df: 2, P: 0.35).

23.

Effect of late corticosteroids on death or BPD at 36 weeks' PMA

Secondary outcomes

Forest plots for the secondary outcome comparisons are available in our data repository.

No effect was observed for the secondary outcomes of cerebral palsy or major neurosensory disability. All treatments compared with control decreased the risk for failure to extubate (high‐dose dexamethasone, RR 0.70, 95% CI 0.62 to 0.79; moderate‐dose dexamethasone, RR 0.64, 95% CI 0.54 to 0.75; low‐dose dexamethasone, RR 0.72, 95% CI 0.61 to 0.84; hydrocortisone, RR 0.70, 95% CI 0.60 to 0.82). Moderate‐dose dexamethasone increased the risk for sepsis compared with hydrocortisone (hydrocortisone versus moderate‐dose dexamethasone, RR 0.63, 95% CI 0.46 to 0.87), as well as compared with control (RR 1.37, 95% CI 1.05 to 1.78). Moderate‐dose dexamethasone increased the risk of hypertension, both compared with low‐dose dexamethasone (low‐dose dexamethasone versus moderate‐dose dexamethasone, RR 0.32, 95% CI 0.12 to 0.82) and with control (RR 2.30, 95% CI 1.13 to 4.70). High‐dose dexamethasone increased the risk of hypertension compared with control (RR 2.21, 95% CI 1.13 to 4.31). No effect was observed for the secondary outcomes of GI perforation or NEC, and there were insufficient data to evaluate the secondary outcome of growth failure, with no included study evaluating this outcome.

P‐Score rankings were scattered amongst treatments for preferred regimens avoiding the seven adverse secondary outcomes to be evaluated. High‐dose dexamethasone was preferable for avoiding GI perforation (P‐Score 0.68). Moderate‐dose dexamethasone was the best treatment for avoiding failure to extubate (P‐Score 0.87). Low‐dose dexamethasone was the preferred treatment for avoiding NEC (P‐Score 0.86) or hypertension (P‐score 0.86). Hydrocortisone was the best treatment for avoiding sepsis (P‐Score 0.88) or CP (P‐Score 0.77). Placebo/no treatment was preferred for avoiding major neurosensory disability (P‐Score 0.64) (Table 6).

6. Late treatment: P values.

Outcome	High‐dose dexamethasone	Moderate‐dose dexamethasone	Low‐dose dexamethasone	Hydrocortisone	Placebo/no treatment
BPD	0.956	0.655	0.551	0.066	0.272
Death	0.707	0.559	0.268	0.711	0.256
Death or BPD	0.999	0.605	0.477	0.247	0.173
Failure to extubate	0.572	0.871	0.472	0.584	0.000
Sepsis	0.508	0.026	0.584	0.878	0.505
GI perforation	0.678	0.433	0.445	0.585	0.358
NEC	0.111	0.720	0.860	0.451	0.357
Hypertension	0.163	0.137	0.860	0.582	0.759
Major neurosensory disability	0.482	0.325	0.486	0.569	0.639
CP	0.401	0.188	0.662	0.768	0.480

BPD: bronchopulmonary dysplasia; CP: cerebral palsy; GI: gastrointestinal; NEC: necrotizing enterocolitis.

Subgroup analyses

Subgroup analysis was not performed, secondary to an insufficient number of studies by any of our pre‐planned stratifications to build a meaningful analysis. This number was deemed insufficient per the prior standard set by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2020).

Sensitivity analyses

Sensitivity analyses were conducted for risk of bias and for trial size (available in our data repository). We were unable to perform sensitivity analysis based on missing data, given the general completeness of included trials. When considering only studies with low or no risk of bias, we found similar primary outcomes to those in the primary analyses for both the early and the late treatment networks. The median sample size of included studies was 50. Upon limiting analysis to only studies including 50 or more infants, we found results again to be largely similar to those in the primary analyses, with a few subtle differences. In sensitivity analysis for larger trial size, late treatment with high‐dose dexamethasone was found to be preferential to placebo for the prevention of mortality (RR 0.36, 95% CI 0.13 to 0.96); and there was likely preference for this treatment in sensitivity analysis for low risk of bias as well (RR 0.39, 95% CI 0.15 to 1.0). Additionally, the strength of the preference for early moderate‐dose dexamethasone over placebo for the prevention of the composite outcome of death or BPD was decreased in the analyses for both larger trial size (RR 0.84, 95% CI 0.65 to 1.09) and low risk of bias (RR 0.84, 95% CI 0.64 to 1.10).

Comparison‐adjusted funnel plots for our primary outcomes were suggestive of possible publication bias, with a tendency towards positive studies in the outcome of BPD for both the early and late treatment networks (Figure 24; Figure 25; other funnel plots available in our data repository).

24.

Comparison‐adjusted funnel plot for the outcome of BPD in the early corticosteroid treatment network

25.

Comparison‐adjusted funnel plot for the outcome of BPD in the late corticosteroid treatment network

Discussion

Systemic corticosteroids are effective in improving survival without BPD; however, these treatments have other significant effects, which must be balanced with an infant’s anticipated benefit from treatment. Concern for adverse effects, notably with regard to neurosensory outcomes, has fueled continued debate over the optimal corticosteroid treatment regimen to strike this balance. Direct evidence to answer this question by comparing these treatment regimens against each other is lacking. Application of network meta‐analysis is an attractive option for modeling indirect comparisons between these treatments based on extant trial information. However, this approach has its own limitations, and results must be interpreted with caution.

Summary of main results

Application of network meta‐analysis to the evaluation of postnatal systemic corticosteroids for BPD added a small number of valuable comparisons between corticosteroid regimens, most notably between the efficacies of different dexamethasone dosing regimens in preventing BPD. The optimal steroid regimen for clinical use, however, remains unknown, given the paucity of trial data with regard to long‐term outcomes.

Our network meta‐analysis found different preferred regimens for our primary outcome of composite death or BPD, depending on the timing of treatment; specifically, moderate‐dose dexamethasone was most effective in the early treatment network and high‐dose dexamethasone most effective in the late treatment network. This emphasizes the core differences between these two networks, with inherently different patient groups being tested. The early group were treated more empirically with corticosteroids for BPD (a practice currently cautioned against by society guidelines), whereas the late group, still judged to be at risk for BPD a week or more later, received more targeted treatment. This is reflected in the different baseline risks shown by the BPD incidence in the placebo groups: 31% in the early group versus 59% in the late group. While more remains to be understood about the physiology behind these treatment effects, the increase in dose required in the later group might also suggest evolving lung inflammation with age that requires stronger treatment.

Evaluation for adverse effects yielded less substantial results, with little available data to guide treatment with consideration of neurosensory risks. For the early treatment network, low‐dose dexamethasone demonstrated clearer harm for GI perforation, hypertension, and CP than either of moderate‐ or high‐dose dexamethasone. The reason for this requires more investigation, but this finding challenges the argument of decreasing dosing for safety. For the late treatment network, moderate‐dose dexamethasone demonstrated the most harm for sepsis and hypertension. Notably missing was a clear winner or loser with regard to long‐term neurologic outcomes. Relatively few studies achieved this follow‐up, and for the studies that did, their ability to reliably detect cerebral palsy or major neurosensory disability was limited. As pointed out by the authors of the original reviews (Doyle 2021a; Doyle 2021b), some included studies reported whether or not infants developed cerebral palsy prior to age five, leaving room for uncertainty in the clinical assessments (Stanley 1982). Moreover, all studies were underpowered to detect clinically important differences in long‐term major neurosensory disability.

Sensitivity analyses considering risk of bias and trial size demonstrated largely similar outcomes. Observed differences included a preference for high‐dose dexamethasone over placebo for the prevention of mortality when analysis was limited to studies including 50 or more infants; and possibly when limited to studies at low risk of bias. Additionally, both analysis limited to larger trials and analysis limited to trials at low risk of bias revealed weaker preference for early moderate‐dose dexamethasone over placebo for the prevention of the composite outcome of death or BPD.

The question of when and how to best approach systemic corticosteroid treatment for the prevention of BPD remains unanswered. More studies are needed to guide the timing of these treatments, with possibly limited efficacy of moderate treatment doses with advanced disease. Those caring for this fragile patient population must carefully consider the risks, benefits, and unknowns of this treatment. While there may be benefits of improved respiratory function; there is reason for concern for neurosensory risk with systemic corticosteroid treatments in immaturity based on animal studies, and more long‐term trial evidence is needed to establish the true risk of these treatments to preterm infants.

Overall completeness and applicability of evidence

Data on our primary outcomes as well as most secondary outcomes was relatively complete. However, data requiring longer‐term follow‐up (including the evaluation of the risks of CP and major neurosensory disability) were incomplete.

It should be noted that P‐Scores are calculated for all comparisons analyzed, regardless of the strength of the actual comparison. It follows that, for many of these rankings, while an intervention was judged to be preferred, it was not shown to be effective; and these scores should be interpreted with caution.

Additionally, while no meaningful differences were observed in the distribution of comparisons with respect to effect modifiers, a substantial portion of the effect modifier data were missing (most notably, only a minority of studies reported on use of rescue corticosteroids; 37.5% of studies in the early group provided this information), suggesting that differences may still exist, possibly violating the transitivity assumption of the network meta‐analyses.

Lastly, the consistency of the networks was found to be maintained for the majority of outcomes in the late treatment group. Due to a lack of direct comparisons, we were unable to establish whether or not consistency was maintained for all outcomes of the early treatment group, for the outcome of GI perforation in the late treatment group, or for the outcomes of the sensitivity analyses.

Quality of the evidence

In addition to risk of bias (see above), all elements of the GRADE framework were assessed. We judged studies as having concerns for indirectness if they had populations enrolled for hypotension or performed in an earlier epoch prior to the availability of surfactant (Figure 26; Figure 27; Figure 28; Figure 29; Figure 30; Figure 31; Figure 32; Figure 33). Two studies were considered to have major concerns for indirectness (Baden 1972; Mukhopadhyay 1998), and 13 studies were found to have some concerns for indirectness (Ariagno 1987; Avery 1985; Batton 2012; Biswas 2003; Halac 1990; Harkavy 1989; Hochwald 2014; Kopelman 1999; Ng 2006; Noble‐Jamieson 1989; Romagnoli 1997; Scott 1997; Wang 1996).

26.

Indirectness contributions, BPD with early treatment.

Figure produced via CINeMA webtool to depict indirectness contributions by network comparison. Green indicates low risk of bias; yellow indicates unclear risk of bias; and red indicates high risk of bias.

27.

Indirectness contributions, death with early treatment.

Figure produced via CINeMA webtool to depict indirectness contributions by network comparison. Green indicates low risk of bias; yellow indicates unclear risk of bias; and red indicates high risk of bias.

28.

Indirectness contributions, death or BPD with early treatment.

Figure produced via CINeMA webtool to depict indirectness contributions by network comparison. Green indicates low risk of bias; yellow indicates unclear risk of bias; and red indicates high risk of bias.

29.

Indirectness contributions, CP with early treatment.

Figure produced via CINeMA webtool to depict indirectness contributions by network comparison. Green indicates low risk of bias; yellow indicates unclear risk of bias; and red indicates high risk of bias.

30.

Indirectness contributions, BPD with late treatment.

Figure produced via CINeMA webtool to depict indirectness contributions by network comparison. Green indicates low risk of bias; yellow indicates unclear risk of bias; and red indicates high risk of bias.

31.

Indirectness contributions, death with late treatment.

Figure produced via CINeMA webtool to depict indirectness contributions by network comparison. Green indicates low risk of bias; yellow indicates unclear risk of bias; and red indicates high risk of bias.

32.

Indirectness contributions, death or BPD with late treatment.

Figure produced via CINeMA webtool to depict indirectness contributions by network comparison. Green indicates low risk of bias; yellow indicates unclear risk of bias; and red indicates high risk of bias.

33.

Indirectness contributions, CP with late treatment.

Figure produced via CINeMA webtool to depict indirectness contributions by network comparison. Green indicates low risk of bias; yellow indicates unclear risk of bias; and red indicates high risk of bias.

On assessment of the certainty of the evidence by CINeMA, further deductions were made for imprecision and heterogeneity (Table 1; Table 2). Indirect comparisons were additionally downgraded for inability to assess incoherence. Therefore, while the certainty of the evidence via direct comparisons was moderate (Table 1; Table 2), certainty of the evidence via indirect comparisons was low.

Potential biases in the review process

While our analysis built two separate networks to address the poor transitivity between infants receiving early versus late corticosteroid treatments, there remains a risk for residual bias due to other shortcomings in transitivity. As above, our evaluation of effect modifiers found no meaningful differences, but was limited for missing data. Moreover, given the wide range of trials in our analysis, including trials performed for hypotension and trials in the pre‐surfactant era, variations in patient population are likely and should be acknowledged.

Agreements and disagreements with other studies or reviews

Ours is the third network meta‐analysis to be performed on this topic. However, it is the only analysis to split early and late treatment into separate network analyses. As discussed above, this is a distinction that we felt important for maintaining network transitivity. This was additionally the first network meta‐analysis to focus on systemic corticosteroid treatments with the exclusion of inhaled corticosteroids, and it includes the largest number of RCTs on this topic. These differences should allow for a more precise analysis. Our analysis agrees to some extent with its predecessors on the superiority of higher dosed dexamethasone for survival without BPD, and on the lack of conclusive evidence for adverse neurologic effects. However, there were other key distinctions between these analyses.

The first network meta‐analysis on the topic (Zeng 2018), included fewer studies and viewed all studies together without the distinction of early and late treatments. By separating our analysis into two separate networks, we were better able to maintain the transitivity of our network, as these patient populations can be assumed to be distinct (e.g. patients requiring mechanical ventilation beyond the first week after birth are likely sicker on average than those requiring mechanical ventilation in the first few days). Zeng and colleagues also limited their safety evaluation to the outcome of CP, whereas we were able to provide a broader description of anticipated adverse effects, further informing the clinical considerations when deciding on corticosteroid treatment and the gaps in the evidence around these considerations.

Our analysis is more similar to the recent network meta‐analysis by Ramaswamy and colleagues (Ramaswamy 2021). While this group did not build separate early and late networks, they excluded early dexamethasone from their analysis. However, the network did combine early and late treatments of other corticosteroids, including hydrocortisone, possibly violating the transitivity assumption. They further split the late treatment group by the cut‐point of two weeks. The group took a similar approach of considering three different dosing groups for dexamethasone (< 2 mg/kg, 2 to 4 mg/kg, and > 4 mg/kg), with the findings for the moderate‐dose and high‐dose group being similar to ours in their efficacy in preventing BPD and the composite outcome of death or BPD.

Authors' conclusions

Implications for practice.

There are insufficient data at this time to guide treatment with regard to the optimal regimen that balances the risks and benefits of postnatal systemic corticosteroid treatment. Treatment with systemic corticosteroids may be considered for improvement in survival without BPD in ventilator‐dependent very preterm infants, but this clinical decision must be approached carefully, given the paucity of data on plausible adverse long‐term neurosensory outcomes.

Implications for research.

Further randomized controlled trials that include direct comparisons between systemic corticosteroid treatments are needed to definitively determine the optimal treatment approach. These studies should evaluate survival without BPD and survival without major neurosensory disability as primary outcomes.

History

Protocol first published: Issue 9, 2020

Appendices

Appendix 1. MEDLINE strategy

	Ovid MEDLINE® and Epub Ahead of Print, In‐Process, In‐Data‐Review & Other Non‐Indexed Citations, Daily and Versions® 1946 to 16 February 2022
#	Searches	Results
1	exp Adrenal Cortex Hormones/	412685
2	exp Steroids/	892035
3	exp Glucocorticoids/	201230
4	(adrenal cortex hormone* or dexamethasone or betamethasone or hydrocortisone or steroid or steroids or corticosteroid* or prednisolone or methylprednisolone or glucocorticoid*).mp.	601914
5	or/1‐4 [Corticosteroids]	1192988
6	exp infant, newborn/ or Intensive Care, Neonatal/ or Intensive Care Units, Neonatal/	648583
7	(baby* or babies or infant? or infantile or infancy or low birth weight or low birthweight or neonat* or neo‐nat* or newborn* or new born? or newly born or premature or pre‐mature or pre‐matures or prematures or prematurity pre‐maturity or preterm or preterms or pre term? or preemie or preemies or premies or premie or VLBW or LBW or ELBW or NICU).ti,ab,kw,kf.	955565
8	or/6‐7 [Filter: Neonatal Population 01‐2022‐‐MEDLINE]	1238911
9	randomized controlled trial.pt.	558823
10	controlled clinical trial.pt.	94699
11	randomized.ti,ab.	597405
12	placebo.ti,ab.	231814
13	drug therapy.fs.	2444352
14	randomly.ti,ab.	377168
15	trial.ti,ab.	683654
16	groups.ti,ab.	2339523
17	or/9‐16 [Cochrane HSSS‐SM Filter; Box 6.4.a Cochrane Handbook]	5328520
18	(quasirandom* or quasi‐random* or randomi* or randomly).ti,ab,kw,kf.	1022990
19	(control* adj2 (group? or random* or trial? or study)).ti,ab,kw,kf.	1017861
20	((single or doubl* or tripl* or treb*) and (blind* or mask*)).ti,ab.	210620
21	or/18‐20 [Additional terms to increase sensitivity]	1637677
22	exp animals/ not humans/	4959959
23	(or/17,21) not 22 [RCT Filter]	4897191
24	5 and 8 and 23 [Corticosteroids AND Neonate AND RCT Filter]	16312
25	("2016" or "2017" or "2018" or "2019" or 202*).yr.	8003992
26	24 and 25	3609

Appendix 2. Embase strategy

	Embase 1974 to 16 February 2022 (OVID)
#	Searches	Results
1	(adrenal cortex hormone* or dexamethasone or betamethasone or hydrocortisone or steroid or steroids or corticosteroid* or prednisolone or methylprednisolone or glucocorticoid*).mp.	1164358
2	exp corticosteroid/	1010877
3	exp *steroid/	572025
4	(adrenal cortex hormone* or dexamethasone or betamethasone or hydrocortisone or steroid or steroids or corticosteroid* or prednisolone or methylprednisolone or glucocorticoid*).ti,ab,kw,kf.	635636
5	or/1‐4 [Corticosteroids/Steroids]	1539498
6	newborn/ or prematurity/ or newborn intensive care/ or newborn care/	640447
7	(baby* or babies or infant? or infantile or infancy or low birth weight or low birthweight or neonat* or neo‐nat* or newborn* or new born? or newly born or premature or pre‐mature or pre‐matures or prematures or prematurity or preterm or preterms or pre term or preemie or preemies or premies or premie or VLBW or LBW or ELBW or NICU).ti,ab,kw,kf.	1123058
8	or/6‐7 [Filter: Neonatal Population 2021‐OVID EMBASE]	1340426
9	Randomized controlled trial/ or Controlled clinical study/	885265
10	random$.ti,ab,kw.	1761493
11	Randomization/	93049
12	placebo.ti,ab,kw.	336924
13	((double or single or doubly or singly) adj (blind or blinded or blindly)).ti,ab,kw.	253415
14	double blind procedure/	192322
15	(controlled adj7 (study or design or trial)).ti,ab,kw.	399997
16	parallel group$1.ti,ab.	28918
17	(crossover or cross over).ti,ab.	114842
18	((assign$ or match or matched or allocation) adj5 (alternate or group$1 or intervention$1 or patient$1 or subject$1 or participant$1)).ti,ab.	373125
19	(open adj label).ti,ab.	94551
20	(quasirandom* or quasi‐random* or randomi* or randomly).ti,ab,kw,kf.	1438413
21	(control* adj2 (group? or random*)).ti,ab,kw,kf.	1168618
22	or/9‐19 [ Terms based on Cochrane Central strategy‐https://www‐cochranelibrary‐com.ezproxy.uvm.edu/central/central‐creation]	2521584
23	(exp animals/ or exp invertebrate/ or animal experiment/ or animal model/ or animal tissue/ or animal cell/ or nonhuman/) and (human/ or normal human/ or human cell/)	23298903
24	exp animals/ or exp invertebrate/ or animal experiment/ or animal model/ or animal tissue/ or animal cell/ or nonhuman/	30141003
25	24 not 23 [Animal Exclusion‐https://community‐cochrane‐org.ezproxy.uvm.edu/sites/default/files/uploads/inline‐files/Embase%20animal%20filter.pdf]	6842100
26	22 not 25 [Filter: RCT‐EMBASE]	2252758
27	5 and 8 and 26 [Corticosteroids/Steroids AND Neonate AND RCT]	5996
28	("2016" or "2017" or "2018" or "2019" or 202*).yr.	10154188
29	27 and 28 [EMBASE Results 2016‐Feb 2022]	2034

Appendix 3. Cochrane CRS strategy

	Cochrane CENTRAL via CRS
	Feburary‐17‐2022
1	MESH DESCRIPTOR Infant, Newborn EXPLODE ALL AND CENTRAL:TARGET	17409
2	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	95692
3	preemie OR preemies or pre‐mature or pre‐matures or pre‐maturity AND CENTRAL:TARGET	54
4	#1 OR #2 OR #3	95701
5	MESH DESCRIPTOR Adrenal Cortex Hormones EXPLODE ALL AND CENTRAL:TARGET	28978
6	MESH DESCRIPTOR Steroids EXPLODE ALL AND CENTRAL:TARGET	62736
7	MESH DESCRIPTOR Glucocorticoids EXPLODE ALL AND CENTRAL:TARGET	19776
8	adrenal cortex hormone* OR dexamethasone OR betamethasone OR hydrocortisone OR steroid OR steroids OR corticosteroid* OR prednisolone OR methylprednisolone OR glucocorticoid* AND CENTRAL:TARGET	77036
9	#5 OR #6 OR #7 OR #8	115266
10	2016 TO 2022:YR AND CENTRAL:TARGET	646748
11	#4 AND #9 AND #10	1780

Appendix 4. Trial registry strategies

March‐6‐2022	clinicaltrials.gov	corticosteroid AND Bronchopulmonary dyspalsia	Child under 7 years	10
March‐6‐2022	clinicaltrials.gov	steroid AND Bronchopulmonary dyspalsia	Child under 7 years	10
March‐6‐2022	clinicaltrials.gov	adrenal cortex hormones AND Bronchopulmonary dyspalsia	Child under 7 years	10
March‐6‐2022	clinicaltrials.gov	dexamethasone AND Bronchopulmonary dyspalsia	Child under 7 years	8
March‐6‐2022	clinicaltrials.gov	betamethasone AND Bronchopulmonary dyspalsia	Child under 7 years	1
March‐6‐2022	clinicaltrials.gov	hydrocortisone AND Bronchopulmonary dyspalsia	Child under 7 years	11
March‐6‐2022	clinicaltrials.gov	prednisolone AND Bronchopulmonary dyspalsia	Child under 7 years	1
March‐6‐2022	clinicaltrials.gov	glucocorticoid AND Bronchopulmonary dyspalsia	Child under 7 years	20
January‐04‐2022	clinicaltrials.gov	corticosteroid Bronchopulmonary dysplasia [Other Terms]	Child under 7 years	17
January‐04‐2022	clinicaltrials.gov	steroid Bronchopulmonary dysplasia [Other terms]		43
January‐04‐2022	clinicaltrials.gov	adrenal cortex hormones Bronchopulmonary dysplasia		17
		Total		148
		Duplicates		39
		Limited by First posted date 2016 forward		14

Appendix 5. Risk of bias

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

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

1. low‐risk (any truly random process [e.g. random number table; computer random number generator]);

2. high‐risk (any nonrandom process [e.g. odd or even date of birth; hospital or clinic record number]); or

3. unclear risk.

2. Allocation concealment (checking for possible selection bias): was allocation adequately concealed?

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

1. low‐risk (e.g. telephone or central randomization; consecutively numbered, sealed, opaque envelopes);

2. high‐risk (e.g. open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth); or

3. unclear risk.

3. 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 categorized 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 class of outcomes. We categorized the methods as:

1. low‐risk, high‐risk, or unclear risk for participants; and

2. low‐risk, high‐risk, or unclear risk for personnel.

4. 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 categorized the methods used to blind outcome assessment. We assessed blinding separately for different outcomes or class of outcomes. We categorized the methods as:

1. low‐risk for outcome assessors;

2. high‐risk for outcome assessors; or

3. unclear risk for outcome assessors.

5. 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 the completeness of data including attrition and exclusions from the analysis. We noted whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomized participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information is reported or supplied by the trial authors, we reincluded missing data in the analyses. We categorized the methods as:

1. low‐risk (< 20% missing data);

2. high‐risk (≥ 20% missing data); or

3. unclear risk.

6. 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. For studies in which study protocols were published in advance, we compared prespecified outcomes versus outcomes eventually reported in the published results. If the study protocol was not published in advance, we contacted the study’s authors to gain access to the study protocol. We assessed the methods as:

1. low‐risk (in which it is clear that all the study’s prespecified outcomes and all expected outcomes of interest to the review have been reported);

2. high‐risk (in which not all the study’s prespecified outcomes have been reported; one or more reported primary outcomes were not prespecified outcomes of interest and are reported incompletely, so cannot be used; the study fails to include results of a key outcome that would have been expected to have been reported); or

3. unclear risk.

7. 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 or whether the trial was stopped early because of some data‐dependent process). We assessed whether each study was free of other problems that could put it at risk of bias as:

1. low‐risk;

2. high‐risk; or

3. unclear risk.

If needed, we planned to explore the impact of the level of bias through undertaking sensitivity analyses.

Appendix 6. Subgroup analyses

Appendix for subgroup analyses

Systemic corticosteroid comparisons (infants < 28 weeks’ gestation)

Systemic corticosteroid comparisons (infants < 28 weeks’ gestation)
Death or BPD at 36 weeks’ PMA
	Studies	Participants
Early low‐dose dexamethasone vs placebo/no treatment	1	70
Early high‐dose dexamethasone vs placebo/no treatment	0	0
Early Hc vs placebo/no treatment	3	581
Early high‐dose dexamethasone vs early low‐dose dexamethasone	0	0
Late low‐dose dexamethasone vs placebo/no treatment	1	70
Late high‐dose dexamethasone vs placebo/no treatment	0	0
Late Hc vs placebo/no treatment	1	308
Late high‐dose dexamethasone (2 mg/kg to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0
Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0
Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0
BPD at 36 weeks’ PMA
	Studies	Participants
Early low‐dose dexamethasone vs placebo/no treatment	1	70
Early high‐dose dexamethasone vs placebo/no treatment	0	0
Early Hc vs placebo/no treatment	2	571
Early high‐dose dexamethasone vs early low‐dose dexamethasone	0	0
Late low‐dose dexamethasone vs placebo/no treatment	1	70
Late high‐dose dexamethasone vs placebo/no treatment	0	0
Late Hc vs placebo/no treatment	0	0
Late high‐dose dexamethasone (2 mg/kg to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0
Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0
Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0
Death at 36 weeks’ PMA
	Studies	Participants
Early low‐dose dexamethasone vs placebo/no treatment	1	70
Early high‐dose dexamethasone vs placebo/no treatment	0	0
Early Hc vs placebo/no treatment	3	573
Early high‐dose dexamethasone vs early low‐dose dexamethasone	0	0
Late low‐dose dexamethasone vs placebo/no treatment	1	18
Late high‐dose dexamethasone vs placebo/no treatment	0	0
Late Hc vs placebo/no treatment	0	0
Late high‐dose dexamethasone (2 mg/kg to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0
Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0
Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0

Systemic corticosteroid comparisons (birthweight < 1000 g)

Systemic corticosteroid comparisons (birthweight < 1000 g)
Death or BPD at 36 weeks’ PMA
	Studies	Participants
Early low‐dose dexamethasone vs placebo/no treatment	3	868
Early high‐dose dexamethasone vs placebo/no treatment	0	0
Early Hc vs placebo/no treatment	3	431
Early high‐dose dexamethasone vs early low‐dose dexamethasone	0	0
Late low‐dose dexamethasone vs placebo/no treatment	1	70
Late high‐dose dexamethasone vs placebo/no treatment	0	0
Late Hc vs placebo/no treatment	1	64
Late high‐dose dexamethasone (2 mg/kg to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0
Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0
Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0
BPD at 36 weeks’ PMA
	Studies	Participants
Early low‐dose dexamethasone vs placebo/no treatment	3	868
Early high‐dose dexamethasone vs placebo/no treatment	0	0
Early Hc vs placebo/no treatment	3	431
Early high‐dose dexamethasone vs early low‐dose dexamethasone	0	0
Late low‐dose dexamethasone vs placebo/no treatment	1	70
Late high‐dose dexamethasone vs placebo/no treatment	0	0
Late Hc vs placebo/no treatment	0	0
Late high‐dose dexamethasone (2 mg/kg to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0
Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0
Late high‐dose dexamethasone vs early high‐dose dexamethasone	1	64
Death at 36 weeks’ PMA
	Studies	Participants
Early low‐dose dexamethasone vs placebo/no treatment	4	938
Early high‐dose dexamethasone vs placebo/no treatment	1	24
Early Hc vs placebo/no treatment	4	437
Early high‐dose dexamethasone vs early low‐dose dexamethasone	0	0
Late low‐dose dexamethasone vs placebo/no treatment	1	70
Late high‐dose dexamethasone vs placebo/no treatment	0	0
Late Hc vs placebo/no treatment	1	64
Late high‐dose dexamethasone (2 mg/kg to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0
Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0
Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0

Systemic corticosteroid comparisons (< 33% rescue treatment)

Systemic corticosteroid comparisons (< 33% rescue treatment)
Death or BPD at 36 weeks’ PMA
	Studies	Participants
Early low‐dose dexamethasone vs placebo/no treatment	4	722
Early high‐dose dexamethasone vs placebo/no treatment	1	70
Early Hc vs placebo/no treatment	2	405
Early high‐dose dexamethasone vs early low‐dose dexamethasone	0	0
Late low‐dose dexamethasone vs placebo/no treatment	1	70
Late high‐dose dexamethasone vs placebo/no treatment	0	0
Late Hc vs placebo/no treatment	1	64
Late high‐dose dexamethasone (2 mg/kg to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0
Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0
Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0
BPD at 36 weeks’ PMA
	Studies	Participants
Early low‐dose dexamethasone vs placebo/no treatment	4	722
Early high‐dose dexamethasone vs placebo/no treatment	1	70
Early Hc vs placebo/no treatment	2	405
Early high‐dose dexamethasone vs early low‐dose dexamethasone	0	0
Late low‐dose dexamethasone vs placebo/no treatment	1	70
Late high‐dose dexamethasone vs placebo/no treatment	0	0
Late Hc vs placebo/no treatment	1	64
Late high‐dose dexamethasone (2 mg/kg to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0
Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0
Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0
Death at 36 weeks’ PMA
	Studies	Participants
Early low‐dose dexamethasone vs placebo/no treatment	4	722
Early high‐dose dexamethasone vs placebo/no treatment	1	70
Early Hc vs placebo/no treatment	1	360
Early high‐dose dexamethasone vs early low‐dose dexamethasone	0	0
Late low‐dose dexamethasone vs placebo/no treatment	1	70
Late high‐dose dexamethasone vs placebo/no treatment	0	0
Late Hc vs placebo/no treatment	1	64
Late high‐dose dexamethasone (2 mg/kg to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0
Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0
Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0

Systemic corticosteroid comparisons (studies at low risk of bias)

Systemic corticosteroid comparisons (studies at low risk of bias)
Death or BPD at 36 weeks’ PMA
	Studies	Participants
Early low‐dose dexamethasone vs placebo/no treatment	9	1960
Early high‐dose dexamethasone vs placebo/no treatment	4	620
Early Hc vs placebo/no treatment	8	1354
Early high‐dose dexamethasone vs early low‐dose dexamethasone	0	0
Late low‐dose dexamethasone vs placebo/no treatment	5	203
Late high‐dose dexamethasone vs placebo/no treatment	4	257
Late Hc vs placebo/no treatment	2	435
Late high‐dose dexamethasone (2 mg/kg to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0
Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0
Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0
BPD at 36 weeks’ PMA
	Studies	Participants
Early low‐dose dexamethasone vs placebo/no treatment	9	1960
Early high‐dose dexamethasone vs placebo/no treatment	4	620
Early Hc vs placebo/no treatment	8	1354
Early high‐dose dexamethasone vs early low‐dose dexamethasone	0	0
Late low‐dose dexamethasone vs placebo/no treatment	5	203
Late high‐dose dexamethasone vs placebo/no treatment	4	257
Late Hc vs placebo/no treatment	2	435
Late high‐dose dexamethasone (2 mg/kg to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0
Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0
Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0
Death at 36 weeks’ PMA
	Studies	Participants
Early low‐dose dexamethasone vs placebo/no treatment	9	1960
Early high‐dose dexamethasone vs placebo/no treatment	4	620
Early Hc vs placebo/no treatment	9	1363
Early high‐dose dexamethasone vs early low‐dose dexamethasone	0	0
Late low‐dose dexamethasone vs placebo/no treatment	5	203
Late high‐dose dexamethasone vs placebo/no treatment	5	298
Late Hc vs placebo/no treatment	2	435
Late high‐dose dexamethasone (2 mg/kg to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0
Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0
Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0

BPD: bronchopulmonary dysplasia; Hc: hydrocortisone; PMA: postmenstrual age

Data and analyses

Comparison 1. Systemic corticosteroid comparisons (all infants).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Death or BPD at 36 weeks' postmenstrual age	40		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.1.1 Early low‐dose dexamethasone vs placebo/no treatment	11	2110	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.81, 0.97]
1.1.2 Early high‐dose dexamethasone vs placebo/no treatment	6	681	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.72, 0.99]
1.1.3 Early hydrocortisone vs placebo/no treatment	9	1376	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.82, 0.99]
1.1.4 Early high‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.1.5 Late low‐dose dexamethasone vs placebo/no treatment	7	266	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.71, 0.95]
1.1.6 Late high‐dose dexamethasone vs placebo/no treatment	5	287	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.59, 0.81]
1.1.7 Late hydrocortisone vs placebo/no treatment	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.88, 1.09]
1.1.8 Late high‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.1.9 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.1.10 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.2 BPD at 36 weeks' postmenstrual age	40		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.2.1 Early low‐dose dexamethasone vs placebo/no treatment	11	2110	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.64, 0.86]
1.2.2 Early high‐dose dexamethasone vs placebo/no treatment	6	681	Risk Ratio (M‐H, Fixed, 95% CI)	0.64 [0.46, 0.87]
1.2.3 Early hydrocortisone vs placebo/no treatment	9	1376	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.81, 1.06]
1.2.4 Early high‐dose dexamethasone vs low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.2.5 Late low‐dose dexamethasone vs placebo/no treatment	7	266	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.64, 0.95]
1.2.6 Late high‐dose dexamethasone vs placebo/no treatment	5	287	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.61, 0.89]
1.2.7 Late hydrocortisone vs placebo/no treatment	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.92, 1.31]
1.2.8 Late high‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.2.9 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.2.10 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.3 Death at 36 weeks' postmenstrual age	42		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.3.1 Early low‐dose dexamethasone vs placebo/no treatment	11	2110	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.93, 1.29]
1.3.2 Early high‐dose dexamethasone vs placebo/no treatment	6	681	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.80, 1.31]
1.3.3 Early hydrocortisone vs placebo/no treatment	10	1385	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.67, 1.06]
1.3.4 Early high‐dose dexamethasone vs low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.3.5 Late low‐dose dexamethasone vs placebo/no treatment	7	266	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.53, 1.76]
1.3.6 Late high‐dose dexamethasone vs placebo/no treatment	6	328	Risk Ratio (M‐H, Fixed, 95% CI)	0.43 [0.20, 0.91]
1.3.7 Late hydrocortisone vs placebo/no treatment	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.49, 1.04]
1.3.8 Late high‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.3.9 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.3.10 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.4 Failure to extubate (within seven days of treatment initiation)	23		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.4.1 Early low‐dose dexamethasone vs placebo/no treatment	3	308	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.57, 1.04]
1.4.2 Early high‐dose dexamethasone vs placebo/no treatment	3	395	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.57, 0.83]
1.4.3 Early hydrocortisone vs placebo/no treatment	2	745	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.69, 0.94]
1.4.4 Early high‐dose dexamethasone vs low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.4.5 Late low‐dose dexamethasone vs placebo/no treatment	7	270	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.52, 0.74]
1.4.6 Late high‐dose dexamethasone vs placebo/no treatment	8	490	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.61, 0.78]
1.4.7 Late hydrocortisone vs placebo/no treatment	1	347	Risk Ratio (M‐H, Fixed, 95% CI)	0.70 [0.60, 0.82]
1.4.8 Late high‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.4.9 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.4.10 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.5 Cerebral palsy (at 24 months of age)	28		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.5.1 Early low‐dose dexamethasone vs placebo/no treatment	5	617	Risk Ratio (M‐H, Fixed, 95% CI)	1.88 [1.24, 2.86]
1.5.2 Early high‐dose dexamethasone vs placebo/no treatment	2	304	Risk Ratio (M‐H, Fixed, 95% CI)	1.50 [0.74, 3.06]
1.5.3 Early hydrocortisone vs placebo/no treatment	6	1052	Risk Ratio (M‐H, Fixed, 95% CI)	1.08 [0.68, 1.69]
1.5.4 Early high‐dose dexamethasone vs low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.5.5 Late low‐dose dexamethasone vs placebo/no treatment	6	249	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.41, 1.52]
1.5.6 Late high‐dose dexamethasone vs placebo/no treatment	8	627	Risk Ratio (M‐H, Fixed, 95% CI)	1.19 [0.80, 1.78]
1.5.7 Late hydrocortisone vs placebo/no treatment	1	371	Risk Ratio (M‐H, Fixed, 95% CI)	0.52 [0.10, 2.83]
1.5.8 Late high‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.5.9 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.5.10 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.6 Major neurodevelopmental disability	17		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.6.1 Early low‐dose dexamethasone vs placebo/no treatment	2	468	Risk Ratio (M‐H, Fixed, 95% CI)	1.35 [0.95, 1.90]
1.6.2 Early high‐dose dexamethasone vs placebo/no treatment	2	304	Risk Ratio (M‐H, Fixed, 95% CI)	1.43 [0.85, 2.42]
1.6.3 Early hydrocortisone vs placebo/no treatment	3	931	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.64, 1.14]
1.6.4 Early high‐dose dexamethasone vs low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.6.5 Late low‐dose dexamethasone vs placebo/no treatment	4	193	Risk Ratio (M‐H, Fixed, 95% CI)	1.20 [0.66, 2.16]
1.6.6 Late high‐dose dexamethasone vs placebo/no treatment	4	462	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.79, 1.69]
1.6.7 Late hydrocortisone vs placebo/no treatment	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.78, 1.35]
1.6.8 Late high‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.6.9 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.6.10 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.7 Gastrointestinal perforation	21		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.7.1 Early low‐dose dexamethasone vs placebo/no treatment	6	1562	Risk Ratio (M‐H, Fixed, 95% CI)	1.75 [1.19, 2.55]
1.7.2 Early high‐dose dexamethasone vs placebo/no treatment	3	374	Risk Ratio (M‐H, Fixed, 95% CI)	1.49 [0.26, 8.58]
1.7.3 Early hydrocortisone vs placebo/no treatment	7	1104	Risk Ratio (M‐H, Fixed, 95% CI)	2.05 [1.21, 3.47]
1.7.4 Early high‐dose dexamethasone vs low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.7.5 Late low‐dose dexamethasone vs placebo/no treatment	2	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.7.6 Late high‐dose dexamethasone vs placebo/no treatment	1	25	Risk Ratio (M‐H, Fixed, 95% CI)	0.36 [0.02, 8.05]
1.7.7 Late hydrocortisone vs placebo/no treatment	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.27, 1.92]
1.7.8 Late high‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.7.9 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.7.10 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.8 Necrotizing enterocolitis ([NEC]; defined as Bell's Stage II or greater)	36		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.8.1 Early low‐dose dexamethasone vs placebo/no treatment	11	2039	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.71, 1.25]
1.8.2 Early high‐dose dexamethasone vs placebo/no treatment	4	622	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.43, 1.18]
1.8.3 Early hydrocortisone vs placebo/no treatment	10	1389	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.66, 1.37]
1.8.4 Early high‐dose dexamethasone vs low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.8.5 Late low‐dose dexamethasone vs placebo/no treatment	3	135	Risk Ratio (M‐H, Fixed, 95% CI)	0.56 [0.14, 2.22]
1.8.6 Late high‐dose dexamethasone vs placebo/no treatment	6	839	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.56, 1.91]
1.8.7 Late hydrocortisone vs placebo/no treatment	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.51, 1.63]
1.8.8 Late high‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.8.9 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.8.10 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.9 Hypertension (systolic blood pressure > 2 standard deviations above normal range)	28		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.9.1 Early low‐dose dexamethasone vs placebo/no treatment	8	1831	Risk Ratio (M‐H, Fixed, 95% CI)	1.85 [1.54, 2.22]
1.9.2 Early high‐dose dexamethasone vs placebo/no treatment	2	112	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.06, 14.51]
1.9.3 Early hydrocortisone vs placebo/no treatment	1	50	Risk Ratio (M‐H, Fixed, 95% CI)	3.00 [0.33, 26.92]
1.9.4 Early high‐dose dexamethasone vs low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.9.5 Late low‐dose dexamethasone vs placebo/no treatment	4	140	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.16, 4.68]
1.9.6 Late high‐dose dexamethasone vs placebo/no treatment	11	1053	Risk Ratio (M‐H, Fixed, 95% CI)	2.73 [1.59, 4.66]
1.9.7 Late hydrocortisone vs placebo/no treatment	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.70, 1.73]
1.9.8 Late high‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.9.9 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.9.10 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.10 Growth failure	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.10.1 Early low‐dose dexamethasone vs placebo/no treatment	1	50	Risk Ratio (M‐H, Fixed, 95% CI)	6.67 [2.27, 19.62]
1.10.2 Early high‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.10.3 Early hydrocortisone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.10.4 Early high‐dose dexamethasone vs low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.10.5 Late low‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.10.6 Late high‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.10.7 Late hydrocortisone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.10.8 Late high‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.10.9 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.10.10 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.11 Culture proven sepsis	45		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.11.1 Early low‐dose dexamethasone vs placebo/no treatment	11	2039	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.91, 1.16]
1.11.2 Early high‐dose dexamethasone vs placebo/no treatment	7	782	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.67, 1.44]
1.11.3 Early hydrocortisone vs placebo/no treatment	7	1280	Risk Ratio (M‐H, Fixed, 95% CI)	1.08 [0.94, 1.25]
1.11.4 Early high‐dose dexamethasone vs low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.11.5 Late low‐dose dexamethasone vs placebo/no treatment	6	229	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.67, 1.28]
1.11.6 Late high‐dose dexamethasone vs placebo/no treatment	12	1078	Risk Ratio (M‐H, Fixed, 95% CI)	1.21 [1.00, 1.48]
1.11.7 Late hydrocortisone vs placebo/no treatment	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.73, 1.04]
1.11.8 Late high‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.11.9 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.11.10 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable

1.1. Analysis.

Comparison 1: Systemic corticosteroid comparisons (all infants), Outcome 1: Death or BPD at 36 weeks' postmenstrual age

1.2. Analysis.

Comparison 1: Systemic corticosteroid comparisons (all infants), Outcome 2: BPD at 36 weeks' postmenstrual age

1.3. Analysis.

Comparison 1: Systemic corticosteroid comparisons (all infants), Outcome 3: Death at 36 weeks' postmenstrual age

1.4. Analysis.

Comparison 1: Systemic corticosteroid comparisons (all infants), Outcome 4: Failure to extubate (within seven days of treatment initiation)

1.5. Analysis.

Comparison 1: Systemic corticosteroid comparisons (all infants), Outcome 5: Cerebral palsy (at 24 months of age)

1.6. Analysis.

Comparison 1: Systemic corticosteroid comparisons (all infants), Outcome 6: Major neurodevelopmental disability

1.7. Analysis.

Comparison 1: Systemic corticosteroid comparisons (all infants), Outcome 7: Gastrointestinal perforation

1.8. Analysis.

Comparison 1: Systemic corticosteroid comparisons (all infants), Outcome 8: Necrotizing enterocolitis ([NEC]; defined as Bell's Stage II or greater)

1.9. Analysis.

Comparison 1: Systemic corticosteroid comparisons (all infants), Outcome 9: Hypertension (systolic blood pressure > 2 standard deviations above normal range)

1.10. Analysis.

Comparison 1: Systemic corticosteroid comparisons (all infants), Outcome 10: Growth failure

1.11. Analysis.

Comparison 1: Systemic corticosteroid comparisons (all infants), Outcome 11: Culture proven sepsis

Comparison 2. Systemic corticosteroid comparisons (infants < 28 weeks).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Death or BPD at 36 weeks' postmenstrual age	6		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
2.1.1 Early low‐dose dexamethasone vs placebo/no treatment	1	70	Risk Ratio (M‐H, Fixed, 95% CI)	1.43 [0.76, 2.69]
2.1.2 Early high‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
2.1.3 Early hydrocortisone vs placebo/no treatment	3	581	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.65, 0.93]
2.1.4 Early high‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
2.1.5 Late low‐dose dexamethasone vs placebo/no treatment	1	70	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.79, 1.11]
2.1.6 Late high‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
2.1.7 Late hydrocortisone vs placebo/no treatment	1	308	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.83, 1.09]
2.1.8 Late high‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
2.1.9 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
2.1.10 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
2.2 BPD at 36 weeks' postmenstrual age	4		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
2.2.1 Early low‐dose dexamethasone vs placebo/no treatment	1	70	Odds Ratio (M‐H, Fixed, 95% CI)	1.08 [0.30, 3.95]
2.2.2 Early high‐dose dexamethasone vs placebo/no treatment	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
2.2.3 Early hydrocortisone vs placebo/no treatment	2	571	Odds Ratio (M‐H, Fixed, 95% CI)	0.76 [0.52, 1.12]
2.2.4 Early high‐dose dexamethasone vs low‐dose dexamethasone	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
2.2.5 Late low‐dose dexamethasone vs placebo/no treatment	1	70	Odds Ratio (M‐H, Fixed, 95% CI)	0.83 [0.25, 2.77]
2.2.6 Late high‐dose dexamethasone vs placebo/no treatment	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
2.2.7 Late hydrocortisone vs placebo/no treatment	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
2.2.8 Late high‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
2.2.9 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
2.2.10 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
2.3 Death at 36 weeks' postmenstrual age	5		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
2.3.1 Early low‐dose dexamethasone vs placebo/no treatment	1	70	Risk Ratio (M‐H, Fixed, 95% CI)	2.68 [0.79, 9.06]
2.3.2 Early high‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
2.3.3 Early hydrocortisone vs placebo/no treatment	3	573	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.54, 1.04]
2.3.4 Early high‐dose dexamethasone vs low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
2.3.5 Late low‐dose dexamethasone vs placebo/no treatment	1	18	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.82, 1.22]
2.3.6 Late high‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
2.3.7 Late hydrocortisone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
2.3.8 Late high‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
2.3.9 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
2.3.10 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable

2.1. Analysis.

Comparison 2: Systemic corticosteroid comparisons (infants < 28 weeks), Outcome 1: Death or BPD at 36 weeks' postmenstrual age

2.2. Analysis.

Comparison 2: Systemic corticosteroid comparisons (infants < 28 weeks), Outcome 2: BPD at 36 weeks' postmenstrual age

2.3. Analysis.

Comparison 2: Systemic corticosteroid comparisons (infants < 28 weeks), Outcome 3: Death at 36 weeks' postmenstrual age

Comparison 3. Systemic corticosteroid comparisons (infants ≥ 28 weeks).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Death or BPD at 36 weeks' postmenstrual age	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
3.1.1 Early low‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
3.1.2 Early high‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
3.1.3 Early hydrocortisone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
3.1.4 Early high‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
3.1.5 Late low‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
3.1.6 Late high‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
3.1.7 Late hydrocortisone vs placebo/no treatment	1	63	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.72, 1.42]
3.1.8 Late high‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
3.1.9 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
3.1.10 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
3.2 BPD at 36 weeks' postmenstrual age	0		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
3.2.1 Early low‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
3.2.2 Early high‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
3.2.3 Early hydrocortisone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
3.2.4 Early high‐dose dexamethasone vs low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
3.2.5 Late low‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
3.2.6 Late high‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
3.2.7 Late hydrocortisone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
3.2.8 Late high‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
3.2.9 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
3.2.10 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
3.3 Death at 36 weeks' postmenstrual age	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
3.3.1 Early low‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
3.3.2 Early high‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
3.3.3 Early hydrocortisone vs placebo/no treatment	1	42	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.35, 2.12]
3.3.4 Early high‐dose dexamethasone vs low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
3.3.5 Late low‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
3.3.6 Late high‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
3.3.7 Late hydrocortisone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
3.3.8 Late high‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
3.3.9 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
3.3.10 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable

3.1. Analysis.

Comparison 3: Systemic corticosteroid comparisons (infants ≥ 28 weeks), Outcome 1: Death or BPD at 36 weeks' postmenstrual age

3.2. Analysis.

Comparison 3: Systemic corticosteroid comparisons (infants ≥ 28 weeks), Outcome 2: BPD at 36 weeks' postmenstrual age

3.3. Analysis.

Comparison 3: Systemic corticosteroid comparisons (infants ≥ 28 weeks), Outcome 3: Death at 36 weeks' postmenstrual age

Comparison 4. Systemic corticosteroid comparisons (birth weight < 1000 grams ).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Death or BPD at 36 weeks' postmenstrual age	8		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
4.1.1 Early low‐dose dexamethasone vs placebo/no treatment	3	868	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.81, 1.03]
4.1.2 Early high‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
4.1.3 Early hydrocortisone vs placebo/no treatment	3	431	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.83, 1.10]
4.1.4 Early high‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
4.1.5 Late low‐dose dexamethasone vs placebo/no treatment	1	70	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.79, 1.11]
4.1.6 Late high‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
4.1.7 Late hydrocortisone vs placebo/no treatment	1	64	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.89, 1.28]
4.1.8 Late high‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
4.1.9 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
4.1.10 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
4.2 BPD at 36 weeks' postmenstrual age	8		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
4.2.1 Early low‐dose dexamethasone vs placebo/no treatment	3	868	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.66, 0.98]
4.2.2 Early high‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
4.2.3 Early hydrocortisone vs placebo/no treatment	3	431	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.79, 1.16]
4.2.4 Early high‐dose dexamethasone vs low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
4.2.5 Late low‐dose dexamethasone vs placebo/no treatment	1	70	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.77, 1.21]
4.2.6 Late high‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
4.2.7 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
4.2.8 Late high‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
4.2.9 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
4.2.10 Late hydrocortisone vs placebo/no treatment	1	64	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.73, 1.56]
4.3 Death at 36 weeks' postmenstrual age	11		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
4.3.1 Early low‐dose dexamethasone vs placebo/no treatment	4	938	Risk Ratio (M‐H, Fixed, 95% CI)	1.13 [0.89, 1.42]
4.3.2 Early high‐dose dexamethasone vs placebo/no treatment	1	24	Risk Ratio (M‐H, Fixed, 95% CI)	3.33 [0.76, 14.68]
4.3.3 Early hydrocortisone vs placebo/no treatment	4	437	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.61, 1.48]
4.3.4 Early high‐dose dexamethasone vs low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
4.3.5 Late low‐dose dexamethasone vs placebo/no treatment	1	70	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.12, 3.75]
4.3.6 Late high‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
4.3.7 Late hydrocortisone vs placebo/no treatment	1	64	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.46, 2.49]
4.3.8 Late high‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
4.3.9 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
4.3.10 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable

4.1. Analysis.

Comparison 4: Systemic corticosteroid comparisons (birth weight < 1000 grams ), Outcome 1: Death or BPD at 36 weeks' postmenstrual age

4.2. Analysis.

Comparison 4: Systemic corticosteroid comparisons (birth weight < 1000 grams ), Outcome 2: BPD at 36 weeks' postmenstrual age

4.3. Analysis.

Comparison 4: Systemic corticosteroid comparisons (birth weight < 1000 grams ), Outcome 3: Death at 36 weeks' postmenstrual age

Comparison 5. Systemic corticosteroid comparisons (birth weight ≥ 1000 grams).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Death or BPD at 36 weeks' postmenstrual age	0		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
5.1.1 Early low‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
5.1.2 Early high‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
5.1.3 Early hydrocortisone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
5.1.4 Early high‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
5.1.5 Late low‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
5.1.6 Late high‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
5.1.7 Late hydrocortisone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
5.1.8 Late high‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
5.1.9 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
5.1.10 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
5.2 BPD at 36 weeks' postmenstrual age	0		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
5.2.1 Early low‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
5.2.2 Early high‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
5.2.3 Early hydrocortisone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
5.2.4 Early high‐dose dexamethasone vs low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
5.2.5 Late low‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
5.2.6 Late high‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
5.2.7 Late hydrocortisone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
5.2.8 Late high‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
5.2.9 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
5.2.10 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
5.3 Death at 36 weeks' postmenstrual age	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
5.3.1 Early low‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
5.3.2 Early high‐dose dexamethasone vs placebo/no treatment	1	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
5.3.3 Early hydrocortisone vs placebo/no treatment	1	41	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.33, 2.01]
5.3.4 Early high‐dose dexamethasone vs low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
5.3.5 Late low‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
5.3.6 Late high‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
5.3.7 Late hydrocortisone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
5.3.8 Late high‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
5.3.9 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
5.3.10 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable

5.1. Analysis.

Comparison 5: Systemic corticosteroid comparisons (birth weight ≥ 1000 grams), Outcome 1: Death or BPD at 36 weeks' postmenstrual age

5.2. Analysis.

Comparison 5: Systemic corticosteroid comparisons (birth weight ≥ 1000 grams), Outcome 2: BPD at 36 weeks' postmenstrual age

5.3. Analysis.

Comparison 5: Systemic corticosteroid comparisons (birth weight ≥ 1000 grams), Outcome 3: Death at 36 weeks' postmenstrual age

Comparison 6. Systemic corticosteroid comparisons (< 33% rescue treatment).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Death or BPD at 36 weeks' postmenstrual age	9	1331	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.86, 1.05]
6.1.1 Early low‐dose dexamethasone vs placebo/no treatment	4	722	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.77, 1.12]
6.1.2 Early high‐dose dexamethasone vs placebo/no treatment	1	70	Risk Ratio (M‐H, Fixed, 95% CI)	0.47 [0.16, 1.43]
6.1.3 Early hydrocortisone vs placebo/no treatment	2	405	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.86, 1.15]
6.1.4 Early high‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
6.1.5 Late low‐dose dexamethasone vs placebo/no treatment	1	70	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.79, 1.11]
6.1.6 Late high‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
6.1.7 Late hydrocortisone vs placebo/no treatment	1	64	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.89, 1.28]
6.1.8 Late high‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
6.1.9 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
6.1.10 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
6.2 BPD at 36 weeks' postmenstrual age	9		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
6.2.1 Early low‐dose dexamethasone vs placebo/no treatment	4	722	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.53, 0.96]
6.2.2 Early high‐dose dexamethasone vs placebo/no treatment	1	70	Risk Ratio (M‐H, Fixed, 95% CI)	0.07 [0.00, 1.24]
6.2.3 Early hydrocortisone vs placebo/no treatment	2	405	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.81, 1.22]
6.2.4 Early high‐dose dexamethasone vs low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
6.2.5 Late low‐dose dexamethasone vs placebo/no treatment	1	70	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.77, 1.21]
6.2.6 Late high‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
6.2.7 Late hydrocortisone vs placebo/no treatment	1	64	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.73, 1.56]
6.2.8 Late high‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
6.2.9 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
6.2.10 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
6.3 Death at 36 weeks' postmenstrual age	8		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
6.3.1 Early low‐dose dexamethasone vs placebo/no treatment	4	722	Risk Ratio (M‐H, Fixed, 95% CI)	1.21 [0.89, 1.65]
6.3.2 Early high‐dose dexamethasone vs placebo/no treatment	1	70	Risk Ratio (M‐H, Fixed, 95% CI)	1.89 [0.37, 9.65]
6.3.3 Early hydrocortisone vs placebo/no treatment	1	360	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.59, 1.57]
6.3.4 Early high‐dose dexamethasone vs low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
6.3.5 Late low‐dose dexamethasone vs placebo/no treatment	1	70	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.12, 3.75]
6.3.6 Late high‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
6.3.7 Late hydrocortisone vs placebo/no treatment	1	64	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.46, 2.49]
6.3.8 Late high‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
6.3.9 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
6.3.10 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable

6.1. Analysis.

Comparison 6: Systemic corticosteroid comparisons (< 33% rescue treatment), Outcome 1: Death or BPD at 36 weeks' postmenstrual age

6.2. Analysis.

Comparison 6: Systemic corticosteroid comparisons (< 33% rescue treatment), Outcome 2: BPD at 36 weeks' postmenstrual age

6.3. Analysis.

Comparison 6: Systemic corticosteroid comparisons (< 33% rescue treatment), Outcome 3: Death at 36 weeks' postmenstrual age

Comparison 7. Systemic corticosteroid comparisons (≥ 33% rescue treatment).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Death or BPD at 36 weeks' postmenstrual age	12	1474	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.76, 0.94]
7.1.1 Early low‐dose dexamethasone vs placebo/no treatment	5	1179	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.80, 1.01]
7.1.2 Early high‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
7.1.3 Early hydrocortisone vs placebo/no treatment	2	101	Risk Ratio (M‐H, Fixed, 95% CI)	0.63 [0.41, 0.98]
7.1.4 Early high‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
7.1.5 Late low‐dose dexamethasone vs placebo/no treatment	3	139	Risk Ratio (M‐H, Fixed, 95% CI)	0.70 [0.50, 0.98]
7.1.6 Late high‐dose dexamethasone vs placebo/no treatment	2	55	Risk Ratio (M‐H, Fixed, 95% CI)	0.63 [0.39, 1.01]
7.1.7 Late hydrocortisone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
7.1.8 Late high‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
7.1.9 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
7.1.10 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
7.2 BPD at 36 weeks' postmenstrual age	12		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
7.2.1 Early low‐dose dexamethasone vs placebo/no treatment	5	1179	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.65, 0.94]
7.2.2 Early high‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
7.2.3 Early hydrocortisone vs placebo/no treatment	2	101	Risk Ratio (M‐H, Fixed, 95% CI)	0.70 [0.39, 1.26]
7.2.4 Early high‐dose dexamethasone vs low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
7.2.5 Late low‐dose dexamethasone vs placebo/no treatment	3	139	Risk Ratio (M‐H, Fixed, 95% CI)	0.53 [0.32, 0.88]
7.2.6 Late high‐dose dexamethasone vs placebo/no treatment	2	55	Risk Ratio (M‐H, Fixed, 95% CI)	0.63 [0.39, 1.01]
7.2.7 Late hydrocortisone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
7.2.8 Late high‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
7.2.9 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
7.2.10 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
7.3 Death at 36 weeks' postmenstrual age	13		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
7.3.1 Early low‐dose dexamethasone vs placebo/no treatment	5	1179	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [0.87, 1.33]
7.3.2 Early high‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
7.3.3 Early hydrocortisone vs placebo/no treatment	2	101	Risk Ratio (M‐H, Fixed, 95% CI)	0.50 [0.19, 1.35]
7.3.4 Early high‐dose dexamethasone vs low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
7.3.5 Late low‐dose dexamethasone vs placebo/no treatment	3	139	Risk Ratio (M‐H, Fixed, 95% CI)	1.19 [0.55, 2.54]
7.3.6 Late high‐dose dexamethasone vs placebo/no treatment	3	96	Risk Ratio (M‐H, Fixed, 95% CI)	0.20 [0.01, 3.61]
7.3.7 Late hydrocortisone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
7.3.8 Late high‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
7.3.9 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
7.3.10 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable

7.1. Analysis.

Comparison 7: Systemic corticosteroid comparisons (≥ 33% rescue treatment), Outcome 1: Death or BPD at 36 weeks' postmenstrual age

7.2. Analysis.

Comparison 7: Systemic corticosteroid comparisons (≥ 33% rescue treatment), Outcome 2: BPD at 36 weeks' postmenstrual age

7.3. Analysis.

Comparison 7: Systemic corticosteroid comparisons (≥ 33% rescue treatment), Outcome 3: Death at 36 weeks' postmenstrual age

Comparison 8. Systemic corticosteroid comparisons (≥ 50 infants enrolled).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
8.1 Death or BPD at 36 weeks' postmenstrual age	24	4643	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.85, 0.94]
8.1.1 Early low‐dose dexamethasone vs placebo/no treatment	10	2070	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.82, 0.98]
8.1.2 Early high‐dose dexamethasone vs placebo/no treatment	3	580	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.70, 1.03]
8.1.3 Early hydrocortisone vs placebo/no treatment	5	1232	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.82, 1.01]
8.1.4 Early high‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
8.1.5 Late low‐dose dexamethasone vs placebo/no treatment	2	130	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.78, 1.13]
8.1.6 Late high‐dose dexamethasone vs placebo/no treatment	2	196	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.59, 0.86]
8.1.7 Late hydrocortisone vs placebo/no treatment	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.88, 1.09]
8.1.8 Late high‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
8.1.9 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
8.1.10 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
8.2 BPD at 36 weeks' postmenstrual age	24		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
8.2.1 Early low‐dose dexamethasone vs placebo/no treatment	10	2070	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.64, 0.87]
8.2.2 Early high‐dose dexamethasone vs placebo/no treatment	3	580	Risk Ratio (M‐H, Fixed, 95% CI)	0.64 [0.43, 0.94]
8.2.3 Early hydrocortisone vs placebo/no treatment	5	1232	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.81, 1.08]
8.2.4 Early high‐dose dexamethasone vs low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
8.2.5 Late low‐dose dexamethasone vs placebo/no treatment	2	130	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.69, 1.13]
8.2.6 Late high‐dose dexamethasone vs placebo/no treatment	2	196	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.64, 1.00]
8.2.7 Late hydrocortisone vs placebo/no treatment	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.92, 1.31]
8.2.8 Late high‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
8.2.9 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
8.2.10 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
8.3 Death at 36 weeks' postmenstrual age	24		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
8.3.1 Early low‐dose dexamethasone vs placebo/no treatment	10	2070	Risk Ratio (M‐H, Fixed, 95% CI)	1.11 [0.94, 1.30]
8.3.2 Early high‐dose dexamethasone vs placebo/no treatment	3	580	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.76, 1.35]
8.3.3 Early hydrocortisone vs placebo/no treatment	5	1235	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.67, 1.10]
8.3.4 Early high‐dose dexamethasone vs low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
8.3.5 Late low‐dose dexamethasone vs placebo/no treatment	2	130	Risk Ratio (M‐H, Fixed, 95% CI)	1.25 [0.54, 2.92]
8.3.6 Late high‐dose dexamethasone vs placebo/no treatment	2	196	Risk Ratio (M‐H, Fixed, 95% CI)	0.34 [0.13, 0.91]
8.3.7 Late hydrocortisone vs placebo/no treatment	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.49, 1.04]
8.3.8 Late high‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
8.3.9 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
8.3.10 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable

8.1. Analysis.

Comparison 8: Systemic corticosteroid comparisons (≥ 50 infants enrolled), Outcome 1: Death or BPD at 36 weeks' postmenstrual age

8.2. Analysis.

Comparison 8: Systemic corticosteroid comparisons (≥ 50 infants enrolled), Outcome 2: BPD at 36 weeks' postmenstrual age

8.3. Analysis.

Comparison 8: Systemic corticosteroid comparisons (≥ 50 infants enrolled), Outcome 3: Death at 36 weeks' postmenstrual age

Comparison 9. Systemic corticosteroid comparisons (studies at low risk of bias).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
9.1 Death or BPD at 36 weeks' postmenstrual age	32	4829	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.85, 0.94]
9.1.1 Early low‐dose dexamethasone vs placebo/no treatment	9	1960	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.83, 1.01]
9.1.2 Early high‐dose dexamethasone vs placebo/no treatment	4	620	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.68, 0.99]
9.1.3 Early hydrocortisone vs placebo/no treatment	8	1354	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.83, 1.01]
9.1.4 Early high‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
9.1.5 Late low‐dose dexamethasone vs placebo/no treatment	5	203	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.75, 1.03]
9.1.6 Late high‐dose dexamethasone vs placebo/no treatment	4	257	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.61, 0.84]
9.1.7 Late hydrocortisone vs placebo/no treatment	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.88, 1.09]
9.1.8 Late high‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
9.1.9 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
9.1.10 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
9.2 BPD at 36 weeks' postmenstrual age	32		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
9.2.1 Early low‐dose dexamethasone vs placebo/no treatment	9	1960	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.66, 0.91]
9.2.2 Early high‐dose dexamethasone vs placebo/no treatment	4	620	Risk Ratio (M‐H, Fixed, 95% CI)	0.59 [0.41, 0.86]
9.2.3 Early hydrocortisone vs placebo/no treatment	8	1354	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.82, 1.07]
9.2.4 Early high‐dose dexamethasone vs low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
9.2.5 Late low‐dose dexamethasone vs placebo/no treatment	5	203	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.69, 1.04]
9.2.6 Late high‐dose dexamethasone vs placebo/no treatment	4	257	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.64, 0.94]
9.2.7 Late hydrocortisone vs placebo/no treatment	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.92, 1.31]
9.2.8 Late high‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
9.2.9 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
9.2.10 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
9.3 Death at 36 weeks' postmenstrual age	34		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
9.3.1 Early low‐dose dexamethasone vs placebo/no treatment	9	1960	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.93, 1.31]
9.3.2 Early high‐dose dexamethasone vs placebo/no treatment	4	620	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.78, 1.35]
9.3.3 Early hydrocortisone vs placebo/no treatment	9	1363	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.68, 1.08]
9.3.4 Early high‐dose dexamethasone vs low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
9.3.5 Late low‐dose dexamethasone vs placebo/no treatment	5	203	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.52, 1.96]
9.3.6 Late high‐dose dexamethasone vs placebo/no treatment	5	298	Risk Ratio (M‐H, Fixed, 95% CI)	0.43 [0.20, 0.91]
9.3.7 Late hydrocortisone vs placebo/no treatment	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.49, 1.04]
9.3.8 Late high‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
9.3.9 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
9.3.10 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable

9.1. Analysis.

Comparison 9: Systemic corticosteroid comparisons (studies at low risk of bias), Outcome 1: Death or BPD at 36 weeks' postmenstrual age

9.2. Analysis.

Comparison 9: Systemic corticosteroid comparisons (studies at low risk of bias), Outcome 2: BPD at 36 weeks' postmenstrual age

9.3. Analysis.

Comparison 9: Systemic corticosteroid comparisons (studies at low risk of bias), Outcome 3: Death at 36 weeks' postmenstrual age

Comparison 10. Systemic corticosteroid comparisons (dose ranges).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
10.1 Death or BPD at 36 weeks' postmenstrual age	45	5317	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.84, 0.93]
10.1.1 Early low‐dose dexamethasone vs placebo/no treatment	8	1412	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.83, 1.04]
10.1.2 Early moderate‐dose dexamethasone vs placebo/no treatment	4	717	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.71, 0.95]
10.1.3 Early high‐dose dexamethasone vs placebo/no treatment	5	662	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.72, 0.99]
10.1.4 Early low‐dose hydrocortisone vs placebo/no treatment	9	1376	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.82, 0.99]
10.1.5 Early high‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.1.6 Late low‐dose dexamethasone vs placebo/no treatment	4	188	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.78, 1.07]
10.1.7 Late moderate‐dose dexamethasone vs placebo/no treatment	4	101	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.54, 0.87]
10.1.8 Late high‐dose dexamethasone vs placebo/no treatment	5	275	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.59, 0.82]
10.1.9 Late low‐dose hydrocortisone vs placebo/no treatment	1	64	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.89, 1.28]
10.1.10 Late moderate‐dose hydrocortisone vs placebo/no treatment	1	371	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.85, 1.09]
10.1.11 Late moderate‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	3	126	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [0.68, 1.97]
10.1.12 Late moderate‐dose dexamethasone (2 to 4 mg/kg) vs late high‐dose dexamethasone (> 4 mg/kg)	1	25	Risk Ratio (M‐H, Fixed, 95% CI)	1.49 [0.94, 2.37]
10.1.13 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.1.14 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.2 BPD at 36 weeks' postmenstrual age	45		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
10.2.1 Early low‐dose dexamethasone vs placebo/no treatment	8	1412	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.69, 1.00]
10.2.2 Early moderate‐dose dexamethasone vs placebo/no treatment	5	787	Risk Ratio (M‐H, Fixed, 95% CI)	0.56 [0.43, 0.73]
10.2.3 Early high‐dose dexamethasone vs placebo/no treatment	4	592	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.50, 0.95]
10.2.4 Early low‐dose hydrocortisone vs placebo/no treatment	9	1376	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.81, 1.06]
10.2.5 Early high‐dose dexamethasone vs low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.2.6 Late low‐dose dexamethasone vs placebo/no treatment	4	188	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.69, 1.05]
10.2.7 Late moderate‐dose dexamethasone vs placebo/no treatment	4	101	Risk Ratio (M‐H, Fixed, 95% CI)	0.65 [0.46, 0.92]
10.2.8 Late high‐dose dexamethasone vs placebo/no treatment	5	275	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.59, 0.88]
10.2.9 Late low‐dose hydrocortisone vs placebo/no treatment	1	64	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.73, 1.56]
10.2.10 Late moderate‐dose hydrocortisone vs placebo/no treatment	1	371	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.91, 1.34]
10.2.11 Late moderate‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	3	126	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.54, 1.67]
10.2.12 Late moderate‐dose dexamethasone (2 to 4 mg/kg) vs late high‐dose dexamethasone (> 4 mg/kg)	1	25	Risk Ratio (M‐H, Fixed, 95% CI)	2.17 [0.87, 5.37]
10.2.13 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.2.14 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.3 Death at 36 weeks' postmenstrual age	47		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
10.3.1 Early low‐dose dexamethasone vs placebo/no treatment	8	1412	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [0.87, 1.32]
10.3.2 Early moderate‐dose dexamethasone vs placebo/no treatment	5	787	Risk Ratio (M‐H, Fixed, 95% CI)	1.14 [0.90, 1.46]
10.3.3 Early high‐dose dexamethasone vs placebo/no treatment	4	592	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.78, 1.32]
10.3.4 Early low‐dose hydrocortisone vs placebo/no treatment	10	1385	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.67, 1.06]
10.3.5 Early high‐dose dexamethasone vs low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.3.6 Late low‐dose dexamethasone vs placebo/no treatment	4	188	Risk Ratio (M‐H, Fixed, 95% CI)	1.27 [0.61, 2.63]
10.3.7 Late moderate‐dose dexamethasone vs placebo/no treatment	5	142	Risk Ratio (M‐H, Fixed, 95% CI)	0.59 [0.26, 1.37]
10.3.8 Late high‐dose dexamethasone vs placebo/no treatment	5	275	Risk Ratio (M‐H, Fixed, 95% CI)	0.52 [0.24, 1.12]
10.3.9 Late low‐dose hydrocortisone vs placebo/no treatment	1	64	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.46, 2.49]
10.3.10 Late moderate‐dose hydrocortisone vs placebo/no treatment	1	371	Risk Ratio (M‐H, Fixed, 95% CI)	0.65 [0.43, 1.00]
10.3.11 Late moderate‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	3	126	Risk Ratio (M‐H, Fixed, 95% CI)	1.87 [0.41, 8.47]
10.3.12 Late moderate‐dose dexamethasone (2 to 4 mg/kg) vs late high‐dose dexamethasone (> 4 mg/kg)	1	25	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.23, 2.91]
10.3.13 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.3.14 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.4 Failure to extubate (within seven days of treatment initiation)	28		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
10.4.1 Early low‐dose dexamethasone vs placebo/no treatment	2	288	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.60, 1.14]
10.4.2 Early moderate‐dose dexamethasone vs placebo/no treatment	2	90	Risk Ratio (M‐H, Fixed, 95% CI)	0.45 [0.28, 0.72]
10.4.3 Early high‐dose dexamethasone vs placebo/no treatment	2	325	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.60, 0.90]
10.4.4 Early low‐dose hydrocortisone vs placebo/no treatment	2	745	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.69, 0.94]
10.4.5 Early high‐dose dexamethasone vs low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.4.6 Late low‐dose dexamethasone vs placebo/no treatment	4	187	Risk Ratio (M‐H, Fixed, 95% CI)	0.65 [0.53, 0.79]
10.4.7 Late moderate‐dose dexamethasone vs placebo/no treatment	5	147	Risk Ratio (M‐H, Fixed, 95% CI)	0.61 [0.48, 0.77]
10.4.8 Late high‐dose dexamethasone vs placebo/no treatment	7	437	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.61, 0.78]
10.4.9 Late low‐dose hydrocortisone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.4.10 Late moderate‐dose hydrocortisone vs placebo/no treatment	1	347	Risk Ratio (M‐H, Fixed, 95% CI)	0.70 [0.60, 0.82]
10.4.11 Late moderate‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	3	126	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.64, 1.07]
10.4.12 Late moderate‐dose dexamethasone (2 to 4 mg/kg) vs late high‐dose dexamethasone (> 4 mg/kg)	1	25	Risk Ratio (M‐H, Fixed, 95% CI)	1.08 [0.67, 1.76]
10.4.13 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.4.14 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.5 Cerebral palsy (at 24 months of age)	32		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
10.5.1 Early low‐dose dexamethasone vs placebo/no treatment	4	567	Risk Ratio (M‐H, Fixed, 95% CI)	2.01 [1.30, 3.11]
10.5.2 Early moderate‐dose dexamethasone vs placebo/no treatment	1	50	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.12, 3.65]
10.5.3 Early high‐dose dexamethasone vs placebo/no treatment	2	304	Risk Ratio (M‐H, Fixed, 95% CI)	1.50 [0.74, 3.06]
10.5.4 Early low‐dose hydrocortisone vs placebo/no treatment	6	1052	Risk Ratio (M‐H, Fixed, 95% CI)	1.08 [0.68, 1.69]
10.5.5 Early high‐dose dexamethasone vs low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.5.6 Late low‐dose dexamethasone vs placebo/no treatment	3	166	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.24, 1.60]
10.5.7 Late moderate‐dose dexamethasone vs placebo/no treatment	4	106	Risk Ratio (M‐H, Fixed, 95% CI)	1.46 [0.66, 3.23]
10.5.8 Late high‐dose dexamethasone vs placebo/no treatment	8	615	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [0.77, 1.75]
10.5.9 Late low‐dose hydrocortisone vs placebo/no treatment	1	371	Risk Ratio (M‐H, Fixed, 95% CI)	0.52 [0.10, 2.83]
10.5.10 Late moderate‐dose hydrocortisone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.5.11 Late moderate‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	2	109	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.29, 4.13]
10.5.12 Late moderate‐dose dexamethasone (2 to 4 mg/kg) vs late high‐dose dexamethasone (> 4 mg/kg)	1	25	Risk Ratio (M‐H, Fixed, 95% CI)	11.85 [0.72, 193.82]
10.5.13 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.5.14 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.6 Major neurodevelopmental disability	21		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
10.6.1 Early low‐dose dexamethasone vs placebo/no treatment	2	468	Risk Ratio (M‐H, Fixed, 95% CI)	1.35 [0.95, 1.90]
10.6.2 Early moderate‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.6.3 Early high‐dose dexamethasone vs placebo/no treatment	2	304	Risk Ratio (M‐H, Fixed, 95% CI)	1.43 [0.85, 2.42]
10.6.4 Early low‐dose hydrocortisone vs placebo/no treatment	3	931	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.64, 1.14]
10.6.5 Early high‐dose dexamethasone vs low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.6.6 Late low‐dose dexamethasone vs placebo/no treatment	2	130	Risk Ratio (M‐H, Fixed, 95% CI)	1.44 [0.69, 3.01]
10.6.7 Late moderate‐dose dexamethasone vs placebo/no treatment	4	109	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.50, 1.76]
10.6.8 Late high‐dose dexamethasone vs placebo/no treatment	3	427	Risk Ratio (M‐H, Fixed, 95% CI)	1.13 [0.75, 1.72]
10.6.9 Late low‐dose hydrocortisone vs placebo/no treatment	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.78, 1.35]
10.6.10 Late moderate‐dose hydrocortisone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.6.11 Late moderate‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	2	109	Risk Ratio (M‐H, Fixed, 95% CI)	1.64 [0.63, 4.28]
10.6.12 Late moderate‐dose dexamethasone (2 to 4 mg/kg) vs late high‐dose dexamethasone (> 4 mg/kg)	1	25	Risk Ratio (M‐H, Fixed, 95% CI)	9.69 [0.58, 163.02]
10.6.13 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.6.14 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.7 Gastrointestinal perforation	24		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
10.7.1 Early low‐dose dexamethasone vs placebo/no treatment	5	1024	Risk Ratio (M‐H, Fixed, 95% CI)	1.99 [1.16, 3.41]
10.7.2 Early moderate‐dose dexamethasone vs placebo/no treatment	2	608	Risk Ratio (M‐H, Fixed, 95% CI)	1.53 [0.89, 2.61]
10.7.3 Early high‐dose dexamethasone vs placebo/no treatment	2	304	Risk Ratio (M‐H, Fixed, 95% CI)	1.49 [0.26, 8.58]
10.7.4 Early low‐dose hydrocortisone vs placebo/no treatment	7	1104	Risk Ratio (M‐H, Fixed, 95% CI)	2.05 [1.21, 3.47]
10.7.5 Early high‐dose dexamethasone vs low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.7.6 Late low‐dose dexamethasone vs placebo/no treatment	2	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.7.7 Late moderate‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.7.8 Late high‐dose dexamethasone vs placebo/no treatment	1	25	Risk Ratio (M‐H, Fixed, 95% CI)	0.36 [0.02, 8.05]
10.7.9 Late low‐dose hydrocortisone vs placebo/no treatment	1	64	Risk Ratio (M‐H, Fixed, 95% CI)	5.31 [0.27, 106.46]
10.7.10 Late moderate‐dose hydrocortisone vs placebo/no treatment	1	371	Risk Ratio (M‐H, Fixed, 95% CI)	0.47 [0.15, 1.49]
10.7.11 Late moderate‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	3	126	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.16, 7.45]
10.7.12 Late moderate‐dose dexamethasone (2 to 4 mg/kg) vs late high‐dose dexamethasone (> 4 mg/kg)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.7.13 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.7.14 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.8 Necrotizing enterocolitis ([NEC]; defined as Bell's Stage II or greater)	38		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
10.8.1 Early low‐dose dexamethasone vs placebo/no treatment	7	1312	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.75, 1.50]
10.8.2 Early moderate‐dose dexamethasone vs placebo/no treatment	5	797	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.48, 1.22]
10.8.3 Early high‐dose dexamethasone vs placebo/no treatment	3	552	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.41, 1.17]
10.8.4 Early low‐dose hydrocortisone vs placebo/no treatment	10	1389	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.66, 1.37]
10.8.5 Early high‐dose dexamethasone vs low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.8.6 Late low‐dose dexamethasone vs placebo/no treatment	2	92	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.14, 3.22]
10.8.7 Late moderate‐dose dexamethasone vs placebo/no treatment	3	455	Risk Ratio (M‐H, Fixed, 95% CI)	0.44 [0.16, 1.25]
10.8.8 Late high‐dose dexamethasone vs placebo/no treatment	4	427	Risk Ratio (M‐H, Fixed, 95% CI)	1.66 [0.76, 3.65]
10.8.9 Late low‐dose hydrocortisone vs placebo/no treatment	1	64	Risk Ratio (M‐H, Fixed, 95% CI)	1.42 [0.35, 5.84]
10.8.10 Late moderate‐dose hydrocortisone vs placebo/no treatment	1	371	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.43, 1.58]
10.8.11 Late moderate‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	2	109	Risk Ratio (M‐H, Fixed, 95% CI)	4.37 [0.51, 37.66]
10.8.12 Late moderate‐dose dexamethasone (2 to 4 mg/kg) vs late high‐dose dexamethasone (> 4 mg/kg)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.8.13 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.8.14 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.9 Hypertension (systolic blood pressure > 2 standard deviations above normal range)	33		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
10.9.1 Early low‐dose dexamethasone vs placebo/no treatment	5	1133	Risk Ratio (M‐H, Fixed, 95% CI)	2.26 [1.81, 2.82]
10.9.2 Early moderate‐dose dexamethasone vs placebo/no treatment	4	768	Risk Ratio (M‐H, Fixed, 95% CI)	1.37 [1.00, 1.87]
10.9.3 Early high‐dose dexamethasone vs placebo/no treatment	1	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.9.4 Early low‐dose hydrocortisone vs placebo/no treatment	1	50	Risk Ratio (M‐H, Fixed, 95% CI)	3.00 [0.33, 26.92]
10.9.5 Early high‐dose dexamethasone vs low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.9.6 Late low‐dose dexamethasone vs placebo/no treatment	2	82	Risk Ratio (M‐H, Fixed, 95% CI)	0.28 [0.01, 6.25]
10.9.7 Late moderate‐dose dexamethasone vs placebo/no treatment	6	516	Risk Ratio (M‐H, Fixed, 95% CI)	2.96 [1.40, 6.27]
10.9.8 Late high‐dose dexamethasone vs placebo/no treatment	8	606	Risk Ratio (M‐H, Fixed, 95% CI)	2.37 [1.15, 4.89]
10.9.9 Late low‐dose hydrocortisone vs placebo/no treatment	1	64	Risk Ratio (M‐H, Fixed, 95% CI)	1.39 [0.82, 2.37]
10.9.10 Late moderate‐dose hydrocortisone vs placebo/no treatment	1	371	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.36, 1.80]
10.9.11 Late moderate‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	3	126	Risk Ratio (M‐H, Fixed, 95% CI)	3.18 [1.15, 8.83]
10.9.12 Late moderate‐dose dexamethasone (2 to 4 mg/kg) vs late high‐dose dexamethasone (> 4 mg/kg)	1	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.9.13 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.9.14 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.10 Growth failure	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
10.10.1 Early low‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.10.2 Early moderate‐dose dexamethasone vs placebo/no treatment	1	50	Risk Ratio (M‐H, Fixed, 95% CI)	6.67 [2.27, 19.62]
10.10.3 Early high‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.10.4 Early low‐dose hydrocortisone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.10.5 Early high‐dose dexamethasone vs low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.10.6 Late low‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.10.7 Late moderate‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.10.8 Late high‐dose dexamethasone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.10.9 Late low‐dose hydrocortisone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.10.10 Late moderate‐dose hydrocortisone vs placebo/no treatment	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.10.11 Late moderate‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.10.12 Late moderate‐dose dexamethasone (2 to 4 mg/kg) vs late high‐dose dexamethasone (> 4 mg/kg)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.10.13 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.10.14 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.11 Culture proven sepsis	49		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
10.11.1 Early low‐dose dexamethasone vs placebo/no treatment	7	1312	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.88, 1.21]
10.11.2 Early moderate‐dose dexamethasone vs placebo/no treatment	5	797	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.84, 1.22]
10.11.3 Early high‐dose dexamethasone vs placebo/no treatment	6	712	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.70, 1.52]
10.11.4 Early low‐dose hydrocortisone vs placebo/no treatment	7	1280	Risk Ratio (M‐H, Fixed, 95% CI)	1.08 [0.94, 1.25]
10.11.5 Early high‐dose dexamethasone vs low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.11.6 Late low‐dose dexamethasone vs placebo/no treatment	3	151	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.67, 1.32]
10.11.7 Late moderate‐dose dexamethasone vs placebo/no treatment	7	536	Risk Ratio (M‐H, Fixed, 95% CI)	1.37 [1.04, 1.82]
10.11.8 Late high‐dose dexamethasone vs placebo/no treatment	9	631	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.80, 1.36]
10.11.9 Late low‐dose hydrocortisone vs placebo/no treatment	1	64	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.53, 1.61]
10.11.10 Late moderate‐dose hydrocortisone vs placebo/no treatment	1	371	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.71, 1.04]
10.11.11 Late moderate‐dose dexamethasone (2 to 4 mg/kg) vs late low‐dose dexamethasone (< 2 mg/kg)	2	109	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.41, 2.94]
10.11.12 Late moderate‐dose dexamethasone (2 to 4 mg/kg) vs late high‐dose dexamethasone (> 4 mg/kg)	1	25	Risk Ratio (M‐H, Fixed, 95% CI)	1.63 [0.60, 4.38]
10.11.13 Late low‐dose dexamethasone vs early low‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.11.14 Late high‐dose dexamethasone vs early high‐dose dexamethasone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable

10.1. Analysis.

Comparison 10: Systemic corticosteroid comparisons (dose ranges), Outcome 1: Death or BPD at 36 weeks' postmenstrual age

10.2. Analysis.

Comparison 10: Systemic corticosteroid comparisons (dose ranges), Outcome 2: BPD at 36 weeks' postmenstrual age

10.3. Analysis.

Comparison 10: Systemic corticosteroid comparisons (dose ranges), Outcome 3: Death at 36 weeks' postmenstrual age

10.4. Analysis.

Comparison 10: Systemic corticosteroid comparisons (dose ranges), Outcome 4: Failure to extubate (within seven days of treatment initiation)

10.5. Analysis.

Comparison 10: Systemic corticosteroid comparisons (dose ranges), Outcome 5: Cerebral palsy (at 24 months of age)

10.6. Analysis.

Comparison 10: Systemic corticosteroid comparisons (dose ranges), Outcome 6: Major neurodevelopmental disability

10.7. Analysis.

Comparison 10: Systemic corticosteroid comparisons (dose ranges), Outcome 7: Gastrointestinal perforation

10.8. Analysis.

Comparison 10: Systemic corticosteroid comparisons (dose ranges), Outcome 8: Necrotizing enterocolitis ([NEC]; defined as Bell's Stage II or greater)

10.9. Analysis.

Comparison 10: Systemic corticosteroid comparisons (dose ranges), Outcome 9: Hypertension (systolic blood pressure > 2 standard deviations above normal range)

10.10. Analysis.

Comparison 10: Systemic corticosteroid comparisons (dose ranges), Outcome 10: Growth failure

10.11. Analysis.

Comparison 10: Systemic corticosteroid comparisons (dose ranges), Outcome 11: Culture proven sepsis

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Anttila 2005.

Study characteristics
Methods	Multicenter double‐blind placebo‐controlled randomized trial
Participants	Inclusion: 109 infants with birthweight 500 g to 999 g, gestation < 32 weeks, need for mechanical ventilation and supplemental oxygen by 4 h of age. Stratified by weight (500 g to 749 g vs 750 g to 999 g) Exclusions: life‐threatening congenital anomalies or known chromosomal anomalies
Interventions	Four doses of dexamethasone 0.25 mg/kg each at 12‐hourly intervals or normal saline as placebo. First dose was given before 6 h. Open‐label dexamethasone was allowed when deemed necessary by attending physician, but its use was discouraged.
Outcomes	Survival to 36 weeks without IVH (grade III to IV) PVL (echodensities after first week or periventricular cysts on ultrasound) BPD (oxygen at 36 weeks) Growth Duration of assisted ventilation and oxygen Late corticosteroid treatment Infection Hyperglycemia Hypertension, ROP PDA GI bleeding and perforation NEC
Notes	This paper also reported a meta‐analysis of early short vs early prolonged dexamethasone treatment.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Random allocation by coded vials prepared in the pharmacy at each center
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 primary and secondary outcomes reported
Other bias	Low risk	None

Ariagno 1987.

Study characteristics
Methods	Double‐blind randomized controlled trial
Participants	Inclusion: 34 preterm infants < 1501 g birthweight, ventilator‐dependent, no weaning from mechanical ventilation at 3 weeks. CXR changes
Interventions	Two regimens were used in this study: 10‐day or 7‐day: 10‐day: intravenous dexamethasone 1 mg/kg/d for 4 days followed by 0.5 mg/kg/d for 6 days; or 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 received the 7‐day protocol. Saline placebos were used during respective treatment periods.
Outcomes	Pulmonary function tests Failure to extubate Mortality Hyperglycemia 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 randomization: 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	Insufficient information
Other bias	Low risk	None

Avery 1985.

Study characteristics
Methods	Randomized controlled trial
Participants	Inclusion: 16 infants < 1500 g birthweight, age 2 to 6 weeks, had 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 h
Interventions	Intravenous dexamethasone 0.5 mg/kg/d every 12 h intravenously for 3 days, 0.3 mg/kg/d for 3 days decreased by 10% every 3 days A placebo was not administered.
Outcomes	Pulmonary function tests Extubation within 3 days Mortality Sepsis Hypertension Hyperglycemia Duration of hospital stay
Notes	n/a
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Random allocation by opening sealed envelopes Stratification by birthweight and sequential analysis
Allocation concealment (selection bias)	Low risk	Random allocation by opening sealed envelopes Stratification by birthweight and sequential analysis Blinding of randomization: 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

Baden 1972.

Study characteristics
Methods	Double‐blind placebo‐controlled randomized trial
Participants	Inclusion: 44 preterm infants < 24 h old with respiratory distress confirmed both clinically and radiologically
Interventions	Hydrocortisone 25 mg/kg on admission and 12 h later intravenously Control group given placebo
Outcomes	Mortality FiO2 Cortisol levels Blood gases
Notes	The oldest study, carried out in 1972, used hydrocortisone in a very short course of treatment.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random allocation via random numbers and sealed envelopes
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

Batton 2012.

Study characteristics
Methods	Multicenter randomized placebo‐controlled trial
Participants	Inclusion: 10 infants at 23 to 26 completed weeks’ gestation with study‐defined low blood pressure
Interventions	Hydrocortisone 1 mg/kg loading, then 0.5 mg/kg at 12‐hourly intervals for 6 doses
Outcomes	Short‐term outcomes during primary hospitalization of mortality BPD (not defined) IVH grade III or IV PVL NEC requiring surgery
Notes	n/a
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Enrolled infants were randomized from a prespecified sequence, allocated by center, and received treatment from an investigational pharmacist.
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)	Unclear risk	The primary outcome of the study was to determine the feasibility of a randomized trial of blood pressure management rather than the effects on bronchopulmonary dysplasia.
Other bias	Low risk	None

Baud 2016.

Study characteristics
Methods	Multicenter double‐blind randomized controlled trial
Participants	Inclusion: 523 inborn infants at 24 to 27 weeks’ gestational age in the first 24 h after birth recruited from 21 French centers with NICU facilities between 25 May 2008 and 31 January 2014 Exclusions: rupture of membranes at < 22 weeks’ gestation; birthweight < 3rd percentile according to French sex‐customized curves; severe perinatal asphyxia (Apgar score = 0 to 3 for longer than 5 min, cord blood pH < 7·00, or both) and expected to die shortly after birth; congenital malformations (birth defects or major structural abnormalities detectable prenatally); known chromosomal aberrations
Interventions	Hydrocortisone hemisuccinate 1 mg/kg/d divided into 2 doses for 7 days, then 0.5 mg/kg/d once per day for 3 days (total dose 8.5 mg/kg) Control infants were given an equivalent volume of 5% glucose placebo. Open‐label corticosteroids were not allowed during first 10 days of treatment.
Outcomes	Short‐term primary outcomes Survival free of BPD at 36 weeks’ postmenstrual age. BPD was diagnosed at 36 weeks (± 3 days) without additional testing if an infant required mechanical ventilation, noninvasive ventilation with continuous positive airway pressure, or 30% or more supplemental oxygen concentration. BPD was diagnosed in infants requiring only 22% to 29% oxygen if the oxygen requirement was confirmed by a standardized oxygen‐reduction test, which was completed by neonatologists masked to treatment groups. Secondary outcomes BDA at 36 weeks’ postmenstrual age Mortality Surgical ligation of PDA Air leaks Pulmonary hemorrhage Insulin requirement Late‐onset sepsis (positive blood culture or symptomatic pneumonia) NEC GI perforation Grade III or IV IVH Cystic PVL Mortality before discharge Severe ROP (requiring laser treatment or surgery) Longer‐term outcome Children were assessed at approximately 22 months’ corrected age. Children underwent a French‐based developmental assessment that was standardized in the mid‐1990s and a standardized neurodevelopmental assessment based on the Amiel‐Tison and Denver scales. NDI was defined as any disability on the standardized neurodevelopmental assessment, cerebral palsy, blindness, deafness, or a formal developmental assessment score < −1 SD (< 85). Moderate‐to‐severe impairment was defined as a developmental quotient < 70 for the approximately 80% of children who had the developmental assessment or moderate or severe disability on the standardized neurodevelopmental assessment in the 20% without the neurodevelopmental assessment. The main publication of outcome data in JAMA (2017) incorrectly included cerebral palsy in the classification of moderate‐to‐severe impairment (Olivier Baud, personal communication 23rd September 2020). No children were blind or deaf.
Notes	Study was stopped early because of lack of funding, rather than because any predetermined threshold had been reached, at approximately 2/3 of projected sample size of 786.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomly assigned (1:1) via a secure study website Strata for 24 to 25 weeks and 26 to 27 weeks’ gestation
Allocation concealment (selection bias)	Low risk	Remote electronic allocation
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Blinding maintained by identical placebo
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcome assessors blinded to knowledge of treatment group at both primary hospitalization phase and 22‐month follow‐up phase
Incomplete outcome data (attrition bias) All outcomes	Low risk	Low risk for short‐term outcomes, as all but 2 randomized participants had short‐term outcomes reported Moderate risk at follow‐up phase because 93% (379/406) of long‐term survivors were assessed at 22 months’ corrected age, but only 75% (304/406) had a full neurological and developmental assessment
Selective reporting (reporting bias)	Low risk	Primary and secondary outcomes reported
Other bias	Unclear risk	Early stopping of trial may or may not introduce bias.

Biswas 2003.

Study characteristics
Methods	Multicenter placebo‐controlled randomized trial
Participants	Inclusion: 253 infants < 30 weeks’ gestation, within 9 h of birth at entry, all mechanically ventilated
Interventions	Hydrocortisone 1 mg/kg/d as continuous infusion for 5 days, then 0.5 mg/kg/d for 2 days Also given T3 at 6 µg/kg/d for 5 days, halving to 3 µg/kg/d for 2 days Controls were given equal‐volume infusion of 5% dextrose.
Outcomes	Primary outcome Mortality or ventilator dependence at 7 days, or mortality or oxygen dependence at 14 days Secondary outcomes Duration of ventilation Oxygen dependence and hospitalization Oxygen dependency at 36 weeks IVH PVL PDA NEC
Notes	Hydrocortisone combined with T3 infusion
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomization by Oxford Perinatal Trials Unit
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

Bonsante 2007.

Study characteristics
Methods	Two‐center randomized double‐blind placebo‐controlled trial
Participants	Inclusion: 50 infants of less than 1250 g or at 24 weeks' to 30 weeks’ gestation who were less than 48 h old and were ventilator‐dependent after surfactant treatment Exclusions: cardiopulmonary malformations, perinatal asphyxia, mortality within 12 h after recruitment, or use of steroids for any reason within 12 days after birth. Researchers excluded no infants for these latter two reasons. Infants were stratified by birthweight (not specified), gestational age (not specified), and antenatal steroid exposure.
Interventions	Active treatment: 12‐day course of hydrocortisone (1.0 mg/kg for 9 days, then 0.5 mg/kg/d for 3 days) (total dose 10.5 mg/kg hydrocortisone over 12 days) (n = 25) Placebo group: equal volume of 0.9% saline (n = 25)
Outcomes	Primary outcomes Survival free of disability at 2 years of age Mortality ≤ 2 years of age Neurological outcome after discharge Secondary outcomes Rate of BPD Mortality or BPD Failure to extubate Other complications during primary hospital stay including GI perforation, severe IVH (grade III or IV), and cystic PVL Long‐term neurosensory impairment (blindness, deafness, developmental delay assessed by MDI on Bayley scales, cerebral palsy) Disabilities Severe: any of severe cerebral palsy (not likely to walk), blindness, or severe developmental delay (MDI < 55) Moderate: moderate cerebral palsy (not walking at 2 years but likely to do so), deafness, moderate developmental delay (MDI 55 to < 70) Mild: mild cerebral palsy (walking at 2 years), or mild developmental delay (MDI 70 to < 85)
Notes	Study authors based the sample size calculation on the results of Watterberg 1999, resulting in an estimate of 138 infants to be recruited. The study was stopped early when 50 infants had been enrolled because of reports from other trials of spontaneous intestinal perforation with early hydrocortisone treatment.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated randomization centrally
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	Outcome assessment blind: yes
Incomplete outcome data (attrition bias) All outcomes	Low risk	Complete follow‐up reporting: yes for outcomes during primary hospital stay; 98% of surviving infants traced to 2 years of age
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported
Other bias	Low risk	None

Brozanski 1995.

Study characteristics
Methods	Double‐blind randomized controlled trial
Participants	Inclusion: 78 infants < 1501 g who were ventilator‐dependent at 7 days Exclusions: complex congenital anomalies, pulmonary hypoplasia, hemodynamic 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) Hyperglycemia Pulmonary air leak Sepsis Worsening IVH (grade > II)
Notes	n/a
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 birthweight (< 1000 grams vs > 999 g)
Allocation concealment (selection bias)	Low risk	Random allocation via sealed envelopes kept in the pharmacy Stratification by sex and birthweight (< 1000 g vs > 999) Blinding of randomization: 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	Multicenter double‐blind randomized 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 Exclusions: major malformations (n = 2)
Interventions	Dexamethasone 0.6 mg/kg/d for 1 week intravenously or orally, with an option to give a 2nd 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	Durations of mechanical ventilation Death, sepsis NEC Pneumothorax Blood pressure Plasma glucose GI bleeding Oxygen 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)	Unclear risk	Random allocation via unmarked vials and telephone randomization Stratification by clinical center and by whether babies were ventilator‐dependent
Allocation concealment (selection bias)	Low risk	Random allocation via unmarked vials and telephone randomization Stratification by clinical center and by whether babies were ventilator‐dependent Blinding of randomization: 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	Single‐center, randomized, double‐blind, placebo‐controlled study investigating a moderate dosage vs a high dosage of dexamethasone vs saline placebo
Participants	Inclusion: 36 preterm infants with a birthweight ≤ 1250 g, a gestational age of ≤ 30 weeks, and a postnatal age of more than 14 days All infants were ventilated with a rate of at least 15 cycles per minute and received more than 30% oxygen. Attempts to wean these settings failed over a period of at least 72 h. Exclusions: infants with a symptomatic PDA, renal failure or sepsis at entry
Interventions	The included infants were randomly assigned to 1 of 3 dosage regimens: a high‐dosage regimen with a cumulative dose of 7.9 mg/kg of dexamethasone administered over a 42‐day course: 0.5 mg/kg/d for 3 days, 0.3 mg/kg/d for 3 days, a 10% decrease every 3 days until 0.1 mg/kg/d, 0.1 mg/kg/d for 3 days, 0.1 mg/kg/d on alternate days for 7 days; a moderate‐dosage regimen with a cumulative dose of 3 mg/kg administered over 18 days: 0.5 mg/kg/d for 3 days, a 50% decrease every 3 days until 0.06 mg/kg/d, 0.06 mg/kg/d for 3 days, 0.06 mg/kg/d on alternate days for 7 days; or saline placebo. Medication was given intravenously and divided into 2 dosages per day. Each infant received the same volume of medication by using different concentrations of dexamethasone. Infants in the low‐dosage regimen group received additional saline injections to complete the 42‐day course. The placebo group was excluded for the purpose of this review. No treatment with corticosteroids outside the protocol was allowed.
Outcomes	Duration of IPPV Duration of oxygen Duration of hospital stay Rates of pneumothorax Rates of hyperglycemia Rates of sepsis Rates of GI bleeding Rates of transfusions Rates of ROP Rates of mortality Growth and development
Notes	The original investigator provided additional data on duration of mechanical ventilation, failure to extubate on day 7 and the total number of participants with a Bayley MDI < 2 SD. There was no statement in the manuscript of funding of the study.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomized allocation to 1 of 3 groups via a table of random numbers kept in the pharmacy
Allocation concealment (selection bias)	Low risk	Performed by a pharmacist unaware of the clinical status of the infant
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Individual daily doses were drawn from a specific vial designated for that treatment day, ensuring the same volume of study medication every day. Infants in the moderate‐dosage regimen received placebo saline for the remaining 24 days.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	All members of the medical team, including the investigators, remained blinded to group assignment throughout the study.
Incomplete outcome data (attrition bias) All outcomes	Low risk	All randomized infants were evaluated and no missing data.
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported
Other bias	Low risk	No concerns of other biases

Cummings 1989a [moderate‐dose vs placebo].

Study characteristics
Methods	Single‐center, randomized, double‐blind, placebo‐controlled study investigating a moderate dosage vs a high dosage of dexamethasone vs saline placebo
Participants	Inclusion: 36 preterm infants with a birthweight ≤ 1250 g, a gestational age of ≤ 30 weeks, and a postnatal age of more than 14 days All infants were ventilated with a rate of at least 15 cycles per minute and received more than 30% oxygen. Attempts to wean these settings failed over a period of at least 72 h. Exclusions: infants with a symptomatic PDA, renal failure or sepsis at entry
Interventions	Note: Cummings 1989a refers only to the comparison of moderate‐dosage regimen vs saline placebo. The included infants were randomly assigned to 1 of 3 dosage regimens: a high‐dosage regimen with a cumulative dose of 7.9 mg/kg of dexamethasone administered over a 42‐day course: 0.5 mg/kg/d for 3 days, 0.3 mg/kg/d for 3 days, a 10% decrease every 3 days until 0.1 mg/kg/d, 0.1 mg/kg/d for 3 days, 0.1 mg/kg/d on alternate days for 7 days; a moderate‐dosage regimen with a cumulative dose of 3 mg/kg administered over 18 days: 0.5 mg/kg/d for 3 days, a 50% decrease every 3 days until 0.06 mg/kg/d, 0.06 mg/kg/d for 3 days, 0.06 mg/kg/d on alternate days for 7 days; or saline placebo. Medication was given intravenously and divided into 2 dosages per day. Each infant received the same volume of medication by using different concentrations of dexamethasone. Infants in the low‐dosage regimen group received additional saline injections to complete the 42‐day course. The placebo group was excluded for the purpose of this review. No treatment with corticosteroids outside the protocol was allowed.
Outcomes	Duration of IPPV Duration of oxygen Duration of hospital stay Rates of pneumothorax Rates of hyperglycemia Rates of sepsis Rates of GI bleeding Rates of transfusions Rates of ROP Rates of mortality Growth and development
Notes	The original investigator provided additional data on duration of mechanical ventilation, failure to extubate on day 7, and the total number of participants with a Bayley MDI < 2 SD. There was no statement in the manuscript of funding of the study.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomized allocation to 1 of 3 groups via a table of random numbers kept in the pharmacy
Allocation concealment (selection bias)	Low risk	Performed by a pharmacist unaware of the clinical status of the infant
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Individual daily doses were drawn from a specific vial designated for that treatment day, ensuring the same volume of study medication every day. Infants in the moderate‐dosage regimen received placebo saline for the remaining 24 days.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	All members of the medical team, including the investigators, remained blinded to group assignment throughout the study.
Incomplete outcome data (attrition bias) All outcomes	Low risk	All randomized infants were evaluated and no missing data
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported
Other bias	Low risk	No concerns of other biases

Cummings 1989b [high‐dose vs placebo].

Study characteristics
Methods	Single‐center, randomized, double‐blind, placebo‐controlled study investigating a moderate dosage vs a high dosage of dexamethasone vs saline placebo
Participants	Inclusion: 36 preterm infants with a birthweight ≤ 1250 g, a gestational age of ≤ 30 weeks, and a postnatal age of more than 14 days All infants were ventilated with a rate of ≥ 15 cycles per minute and received > 30% oxygen. Attempts to wean these settings failed over a period of ≥ 72 h. Exclusions: infants with a symptomatic PDA, renal failure, or sepsis at entry
Interventions	Note: Cummings 1989b refers only to the comparison of high‐dosage regimen vs saline placebo. The included infants were randomly assigned to 1 of 3 dosage regimens: a high‐dosage regimen with a cumulative dose of 7.9 mg/kg of dexamethasone administered over a 42‐day course: 0.5 mg/kg/d for 3 days, 0.3 mg/kg/d for 3 days, a 10% decrease every 3 days until 0.1 mg/kg/d, 0.1 mg/kg/d for 3 days, 0.1 mg/kg/d on alternate days for 7 days; a moderate‐dosage regimen with a cumulative dose of 3 mg/kg administered over 18 days: 0.5 mg/kg/d for 3 days, a 50% decrease every 3 days until 0.06 mg/kg/d, 0.06 mg/kg/d for 3 days, 0.06 mg/kg/d on alternate days for 7 days; or saline placebo. Medication was given intravenously and divided into 2 dosages per day. Each infant received the same volume of medication by using different concentrations of dexamethasone. Infants in the low‐dosage regimen group received additional saline injections to complete the 42‐day course. The placebo group was excluded for the purpose of this review. No treatment with corticosteroids outside the protocol was allowed.
Outcomes	Duration of IPPV Duration of oxygen Duration of hospital stay Rates of pneumothorax Rates of hyperglycemia Rates of sepsis Rates of GI bleeding Rates of transfusions Rates of ROP Rates of mortality Growth and development
Notes	The original investigator provided additional data on duration of mechanical ventilation, failure to extubate on day 7 and the total number of participants with a Bayley MDI < 2 SD. There was no statement in the manuscript of funding of the study.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomized allocation to 1 of 3 groups via a table of random numbers kept in the pharmacy
Allocation concealment (selection bias)	Low risk	Performed by a pharmacist unaware of the clinical status of the infant
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Individual daily doses were drawn from a specific vial designated for that treatment day, ensuring the same volume of study medication every day. Infants in the moderate‐dosage regimen received placebo saline for the remaining 24 days.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	All members of the medical team, including the investigators, remained blinded to group assignment throughout the study.
Incomplete outcome data (attrition bias) All outcomes	Low risk	All randomized infants were evaluated and no missing data
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported
Other bias	Low risk	No concerns of other biases

Cummings 1989c [moderate‐dose vs high‐dose].

Study characteristics
Methods	Single‐center, randomized, double‐blind, placebo‐controlled study investigating a moderate dosage vs a high dosage of dexamethasone vs saline placebo
Participants	Inclusion: 36 preterm infants with a birthweight ≤ 1250 g, a gestational age of ≤ 30 weeks, and a postnatal age of > 14 days All infants were ventilated with a rate of ≥ 15 cycles per minute and received > 30% oxygen. Attempts to wean these settings failed over a period of ≥ 72 h. Exclusions: infants with a symptomatic PDA, renal failure, or sepsis at entry
Interventions	Note: Cummings 1989c refers only to the comparison of moderate‐dosage regimen vs high‐dosage regimen. The included infants were randomly assigned to 1 of 3 dosage regimens: a high‐dosage regimen with a cumulative dose of 7.9 mg/kg of dexamethasone administered over a 42‐day course: 0.5 mg/kg/d for 3 days, 0.3 mg/kg/d for 3 days, a 10% decrease every 3 days until 0.1 mg/kg/d, 0.1 mg/kg/d for 3 days, 0.1 mg/kg/d on alternate days for 7 days; a moderate‐dosage regimen with a cumulative dose of 3 mg/kg administered over 18 days: 0.5 mg/kg/d for 3 days, a 50% decrease every 3 days until 0.06 mg/kg/d, 0.06 mg/kg/d for 3 days, 0.06 mg/kg/d on alternate days for 7 days; or saline placebo. Medication was given intravenously and divided into 2 dosages per day. Each infant received the same volume of medication by using different concentrations of dexamethasone. Infants in the low‐dosage regimen group received additional saline injections to complete the 42‐day course. The placebo group was excluded for the purpose of this review. No treatment with corticosteroids outside the protocol was allowed.
Outcomes	Duration of IPPV Duration of oxygen Duration of hospital stay Rates of pneumothorax Rates of hyperglycemia Rates of sepsis Rates of GI bleeding Rates of transfusions Rates of ROP Rates of mortality Growth and development
Notes	The original investigator provided additional data on duration of mechanical ventilation, failure to extubate on day 7 and the total number of participants with a Bayley MDI < 2 SD. There was no statement in the manuscript of funding of the study.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomized allocation to 1 of 3 groups via a table of random numbers kept in the pharmacy
Allocation concealment (selection bias)	Low risk	Performed by a pharmacist unaware of the clinical status of the infant
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Individual daily doses were drawn from a specific vial designated for that treatment day, ensuring the same volume of study medication every day. Infants in the moderate‐dosage regimen received placebo saline for the remaining 24 days.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	All members of the medical team, including the investigators, remained blinded to group assignment throughout the study.
Incomplete outcome data (attrition bias) All outcomes	Low risk	All randomized infants were evaluated and no data were missing.
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported
Other bias	Low risk	No concerns of other biases

Da Silva 2002.

Study characteristics
Methods	Single‐center, double‐blind randomized trial on moderate‐ vs low‐dosage regimen of dexamethasone
Participants	Inclusion: extremely low birthweight infants (≤ 1500 g), initial starting administration between 7 and 21 days
Interventions	The included infants were randomly assigned to 1 of 2 dosage regimens: a moderate‐dosage regimen with an unknown cumulative dose of dexamethasone administered over a 7‐day course, starting with 0.5 mg/kg/d, and then tapered during 7 days with unknown schedule; or a low‐dosage regimen with a cumulative dose of 0.7 mg/kg administered over 7 days: 0.1 mg/kg/d for 7 days.
Outcomes	Primary outcomes were growth parameters (weight, length, and head circumference) at 36 weeks’ corrected gestational age. Secondary outcomes were documented sepsis and long‐term growth parameters at 9 months of corrected age (actual numbers not provided).
Notes	The trial was only published as an abstract, and the original authors could not provide any additional data. No statement in manuscript on funding of the study
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described in abstract
Allocation concealment (selection bias)	Unclear risk	Not described in abstract
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Stated in the abstract as being double‐blinded; actual procedure not described
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Stated in the abstract as being double‐blinded; actual procedure not described
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Unknown
Selective reporting (reporting bias)	Unclear risk	Unknown
Other bias	Low risk	Unknown

Doyle 2006.

Study characteristics
Methods	Multicenter, double‐blind, randomized controlled trial
Participants	Inclusion: 70 infants < 28 weeks’ gestation or < 1000 g birthweight, 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), with a 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 Hyperglycemia 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 There was a long‐term follow‐up at 2 years of age by staff blinded to treatment allocation for neurological impairments and disabilities, including cerebral palsy.
Notes	The sample size estimate was 814, but the 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 center, with randomly permuted blocks of 2 to 8 infants.
Allocation concealment (selection bias)	Low risk	Blinding of randomization: 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	Unclear risk	Early stopping of trial may or may not introduce bias.

Durand 1995.

Study characteristics
Methods	Randomized controlled trial
Participants	Inclusion: 43 preterm babies 7 to 14 days old with birthweight 501 g to 1500 g, 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	n/a
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)	Low risk	All prespecified outcomes reported
Other bias	Low risk	None

Durand 2002.

Study characteristics
Methods	Single‐center randomized controlled trial
Participants	Inclusion: infants having a birthweight between 501 g and 1500 g, a gestational age between 24 weeks and 32 weeks, postnatal age between 7 days and 14 days, and at entry on ventilation support with a rate of 15 cycles per minute or more, and 30% supplemental oxygen or more to maintain a pulse oximeter oxygen saturation of 90% or higher, despite weaning trials Exclusions: infants with multiple congenital anomalies or chromosomal abnormalities, systemic hypertension, congenital heart disease, IVH grade IV, renal failure, or sepsis at entry
Interventions	The included infants were randomly assigned to 1 of 2 dosage regimens: a moderate‐dosage regimen with a cumulative dose of 2.4 mg/kg of dexamethasone administered over a 7‐day course: 0.5 mg/kg/d for 3 days, 0.25 mg/kg/d for 3 days, then 0.1 mg/kg/d for 1 day; or a low‐dosage regimen with a cumulative dose of 1.0 mg/kg of dexamethasone administered over a 7‐day course: 0.2 mg/kg/d for 3 d, then 0.1 mg/kg/d for 4 days. All medication was given divided into 2 dosages per day. Administration of open‐label dexamethasone was allowed after the study period at the discretion of the attending neonatologist.
Outcomes	Primary outcomes Dynamic respiratory mechanics, measured before and on days 2, 5, and 7 of dexamethasone therapy Secondary outcomes Ventilator settings Occurrence of CLD, defined as dependence on oxygen supplementation at 36 weeks’ PMA Survival without CLD Duration of mechanical ventilation Duration of hospitalizations Hyperglycemia Hypertension ROP NEC Spontaneous GI perforation Sepsis Pulmonary air leaks
Notes	Data of the long‐term follow‐up were retrieved from the original investigator. No statement on funding in the manuscript
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Blind drawing of random cards
Allocation concealment (selection bias)	Unclear risk	Opaque sealed envelopes
Blinding of participants and personnel (performance bias) All outcomes	High risk	No blinding
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	An outside investigator blinded to the group assignment evaluated the dynamic pulmonary mechanics and graphics. However, the assessment of clinical diagnosis was not blinded.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Of the 59 infants eligible, 7 parents were unavailable and 5 parents refused. One included participant had a few doses of dexamethasone withheld because of suspected infection.
Selective reporting (reporting bias)	Low risk	All predefined outcomes were mentioned in the manuscript.
Other bias	Low risk	No concerns of other biases

Efird 2005.

Study characteristics
Methods	Randomized double‐blind, placebo‐controlled trial
Participants	Inclusion: 34 infants of gestation > 23 weeks and < 29 weeks, and birthweight > 500 g and < 1000 g enrolled by 2 h of age Exclusions: major malformations, chromosomal abnormalities, congenital heart disease
Interventions	Hydrocortisone intravenously at dose of 1 mg/kg every 12 h for 2 days, followed by 0.3 mg/kg every 12 h for 3 days Control infants received an equivalent volume of normal saline as placebo.
Outcomes	Blood pressure Urine output Hyperglycemia Mortality Durations of mechanical ventilation and hospital stay BPD (oxygen at 36 weeks) Infection NEC Intestinal perforation PDA IVH PVL Cortisol levels
Notes	n/a
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random allocation via sequentially numbered; preassigned treatment designations in sealed, opaque envelopes
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

Garland 1999.

Study characteristics
Methods	Multicenter placebo‐controlled, randomized trial
Participants	Inclusion: 241 infants weighing between 500 g and 1500 g, received surfactant, at significant risk for BPD or mortality using a model to predict at 24 h
Interventions	3‐day course of dexamethasone beginning at 24 h to 48 h. First 2 doses were 0.4 mg/kg, 3rd and 4th doses 0.2 mg/kg, and 5th and 6th doses 0.1 mg/kg and 0.05 mg/kg, respectively. Dexamethasone dose reduced slightly after first interim analysis (see Notes) Similar volume of normal saline was given to control infants.
Outcomes	Primary outcomes Survival without BPD defined as oxygen therapy at 36 weeks to maintain arterial oxygen saturation above 91% Mortality Secondary outcomes Duration of ventilation and supplemental oxygen Respiratory support at 28 days of life Length of stay for survivors Use of subsequent dexamethasone therapy Usual complications of prematurity
Notes	At first interim analysis (n = 75), increased risk of GI perforation was noted in the dexamethasone group. Data Monitoring Committee recommended reducing the dexamethasone dose to 4 doses of 0.25 mg/kg/dose every 12 h begun at 24 to 48 h, followed by doses of 0.125 mg/kg and 0.05 mg/kg at the next 2 12‐hour periods, respectively.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomization by study pharmacists at each center
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

Halac 1990.

Study characteristics
Methods	Placebo‐controlled, randomized trial
Participants	Inclusion: 248 infants, birthweight ≤ 1500 g, gestation < 34 weeks, with evidence of “birth asphyxia” (1‐minute Apgar score < 5, prolonged resuscitation, and metabolic acidosis [bicarbonate < 15 mmol/L within 1 h of birth])
Interventions	Seven‐day course of dexamethasone 1 mg/kg 12‐hourly beginning on 1st day of life
Outcomes	Neonatal mortality Mortality to discharge NEC PDA Sepsis Severe IVH
Notes	Possible exclusion of 5 deaths after randomization, but not clear from which group the exclusions came
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random allocation via list 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 measurement: yes
Incomplete outcome data (attrition bias) All outcomes	Low risk	Complete follow‐up: yes
Selective reporting (reporting bias)	Low risk	Primary prespecified outcome of NEC was reported, as were many other outcomes.
Other bias	Low risk	None

Harkavy 1989.

Study characteristics
Methods	Double‐blind, randomized controlled trial
Participants	Inclusion: 21 preterm infants with ventilator and oxygen dependency at 30 days
Interventions	Dexamethasone 0.5 mg/kg/d every 12 h for 2 weeks intravenously or orally Saline placebo given to controls
Outcomes	Inspired oxygen concentration Duration of oxygen Mortality Hypertension Hyperglycemia Infection ROP
Notes	n/a
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)	Low risk	All prespecified outcomes reported
Other bias	Low risk	None

Hochwald 2014.

Study characteristics
Methods	Placebo‐controlled, randomized trial
Participants	Inclusion: 22 infants, gestational age ≤ 30 weeks or birthweight ≤ 1250 g, and < 48 h after birth with an arterial catheter in place, invasive mean blood pressure < gestational age on 3 consecutive measurements 10 min apart, and after treatment with 1 or 2 boluses of 10 mL of 0.9% saline Exclusions: blood loss, hydrops, or major cardiac lesions
Interventions	Hydrocortisone 7 mg/kg total over 48 h, or equal volume of 0.9% saline placebo
Outcomes	Mortality (presumably to discharge) NEC BPD Positive blood culture Insulin treatment
Notes	The major outcome was to determine whether hydrocortisone reduced vasopressor doses.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of randomization not stated
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Placebo‐controlled
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not stated
Incomplete outcome data (attrition bias) All outcomes	Low risk	Short‐term outcomes reported for all participants
Selective reporting (reporting bias)	Unclear risk	Only short‐term outcomes reported, but major outcome of effects on vasopressor doses not reported
Other bias	Low risk	None

Kari 1993.

Study characteristics
Methods	Multicenter double‐blind, randomized controlled trial
Participants	Inclusion: 41 preterm infants 10 days old, weighing < 1501 g 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 Hyperglycemia Sepsis Perforated colon Cryotherapy for ROP
Notes	n/a
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)	Low risk	All prespecified outcomes reported
Other bias	Low risk	None

Kazzi 1990.

Study characteristics
Methods	Double‐blind, randomized controlled trial
Participants	Inclusion: 23 preterm infants, 3 weeks to 4 weeks old, who weighed < 1500 g 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 h for 10 days Infants in the control group received equal volumes of saline.
Outcomes	Inspired oxygen concentration Ventilator settings Extubation < 9 days Hyperglycemia Sepsis Hypertension ROP Durations of oxygen Mechanical ventilation Hospital stay
Notes	n/a
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 number tables in the pharmacy Stratification for birthweight (< 1000 g, 1000 g to 1250 g, and 1251 g to 1500 g)
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)	Low risk	All prespecified outcomes reported
Other bias	Low risk	None

Kopelman 1999.

Study characteristics
Methods	Two‐center randomized, placebo‐controlled trial
Participants	Inclusion: 70 infants < 28 weeks’ gestation, requiring intermittent mandatory ventilation and arterial catheterization
Interventions	Dexamethasone 0.2 mg/kg within 2 h of delivery Control infants were given an equal volume of saline.
Outcomes	Ventilation Index IMV rate Mean blood pressure Incidence of PDA Need for indomethacin Number extubated during first week Usual complications of RDS
Notes	After an interim analysis showed that the incidence of IVH was much lower than expected, enrollment was stopped and analysis was limited to a comparison of ventilator settings, blood pressure, and pressor use during first 7 days. Outcome of successful extubation was available at only 1 hospital, where 38 infants were enrolled.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Random allocation in the hospital pharmacy stratified by use of antenatal corticosteroids Exact method of randomization 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)	Low risk	All prespecified outcomes reported, but others reported too
Other bias	Low risk	None

Kothadia 1999.

Study characteristics
Methods	Double‐blind, randomized controlled trial
Participants	Inclusion: 118 preterm infants, < 1501 g, age 15 days to 25 days, ventilator‐dependent > 30% oxygen Exclusions: 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 III) Infection Hypertension Hyperglycemia Follow‐up: Bayley MDI and PDI, cerebral palsy, abnormal neurological examination findings
Notes	n/a
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random allocation within 6 strata according to birthweight (500 g to 800 g, 801 g to 1100 g, and 1101 g to 1500 g) and sex Method not stated
Allocation concealment (selection bias)	Low risk	Random allocation within 6 strata according to birthweight (500 g to 800 g, 801 g to 1100 g, and 1101 g to 1500 g) and sex Method not stated Blinding of randomization: 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)	Low risk	All prespecified outcomes reported
Other bias	Low risk	None

Kovacs 1998.

Study characteristics
Methods	Double‐blind, randomized controlled trial
Participants	Inclusion: 60 ventilator‐dependent infants of < 30 weeks’ gestation and < 1501 g birthweight
Interventions	Dexamethasone given systemically at a dose of 0.25 mg/kg twice daily for 3 days followed by nebulized budesonide 500 µg twice daily for 18 days Control infants received systemic and inhaled saline placebos.
Outcomes	Survival to discharge Ventilatory support between 9 days and 17 days Supplemental oxygen between 8 days 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	n/a
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 weeks to 26 weeks vs 27 weeks 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)	Low risk	All prespecified outcomes reported
Other bias	Low risk	None

Lauterbach 2006.

Study characteristics
Methods	Three‐armed randomized controlled trial: Nebulized pentoxifylline Intravenous dexamethasone Nebulized water placebo
Participants	Inclusion: 150 infants < 1500 g birthweight who needed oxygen on 4th day of life, regardless of the need for assisted ventilation Exclusions: major malformations and grade III or IV IVH
Interventions	Dexamethasone 0.25 mg/kg/dose every 12 h for 3 days
Outcomes	Primary outcome BPD (oxygen dependency at 36 weeks) Secondary outcomes PDA IVH PVL
Notes	All prespecified outcomes reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated randomization table
Allocation concealment (selection bias)	Unclear risk	Not clearly stated
Blinding of participants and personnel (performance bias) All outcomes	High risk	Unable to blind treatment groups for comparison of dexamethasone vs nebulized water placebo
Blinding of outcome assessment (detection bias) All outcomes	High risk	Unable to blind treatment groups for comparison of dexamethasone vs nebulized water placebo
Incomplete outcome data (attrition bias) All outcomes	Low risk	Short‐term outcomes reported for all participants
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported
Other bias	Low risk	None

Lin 1999.

Study characteristics
Methods	Placebo‐controlled randomized trial
Participants	Inclusion: 40 infants of 500 g to 1999 g with severe RDS, needing IPPV within 6 h of birth
Interventions	Dexamethasone 0.25 mg/kg 12‐hourly from 1 day to 7 days, 0.12 mg/kg 12‐hourly from 8 days to 14 days, 0.05 mg/kg 12‐hourly from 15 days to 21 days, 0.02 mg/kg 12‐hourly from 22 days to 28 days A saline placebo was given to controls.
Outcomes	Mortality at 28 days Discharge Failure to extubate (during study) Mortality or BPD (36 weeks) BPD (28 days and 36 weeks) Infection (clinical) Severe IVH Plasma glucose Mean blood pressure on days 2, 5, 7, and 16 Weight at 2 weeks
Notes	Sequential analysis for 12 pairs Data given for 40 infants as randomized into the 2 groups
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Random allocation in a paired sequential trial Assignment determined by pharmacist and groups stratified by birthweight (500 g to 999 g, 1000 g to 1500 g, and 1501 g to 1999 g) Allocation by drawing lots
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

Malloy 2005.

Study characteristics
Methods	Single‐center, randomized double‐blinded controlled trial
Participants	Inclusion: 17 infants of birthweight < 1500 g and gestational age of 34 weeks, randomized before the 28th day
Interventions	The included infants were randomly assigned to 1 of 2 dosage regimens: a moderate‐dosage schedule of a cumulative dose of 2.7 mg/kg of dexamethasone administered over 7‐day course: 0.5 mg/kg/d for 3 days, followed by 0.3 mg/kg for 4 days; or a low‐dosage regimen of a cumulative dose of 0.56 mg/kg administered over a 7‐day course: 0.08 mg/kg for 7 days.
Outcomes	Clinical outcomes Mortality on discharge Duration of mechanical ventilation and oxygen dependence Survival without CLD Retreatment with dexamethasone Number of days on oxygen supplementation Number of hospital days IVH NEC GI perforation ROP requiring laser photocoagulation Hypertension Hyperglycemia Long‐term follow‐up was performed through 3 years of age and neurodevelopmental status was assessed by using the modified Gesell Developmental Appraisal.
Notes	Additional data on failure to extubate on day 3, days on mechanical ventilation and blindness or poor vision were retrieved from the original investigator. There was no statement in the manuscript on funding of the study.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	By personal communication; method not specified
Allocation concealment (selection bias)	Low risk	By personal communication; method not specified Infants were stratified into 3 groups according to birthweight
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Only study pharmacist, with no clinical involvement, was aware of doses administered.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	See above
Incomplete outcome data (attrition bias) All outcomes	High risk	One infant in the high‐dose group died on the 2nd day, whereas an infant in the low‐dose died at 4 months of age (1 month after hospital discharge). These infants were included in the analyses of the review. Two infants in the moderate allocation group were withdrawn from the study on the 6th day of study medication.
Selective reporting (reporting bias)	Low risk	All predefined outcomes were mentioned in the manuscript.
Other bias	Unclear risk	This study was terminated prematurely because of the 2002 statement from the American Academy of Pediatrics and the Canadian Paediatric Society.

McEvoy 2004.

Study characteristics
Methods	Single‐center randomized controlled trial
Participants	Inclusion: 62 infants were included when between 7 days and 21 days of postnatal age, with a birthweight of > 501 g and < 1500 g, a gestational age of > 24 weeks and < 32 weeks. The infants were dependent on ventilation support with ≥ 15 cycles per minute and oxygen levels of ≥ 30% at entry. Exclusions: infants with multiple congenital anomalies, systemic hypertension, congenital heart disease, IVH grade IV, renal failure, and sepsis at entry
Interventions	The included infants were randomly assigned to 1 of 2 dosage regimens: a moderate‐dosage regimen with a cumulative dose of 2.4 mg/kg of dexamethasone administered over a 7‐day course: 0.5 mg/kg/d for 3 days, then 0.25 mg/kg/d for 3 days, then 0.1 mg/kg/d for 1 day; or a low‐dosage regimen with a cumulative dose of 1.0 mg/kg of dexamethasone administered over a 7‐day course: 0.2 mg/kg/d for 3 days, then 0.1 mg/kg/d for 4 days. All medication was given divided into 2 dosages per day. The use of open‐label dexamethasone therapy was discouraged, but could be administered at the discretion of the attending neonatologist.
Outcomes	Primary outcome Functional residual capacity and passive respiratory compliance before and during the 7‐day therapy Secondary outcomes Ventilator settings Duration of mechanical ventilation Duration of hospitalizations CLD (defined as oxygen dependence at 36 weeks’ PMA) Survival without CLD PDA Hyperglycemia Hypertension IVH Periventricular leukomalacia ROP NEC Spontaneous GI perforation Sepsis Pulmonary air leaks At 1 year of corrected age, the infants were assessed for early neurodevelopmental follow‐up (cerebral palsy and Bayley Scales of Infant Development) by a developmental pediatrician, a pediatric neurologist, and specialized personnel. Cerebral palsy was defined as nonprogressive motor impairment, characterized by abnormal muscle tone and decreased range/control of movements. Severe cognitive delay was defined as lower than 70 on the MDI score.
Notes	Additional data on duration of mechanical ventilation, and failure to extubate on day 3 and 7, were retrieved from the original investigator. The study was funded by the American Lung Association.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Group assignment done by the pharmacy using a randomization table
Allocation concealment (selection bias)	Low risk	Investigators and clinical staff was unaware of treatment allocation because a staff pharmacist was in charge of randomization and study drug preparation.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Method not specified in manuscripts
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Method not specified in manuscripts
Incomplete outcome data (attrition bias) All outcomes	High risk	In 3 participants of the high‐dose group, 1 dose of dexamethasone was withheld due to blood in the gastric tube or hypertension. For 1 participant of the low‐dose group, a dose was inadvertently not given. Sixty‐six percent of the survivors were assessed for follow‐up. No statement on the influence on the neurodevelopmental outcome was given.
Selective reporting (reporting bias)	Low risk	All predefined outcomes were mentioned in the manuscript.
Other bias	Low risk	No concerns of other biases

Mukhopadhyay 1998.

Study characteristics
Methods	Single‐center randomized controlled trial
Participants	Inclusion: 19 infants < 34 weeks and < 2000 g who could be provided with ventilation. Clinical and radiographic evidence of RDS; IPPV with oxygen > 30%
Interventions	Dexamethasone 0.5 mg/kg/dose 12‐hourly for 3 days starting within 6 h of birth The control group did not receive any drug.
Outcomes	Changes in oxygen requirements Mean duration of ventilation Culture‐positive sepsis PDA BPD (not defined) Pneumothorax Mortality
Notes	Infants were entered into the trial only if a ventilator was available. Surfactant was not given.
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	Allocation concealment: not sure
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: no
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

Ng 2006.

Study characteristics
Methods	Double‐blind randomized controlled trial
Participants	Inclusion: 48 infants of gestation < 32 weeks and birthweight < 1500 g who had systemic hypotension despite treatment with volume expanders and dopamine within the first 7 days of life; infants also had to have an indwelling arterial catheter for continuous BP monitoring Exclusions: major or lethal congenital or chromosomal abnormalities, congenital heart defects, previous postnatal systemic or inhaled corticosteroids, proven infection, NEC
Interventions	Hydrocortisone 1 mg/kg every 8 h for 5 days Control infants received isotonic saline as placebo for 5 days.
Outcomes	BP Use of vasopressors Duration of ventilation Oxygen and hospital stay PIE Pulmonary hemorrhage Pneumothorax Hyperglycemia, glycosuria, IVH (grade III or IV) PVL NEC GI perforation Sepsis ROP (> stage II) Mortality
Notes	n/a
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random allocation in blocks of 6 by computer‐generated random numbers and opening numbered, sealed, opaque envelopes
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	The primary outcome was blood pressure, which was reported.
Other bias	Low risk	None

Noble‐Jamieson 1989.

Study characteristics
Methods	Double‐blind randomized controlled trial
Participants	Inclusion: 18 preterm infants > 4 weeks old and needing > 30% oxygen Exclusions: congenital anomalies, infection, gastric erosion, and 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 A saline placebo was 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 randomization: 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

Odd 2004.

Study characteristics
Methods	Single‐center randomized controlled trial investigating a continuous‐dosage regimen vs an individualized course tailored to the infants’ respiratory status
Participants	Inclusion: infants ≤ 1250 g, ventilated between postnatal age of 7 days and 28 days for which dexamethasone was indicated Exclusions: infants with congenital anomalies and surgical problems
Interventions	The included infants were randomly assigned to 1 of 2 regimens: continuous‐dosage regimen: 0.5 mg/kg/d for 3 days, 0.3 mg/kg/d for 3 days, then a dose decreasing by 10% every 3 days to 0.1 mg/kg/d over a further 30 days, followed by 0.1 mg/kg/d on alternate days for 1 week for a total duration of 42 days; or individual course: 0.5 mg/kg/d for 3 days, 0.3 mg/kg/d for 3 days, 0.1 mg/kg/d for 3 days, followed by 0.1 mg/kg every 72 h until the infant was extubated and required an FiO₂ ≤ 0.25 for 3 doses. In case of clinical deterioration (increase in FiO₂ ≥ 0.15 or MAP ≥ 2 cm H₂O) the dose reverted to 0.3 mg/kg/d for 3 days, after which the same schedule was followed.
Outcomes	Primary outcome Linear growth, measured by knemometry, weight, crown‐heel length, and head circumference Secondary outcomes Hypertension Myocardial hypertrophy Respiratory status (mode, peak inspiratory pressure, and end‐expiratory pressure and FiO₂ at enrollment, study days 14 and 42, 28 days’ postnatal age, and 36 weeks’ corrected gestational age) Hyperglycemia requiring insulin therapy Renal and cranial ultrasounds Proven and suspected infections In addition, a synacthen test was performed 1 week after discontinuation of the dexamethasone. The long‐term neurodevelopmental outcomes were assessed at 9 and 18 months using the Bayley Scales of Infant Development II. Infants were classified into 1 of 4 outcome categories defined and modified from Kitchen 1987.
Notes	No statement in manuscript on funding of the study
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	By computer‐generated random numbers
Allocation concealment (selection bias)	Low risk	Stratified by sex and birthweight
Blinding of participants and personnel (performance bias) All outcomes	High risk	Parents and personnel were aware of the allocation of the participant.
Blinding of outcome assessment (detection bias) All outcomes	High risk	Clinical outcome assessment was not blinded, though the primary outcome was (knemometry), as well as ultrasounds performed by staff unaware of treatment allocation. The developmental psychologist was also unaware of the treatment allocation.
Incomplete outcome data (attrition bias) All outcomes	Low risk	In 1 infant in the individual group, the dexamethasone treatment was stopped on day 10. Intention‐to‐treat analyses were performed.
Selective reporting (reporting bias)	Low risk	All predefined outcomes were mentioned in the manuscript.
Other bias	Low risk	No concerns of other biases

Ohlsson 1992.

Study characteristics
Methods	Double‐blind randomized controlled trial
Participants	Inclusion: 25 preterm infants, 21 days to 35 days old, weighing < 1501 g birthweight, and needing mechanical ventilation > 29% oxygen, chest radiograph consistent with BPD Exclusions: infection, congenital anomalies, 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. A 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 in the study. A plaster 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	n/a
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	Systemic hydrocortisone to prevent BPD trial is a randomized double‐blind placebo‐controlled multicenter 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	Inclusion: 371 very low birthweight infants (gestational age < 30 weeks or birthweight < 1250 g, or both) who were ventilator‐dependent at a postnatal age of 7 days 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 hospitalization Long‐term neurodevelopmental sequelae at 2 years’ corrected gestational age included cerebral palsy and neurodevelopmental impairment. Analysis was performed on an intention‐to‐treat basis.
Notes	NTR: NTR2768 This trial was funded by a Project Grant from The Netherlands Organization 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	Multicenter double‐blind randomized controlled trial
Participants	Inclusion: ventilator‐dependent infants with birthweight 501 g to 1500 g, at a postnatal age between 13 days and 15 days, with a respiratory index of ≥ 2.4 Exclusions: infants who received glucocorticoid therapy after birth, had proven or suspected sepsis, or congenital anomaly of cardiovascular, pulmonary, or central nervous system
Interventions	The included infants were randomly assigned to 1 of 2 regimens: moderately‐early initiation: infants received 2 weeks of dexamethasone regimen, followed by 2 weeks’ saline; or late initiation: infants started with 2 weeks of saline, after which they started with 2 weeks of dexamethasone if the respiratory index still was ≥ 2.4. Both dexamethasone regimens started with 0.5 mg/kg/d (divided in 2 doses) for 5 days, followed by 0.15 mg/kg, 0.07 mg/kg, and 0.03 mg/kg for 3 days each.
Outcomes	Primary outcome The number of days from randomization to ventilator independence Secondary outcomes Death before hospital discharge Duration of assisted ventilation, supplemental oxygen, and hospital stay BPD at 36 weeks Hyperglycemia Hypertension Changes in weight and head circumference Proven sepsis NEC Gastric hemorrhage
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. No long‐term follow‐up was performed. Funded by National Institute of Child Health and Human Development and by the General Clinical Research Center grants. Dexamethasone was provided by Merck Sharp & Dohme.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	An order form was sent to each center's pharmacy, where the infants were randomly assigned to 1 of 2 treatment groups.
Allocation concealment (selection bias)	Unclear risk	No information provided
Blinding of participants and personnel (performance bias) All outcomes	Low risk	To blind clinical staff, different volumes of placebo were prepared to match the various doses of dexamethasone.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	See above
Incomplete outcome data (attrition bias) All outcomes	Low risk	Three infants did not receive any of the assigned treatments. Of the 173 infants in the late dexamethasone group who were alive on treatment day 14, 31 did not meet the criteria for starting dexamethasone treatment. The results were analyzed on an intention‐to‐treat method.
Selective reporting (reporting bias)	Low risk	All predefined outcomes were mentioned in the manuscript.
Other bias	Low risk	No concerns for other biases

Parikh 2013.

Study characteristics
Methods	Double‐blind randomized controlled trial
Participants	Inclusion: 64 infants with birthweight < 1001 g, ventilator‐dependent between 10 days and 21 days of age, with a respiratory index ≥ 2 with 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 months to 22 months of age, corrected for prematurity, were also reported.
Notes	n/a
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 randomization not described Birthweight (≤ 750 g vs 751 g to 1000 g) 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

Peltoniemi 2005.

Study characteristics
Methods	Multicenter double‐blind randomized controlled trial
Participants	Inclusion: 51 infants with birthweight 501 g to 1250 g, gestation 23 weeks to 30 weeks, needing mechanical ventilation before the age of 24 h. The subgroup, 1000 g to 1250 g, had to need supplemental oxygen and mechanical ventilation > 24 h despite surfactant. Exclusions: lethal malformations and suspected chromosomal abnormalities
Interventions	Hydrocortisone 2.0 mg/kg/d intravenously 8‐hourly for 2 days, 1.5 mg/kg/d 8‐hourly for 2 days, 0.75 mg/kg/d 12‐hourly for 6 days Control infants received isotonic saline as placebo. First dose was given before 36 h. Use of open‐label corticosteroids was discouraged.
Outcomes	Survival without BPD (oxygen at 36 weeks) IVH (grades III or IV) Cystic PVL Durations of ventilation Oxygen and hospital stay Sepsis Hyperglycemia Hypertension PDA GI bleeding GI perforation NEC ROP Cortisol levels Long‐term outcomes At 2 years: neurosensory impairments (blindness, deafness, developmental delay assessed by MDI on Bayley Scales, cerebral palsy) and disabilities Severe: any kind of severe cerebral palsy (not likely to walk), blindness, or severe developmental delay (MDI < 55) Moderate: moderate cerebral palsy (not walking at 2 years but likely to do so), deafness, moderate developmental delay (MDI 55 to < 70) Mild: mild cerebral palsy (walking at 2 years), or mild developmental delay (MDI 70 to < 85) Follow‐up rate was 87% (40/46) At 6 years, the following were assessed: IQ (Wechsler Preschool and Primary Scale of Intelligence, Revised) Language (Reynell Developmental Language Scale III) Diagnoses of cerebral palsy, blindness, and deafness Follow‐up rate was 80% (37 of the 46 survivors)
Notes	n/a
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Random allocation at each center via identical coded syringes Exact method of randomization not stated Stratified by birthweight (501 g to 750 g vs 750 g to 999 g vs 1000 g to 1250 g)
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 (for primary hospital outcomes) Follow‐up rates at 2 years and 6 years listed above
Selective reporting (reporting bias)	Low risk	Primary outcome was reported as specified.
Other bias	Low risk	None

Rastogi 1996.

Study characteristics
Methods	Double‐blind randomized controlled trial
Participants	Inclusion: 70 preterm infants < 12 h old, weighing 700 g to 1500 g with RDS confirmed clinically and radiologically; infants needed mechanical ventilation > 30% oxygen or MAP 7 cm H2O a/A < 0.25 after surfactant treatment, or both. Exclusions: major malformations, chromosome abnormalities, severe infection, Apgar < 3 at 5 min
Interventions	Intravenous dexamethasone 0.5 mg/kg/d for 3 days, 0.3 mg/kg/d for 3 days, 0.2 mg/kg/d for 3 days, 0.1 mg/kg/d for 3 days Control group given saline placebo
Outcomes	FiO2 MAP BPD (28 days and CXR) Severe BPD (36 weeks) Duration of oxygen Infections Deaths Pneumothorax Pulmonary hemorrhage PDA IVH NEC Hyperglycemia Insulin use Hypertension ROP
Notes	n/a
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random allocation: via a pharmacy list Stratified for birthweight
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	Randomized controlled trial
Participants	Inclusion: 30 preterm infants, oxygen‐ and ventilator‐dependent on 10th day and 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 Hyperglycemia Hypertension PDA Severe IVH NEC Received late steroids Severe ROP Left ventricular hypertrophy
Notes	n/a
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	Allocation 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

Romagnoli 1999.

Study characteristics
Methods	Randomized nonblinded controlled trial
Participants	Inclusion: 50 infants < 1251 g or < 33 weeks, oxygen‐dependent at 72 h, and at high risk of BPD according to a scoring system predicting 90% risk of BPD
Interventions	Dexamethasone 0.5 mg/kg/d for 3 days, 0.25 mg/kg/d for 3 days, and 0.125 mg/kg/d for 1 day Control group: no mention of placebo
Outcomes	Survival to 28 days Survival to discharge PDA IVH (grades III and IV) PVL Sepsis NEC ROP (stages III and above) Requiring ventilation at 28 days BPD at 28 days and 36 weeks Hyperglycemia Hypertension Needed late corticosteroids Growth failure Left ventricular hypertrophy
Notes	n/a
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random allocation via random numbers, concealed in numbered sealed envelopes
Allocation concealment (selection bias)	Low risk	Allocation 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	High risk	Blinding of outcome measurements: no
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

Sanders 1994.

Study characteristics
Methods	Randomized double‐blind controlled trial
Participants	Inclusion: 40 infants < 30 weeks’ gestation and 12 h to 18 h old with RDS, both clinical and radiological. Infants were treated with mechanical ventilation and surfactant. Exclusions: sepsis, congenital heart disease, chromosome abnormalities, need for exchange transfusion
Interventions	Dexamethasone 0.5 mg/kg twice, 12 h apart Control group given saline placebo
Outcomes	MAP FiO2 Mortality Extubation < 7 days Pulmonary function tests Duration IPPV Oxygen Hospital Mortality BPD (36 weeks oxygen) Late corticosteroids
Notes	n/a
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Random allocation in the pharmacy via sealed envelopes Method of randomization not described
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	Prespecified outcomes reported, but definitions vague
Other bias	Low risk	None

Scott 1997.

Study characteristics
Methods	Double‐blind randomized controlled trial
Participants	Inclusion: 15 infants ventilator‐dependent between 11 days 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 included Mortality Acute complications
Notes	n/a
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random allocation via a random number table
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

Shinwell 1996.

Study characteristics
Methods	Multicenter, double‐blind randomized controlled trial
Participants	Inclusion: 248 preterm infants with birth weight 500 g to 2000 g, 1 day to 3 days old, requiring mechanical ventilation with more than 40% oxygen Exclusions: active bleeding, hypertension, hyperglycemia, active infection, lethal congenital anomalies
Interventions	Intravenous dexamethasone 0.25 mg/kg every 12 h 6 times Controls given saline placebo
Outcomes	Mortality Survival with no oxygen Mechanical ventilation at 3 days and 7 days BPD Duration in hospital IVH PVL Pneumothorax PIE PDA Sepsis Hypertension Hyperglycemia
Notes	n/a
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random allocation, stratified by center and birth weight, from random numbers list in the pharmacy
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 for short‐term; 84% for long‐term
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported
Other bias	Low risk	None

Sinkin 2000.

Study characteristics
Methods	Multicenter, randomized double‐blind trial
Participants	Inclusion: 384 infants < 30 weeks’ gestation with RDS by clinical and radiographic signs, needing IPPV at 12 h to 18 h of age; had received at least 1 dose of surfactant
Interventions	Dexamethasone 0.5 mg/kg at 12 h to 18 h of age, 2nd dose 12 h later Control group given an equal volume of placebo
Outcomes	Primary outcomes Survival: Survival without oxygen at 28 days or 36 weeks Survival without oxygen at 28 days or 36 weeks and without late corticosteroids Length of time: In oxygen On ventilation To regain birthweight In hospital Hyperglycemia Hypertension IVH PDA Sepsis NEC Isolated GI perforation ROP Air leak Discharged home on oxygen
Notes	n/a
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Random allocation in the pharmacy via labeled syringes Stratification by center Exact method of randomization 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)	Low risk	All prespecified outcomes reported
Other bias	Low risk	None

Soll 1999.

Study characteristics
Methods	Multicenter, randomized double‐blind trial
Participants	Inclusion: 542 infants weighing 501 g to 1000 g who required assisted ventilation < 12 h, had received surfactant by 12 h, were physiologically stable, and had no life‐threatening congenital anomalies
Interventions	Dexamethasone 0.5 mg/kg/d for 3 days, 0.25 mg/kg/d for 3 days, 0.10 mg/kg/d for 3 days, and 0.05 mg/kg/d for 3 days Control infants received a similar volume of normal saline. Infants in either group could receive late postnatal corticosteroids beginning on day 14 if they were on assisted ventilation with supplemental oxygen > 30%.
Outcomes	Primary outcome BPD or mortality at 36 weeks’ adjusted age Secondary outcomes Clinical status at 14 days and 28 days Duration of assisted ventilation Supplemental oxygen and hospital stay Treatment with late postnatal corticosteroids Proven sepsis Hypertension Hyperglycemia requiring therapy Weight at 36 weeks Usual complications of prematurity
Notes	Published as an extended abstract and presented at a clinical meeting
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Random allocation in hospital pharmacies by opening opaque, sealed envelopes Precise method of randomization 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)	Low risk	All prespecified outcomes reported
Other bias	Unclear risk	Early stopping of trial may or may not introduce bias.

Stark 2001.

Study characteristics
Methods	Multicenter, randomized double‐blind trial
Participants	Inclusion: 220 infants with birthweight 501 g to 1000 g, mechanically ventilated < 12 h. Infants > 750 g also needed to receive surfactant and have FiO2 > 0.29.
Interventions	Dexamethasone 0.15 mg/kg/d for 3 days, then tapered over 7 days Saline placebo for control
Outcomes	Mortality or BPD Oxygen at 28 days PIE Late corticosteroid treatment Hypertension Hyperglycemia GI perforation
Notes	Factorial design; infants also randomized to routine ventilator management or a strategy of minimal ventilator support to reduce mechanical lung injury. After enrolling 220 infants (sample size estimate was 1200), the trial was halted owing to unanticipated adverse events.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random allocation via numbers generated by a random, permuted block algorithm, stratified by birthweight
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	Unclear risk	Early stopping of trial may or may not introduce bias.

Subhedar 1997.

Study characteristics
Methods	Randomized controlled trial: factorial design
Participants	Inclusion: 42 preterm infants, entry at 96 h if gestation < 32 weeks, mechanical ventilation from birth, surfactant treatment, and high risk of developing BPD based on score (Ryan 1996) Exclusions: major congenital anomaly, structural cardiac defect, significant ductus shunting, culture‐positive sepsis, IVH with parenchymal involvement, pulmonary or GI hemorrhage, abnormal coagulation, thrombocytopenia (platelets < 50,000)
Interventions	Intravenous dexamethasone at 12‐hourly intervals for 6 days; 0.5 mg/kg/dose for 6 doses and 0.25 mg/kg/dose for a further 6 doses Inhaled NO 5 ppm to 20 ppm for 72 h Control groups were not given placebo.
Outcomes	Mortality BPD at 28 days and > 36 weeks with abnormal chest radiograph Duration of ventilation Time to extubation Duration of hospitalization Maximum grade of IVH Pulmonary hemorrhage Pneumothorax Severe PDA NEC ROP (stage III or IV) Complications including ileal perforation, upper GI hemorrhage, hyperglycemia, hypertension, septicemia
Notes	Note factorial design, which means that half of treated infants and half of control infants also received 72 h of inhaled NO.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random allocation by computer‐generated random numbers and sealed envelopes Factorial design provided 4 groups: early dexamethasone, inhaled NO, both drugs together, and neither drug
Allocation concealment (selection bias)	Low risk	Allocation 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	High risk	Blinding of outcome measurements: no
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

Suske 1996.

Study characteristics
Methods	Randomized controlled trial
Participants	Inclusion: 26 preterm infants < 2 h old, with birthweight < 1500 g if FiO2 > 0.50, or > 1500 g birthweight with FiO2 > 0.70 Exclusions: known sepsis, cardiac anomalies, malformations of lung or CNS
Interventions	Intravenous dexamethasone 0.5 mg/kg/d for 5 days Controls were not given placebo.
Outcomes	Blood gases Ventilator settings Mortality IVH BPD (oxygen 28 days) NEC Late sepsis PDA ROP Air leak Duration in hospital
Notes	n/a
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Random allocation via sealed envelopes Randomization achieved by drawing lots
Allocation concealment (selection bias)	Low risk	Allocation 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	High risk	Blinding of outcome measurement: no
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

Tapia 1998.

Study characteristics
Methods	Multicenter, double‐blind placebo‐controlled randomized trial
Participants	Inclusion: 113 (4 exclusions for congenital abnormality, early sepsis, and failure to obtain follow‐up data) infants with birthweight between 700 g and 1600 g, clinical and radiological diagnosis of RDS, needing mechanical ventilation, and < 36 h of age Exclusions: life‐threatening congenital malformation or chromosome abnormality, strong suspicion of infection at birth (maternal chorioamnionitis) or early sepsis (positive blood culture in the first 36 h of life)
Interventions	Intravenous dexamethasone 0.5 mg/kg/d for 3 days, 0.25 mg/kg/d for 3 days, 0.12 mg/kg/d for 3 days, and 0.06 mg/kg/d for 3 days Placebo group received an equivalent volume of saline solution.
Outcomes	Primary outcomes Mortality before hospital discharge BPD (oxygen need at 28 days and x‐ray changes) Mortality or BPD Oxygen need at 36 weeks Other outcomes Time on ventilator Time in over 40% oxygen Time in oxygen Major morbidity and complications included: pneumothorax; PIE; PDA; pulmonary hemorrhage; pneumonia; sepsis; NEC; ROP; hypertension; hyperglycemia; and IVH (grades I to II and III to IV).
Notes	n/a
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Random allocation via ampoules of dexamethasone and saline prepared in the hospital pharmacy Exact method of randomization not described
Allocation concealment (selection bias)	Low risk	Blinding of randomization: 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: almost (109/113)
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported
Other bias	Low risk	None

Vento 2004.

Study characteristics
Methods	Randomized controlled trial
Participants	Inclusion: 20 infants with birthweight < 1251 g and gestation < 33 weeks who were oxygen‐ and ventilator‐dependent on 4th day of life and were at high risk of BPD by study authors’ own scoring system Exclusions: none stated
Interventions	Intravenous dexamethasone 0.5 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 corticosteroid treatment.
Outcomes	Tracheal aspirates for cell counts Pulmonary mechanics PDA Extubation during study period IVH (grades III and IV)
Notes	n/a
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Random allocation but method not stated
Allocation concealment (selection bias)	Unclear risk	Allocation concealment: uncertain
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Blinding of intervention: uncertain
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Blinding of outcome measurement: 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

Vincer 1998.

Study characteristics
Methods	Double‐blind, randomized controlled trial
Participants	Inclusion: 20 very low birthweight 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 the final 3 days Equal volume of saline placebo
Outcomes	Mortality Median number of days ventilated after treatment Days of apneic 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, randomized controlled trial
Participants	Inclusion: 36 infants of gestation 24 weeks to 32 weeks and birthweight > 599 g 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 days to 14 days Hyperglycemia Hypertension Serum cortisol Received late dexamethasone BPD (oxygen at 36 weeks’ PMA) Survival without BPD
Notes	n/a
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

Wang 1996.

Study characteristics
Methods	Double‐blind, randomized controlled trial
Participants	Inclusion: 63 infants with birthweight from 1000 g to 1999 g, AGA, clinical and radiographic RDS, IPPV (0 to 12, age after birth)
Interventions	Dexamethasone 0.25 mg/kg 12‐hourly from 1 day to 7 days, 0.125 mg/kg 12‐hourly from 8 days to 14 days, 0.05 mg/kg 12‐hourly from 15 days to 21 days First dose administered at < 12 h Controls received saline placebo.
Outcomes	Oxygen requirements Partial pressure of carbon dioxide MAP SP‐A and SP‐D in tracheal aspirate Failure to extubate by 3rd day, 7th day, 14th day, and 28th day Mortality before discharge Sepsis BPD at 28 days
Notes	n/a
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Random allocation in a double‐blind fashion 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 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

Watterberg 1999.

Study characteristics
Methods	Two‐center, double‐blind randomized controlled trial
Participants	Inclusion: 40 infants weighing between 500 g and 999 g who were AGA and needed mechanical ventilation < 48 h of age Exclusions: maternal diabetes, congenital sepsis, small for gestational age
Interventions	Hydrocortisone 1.0 mg/kg/d every 12 h for 9 days, 0.5 mg/kg/d for 3 days Control infants were given an equal volume of normal saline.
Outcomes	Primary outcome Survival without supplemental oxygen at 36 weeks’ postconception Secondary outcomes amongst survivors BPD at 36 weeks Duration of mechanical ventilation, > 40% oxygen, > 25% oxygen Hospital stay Weight and head circumference at 36 weeks
Notes	n/a
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random allocation at each center by constant block design with 4 participants per block to minimize bias over time Separate randomization tables were used for infants exposed to antenatal corticosteroids.
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

Watterberg 2004.

Study characteristics
Methods	Multicenter, double‐blind randomized controlled trial
Participants	Inclusion: 360 infants of 500 g to 999 g birthweight, needing mechanical ventilation, aged 12 h to 48 h Exclusions: major congenital anomaly, congenital sepsis, postnatal corticosteroids, triplet or higher‐order gestation
Interventions	Hydrocortisone 1 mg/kg/d 12‐hourly for 12 days, then 0.5 mg/kg/d for 3 days Control group infants received an equal volume of normal saline placebo.
Outcomes	Survival without BPD (oxygen at 36 weeks) Physiological BPD Mortality before 36 weeks Death before discharge BPD in survivors Durations of mechanical ventilation and oxygen Hospital stay Weight and OFC at 36 weeks PDA Infection NEC GI perforation Major IVH (grade III or IV) Cystic PVL ROP Open‐label corticosteroid therapy Longer‐term outcomes included Neurosensory impairments (any of cerebral palsy, blindness, deafness, or developmental or motor delay, as assessed by Bayley Scales [MDI or PDI, respectively])
Notes	Sample size estimate was 712, but the study was stopped early because of increased incidence of apparently spontaneous GI perforation in the hydrocortisone group.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random allocation stratified by center and birthweight (500 g to 749 g vs 750 g to 999 g) via a permuted block scheme with blocks of 6 in each stratum Randomization lists in each pharmacy in a sealed envelope
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	Unclear risk	Early stopping of trial may or may not introduce bias

Yates 2019.

Study characteristics
Methods	Double‐blind, randomized controlled trial
Participants	Inclusion: 22 infants gestational age < 30 weeks between 10 days 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, and unlikely to be extubated within 48 h [in clinician's opinion]) Exclusions: unlikely to survive, on steroids for lung disease, major malformations, previous abdominal surgery, surgery for PDA, or contraindications to corticosteroids
Interventions	Dexamethasone 0.05 mg/kg once daily on days 1 to 10 after randomization, 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 h Secondary outcomes Time to first extubation after first IMP dose (whether > 24 h) Extubation by day 7 (when the baby remained extubated for at least 24 h) Extubation by day 7 (whether the baby remained extubated for at least 24 h) Survival to 36 weeks’ PMA
Notes	n/a
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomization was managed centrally, with telephone backup available all at times. Randomization used a minimization algorithm to ensure balance between trial groups in collaborating hospital, sex, multiple births, gestational age at birth and existing diuretic therapy for the 24 h prior to randomization. Babies from multiple births were randomized 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	The major endpoint of time to extubation was heavily censored by dropouts for either sepsis or for open‐label corticosteroids. Fewer 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

Yeh 1990.

Study characteristics
Methods	Double‐blind, randomized controlled trial
Participants	Inclusion: 57 preterm infants weighing between 700 g and 1999 g, < 13 h old, with severe RDS both clinically and radiologically. They needed mechanical ventilation < 4 h and were excluded if they had infection.
Interventions	Intravenous dexamethasone 0.50 mg/kg/d for 3 days, 0.25 mg/kg/d for 3 days, 0.12 mg/kg/d for 3 days, 0.05 mg/kg/d for 3 days Control infants were given saline placebo.
Outcomes	MAP FiO2 Pulmonary function tests BP Glucose Mortality BPD Duration in oxygen Hospital Weight loss Sepsis PDA IVH (> grade I) ROP
Notes	n/a
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Random allocation in blocks of 10 via a pharmacy list Exact method of randomization not described
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: almost
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported
Other bias	Low risk	None

Yeh 1997.

Study characteristics
Methods	Multicenter, double‐blind randomized controlled trial
Participants	Inclusion: 262 infants of birthweight < 2000 g with RDS and requiring mechanical ventilation after birth
Interventions	Dexamethasone 0.25 mg/kg/dose every 12 h intravenously on days 1 to 7; 0.12 mg/kg/dose every 12 h intravenously from days 8 to 14; 0.05 mg/kg/dose every 12 h intravenously from days 15 to 21; and 0.02 mg/kg/dose every 12 h intravenously from days 22 to 28 Control infants were given saline placebo.
Outcomes	BPD judged at 28 days or at 36 weeks Extubation during the study Mortality Bacteremia or clinical sepsis Side effects of hyperglycemia Hypertension Cardiac hypertrophy Hyperparathyroidism Growth failure
Notes	n/a
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Random allocation via central pharmacy random number list Exact method of randomization not described
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: almost for short‐term; 81% for long‐term
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported
Other bias	Low risk	None

ACTH: adrenocorticotropic hormone; AGA: appropriate for gestational age; Apgar: ; BDA: ; BP: blood pressure; BPD: bronchopulmonary dysplasia; CLD: chronic lung disease; CNS: central nervous system; CP: cerebral palsy; CXR: chest x‐ray; FiO₂: fraction of inspired oxygen; GI: gastrointestinal; HIV: ; IMP: investigational medical product; IMV: intermittent mandatory ventilation; IPPV: intermittent positive‐pressure ventilation; IQ: intelligence quotient; IVH: intraventricular hemorrhage; IV: intravenous; MAP: mean airway pressure; MDI: Mental Developmental Index; MRI: magnetic resonance imaging; n/a: not applicable; NDI: neurodevelopmental impairment; NEC: necrotizing enterocolitis; NICU: neonatal intensive care unit; NO: nitric oxide; OFC: occipitofrontal circumference; NTR: Netherlands Trial Register; PDA: patent ductus arteriosus; PDI: Psychomotor Developmental Index; PIE: pulmonary interstitial emphysema; PMA: postmenstrual age; PNA: postnatal age; ppm: parts per million; PVL: periventricular leukomalacia; RDS: respiratory distress syndrome; ROP: retinopathy of prematurity; SD: standard deviation; SP‐A: surfactant protein‐A; SP‐D: surfactant protein‐D; T3: tri‐iodothyronine; vs:

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Barkemeyer 2000	Randomized controlled trial investigating a pulse‐dosage vs continuous‐dosage regimen Infants were eligible for enrollment with birthweight < 1500 g, a history of respiratory distress syndrome, and ventilator dependence at 7 days to 21 days after birth. Infants were excluded if significant anomalies of cardiac or respiratory systems, or clinically significant patent ductus arteriosus at the time of enrollment. The infants were randomly assigned to 1 of 2 regimens: pulse arm: infants received dexamethasone 0.5 mg/kg/d for 3 consecutive days followed by 7 days of placebo, then repeated to complete a 23‐day course with a total dexamethasone dose of 4.5 mg/kg; or continuous arm: infants received dexamethasone 0.5 mg/kg/d for 3 consecutive days, then 0.25 mg/kg/d for 4 days, 0.2 mg/kg/d for 4 days, 0.15 mg/kg/d for 4 days, 0.1 mg/kg/d for 4 days, then 0.1 mg/kg/d every other day for 4 days to complete a 23‐day course with a total of 4.5 mg/kg. All administrations were in 2 divided doses. Did not provide relevant comparisons for our predetermined networks and cut‐points
Bloomfield 1998	Randomized controlled trial comparing a pulse course against high‐dosage regimen dexamethasone Infants with a birthweight ≤ 1250 g, and ventilated at ≥ 15 cycles per minute at 7 days of age were included. Infants with major congenital malformations or who were ventilated for surgical reasons were excluded. The infants were randomly assigned to 1 of 2 regimens: pulse arm: infants received dexamethasone 0.5 mg/kg/d for 3 consecutive days. The pulse course was repeatable every 10 days if still ventilated or supplemental oxygen and < 36 weeks’ PMA; or continuous arm: starting at 14 days of age if still ventilated at ≥ 15 cycles per minute and ≥ 30% supplemental oxygen, a high‐dosage regimen with a cumulative dose of 7.9 mg/kg of dexamethasone administered over a 42‐day course: 0.5 mg/kg/d for 3 days, 0.3 mg/kg/d for 3 days, a 10% decrease every 3 days until 0.1 mg/kg/d, 0.1 mg/kg/d for 3 days, 0.1 mg/kg/d on alternate days for 7 days. The initial dosage administration of 0.5 mg/kg/d was in 2 divided doses. Did not provide relevant comparisons for our predetermined networks and cut‐points
DeMartini 1999	Single‐center, randomized controlled trial Intubated preterm infants were included. The infants were randomly assigned to 1 of 2 dosage regimens: high‐dosage regimen with a cumulative dose of 4.1 mg/kg of dexamethasone administered over a 21‐day course: 0.5 mg/kg/d for 2 days, then 0.3 mg/kg/d for 3 days, then 0.24 mg/kg/d for 3 days, then 0.2 mg/kg/d for 3 days, then 0.14 mg/kg/d for 3 days, then 0.1 mg/kg/d for 3 days, followed by 2 doses of 0.1 mg/kg every 48 h; or low‐dosage regimen with a cumulative dose of 2.7 mg/kg of dexamethasone administered over a 7‐day course: 0.5 mg/kg/d for 3 days, then 0.3 mg/kg/d for 4 days. All medication was given divided into 2 dosages per day. No participants were treated with any corticosteroids outside the study protocol. Did not provide relevant comparisons for our predetermined networks and cut‐points.
Halliday 2001	Multicenter, partly double‐blinded, randomized controlled trial with a factorial design investigating early vs late administration of inhaled and systemic dexamethasone Intubated infants < 30 weeks’ gestational age, a postnatal age < 72 h and with an inspired oxygen concentration > 30% were included. Infants with a gestational age between 30 weeks and 31 weeks could be included if needing inspired oxygen > 50%. Infants with lethal congenital anomalies, severe IVH over stage III, and proven infections were excluded. When strong suspicion of infection, hypertension or hyperglycemia, inclusion was postponed until resolved. Eligible infants were randomized in 1 of 4 arms, of which 2 contained inhaled corticosteroids. These infants were excluded from this review. The remaining infants were randomized into 1 of 2 arms: early (< 72 h) dexamethasone: initial dose of 0.5 mg/kg/d for 3 days, followed by 0.25 mg/kg/d for 3 days, 0.1 mg/kg/d for 3 days, and finally 0.05 mg/kg/d for 3 days; or moderate early (15 days postnatal age) dexamethasone: infants randomized to the late dexamethasone group had to fulfill the inclusion criteria at 15 days to be eligible for treatment. Initial dose of 0.5 mg/kg/d for 3 days, followed by 0.25 mg/kg/d for 3 days, 0.1 mg/kg/d for 3 days, and finally 0.05 mg/kg/d for 3 days. All medication was given divided into 2 dosages per day. Not included in the network meta‐analysis because it was the only study that informed the “late low‐dose dexamethasone vs early low‐dose dexamethasone” comparison Sole study addressing early low‐dose dexamethasone to late low‐dose dexamethasone Did not provide data for network analysis
Marr 2019	Single‐center, randomized controlled trial Infants were eligible for study if they were born at a gestation between 24 weeks and 27 weeks and were between 10 days and 21 days after birth. Further inclusion criteria were radiographic findings consistent with the diagnosis of evolving BPD with ventilator support with sustained (≥ 18 h) FiO2 ≥ 60% and MAP ≥ 8 cm H2O. Infants were excluded in case of a birthweight or head circumference < 10th percentile for gestational age, chromosomal anomalies and congenital heart disease, grade IV IVH, a low 5‐minute Apgar score < 3, or a history of seizures or base deficit of > 15. Infants with sepsis or significant patent ductus arteriosus became study eligible if these issues were treated before the end of the enrollment window. The included infants were randomly assigned to 1 of 2 dosage regimens: 42‐day tapering course of dexamethasone, receiving 0.5 mg/kg/d for the first 3 days, followed by 0.3 mg/kg/d for the next 3 days. The dose was then reduced by 10% every 3 days until a dose of 0.1 mg/kg was reached on day 34. Thereafter, this dose of dexamethasone was maintained for 3 days, alternated daily with saline placebo for 1 week; or 9‐day tapering course of dexamethasone, receiving 0.5 mg/kg/d for the first 3 days, 0.25 mg/kg/d for the next 3 days and then 0.125 mg/kg/d for 3 days, followed by saline placebo. If entry respiratory criteria were again met within the 42‐day study window, two 9‐day courses were allowed according to study protocol. Did not provide relevant comparisons for our predetermined networks and cut‐points
Merz 1999	Single‐center, randomized controlled study investigating moderately‐early vs late administration of dexamethasone Infants with birth weight ≤ 1250 g, gestational age between 24 weeks and 30 weeks, ventilator‐dependent at 7 days of age with rate ≥ 15 cycles per minute and oxygen requirement 25% were included. Infants with sepsis, multiple or severe congenital anomalies, or evidence of hypertension were excluded. The included infants were randomly assigned to 1 of 2 regimens: moderately‐early administration: initiation 7th day after birth; or late administration: initiation 14th day after birth. Both arms received a starting dose of 0.5 mg/kg/d for 3 days, followed by 0.3 mg/kg/d for 3 days, 0.1 mg/kg/d, and followed by this dose alternatively every 2nd day until day 16. All medication was given divided into 2 dosages per day. Did not provide relevant comparisons for our predetermined networks and cut‐points
Ramanathan 1994	Single‐center, randomized controlled trial 28 infants of birthweight between 520 g and 1440 g and gestational age of 27 weeks were included. The included infants were randomly assigned at 10 days to 14 days of age to 1 of 2 dosage regimens: moderate‐dosage schedule of an estimated cumulative dose of 1.9 mg/kg of dexamethasone administered over 7‐day course: 0.4 mg/kg/d for 2 days and tapered for the succeeding 5 days; or low‐dosage regimen of an estimated cumulative dose of 1.0 mg/kg administered over a 7‐day course: 0.2 mg/kg for 2 days, then tapered for the 5 succeeding days. Did not provide relevant comparisons for our predetermined networks and cut‐points

Apgar: :BPD: bronchopulmonary dysplasia; FiO₂: fraction of inspired oxygen; IVH: intraventricular hemorrhage; MAP: mean airway pressure; PMA: postmenstrual age

Characteristics of studies awaiting classification [ordered by study ID]

Watterberg 2022.

Methods	Randomized controlled trial comparing hydrocortisone vs placebo
Participants	Infants < 30 weeks’ gestational age intubated between 14 days and 28 days after birth with high risk of developing BPD were included.
Interventions	Hydrocortisone: 4 mg/kg/d every 6 h for 2 days; then 2 mg/kg/d every 6 h for 3 days; 1 mg/kg/d every 12 h for 3 days; and 0.5 mg/kg/d as a single dose for 2 days (total dose 18 mg/kg) Equal volume of saline placebo
Outcomes	Improvement in survival without physiologically defined moderate to severe BPD Survival without moderate or severe neurodevelopmental impairment at 18 months’ to 22 months’ corrected age
Notes	clinicaltrials.gov/ct2/show/NCT01353313a?term=watterberg+AND+hydrocortisone&rank=1

BPD: bronchopulmonary dysplasia

Characteristics of ongoing studies [ordered by study ID]

He 2020.

Study name	Hydrocortisone to treat early BPD in very preterm infants: study protocol for a randomized controlled trial
Methods	Randomized controlled trial comparing hydrocortisone vs placebo
Participants	Infants between 26 weeks and 30 weeks and 6 days’ gestational age and with birthweight < 1500 g who are not receiving invasive ventilation at 28 days after birth but who have either an oxygen dependency > 30% or who are on noninvasive ventilation support or nasal cannula oxygen > 21%
Interventions	Hydrocortisone 0.5 mg/kg twice a day for 7 days and then 0.5 mg/kg once a day for 3 days (total dose of hydrocortisone 8.5 mg/kg), or equal volume of 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

BPD: bronchopulmonary dysplasia

Differences between protocol and review

We made the following changes to the published protocol (Hay 2020).

PICO

1. We changed the definition for early corticosteroid administration to < seven days after birth and late corticosteroid administration to ≥ seven days after birth.

Types of interventions

1. We defined high‐dose versus moderate‐dose versus low‐dose dexamethasone relative to 2.0 mg/kg and 4.0 mg/kg cumulative dose cut‐points, as per previous analyses (Onland 2009).

Types of outcomes

1. We limited the primary outcome of death to death at 36 weeks' postmenstrual age. We modified the definitions of several secondary outcomes to align with the contributing reviews: cerebral palsy, major neurosensory disability, necrotizing enterocolitis, infection, hypertension, and major neurosensory disability.

Electronic searches

1. Searches were conducted at a number of points between 2016 and February 2022, given an unexpectedly extended timeline for this project.

Assessment of risk of bias

1. We deviated from the original risk of bias assessments of the Cochrane Neonatal authors in the rare instances where the Risk of bias tool was found to have been applied inconsistently between the contributing systematic reviews.

Methods for indirect and network comparisons

1. We analyzed each network to effectively assess the extant trial evidence. Many of these networks were generally poorly connected, and we have stated the subsequent limitations to interpretation within the manuscript.

Assessment of clinical and methodological heterogeneity within treatment comparisons

1. We did not remove studies from our analyses based on heterogeneity. This was in order to provide a complete picture to knowledge users, albeit with discussion of caveats.

Summary of Findings tables

1. For clarity and ease of interpretation, we presented one composite Summary of Findings table for each network (early treatment, late treatment) including all primary outcomes as well as the balancing secondary outcome of CP.

Relative treatment ranking

1. P‐Scores were used instead of SUCRA to establish treatment rankings.

Search

1. We planned to search CINAHL but did not do so. CINAHL records are added to CENTRAL on a routine basis.

Contributions of authors

Drs Hay, Zupancic, and Soll conceived of and crafted the project, collected data, synthesized data, and wrote the final report.

Ms. Ovelman assisted with the project development, literature search, identification of studies, data synthesis, and development of the final report.

Mr. Konstantinidis reviewed and gave feedback on the project, assisted in data collection, conducted the network meta‐analyses, and reviewed and gave feedback on the final report.

Drs Doyle, Onland, and Shah reviewed and gave feedback on the project and final report.

Sources of support

Internal sources

• 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.

External sources

• Noonan Foundation, USA

  This review is funded in part by a grant from the Noonan Foundation. SH, CO , MK, JAFZ, and RS received support to work on the protocol and review from the Deborah Munroe Noonan Memorial Research Fund Award.

Declarations of interest

SH does has not have any interests to disclose at this time.

CO was a former Managing Editor at Cochrane Neonatal and a Managing Editor with the Cochrane Central Editorial Team, during the research and writing of the review. She no longer works with Cochrane and has not provided editorial input on the review or the protocol. Jane Cracknell, Managing Editor, handled the editorial process for the protocol (Hay 2020).

JAFZ: is a member of the American Academy of Pediatrics, which has previously published guidance on this topic. He was not involved in developing that document. He is an Associate Editor for Cochrane Neonatal; however, he had no involvement in the editorial processing of this overview.

LWD: was a grant recipient through his university for a project grant from the National Health and Medical Research Council of Australia for one of the included studies (Doyle 2006; data from this study were extracted by independent authors [SH and MK]). He is also the lead author of two Cochrane Reviews relevant to the topic (Doyle 2021a; Doyle 2021b).

WO is the author of one of the included studies (Onland 2019); data from this study were extracted independently by two authors (SH and MK); there was no funding source for that review. He is also the lead author of one Cochrane Review relevant to the topic (Onland 2017).

MK is a Statistical Editor of Cochrane Acute Respiratory Infections and a Statistical Consultant for Cochrane Neonatal. However, he has not had any part in the editorial process of this review.

PSS is a Senior Editor for Cochrane Neonatal. However, he had no involvement in the editorial processing of this review.

RS is the author of an included study (Soll 1999); data from this study were extracted independently by two authors (SH and MK). Roger Soll is a Co‐ordinating Editor of Cochrane Neonatal, but was not involved in the editorial processes or acceptance for this review.

(see Sources of support)

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