Early (< 7 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants

Lex W Doyle; Jeanie L Cheong; Susanne Hay; Brett J Manley; Henry L Halliday; Roger Soll

doi:10.1002/14651858.CD001146.pub6

Cochrane Database of Systematic Reviews

بررسی تاثیر استفاده زودهنگام (< 7 روز) از کورتیکواستروئیدهای سیستمیک پس از زایمان برای پیشگیری از بروز دیسپلازی برونکوپولمونری در نوزادان نارس

Información

DOI:

https://doi.org/10.1002/14651858.CD001146.pub6 Copiar DOI

Base de datos:

Cochrane Database of Systematic Reviews

Versión publicada:

21 octubre 2021see what's new

Tipo:

Intervention

Etapa:

Review

Grupo Editorial Cochrane:

Grupo Cochrane de Neonatología

Copyright:

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

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Autores

Lex W Doyle

Correspondencia a: Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Australia

[email protected]

Clinical Sciences, Murdoch Children's Research Institute, Parkville, Australia

Department of Paediatrics, University of Melbourne, Parkville, Australia

Newborn Research, The Royal Women's Hospital, Parkville, Australia
Jeanie L Cheong

Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Australia

Clinical Sciences, Murdoch Children's Research Institute, Parkville, Australia

Newborn Research, The Royal Women's Hospital, Parkville, Australia
Susanne Hay

Department of Neonatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
Brett J Manley

Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Australia

Newborn Research, The Royal Women's Hospital, Parkville, Australia
Henry L Halliday

Retired Honorary Professor of Child Health, Queen's University Belfast, Belfast, UK
Roger Soll

Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Larner College of Medicine at the University of Vermont, Burlington, USA

Contributions of authors

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

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

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

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

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

Sources of support

Internal sources

Action Research UK, UK

Grant to study effects of postnatal steroids
Action Research UK, UK

Grant to study long‐term follow‐up

External sources

National Health and Medical Research Council, Australia

Various project grants and Centre for Research Excellence (1153176)
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

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

Lex Doyle's institution received grant funding from the National Health and Medical Research Council (NHMRC) of Australia.

Henry Halliday declared no conflicts of interest.

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

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

Acknowledgements

We acknowledge the contribution of Richard Ehrenkranz (deceased) to earlier versions of this review.

We would like to thank Cochrane Neonatal: Colleen Ovelman, (former) Managing Editor; Jane Cracknell, Managing Editor; Michelle Fiander, Information Specialist; Roger Soll, Co‐coordinating Editor; and Bill McGuire, Co‐coordinating Editor; who provided editorial and administrative support.

Carol Friesen, (former) Information Specialist, designed and ran literature searches for the 2020 update, and Colleen Ovelman peer‐reviewed the OVID MEDLINE search strategy.

Sarah Hodgkinson, Bob Boyle, Roger Soll, and Vibhuti Shah peer‐reviewed and offered feedback on this updated review.

Version history

Published

Title

Stage

Authors

Version

2021 Oct 21

Early (< 7 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants

Review

Lex W Doyle, Jeanie L Cheong, Susanne Hay, Brett J Manley, Henry L Halliday, Roger Soll

https://doi.org/10.1002/14651858.CD001146.pub6

2017 Oct 24

Early (< 8 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants

Review

Lex W Doyle, Jeanie L Cheong, Richard A Ehrenkranz, Henry L Halliday

https://doi.org/10.1002/14651858.CD001146.pub5

2014 May 13

Early (< 8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants

Review

Lex W Doyle, Richard A Ehrenkranz, Henry L Halliday

https://doi.org/10.1002/14651858.CD001146.pub4

2010 Jan 20

Early (< 8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants

Review

Henry L Halliday, Richard A Ehrenkranz, Lex W Doyle

https://doi.org/10.1002/14651858.CD001146.pub3

2009 Jan 21

Early (< 8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants

Review

Henry L Halliday, Richard A Ehrenkranz, Lex W Doyle

https://doi.org/10.1002/14651858.CD001146.pub2

2003 Jan 20

Early postnatal (<96 hours) corticosteroids for preventing chronic lung disease in preterm infants

Review

Henry L Halliday, Richard A Ehrenkranz, L W Doyle, LEX W DOYLE

https://doi.org/10.1002/14651858.CD001146

Differences between protocol and review

We added the methods and plan for 'Summary of findings' tables and GRADE recommendations, which were not included in the original protocol (Halliday 2000), nor in earlier versions of this review (Doyle 2014a; Halliday 2003; Halliday 2009; Halliday 2010). For the 2017 update (Doyle 2017a), we changed the title to "Early (< 8 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants". For the 2021 update, we changed the title further to "Early (< 7 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants"; because two trials started treatment with systemic corticosteroids on Day 7 after birth, they were included in the "late" review
As of July 2019, Cochrane Neonatal no longer searches Embase for its reviews. RCTs and controlled clinical trials (CCTs) from Embase are added to the Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library, via a robust process (see How CENTRAL is created). Cochrane Neonatal has validated its searches to ensure that relevant Embase records are found while searching CENTRAL (Ovelman 2020).
Also starting in July 2019, Cochrane Neonatal no longer searches for RCTs and CCTs on the following platforms: ClinicalTrials.gov or World Health Organization’s International Clinical Trials Registry Platform (ICTRP), as records from both platforms are added to CENTRAL on a monthly basis (see How CENTRAL is created). Comprehensive search strategies are executed in CENTRAL to retrieve relevant records. The ISRCTN Registry (at www.isrctn.com/; formerly Controlled‐trials.com) is searched separately
Starting in September 2020, Cochrane Neonatal no longer searches for RCTs and quasi‐RCTs from the Cumulative Index to Nursing and Allied Health Literature (CINAHL), as records are identified and added to CENTRAL on a monthly basis through Cochrane's Centralised Search Service project (see How CENTRAL is created at https://www.cochranelibrary.com/central/central-creation#CINAHL%20section)
For the 2020 update, we ran searches in the following databases: CENTRAL via CRS Web and MEDLINE via OVID. Search strategies are available in Appendix 1. Previous search methods are available in Appendix 2 and Appendix 3
Because the indication for early hydrocortisone treatment might be primarily to treat lung problems or low blood pressure, we performed for the 2021 review a sensitivity analysis by indication for hydrocortisone for major outcomes of mortality at latest age, BPD at 36 weeks, and mortality or BPD at 36 weeks

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Humans; Infant; Infant, Newborn;

PICO

Population

Intervention

Comparison

Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Figure 1

Study flow diagram: review update.

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Figure 2

Risk of bias table.

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Figure 3

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

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Figure 4

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

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Figure 5

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

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Figure 6

Funnel plot of comparison: 3 Death or bronchopulmonary dysplasia (BPD), outcome: 3.2 Death or BPD at 36 weeks' postmenstrual age.

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Figure 7

Funnel plot of comparison: 5 Complications during primary hospitalisation, outcome: 5.15 Gastrointestinal perforation.

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Figure 8

Funnel plot of comparison: 6 Long‐term follow‐up, outcome: 6.11 Cerebral palsy.

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Figure 9

Funnel plot of comparison: 6 Long‐term follow‐up, outcome: 6.13 Death or cerebral palsy.

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Analysis 1.1

Comparison 1: Mortality at different ages, Outcome 1: Neonatal mortality (up to 28 days)

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Analysis 1.2

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

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Analysis 1.3

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

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Analysis 1.4

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

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Analysis 2.1

Comparison 2: Bronchopulmonary dysplasia (BPD) at different ages, Outcome 1: BPD (28 days of life)

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Analysis 2.2

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

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Analysis 2.3

Comparison 2: Bronchopulmonary dysplasia (BPD) at different ages, Outcome 3: BPD at 36 weeks' postmenstrual age in survivors to 36 weeks

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Analysis 2.4

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

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Analysis 2.5

Comparison 2: Bronchopulmonary dysplasia (BPD) at different ages, Outcome 5: Survivors who had late rescue with corticosteroids

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Analysis 2.6

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

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Analysis 3.1

Comparison 3: Mortality or bronchopulmonary dysplasia (BPD) at different ages, Outcome 1: Death or BPD at 28 days of life

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Analysis 3.2

Comparison 3: Mortality or bronchopulmonary dysplasia (BPD) at different ages, Outcome 2: Death or BPD at 36 weeks' postmenstrual age

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Analysis 4.1

Comparison 4: Failure to extubate at different ages, Outcome 1: Failure to extubate by third day

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Analysis 4.2

Comparison 4: Failure to extubate at different ages, Outcome 2: Failure to extubate by seventh day

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Analysis 4.3

Comparison 4: Failure to extubate at different ages, Outcome 3: Failure to extubate by 14th day

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Analysis 4.4

Comparison 4: Failure to extubate at different ages, Outcome 4: Failure to extubate by 28th day

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Analysis 5.1

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

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Analysis 5.2

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

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Analysis 5.3

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

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Analysis 5.4

Comparison 5: Complications during primary hospitalisation, Outcome 4: Hypertrophic cardiomyopathy

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Analysis 5.5

Comparison 5: Complications during primary hospitalisation, Outcome 5: Growth failure

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Analysis 5.6

Comparison 5: Complications during primary hospitalisation, Outcome 6: Pulmonary air leak

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Analysis 5.7

Comparison 5: Complications during primary hospitalisation, Outcome 7: Patent ductus arteriosus (PDA)

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Analysis 5.8

Comparison 5: Complications during primary hospitalisation, Outcome 8: Severe IVH

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Analysis 5.9

Comparison 5: Complications during primary hospitalisation, Outcome 9: Severe intraventricular haemorrhage (IVH) in infants examined

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Analysis 5.10

Comparison 5: Complications during primary hospitalisation, Outcome 10: Periventricular leukomalacia (PVL)

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Analysis 5.11

Comparison 5: Complications during primary hospitalisation, Outcome 11: PVL in infants with cranial ultrasound scans

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Analysis 5.12

Comparison 5: Complications during primary hospitalisation, Outcome 12: PVL in survivors seen at follow‐up

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Analysis 5.13

Comparison 5: Complications during primary hospitalisation, Outcome 13: Necrotising enterocolitis (NEC)

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Analysis 5.14

Comparison 5: Complications during primary hospitalisation, Outcome 14: Gastrointestinal bleeding

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Analysis 5.15

Comparison 5: Complications during primary hospitalisation, Outcome 15: Gastrointestinal perforation

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Analysis 5.16

Comparison 5: Complications during primary hospitalisation, Outcome 16: Pulmonary haemorrhage

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Analysis 5.17

Comparison 5: Complications during primary hospitalisation, Outcome 17: Any retinopathy of prematurity (ROP)

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Analysis 5.18

Comparison 5: Complications during primary hospitalisation, Outcome 18: Severe ROP

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Analysis 5.19

Comparison 5: Complications during primary hospitalisation, Outcome 19: Severe ROP in survivors

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Analysis 6.1

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

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Analysis 6.2

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

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Analysis 6.3

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

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Analysis 6.4

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

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Analysis 6.5

Comparison 6: Long‐term follow‐up into later childhood, Outcome 5: Developmental delay (other criteria)

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Analysis 6.6

Comparison 6: Long‐term follow‐up into later childhood, Outcome 6: Developmental delay (other criteria) in tested survivors

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Analysis 6.7

Comparison 6: Long‐term follow‐up into later childhood, Outcome 7: Blindness

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Analysis 6.8

Comparison 6: Long‐term follow‐up into later childhood, Outcome 8: Blindness in survivors assessed

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Analysis 6.9

Comparison 6: Long‐term follow‐up into later childhood, Outcome 9: Deafness

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Analysis 6.10

Comparison 6: Long‐term follow‐up into later childhood, Outcome 10: Deafness in survivors assessed

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Analysis 6.11

Comparison 6: Long‐term follow‐up into later childhood, Outcome 11: Cerebral palsy

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Analysis 6.12

Comparison 6: Long‐term follow‐up into later childhood, Outcome 12: Death before follow‐up in trials assessing cerebral palsy

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Analysis 6.13

Comparison 6: Long‐term follow‐up into later childhood, Outcome 13: Death or cerebral palsy

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Analysis 6.14

Comparison 6: Long‐term follow‐up into later childhood, Outcome 14: Cerebral palsy in survivors assessed

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Analysis 6.15

Comparison 6: Long‐term follow‐up into later childhood, Outcome 15: Major neurosensory disability (variable criteria ‐ see individual studies)

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Analysis 6.16

Comparison 6: Long‐term follow‐up into later childhood, Outcome 16: Death before follow‐up in trials assessing major neurosensory disability (variable criteria)

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Analysis 6.17

Comparison 6: Long‐term follow‐up into later childhood, Outcome 17: Death or major neurosensory disability (variable criteria)

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Analysis 6.18

Comparison 6: Long‐term follow‐up into later childhood, Outcome 18: Major neurosensory disability in survivors examined (variable criteria)

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Analysis 6.19

Comparison 6: Long‐term follow‐up into later childhood, Outcome 19: Abnormal neurological exam (variable criteria ‐ see individual studies)

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Analysis 6.20

Comparison 6: Long‐term follow‐up into later childhood, Outcome 20: Death before follow‐up in trials assessing abnormal neurological exam (variable criteria)

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Analysis 6.21

Comparison 6: Long‐term follow‐up into later childhood, Outcome 21: Death or abnormal neurological exam (variable criteria)

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Analysis 6.22

Comparison 6: Long‐term follow‐up into later childhood, Outcome 22: Abnormal neurological exam in tested survivors (variable criteria)

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Analysis 6.23

Comparison 6: Long‐term follow‐up into later childhood, Outcome 23: Intellectual impairment (IQ < 70)

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Analysis 6.24

Comparison 6: Long‐term follow‐up into later childhood, Outcome 24: Intellectual impairment (IQ < 70) in survivors assessed

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Analysis 6.25

Comparison 6: Long‐term follow‐up into later childhood, Outcome 25: "Major neurosensory impairment" ‐ blindness or deafness

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Analysis 6.26

Comparison 6: Long‐term follow‐up into later childhood, Outcome 26: "Major neurosensory impairment" ‐ blindness or deafness ‐ in survivors assessed

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Analysis 6.27

Comparison 6: Long‐term follow‐up into later childhood, Outcome 27: Behaviour abnormalities

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Analysis 6.28

Comparison 6: Long‐term follow‐up into later childhood, Outcome 28: Behaviour abnormalities in 3‐year‐old survivors assessed

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Analysis 6.29

Comparison 6: Long‐term follow‐up into later childhood, Outcome 29: Abnormal EEG

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Analysis 6.30

Comparison 6: Long‐term follow‐up into later childhood, Outcome 30: Abnormal EEG in tested survivors

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Analysis 6.31

Comparison 6: Long‐term follow‐up into later childhood, Outcome 31: Re‐hospitalisation in infancy

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Analysis 6.32

Comparison 6: Long‐term follow‐up into later childhood, Outcome 32: Re‐hospitalisation in infancy in survivors

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Analysis 7.1

Comparison 7: Sensitivity analyses by indication for hydrocortisone, Outcome 1: Mortality to latest age

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Analysis 7.2

Comparison 7: Sensitivity analyses by indication for hydrocortisone, Outcome 2: Bronchopulmonary dysplasia at 36 weeks

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Analysis 7.3

Comparison 7: Sensitivity analyses by indication for hydrocortisone, Outcome 3: Mortality or bronchopulmonary dysplasia at 36 weeks

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Summary of findings 1. Early systemic postnatal corticosteroids compared with placebo or no treatment for preventing bronchopulmonary dysplasia in preterm infants

Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
Early systemic postnatal corticosteroids (dexamethasone and hydrocortisone) compared with placebo or no treatment for preventing bronchopulmonary dysplasia in preterm infants
Patient or population: preventing bronchopulmonary dysplasia in preterm infants Setting: multiple neonatal intensive care units, most from high‐income countries Intervention: early systemic postnatal corticosteroids Comparison: placebo or no treatment
Outcomes	Risk with placebo or no treatment	Risk with early systemic postnatal corticosteroids	Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
Mortality at latest reported age	Study population (studies treating with dexamethasone or hydrocortisone)		RR 0.95 (0.85 to 1.06)	4373 (31 RCTs)	⊕⊕⊕⊕ HIGH	critical P = 0.05 for subgroup differences
	232 per 1000	221 per 1000 (197 to 246)	RR 0.95 (0.85 to 1.06)	4373 (31 RCTs)	⊕⊕⊕⊕ HIGH	critical P = 0.05 for subgroup differences
	Study population (subgroup of studies treating with dexamethasone)		RR 1.02 (0.90 to 1.16)	2940 (20 RCTs)	⊕⊕⊕⊕ HIGH	critical
	236 per 1000	241 per 1000 (212 to 274)	RR 1.02 (0.90 to 1.16)	2940 (20 RCTs)	⊕⊕⊕⊕ HIGH	critical
	Study population (subgroup of studies treating with hydrocortisone)		RR 0.80 (0.65 to 0.99)	1433 (11 RCTs)	⊕⊕⊕⊕ HIGH	critical
	225 per 1000	180 per 1000 (146 to 222)	RR 0.80 (0.65 to 0.99)	1433 (11 RCTs)	⊕⊕⊕⊕ HIGH	critical
BPD (36 weeks' PMA)	Study population (studies treating with dexamethasone or hydrocortisone)		RR 0.80 (0.73 to 0.88)	4167 (26 RCTs)	⊕⊕⊕⊝ MODERATE^a	important P = 0.01 for subgroup differences
	308 per 1000	247 per 1000 (225 to 271)	RR 0.80 (0.73 to 0.88)	4167 (26 RCTs)	⊕⊕⊕⊝ MODERATE^a	important P = 0.01 for subgroup differences
	Study population (subgroup of studies treating with dexamethasone)		RR 0.72 (0.63 to 0.82)	2791 (17 RCTs)	⊕⊕⊕⊕ HIGH	important
	269 per 1000	194 per 1000 (170 to 221)	RR 0.72 (0.63 to 0.82)	2791 (17 RCTs)	⊕⊕⊕⊕ HIGH	important
	Study population (subgroup of studies treating with hydrocortisone)		RR 0.92 (0.81 to 1.06)	1376 (9 RCTs)	⊕⊕⊕⊕ HIGH	important
	385 per 1000	354 per 1000 (312 to 408)	RR 0.92 (0.81 to 1.06)	1376 (9 RCTs)	⊕⊕⊕⊕ HIGH	important
Mortality or BPD at 36 weeks' PMA	Study population (studies treating with dexamethasone or hydrocortisone)		RR 0.89 (0.84 to 0.94)	4167 (26 RCTs)	⊕⊕⊕⊕ HIGH	critical
	515 per 1000	458 per 1000 (432 to 484)	RR 0.89 (0.84 to 0.94)	4167 (26 RCTs)	⊕⊕⊕⊕ HIGH	critical
	Study population (subgroup of studies treating with dexamethasone)		RR 0.88 (0.81 to 0.95	2791 (17 RCTs)	⊕⊕⊕⊕ HIGH	critical
	487 per 1000	429 per 1000 (395 to 463)	RR 0.88 (0.81 to 0.95	2791 (17 RCTs)	⊕⊕⊕⊕ HIGH	critical
	Study population (subgroup of studies treating with hydrocortisone)		RR 0.90 (0.82 to 0.99	1376 (9 RCTs)	⊕⊕⊕⊕ HIGH	critical
	569 per 1000	512 per 1000 (467 to 563)	RR 0.90 (0.82 to 0.99	1376 (9 RCTs)	⊕⊕⊕⊕ HIGH	critical
Gastrointestinal perforation during primary hospitalisation	Study population (studies treating with dexamethasone or hydrocortisone)		RR 1.84 (1.36 to 2.49)	3040 (16 RCTs)	⊕⊕⊕⊕ HIGH	important
	39 per 1000	71 per 1000 (53 to 96)	RR 1.84 (1.36 to 2.49)	3040 (16 RCTs)	⊕⊕⊕⊕ HIGH	important
	Study population (subgroup of studies treating with dexamethasone)		RR 1.73 (1.20 to 2.51	1936 (9 RCTs)	⊕⊕⊕⊕ HIGH	important
	41 per 1000	71 per 1000 (50 to 104)	RR 1.73 (1.20 to 2.51	1936 (9 RCTs)	⊕⊕⊕⊕ HIGH	important
	Study population (subgroup of infants treated with hydrocortisone		RR 2.05 (1.21 to 3.47	1104 (7 RCTs)	⊕⊕⊕⊕ HIGH	important
	34 per 1000	70 per 1000 (41 to 118)	RR 2.05 (1.21 to 3.47	1104 (7 RCTs)	⊕⊕⊕⊕ HIGH	important
Cerebral palsy at latest reported age	Study population (studies treating with dexamethasone or hydrocortisone)		RR 1.42 (1.06 to 1.91)	1973 (13 RCTs)	⊕⊕⊕⊕ HIGH	critical P = 0.09 for subgroup differences
	74 per 1000	106 per 1000 (79 to 142)	RR 1.42 (1.06 to 1.91)	1973 (13 RCTs)	⊕⊕⊕⊕ HIGH	critical P = 0.09 for subgroup differences
	Study population (subgroup of studies treating with dexamethasone)		RR 1.77 (1.21 to 2.58)	921 (7 RCTs)	⊕⊕⊕⊕ HIGH	critical
	89 per 1000	158 per 1000 (108 to 230)	RR 1.77 (1.21 to 2.58)	921 (7 RCTs)	⊕⊕⊕⊕ HIGH	critical
	Study population (subgroup of studies treating with hydrocortisone)		RR 1.05 (0.66 to 1.66)	1052 (6 RCTs)	⊕⊕⊕⊕ HIGH	critical
	62 per 1000	65 per 1000 (41 to 103)	RR 1.05 (0.66 to 1.66)	1052 (6 RCTs)	⊕⊕⊕⊕ HIGH	critical
Mortality or cerebral palsy at latest reported age	Study population (studies treating with dexamethasone or hydrocortisone)		RR 1.03 (0.91 to 1.16)	1973 (13 RCTs)	⊕⊕⊕⊕ HIGH	critical P = 0.02 for subgroup differences
	335 per 1000	345 per 1000 (305 to 389)	RR 1.03 (0.91 to 1.16)	1973 (13 RCTs)	⊕⊕⊕⊕ HIGH	critical P = 0.02 for subgroup differences
	Study population (subgroup of studies treating with dexamethasone)		RR 1.18 (1.01 to 1.37)	921 (7 RCTs)	⊕⊕⊕⊕ HIGH	critical
	383 per 1000	452 per 1000 (387 to 525)	RR 1.18 (1.01 to 1.37)	921 (7 RCTs)	⊕⊕⊕⊕ HIGH	critical
	Study population (subgroup of studies treating with hydrocortisone)		RR 0.86 (0.71 to 1.05)	1052 (6 RCTs)	⊕⊕⊕⊕ HIGH	critical
	295 per 1000	254 per 1000 (210 to 310)	RR 0.86 (0.71 to 1.05)	1052 (6 RCTs)	⊕⊕⊕⊕ HIGH	critical
*The risk in the intervention group (and its 95% confidence interval) is based on assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). BPD: bronchopulmonary dysplasia; CI: confidence interval; PMA: postmenstrual age; RCT: randomised controlled trial; RR: risk ratio.
GRADE Working Group grades of evidence. High certainty: further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low certainty: we are very uncertain about the estimate.
^aDowngraded one level for serious study limitations owing to evidence of publication bias for studies overall, but not within subgroups.

Summary of findings 1. Early systemic postnatal corticosteroids compared with placebo or no treatment for preventing bronchopulmonary dysplasia in preterm infants

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Comparison 1. Mortality at different ages

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Neonatal mortality (up to 28 days) Show forest plot	20	2933	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.87, 1.18]

1.1.1 Dexamethasone	16	2576	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.90, 1.23]
1.1.2 Hydrocortisone	4	357	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.49, 1.21]
1.2 Mortality at 36 weeks Show forest plot	27	4176	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.90, 1.13]

1.2.1 Dexamethasone	17	2791	Risk Ratio (M‐H, Fixed, 95% CI)	1.08 [0.94, 1.23]
1.2.2 Hydrocortisone	10	1385	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.67, 1.06]
1.3 Mortality to hospital discharge Show forest plot	29	4164	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.85, 1.07]

1.3.1 Dexamethasone	18	2731	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.90, 1.19]
1.3.2 Hydrocortisone	11	1433	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.65, 0.99]
1.4 Mortality at latest reported age Show forest plot	31	4373	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.85, 1.06]

1.4.1 Dexamethasone	20	2940	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.90, 1.16]
1.4.2 Hydrocortisone	11	1433	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.65, 0.99]

Comparison 1. Mortality at different ages

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Comparison 2. Bronchopulmonary dysplasia (BPD) at different ages

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 BPD (28 days of life) Show forest plot	15	2580	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.80, 0.93]

2.1.1 Dexamethasone	14	2327	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.78, 0.91]
2.1.2 Hydrocortisone	1	253	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.85, 1.18]
2.2 BPD (36 weeks' postmenstrual age) Show forest plot	26	4167	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.73, 0.88]

2.2.1 Dexamethasone	17	2791	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.63, 0.82]
2.2.2 Hydrocortisone	9	1376	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.81, 1.06]
2.3 BPD at 36 weeks' postmenstrual age in survivors to 36 weeks Show forest plot	24	3093	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.72, 0.87]

2.3.1 Dexamethasone	15	1948	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.63, 0.82]
2.3.2 Hydrocortisone	9	1145	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.78, 1.02]
2.4 Late rescue with corticosteroids Show forest plot	15	3004	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.73, 0.86]

2.4.1 Dexamethasone	10	1974	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.65, 0.80]
2.4.2 Hydrocortisone	5	1030	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.81, 1.09]
2.5 Survivors who had late rescue with corticosteroids Show forest plot	7	895	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.67, 0.89]

2.5.1 Dexamethasone	6	853	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.68, 0.91]
2.5.2 Hydrocortisone	1	42	Risk Ratio (M‐H, Fixed, 95% CI)	0.48 [0.24, 0.98]
2.6 Survivors discharged home on oxygen Show forest plot	9	1442	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.70, 1.07]

2.6.1 Dexamethasone	3	406	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.48, 1.26]
2.6.2 Hydrocortisone	6	1036	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.70, 1.13]

Comparison 2. Bronchopulmonary dysplasia (BPD) at different ages

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Comparison 3. Mortality or bronchopulmonary dysplasia (BPD) at different ages

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Death or BPD at 28 days of life Show forest plot	14	2471	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.87, 0.96]

3.1.1 Dexamethasone	13	2218	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.86, 0.95]
3.1.2 Hydrocortisone	1	253	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.90, 1.12]
3.2 Death or BPD at 36 weeks' postmenstrual age Show forest plot	26	4167	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.83, 0.94]

3.2.1 Dexamethasone	17	2791	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.81, 0.95]
3.2.2 Hydrocortisone	9	1376	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.82, 0.99]

Comparison 3. Mortality or bronchopulmonary dysplasia (BPD) at different ages

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Comparison 4. Failure to extubate at different ages

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Failure to extubate by third day Show forest plot	4	887	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.75, 0.95]

4.1.1 Dexamethasone	3	381	Risk Ratio (M‐H, Fixed, 95% CI)	0.73 [0.62, 0.86]
4.1.2 Hydrocortisone	1	506	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.82, 1.14]
4.2 Failure to extubate by seventh day Show forest plot	8	1448	Risk Ratio (M‐H, Fixed, 95% CI)	0.76 [0.68, 0.85]

4.2.1 Dexamethasone	6	703	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.61, 0.84]
4.2.2 Hydrocortisone	2	745	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.69, 0.94]
4.3 Failure to extubate by 14th day Show forest plot	4	443	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.62, 0.97]

4.4 Failure to extubate by 28th day Show forest plot	7	902	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.72, 0.98]

Comparison 4. Failure to extubate at different ages

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Comparison 5. Complications during primary hospitalisation

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Infection Show forest plot	25	4101	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.96, 1.15]

5.1.1 Dexamethasone	18	2821	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.91, 1.15]
5.1.2 Hydrocortisone	7	1280	Risk Ratio (M‐H, Fixed, 95% CI)	1.08 [0.94, 1.25]
5.2 Hyperglycaemia Show forest plot	14	2688	Risk Ratio (M‐H, Fixed, 95% CI)	1.26 [1.15, 1.37]

5.2.1 Dexamethasone	12	2117	Risk Ratio (M‐H, Fixed, 95% CI)	1.35 [1.21, 1.49]
5.2.2 Hydrocortisone	2	571	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.84, 1.22]
5.3 Hypertension Show forest plot	11	1993	Risk Ratio (M‐H, Fixed, 95% CI)	1.85 [1.54, 2.22]

5.3.1 Dexamethasone	10	1943	Risk Ratio (M‐H, Fixed, 95% CI)	1.84 [1.53, 2.21]
5.3.2 Hydrocortisone	1	50	Risk Ratio (M‐H, Fixed, 95% CI)	3.00 [0.33, 26.92]
5.4 Hypertrophic cardiomyopathy Show forest plot	1	50	Risk Ratio (M‐H, Fixed, 95% CI)	4.33 [1.40, 13.37]

5.5 Growth failure Show forest plot	1	50	Risk Ratio (M‐H, Fixed, 95% CI)	6.67 [2.27, 19.62]

5.6 Pulmonary air leak Show forest plot	17	3276	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.73, 1.11]

5.6.1 Dexamethasone	12	2041	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.66, 1.08]
5.6.2 Hydrocortisone	5	1235	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.72, 1.56]
5.7 Patent ductus arteriosus (PDA) Show forest plot	24	4013	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.72, 0.85]

5.7.1 Dexamethasone	17	2706	Risk Ratio (M‐H, Fixed, 95% CI)	0.76 [0.69, 0.84]
5.7.2 Hydrocortisone	7	1307	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.71, 0.95]
5.8 Severe IVH Show forest plot	26	4103	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.84, 1.12]

5.8.1 Dexamethasone	17	2736	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.81, 1.14]
5.8.2 Hydrocortisone	9	1367	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.76, 1.27]
5.9 Severe intraventricular haemorrhage (IVH) in infants examined Show forest plot	8	1964	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.75, 1.12]

5.9.1 Dexamethasone	4	994	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.59, 1.03]
5.9.2 Hydrocortisone	4	970	Risk Ratio (M‐H, Fixed, 95% CI)	1.11 [0.82, 1.49]
5.10 Periventricular leukomalacia (PVL) Show forest plot	15	2807	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.83, 1.53]

5.10.1 Dexamethasone	8	1514	Risk Ratio (M‐H, Fixed, 95% CI)	1.23 [0.84, 1.81]
5.10.2 Hydrocortisone	7	1293	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.58, 1.59]
5.11 PVL in infants with cranial ultrasound scans Show forest plot	7	1841	Risk Ratio (M‐H, Fixed, 95% CI)	1.13 [0.79, 1.60]

5.12 PVL in survivors seen at follow‐up Show forest plot	2	183	Risk Ratio (M‐H, Fixed, 95% CI)	1.22 [0.60, 2.48]

5.13 Necrotising enterocolitis (NEC) Show forest plot	25	4050	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.74, 1.11]

5.13.1 Dexamethasone	15	2661	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.69, 1.13]
5.13.2 Hydrocortisone	10	1389	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.66, 1.37]
5.14 Gastrointestinal bleeding Show forest plot	12	1816	Risk Ratio (M‐H, Fixed, 95% CI)	1.86 [1.35, 2.55]

5.14.1 Dexamethasone	10	1725	Risk Ratio (M‐H, Fixed, 95% CI)	1.87 [1.35, 2.58]
5.14.2 Hydrocortisone	2	91	Risk Ratio (M‐H, Fixed, 95% CI)	1.53 [0.27, 8.74]
5.15 Gastrointestinal perforation Show forest plot	16	3040	Risk Ratio (M‐H, Fixed, 95% CI)	1.84 [1.36, 2.49]

5.15.1 Dexamethasone	9	1936	Risk Ratio (M‐H, Fixed, 95% CI)	1.73 [1.20, 2.51]
5.15.2 Hydrocortisone	7	1104	Risk Ratio (M‐H, Fixed, 95% CI)	2.05 [1.21, 3.47]
5.16 Pulmonary haemorrhage Show forest plot	10	1820	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [0.87, 1.54]

5.16.1 Dexamethasone	7	686	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.65, 1.45]
5.16.2 Hydrocortisone	3	1134	Risk Ratio (M‐H, Fixed, 95% CI)	1.36 [0.92, 2.03]
5.17 Any retinopathy of prematurity (ROP) Show forest plot	9	1345	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.80, 0.97]

5.17.1 Dexamethasone	8	1042	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.72, 0.99]
5.17.2 Hydrocortisone	1	303	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.84, 1.04]
5.18 Severe ROP Show forest plot	14	2577	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.67, 0.99]

5.18.1 Dexamethasone	8	1507	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.60, 0.99]
5.18.2 Hydrocortisone	6	1070	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.65, 1.23]
5.19 Severe ROP in survivors Show forest plot	12	1575	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.64, 0.94]

5.19.1 Dexamethasone	10	1238	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.59, 0.95]
5.19.2 Hydrocortisone	2	337	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.60, 1.17]

Comparison 5. Complications during primary hospitalisation

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Comparison 6. Long‐term follow‐up into later childhood

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Bayley Mental Developmental Index (MDI) < ‐2 SD Show forest plot	3	842	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.78, 1.29]

6.2 Bayley MDI < ‐2 SD in tested survivors Show forest plot	3	528	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.79, 1.25]

6.3 Bayley Psychomotor Developmental Index (PDI) < ‐2 SD Show forest plot	3	842	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.85, 1.60]

6.4 Bayley PDI < ‐2 SD in tested survivors Show forest plot	3	528	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.87, 1.57]

6.5 Developmental delay (other criteria) Show forest plot	2	769	Risk Ratio (M‐H, Fixed, 95% CI)	1.37 [0.93, 2.03]

6.5.1 Dexamethasone	1	248	Risk Ratio (M‐H, Fixed, 95% CI)	1.68 [1.08, 2.61]
6.5.2 Hydrocortisone	1	521	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.26, 1.69]
6.6 Developmental delay (other criteria) in tested survivors Show forest plot	2	538	Risk Ratio (M‐H, Fixed, 95% CI)	1.50 [1.05, 2.15]

6.6.1 Dexamethasone	1	159	Risk Ratio (M‐H, Fixed, 95% CI)	1.94 [1.30, 2.88]
6.6.2 Hydrocortisone	1	379	Risk Ratio (M‐H, Fixed, 95% CI)	0.61 [0.24, 1.53]
6.7 Blindness Show forest plot	9	1318	Risk Ratio (M‐H, Fixed, 95% CI)	2.01 [0.74, 5.50]

6.7.1 Dexamethasone	6	862	Risk Ratio (M‐H, Fixed, 95% CI)	2.01 [0.74, 5.50]
6.7.2 Hydrocortisone	3	456	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
6.8 Blindness in survivors assessed Show forest plot	9	964	Risk Ratio (M‐H, Fixed, 95% CI)	2.16 [0.80, 5.86]

6.8.1 Dexamethasone	6	532	Risk Ratio (M‐H, Fixed, 95% CI)	2.16 [0.80, 5.86]
6.8.2 Hydrocortisone	3	432	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
6.9 Deafness Show forest plot	9	1100	Risk Ratio (M‐H, Fixed, 95% CI)	1.14 [0.39, 3.37]

6.9.1 Dexamethasone	5	600	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.30, 3.14]
6.9.2 Hydrocortisone	4	500	Risk Ratio (M‐H, Fixed, 95% CI)	3.12 [0.13, 73.06]
6.10 Deafness in survivors assessed Show forest plot	8	476	Risk Ratio (M‐H, Fixed, 95% CI)	1.14 [0.40, 3.29]

6.11 Cerebral palsy Show forest plot	13	1973	Risk Ratio (IV, Fixed, 95% CI)	1.43 [1.07, 1.92]

6.11.1 Dexamethasone	7	921	Risk Ratio (IV, Fixed, 95% CI)	1.77 [1.21, 2.58]
6.11.2 Hydrocortisone	6	1052	Risk Ratio (IV, Fixed, 95% CI)	1.05 [0.66, 1.66]
6.12 Death before follow‐up in trials assessing cerebral palsy Show forest plot	13	1973	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.78, 1.05]

6.12.1 Dexamethasone	7	921	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.81, 1.21]
6.12.2 Hydrocortisone	6	1052	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.64, 1.02]
6.13 Death or cerebral palsy Show forest plot	13	1973	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.91, 1.16]

6.13.1 Dexamethasone	7	921	Risk Ratio (M‐H, Fixed, 95% CI)	1.18 [1.01, 1.37]
6.13.2 Hydrocortisone	6	1052	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.71, 1.05]
6.14 Cerebral palsy in survivors assessed Show forest plot	13	1329	Risk Ratio (M‐H, Fixed, 95% CI)	1.47 [1.12, 1.92]

6.14.1 Dexamethasone	7	587	Risk Ratio (M‐H, Fixed, 95% CI)	1.85 [1.31, 2.61]
6.14.2 Hydrocortisone	6	742	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.65, 1.58]
6.15 Major neurosensory disability (variable criteria ‐ see individual studies) Show forest plot	7	1703	Risk Ratio (M‐H, Fixed, 95% CI)	1.08 [0.89, 1.33]

6.15.1 Dexamethasone	4	772	Risk Ratio (M‐H, Fixed, 95% CI)	1.37 [1.03, 1.83]
6.15.2 Hydrocortisone	3	931	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.64, 1.14]
6.16 Death before follow‐up in trials assessing major neurosensory disability (variable criteria) Show forest plot	8	1754	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.77, 1.06]

6.16.1 Dexamethasone	4	772	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.82, 1.25]
6.16.2 Hydrocortisone	4	982	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.62, 1.01]
6.17 Death or major neurosensory disability (variable criteria) Show forest plot	7	1703	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.87, 1.08]

6.17.1 Dexamethasone	4	772	Risk Ratio (M‐H, Fixed, 95% CI)	1.13 [0.99, 1.30]
6.17.2 Hydrocortisone	3	931	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.69, 0.97]
6.18 Major neurosensory disability in survivors examined (variable criteria) Show forest plot	8	1178	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [0.89, 1.28]

6.18.1 Dexamethasone	4	469	Risk Ratio (M‐H, Fixed, 95% CI)	1.36 [1.05, 1.77]
6.18.2 Hydrocortisone	4	709	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.65, 1.10]
6.19 Abnormal neurological exam (variable criteria ‐ see individual studies) Show forest plot	5	829	Risk Ratio (M‐H, Fixed, 95% CI)	1.81 [1.33, 2.47]

6.20 Death before follow‐up in trials assessing abnormal neurological exam (variable criteria) Show forest plot	6	1350	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.75, 1.07]

6.20.1 Dexamethasone	5	829	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.79, 1.21]
6.20.2 Hydrocortisone	1	521	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.54, 1.04]
6.21 Death or abnormal neurological exam (variable criteria) Show forest plot	5	829	Risk Ratio (M‐H, Fixed, 95% CI)	1.23 [1.06, 1.42]

6.22 Abnormal neurological exam in tested survivors (variable criteria) Show forest plot	5	508	Risk Ratio (M‐H, Fixed, 95% CI)	1.89 [1.41, 2.52]

6.23 Intellectual impairment (IQ < 70) Show forest plot	3	125	Risk Ratio (M‐H, Fixed, 95% CI)	1.46 [0.64, 3.33]

6.23.1 Dexamethasone	2	90	Risk Ratio (M‐H, Fixed, 95% CI)	1.37 [0.57, 3.31]
6.23.2 Hydrocortisone	1	35	Risk Ratio (M‐H, Fixed, 95% CI)	2.12 [0.21, 21.27]
6.24 Intellectual impairment (IQ < 70) in survivors assessed Show forest plot	2	76	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.47, 2.65]

6.25 "Major neurosensory impairment" ‐ blindness or deafness Show forest plot	1	50	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.16, 2.25]

6.26 "Major neurosensory impairment" ‐ blindness or deafness ‐ in survivors assessed Show forest plot	1	45	Risk Ratio (M‐H, Fixed, 95% CI)	0.57 [0.16, 2.12]

6.27 Behaviour abnormalities Show forest plot	1	50	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.16, 2.25]

6.28 Behaviour abnormalities in 3‐year‐old survivors assessed Show forest plot	1	46	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.16, 2.22]

6.29 Abnormal EEG Show forest plot	2	306	Risk Ratio (M‐H, Fixed, 95% CI)	1.24 [0.66, 2.33]

6.30 Abnormal EEG in tested survivors Show forest plot	2	146	Risk Ratio (M‐H, Fixed, 95% CI)	1.13 [0.61, 2.08]

6.31 Re‐hospitalisation in infancy Show forest plot	3	672	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.68, 1.08]

6.32 Re‐hospitalisation in infancy in survivors Show forest plot	3	430	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.71, 1.07]

Comparison 6. Long‐term follow‐up into later childhood

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Comparison 7. Sensitivity analyses by indication for hydrocortisone

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Mortality to latest age Show forest plot	11	1433	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.65, 0.99]

7.1.1 Lung	7	1319	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.66, 1.01]
7.1.2 Blood pressure	4	114	Risk Ratio (M‐H, Fixed, 95% CI)	0.58 [0.24, 1.38]
7.2 Bronchopulmonary dysplasia at 36 weeks Show forest plot	9	1152	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.80, 1.02]

7.2.1 Lung	6	1058	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.79, 1.02]
7.2.2 Blood pressure	3	94	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.66, 1.54]
7.3 Mortality or bronchopulmonary dysplasia at 36 weeks Show forest plot	7	1297	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.80, 0.98]

7.3.1 Lung	6	1275	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.81, 0.99]
7.3.2 Blood pressure	1	22	Risk Ratio (M‐H, Fixed, 95% CI)	0.44 [0.19, 1.02]

Comparison 7. Sensitivity analyses by indication for hydrocortisone

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بررسی تاثیر استفاده زودهنگام (< 7 روز) از کورتیکواستروئیدهای سیستمیک پس از زایمان برای پیشگیری از بروز دیسپلازی برونکوپولمونری در نوزادان نارس

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