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

Wes Onland; Martin Offringa; Anton van Kaam

doi:10.1002/14651858.CD002311.pub5

Cochrane Database of Systematic Reviews

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

Information

DOI:

https://doi.org/10.1002/14651858.CD002311.pub5 Copy DOI

Database:

Cochrane Database of Systematic Reviews

Version published:

15 December 2022see what's new

Type:

Intervention

Stage:

Review

Cochrane Editorial Group:

Cochrane Neonatal Group

Copyright:

Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Article metrics

Altmetric:

Cited by:

Cited 0 times via Crossref Cited-by Linking

Collapse

Authors

Wes Onland

Correspondence to: Department of Neonatology, Emma Children's Hospital Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands

[email protected]
Martin Offringa

Child Health Evaluative Sciences, Hospital for Sick Children, Toronto, Canada
Anton van Kaam

Department of Neonatology, Emma Children's Hospital Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands

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

Acknowledgements

We would like to thank Dr P Lister, Dr R Iles, Dr B Shaw, and Dr F Ducharme for writing the previous version of this review, named 'Inhaled steroids for neonatal chronic lung disease' (Lister 2000).
We are grateful to Dr David Schwartz, Dr T Giep, Prof M Silverman, and Dr Spencer Brudno for providing additional information for the previous version of this review.
We would also like to thank Prof Silverman and Dr Jonsson, who provided precious additional data for the first update of the review.
The search strategy was designed by Cochrane Neonatal, and Colleen Ovelman ran the searches.

We would like to thank the following members of Cochrane Neonatal for providing editorial and administrative support: Colleen Ovelman and Jane Cracknell (Managing Editors), Michelle Fiander and Chris Cooper (Information Specialists), and Roger Soll and William McGuire (Co‐ordinating Editors).

Cochrane Neonatal supported the review authors in the development of this updated review.

The following people conducted the editorial process for this article:

Sign‐off Editor (final editorial decision): Robert Boyle, Imperial College London, UK; Co‐ordinating Editor of the Cochrane Skin Group.
Managing Editor (selected peer reviewers, provided comments, collated peer‐reviewer comments, provided editorial guidance to the review authors, edited the article): Lara Kahale, Cochrane Central Editorial Service
Editorial Assistant (conducted editorial policy checks and supported editorial team): Lisa Wydrzynski, Cochrane Central Editorial Service
Copy Editor (copy‐editing and production): Julia Turner
Peer‐reviewers (provided comments and recommended an editorial decision): Augusto F Schmidt, University of Miami Miller School of Medicine, USA; Jana Tukova, Charles University in Prague and General University Hospital in Prague, Czech Republic; Faouzi I Maalouf, American University of Beirut, Lebanon (clinical/content review); Jamale Eleid, American University of Beirut, Lebanon (consumer review); Nuala Livingstone, Associate Editor, Cochrane Evidence Production and Methods Directorate (methods review); and Robin Featherstone, Cochrane Central Editorial Service (search review).

Version history

Published

Title

Stage

Authors

Version

2022 Dec 15

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

Review

Wes Onland, Martin Offringa, Anton Kaam

https://doi.org/10.1002/14651858.CD002311.pub5

2017 Aug 24

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

Review

Wes Onland, Martin Offringa, Anton van Kaam

https://doi.org/10.1002/14651858.CD002311.pub4

2012 Apr 18

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

Review

Wes Onland, Martin Offringa, Anton van Kaam

https://doi.org/10.1002/14651858.CD002311.pub3

2010 Jan 20

Inhaled steroids for neonatal chronic lung disease

Review

Paula Lister, Richard Iles, Ben NJ Shaw, Francine M Ducharme

https://doi.org/10.1002/14651858.CD002311.pub2

1999 Oct 25

Inhaled steroids for neonatal chronic lung disease

Review

Paula Lister, Richard Iles, Ben NJ Shaw, Francine Ducharme

https://doi.org/10.1002/14651858.CD002311

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.

Notes

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Humans; Infant; Infant, Newborn;

PICOs

Population

Intervention

Comparison

Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

Figure 1

Study flow diagram.

Navigate to figure in ReviewOpen in new tab

Figure 2

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

Navigate to figure in ReviewOpen in new tab

Figure 3

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

Navigate to figure in ReviewOpen in new tab

Analysis 1.1

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

Navigate to figure in ReviewOpen in new tab

Analysis 1.2

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

Navigate to figure in ReviewOpen in new tab

Analysis 1.3

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

Navigate to figure in ReviewOpen in new tab

Analysis 1.4

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

Navigate to figure in ReviewOpen in new tab

Analysis 1.5

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

Navigate to figure in ReviewOpen in new tab

Analysis 1.6

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

Navigate to figure in ReviewOpen in new tab

Analysis 1.7

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

Navigate to figure in ReviewOpen in new tab

Analysis 1.8

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

Navigate to figure in ReviewOpen in new tab

Analysis 1.9

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

Navigate to figure in ReviewOpen in new tab

Analysis 1.10

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

Navigate to figure in ReviewOpen in new tab

Analysis 1.11

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

Navigate to figure in ReviewOpen in new tab

Analysis 1.12

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

Navigate to figure in ReviewOpen in new tab

Analysis 1.13

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

Navigate to figure in ReviewOpen in new tab

Analysis 1.14

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

Navigate to figure in ReviewOpen in new tab

Analysis 1.15

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

Navigate to figure in ReviewOpen in new tab

Analysis 1.16

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

Navigate to figure in ReviewOpen in new tab

Analysis 1.17

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

Navigate to figure in ReviewOpen in new tab

Analysis 1.18

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

Navigate to figure in ReviewOpen in new tab

Analysis 1.19

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

Navigate to figure in ReviewOpen in new tab

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

Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
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	Risk with placebo	Risk with inhaled corticosteroids	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Combined outcome of mortality or BPD at 36 weeks' PMA	Study population		RR 1.10 (0.74 to 1.63)	30 (1 RCT)	⊕⊝⊝⊝ Very low^a,b,c	—
Combined outcome of mortality or BPD at 36 weeks' PMA	533 per 1000	587 per 1000 (395 to 869)	RR 1.10 (0.74 to 1.63)	30 (1 RCT)	⊕⊝⊝⊝ Very low^a,b,c	—
Mortality at 36 weeks' PMA	Study population		RR 3.00 (0.35 to 25.78)	61 (3 RCTs)	⊕ ⊝ ⊝⊝ Very low^c,d	—
Mortality at 36 weeks' PMA	0 per 1000	1 per 1000 (0 to 8)	RR 3.00 (0.35 to 25.78)	61 (3 RCTs)	⊕ ⊝ ⊝⊝ Very low^c,d	—
BPD at 36 weeks' PMA	Study population		RR 1.00 (0.59 to 1.70)	30 (1 RCT)	⊕⊝⊝⊝ Very low^a,b,c	—
BPD at 36 weeks' PMA	600 per 1000	600 per 1000 (354 to 1000)	RR 1.00 (0.59 to 1.70)	30 (1 RCT)	⊕⊝⊝⊝ Very low^a,b,c	—
Open‐label use of systemic corticosteroids	Study population		RR 0.51 (0.26 to 1.00)	74 (4 RCTs)	⊕⊝⊝⊝ Very low^c,e	—
Open‐label use of systemic corticosteroids	432 per 1000	221 per 1000 (112 to 432)	RR 0.51 (0.26 to 1.00)	74 (4 RCTs)	⊕⊝⊝⊝ Very low^c,e	—
*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.

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

Navigate to table in Review

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 Show forest plot	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 Show forest plot	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 Show forest plot	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 Show forest plot	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 Show forest plot	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 Show forest plot	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 Show forest plot	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 Show forest plot	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 Show forest plot	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 Show forest plot	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) Show forest plot	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) Show forest plot	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) Show forest plot	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 Show forest plot	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 Show forest plot	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 Show forest plot	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 Show forest plot	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 Show forest plot	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 Show forest plot	5	76	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.46, 0.84]

Comparison 1. Inhaled corticosteroids (ICS) versus placebo

Navigate to table in Review

The Cochrane Library

Scolaris Language Selector Scolaris Language Selector

Cochrane Review language

Website language

Scolaris Content Language Banner Portlet Scolaris Content Language Banner Portlet

Scolaris Content Display Scolaris Content Display

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

Information