Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth

Devender Roberts; Julie Brown; Nancy Medley; Stuart R Dalziel

doi:10.1002/14651858.CD004454.pub3

Cochrane Database of Systematic Reviews

Corticosteroides prenatales para acelerar la maduración del pulmón fetal en mujeres con riesgo de parto prematuro

Información

DOI:

https://doi.org/10.1002/14651858.CD004454.pub3 Copiar DOI

Base de datos:

Cochrane Database of Systematic Reviews

Versión publicada:

21 marzo 2017see what's new

Tipo:

Intervention

Etapa:

Review

Grupo Editorial Cochrane:

Grupo Cochrane de Embarazo y parto

Copyright:

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Contraer

Autores

Devender Roberts

Correspondencia a: Obstetrics Directorate, Liverpool Women's NHS Foundation Trust, Liverpool, UK

[email protected]
Julie Brown

Auckland, New Zealand
Nancy Medley

Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK
Stuart R Dalziel

Departments of Surgery and Paediatrics: Child and Youth Health, The University of Auckland, Auckland, New Zealand

Children's Emergency Department, Starship Children's Hospital, Auckland, New Zealand

Contributions of authors

P Crowley prepared the first version of the Cochrane Review in 1996.

S Dalziel and D Roberts revised the protocol for the 2005 update. Both review authors identified included and excluded studies, extracted the data and wrote the discussion. S Dalziel entered the data and re‐analysed data from the New Zealand Trial using intention to treat. D Roberts entered the tables and contacted study authors for additional data.

In 2016 J Brown and N Medley assisted S Dalziel and D Roberts to update the review by entering and re‐analysing the data and drafting text of the review. J Brown created Table 1. N Medley created summary of findings Table 1.

Sources of support

Internal sources

University of Auckland, New Zealand
The University of Liverpool, UK
Liverpool Women's NHS Foundation Trust, UK

External sources

Harris‐Wellbeing of Women Preterm Birth Centre, UK
Health Research Council of New Zealand (HRC13/556), New Zealand

Declarations of interest

Devender Roberts: none known.

Julie Brown: none known.

Nancy Medley: Nancy Medley's work was financially supported by the a grant to University of Liverpool from the Harris‐Wellbeing Preterm Birth Centre.

Stuart R Dalziel: none known.

Acknowledgements

P Crowley's first, unstructured review of antenatal corticosteroids was conducted at the suggestion of Professor Dennis Hawkins in 1980. Dr Anne Anderson encouraged her to use it as a basis for an early meta‐analysis in 1981. Her work at the National Perinatal Epidemiology Unit in 1980 to 1981 was funded by the National Maternity Hospital, Dublin at the suggestion of the then Master, Dr Dermot MacDonald. This review was first published in structured form on the Oxford Database of Perinatal Trials in 1989. The preparation and continued updating of the original review would have been impossible without the help of Iain and Jan Chalmers, Marc Keirse, Jini Hetherington, Sonja Henderson and Professor Zarko Alfirevic.

Acknowledgements to Professor James Neilson and Professor Jane Harding for their help with the previous update. Many thanks to Sonja Henderson for sound advice at all times. Acknowledgements also to all the study authors who provided us with additional data.

Thanks to Almira Opardija for translating Grgic 2003. Thanks also to Bita Mesgarpour for translating Mansouri 2010.

In the 2016 update we would like to thank Tineke Crawford for her contribution to editing the review and updating some of the evidence. We would also like to thank Leanne Jones and Therese Dowswell for their contribution to editing the review.

This project was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to Cochrane Pregnancy and Childbirth. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health.

N Medley's work on this project was supported by the University of Liverpool's Harris‐Wellbeing of Women Preterm Birth Centre research award.

S Dalziel's time was supported by the Health Research Council of New Zealand (HRC13/556).

As part of the pre‐publication editorial process, this review has been commented on by three peers (an editor and two referees who are external to the editorial team), a member of the Pregnancy and Childbirth Group's international panel of consumers and the Group's Statistical Adviser.

Version history

Published

Title

Stage

Authors

Version

2020 Dec 25

Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth

Review

Emma McGoldrick, Fiona Stewart, Roses Parker, Stuart R Dalziel

https://doi.org/10.1002/14651858.CD004454.pub4

2017 Mar 21

Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth

Review

Devender Roberts, Julie Brown, Nancy Medley, Stuart R Dalziel

https://doi.org/10.1002/14651858.CD004454.pub3

2006 Jul 19

Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth

Review

Devender Roberts, Stuart R Dalziel

https://doi.org/10.1002/14651858.CD004454.pub2

2003 Oct 20

Antenatal corticosteroids to accelerate fetal lung maturation for women at risk of preterm birth

Protocol

Patricia Crowley, Devender Roberts, Stuart R Dalziel, Ben NJ Shaw

https://doi.org/10.1002/14651858.CD004454

Differences between protocol and review

The methods have been updated to current standard methods text for the Cochrane Pregnancy and Childbirth Group.

The following subgroups were not pre‐specified in the protocol:

decade of trial;
gestational age at trial entry;
protocol with weekly repeats.

In the 2016 update, comparison one has been re‐structured to include only the main analysis, with all clinical groups moved to subsequent comparisons. We have also deleted subgroups from previous versions of the review related to post‐randomisation variables (gestational age to delivery and ruptured membranes at specific time points). A 'Summary of findings' table has been incorporated in this update (2016).

We clarified the primary outcome of deaths (fetal/neonatal) to perinatal deaths. Neonatal deaths and fetal deaths are still presented separately as primary outcomes.

We renamed outcomes of mean length for children and adults as mean height.

In response to referee feedback we changed the name of the primary outcome 'puerperal sepsis' to 'endometritis (including infections)'. Most trials (7/10) in this analysis specifically reported endometritis.

Notes

An update of this review is currently underway and will be completed and published following publication of the WHO ACTION trial.

Following feedback, we are aware that there are some inconsistencies in the way that the data for intraventricular haemorrhage have been reported and analysed in this and the previous version of this review (Roberts 2006). This is currently being corrected for the next update.

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Female; Humans; Infant, Newborn; Pregnancy;

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

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

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Figure 2

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

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Figure 3

Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.2 Chorioamnionitis

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Figure 4

Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.4 Perinatal deaths

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Figure 5

Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.5 Neonatal deaths

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Figure 6

Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.6 Fetal deaths

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Figure 7

Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.7 Respiratory distress syndrome

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Figure 8

Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.10 Intraventricular haemorrhage

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Figure 9

Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.11 Mean birthweight (g)

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Figure 10

Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.25 Need for mechanical ventilation/CPAP

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Figure 11

Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.30 Apgar < 7 at 5 minutes

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Analysis 1.1

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 1: Maternal death

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Analysis 1.2

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 2: Chorioamnionitis

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Analysis 1.3

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 3: Endometritis

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Analysis 1.4

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 4: Perinatal deaths

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Analysis 1.5

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 5: Neonatal deaths

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Analysis 1.6

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 6: Fetal deaths

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Analysis 1.7

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 7: Respiratory distress syndrome

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Analysis 1.8

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 8: Moderate/severe respiratory distress syndrome

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Analysis 1.9

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 9: Chronic lung disease

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Analysis 1.10

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 10: Intraventricular haemorrhage

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Analysis 1.11

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 11: Mean birthweight (g)

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Analysis 1.12

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 12: Death in childhood

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Analysis 1.13

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 13: Neurodevelopmental delay in childhood

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Analysis 1.14

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 14: Death into adulthood

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Analysis 1.15

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 15: Fever in women after trial entry requiring the use of antibiotics

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Analysis 1.16

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 16: Intrapartum fever in woman requiring the use of antibiotics

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Analysis 1.17

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 17: Side effects of therapy in women

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Analysis 1.18

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 18: Admission into adult intensive care unit

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Analysis 1.19

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 19: Hypertension

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Analysis 1.20

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 20: Postnatal fever in woman

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Analysis 1.21

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 21: Glucose intolerance

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Analysis 1.22

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 22: Necrotising enterocolitis

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Analysis 1.23

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 23: Systemic infection in the first 48 hours of life

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Analysis 1.24

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 24: Proven infection while in the neonatal intensive care unit

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Analysis 1.25

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 25: Need for mechanical ventilation/CPAP

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Analysis 1.26

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 26: Mean duration of mechanical ventilation/CPAP (days)

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Analysis 1.27

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 27: Mean duration of oxygen supplementation (days)

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Analysis 1.28

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 28: Surfactant use

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Analysis 1.29

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 29: Air leak syndrome

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Analysis 1.30

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 30: Apgar < 7 at 5 minutes

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Analysis 1.31

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 31: Mean interval between trial entry and birth (days)

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Analysis 1.32

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 32: Small‐for‐gestational age

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Analysis 1.33

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 33: Mean infant HPA axis function (cortisol)

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Analysis 1.34

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 34: Admission to neonatal intensive care unit

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Analysis 1.35

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 35: Developmental delay in childhood

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Analysis 1.36

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 36: Cerebral palsy in childhood

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Analysis 1.37

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 37: Mean childhood weight (kg)

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Analysis 1.38

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 38: Mean childhood height (cm)

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Analysis 1.39

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 39: Mean childhood head circumference (cm)

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Analysis 1.40

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 40: Mean childhood VC (% predicted)

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Analysis 1.41

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 41: Mean childhood FEV1 (% predicted)

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Analysis 1.42

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 42: Mean childhood FEV1/VC

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Analysis 1.43

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 43: Mean childhood systolic blood pressure (mmHg)

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Analysis 1.44

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 44: Visual impairment in childhood

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Analysis 1.45

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 45: Hearing impairment in childhood

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Analysis 1.46

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 46: Intellectual impairment in childhood

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Analysis 1.47

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 47: Behavioural/learning difficulties in childhood

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Analysis 1.48

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 48: Mean adult insulin (log values)

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Analysis 1.49

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 49: Mean adult glucose (mmol/L)

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Analysis 1.50

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 50: Mean adult weight (kg)

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Analysis 1.51

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 51: Mean adult height (cm)

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Analysis 1.52

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 52: Mean adult head circumference (cm)

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Analysis 1.53

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 53: Mean adult skinfold thickness (log values)

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Analysis 1.54

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 54: Mean adult systolic blood pressure (mmHg)

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Analysis 1.55

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 55: Mean adult HPA axis function (mean log fasting cortisol)

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Analysis 1.56

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 56: Mean cholesterol in adulthood (mmol/L)

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Analysis 1.57

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 57: Mean age at puberty (years)

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Analysis 1.58

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 58: Educational achievement by adulthood (university or polytechnic education)

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Analysis 1.59

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 59: Visual impairment in adulthood

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Analysis 1.60

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 60: Hearing impairment in adulthood

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Analysis 1.61

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 61: Intellectual impairment in adulthood

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Analysis 1.62

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 62: Mean adult FVC (% predicted)

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Analysis 1.63

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 63: Mean adult FEV1 (% predicted)

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Analysis 1.64

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 64: Mean adult FEV1/FVC

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Analysis 1.65

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 65: Mean adult PEF

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Analysis 1.66

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 66: Mean adult F50

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Analysis 1.67

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 67: Mean adult F25

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Analysis 1.68

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 68: Mean adult FEF 25%‐75%

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Analysis 1.69

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 69: FEV1/FVC < 70%

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Analysis 1.70

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 70: Asthma diagnosed by Doctor in lifetime

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Analysis 1.71

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 71: Wheezing in last 12 months

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Analysis 1.72

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 72: Current Asthma

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Analysis 1.73

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 73: Further respiratory diagnosis (includes pneumonia, upper airway conditions and bronchitis)

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Analysis 1.74

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 74: Spontaneous pneumothorax

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Analysis 1.75

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 75: Shortness of breath at anytime in the last 12 months

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Analysis 1.76

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 76: Mean adult lumbar spine aBMD (g/cm2) areal bone mineral density

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Analysis 1.77

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 77: Mean adult lumbar spine vBMD (g/cm3) volumetric bone mineral density

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Analysis 1.78

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 78: Mean adult total body BMC (grams) bone mineral content

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Analysis 1.79

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 79: Mean adult total body aBMD (g/cm3) areal bone mineral density

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Analysis 1.80

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 80: Mean adult femoral neck aBMD (g/cm2) areal bone mineral density

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Analysis 1.81

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 81: Mean adult femoral trochanter aBMD (g/cm2) areal bone mineral density

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Analysis 1.82

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 82: Mean adult femoral shaft aBMD (g/cm2) areal bone mineral density

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Analysis 1.83

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 83: Mean total proximal femur aBMD (g/cm2) areal bone mineral density

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Analysis 1.84

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 84: Mean length of antenatal hospitalisation (days)

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Analysis 1.85

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 85: Mean length of postnatal hospitalisation (days)

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Analysis 1.86

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 86: Mean length of neonatal hospitalisation (days)

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Analysis 2.1

Comparison 2: Corticosteroids versus placebo or no treatment ‐ single or multiple pregnancy, Outcome 1: Chorioamnionitis ‐ single or multiple pregnancy

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Analysis 2.2

Comparison 2: Corticosteroids versus placebo or no treatment ‐ single or multiple pregnancy, Outcome 2: Perinatal death ‐ single or multiple pregnancy

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Analysis 2.3

Comparison 2: Corticosteroids versus placebo or no treatment ‐ single or multiple pregnancy, Outcome 3: Neonatal death ‐ single or multiple pregnancy

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Analysis 2.4

Comparison 2: Corticosteroids versus placebo or no treatment ‐ single or multiple pregnancy, Outcome 4: Fetal death ‐ single or multiple pregnancy

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Analysis 2.5

Comparison 2: Corticosteroids versus placebo or no treatment ‐ single or multiple pregnancy, Outcome 5: Respiratory distress syndrome ‐ single or multiple pregnancy

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Analysis 2.6

Comparison 2: Corticosteroids versus placebo or no treatment ‐ single or multiple pregnancy, Outcome 6: IVH ‐ single or multiple pregnancy

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Analysis 2.7

Comparison 2: Corticosteroids versus placebo or no treatment ‐ single or multiple pregnancy, Outcome 7: Birthweight ‐ single or multiple pregnancy

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Analysis 3.1

Comparison 3: Corticosteroids versus placebo or no treatment ‐ intact membranes versus ruptured membranes at first dose, Outcome 1: Chorioamnionitis ‐ intact or ruptured membranes

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Analysis 3.2

Comparison 3: Corticosteroids versus placebo or no treatment ‐ intact membranes versus ruptured membranes at first dose, Outcome 2: Endometritis ‐ intact or ruptured membranes

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Analysis 3.3

Comparison 3: Corticosteroids versus placebo or no treatment ‐ intact membranes versus ruptured membranes at first dose, Outcome 3: Perinatal death ‐ intact or ruptured membranes

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Analysis 3.4

Comparison 3: Corticosteroids versus placebo or no treatment ‐ intact membranes versus ruptured membranes at first dose, Outcome 4: Neonatal deaths ‐ intact or ruptured membranes

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Analysis 3.5

Comparison 3: Corticosteroids versus placebo or no treatment ‐ intact membranes versus ruptured membranes at first dose, Outcome 5: Fetal death ‐ intact or ruptured membranes

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Analysis 3.6

Comparison 3: Corticosteroids versus placebo or no treatment ‐ intact membranes versus ruptured membranes at first dose, Outcome 6: RDS ‐ intact or ruptured membranes

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Analysis 3.7

Comparison 3: Corticosteroids versus placebo or no treatment ‐ intact membranes versus ruptured membranes at first dose, Outcome 7: IVH ‐ intact or ruptured membranes

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Analysis 3.8

Comparison 3: Corticosteroids versus placebo or no treatment ‐ intact membranes versus ruptured membranes at first dose, Outcome 8: Birthweight ‐ intact or ruptured membranes

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Analysis 4.1

Comparison 4: Corticosteroids versus placebo or no treatment ‐ hypertension syndrome versus all other trials, Outcome 1: RDS

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Analysis 4.2

Comparison 4: Corticosteroids versus placebo or no treatment ‐ hypertension syndrome versus all other trials, Outcome 2: Perinatal deaths

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Analysis 4.3

Comparison 4: Corticosteroids versus placebo or no treatment ‐ hypertension syndrome versus all other trials, Outcome 3: Fetal deaths

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Analysis 4.4

Comparison 4: Corticosteroids versus placebo or no treatment ‐ hypertension syndrome versus all other trials, Outcome 4: Neonatal deaths

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Analysis 5.1

Comparison 5: Corticosteroids versus placebo or no treatment ‐ type of steroid, Outcome 1: Chorioamnionitis ‐ type of steroid

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Analysis 5.2

Comparison 5: Corticosteroids versus placebo or no treatment ‐ type of steroid, Outcome 2: Endometritis ‐ type of steroid

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Analysis 5.3

Comparison 5: Corticosteroids versus placebo or no treatment ‐ type of steroid, Outcome 3: Perinatal death ‐ type of steroid

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Analysis 5.4

Comparison 5: Corticosteroids versus placebo or no treatment ‐ type of steroid, Outcome 4: Neonatal deaths by steroid type

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Analysis 5.5

Comparison 5: Corticosteroids versus placebo or no treatment ‐ type of steroid, Outcome 5: Fetal death ‐ type of steroid

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Analysis 5.6

Comparison 5: Corticosteroids versus placebo or no treatment ‐ type of steroid, Outcome 6: Respiratory distress syndrome ‐ type of steroid

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Analysis 5.7

Comparison 5: Corticosteroids versus placebo or no treatment ‐ type of steroid, Outcome 7: IVH ‐ type of steroid

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Analysis 5.8

Comparison 5: Corticosteroids versus placebo or no treatment ‐ type of steroid, Outcome 8: Birthweight ‐ type of steroid

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Analysis 5.9

Comparison 5: Corticosteroids versus placebo or no treatment ‐ type of steroid, Outcome 9: Moderate/severe respiratory distress syndrome ‐ type of steroid

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Analysis 5.10

Comparison 5: Corticosteroids versus placebo or no treatment ‐ type of steroid, Outcome 10: Chronic lung disease ‐ type of steroid

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Analysis 6.1

Comparison 6: Corticosteroids versus placebo or no treatment ‐ decade of trial, Outcome 1: Chorioamnionitis ‐ decade of trial

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Analysis 6.2

Comparison 6: Corticosteroids versus placebo or no treatment ‐ decade of trial, Outcome 2: Endometritis ‐ decade of trial

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Analysis 6.3

Comparison 6: Corticosteroids versus placebo or no treatment ‐ decade of trial, Outcome 3: Perinatal deaths ‐ decade of trial

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Analysis 6.4

Comparison 6: Corticosteroids versus placebo or no treatment ‐ decade of trial, Outcome 4: Neonatal deaths decade of trial

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Analysis 6.5

Comparison 6: Corticosteroids versus placebo or no treatment ‐ decade of trial, Outcome 5: Fetal death ‐ decade of trial

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Analysis 6.6

Comparison 6: Corticosteroids versus placebo or no treatment ‐ decade of trial, Outcome 6: RDS ‐ decade of trial

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Analysis 6.7

Comparison 6: Corticosteroids versus placebo or no treatment ‐ decade of trial, Outcome 7: IVH ‐ decade of trial

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Analysis 6.8

Comparison 6: Corticosteroids versus placebo or no treatment ‐ decade of trial, Outcome 8: Birthweight ‐ decade of trial

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Analysis 7.1

Comparison 7: Corticosteroids versus placebo or no treatment ‐ weekly repeats, Outcome 1: Chorioamnionitis ‐ Protocol with weekly repeats

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Analysis 7.2

Comparison 7: Corticosteroids versus placebo or no treatment ‐ weekly repeats, Outcome 2: Endometritis ‐ protocol with weekly repeats

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Analysis 7.3

Comparison 7: Corticosteroids versus placebo or no treatment ‐ weekly repeats, Outcome 3: Perinatal death ‐ protocol with weekly repeats

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Analysis 7.4

Comparison 7: Corticosteroids versus placebo or no treatment ‐ weekly repeats, Outcome 4: Neonatal death ‐ protocol with weekly repeats

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Analysis 7.5

Comparison 7: Corticosteroids versus placebo or no treatment ‐ weekly repeats, Outcome 5: Fetal death ‐ protocol with weekly repeats

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Analysis 7.6

Comparison 7: Corticosteroids versus placebo or no treatment ‐ weekly repeats, Outcome 6: RDS ‐ protocol with weekly repeats

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Analysis 7.7

Comparison 7: Corticosteroids versus placebo or no treatment ‐ weekly repeats, Outcome 7: IVH‐ protocol with weekly repeats

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Analysis 7.8

Comparison 7: Corticosteroids versus placebo or no treatment ‐ weekly repeats, Outcome 8: Birthweight ‐ protocol with weekly repeats

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Analysis 7.9

Comparison 7: Corticosteroids versus placebo or no treatment ‐ weekly repeats, Outcome 9: Moderate/severe respiratory distress syndrome

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Analysis 8.1

Comparison 8: Corticosteroids versus placebo or no treatment ‐ gestational age at trial entry, Outcome 1: Chorioamnionitis ‐ gestational age at trial entry

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Analysis 8.2

Comparison 8: Corticosteroids versus placebo or no treatment ‐ gestational age at trial entry, Outcome 2: Perinatal death ‐ gestational age at trial entry

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Analysis 8.3

Comparison 8: Corticosteroids versus placebo or no treatment ‐ gestational age at trial entry, Outcome 3: Neonatal death ‐ gestational age at trial engry

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Analysis 8.4

Comparison 8: Corticosteroids versus placebo or no treatment ‐ gestational age at trial entry, Outcome 4: Fetal death ‐ gestational age at trial entry

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Analysis 8.5

Comparison 8: Corticosteroids versus placebo or no treatment ‐ gestational age at trial entry, Outcome 5: RDS‐ gestational age at trial entry

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Analysis 8.6

Comparison 8: Corticosteroids versus placebo or no treatment ‐ gestational age at trial entry, Outcome 6: IVH ‐ gestational age at trial entry

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Analysis 8.7

Comparison 8: Corticosteroids versus placebo or no treatment ‐ gestational age at trial entry, Outcome 7: Birthweight ‐ gestational age at trial entry

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Summary of findings 1. Corticosteroids versus placebo or no treatment

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
Corticosteroids versus placebo or no treatment
Patient or population: pregnant women at high risk of preterm birth receiving a corticosteroid or placebo/no treatment; women with singleton and multiple pregnancy and intact and ruptured membranes Setting: hospital settings in high‐income countries. For example, data for RDS come from 28 trials in 15 different countries, but only one of these countries is of lower income (Tunisia) Intervention: corticosteroids (dexamethasone or betamethasone) according to various doses and regimens; some trials with weekly repeats Comparison: placebo (usually normal saline) or no treatment
Outcomes	Risk with placebo or no treatment	Risk with corticosteroids	Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
Maternal death	Study population		RR 0.98 (0.06 to 15.50)	3392 (5 RCTs)	⊕⊕⊕⊝ Moderate¹	RR based on 2 deaths in a single trial (1 death in each group). Four trials reported zero events
Maternal death	1 per 1000	1 per 1000 (0 to 9)	RR 0.98 (0.06 to 15.50)	3392 (5 RCTs)	⊕⊕⊕⊝ Moderate¹
Chorioamnionitis	Study population		RR 0.83 (0.66 to 1.06)	5546 (15 RCTs)	⊕⊕⊕⊝ Moderate²
Chorioamnionitis	48 per 1000	40 per 1000 (32 to 51)	RR 0.83 (0.66 to 1.06)	5546 (15 RCTs)	⊕⊕⊕⊝ Moderate²
Endometritis (infections)	Study population		RR 1.20 (0.87 to 1.63)	4030 (10 RCTs)	⊕⊕⊕⊝ Moderate^2,3	7 of 10 trials reported endometritis; the remaining trials report 'infections'
Endometritis (infections)	33 per 1000	39 per 1000 (27 to 59)	RR 1.20 (0.87 to 1.63)	4030 (10 RCTs)	⊕⊕⊕⊝ Moderate^2,3
Perinatal deaths	Study population		average RR 0.72 (0.58 to 0.89)	6729 (15 RCTs)	⊕⊕⊕ Moderate⁴
Perinatal deaths	102 per 1000	73 per 1000 (59 to 91)	average RR 0.72 (0.58 to 0.89)	6729 (15 RCTs)	⊕⊕⊕ Moderate⁴
Respiratory distress syndrome	Study population		average RR 0.66 (0.56 to 0.77)	7764 (28 RCTs)	⊕⊕⊕ Moderate⁵
Respiratory distress syndrome	176 per 1000	116 per 1000 (98 to 135)	average RR 0.66 (0.56 to 0.77)	7764 (28 RCTs)	⊕⊕⊕ Moderate⁵
Intraventricular haemorrhage	Study population		average RR 0.55 (0.40 to 0.76)	6093 (16 RCTs)	⊕⊕⊕ Moderate⁶
Intraventricular haemorrhage	51 per 1000	28 per 1000 (20 to 39)	average RR 0.55 (0.40 to 0.76)	6093 (16 RCTs)	⊕⊕⊕ Moderate⁶
Mean birthweight (grams) (less is worse)	Absolute risks not calculated		The mean birthweight was 18.47g less (40.83g less to 3.90g more)	6182 (16 RCTs)	⊕⊕⊕ Moderate⁷
*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). CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: 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 quality: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low quality: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
¹Few events and wide confidence interval led to a downgrade for imprecision (‐1). Because maternal death is a rare event and the total population is over 3000 women, we have opted for (‐1) rather than (‐2). ²Wide confidence interval crossing the line of no effect (‐1). ³Value of I² = 34% with random‐effects model. We have not downgraded evidence for heterogeneity. ⁴Value of I² = 37% with random‐effects model. We have not downgraded for heterogeneity. Result downgraded once for risks of bias in included trials (‐1). ⁵Value of I² = 47% with random‐effects model. We have not downgraded for heterogeneity. Result downgraded once for risks of bias in included trials (‐1). ⁶Value of I² = 33% with random‐effects model. We have not downgraded for heterogeneity. Result downgraded once for risks of bias in included trials (‐1). ⁷The confidence interval showed a difference at most on average of 40 g in weight; because this is less than 10% of the lightest average for babies in any trial, we have not downgraded evidence for imprecision. We have downgraded the result for risks of bias concerns in included trials (‐1).

Summary of findings 1. Corticosteroids versus placebo or no treatment

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Table 1. Gestational age parameters for included trials

Trial	Year	Minimum (weeks^+days)	Maximum (weeks^+days)
Amorim 1999	1999	28⁺⁰	34⁺⁶
Attawattanakul 2015	2015	34⁺⁰	36⁺⁶
Balci 2010	2010	34⁺⁰	36⁺⁶
Block 1977	1976	Not reported	36⁺⁶
Carlan 1991	1991	24⁺⁰	34⁺⁶
Cararach 1991	1994	28⁺⁰	30⁺⁶
Collaborative 1981	1981	26⁺⁰	37⁺⁰
Dexiprom 1999	1999	28⁺⁰	34⁺⁶
Doran 1980	1980	24⁺⁰	34⁺⁶
Fekih 2002	2002	26⁺⁰	34⁺⁶
Gamsu 1989	1989	Not reported	34⁺⁶
Garite 1992	1992	24⁺⁰	27⁺⁶
Goodner 1979	1979	Not reported	33⁺⁶
Gyamfi‐Bannerman 2016	2016	34⁺⁰	36⁺⁶
Kari 1994	1994	24⁺⁰	31⁺⁶
Khazardoust 2012 (no outcome data)	2012	34⁺⁰	37⁺⁰
Lewis 1996	1996	24⁺⁰	34⁺⁶
Liggins 1972b	1972	24⁺⁰	36⁺⁶
Lopez 1989	1989	27⁺⁰	35⁺⁰
Mansouri 2010	2010	35⁺⁰	36⁺⁶
Morales 1989	1989	26⁺⁰	34⁺⁶
Nelson 1985	1985	28⁺⁰	34⁺⁶
Parsons 1988	1988	25⁺⁰	32⁺⁶
Porto 2011	2011	34⁺⁰	36⁺⁶
Qublan 2001	2001	27⁺⁰	34⁺⁶
Schutte 1980	1980	26⁺⁰	32⁺⁶
Shanks 2010	2010	34⁺⁰	36⁺⁶
Silver 1996	1996	24⁺⁰	29⁺⁶
Taeusch 1979	1979	Not reported	33⁺⁶
Teramo 1980	1980	28⁺⁰	35⁺⁶

Table 1. Gestational age parameters for included trials

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Comparison 1. Corticosteroids versus placebo or no treatment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Maternal death Show forest plot	5	3392	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.06, 15.50]

1.2 Chorioamnionitis Show forest plot	15	5546	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.66, 1.06]

1.3 Endometritis Show forest plot	10	4030	Risk Ratio (M‐H, Fixed, 95% CI)	1.20 [0.87, 1.63]

1.4 Perinatal deaths Show forest plot	15	6729	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.58, 0.89]

1.5 Neonatal deaths Show forest plot	22	7188	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.59, 0.81]

1.6 Fetal deaths Show forest plot	15	6729	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.74, 1.30]

1.7 Respiratory distress syndrome Show forest plot	28	7764	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.56, 0.77]

1.8 Moderate/severe respiratory distress syndrome Show forest plot	6	1686	Risk Ratio (M‐H, Random, 95% CI)	0.59 [0.38, 0.91]

1.9 Chronic lung disease Show forest plot	6	818	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.42, 1.79]

1.10 Intraventricular haemorrhage Show forest plot	16	6093	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.40, 0.76]

1.11 Mean birthweight (g) Show forest plot	16	6182	Mean Difference (IV, Fixed, 95% CI)	‐18.47 [‐40.83, 3.90]

1.12 Death in childhood Show forest plot	4	1010	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.36, 1.27]

1.13 Neurodevelopmental delay in childhood Show forest plot	1	82	Risk Ratio (M‐H, Fixed, 95% CI)	0.64 [0.14, 2.98]

1.14 Death into adulthood Show forest plot	1	988	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.56, 1.81]

1.15 Fever in women after trial entry requiring the use of antibiotics Show forest plot	4	481	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.43, 2.06]

1.16 Intrapartum fever in woman requiring the use of antibiotics Show forest plot	2	319	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.09, 4.89]

1.17 Side effects of therapy in women Show forest plot	6	3572	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.59, 0.82]

1.18 Admission into adult intensive care unit Show forest plot	2	319	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.26, 2.05]

1.19 Hypertension Show forest plot	1	220	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.36, 2.76]

1.20 Postnatal fever in woman Show forest plot	5	1323	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.64, 1.33]

1.21 Glucose intolerance Show forest plot	1	123	Risk Ratio (M‐H, Fixed, 95% CI)	2.71 [1.14, 6.46]

1.22 Necrotising enterocolitis Show forest plot	10	4702	Risk Ratio (M‐H, Fixed, 95% CI)	0.50 [0.32, 0.78]

1.23 Systemic infection in the first 48 hours of life Show forest plot	8	1753	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.41, 0.88]

1.24 Proven infection while in the neonatal intensive care unit Show forest plot	13	5707	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.55, 1.08]

1.25 Need for mechanical ventilation/CPAP Show forest plot	9	1368	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.56, 0.84]

1.26 Mean duration of mechanical ventilation/CPAP (days) Show forest plot	3	471	Mean Difference (IV, Random, 95% CI)	‐1.91 [‐4.59, 0.76]

1.27 Mean duration of oxygen supplementation (days) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.28 Surfactant use Show forest plot	5	3556	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.51, 0.90]

1.29 Air leak syndrome Show forest plot	2	2965	Risk Ratio (M‐H, Fixed, 95% CI)	0.76 [0.32, 1.80]

1.30 Apgar < 7 at 5 minutes Show forest plot	10	2419	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.67, 0.98]

1.31 Mean interval between trial entry and birth (days) Show forest plot	3	1513	Mean Difference (IV, Fixed, 95% CI)	0.23 [‐1.86, 2.32]

1.32 Small‐for‐gestational age Show forest plot	5	3478	Risk Ratio (M‐H, Fixed, 95% CI)	1.11 [0.96, 1.28]

1.33 Mean infant HPA axis function (cortisol) Show forest plot	1	27	Mean Difference (IV, Fixed, 95% CI)	3.94 [‐3.12, 11.00]

1.33.1 In babies born < 24 hours after 1st dose	1	6	Mean Difference (IV, Fixed, 95% CI)	9.00 [‐11.93, 29.93]
1.33.2 In babies born 24‐48 hours after 1st dose	1	10	Mean Difference (IV, Fixed, 95% CI)	0.00 [‐8.68, 8.68]
1.33.3 In babies born > 48 hours after 1st dose	1	11	Mean Difference (IV, Fixed, 95% CI)	13.00 [‐1.90, 27.90]
1.34 Admission to neonatal intensive care unit Show forest plot	7	3803	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.84, 0.97]

1.35 Developmental delay in childhood Show forest plot	2	518	Risk Ratio (M‐H, Fixed, 95% CI)	0.49 [0.24, 1.00]

1.36 Cerebral palsy in childhood Show forest plot	5	904	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.34, 1.03]

1.37 Mean childhood weight (kg) Show forest plot	2	333	Mean Difference (IV, Fixed, 95% CI)	0.30 [‐0.39, 1.00]

1.37.1 Liggins	1	250	Mean Difference (IV, Fixed, 95% CI)	0.40 [‐0.32, 1.12]
1.37.2 Schutte (females)	1	39	Mean Difference (IV, Fixed, 95% CI)	‐2.40 [‐6.55, 1.75]
1.37.3 Schutte (males)	1	44	Mean Difference (IV, Fixed, 95% CI)	‐0.10 [‐3.88, 3.68]
1.38 Mean childhood height (cm) Show forest plot	2	334	Mean Difference (IV, Fixed, 95% CI)	1.02 [‐0.26, 2.29]

1.38.1 Liggins	1	250	Mean Difference (IV, Fixed, 95% CI)	1.00 [‐0.39, 2.39]
1.38.2 Schutte (females)	1	39	Mean Difference (IV, Fixed, 95% CI)	1.70 [‐3.08, 6.48]
1.38.3 Schutte (males)	1	45	Mean Difference (IV, Fixed, 95% CI)	0.60 [‐3.79, 4.99]
1.39 Mean childhood head circumference (cm) Show forest plot	2	328	Mean Difference (IV, Fixed, 95% CI)	0.27 [‐0.08, 0.63]

1.39.1 Liggins	1	250	Mean Difference (IV, Fixed, 95% CI)	0.30 [‐0.11, 0.71]
1.39.2 Schutte (females)	1	36	Mean Difference (IV, Fixed, 95% CI)	‐0.10 [‐1.05, 0.85]
1.39.3 Schutte (males)	1	42	Mean Difference (IV, Fixed, 95% CI)	0.60 [‐0.51, 1.71]
1.40 Mean childhood VC (% predicted) Show forest plot	2	150	Mean Difference (IV, Fixed, 95% CI)	‐1.68 [‐5.12, 1.75]

1.40.1 Liggins	1	75	Mean Difference (IV, Fixed, 95% CI)	0.70 [‐5.12, 6.52]
1.40.2 Schutte (females)	1	36	Mean Difference (IV, Fixed, 95% CI)	‐2.60 [‐8.65, 3.45]
1.40.3 Schutte (males)	1	39	Mean Difference (IV, Fixed, 95% CI)	‐3.30 [‐9.27, 2.67]
1.41 Mean childhood FEV1 (% predicted) Show forest plot	1	75	Mean Difference (IV, Fixed, 95% CI)	‐4.73 [‐10.13, 0.67]

1.41.1 Schutte (females)	1	36	Mean Difference (IV, Fixed, 95% CI)	‐2.50 [‐11.24, 6.24]
1.41.2 Schutte (males)	1	39	Mean Difference (IV, Fixed, 95% CI)	‐6.10 [‐12.96, 0.76]
1.42 Mean childhood FEV1/VC Show forest plot	2	150	Mean Difference (IV, Random, 95% CI)	‐0.94 [‐3.63, 1.76]

1.42.1 Liggins	1	75	Mean Difference (IV, Random, 95% CI)	1.00 [‐2.57, 4.57]
1.42.2 Schutte (females)	1	36	Mean Difference (IV, Random, 95% CI)	0.00 [‐5.56, 5.56]
1.42.3 Schutte (males)	1	39	Mean Difference (IV, Random, 95% CI)	‐3.00 [‐6.14, 0.14]
1.43 Mean childhood systolic blood pressure (mmHg) Show forest plot	1	223	Mean Difference (IV, Fixed, 95% CI)	‐1.60 [‐4.06, 0.86]

1.44 Visual impairment in childhood Show forest plot	2	166	Risk Ratio (M‐H, Fixed, 95% CI)	0.55 [0.24, 1.23]

1.45 Hearing impairment in childhood Show forest plot	2	166	Risk Ratio (M‐H, Fixed, 95% CI)	0.64 [0.04, 9.87]

1.46 Intellectual impairment in childhood Show forest plot	3	778	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.44, 1.69]

1.47 Behavioural/learning difficulties in childhood Show forest plot	1	90	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.35, 2.09]

1.48 Mean adult insulin (log values) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.48.1 Fasting	1	435	Mean Difference (IV, Fixed, 95% CI)	0.08 [‐0.03, 0.19]
1.48.2 30 minutes following a 75 g oral glucose tolerance test	1	412	Mean Difference (IV, Fixed, 95% CI)	0.16 [0.04, 0.28]
1.48.3 120 minutes following a 75 g oral glucose tolerance test	1	428	Mean Difference (IV, Fixed, 95% CI)	‐0.10 [‐0.27, 0.07]
1.49 Mean adult glucose (mmol/L) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.49.1 Fasting	1	432	Mean Difference (IV, Fixed, 95% CI)	0.01 [‐0.09, 0.11]
1.49.2 30 minutes following a 75 g oral glucose tolerance test	1	413	Mean Difference (IV, Fixed, 95% CI)	0.19 [‐0.14, 0.52]
1.49.3 120 minutes following a 75 g oral glucose tolerance test	1	410	Mean Difference (IV, Fixed, 95% CI)	‐0.27 [‐0.52, ‐0.02]
1.50 Mean adult weight (kg) Show forest plot	2	538	Mean Difference (IV, Random, 95% CI)	‐0.83 [‐6.41, 4.76]

1.50.1 Schutte (females)	1	37	Mean Difference (IV, Random, 95% CI)	‐6.00 [‐12.93, 0.93]
1.50.2 Schutte (males)	1	43	Mean Difference (IV, Random, 95% CI)	‐1.00 [‐9.91, 7.91]
1.50.3 Liggins	1	458	Mean Difference (IV, Random, 95% CI)	2.57 [‐0.72, 5.86]
1.51 Mean adult height (cm) Show forest plot	2	537	Mean Difference (IV, Fixed, 95% CI)	0.91 [‐0.28, 2.10]

1.51.1 Schutte (females)	1	36	Mean Difference (IV, Fixed, 95% CI)	‐1.00 [‐5.37, 3.37]
1.51.2 Schutte (males)	1	43	Mean Difference (IV, Fixed, 95% CI)	3.00 [‐2.30, 8.30]
1.51.3 Liggins (females)	1	234	Mean Difference (IV, Fixed, 95% CI)	1.17 [‐0.65, 2.99]
1.51.4 Liggins (males)	1	224	Mean Difference (IV, Fixed, 95% CI)	0.75 [‐1.03, 2.53]
1.52 Mean adult head circumference (cm) Show forest plot	2	537	Mean Difference (IV, Fixed, 95% CI)	0.03 [‐0.33, 0.38]

1.52.1 Schutte (females)	1	37	Mean Difference (IV, Fixed, 95% CI)	0.00 [‐1.03, 1.03]
1.52.2 Schutte (males)	1	42	Mean Difference (IV, Fixed, 95% CI)	‐0.20 [‐1.37, 0.97]
1.52.3 Liggins	1	458	Mean Difference (IV, Fixed, 95% CI)	0.06 [‐0.34, 0.46]
1.53 Mean adult skinfold thickness (log values) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.53.1 Triceps	1	456	Mean Difference (IV, Fixed, 95% CI)	‐0.02 [‐0.11, 0.07]
1.53.2 Biceps	1	456	Mean Difference (IV, Fixed, 95% CI)	‐0.01 [‐0.11, 0.09]
1.53.3 Subscapular	1	441	Mean Difference (IV, Fixed, 95% CI)	0.01 [‐0.08, 0.10]
1.53.4 Suprailiac	1	452	Mean Difference (IV, Fixed, 95% CI)	‐0.01 [‐0.12, 0.10]
1.54 Mean adult systolic blood pressure (mmHg) Show forest plot	2	545	Mean Difference (IV, Random, 95% CI)	‐1.53 [‐4.50, 1.44]

1.54.1 Schutte (females)	1	38	Mean Difference (IV, Random, 95% CI)	‐4.00 [‐9.12, 1.12]
1.54.2 Schutte (males)	1	52	Mean Difference (IV, Random, 95% CI)	‐3.00 [‐7.17, 1.17]
1.54.3 Liggins	1	455	Mean Difference (IV, Random, 95% CI)	0.55 [‐1.88, 2.98]
1.55 Mean adult HPA axis function (mean log fasting cortisol) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.56 Mean cholesterol in adulthood (mmol/L) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.57 Mean age at puberty (years) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.57.1 Schutte (females)	1	38	Mean Difference (IV, Fixed, 95% CI)	0.00 [‐0.94, 0.94]
1.58 Educational achievement by adulthood (university or polytechnic education) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.59 Visual impairment in adulthood Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.60 Hearing impairment in adulthood Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.61 Intellectual impairment in adulthood Show forest plot	2	273	Risk Ratio (M‐H, Fixed, 95% CI)	0.24 [0.01, 4.95]

1.62 Mean adult FVC (% predicted) Show forest plot	1	383	Mean Difference (IV, Fixed, 95% CI)	‐0.70 [‐3.16, 1.76]

1.63 Mean adult FEV1 (% predicted) Show forest plot	1	383	Mean Difference (IV, Fixed, 95% CI)	0.40 [‐2.31, 3.11]

1.64 Mean adult FEV1/FVC Show forest plot	1	383	Mean Difference (IV, Fixed, 95% CI)	0.01 [‐0.01, 0.03]

1.65 Mean adult PEF Show forest plot	1	383	Mean Difference (IV, Fixed, 95% CI)	2.20 [‐0.77, 5.17]

1.66 Mean adult F50 Show forest plot	1	383	Mean Difference (IV, Fixed, 95% CI)	3.00 [‐1.57, 7.57]

1.67 Mean adult F25 Show forest plot	1	383	Mean Difference (IV, Fixed, 95% CI)	0.40 [‐3.82, 4.62]

1.68 Mean adult FEF 25%‐75% Show forest plot	1	383	Mean Difference (IV, Fixed, 95% CI)	2.20 [‐2.10, 6.50]

1.69 FEV1/FVC < 70% Show forest plot	1	383	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.49, 1.57]

1.70 Asthma diagnosed by Doctor in lifetime Show forest plot	1	534	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.74, 1.30]

1.71 Wheezing in last 12 months Show forest plot	1	534	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.84, 1.35]

1.72 Current Asthma Show forest plot	1	534	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.74, 1.48]

1.73 Further respiratory diagnosis (includes pneumonia, upper airway conditions and bronchitis) Show forest plot	1	534	Risk Ratio (M‐H, Fixed, 95% CI)	1.33 [0.69, 2.59]

1.74 Spontaneous pneumothorax Show forest plot	1	534	Risk Ratio (M‐H, Fixed, 95% CI)	1.11 [0.07, 17.66]

1.75 Shortness of breath at anytime in the last 12 months Show forest plot	1	534	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.80, 1.31]

1.76 Mean adult lumbar spine aBMD (g/cm2) areal bone mineral density Show forest plot	1	174	Mean Difference (IV, Fixed, 95% CI)	0.00 [‐0.04, 0.04]

1.77 Mean adult lumbar spine vBMD (g/cm3) volumetric bone mineral density Show forest plot	1	174	Mean Difference (IV, Fixed, 95% CI)	0.00 [‐0.01, 0.01]

1.78 Mean adult total body BMC (grams) bone mineral content Show forest plot	1	174	Mean Difference (IV, Fixed, 95% CI)	18.00 [‐151.30, 187.30]

1.79 Mean adult total body aBMD (g/cm3) areal bone mineral density Show forest plot	1	174	Mean Difference (IV, Fixed, 95% CI)	0.00 [‐0.03, 0.03]

1.80 Mean adult femoral neck aBMD (g/cm2) areal bone mineral density Show forest plot	1	174	Mean Difference (IV, Fixed, 95% CI)	0.02 [‐0.03, 0.07]

1.81 Mean adult femoral trochanter aBMD (g/cm2) areal bone mineral density Show forest plot	1	174	Mean Difference (IV, Fixed, 95% CI)	0.02 [‐0.02, 0.06]

1.82 Mean adult femoral shaft aBMD (g/cm2) areal bone mineral density Show forest plot	1	174	Mean Difference (IV, Fixed, 95% CI)	0.01 [‐0.04, 0.06]

1.83 Mean total proximal femur aBMD (g/cm2) areal bone mineral density Show forest plot	1	174	Mean Difference (IV, Fixed, 95% CI)	0.02 [‐0.03, 0.07]

1.84 Mean length of antenatal hospitalisation (days) Show forest plot	1	218	Mean Difference (IV, Fixed, 95% CI)	0.50 [‐1.40, 2.40]

1.85 Mean length of postnatal hospitalisation (days) Show forest plot	1	218	Mean Difference (IV, Fixed, 95% CI)	0.00 [‐1.72, 1.72]

1.86 Mean length of neonatal hospitalisation (days) Show forest plot	5	788	Mean Difference (IV, Fixed, 95% CI)	0.18 [‐0.51, 0.87]

Comparison 1. Corticosteroids versus placebo or no treatment

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Comparison 2. Corticosteroids versus placebo or no treatment ‐ single or multiple pregnancy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Chorioamnionitis ‐ single or multiple pregnancy Show forest plot	15	5546	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.66, 1.06]

2.1.1 In women delivering singleton pregnancies	7	4682	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.56, 1.01]
2.1.2 In women delivering multiple pregnancies	1	74	Risk Ratio (M‐H, Fixed, 95% CI)	0.42 [0.04, 4.49]
2.1.3 Mixed population	8	790	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.70, 1.57]
2.2 Perinatal death ‐ single or multiple pregnancy Show forest plot	15	6729	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.59, 0.89]

2.2.1 In babies born from singleton pregnancies	6	5182	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.54, 1.05]
2.2.2 In babies born from multiple pregnancies	2	252	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.37, 1.47]
2.2.3 Mixed population	9	1295	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.49, 0.94]
2.3 Neonatal death ‐ single or multiple pregnancy Show forest plot	22	7188	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.59, 0.81]

2.3.1 In babies born from singleton pregnancies	9	5335	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.61, 0.92]
2.3.2 In babies born from multiple pregnancies	2	236	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.39, 1.61]
2.3.3 Mixed population	13	1617	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.46, 0.78]
2.4 Fetal death ‐ single or multiple pregnancy Show forest plot	15	6729	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.73, 1.29]

2.4.1 In babies born from singleton pregnancies	6	5182	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.75, 1.45]
2.4.2 In babies born from multiple pregnancies	2	252	Risk Ratio (M‐H, Fixed, 95% CI)	0.53 [0.20, 1.40]
2.4.3 Mixed population	9	1295	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.50, 1.99]
2.5 Respiratory distress syndrome ‐ single or multiple pregnancy Show forest plot	28	7762	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.59, 0.78]

2.5.1 In babies born from singleton pregnancies	15	6081	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.50, 0.77]
2.5.2 In babies born from multiple pregnancies	4	320	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.67, 1.22]
2.5.3 Mixed population	13	1361	Risk Ratio (M‐H, Random, 95% CI)	0.69 [0.53, 0.89]
2.6 IVH ‐ single or multiple pregnancy Show forest plot	16	6093	Risk Ratio (M‐H, Fixed, 95% CI)	0.56 [0.44, 0.70]

2.6.1 In babies born from singleton pregnancies	8	4782	Risk Ratio (M‐H, Fixed, 95% CI)	0.52 [0.36, 0.75]
2.6.2 In babies born from multiple pregnancies	1	137	Risk Ratio (M‐H, Fixed, 95% CI)	0.39 [0.07, 2.06]
2.6.3 Mixed population	8	1174	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.44, 0.81]
2.7 Birthweight ‐ single or multiple pregnancy Show forest plot	16	6182	Mean Difference (IV, Fixed, 95% CI)	‐17.61 [‐39.95, 4.74]

2.7.1 In babies born from singleton pregnancy	9	4948	Mean Difference (IV, Fixed, 95% CI)	‐24.12 [‐48.27, 0.03]
2.7.2 In babies born from multiple pregnancies	1	150	Mean Difference (IV, Fixed, 95% CI)	82.36 [‐146.23, 310.95]
2.7.3 Mixed population	7	1084	Mean Difference (IV, Fixed, 95% CI)	16.77 [‐44.16, 77.69]

Comparison 2. Corticosteroids versus placebo or no treatment ‐ single or multiple pregnancy

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Comparison 3. Corticosteroids versus placebo or no treatment ‐ intact membranes versus ruptured membranes at first dose

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Chorioamnionitis ‐ intact or ruptured membranes Show forest plot	15	5517	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.67, 1.07]

3.1.1 In women with intact membranes at 1st dose	5	1437	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.50, 1.40]
3.1.2 In women with ruptured membranes at 1st dose	7	959	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.69, 1.40]
3.1.3 Not reported or mixed population	4	3121	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.47, 1.06]
3.2 Endometritis ‐ intact or ruptured membranes Show forest plot	10	4030	Risk Ratio (M‐H, Random, 95% CI)	1.20 [0.80, 1.80]

3.2.1 In women with intact membranes at 1st dose	2	289	Risk Ratio (M‐H, Random, 95% CI)	1.21 [0.37, 4.01]
3.2.2 In women with ruptured membranes at 1st dose	4	477	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.35, 2.97]
3.2.3 Not reported or mixed population	5	3264	Risk Ratio (M‐H, Random, 95% CI)	1.31 [0.81, 2.13]
3.3 Perinatal death ‐ intact or ruptured membranes Show forest plot	15	6700	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.60, 0.90]

3.3.1 In babies born from pregnancies with intact membranes at 1st dose	4	1332	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.70, 1.08]
3.3.2 In babies born from pregnancies with ruptured membranes at 1st dose	4	733	Risk Ratio (M‐H, Random, 95% CI)	0.59 [0.39, 0.90]
3.3.3 Not reported or mixed population	8	4635	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.49, 1.03]
3.4 Neonatal deaths ‐ intact or ruptured membranes Show forest plot	22	7163	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.59, 0.81]

3.4.1 In babies born from pregnancies with intact membranes at 1st dose	4	1236	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.58, 1.03]
3.4.2 In babies born from pregnancies with ruptured membranes at 1st dose	8	1024	Risk Ratio (M‐H, Fixed, 95% CI)	0.61 [0.46, 0.83]
3.4.3 Not reported or mixed population	11	4903	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.53, 0.88]
3.5 Fetal death ‐ intact or ruptured membranes Show forest plot	15	6634	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.71, 1.26]

3.5.1 In babies born from pregnancies with intact membranes at 1st dose	4	1332	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.73, 1.64]
3.5.2 In babies born from pregnancies with ruptured membranes at 1st dose	5	790	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.46, 1.61]
3.5.3 Not reported or mixed population	7	4512	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.44, 1.35]
3.6 RDS ‐ intact or ruptured membranes Show forest plot	28	7738	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.56, 0.76]

3.6.1 In babies born from pregnancies with intact membranes at 1st dose	6	1721	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.50, 0.80]
3.6.2 In babies born from pregnancies with ruptured membranes at 1st dose	12	1129	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.55, 0.90]
3.6.3 Not reported or mixed population	14	4888	Risk Ratio (M‐H, Random, 95% CI)	0.61 [0.46, 0.81]
3.7 IVH ‐ intact or ruptured membranes Show forest plot	15	5868	Risk Ratio (M‐H, Fixed, 95% CI)	0.56 [0.44, 0.70]

3.7.1 In babies born from pregnancies with intact membranes at 1st dose	5	1394	Risk Ratio (M‐H, Fixed, 95% CI)	0.50 [0.35, 0.72]
3.7.2 In babies born from pregnancies with ruptured membranes at 1st dose	5	895	Risk Ratio (M‐H, Fixed, 95% CI)	0.47 [0.28, 0.79]
3.7.3 Not reported or mixed population	6	3579	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.49, 1.07]
3.8 Birthweight ‐ intact or ruptured membranes Show forest plot	16	6153	Mean Difference (IV, Fixed, 95% CI)	‐19.52 [‐41.81, 2.78]

3.8.1 In babies born from pregnancies with intact membranes at 1st dose	4	1301	Mean Difference (IV, Fixed, 95% CI)	‐30.27 [‐100.43, 39.89]
3.8.2 In babies born from pregnancies with ruptured membranes at 1st dose	5	835	Mean Difference (IV, Fixed, 95% CI)	‐49.72 [‐113.91, 14.46]
3.8.3 Not reported or mixed population	8	4017	Mean Difference (IV, Fixed, 95% CI)	‐13.44 [‐38.71, 11.83]

Comparison 3. Corticosteroids versus placebo or no treatment ‐ intact membranes versus ruptured membranes at first dose

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Comparison 4. Corticosteroids versus placebo or no treatment ‐ hypertension syndrome versus all other trials

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 RDS Show forest plot	28	7764	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.60, 0.74]

4.1.1 Hypertension syndrome	5	382	Risk Ratio (M‐H, Fixed, 95% CI)	0.50 [0.35, 0.72]
4.1.2 No hypertension syndrome or hypertension syndromes excluded	9	2660	Risk Ratio (M‐H, Fixed, 95% CI)	0.58 [0.47, 0.71]
4.1.3 Hypertension not reported separately	18	4722	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.66, 0.85]
4.2 Perinatal deaths Show forest plot	15	6729	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.60, 0.92]

4.2.1 Hypertension syndrome	2	313	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.42, 2.10]
4.2.2 No hypertension syndrome or hypertension syndromes excluded	3	1394	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.39, 1.29]
4.2.3 Hypertension not reported separately	11	5022	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.52, 0.93]
4.3 Fetal deaths Show forest plot	15	6729	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.74, 1.30]

4.3.1 Women with hypertension syndrome	3	331	Risk Ratio (M‐H, Fixed, 95% CI)	1.73 [0.91, 3.28]
4.3.2 No hypertension syndrome or hypertension syndromes excluded	4	1644	Risk Ratio (M‐H, Fixed, 95% CI)	0.73 [0.49, 1.08]
4.3.3 Hypertension not reported separately	10	4754	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.67, 1.98]
4.4 Neonatal deaths Show forest plot	22	7188	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.59, 0.81]

4.4.1 Hypertension syndrome	2	278	Risk Ratio (M‐H, Fixed, 95% CI)	0.50 [0.29, 0.87]
4.4.2 No hypertension syndrome or hypertension syndromes excluded	3	1306	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.61, 1.09]
4.4.3 Hypertension not reported separately	18	5604	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.54, 0.82]

Comparison 4. Corticosteroids versus placebo or no treatment ‐ hypertension syndrome versus all other trials

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Comparison 5. Corticosteroids versus placebo or no treatment ‐ type of steroid

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Chorioamnionitis ‐ type of steroid Show forest plot	15	5546	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.66, 1.06]

5.1.1 In women treated with dexamethasone	5	769	Risk Ratio (M‐H, Fixed, 95% CI)	1.35 [0.89, 2.05]
5.1.2 In women treated with betamethasone	10	4777	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.50, 0.90]
5.2 Endometritis ‐ type of steroid Show forest plot	10	4030	Risk Ratio (M‐H, Random, 95% CI)	1.20 [0.81, 1.80]

5.2.1 In women treated with dexamethasone	4	536	Risk Ratio (M‐H, Random, 95% CI)	1.71 [0.86, 3.43]
5.2.2 In women treated with betamethasone	6	3494	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.63, 1.45]
5.3 Perinatal death ‐ type of steroid Show forest plot	15	6729	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.58, 0.89]

5.3.1 In babies treated with dexamethasone	5	1420	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.46, 1.11]
5.3.2 In babies treated with betamethasone	10	5309	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.56, 0.94]
5.4 Neonatal deaths by steroid type Show forest plot	22	7188	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.59, 0.81]

5.4.1 In babies treated with dexamethasone	6	1468	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.55, 0.94]
5.4.2 In babies treated with betamethasone	16	5720	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.55, 0.83]
5.5 Fetal death ‐ type of steroid Show forest plot	15	6729	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.74, 1.30]

5.5.1 In babies treated with dexamethasone	5	1420	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.48, 1.60]
5.5.2 In babies treated with betamethasone	10	5309	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.73, 1.39]
5.6 Respiratory distress syndrome ‐ type of steroid Show forest plot	28	7764	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.56, 0.77]

5.6.1 In babies treated with dexamethasone	7	1651	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.61, 0.98]
5.6.2 In babies treated with betamethasone	20	6095	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.50, 0.73]
5.6.3 Steroid type not reported	1	18	Risk Ratio (M‐H, Random, 95% CI)	1.62 [0.08, 34.66]
5.7 IVH ‐ type of steroid Show forest plot	16	6093	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.40, 0.76]

5.7.1 In babies treated with dexamethasone	6	897	Risk Ratio (M‐H, Random, 95% CI)	0.48 [0.18, 1.26]
5.7.2 In babies treated with betamethasone	10	5196	Risk Ratio (M‐H, Random, 95% CI)	0.53 [0.40, 0.72]
5.8 Birthweight ‐ type of steroid Show forest plot	16	6182	Mean Difference (IV, Fixed, 95% CI)	‐18.47 [‐40.83, 3.90]

5.8.1 In babies treated with dexamethasone	4	686	Mean Difference (IV, Fixed, 95% CI)	‐17.04 [‐75.48, 41.41]
5.8.2 In babies treated with betamethasone	12	5496	Mean Difference (IV, Fixed, 95% CI)	‐18.71 [‐42.92, 5.50]
5.9 Moderate/severe respiratory distress syndrome ‐ type of steroid Show forest plot	6	1686	Risk Ratio (M‐H, Random, 95% CI)	0.59 [0.38, 0.91]

5.9.1 Dexamethasone	2	219	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.46, 1.44]
5.9.2 Betamethasone	4	1467	Risk Ratio (M‐H, Random, 95% CI)	0.49 [0.27, 0.90]
5.10 Chronic lung disease ‐ type of steroid Show forest plot	6	818	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.42, 1.79]

5.10.1 Dexamethasone	2	219	Risk Ratio (M‐H, Random, 95% CI)	1.17 [0.72, 1.90]
5.10.2 Betamethasone	4	599	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.26, 2.28]

Comparison 5. Corticosteroids versus placebo or no treatment ‐ type of steroid

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Comparison 6. Corticosteroids versus placebo or no treatment ‐ decade of trial

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Chorioamnionitis ‐ decade of trial Show forest plot	15	5546	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.66, 1.06]

6.1.1 In women from trials conducted in 1970s	2	1237	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.46, 1.17]
6.1.2 In women from trials conducted in 1980s	3	276	Risk Ratio (M‐H, Fixed, 95% CI)	0.50 [0.25, 1.01]
6.1.3 In women from trials conducted in 1990s	6	755	Risk Ratio (M‐H, Fixed, 95% CI)	1.18 [0.80, 1.74]
6.1.4 in women from trials conducted in the 2000's	2	257	Risk Ratio (M‐H, Fixed, 95% CI)	2.02 [0.59, 6.95]
6.1.5 In trials from 2010s	2	3021	Risk Ratio (M‐H, Fixed, 95% CI)	0.61 [0.35, 1.07]
6.2 Endometritis ‐ decade of trial Show forest plot	10	4030	Risk Ratio (M‐H, Fixed, 95% CI)	1.20 [0.87, 1.63]

6.2.1 In women from trials conducted in 1970s	2	219	Risk Ratio (M‐H, Fixed, 95% CI)	1.86 [0.81, 4.27]
6.2.2 In women from trials conducted in 1980s	1	71	Risk Ratio (M‐H, Fixed, 95% CI)	2.30 [0.88, 6.06]
6.2.3 In women from trials conducted in 1990s	4	574	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.53, 1.44]
6.2.4 In women from trials conducted in the 2000's	3	3166	Risk Ratio (M‐H, Fixed, 95% CI)	1.18 [0.69, 2.01]
6.3 Perinatal deaths ‐ decade of trial Show forest plot	15	6729	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.58, 0.89]

6.3.1 In babies from trials conducted in 1970s	6	1994	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.50, 1.00]
6.3.2 In babies from trials conducted in 1980s	3	879	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.74, 1.42]
6.3.3 In babies from trials conducted in 1990s	3	615	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.43, 0.93]
6.3.4 in babies from trials conducted in 2000's	2	414	Risk Ratio (M‐H, Random, 95% CI)	0.47 [0.31, 0.70]
6.3.5 In trials conducted in 2010s	1	2827	Risk Ratio (M‐H, Random, 95% CI)	4.91 [0.24, 102.09]
6.4 Neonatal deaths decade of trial Show forest plot	22	7188	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.59, 0.81]

6.4.1 In babies from trials conducted in 1970s	7	1968	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.56, 0.92]
6.4.2 In babies from trials conducted in 1980s	6	1096	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.70, 1.37]
6.4.3 In babies from trials conducted in 1990s	5	758	Risk Ratio (M‐H, Fixed, 95% CI)	0.55 [0.36, 0.84]
6.4.4 In babies from trials conducted in 2000s	3	539	Risk Ratio (M‐H, Fixed, 95% CI)	0.44 [0.31, 0.64]
6.4.5 In trials conducted in 2010s	1	2827	Risk Ratio (M‐H, Fixed, 95% CI)	4.91 [0.24, 102.09]
6.5 Fetal death ‐ decade of trial Show forest plot	15	6729	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.74, 1.30]

6.5.1 In babies from trials conducted in 1970s	6	1994	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.67, 1.34]
6.5.2 In babies from trials conducted in 1980s	3	879	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.52, 2.00]
6.5.3 In babies from trials conducted in 1990s	3	615	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [0.49, 2.36]
6.5.4 In babies from trials conducted in 2000's	2	414	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.19, 4.50]
6.5.5 In trials conducted in 2010s	1	2827	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
6.6 RDS ‐ decade of trial Show forest plot	28	7764	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.60, 0.74]

6.6.1 In babies from trials conducted in 1970s	7	1939	Risk Ratio (M‐H, Fixed, 95% CI)	0.54 [0.43, 0.69]
6.6.2 In babies from trials conducted in 1980s	7	1167	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.59, 0.88]
6.6.3 In babies from trials conducted in 1990s	7	798	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.65, 0.91]
6.6.4 In babies from trials conducted in 2000s	5	839	Risk Ratio (M‐H, Fixed, 95% CI)	0.39 [0.26, 0.59]
6.6.5 In trials from 2010s	2	3021	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.61, 1.04]
6.7 IVH ‐ decade of trial Show forest plot	16	6093	Risk Ratio (M‐H, Fixed, 95% CI)	0.56 [0.44, 0.70]

6.7.1 In babies from trials conducted in 1970s	4	1646	Risk Ratio (M‐H, Fixed, 95% CI)	0.50 [0.29, 0.85]
6.7.2 In babies from trials conducted in 1980s	2	238	Risk Ratio (M‐H, Fixed, 95% CI)	0.61 [0.39, 0.94]
6.7.3 In babies from trials conducted in 1990s	5	722	Risk Ratio (M‐H, Fixed, 95% CI)	0.61 [0.42, 0.87]
6.7.4 In babies from trials conducted in 2000s	3	466	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.15, 0.73]
6.7.5 In trials from 2010s	2	3021	Risk Ratio (M‐H, Fixed, 95% CI)	4.91 [0.24, 102.09]
6.8 Birthweight ‐ decade of trial Show forest plot	16	6182	Mean Difference (IV, Fixed, 95% CI)	‐18.47 [‐40.83, 3.90]

6.8.1 In babies from trials conducted in 1970s	4	1739	Mean Difference (IV, Fixed, 95% CI)	‐9.54 [‐83.55, 64.47]
6.8.2 In babies from trials conducted in 1980s	3	280	Mean Difference (IV, Fixed, 95% CI)	‐19.60 [‐108.55, 69.35]
6.8.3 In babies from trials conducted in 1990s	4	569	Mean Difference (IV, Fixed, 95% CI)	‐33.13 [‐102.39, 36.13]
6.8.4 In babies from trials conducted in 2000s	3	573	Mean Difference (IV, Fixed, 95% CI)	‐20.77 [‐61.95, 20.41]
6.8.5 In trials in 2010s	2	3021	Mean Difference (IV, Fixed, 95% CI)	‐15.18 [‐48.66, 18.29]

Comparison 6. Corticosteroids versus placebo or no treatment ‐ decade of trial

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Comparison 7. Corticosteroids versus placebo or no treatment ‐ weekly repeats

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Chorioamnionitis ‐ Protocol with weekly repeats Show forest plot	15	5546	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.66, 1.06]

7.1.1 In women treated with single courses only	7	4659	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.61, 1.11]
7.1.2 In women treated with courses including weekly repeats	8	887	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.57, 1.25]
7.2 Endometritis ‐ protocol with weekly repeats Show forest plot	10	4030	Risk Ratio (M‐H, Random, 95% CI)	1.20 [0.81, 1.80]

7.2.1 In women treated with single courses only	5	3450	Risk Ratio (M‐H, Random, 95% CI)	1.04 [0.66, 1.64]
7.2.2 In women treated with courses including weekly repeats	5	580	Risk Ratio (M‐H, Random, 95% CI)	1.46 [0.72, 2.95]
7.3 Perinatal death ‐ protocol with weekly repeats Show forest plot	15	6729	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.58, 0.89]

7.3.1 In babies treated with single course only	11	6250	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.61, 0.99]
7.3.2 In babies treated with courses including weekly repeats	4	479	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.44, 0.97]
7.4 Neonatal death ‐ protocol with weekly repeats Show forest plot	22	7188	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.59, 0.81]

7.4.1 In babies treated with single course only	14	6266	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.63, 0.95]
7.4.2 In babies treated with courses including weekly repeats	8	922	Risk Ratio (M‐H, Fixed, 95% CI)	0.55 [0.43, 0.72]
7.5 Fetal death ‐ protocol with weekly repeats Show forest plot	15	6729	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.74, 1.30]

7.5.1 In babies treated with single course only	11	6250	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.68, 1.25]
7.5.2 In babies treated with courses including weekly repeats	4	479	Risk Ratio (M‐H, Fixed, 95% CI)	1.36 [0.64, 2.87]
7.6 RDS ‐ protocol with weekly repeats Show forest plot	28	7764	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.60, 0.74]

7.6.1 In babies treated with single course only	19	6818	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.61, 0.79]
7.6.2 In babies treated with courses including weekly repeats	9	946	Risk Ratio (M‐H, Fixed, 95% CI)	0.61 [0.52, 0.72]
7.7 IVH‐ protocol with weekly repeats Show forest plot	16	6093	Risk Ratio (M‐H, Fixed, 95% CI)	0.56 [0.44, 0.70]

7.7.1 In babies treated with single course only	9	5216	Risk Ratio (M‐H, Fixed, 95% CI)	0.50 [0.33, 0.76]
7.7.2 In babies treated with courses including weekly repeats	7	877	Risk Ratio (M‐H, Fixed, 95% CI)	0.59 [0.45, 0.78]
7.8 Birthweight ‐ protocol with weekly repeats Show forest plot	16	6182	Mean Difference (IV, Fixed, 95% CI)	‐18.47 [‐40.83, 3.90]

7.8.1 In babies treated with single course only	12	5773	Mean Difference (IV, Fixed, 95% CI)	‐18.24 [‐42.12, 5.65]
7.8.2 In babies treated with courses including weekly repeats	4	409	Mean Difference (IV, Fixed, 95% CI)	‐20.10 [‐83.79, 43.60]
7.9 Moderate/severe respiratory distress syndrome Show forest plot	6	1686	Risk Ratio (M‐H, Random, 95% CI)	0.59 [0.38, 0.91]

7.9.1 Single course	3	1259	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.44, 0.83]
7.9.2 Weekly repeats	3	427	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.13, 1.32]

Comparison 7. Corticosteroids versus placebo or no treatment ‐ weekly repeats

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Comparison 8. Corticosteroids versus placebo or no treatment ‐ gestational age at trial entry

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
8.1 Chorioamnionitis ‐ gestational age at trial entry Show forest plot	15	5506	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.65, 1.05]

8.1.1 Less than or equal to 35 weeks + 0 days	13	2304	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.70, 1.19]
8.1.2 Greater than or equal to 34 weeks + 0 days	3	3202	Risk Ratio (M‐H, Fixed, 95% CI)	0.57 [0.33, 0.99]
8.2 Perinatal death ‐ gestational age at trial entry Show forest plot	15	6687	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.59, 0.88]

8.2.1 Less than or equal to 35 weeks + 0 days	13	3391	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.58, 0.87]
8.2.2 Greater than or equal to 34 weeks + 0 days	3	3296	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.29, 3.67]
8.3 Neonatal death ‐ gestational age at trial engry Show forest plot	22	7146	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.57, 0.79]

8.3.1 Less than or equal to 35 weeks + 0 days	20	3855	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.57, 0.79]
8.3.2 Greater than or equal to 34 weeks + 0 days	3	3291	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.22, 3.07]
8.4 Fetal death ‐ gestational age at trial entry Show forest plot	15	6687	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.72, 1.27]

8.4.1 Less than or equal to 35 weeks + 0 days	13	3391	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.71, 1.25]
8.4.2 Greater than or equal to 34 weeks + 0 days	3	3296	Risk Ratio (M‐H, Fixed, 95% CI)	1.62 [0.28, 9.37]
8.5 RDS‐ gestational age at trial entry Show forest plot	28	7722	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.60, 0.73]

8.5.1 Less than or equal to 35 weeks + 0 days	23	3939	Risk Ratio (M‐H, Fixed, 95% CI)	0.65 [0.58, 0.73]
8.5.2 Greater than or equal to 34 weeks + 0 days	6	3783	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.56, 0.91]
8.6 IVH ‐ gestational age at trial entry Show forest plot	16	6051	Risk Ratio (M‐H, Fixed, 95% CI)	0.55 [0.44, 0.70]

8.6.1 Less than or equal to 35 weeks + 0 days	13	2639	Risk Ratio (M‐H, Fixed, 95% CI)	0.54 [0.42, 0.68]
8.6.2 Greater than or equal to 34 weeks + 0 days	4	3412	Risk Ratio (M‐H, Fixed, 95% CI)	4.91 [0.24, 102.09]
8.7 Birthweight ‐ gestational age at trial entry Show forest plot	16	6140	Mean Difference (IV, Fixed, 95% CI)	‐17.45 [‐39.76, 4.86]

8.7.1 Less than or equal to 35 weeks + 0 days	11	2352	Mean Difference (IV, Fixed, 95% CI)	‐17.89 [‐63.14, 27.36]
8.7.2 Greater than or equal to 34 weeks + 0 days	6	3788	Mean Difference (IV, Fixed, 95% CI)	‐17.31 [‐42.96, 8.34]

Comparison 8. Corticosteroids versus placebo or no treatment ‐ gestational age at trial entry

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Corticosteroides prenatales para acelerar la maduración del pulmón fetal en mujeres con riesgo de parto prematuro

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