Late (≥ 7 days) inhaled corticosteroids to reduce bronchopulmonary dysplasia in preterm infants

Abstract

Background

Bronchopulmonary dysplasia (BPD), defined as oxygen dependence at 36 weeks' postmenstrual age (PMA), remains an important complication of prematurity. Pulmonary inflammation plays a central role in the pathogenesis of BPD. Attenuating pulmonary inflammation with postnatal systemic corticosteroids reduces the incidence of BPD in preterm infants but may be associated with an increased risk of adverse neurodevelopmental outcomes. Local administration of corticosteroids via inhalation may be an effective and safe alternative.

Objectives

To assess the benefits and harms of inhaled corticosteroids versus placebo, initiated between seven days of postnatal life and 36 weeks' postmenstrual age, to preterm infants at risk of developing bronchopulmonary dysplasia.

Search methods

We searched CENTRAL, MEDLINE, Embase, CINAHL, and three trials registries to August 2022. We searched conference proceedings and the reference lists of retrieved articles for additional studies.

Selection criteria

We included randomised controlled trials (RCTs) comparing inhaled corticosteroids to placebo, started between seven days' postnatal age (PNA) and 36 weeks' PMA, in infants at risk of BPD. We excluded trials investigating systemic corticosteroids versus inhaled corticosteroids.

Data collection and analysis

We collected data on participant characteristics, trial methodology, and inhalation regimens. The primary outcomes were mortality, BPD, or both at 36 weeks' PMA. Secondary outcomes included short‐term respiratory outcomes (mortality or BPD at 28 days' PNA, failure to extubate, total days of mechanical ventilation and oxygen use, and need for systemic corticosteroids) and adverse effects. We contacted the trial authors to verify the validity of extracted data and to request missing data. We analysed all data using Review Manager 5. Where possible, we reported the results of meta‐analyses using risk ratios (RRs) and risk differences (RDs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, along with their 95% confidence intervals (CIs). We analysed ventilated and non‐ventilated participants separately. We used the GRADE approach to assess the certainty of the evidence.

Main results

We included seven trials involving 218 preterm infants in this review. We identified no new eligible studies in this update. The evidence is very uncertain regarding whether inhaled corticosteroids affects the combined outcome of mortality or BPD at 36 weeks' PMA (RR 1.10, 95% CI 0.74 to 1.63; RD 0.07, 95% CI −0.21 to 0.34; 1 study, 30 infants; very low‐certainty) or its separate components: mortality (RR 3.00, 95% CI 0.35 to 25.78; RD 0.07, 95% CI −0.08 to 0.21; 3 studies, 61 infants; very low‐certainty) and BPD (RR 1.00, 95% CI 0.59 to 1.70; RD 0.00, 95% CI −0.31 to 0.31; 1 study, 30 infants; very low‐certainty) at 36 weeks' PMA. Inhaled corticosteroids may reduce the need for systemic corticosteroids, but the evidence is very uncertain (RR 0.51, 95% CI 0.26 to 1.00; RD −0.22, 95% CI −0.42 to −0.02; number needed to treat for an additional beneficial outcome 5, 95% CI 2 to 115; 4 studies, 74 infants; very low‐certainty). There was a paucity of data on short‐term and long‐term adverse effects. Despite a low risk of bias in the individual studies, we considered the certainty of the evidence for all comparisons discussed above to be very low, because the studies had few participants, there was substantial clinical heterogeneity between studies, and only three studies reported the primary outcome of this review.

Authors' conclusions

Based on the available evidence, we do not know if inhaled corticosteroids initiated from seven days of life in preterm infants at risk of developing BPD reduces mortality or BPD at 36 weeks' PMA. There is a need for larger randomised placebo‐controlled trials to establish the benefits and harms of inhaled corticosteroids.

Plain language summary

Inhaled steroids for lung disease in newborns

What is bronchopulmonary dysplasia and how can it be treated?

Infants born prematurely are at risk of developing a chronic lung condition called bronchopulmonary dysplasia (BPD). Inflammation in the premature lung seems to play an important role in the development of BPD. Research has shown that medicines that suppress inflammation (corticosteroids) injected into the bloodstream reduce the risk of BPD but may also have serious side effects on other parts of the body, such as the brain. Corticosteroids given by inhalation may reduce these unwanted effects, because in theory these medicines should mainly stay in the lungs and not cause unwanted effects in other parts of the body.

What did we want to find out?

We wanted to find out if inhaled corticosteroids, compared to dummy treatment (placebo), given to premature infants from seven days of life could improve survival and reduce BPD. We also wanted to find out if inhaled corticosteroids produced unwanted effects.

What did we do?

We searched for studies that compared inhaled corticosteroids to placebo in premature infants who were at risk of BPD. We compared and summarised the results of the included studies, and rated our confidence in the evidence based on factors such as study methods and sizes.

What did we find?

We identified seven studies that had investigated this therapy in 218 premature infants. We do not know whether inhaled corticosteroids compared with placebo started from seven days of life reduces death or BPD in premature infants who are at risk of BPD. Nor do we know whether this treatment has any unwanted effects. More research is needed to investigate the potential benefits and harms of inhaled corticosteroids in this population.

What are the limitations of the evidence?

We are not confident in the evidence, because it is based on very few cases, and because very few studies reported our main outcome of death or BPD.

How up to date is the evidence?

The evidence is up to date to 29 August 2022.

Summary of findings

Summary of findings 1. Inhaled corticosteroids compared to placebo in preterm infants.

Inhaled corticosteroids compared to placebo in preterm infants
Patient or population: preterm infants Setting: NICU in the USA, UK, Canada, France, Portugal and Sweden Intervention: inhaled corticosteroids Comparison: placebo
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo	Risk with inhaled corticosteroids
Combined outcome of mortality or BPD at 36 weeks' PMA	Study population		RR 1.10 (0.74 to 1.63)	30 (1 RCT)	⊕⊝⊝⊝ Very lowa,b,c	—
	533 per 1000	587 per 1000 (395 to 869)
Mortality at 36 weeks' PMA	Study population		RR 3.00 (0.35 to 25.78)	61 (3 RCTs)	⊕ ⊝ ⊝⊝ Very lowc,d	—
	0 per 1000	1 per 1000 (0 to 8)
BPD at 36 weeks' PMA	Study population		RR 1.00 (0.59 to 1.70)	30 (1 RCT)	⊕⊝⊝⊝ Very lowa,b,c	—
	600 per 1000	600 per 1000 (354 to 1000)
Open‐label use of systemic corticosteroids	Study population		RR 0.51 (0.26 to 1.00)	74 (4 RCTs)	⊕⊝⊝⊝ Very lowc,e	—
	432 per 1000	221 per 1000 (112 to 432)
*The risk in the intervention group (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% CI). BPD: bronchopulmonary dysplasia; CI: confidence interval; NICU: neonatal intensive care unit; OR: odds ratio; PMA: postmenstrual age; RCT: randomised controlled trial; RR: risk ratio.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

^aDowngraded one level for publication bias: only one trial reported this outcome for ventilated and non‐ventilated infants separately.
^bDowngraded one level for inconsistency: difference in effect estimates might be explained by inclusion of both ventilated and non‐ventilated infants.
^cDowngraded two levels for imprecision: number of participants less than optimal information size calculation, few events and very wide CI.
^dDowngraded one level for publication bias: only 2/7 RCTs reported this outcome.
^eDowngraded one level for inconsistency: trials investigated different inhaled drugs.

Background

Description of the condition

Bronchopulmonary dysplasia (BPD), defined as oxygen or respiratory support dependency at 36 weeks' postmenstrual age (PMA), is the most frequent complication of prematurity, with a reported incidence of 23% in infants born at 28 weeks, increasing to 73% in infants born at 23 weeks (Stoll 2010). Since the original description of BPD (Northway 1967), the diagnostic criteria and classification have been revisited, adapted and implemented several times. The National Institutes of Health (NIH) published the current internationally accepted criteria for diagnosing BPD in 2001 (Jobe 2001). BPD is characterised by prolonged respiratory support, compromised lung function, and recurrent respiratory infections, such as viral‐induced wheezing and bronchiolitis during the first years of life (Bolton 2015; Doyle 2006). Furthermore, BPD is considered an independent risk factor for neurodevelopmental impairment (Short 2007; Walsh 2005). BPD is a multifactorial disease of arrest of pulmonary development. The most important risk factors are mechanical ventilation, oxygen toxicity, and pre‐ and postnatal infection; and pulmonary inflammation plays an important mediating role.

Description of the intervention

The intervention of interest is inhaled corticosteroids administered to ventilated or non‐ventilated newborn infants at risk of developing BPD. Budesonide, beclomethasone and fluticasone are the most frequently used inhaled corticosteroids in newborn infants. These drugs are almost exclusively delivered using a pressurised metered‐dose inhaler (MDI) with a spacer, or using nebuliser. Studies in preterm infants revealed that metered‐dose inhalation with a spacer results in a far better deposition than nebulisation. In addition, inhalation via an endotracheal tube provides better deposition than inhalation via a face mask (Fok 1996).

How the intervention might work

Pulmonary inflammation plays a central, modulating role in the pathogenesis of BPD (Jobe 2001; McEvoy 2014; Pierce 1995). Corticosteroids have a strong anti‐inflammatory effect, making them an ideal candidate to attenuate the inflammatory response associated with BPD. Randomised controlled trials (RCTs) have shown that systemic administration of corticosteroids reduces the incidence of BPD and the combined outcome of mortality or BPD in ventilated preterm infants (Doyle 2021a; Doyle 2021b). However, systemic corticosteroids are also associated with short‐term adverse effects (e.g. hyperglycaemia, hypertension, infection) and long‐term adverse effects (neurodevelopmental impairment). The balance between beneficial and adverse effects of corticosteroids may be more favourable when using the inhalation route because, ideally, inhaled corticosteroids should demonstrate high pulmonary deposition in addition to a low systemic bioavailability and rapid systemic clearance.

Why it is important to do this review

The association between early systemic corticosteroid use (initiated before seven days of life) and adverse neurodevelopmental outcomes has led to a reduction in the overall use of corticosteroids in ventilated preterm infants (Cheong 2013; Yoder 2009). Administering corticosteroids by inhalation may be a safe and effective alternative. Inhaled corticosteroid administration is common (Job 2015; Maas 2010; Slaughter 2014). The first Cochrane Review of the randomised evidence on inhaled corticosteroids in preterm infants was first published in 1999 (Lister 2000). Subsequent updates extended the eligibility criteria to include RCTs that initiated inhaled corticosteroids after the first week of postnatal life (Onland 2012; Onland 2017a), in line with the Cochrane Reviews on systemic corticosteroids (Doyle 2021a; Doyle 2021b). The 2017 update concluded that in ventilated infants, administration of inhaled corticosteroids improved rate of extubation without any apparent adverse effects; the evidence was inconclusive regarding the effects on non‐ventilated infants (Onland 2017a). With this update, we aimed to identify any additional eligible studies that could help us to draw firmer conclusions.

Other Cochrane Neonatal systematic reviews of corticosteroids in the Cochrane Library

Additional neonatal systematic reviews in the Cochrane Library address the use of corticosteroids in the prevention or treatment of BPD. Three focused on the systemic administration of postnatal steroids (Doyle 2021b; Doyle 2021a; Onland 2017b); one summarised the available evidence on early administration of inhaled corticosteroids for preventing BPD in ventilated preterm very low birth weight neonates (Shah 2017a); and two identified, appraised and summarised all trials comparing inhaled versus systemic corticosteroid administration for preventing or treating BPD in ventilated preterm very low birth weight neonates (Shah 2017b; Shah 2017c).

Objectives

To assess the benefits and harms of inhaled corticosteroids versus placebo, initiated between seven days of postnatal life and 36 weeks' postmenstrual age, to preterm infants at risk of developing bronchopulmonary dysplasia.

Methods

Criteria for considering studies for this review

Types of studies

Randomised or quasi‐randomised (predictable allocation) placebo‐controlled trials, including cluster‐RCTs, were eligible for this review. We considered non‐randomised cohort studies and cross‐over studies to be ineligible, in view of the potential confounding by indication or residual confounding of such study designs (Fewell 2007; Kyriacou 2016).

Types of participants

Preterm infants between seven days' postnatal age (PNA) and 36 weeks' PMA who needed mechanical ventilation or supplemental oxygen, or both.

Types of interventions

We included trials that randomised infants to treatment with inhaled corticosteroid or placebo. The intervention had to be a standardised (non‐individualised) dosage regimen of inhaled corticosteroids, initiated between seven days of life and 36 weeks' PMA. We excluded studies that investigated inhaled corticosteroids compared to or in addition to systemic corticosteroids (dexamethasone, hydrocortisone, or methylprednisolone).

Types of outcome measures

Primary outcomes

• Combined outcome of mortality or BPD at 36 weeks' PMA (BPD defined as oxygen dependency, respiratory support dependency, or both, at 36 weeks' PMA)

• Mortality at 36 weeks' PMA

• BPD at 36 weeks' PMA

Secondary outcomes

Secondary outcomes in ventilated and non‐ventilated infants 

• Combined outcome of mortality or BPD at 28 days' PNA

• Mortality at 28 days' PNA

• BPD at 28 days' PNA

• Mortality at hospital discharge

• Open‐label use of systemic corticosteroids

• Persistent ductus arteriosus

• Necrotising enterocolitis

• Solitary intestinal perforation

• Hypertension

• Sepsis (clinically suspected or culture‐proven)

• Hyperglycaemia

• Periventricular leukomalacia

• Intraventricular haemorrhage

• Retinopathy of prematurity

• Days of supplemental oxygen

• Days of hospitalisation

• Long‐term neurodevelopmental sequelae, assessed after at least one year of corrected gestational age (CGA) and before four years' CGA, including cerebral palsy, blindness, deafness, and an abnormal score on Bayley Scales of Infant Development

Secondary outcomes in ventilated infants 

• Days of mechanical ventilation

• Failure to extubate within seven days of initiating therapy

• Failure to extubate within 14 days of initiating therapy

• Failure to extubate by end of follow‐up

Search methods for identification of studies

An Information Specialist (MF) revised the search strategies for this update to increase sensitivity.

Electronic searches

For this update we conducted searches from 2017 to 29 August 2022. We used the Cochrane Highly Sensitive Search Strategy to limit retrieval to RCTs (as described in Criteria for considering studies for this review) and systematic reviews (Lefebvre 2022). We searched the following databases without restrictions on language or publication type:

• Cochrane Library (CENTRAL, CDSR, and Cochrane Clinical Answers) via Wiley (Issue 8, 2022);

• Ovid MEDLINE (R) and Epub Ahead of Print, In‐Process, In‐Data‐Review & Other Non‐Indexed Citations, Daily and Versions (1946 to 29 August 2022);

• Embase via Ovid (1974 to 29 August 2022); and

• CINAHL via EBSCOhost (1982 to 29 August 2022).

Database search strategies are available in Appendix 1, Appendix 2, Appendix 3, and Appendix 4.

We searched the following clinical trials registries for ongoing or completed trials on 3 September 2022:

• United States National Library of Medicine clinical trials registry ClinicalTrials.gov (clinicaltrials.gov);

• World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP; www.who.int/clinical-trials-registry-platform); and

• ISRCTN registry (www.isrctn.com)

Trial registry strategies are available in Appendix 5.

Searching other resources

We searched the reference lists of reports included in this review for studies not identified by our database and trial registry searches. We handsearched the Pediatric Academic Societies conference proceedings from 1990 to 2000, and performed an electronic search of the conference proceedings published from 2000. We contacted authors of all relevant or potentially relevant studies to confirm details of reported follow‐up studies or to obtain information about long‐term follow‐up where necessary.

Data collection and analysis

Selection of studies

Two review authors (WO and AvK) classified the citations retrieved through the database search into three groups: 'clearly an RCT', 'possibly an RCT' and 'clearly not an RCT'. The same two review authors independently assessed the full‐text articles of all citations in the first two groups against our eligibility criteria. We resolved any disagreements by consensus.

Data extraction and management

Two review authors (WO and, AvK) independently extracted the following clinical data from the included trials (in addition to the predefined outcome measures) using a piloted data extraction form:

• participant characteristics (birth weight, gestational age, sex);

• number of infants randomised;

• treatment with antenatal glucocorticoids; and

• postnatal surfactant therapy.

We resolved any disagreement by consensus.

We contacted the trial authors to request that they verify the data extraction and, where necessary, provide additional (unpublished) data.

Assessment of risk of bias in included studies

Two review authors (WO and AvK) independently assessed the risk of bias (low, high, or unclear) of the included trials using the Cochrane risk of bias tool (RoB 1), which covers the following domains:

• sequence generation (selection bias);

• allocation concealment (selection bias);

• blinding of participants and personnel (performance bias);

• blinding of outcome assessment (detection bias);

• incomplete outcome data (attrition bias);

• selective reporting (reporting bias); and

• any other bias (Higgins 2011).

We resolved any disagreements by discussion or by consulting a third assessor. See Appendix 6 for a detailed description of the risk of bias assessment process.

Measures of treatment effect

We meta‐analysed the extracted data using standard Cochrane methods (Higgins 2020). We processed the extracted data using Cochrane Review Manager 5 software (RevMan 5; Review Manager 2020). We calculated treatment effect estimates for all trials as risk ratio (RR) and risk difference (RD) for dichotomous outcomes, including number needed to treat for an additional beneficial outcome (NNTB) or number needed to treat for an additional harmful outcome (NNTH), all with 95% confidence intervals (CIs). For continuous outcomes, we calculated mean differences (MDs) with 95% CIs.

Unit of analysis issues

The unit of analysis was the participating infant in individually randomised trials. Had we identified any cluster‐randomised trials, we would have considered the unit of analysis to be the neonatal unit (or subunit). We would have undertaken analyses at the level of the individual while accounting for the clustering in the data using the methods recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2020). Because this review included no trials with non‐standard designs, no effect measures for counts and rates were necessary.

Dealing with missing data

We followed the intention‐to‐treat principle in the analyses by including data from all randomised trial participants irrespective of their compliance to the assigned intervention (Higgins 2020). We requested additional (unpublished) data from trial authors.

Assessment of heterogeneity

We assessed heterogeneity between trials by inspecting the forest plots and calculating the I² statistic. To interpret I² values, we applied the following categories, as defined by Cochrane Neonatal:

• less than 25%: no heterogeneity;

• 25% to 49%: low heterogeneity;

• 50% to 74%: moderate heterogeneity; and

• 75% or greater: high heterogeneity.

We explored possible causes of statistical heterogeneity using prespecified subgroup analyses (e.g. differences in inclusions of ventilated and non‐ventilated infants). We used fixed‐effect models for the meta‐analyses.

Assessment of reporting biases

Had we included more than 10 studies in any meta‐analysis, we would have created funnel plots to assess possible reporting biases. We applied no language restrictions in the search strategy.

Data synthesis

We meta‐analysed the extracted data with RevMan 5 using standard Cochrane methods (Review Manager 2020; Higgins 2020). We expressed treatment effects for dichotomous outcomes as typical RRs, typical RDs, and NNTB or NNTH where there was a difference, all with 95% CIs. We used MDs for continuous outcomes. If trials had used different scales to measure the same outcome, we would have calculated the standardised mean difference (SMD).

Subgroup analysis and investigation of heterogeneity

We handled data on infants who were ventilated and non‐ventilated at trial entry as two separate subgroups. Furthermore, we had planned to perform subgroup analyses on:

• timing of therapy onset;

• type and dose of inhaled corticosteroid;

• duration of treatment and delivery system; and

• difference in effect estimates for ventilated and non‐ventilated infants.

Sensitivity analysis

We had planned to perform sensitivity analyses to examine how estimates were affected by including only studies at low risk of:

• selection bias (adequate randomisation and allocation concealment);

• detection or performance bias (adequate masking of intervention and measurement);

• attrition bias (less than 20% loss to follow‐up for primary outcome assessment); and

• reporting bias (selective reporting).

Summary of findings and assessment of the certainty of the evidence

We used the GRADE approach, as outlined in the GRADE Handbook (Schünemann 2013), to assess the certainty of evidence for the following clinically relevant outcomes:

• combined outcome of BPD or mortality at 36 weeks' PMA;

• mortality at 36 weeks' PMA;

• BPD at 36 weeks' PMA; and

• open‐label rescue therapy with systemic corticosteroids together with study medication or after study medication was stopped

Two review authors (WO and AvK) independently performed the GRADE assessment. We considered evidence from RCTs as high quality to start with, but downgraded the evidence one level for serious (or two levels for very serious) limitations based on the following considerations:

• design (risk of bias);

• consistency across studies;

• directness of the evidence;

• precision of estimates; and

• presence of publication bias.

We used the GRADEpro GDT Guideline Development Tool to create the summary of findings table.

The GRADE assessment results in one of the following four ratings, which we interpreted according to the GRADE guidelines 26 (Santesso 2020).

• High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.

• Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.

• Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.

• Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

Results

Description of studies

See Characteristics of included studies.

Results of the search

Literature searches from 2017 to August 2022 identified 833 references. After deduplication, 481 references were available for screening. All searches of this and previous versions of the review recovered a total of 1101 references (Figure 1). We excluded 1081 references in the title and abstract screen, and reviewed 20 full‐text reports or trial registry records. From these 20 references, we excluded nine full‐text reports: two RCTs (six reports) initiated therapy within the first week of life (Cole 1999; Rajamani 1998), two trials (two reports) did not perform the intervention in our target population (Kugelman 2017; Pokriefka 1993), and one citation was a trial registration of a withdrawn study (NCT01895075). We included seven studies (11 reports) in our analysis. There was consensus among the review authors.

1.

Study flow diagram.

Included studies

See Characteristics of included studies

We included seven RCTs (11 reports), all of which were available as full‐text publications (Arnon 1996; Denjean 1998; Dugas 2005; Giep 1996; LaForce 1993; Jonsson 2000; Pappagallo 1998). Appendix 7 provides a description of each trial. The RCTs recruited between 1989 and 2000 in the USA (Giep 1996; LaForce 1993; Pappagallo 1998), Europe (Denjean 1998; Jonsson 2000), Canada (Dugas 2005), and the UK (Arnon 1996). Two RCTs were multicenter studies (Denjean 1998; Dugas 2005), and none had a cluster‐randomised design.

Population

There were 218 participants in the seven trials. The median number of participants was 19 (range 13 to 86). Four trials included only infants who were ventilated at trial entry (Arnon 1996; Giep 1996; LaForce 1993; Pappagallo 1998), whereas three trials included both ventilated and non‐ventilated preterm infants (Denjean 1998; Dugas 2005; Jonsson 2000). Inclusion criteria were comparable between trials (ventilator dependency, oxygen dependency, or both, from seven days' PNA). The exclusion criteria were persistent ductus arteriosus, signs of sepsis, congenital malformations, and treatment with postnatal corticosteroids prior to inclusion. Six trials started therapy between seven and 21 days' PNA, whereas Dugas 2005 started therapy after 21 days' PNA (delayed onset). The gestational age and birth weight of the included infants were comparable between trials (before 33 weeks' gestation and below 1500 g).

Two trials did not report use of antenatal corticosteroids or postnatal surfactant (LaForce 1993; Pappagallo 1998). In the remaining trials, between 25% and 80% of participants received antenatal corticosteroids, and between 69% and 100% of participants received postnatal surfactant. Within the trials, participants in the treatment and placebo groups were similar in terms of clinical characteristics (e.g. birth weight, gestational age, sex, use of antenatal corticosteroids and surfactant, Apgar scores, fraction of inspired oxygen (FiO₂₎ and ventilator settings, and respiratory support at trial entry).

Interventions

Interventions differed between trials with regard to the type of corticosteroid, dosage, delivery system, and duration of treatment. The corticosteroids administered were beclomethasone (Denjean 1998; Giep 1996; LaForce 1993), fluticasone (Dugas 2005), budesonide (Arnon 1996; Jonsson 2000), and dexamethasone (Pappagallo 1998). The dose for beclomethasone varied from 1 mg/kg/day (divided over three or four doses; Denjean 1998; Giep 1996) to 0.15 mg/day (divided over three doses; LaForce 1993). Delivery systems included metered‐dose inhalation with a spacer device, and nebulisation. Total duration of study medication ranged from seven to 28 days.

Comparisons

All trials used a placebo, though only two described the placebo in the reports (physiological saline in both cases; LaForce 1993; Pappagallo 1998).

Outcome parameters

Dugas 2005, Jonsson 2000 and LaForce 1993 reported or provided data on mortality in the ventilated infants at the different points in hospitalisation (28 days' PNA, 36 weeks' PMA, and hospital discharge), and Jonsson 2000 provided us with additional data on non‐ventilated infants.

No studies reported the incidence of BPD at 28 days' PNA or 36 weeks' PMA for the ventilated and non‐ventilated infants separately; however, we obtained these data for Jonsson 2000 through personal communication with the trial authors.

Five trials reported failure to extubate by seven days after treatment initiation (Arnon 1996; Dugas 2005; Giep 1996; Jonsson 2000; Pappagallo 1998). Three trials reported the duration of mechanical ventilation for the subgroup of infants who were ventilated at trial entry (Dugas 2005; Jonsson 2000; Pappagallo 1998). Four trials reported the total days of supplemental oxygen in the subgroup of ventilated infants (Denjean 1998; Dugas 2005; Jonsson 2000; Pappagallo 1998), and two in the subgroup of non‐ventilated infants (Denjean 1998; Jonsson 2000). Pappagallo 1998 reported total days of hospitalisation in the intervention and placebo arms.

Five trials reported the incidence of open‐label corticosteroid use outside the study protocol in both arms (Denjean 1998; Dugas 2005; Giep 1996; Jonsson 2000; Pappagallo 1998). The authors of four studies reported or provided additional data on the outcome of sepsis, and on one of the following outcomes in both arms: persistent ductus arteriosus, hypertension, necrotising enterocolitis, or intraventricular haemorrhage (Arnon 1996; Giep 1996; Jonsson 2000; LaForce 1993).

Two studies reported no increase in adverse side effects (e.g. impaired glucose homeostasis or hypertension), but did not provide the data to support these results (Arnon 1996; Giep 1996).

No trials reported gastrointestinal bleeding or perforation, periventricular leukomalacia, retinopathy of prematurity, or long‐term neurodevelopmental sequelae. We were unable to obtain data on these outcomes from trial authors.

Excluded studies

See table Characteristics of excluded studies.

We excluded five trials (nine reports; Cole 1999; Kugelman 2017; NCT01895075; Pokriefka 1993; Rajamani 1998).

Two trials (six reports) may have included participants that met the eligibility criteria of this review, but we excluded these trials because all attempts to contact the trial authors to request subgroup data were unsuccessful (Cole 1999; Rajamani 1998). We excluded two studies because they were conducted in infants with established BPD (Kugelman 2017; Pokriefka 1993). We excluded one reference to a study registration because the study was stopped early due to lack of funding; we found no published results (NCT01895075).

Risk of bias in included studies

All trials were randomised, double‐blind, and placebo‐controlled. The authors of four trials provided additional information (Arnon 1996; Giep 1996; Jonsson 2000; LaForce 1993).

Risk of bias in individual studies

Arnon 1996 did not describe the method of randomisation in the manuscript. Through personal communication, we discovered that a pharmacist had performed the randomisation. The code and drugs were stored until the end of the trial, when they were released from the hospital pharmacy in sealed envelopes. The investigators ensured blinding by using identical MDIs for corticosteroids and placebo administration. Ten infants were withdrawn and did not complete the study: five because of sepsis (three in placebo group, two in treatment group), four because of persistent ductus arteriosus (two in each group) and one because of an air leak (treatment group). The trial authors had excluded these infants from their analysis, but we included them in this review. It was unclear whether the study was free of selective reporting.

Denjean 1998 did not mention the methods of allocation concealment or randomisation in the manuscript. Through personal communication, we discovered that the investigators had stratified participants by centre, gestational age, and type of ventilator support before randomisation by pre‐established tables. The manuscript did not clearly describe the method of blinding, but when we contacted the trial authors, they assured us the blinding methods were adequate. The investigators had to break the code for three participants due to severe clinical deterioration. Informed consent was either not obtained or withdrawn for 5/178 infants randomised for unclear reasons. It was unclear whether the study was free of selective reporting.

Dugas 2005 did not describe the method of allocation concealment in the manuscripts. The investigators assigned infants to the treatment or placebo arm by block randomisation with stratification of intubated and extubated infants. They ensured blinding by administering the treatment and placebo with identical MDIs supplied by the drug manufacturer. The pharmacist in charge of the medication, the treating physician, and the investigators were unaware of treatment allocation. Three infants in the placebo group did not complete the study protocol (two because of clinical pulmonary deterioration and one because of central line sepsis). All participants were analysed on an intention‐to‐treat basis. Mean supplemental oxygen at study enrolment was significantly lower in the treatment group that in the placebo group. The trial authors reported all predefined outcomes.

Giep 1996 did not describe methods of randomisation or allocation concealment in the manuscript. It stated that observers were blinded to treatment allocation but did not describe the method of ensuring blinding. Three infants in the placebo group and two in the treatment group received systemic corticosteroids after study entry, and continuous data that were not of interest for this review were excluded from the analysis thereafter.

Jonsson 2000 used a computer‐generated randomisation sequence and consecutively numbered sealed envelopes. Clinical staff were blinded to group assignment, and the code was broken after the last participant finished treatment. The investigators ensured blinding by supplying the study drug in identical, opaque, unmarked plastic vials. Outcome assessors were also blinded. Two participants were withdrawn by their attending clinician due to deterioration and received systemic corticosteroids; one of them died on the ninth day of life. The study reported all predefined outcomes for all enrolled infants.

In LaForce 1993, the attending neonatologist was unaware of the treatment regimen, although the precise method of blinding was not described. The method of allocation concealment was unclear. Nine participants were withdrawn from the analysis due to: technical problems with equipment (two in each group), loss to referring hospital (two in each group), and sudden death before study commencement (one in treatment group). The trial authors did not include these participants in their analyses, but we included them in the meta‐analysis of dichotomous outcomes in our review. It was unclear whether the study was free of selective reporting.

Pappagallo 1998 provided no information regarding the method of sequence generation, allocation concealment, or randomisation in the manuscript. Clinical staff were unaware of the intervention because the vials were prepared by the pharmacist and labelled with a code, both the study and placebo medications were clear solutions, and the dosage was calculated on the basis of volume. The study reported outcomes for all infants enrolled. 

Summarised risk of bias

The overall risk of bias was low because all studies had a double‐blind placebo‐controlled study design (Figure 2; Figure 3). Some studies did not state explicitly the method of random sequence generation, one study had high risk of attrition bias (Denjean 1998), and we were not able to assess the criterion of selective reporting.

2.

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

3.

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

Allocation

We judged two trials at low risk of selection bias because they had adequate allocation concealment (Arnon 1996; Jonsson 2000), while the remaining trials provided insufficient information for us to judge. We considered only two trials at low risk of bias with regard to random sequence generation (Denjean 1998; Jonsson 2000), while the rest were at unclear risk of bias.

Blinding

Based on the reported data and personal communications, we considered all studies had a double‐blind design and were at low risk of performance and detection bias.

Incomplete outcome data

Four trials reported the outcomes of all included participants (Dugas 2005; Giep 1996; Jonsson 2000; Pappagallo 1998), whereas three trials could not include some participants owing to lack of informed consent, or excluded participants in view of their outcomes (Arnon 1996; Denjean 1998; LaForce 1993).

Selective reporting

Four trials reported all predefined outcomes (Dugas 2005; Giep 1996; Jonsson 2000; Pappagallo 1998). It was unclear whether the remaining three trials had reported all predefined outcome data (Arnon 1996; Denjean 1998; LaForce 1993). No studies had a previously published protocol, so we judged all of them at unclear risk of reporting bias.

Other potential sources of bias

With the exception of three trials (Arnon 1996; Giep 1996; Jonsson 2000), other potential sources of bias could not be excluded based on the available information.

Effects of interventions

See: Table 1

Primary outcomes in ventilated and non‐ventilated infants

Due to paucity of data in the eligible studies, no subgroup or sensitivity analyses were possible for these outcomes.

Combined outcome of mortality or bronchopulmonary dysplasia at 36 weeks' postmenstrual age

See Table 1. 

Jonsson 2000 reported the combined outcome of mortality or BPD at 36 weeks' PMA in both ventilated and non‐ventilated infants. Meta‐analysis showed no difference between the treatment and placebo arms in all participants (RR 1.10, 95% CI 0.74 to 1.63; RD −0.07, 95% CI −0.21 to 0.34; I² = 2%; 30 infants; test for subgroup differences: Chi² = 0.72, P = 0.40; very low‐certainty evidence; Analysis 1.1) or in either of the subgroups (ventilated or non‐ventilated infants). 

1.1. Analysis.

Comparison 1: Inhaled corticosteroids (ICS) versus placebo, Outcome 1: Combined outcome of mortality or bronchopulmonary dysplasia at 36 weeks' postmenstrual age

Mortality at 36 weeks' postmenstrual age

See Table 1.

Dugas 2005, Jonsson 2000, and LaForce 1993 reported mortality at 36 weeks' PMA. It is unclear if inhaled corticosteroid treatment compared to placebo has an effect on this outcome (RR 3.00, 95% CI 0.35 to 25.78; RD 0.08, 95% CI −0.08 to 0.24; I² = 0%; 3 studies, 61 infants; test for subgroup differences not applicable; very low‐certainty evidence; Analysis 1.2). 

1.2. Analysis.

Comparison 1: Inhaled corticosteroids (ICS) versus placebo, Outcome 2: Mortality at 36 weeks' postmenstrual age

Bronchopulmonary dysplasia at 36 weeks' postmenstrual age

See Table 1.

Jonsson 2000 reported BPD at 36 weeks' PMA in both ventilated and non‐ventilated infants. It is unclear if inhaled corticosteroid treatment compared to placebo has an effect on this outcome (RR 1.00, 95% CI 0.59 to 1.70; RD 0.10, 95% CI −0.28 to 0.48; I² = 0%; 30 infants; test for subgroup differences: Chi² = 0.59, P = 0.44; very low‐certainty evidence; Analysis 1.3). 

1.3. Analysis.

Comparison 1: Inhaled corticosteroids (ICS) versus placebo, Outcome 3: Bronchopulmonary dysplasia at 36 weeks' postmenstrual age

Secondary outcomes in ventilated and non‐ventilated infants

Due to paucity of data in the eligible studies, no subgroup or sensitivity analyses were possible for these outcomes.

Combined outcome of mortality or bronchopulmonary dysplasia at 28 days' postnatal age

Jonsson 2000 reported the combined outcome of mortality and BPD at 28 days' PNA in both ventilated and non‐ventilated infants. Meta‐analysis showed no difference between the treatment and placebo arms in all participants (RR 1.00, 95% CI 0.85 to 1.18; RD 0.00, 95% CI −0.17 to 0.17; I² = 0%; 30 infants; test for subgroup differences: Chi² = 0.00, P = 1.00; Analysis 1.4) or in either subgroup (ventilated or non‐ventilated infants). 

1.4. Analysis.

Comparison 1: Inhaled corticosteroids (ICS) versus placebo, Outcome 4: Combined outcome of mortality or bronchopulmonary dysplasia at 28 days' postnatal age

Mortality at 28 days' postnatal age

Jonsson 2000 and LaForce 1993 reported mortality at 28 days' PNA in both ventilated and non‐ventilated infants. Meta‐analysis showed no difference between the treatment and placebo arms (RR 3.00, 95% CI 0.14 to 65.90; RD 0.05, 95% CI −0.11 to 0.21; I² = not applicable; 2 studies, 51 infants; test for subgroup differences not applicable; Analysis 1.5).

1.5. Analysis.

Comparison 1: Inhaled corticosteroids (ICS) versus placebo, Outcome 5: Mortality at 28 days' postnatal age

Bronchopulmonary dysplasia at 28 days' postnatal age

Jonsson 2000 reported BPD at 28 days' PNA in both ventilated and non‐ventilated infants. Meta‐analysis showed no difference between the treatment and placebo arms (RR 0.93, 95% CI 0.72 to 1.21; RD = 0.07, 95% CI −0.31 to 0.17; I² = 0%; 30 infants; test for subgroup differences: Chi² = 0.21, P = 0.66; very low‐certainty evidence; Analysis 1.6). 

1.6. Analysis.

Comparison 1: Inhaled corticosteroids (ICS) versus placebo, Outcome 6: Bronchopulmonary dysplasia at 28 days' postnatal age

Mortality at hospital discharge

Dugas 2005, Jonsson 2000, and LaForce 1993 reported mortality at hospital discharge. Meta‐analysis showed no difference between the treatment and placebo arms in all participants (RR 3.00, 95% CI 0.35 to 25.78; RD 0.09, 95% CI −0.10 to 0.28; I² = 0%; 3 studies, 53 infants; test for subgroup differences not applicable; Analysis 1.7) or in either subgroup (ventilated or non‐ventilated infants).

1.7. Analysis.

Comparison 1: Inhaled corticosteroids (ICS) versus placebo, Outcome 7: Mortality at hospital discharge

Open‐label use of systemic corticosteroids

See Table 1.

Dugas 2005, Giep 1996, Jonsson 2000, and Pappagallo 1998 reported open‐label use of systemic corticosteroids. Meta‐analysis showed that infants treated with inhaled corticosteroids were more likely to receive open‐label intravenous corticosteroids than the infants treated with placebo, but this difference was very uncertain (RR 0.51, 95% CI 0.26 to 1.00; RD −0.22, 95% CI −0.42 to −0.02; NNTB 5, 95% CI 2 to 115; I² = 0%; 4 studies, 74 infants; test for subgroup differences not applicable; very low‐certainty evidence; Analysis 1.8). Only Jonsson 2000 reported use of open‐label intravenous corticosteroids in non‐ventilated infants, finding that no infants received this intervention.

1.8. Analysis.

Comparison 1: Inhaled corticosteroids (ICS) versus placebo, Outcome 8: Open‐label use of systemic corticosteroids

Persistent ductus arteriosus

Arnon 1996 reported persistent ductus arteriosus in ventilated infants. The analysis of this single trial showed no difference between the treatment and placebo arms (RR 1.00, 95% CI 0.16 to 6.20; RD = 0.00, 95% CI −0.24 to 0.24; I² = not applicable; 30 infants; test for subgroup differences: not applicable, P = 1.00; Analysis 1.9). 

1.9. Analysis.

Comparison 1: Inhaled corticosteroids (ICS) versus placebo, Outcome 9: Persistent ductus arteriosus

Necrotising enterocolitis

Jonsson 2000 reported necrotising enterocolitis in both ventilated and non‐ventilated infants, finding that no infants in either treatment arm had this diagnosis.

Solitary intestinal perforation

No trials reported solitary intestinal perforation.

Hypertension

Jonsson 2000 reported hypertension, defined as more than two standard deviations above the mean, in both non‐ventilated and ventilated infants. No infants in either treatment arm had this diagnosis.

Sepsis (clinically suspected or culture‐proven)

Giep 1996 reported rates of suspected sepsis, and four trials reported rates of documented sepsis (Arnon 1996; Dugas 2005; Jonsson 2000; LaForce 1993). Meta‐analysis of these results showed no difference between the treatment and placebo groups in all participants (RR 0.90, 95% CI 0.50 to 1.64; RD −0.03, 95% CI −0.19 to 0.13; I² = 0%; 5 studies, 107 infants; test for subgroup differences: Chi² = 0.04, P = 0.84; Analysis 1.12) or in either subgroup (ventilated or non‐ventilated infants).

1.12. Analysis.

Comparison 1: Inhaled corticosteroids (ICS) versus placebo, Outcome 12: Sepsis (clinically suspected or culture‐proven)

Hyperglycaemia

No trials reported hyperglycemia.

Periventricular leukomalacia

No trials reported periventricular leucomalacia.

Intraventricular haemorrhage

Giep 1996 reported intraventricular haemorrhage in ventilated infants. The analysis of this single trial showed no difference between the treatment and placebo arms (RR 0.60, 95% CI 0.13 to 2.82; RD = 0.00, 95% CI −0.24 to 0.24; I² = not applicable; 19 infants; test for subgroup differences: not applicable, P = 0.52; Analysis 1.13). 

1.13. Analysis.

Comparison 1: Inhaled corticosteroids (ICS) versus placebo, Outcome 13: Intraventricular haemorrhage (any grade)

Retinopathy of prematurity

No trials reported retinopathy of prematurity.

Days of supplemental oxygen

Dugas 2005, Denjean 1998, Jonsson 2000, and Pappagallo 1998 reported days of supplemental oxygen. Meta‐analysis showed no difference between the treatment and placebo arms in all participants (MD 0.57, 95% CI −5.92 to 7.07; I² = 48.6%; 4 studies, 141 infants; test for subgroup differences: Chi² = 1.95, P = 0.16; Analysis 1.14) or in either subgroup (ventilated or non‐ventilated infants).

1.14. Analysis.

Comparison 1: Inhaled corticosteroids (ICS) versus placebo, Outcome 14: Days of supplemental oxygen

Days of hospitalisation

Evidence from Pappagallo 1998 suggested that use of inhaled corticosteroids compared to placebo reduced total days of hospitalisation (MD −24.70, 95% CI −41.75 to −7.65; 18 infants; test for subgroup differences not applicable; Analysis 1.15). 

1.15. Analysis.

Comparison 1: Inhaled corticosteroids (ICS) versus placebo, Outcome 15: Days of hospitalisation

Long‐term neurodevelopmental sequelae

No trials reported long‐term neurodevelopmental sequelae.

Secondary outcomes in ventilated infants

Due to paucity of data in the eligible studies, no subgroup or sensitivity analyses were possible for these outcomes.

Days of mechanical ventilation

Dugas 2005, Jonsson 2000 and Pappagallo 1998 reported days of mechanical ventilation. Meta‐analysis showed no difference between the treatment and placebo arms (MD 3.42, 95% CI −1.30 to 8.13; I² = 39%; 3 studies, 45 infants; test for subgroup differences not applicable; Analysis 1.16).

1.16. Analysis.

Comparison 1: Inhaled corticosteroids (ICS) versus placebo, Outcome 16: Days of mechanical ventilation

Failure to extubate within seven days of initiating therapy

Arnon 1996, Dugas 2005, Giep 1996, Jonsson 2000, and Pappagallo 1998 reported failure to extubate within seven days of initiating therapy. Compared to the infants allocated to the placebo group, the infants treated with inhaled corticosteroids had a lower risk of failure to extubate by day seven (RR 0.80, 95% CI 0.66 to 0.98; RD −0.19, 95% CI −0.34 to −0.05; NNTB 5, 95% CI 3 to 19; 5 studies, 79 infants; test for subgroup differences not applicable; Analysis 1.17). However, statistical heterogeneity for this analysis was borderline high (I² = 73%).

1.17. Analysis.

Comparison 1: Inhaled corticosteroids (ICS) versus placebo, Outcome 17: Failure to extubate within 7 days of initiating therapy

Failure to extubate within 14 days of initiating therapy

Dugas 2005 and Jonsson 2000 reported the outcome failure to extubate within 14 days of initiating therapy. Meta‐analysis showed no difference between the treatment and placebo arms (RR 0.36, 95% CI 0.10 to 1.33; I² = 62%; 2 studies, 27 infants; test for subgroup differences not applicable; Analysis 1.18).

1.18. Analysis.

Comparison 1: Inhaled corticosteroids (ICS) versus placebo, Outcome 18: Failure to extubate within 14 days of initiating therapy

Failure to extubate by end of follow‐up

Arnon 1996, Dugas 2005, Giep 1996, Jonsson 2000, and Pappagallo 1998 reported failure to extubate by end of follow‐up. Compared to the infants allocated to the placebo group, the infants treated with inhaled corticosteroids had a lower risk of failure to extubate by end of follow‐up (RR 0.62, 95% CI 0.46 to 0.84; RD −0.35, 95% CI −0.51 to −0.18; NNTB 3, 95% CI 2 to 6; 5 studies, 76 infants; test for subgroup differences not applicable; Analysis 1.19). However, this analysis showed high statistical heterogeneity (I² = 87%).

1.19. Analysis.

Comparison 1: Inhaled corticosteroids (ICS) versus placebo, Outcome 19: Failure to extubate by end of follow‐up

Discussion

Summary of main results

Compared with the previous version of this review, this update contains no new studies (Onland 2017a); in fact, it contains one less study. We excluded Pokriefka 1993 because it included infants with established BPD and therefore did not meet our eligibility criteria. This exclusion did not change the results of the review.

Based on the predefined inclusion criteria, this systematic review identified seven relatively small RCTs comparing inhaled corticosteroids to placebo in a total of 218 ventilated and non‐ventilated preterm infants. The trials differed considerably in participant characteristics, the intervention (medication, dose, duration, and delivery), reported outcomes, and the definitions of these outcomes. It is important to take this heterogeneity and the small sample sizes into account when interpreting the results of this review.

As the aim of our review was to examine effects of interventions to prevent BPD, we excluded trials that had investigated inhaled glucocorticoids in preterms with established BPD at baseline. To the best of our knowledge, it is unclear how many weeks of inhaled corticosteroid are needed to prevent BPD. There needs to be an exposure for some time to reduce inflammation. The only trial that could have theoretically included infants around 36 weeks' PMA could not provide us with data on the primary outcome BPD at 36 weeks' PMA (Dugas 2005). All other trials treated infants for eight weeks until 36 weeks' PMA (on average). Therefore, we feel that the inclusion criteria fulfil the purpose of this review. However, since no long‐term respiratory outcomes assessed during childhood were available from any study, we could not assess the effect of inhaled corticosteroids after 36 weeks' PMA. 

The optimal definition of BPD at 36 weeks' PMA is disputed (Bancalari 2018). However, to date, most RCTs have used the definition provided by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) in 2001 (Jobe 2001). For this review, we used the BPD classifications adopted by the authors of each trial.

Meta‐analysis of data reported in the publications and provided by trial authors produced very low‐certainty evidence that inhaled corticosteroids does not improve the separate or combined outcomes mortality or BPD at any time point during hospitalisation. Our findings showed that the intervention may have reduced the short‐term respiratory outcome of failure to extubate at day seven after randomisation and at end of follow‐up; however, given the high statistical heterogeneity identified in these meta‐analyses, these results should be interpreted with caution. Indeed, it is unclear if combining these studies in a meta‐analysis was justified. We found no evidence of a difference in the other short‐term respiratory outcomes (e.g. failure to extubate by day 14, days of mechanical ventilation, or days of supplemental oxygen), despite the fact that inhaled corticosteroids improved resistance and compliance of the respiratory system in several studies, sometimes resulting in a reduction in FiO₂ or respiratory rate. However, the heterogeneity in lung function measurement and data reporting prevented a valid meta‐analysis of these outcomes (Arnon 1996; Giep 1996; LaForce 1993; Pappagallo 1998).

Our meta‐analysis suggested that inhaled corticosteroids may reduce use of systemic corticosteroids for the reduction of BPD, although the results were very uncertain. In light of the growing concerns about the adverse effects of systemic corticosteroids, this might prove an important and clinically relevant finding. However, the lack of data on short‐ and long‐term adverse effects in most trials precludes firm conclusions at this point in time.

Overall completeness and applicability of evidence

We have some concerns regarding the overall completeness and applicability of this review. First, we identified few trials with a randomised, placebo‐controlled design that were eligible for inclusion, and each included trial enrolled few participants, which limited their power to detect small but clinically important effects of treatment. Second, there were important differences between the trials in terms of participant characteristics and study design, including differences in type of inhaled medication, dose, duration of therapy, and delivery systems. We do not know if or how these factors modified the treatment effect of inhaled corticosteroids on the outcome parameters reported in this review, as we were unable to perform sensitivity analyses to assess the impact of different drugs, dosages, delivery systems, and treatment duration on the magnitude of the expected benefit. Third, not all trials reported the primary and secondary outcomes of interest for this review. The trials adopted various definitions and assessed outcomes at different time points. Our renewed attempts to retrieve unpublished data did not change this shortcoming. Finally, the primary objective of this review was to investigate the benefits and harms of inhaled corticosteroids started from seven days of life for the relatively short‐term outcome BPD at 36 weeks' PMA. Long‐term postdischarge effects of the intervention were not within the scope of this review.

Quality of the evidence

Four of the seven included studies did not report allocation concealment, and five did not adequately describe the random sequence generation process. As all trials reported adequate blinding of the intervention, we judged them at low risk of bias in this domain. However, the overall certainty of the evidence provided by the meta‐analyses was very low for all key outcomes, due to inconsistency and imprecision of the effect estimates, and risk of publication bias. The sample sizes for the reported outcomes were small, providing inadequate power to detect clinically relevant differences. Even if all trials had reported the same outcomes, the considerable clinical heterogeneity between them put the meta‐analysis findings at high risk of inconsistency.

Potential biases in the review process

Due to the lack of eligible trials, we could not create any funnel plots. Therefore, we could not assess a potential risk of publication bias. Furthermore, because we decided to analyse the outcomes of ventilated and non‐ventilated participants in this review separately, we were unable to use data from two RCTs (Denjean 1998; Dugas 2005). With the exception of total duration of supplemental oxygen, all outcomes of interest for this review were presented in these RCTs for the combined group of ventilated and non‐ventilated infants and were therefore excluded from the meta‐analysis. Since both RCTs found no differences between the treatment and placebo groups in any outcome in the ventilated and non‐ventilated participants combined, we consider that including the data they provided in our meta‐analysis is unlikely to have had any effect on the results.

Agreements and disagreements with other studies or reviews

Several reviews have investigated the use of inhaled corticosteroids for the prevention of BPD in preterm infants before seven days of life (Delara 2019; Shah 2017a; Venkataraman 2017). Although there is high‐quality evidence that early administration of inhaled corticosteroids reduces the incidence of mortality or BPD at 36 weeks' PMA, the clinical relevance of this finding is questionable because the upper CI limit goes to infinity (Shah 2017a). Furthermore, there is concern about an increased risk of mortality in infants who receive early inhaled corticosteroids (Bassler 2018). No other review has specifically investigated inhaled corticosteroids in preterm infants from seven days of life.

Authors' conclusions

Implications for practice.

We do not have sufficient high‐certainty evidence to determine whether inhaled corticosteroids administered from seven days of life to preterm infants have any effect on the incidence of mortality or bronchopulmonary dysplasia (BPD), as a combined outcome or as separate components, at any time point during hospitalisation. Although inhaled corticosteroids may improve short term lung function as shown by a reduced incidence of failure to extubate by seven days and by end of follow‐up in the treatment group, this improvement does not seem to impact the duration of mechanical ventilation, and we found high heterogeneity among the data included in the meta‐analyses. One possible explanation for this heterogeneity is that the trials used different type of drugs, dosages and delivery systems. Inhaled corticosteroids may reduce the use of systemic corticosteroids, but the certainty of the evidence is very low, and the clinical relevance of this treatment effect is unclear, as we have very little data on short‐ and long‐term adverse effects of inhaled corticosteroids. The results of this meta‐analysis are compromised by the fact that most trials were underpowered, and the fact that the group of included trials was methodologically diverse. Based on the results of the currently available evidence, we do not know if inhaled corticosteroids initiated from seven days of life in preterm infants at risk of developing BPD reduce mortality or BPD at 36 weeks' postmenstrual age (PMA).

Implications for research.

There is a need for large, randomised, placebo‐controlled trials to establish the benefits and harms of inhaled corticosteroids. Future studies should aim to determine the optimal inhaled corticosteroid drug, dose, duration, and device, using the short‐term markers lung function and inflammation. The optimal treatment regimen should be tested in a randomised placebo‐controlled trial with a large number of preterm infants at risk of developing BPD. The trial design should avoid bias by using adequate allocation concealment and a double‐blinded intervention and outcome assessment. Outcomes should use predefined modern definitions and timing, and be based on accepted diagnostic tests. Key outcomes include BPD at 36 weeks' PMA, mortality at 36 weeks' PMA and at discharge, and a complete assessment of major neurosensory impairment using predefined definitions. Short‐term benefits (e.g. time to extubation and duration of ventilation) and adverse effects (e.g. hypertension, infection, hyperglycaemia, and use of open‐label intravenous corticosteroids) constitute useful secondary outcomes.

What's new

Date	Event	Description
15 December 2022	New citation required but conclusions have not changed	The conclusions of this review did not change.
15 December 2022	New search has been performed	We ran searches from 2017 to August 29, 2022. We identified no new studies, but we did exclude one study that was included in the previous version of the review because participants did not meet our eligibility criteria (included infants with established bronchopulmonary dysplasia; Pokriefka 1993).

History

Protocol first published: Issue 4, 1999
Review first published: Issue 2, 2001

Date	Event	Description
12 June 2017	New search has been performed	Updated search till May 2017, no new studies identified. GRADE assessment included into review. Conclusions are not changed.
4 February 2011	New search has been performed	This updates the review "Inhaled steroids for neonatal chronic lung disease" published in the Cochrane Database of Systematic Reviews (Lister 2000). In October 2009, editorial responsibility for this review was transferred to the Neonatal Group from Airways Group. New authorship assigned. The revised title is "Late (≥ 7 days) inhalation corticosteroids to reduce bronchopulmonary dysplasia in preterm infants". The inclusion criteria for this review have been changed from the previous version (inclusion of studies initiating therapy ≥ 7 days postnatal age and exclusion of studies initiating therapy ≥ 36 weeks postmenstrual age).
24 January 2011	New citation required and conclusions have changed	Conclusions have changed. New authorship.
23 October 2009	Amended	October 2009, editorial responsibility for review transferred to Neonatal Group from Airways Group. New authorship assigned.
5 August 2008	Amended	Converted to new review format.
6 August 1999	New citation required and conclusions have changed	Substantive amendment

Appendices

Appendix 1. Cochrane Library strategy (Wiley; 30 August 2022)

ID	Search	Results
#1	MeSH descriptor: [Adrenal Cortex Hormones] explode all trees	15283
#2	MeSH descriptor: [Steroids] explode all trees	62754
#3	(adrenal cortex hormone* or adrenal cortical hormone* or adrenocorticosteroid* or adrenocortical hormone* or becotide or beclomethasone or betamethasone or budenosid* or corticoid? or corticosteroid* or dexamethason* or flixotid* or fluticason* or glucocorticoid* or hydrocortison* or methylprednisolon* or prednisolon* or pulmicort or steroid? or steroid):ti,ab,kw	78208
#4	#1 OR #2 OR #3	115669
#5	MeSH descriptor: [Administration, Inhalation] this term only	5647
#6	MeSH descriptor: [Aerosols] explode all trees	2492
#7	MeSH descriptor: [Nebulizers and Vaporizers] explode all trees	2450
#8	(aerosol* or aeroliz* or aerolis* or inhal* or nebulis* or nebuliz* or vapori*):ti,ab,kw OR ((vapor? or vapour?) NEAR/2 therap*):ti,ab,kw	44868
#9	#5 OR #6 OR #7 OR #8	45099
#10	MeSH descriptor: [Infant, Newborn] explode all trees	17650
#11	MeSH descriptor: [Intensive Care, Neonatal] this term only	353
#12	MeSH descriptor: [Intensive Care Units, Neonatal] this term only	867
#13	MeSH descriptor: [Gestational Age] this term only	2784
#14	("babe" or "babes" or baby* or "babies" or "gestational age" or "gestational ages" or infant? or "infantile" or infancy or "low birth weight" OR "low birth weights" or "low birthweight" or "low birthweights" 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 "pre‐maturity" or "preterm" or "preterms" or "pre term?" or "preemie" or "preemies" or "premies" or "premie" or "VLBW" or "VLBWI" or "VLBW‐I" or "VLBWs" or "LBW" or "LBWI" or "LBWs" or "ELBW" or "ELBWI" or "ELBWs" or "NICU" or "NICUs"):ti,ab,kw	99674
#15	#10 OR #11 OR #12 OR #13 OR #14	99674
#16	#4 AND #9 AND #15 with Cochrane Library publication date Between Jan 2017 and Aug 2020	192

Appendix 2. Embase strategy (1974–20 August 2022)

#	Searches	Results
1	corticosteroid/	265564
2	exp steroid/	1685675
3	(adrenal cortex hormone* or adrenal cortical hormone* or adrenocorticosteroid* or adrenocortical hormone* or becotide or beclomethasone or betamethasone or budenosid* or corticoid? or corticosteroid* or dexamethason* or flixotid* or fluticason* or glucocorticoid* or hydrocortison* or methylprednisolon* or prednisolon* or pulmicort or steroid*).ti,ab,kw,kf.	716471
4	or/1‐3 [Steroids Embase]	1839297
5	inhalational drug administration/	49095
6	aerosol/	61262
7	exp nebulizer/	12651
8	vaporizer/	1068
9	(aerosol* or aeroliz* or aerolis* or inhal* or nebulis* or nebuliz* or vapori* or ((vapor? or vapour?) adj2 therap*)).ti,ab,kw,kf.	242561
10	or/5‐9 [Inhalation‐‐administration EMBASE]	285890
11	newborn/ or prematurity/ or newborn intensive care/ or newborn care/ or gestational age/	754877
12	(babe or babes or baby* or babies or gestational age? 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 pre‐maturity or preterm or preterms or pre term? or preemie or preemies or premies or premie or VLBW or VLBWI or VLBW‐I or VLBWs or LBW or LBWI or LBWs or ELBW or ELBWI or ELBWs or NICU or NICUs).ti,ab,kw,kf.	1189369
13	or/11‐12 [Filter: Neonatal Population 03‐2022‐OVID EMBASE]	1448848
14	Randomized controlled trial/ or Controlled clinical study/	914894
15	random$.ti,ab,kw.	1831852
16	Randomization/	94691
17	placebo.ti,ab,kw.	345825
18	((double or single or doubly or singly) adj (blind or blinded or blindly)).ti,ab,kw.	259817
19	double blind procedure/	198020
20	(controlled adj7 (study or design or trial)).ti,ab,kw.	416530
21	parallel group$1.ti,ab.	29916
22	(crossover or cross over).ti,ab.	117801
23	((assign$ 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.	386660
24	(open adj label).ti,ab.	99147
25	(quasirandom* or quasi‐random* or randomi* or randomly).ti,ab,kw,kf.	1493735
26	(control* adj2 (group? or random*)).ti,ab,kw,kf.	1216645
27	or/14‐26 [ Terms based on Cochrane Central strategy‐ How Central is Created]	3130665
28	(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/)	24031634
29	exp animals/ or exp invertebrate/ or animal experiment/ or animal model/ or animal tissue/ or animal cell/ or nonhuman/	31000055
30	29 not 28 [Animal Exclusion‐https://community‐cochrane‐org.ezproxy.uvm.edu/sites/default/files/uploads/inline‐files/Embase%20animal%20filter.pdf]	6968421
31	27 not 30 [Filter: RCT‐EMBASE]	2691590
32	meta‐analysis/ or "systematic review"/ or "meta analysis (topic)"/ [EMTREE]	524408
33	((systematic* adj3 (review* or overview*)) or (methodologic* adj3 (review* or overview*))).ti,ab,kw.	342119
34	((integrative adj3 (review* or overview*)) or (collaborative adj3 (review* or overview*)) or (pool* adj3 analy*)).ti,ab,kw.	49952
35	(data synthes* or data extraction* or data abstraction*).ti,ab,kw.	44514
36	(hand search* or handsearch*).ti,ab,kw.	12934
37	(mantel haenszel or peto or der simonian or dersimonian or fixed effect* or latin square*).ti,ab,kw.	43415
38	(meta analy* or metanaly* or meta regression* or metaregression*).ti,ab,kw.	313510
39	(medline or cochrane or pubmed or medlars or embase or cinahl).ab.	377792
40	(cochrane or systematic review?).jn,jx.	30557
41	(overview adj2 reviews).ti.	119
42	or/32‐41 [SR Filter: EMBASE based on CADTH filter: https://searchfilters.cadth.ca]	806102
43	4 and 10 and 13 [Steroids AND Inhalation AND Neonate]	2697
44	43 and 42 and 202*.yr. [Systematic review results 2020‐]	32
45	43 and 31 and (2017* or 2018* or 2019* or 202*).yr. [RCT Results 2017‐]	136
46	or/44‐45 [All results EMBASE]	151

Appendix 3. MEDLINE strategy: Ovid MEDLINE(R) and Epub Ahead of Print, In‐Process, In‐Data‐Review & Other Non‐Indexed Citations, Daily and Versions (1946–29 August 2022)

#	Searches	Results
1	exp Adrenal Cortex Hormones/	417823
2	exp Steroids/	904908
3	(adrenal cortex hormone* or adrenal cortical hormone* or adrenocorticosteroid* or adrenocortical hormone* or becotide or beclomethasone or betamethasone or budenosid* or corticoid? or corticosteroid* or dexamethason* or flixotid* or fluticason* or glucocorticoid* or hydrocortison* or methylprednisolon* or prednisolon* or pulmicort or steroid*).mp.	713253
4	or/1‐3 [Steroids]	1216979
5	Administration, Inhalation/	33429
6	exp Aerosols/	35335
7	exp "nebulizers and vaporizers"/ or metered dose inhalers/ or inhalation spacers/	12500
8	(aerosol* or aeroliz* or aerolis* or inhal* or nebulis* or nebuliz* or vapori* or ((vapor? or vapour?) adj2 therap*)).mp.	237515
9	or/5‐8 [Inhalation ‐‐administration]	238276
10	exp Infant, Newborn/ or Intensive Care, Neonatal/ or Intensive Care Units, Neonatal/ or Gestational Age/	708315
11	(babe or babes or baby* or babies or gestational age? 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 pre‐maturity or preterm or preterms or pre term? or preemie or preemies or premies or premie or VLBW or VLBWI or VLBW‐I or VLBWs or LBW or LBWI or LBWs or ELBW or ELBWI or ELBWs or NICU or NICUs).ti,ab,kw,kf.	1007889
12	or/10‐11 [Filter: Neonatal Population 04‐2022‐MEDLINE]	1317487
13	randomized controlled trial.pt.	575980
14	controlled clinical trial.pt.	95010
15	randomized.ti,ab.	623063
16	placebo.ti,ab.	237532
17	drug therapy.fs.	2525004
18	randomly.ti,ab.	391215
19	trial.ti,ab.	713575
20	groups.ti,ab.	2428639
21	or/13‐20 [Cochrane HSSS‐SM Filter; Box 6.4.a Cochrane Handbook]	5514162
22	(quasirandom* or quasi‐random* or randomi* or randomly).ti,ab,kw,kf.	1064289
23	(control* adj2 (group? or random* or trial? or study)).ti,ab,kw,kf.	1060436
24	or/22‐23 [Additional terms to increase sensitivity]	1645861
25	exp animals/ not humans/	5041586
26	(or/21,24) not 25 [RCT Filter: Medline]	5056374
27	meta‐analysis/ or "systematic review"/ or network meta‐analysis/ [/ finds same as.pt. syntax]	284592
28	((systematic* adj3 (review* or overview*)) or (methodologic* adj3 (review* or overview*))).ti,ab,kf,kw.	282815
29	((integrative adj3 (review* or overview*)) or (collaborative adj3 (review* or overview*)) or (pool* adj3 analy*)).ti,ab,kf,kw.	35637
30	(data synthes* or data extraction* or data abstraction*).ti,ab,kf,kw.	36584
31	(hand search* or handsearch*).ti,ab,kf,kw.	10647
32	(mantel haenszel or peto or der simonian or dersimonian or fixed effect* or latin square*).ti,ab,kf,kw.	32988
33	meta‐analysis as topic/ or network meta‐analysis/	25531
34	(meta analy* or metanaly* or meta regression* or metaregression*).ti,ab,kf,kw.	246611
35	(medline or cochrane or pubmed or medlars or embase or cinahl).ab.	301086
36	(cochrane or systematic review?).jw.	19451
37	or/27‐36 [SR filter‐Medline; based on CADTH https://searchfilters.cadth.ca]	568750
38	4 and 9 and 12 [Steroids AND Inhalation‐‐Administration AND Neonate]	1682
39	38 and 37 and 202*.yr. [Systematic Review Results 2020‐]	21
40	38 and 26 [RCT Results]	1031
41	40 and (2017* or 2018* or 2019* or 202*).yr. [RCT Results 2017‐]	172

Appendix 4. CINAHL EBSCOhost strategy (30 August 2022)

#	Query	Results
1	(MH "Adrenal Cortex Hormones+")	40,637
2	(MH "Steroids+")	84,298
3	( TI ((adrenal cortex hormone* or adrenal cortical hormone* or adrenocorticosteroid* or adrenocortical hormone* or becotide or beclomethasone or betamethasone or budenosid* or corticoid# or corticosteroid* or dexamethason* or flixotid* or fluticason* or glucocorticoid* or hydrocortison* or methylprednisolon* or prednisolon* or pulmicort or steroid#) ) OR ( AB (adrenal cortex hormone* or adrenal cortical hormone* or adrenocorticosteroid* or adrenocortical hormone* or becotide or beclomethasone or betamethasone or budenosid* or corticoid# or corticosteroid* or dexamethason* or flixotid* or fluticason* or glucocorticoid* or hydrocortison* or methylprednisolon* or prednisolon* or pulmicort or steroid#) )	63,529
4	S1 OR S2 OR S3	138,223
5	(MH "Nebulizers and Vaporizers")	5,583
6	MM "Administration, Inhalation"	1,759
7	(MH "Aerosols")	3,738
8	( TI (aerosol* or aeroliz* or aerolis* or inhal* or nebulis* or nebuliz* or vapori* or ((vapor? or vapour?) N2 therap*)) ) OR ( AB (aerosol* or aeroliz* or aerolis* or inhal* or nebulis* or nebuliz* or vapori* or ((vapor? or vapour?) N2 therap*)) )	29,042
9	S5 OR S6 OR S7 OR S8	32,272
10	(MH "Infant, Newborn+") OR (MH "Infant, Large for Gestational Age") OR (MH "Infant, Low Birth Weight+") OR (MH "Infant, Postmature") OR (MH "Infant, Premature") OR (MH "Intensive Care, Neonatal+") OR (MH "Intensive Care Units, Neonatal") OR (MH "Gestational Age")	172,373
11	TI ((babe or babes or baby* or babies or gestational age# 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 pre‐maturity or preterm or preterms or pre term# or preemie or preemies or premies or premie or VLBW or VLBWI or VLBW‐I or VLBWs or LBW or LBWI or LBWs or ELBW or ELBWI or ELBWs or NICU or NICUs) OR AB (babe or babes or baby* or babies or gestational age# 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 pre‐maturity or preterm or preterms or pre term# or preemie or preemies or premies or premie or VLBW or VLBWI or VLBW‐I or VLBWs or LBW or LBWI or LBWs or ELBW or ELBWI or ELBWs or NICU or NICUs)	259,238
12	S10 OR S11	322,681
13	(MH "Single‐Blind Studies") OR (MH "Triple‐Blind Studies") OR (MH "Randomized Controlled Trials+") OR (MH "Double‐Blind Studies")	172,592
14	(MH "Clinical Trials+")	342,920
15	TI (randomi#ed or randomly) OR AB (randomi#ed or randomly) OR AB (randomi#ed or randomly) OR AB (randomi#ed or randomly)	361,856
16	AB randomly	105,545
17	AB placebo	65,266
18	AB (trial)	333,463
19	AB groups	882,362
20	TI (quasirandom* or quasi‐random*) OR AB (quasirandom* or quasi‐random*)	2,200
21	S13 OR S14 OR S15 OR S16 OR S17 OR S18 OR S19 OR S20	1,291,136
22	(MH "Animal Studies")	148,740
23	(MH "Human")	2,594,571
24	S22 NOT S23	123,854
25	S21 NOT S24	1,251,917
26	(MH "Systematic Review")	113,098
27	(MH "Meta Analysis")	64,854
28	( TI ((systematic* N3 (review* or overview*)) or (methodologic* N3 (review* or overview*))) ) OR ( AB ((systematic* N3 (review* or overview*)) or (methodologic* N3 (review* or overview*))) )	139,572
31	AB (hand search* or handsearch*)	4,894
32	AB (mantel haenszel or peto or der simonian or dersimonian or fixed effect* or latin square*)	9,488
33	( TI met analy* or metanaly* or meta regression* or metaregression*) ) OR ( AB met analy* or metanaly* or meta regression* or metaregression*) )	4,857
34	AB (medline or cochrane or pubmed or medlars or embase OR CINAHL)	116,639
35	S26 OR S27 OR S28 OR S29 OR S30 OR S31 OR S32 OR S33 OR S34	246,445
36	S4 AND S9 AND S12 AND S25	165
37	S4 AND S9 AND S12 AND S35	40
38	S36 OR S37 AND Published Date: 20170101‐20221231	41

Appendix 5. Trial registry strategies

Date	Site	Terms	Results
2 September 2022	clinicaltrials.gov	Bronchopulmonary Dysplasia [Condition] AND Steroid [Other term]	36
2 September 2022	clinicaltrials.gov	Bronchopulmonary Dysplasia [Condition] AND corticosteroid [Other term]	11
3 September 2022	clinicaltrials.gov	Bronchopulmonary Dysplasia [Condition] AND adrenocorticosteroid OR adrenocortical hormone OR becotide OR beclomethasone OR betamethasone OR budenoside OR corticoid OR corticosteroid OR dexamethasone OR flixotide OR fluticasone OR glucocorticoid OR hydrocortisone OR methylprednisolone OR prednisolone OR pulmicort OR steroid [other term]	33
3 September 2022	ICTRP	Bronchopulmonary Dysplasia corticosteroids [Title]	5
3 September 2022	ICTRP	Bronchopulmonary Dysplasia corticosteroid [Title]	4
3 September 2022	ICTRP	Bronchopulmonary Dysplasia steroid [Title]
3 September 2022	ICTRP	Bronchopulmonary Dysplasia [Condition] corticosteroid [Intervention]	0
3 September 2022	ICTRP	Bronchopulmonary Dysplasia [Condition] steroid [Intervention]	0
3 September 2022	ICTRP	Bronchopulmonary Dysplasia [Condition] steroids [Intervention]	2
3 September 2022	ICTRP	Bronchopulmonary Dysplasia [Condition] corticosteroids [Intervention]	0
3 September 2022	ICTRP	Bronchopulmonary Dysplasia [Condition] adrenocorticosteroids [Intervention] also tried singular	0
3 September 2022	ICTRP	becotide ror budenosid
3 September 2022	ICTRP	Bronchopulmonary Dysplasia [Condition] becomethasone [intervention]	1
3 September 2022	ICTRP	Bronchopulmonary Dysplasia [Condition] beclomethasone [Intervention]	1
3 September 2022	ICTRP	Bronchopulmonary Dysplasia [Condition] betamethasone [Intervention]	0
3 September 2022	ICTRP	Bronchopulmonary Dysplasia [Condition] becotide [Intervention]	0
3 September 2022	ICTRP	Bronchopulmonary Dysplasia [Condition] budenosid or budenoside [Intervention]	0
3 September 2022	ICTRP	Bronchopulmonary Dysplasia [Condition] cortocoid(s) [Intervention]	0
3 September 2022	ICTRP	Bronchopulmonary Dysplasia [Condition] flixotide or fluticasone or glucocorticoid or hydrocortisone or methylprednisolone or prednisolone or pulmicort [Intervention]	6
3 September 2022	ISRCTN	Bronchopulmonary Dysplasia [Condition]	7
			106

Appendix 6. Cochrane risk of bias tool (RoB 1)

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

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

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

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

• unclear risk.

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

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

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

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

• unclear risk.

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

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

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

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

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

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

• low risk for outcome assessors;

• high risk for outcome assessors; or

• unclear risk for outcome assessors.

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

For each included study and for each outcome, we described 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 randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where the trial authors had reported or supplied sufficient information, we re‐included missing data in the analyses. We categorised the methods as:

• low risk (less than 20% missing data);

• high risk (at least 20% missing data); or

• unclear risk.

Selective reporting bias. Are reports of the study free of 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 with previously published protocols, we compared the prespecified outcomes to the reported outcomes. If the study protocol was not published in advance, we contacted trial authors to request the study protocol. We assessed the methods as:

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

• high risk (where 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 and so cannot be used, study fails to include results of an expected key outcome); or

• unclear risk.

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

For each included study, we described any important concerns regarding other possible sources of bias (e.g. related to the study design or early termination due to some data‐dependent process). We assessed each study as:

• low risk;

• high risk; or

• unclear risk.

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

Appendix 7. Description of separate trials

Arnon 1996: this double‐blind trial included 20 preterm infants with birthweight below 2000 g and gestational age below 33 weeks who were still in need of mechanical ventilation at 14 days' postnatal age (PNA) with fraction of inspired oxygen (FiO₂) of 0.30 or more. The exclusion criteria were persistent ductus arteriosus (PDA), sepsis, air leak, and congenital malformation. Eligible infants were randomly assigned to budesonide 600 μg twice daily or placebo given by metered‐dose inhaler (MDI), inserted into a small volume spacer, for seven days or until extubation, whichever came first. Of the reported outcome parameters, we could only use rate of PDA and sepsis during the study period for this review. The trial authors provided additional data on extubation rate.

Denjean 1998: this was a double‐blind placebo‐controlled multicentre trial conducted in six centres in France and Portugal over a two‐year period. It included 86 preterm infants with gestational age below 31 weeks, respiratory distress syndrome (RDS), and who needed mechanical ventilation, nasal ventilation or continuous positive airway pressure (CPAP) at 10 days' PNA. The exclusion criteria were PDA, sepsis, pulmonary infections, major malformation, and prior treatment with corticosteroids or bronchodilators. Although this study consisted of four treatment arms, in our review we included only those infants treated with beclomethasone 250 μg/puff delivered by an MDI (inserted into a small volume spacer) four times daily, and those who received placebo only. Therapy was started on day 10 or 11 and was administered for 28 days with a tapering dose for the last eight days. The primary outcome was bronchopulmonary dysplasia (BPD), defined as oxygen dependency at 28 days' PNA in combination with radiographic abnormalities consistent with BPD. However, all outcomes of interest for this review (with the exception of total duration of supplemental oxygen) were presented for the combined group of ventilated and non‐ventilated infants and were therefore excluded from the final analysis. One trial author provided additional data on the randomisation process. 

Dugas 2005: this was a double‐blind randomised trial of 32 infants with gestational age under 32 weeks, PNA between 28 and 60 days, and a diagnosis of BPD, defined as FiO₂ of 0.25 or more to maintain oxygen saturation between 88% and 92%, pCO₂ of 45 mmHg or more, and chest radiography consistent with BPD. Reasons for exclusion were hypertension, hyperglycaemia, sepsis, pneumonia, renal failure, treatment with corticosteroids five days prior to inclusion, FiO₂ of 0.30 or more in ventilated infants or FiO₂ of 0.40 or more in non‐ventilated infants, and congenital heart disease. The participants received either placebo or fluticasone propionate 125 μg/puff given by MDI inserted into a small volume spacer and interposed between an anaesthesia bag and the tube or a face mask. Infants with a birth weight between 500 g and 1200 g received one puff twice daily for three weeks and once daily in the fourth week. The number of puffs was double if the infant's weight was 1200 g or greater. The primary outcome was total duration of supplemental oxygen. Other outcomes, such as total duration of hospitalisation or duration of mechanical ventilation, were only reported for the combined group of ventilated and non‐ventilated infants and could therefore not be used for this review. From the reported outcome parameters, we could only use mortality at 36 weeks' postmenstrual age (PMA), mortality at hospital discharge, open‐label intravenous glucocorticoids, and hyperglycaemia during the study period in the ventilated subgroup. The trial authors did not provide additional data.

Giep 1996: this feasibility and safety study with a randomised design included 19 infants. Eligible infants had a birth weight between 500 g and 1500 g, X‐ray evidence of RDS or BPD, PNA of 14 days, and need for mechanical ventilation with FiO₂ above 0.40 and a peak inspiratory pressure (PIP) above 14 cm H₂O after failing an extubation attempt. Exclusion criteria were PDA, sepsis, congenital heart disease, congenital malformations, and previous postnatal or concurrent administration of corticosteroids. The participating infants were randomised to either beclomethasone (1 mg/kg/day) or placebo delivered by MDI and an Aerochamber. The treatment or placebo was administered every eight hours for seven days. The number of puffs per dose varied with the weight of the infant, as follows:

• 500 g to 799 g: three puffs;

• 800 g to 1000 g: four puffs;

• 1001 g to 1300 g: five puffs; and

• more than 1300 g: six puffs.

We included the following reported outcomes in our review: failure to extubate, use of systemic corticosteroids, sepsis rate, and intraventricular haemorrhage (IVH). Although blood pressure and blood glucose were recorded every day, the study did not report the number of infants with hypertension and hyperglycaemia. Attempts to contact the trial authors were unsuccessful.

Jonsson 2000: in this double‐blind placebo‐controlled study, 30 very low‐birth weight infants, either mechanically ventilated or supported by CPAP with FiO₂ of 0.3 or more, were randomised to budesonide or placebo, delivered by an electronic dosimetric jet nebuliser. The exclusion criteria were malformations, congenital heart disease, IVH grades III to IV, deteriorating ventilator settings, and need for high‐frequency ventilation. From day seven of life, infants received a dose of 500 μg twice daily for 14 days. Reported outcomes of interest for this review were use of open‐label corticosteroids, failure to extubate on day 14 in the ventilated subgroup, mortality at hospital discharge, and mortality at 36 weeks' PMA. The trial authors provided data on the outcomes, oxygen requirements at 28 days' PNA and 36 weeks' PMA, duration of supplemental oxygen, duration of mechanical ventilation, failure to extubate, and adverse outcomes (hyperglycaemia, hypertension, and sepsis, for the ventilated and non‐ventilated subgroups separately).

LaForce 1993: this prospective, randomised, paired analysis study included infants with birth weight below 1500 g and RDS who were ventilator‐dependent at 14 days with X‐ray abnormalities indicative of BPD. The exclusion criteria were PDA, pneumonia, sepsis, congenital heart disease, and air leak. Infants allocated to the intervention group received nebulised beclomethasone dipropionate 50 μg three times daily for 28 days. Medication was delivered to ventilated infants via a Whisper Jet nebuliser system in the ventilator circuit, and to non‐ventilated infants via a blow‐by system with 8 L humidified gas/minute. The reported outcome of interest for this review was mortality at hospital discharge. The trial authors provided data on randomisation and sepsis rates.

Pappagallo 1998: this single‐centre study included preterm infants with birthweight below 1500 g and fewer than seven days' PNA with a high probability of developing BPD based on a prediction model or ventilator dependency. This study had two phases, and only the second phase had a randomised placebo‐controlled design. For this review, we used the data on the 18 infants included in the second phase. The exclusion criteria were sepsis, pulmonary hypoplasia, congenital anomalies, and heart disease. Infants were randomly assigned to dexamethasone inhalation 1 mg/kg every eight hours for seven days followed by 0.5 mg/kg every eight hours for three days or placebo using a jet nebuliser. The reported outcomes of interest for this review were the use of intravenous corticosteroids, duration of mechanical ventilation, days on supplemental oxygen, and total duration of hospitalisation. Through handsearching, we found an abstract that reported the rate of failure to extubate in 10 infants. The trial authors could not provide additional data.

Data and analyses

Comparison 1. Inhaled corticosteroids (ICS) versus placebo.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Combined outcome of mortality or bronchopulmonary dysplasia at 36 weeks' postmenstrual age	1	30	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.74, 1.63]
1.1.1 Ventilated infants	1	20	Risk Ratio (M‐H, Fixed, 95% CI)	1.24 [0.87, 1.75]
1.1.2 Non‐ventilated infants	1	10	Risk Ratio (M‐H, Fixed, 95% CI)	0.50 [0.06, 3.91]
1.2 Mortality at 36 weeks' postmenstrual age	3	61	Risk Ratio (M‐H, Fixed, 95% CI)	3.00 [0.35, 25.78]
1.2.1 Ventilated infants	3	51	Risk Ratio (M‐H, Fixed, 95% CI)	3.00 [0.35, 25.78]
1.2.2 Non‐ventilated infants	1	10	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.3 Bronchopulmonary dysplasia at 36 weeks' postmenstrual age	1	30	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.59, 1.70]
1.3.1 Ventilated infants	1	20	Risk Ratio (M‐H, Fixed, 95% CI)	1.14 [0.69, 1.90]
1.3.2 Non‐ventilated infants	1	10	Risk Ratio (M‐H, Fixed, 95% CI)	0.50 [0.06, 3.91]
1.4 Combined outcome of mortality or bronchopulmonary dysplasia at 28 days' postnatal age	1	30	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.85, 1.18]
1.4.1 Ventilated infants	1	20	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.83, 1.20]
1.4.2 Non‐ventilated infants	1	10	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.71, 1.41]
1.5 Mortality at 28 days' postnatal age	2	51	Risk Ratio (M‐H, Fixed, 95% CI)	3.00 [0.14, 65.90]
1.5.1 Ventilated infants	2	41	Risk Ratio (M‐H, Fixed, 95% CI)	3.00 [0.14, 65.90]
1.5.2 Non‐ventilated infants	1	10	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.6 Bronchopulmonary dysplasia at 28 days' postnatal age	1	30	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.72, 1.21]
1.6.1 Ventilated infants	1	20	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.61, 1.29]
1.6.2 Non‐ventilated infants	1	10	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.71, 1.41]
1.7 Mortality at hospital discharge	3	53	Risk Ratio (M‐H, Fixed, 95% CI)	3.00 [0.35, 25.78]
1.7.1 Ventilated infants	3	43	Risk Ratio (M‐H, Fixed, 95% CI)	3.00 [0.35, 25.78]
1.7.2 Non‐ventilated infants	1	10	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.8 Open‐label use of systemic corticosteroids	4	74	Risk Ratio (M‐H, Fixed, 95% CI)	0.51 [0.26, 1.00]
1.8.1 Ventilated infants	4	64	Risk Ratio (M‐H, Fixed, 95% CI)	0.51 [0.26, 1.00]
1.8.2 Non‐ventilated infants	1	10	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.9 Persistent ductus arteriosus	1	30	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.16, 6.20]
1.9.1 Ventilated infants	1	30	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.16, 6.20]
1.10 Necrotising enterocolitis	1	27	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.10.1 Ventilated infants	1	17	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.10.2 Non‐ventilated infants	1	10	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.11 Hypertension (> 2 standard deviations above the mean)	1	27	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.11.1 Ventilated infants	1	17	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.11.2 Non‐ventilated infants	1	10	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.12 Sepsis (clinically suspected or culture‐proven)	5	107	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.50, 1.64]
1.12.1 Ventilated infants	5	97	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.44, 1.77]
1.12.2 Non‐ventilated infants	1	10	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.36, 2.75]
1.13 Intraventricular haemorrhage (any grade)	1	19	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.13, 2.82]
1.13.1 Ventilated infants	1	19	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.13, 2.82]
1.14 Days of supplemental oxygen	4	141	Mean Difference (IV, Fixed, 95% CI)	0.57 [‐5.92, 7.07]
1.14.1 Ventilated infants	4	100	Mean Difference (IV, Fixed, 95% CI)	5.53 [‐3.99, 15.05]
1.14.2 Non‐ventilated infants	2	41	Mean Difference (IV, Fixed, 95% CI)	‐3.74 [‐12.63, 5.14]
1.15 Days of hospitalisation	1	18	Mean Difference (IV, Fixed, 95% CI)	‐24.70 [‐41.75, ‐7.65]
1.15.1 Ventilated infants	1	18	Mean Difference (IV, Fixed, 95% CI)	‐24.70 [‐41.75, ‐7.65]
1.16 Days of mechanical ventilation	3	45	Mean Difference (IV, Fixed, 95% CI)	3.42 [‐1.30, 8.13]
1.17 Failure to extubate within 7 days of initiating therapy	5	79	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.66, 0.98]
1.18 Failure to extubate within 14 days of initiating therapy	2	27	Risk Ratio (M‐H, Fixed, 95% CI)	0.36 [0.10, 1.33]
1.19 Failure to extubate by end of follow‐up	5	76	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.46, 0.84]

1.10. Analysis.

Comparison 1: Inhaled corticosteroids (ICS) versus placebo, Outcome 10: Necrotising enterocolitis

1.11. Analysis.

Comparison 1: Inhaled corticosteroids (ICS) versus placebo, Outcome 11: Hypertension (> 2 standard deviations above the mean)

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Arnon 1996.

Study characteristics
Methods	Study design: single‐centre, double‐blind, placebo‐controlled trial Setting: UK
Participants	Ventilated/non‐ventilated: ventilated Number randomised: 30 (treatment group: 14; control group: 16) Stratification: no Number analysed: 20 (treatment group: 9; control group: 11) PNA at trial entry: treatment group: mean 15 (SD 0.6) days; control group: mean 14 (SD 0.5) days Comparability: no important differences between groups with regard to birth weight, gestational age, PNA, sex, Apgar scores, rates of maternal infection, or use of antenatal steroids Inclusion criteria Preterm birth Birthweight < 2000 g  Gestational age < 33 weeks Need for mechanical ventilation at 14 days' PNA with FiO2 ≥ 0.30 and no significant changes in respiratory support 3 days prior to study entry Exclusion criteria PDA Sepsis Air leak Congenital malformation
Interventions	Treatment: budesonide (Astro Draco, UK) 200 μg/puff, 600 μg twice daily for 7 days or until extubation (whichever came first), administered by MDI. MDI was inserted into small volume spacer (Aerochamber MV15, Trudell Medical, Ontario, Canada), and filled with oxygen without a rubber flap valve. Distal end of spacer was directly connected onto the endotracheal tube. Control: same as treatment, but with placebo in place of budesonide
Outcomes	Primary outcome Extubation for 24 hours within the 7‐day period Secondary outcomes Ventilation efficiency index* FiO2 Alveolar‐arterial oxygen difference calculated on 1st daily arterial blood gas measurement Serum cortisol Sepsis rates Bronchoalveolar lavage *Ventilation efficiency index = k/f × (PIP−PEEP) × PaCO2, where k is a constant, f is the respiratory rate, PIP is the peak inspiratory pressure, PEEP is the positive end‐expiratory pressure, and PaCO2 is the arterial partial pressure of carbon dioxide)
Notes	Trial authors provided data on extubation rate. Supported by a grant from Action Research UK. MDIs were provided by Astra Draco, Edinburgh, UK, and the spacers by Trudell Medical, London, Canada.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No information on sequence generation.
Allocation concealment (selection bias)	Low risk	Randomisation by pharmacy. Code and drugs released from hospital pharmacy in sealed envelopes and code concealed until end of trial. Investigators unaware of treatment group assignment.
Blinding (performance bias and detection bias) All outcomes	Low risk	MDI of placebo and steroid. Pharmacy randomised and issued drugs ensuring double‐blinding.
Incomplete outcome data (attrition bias) All outcomes	High risk	10 participants were withdrawn and did not complete the study: 5 due to sepsis (3 in placebo group, 2 in treatment group), 4 due to PDA (2 in each group), 1 due to (treatment group). No intention‐to‐treat analysis.
Selective reporting (reporting bias)	Unclear risk	Study protocol not published, therefore unclear if any protocol deviations occurred.
Other bias	Low risk	Appears to be free of other bias.

Denjean 1998.

Study characteristics
Methods	Study design: multicentre, double‐blind, placebo‐controlled trial Setting: 6 hospitals in France and Portugal
Participants	Ventilated/non‐ventilated: both Number randomised: 178. Infants were randomised into 1 of 4 groups: placebo + placebo, placebo + beclomethasone, placebo + salbutamol, and beclomethasone + salbutamol. For this review we analysed only infants treated with placebo + placebo (as the control group) and placebo + beclomethasone (as the treatment group). Stratification: by centre, gestational age ≤ 28 weeks versus 29 to 30 weeks, and type of ventilator support Number analysed: 173 (treatment group: 43; control group: 43) PNA at trial entry: treatment group: mean 10.1 (SD 1.5) days; control group: mean 9.7 (SD 1.6) days Comparability: no important differences between groups with regard to birth weight, gestational age, mode of delivery, multiple pregnancy, or use of antenatal steroids. No significant differences in outcome criteria at start of study. Inclusion criteria Preterm birth Gestational age < 31 weeks RDS and need for mechanical ventilation, nasal ventilation or CPAP at 10 days' PNA and no significant changes in respiratory support 3 days prior to study entry Exclusion criteria PDA Sepsis Pulmonary infections Major malformation or prior treatment with corticosteroids or bronchodilators
Interventions	Treatment: beclomethasone (Glaxo France) 250 μg/puff, administered 4 times daily by MDI inserted into small volume spacer (Aerochamber MV15, Trudell Medical, Ontario, Canada). Therapy started on day 10 or 11 and given for 1 month with a tapering course over the last 8 days. Control: same as treatment, but with placebo in place of beclomethasone
Outcomes	Primary outcomes BPD, based on oxygen dependency at 28 days' PNA and radiographic criteria BPD severity, defined as severe when ventilation > 3 months or oxygen supplementation > 4 months; moderate when ventilation > 1 month or oxygen > 2 months; mild when ventilation < 1 month and oxygen < 2 months Secondary outcomes Ventilatory index (FiO2 × main airway pressure) Pneumothorax Interstitial emphysema Need for IV corticosteroid treatment Infections Hypertension Blood glucoses Plasma electrolytes
Notes	Trial author provided additional information on randomisation process. Glaxo France provided the therapeutic units (placebo and drugs), and Trudell Medical London, Ontario, Canada supplied the aerochamber spacer devices. Supported by a grant from Assistance Publique Hopitaux de Paris.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Decision based on information obtained through personal communication. Stratification by centre, gestational age ≤ 28 weeks versus 29 to 30 weeks and type of ventilator support.
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment unknown.
Blinding (performance bias and detection bias) All outcomes	Low risk	Participants, personnel and outcome assessors blinded to allocation, although the code was broken in 3 participants because of severe clinical deterioration.
Incomplete outcome data (attrition bias) All outcomes	High risk	Of 178 infants randomised, 5 were withdrawn or informed consent not obtained without explanation.
Selective reporting (reporting bias)	Unclear risk	Study protocol not published, therefore unclear if any protocol deviations occurred.
Other bias	Unclear risk	We could not exclude other potential sources of bias.

Dugas 2005.

Study characteristics
Methods	Study design: multicentre, double‐blind, placebo‐controlled trial Setting: 2 hospitals in Canada
Participants	Ventilated/non‐ventilated: both Number randomised: 32 (treatment group: 16; control group: 16) Stratification: intubated and extubated infants were stratified seperately at randomisation Number analysed: 32 (treatment group: 16; control group: 16). 3 infants did not complete the study (2 treatment discontinuation due to pulmonary deterioration and 1 due toline sepsis, all placebo group).  PNA at trial entry: treatment group: mean 44.8 (SD 11) days; control group: mean 45.4 (SD 10) days Comparability: no significant differences between groups in birth weight, gestational age, multiple pregnancy, use of antenatal steroids, or clinical diagnoses such as PDA, necrotising enterocolitis, IVH, hypotension, or sepsis. No significant differences in outcome criteria at start of study, except FiO2, which was significantly lower in the treatment group Inclusion criteria Preterm birth Gestational age < 32 weeks PNA 28–60 days Diagnosis of BPD (FiO2 ≥ 0.25 to maintain oxygen saturation at 88%–92%, pCO2 ≥ 45 mmHg, and chest radiography consistent with BPD) Exclusion criteria Hypertension Hyperglycaemia Sepsis Pneumonia Renal failure Treatment with corticosteroids 5 days prior to inclusion Mechanical ventilation with FiO2 ≥ 0.30 or oxygen dependency FiO2 ≥ 0.40 if non‐intubated Congenital heart disease
Interventions	Treatment: fluticasone propionate (Flovent; Glaxo‐SmithKline, St‐Laurent, Quebec, Canada; 125 μg/puff) administered by MDI inserted into small volume spacer (Aerochamber MV15, Trudell Medical, Ontario, Canada) and interposed between an anaesthesia bag and the tube or a face mask. Infants weighing 500g–1200 g received 1 puff twice daily for 3 weeks, then once daily in the 4th week. Infants weighing ≥ 1200 g received twice the number of puffs. Control: same as treatment, but with placebo in place instead of fluticasone. Systemic corticosteroids were allowed at the discretion of the attending physician, after which the inhaled medication was stopped.
Outcomes	Primary outcome Mean difference in duration of oxygen supplementation Secondary outcomes Survival without supplemental oxygen at the end of the study protocol Duration of ventilatory support Blood glucose Hypertension Diuresis Growth Cortisol axis Chest radiography score Duration of hospital stay
Notes	Trial authors did not respond to queries. Supported by GlaxoSmithKline. Dr Piedboeuf was supported by the Fonds de Recherche en Santé de Québec.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No information on sequence generation.
Allocation concealment (selection bias)	Unclear risk	No information on allocation concealment. Block randomisation, stratified intubated and extubated infants separately.
Blinding (performance bias and detection bias) All outcomes	Low risk	Identical format of MDIs supplied by the drug manufacturer. Pharmacist in charge of the medication, the treating physician and the investigators were unaware of treatment allocation.
Incomplete outcome data (attrition bias) All outcomes	Low risk	3 infants in the placebo group did not complete the study protocol (2 because of clinical pulmonary deterioration and 1 because central line sepsis). All analysed on intention‐to‐treat basis.
Selective reporting (reporting bias)	Unclear risk	Study protocol not published, therefore unclear if any protocol deviations occurred.
Other bias	Unclear risk	Mean FiO2 significantly lower in treatment group.

Giep 1996.

Study characteristics
Methods	Study design: single‐centre, double‐blind, placebo‐controlled trial Setting: USA
Participants	Ventilated/non‐ventilated: ventilated only Number randomised: 19 (treatment group: 10; control group: 9) Stratification: no Number analysed: 19 (treatment group: 10; control group: 9) PNA at trial entry: treatment group: 18 days; control group: 20 days Comparibility: no significant differences between groups with respect to birth weight, gestational age, antenatal steroid usage, sex, race, mode of delivery, or use of surfactant. At baseline, there were no significant differences in the outcome variables between groups. Inclusion criteria Preterm birth Birthweight 500g–1500 g Clinical and X‐ray changes consistent with RDS and BPD Age ≥ 14 days Still on mechanical ventilator with FiO2 > 0.40 and PIP > 14 cm H2O Failing previous extubation attempt Exclusion criteria PDA Sepsis Congenital heart disease Congenital malformations Previous postnatal or concurrent administration of corticosteroids
Interventions	Treatment: beclomethasone by MDI (Allen and Hansburys, Division of Glaxo, Research Triangle Park, NC) and Aerochamber (Mongahan Medical Corp, Plattsburgh, NE). The infants received an approximate dose of 1 mg/kg/day in 3 doses. Infants weighing 500 g–799 g received 3 puffs, those weighing 800 g–1000 g, 4 puffs, those weighing 1001 g–1300 g, 5 puffs, and > 1301 g, 6 puffs every 8 hours. Total duration of therapy was 7 days Control: same as treatment, but with placebo in place of beclomethasone
Outcomes	Primary outcome: no primary outcomes as this was a feasibility and safety of administration trial Secondary outcomes Respiratory rate FiO2 PIP PEEP Mean airway pressure Inspiration time and time to extubation Heart rate Blood pressure Infection rate IVH rate Retinopathy of prematurity Weight and caloric intake Cortisol and ACTH levels
Notes	Trial authors did not respond to queries. We found no information on funding.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of sequence generation not provided.
Allocation concealment (selection bias)	Unclear risk	Information not available.
Blinding (performance bias and detection bias) All outcomes	Low risk	Respiratory therapists, nurses, medical staff, investigators, and parents all blinded.
Incomplete outcome data (attrition bias) All outcomes	Low risk	3 infants in placebo group and 2 in treatment group received systemic corticosteroids after study entry, and continuous data were excluded from analysis thereafter.
Selective reporting (reporting bias)	Unclear risk	Study protocol not published, therefore unclear if any protocol deviations occurred.
Other bias	Low risk	Appears to be free of other bias.

Jonsson 2000.

Study characteristics
Methods	Study design: single‐centre, randomised, double‐blind, placebo‐controlled trial Setting: Sweden
Participants	Ventilated/non‐ventilated: both Number randomised: 30 (treatment group: 15; control group: 15) Stratification: no Number analysed: 27 (treatment group: 13; control group: 14) PNA at trial entry: 7 days Comparibility: no significant differences between groups with regard to birth weight, gestational age, PNA, sex, Apgar scores, rates of maternal infection, or use of antenatal steroids. All participants except 1 received surfactant treatment. No significant differences in outcome criteria at start of study. Inclusion criteria:  Very low birth weight On mechanical ventilator postnatal day 6, or, if extubated, nasal CPAP with FiO2 ≥ 0.3 Exclusion criteria Congenital malformations Congenital heart disease IVH (grades III to IV) On ventilator with increasing FiO2 > 60% or PCO2 > 8.5 kPa  On high frequency oscillatory ventilation on day 7
Interventions	Treatment: budesonide aerosol (Pulmicort; Astra‐Draco Pharmaceuticals, AB, Lund, Sweden). In ventilated infants, the drug was delivered with an electronic dosimetric jet nebuliser (Spira Electro 4, Respiratory Center, Hameenlinna, Finland) during the inspiration but not the expiration phase of mechanical breaths. In non‐ventilated infants, the drug was delivered through a Laerdal mask modified to fit to the inhalator nozzle. The infants received a dose of 500 μg twice daily, starting on day 7 of life, for 14 days. Control: same as treatment, but with placebo in place of budesonide
Outcomes	Primary outcome Change in FiO2 Secondary outcomes Duration of supplemental oxygen Duration of mechanical ventilation Duration of nasal CPAP Oxygen requirements at 28 days of age and at 36 weeks' PMA Adrenal cortisol response to stimulation at baseline and at the end of the study period The investigators collected information on adverse events, such as hyperglycaemia, hypertension, sepsis, PDA, IVH, and gastrointestinal problems.
Notes	Trial author provided additional outcome data and checked data extraction. Trial received grants from Sällskapet Barnavård and Stilftesen Barnhuset, Stockholm.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated randomisation.
Allocation concealment (selection bias)	Low risk	Consecutively numbered sealed envelopes.
Blinding (performance bias and detection bias) All outcomes	Low risk	Clinical staff blinded to group assignment. Code broken after last participant finished inhalations. Vials kept in hospital pharmacy in consecutively numbered cartons.
Incomplete outcome data (attrition bias) All outcomes	Low risk	2 infants withdrawn by attending clinician due to deterioration (they received systemic corticosteroids); 1 died on 9th day of life due to sepsis, disseminated intravascular coagulation and IVH grade IV.
Selective reporting (reporting bias)	Unclear risk	Study protocol not published, therefore unclear if any protocol deviations occurred.
Other bias	Low risk	Appears to be free of risk of bias.

LaForce 1993.

Study characteristics
Methods	Study design: single‐centre, randomised, double‐blind, placebo‐controlled trial Setting: USA
Participants	Ventilated/non‐ventilated: ventilated infants only Number randomised: 22 (treatment group: 11; control group: 11) Stratification: paired by birth weight (> 1000 g and < 1000 g) Number analysed: 13 (treatment group: 6; control group: 7) PNA at trial entry: unknown Comparibility: no significant differences between groups with regard to initial inspired oxygen concentration, ventilator settings, or respiratory rate. All participants were treated with Exosurf Inclusion criteria Birth weight < 1500 g Clinical and X‐ray signs of RDS Ventilated at 14 days X‐ray changes consistent with BPD Exclusion criteria PDA Pneumonia Sepsis Congenital heart disease Air leak
Interventions	Treatment: nebulisation with beclomethasone dipropionate (Vancenase AQ Nasal, Schering) 50 μg every 8 hours for 28 days. Treatments delivered through ventilator circuit with a Whisper Jet nebuliser system (model No. 123025; Marquest Medical Products, Inc., Englewood, Colo.) in ventilated infants and through blow by with 8 litres of humidified gas per minute. Control: same as treatment, but with placebo in place of beclomethasone
Outcomes	No prespecified primary or secondary outcomes. Reported outcomes were weekly measurements of lung compliance and airway resistance, sepsis rate, and weekly tracheal cultures.
Notes	Trial author provided data on randomisation process and sepsis rates. Trial supported by the Pediatric Research Fund, Medical College of Georgia, Augusta, GA.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of random sequence generation not mentioned.
Allocation concealment (selection bias)	Unclear risk	Investigators unaware of order of treatment group assignment.
Blinding (performance bias and detection bias) All outcomes	Low risk	Attending neonatologist unaware of treatment regimen.
Incomplete outcome data (attrition bias) All outcomes	High risk	9 infants withdrawn/lost to follow‐up: 4 due to technical problems with equipment (2 in each group), 4 lost to referring hospital (2 in each group), and 1 sudden death before start of study (in treatment group).
Selective reporting (reporting bias)	Unclear risk	Study protocol not published, therefore unclear if any protocol deviations occurred.
Other bias	Unclear risk	We could not exclude other potential sources of bias.

Pappagallo 1998.

Study characteristics
Methods	Study design: single‐centre, randomised, double‐blind, placebo‐controlled trial Setting: USA
Participants	Ventilated/non‐ventilated: ventilated only Number randomised: 18 (treatment group: 9; control group: 9) Stratification: no Number analysed: 18 (treatment group: 9; control group: 9) PNA at trial entry: treatment group: mean 22.6 (SD 3.0) days; control group: mean 19.13 (SD 1.6) days Comparability: no differences between groups in gestational age, birth weight, study age, or study weight Inclusion criteria Preterm birth Birthweight < 1500 g Age ≥ 7 days High probability of BPD based on a prediction model or being ventilator‐dependent Exclusion criteria Sepsis Pulmonary hypoplasia Congenital anomalies Heart diseases
Interventions	Treatment: dexamethasone 1 mg/kg for every 8 hours for 7 days followed by 0.5 mg/kg from day 8 to 10 by jet nebuliser Control: same as treatment, but with placebo in place of dexamethasone
Outcomes	Changes in tidal volume Minute ventilation Dynamic compliance Airway resistance Work of breathing Peak oesophageal pressure Extubation rates Cortisol levels and mucosal changes on bronchoscopy
Notes	Manuscript reported 2 study phases: a non‐randomised pilot study followed by an RCT. We included only the second phase in this review. Trial authors could not provide additional data. There was no information about funding.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Information not available.
Allocation concealment (selection bias)	Unclear risk	Information not available.
Blinding (performance bias and detection bias) All outcomes	Low risk	Vials prepared by the pharmacist and labelled with a code. Since both study and placebo medications were clear solutions and dosage was calculated on basis of volume, the clinical staff was unaware of intervention.
Incomplete outcome data (attrition bias) All outcomes	Low risk	No attrition bias detected.
Selective reporting (reporting bias)	Unclear risk	Study protocol not published, therefore unclear if any protocol deviations occurred.
Other bias	Unclear risk	We could not exclude other potential sources of bias.

ACTH: adrenocorticotropic hormone; BPD: bronchopulmonary dysplasia; CPAP: continuous positive airway pressure; FiO₂: fraction of inspired oxygen; IV: intravenous; IVH:intraventricular haemorrhage; MDI: metered‐dose inhaler; pCO₂: partial pressure of carbon dioxide; PDA: persistent ductus arteriosus; PEEP: positive end‐expiratory pressure; PIP: peak inspiratory pressure; PMA: postmenstrual age; PNA: postnatal age; RCT: randomised controlled trial; RDS: respiratory distress syndrome.

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Cole 1999	RCT including infants between 3 and 14 days' PNA. Attempts to contact the trial authors for separate data in ventilated and non‐ventilated infants were unsuccessful.
Kugelman 2017	RCT investigating inhaled corticosteroids in preterm infants with established BPD. All infants were randomised > 36 weeks' PMA.
NCT01895075	Study registered, but withdrawn due to lack of funding.
Pokriefka 1993	All infants diagnosed with moderate or severe BPD at 36 weeks' PMA.
Rajamani 1998	Only in abstract form. RCT including infants from day 6 PNA. Attempts to contact the trial authors for separate data for ventilated and non‐ventilated infants were unsuccessful.

BPD: bronchopulmonary dysplasia; PMA: postmenstrual age; PNA: postnatal age; RCT: randomised controlled trial.

Differences between protocol and review

• Compared to the previous update (Onland 2017a), we interpreted our findings using GRADE guidance 26 (Santesso 2020) and the updated Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2020).

• This update reports risk differences of the outcome analyses as well as risk ratios, while the previous update reported risk ratios without risk differences, as per standard Cochrane methods (Onland 2017a; Higgins 2020).

• We moved the description of the individual studies to the Appendix section.

Contributions of authors

WO and AvK have full access to all the data in the review and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: WO, AvK
Acquisition of data: WO, AvK
Analysis and interpretation of data: WO, MO, AvK
Drafting of the manuscript: WO, AvK
Critical revision of the manuscript for important intellectual content: WO, MO, AvK
Statistical analysis: WO
Study supervision: MO, AvK

Sources of support

Internal sources

• No sources of support provided

External 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.

Declarations of interest

WO: none
MO: none
AvK: none

New search for studies and content updated (no change to conclusions)