Cochrane Database of Systematic Reviews (Reviews) || Early (< 8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants

Early (< 8 days) postnatal corticosteroids for preventing

chronic lung disease in preterm infants (Review)

Halliday HL, Ehrenkranz RA, Doyle LW

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library

2010, Issue 1

http://www.thecochranelibrary.com

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

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

15DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

16AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

17REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

21CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

38DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Mortality, Outcome 1 Neonatal mortality (up to 28 days). . . . . . . . . . . . 42

Analysis 1.2. Comparison 1 Mortality, Outcome 2 Mortality to hospital discharge. . . . . . . . . . . . . 44

Analysis 1.3. Comparison 1 Mortality, Outcome 3 Mortality at latest reported age. . . . . . . . . . . . . 46

Analysis 2.1. Comparison 2 Chronic lung disease (CLD)/bronchopulmonary dysplasia (BPD), Outcome 1 CLD (28

days). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

Analysis 2.2. Comparison 2 Chronic lung disease (CLD)/bronchopulmonary dysplasia (BPD), Outcome 2 CLD (36

weeks). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

Analysis 2.3. Comparison 2 Chronic lung disease (CLD)/bronchopulmonary dysplasia (BPD), Outcome 3 CLD at 36

weeks in survivors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51

Analysis 2.4. Comparison 2 Chronic lung disease (CLD)/bronchopulmonary dysplasia (BPD), Outcome 4 Late rescue with

corticosteroids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

Analysis 2.5. Comparison 2 Chronic lung disease (CLD)/bronchopulmonary dysplasia (BPD), Outcome 5 Survivors who

had late rescue with corticosteroids. . . . . . . . . . . . . . . . . . . . . . . . . . . 54

Analysis 2.6. Comparison 2 Chronic lung disease (CLD)/bronchopulmonary dysplasia (BPD), Outcome 6 Survivors

discharged home on oxygen. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55

Analysis 3.1. Comparison 3 Death or CLD, Outcome 1 Death or CLD at 28 days. . . . . . . . . . . . . 56

Analysis 3.2. Comparison 3 Death or CLD, Outcome 2 Death or CLD at 36 weeks. . . . . . . . . . . . 57

Analysis 4.1. Comparison 4 Failure to extubate, Outcome 1 Failure to extubate by 3rd day. . . . . . . . . . 58

Analysis 4.2. Comparison 4 Failure to extubate, Outcome 2 Failure to extubate by 7th day. . . . . . . . . . 59



Analysis 5.1. Comparison 5 Complications during primary hospitalisation, Outcome 1 Infection. . . . . . . . 62

Analysis 5.2. Comparison 5 Complications during primary hospitalisation, Outcome 2 Hyperglycaemia. . . . . 63

Analysis 5.3. Comparison 5 Complications during primary hospitalisation, Outcome 3 Hypertension. . . . . . 65

Analysis 5.4. Comparison 5 Complications during primary hospitalisation, Outcome 4 Hypertrophic cardiomyopathy. 66

Analysis 5.5. Comparison 5 Complications during primary hospitalisation, Outcome 5 Growth failure. . . . . . 66

Analysis 5.6. Comparison 5 Complications during primary hospitalisation, Outcome 6 Pulmonary air leak. . . . 67

Analysis 5.7. Comparison 5 Complications during primary hospitalisation, Outcome 7 PDA. . . . . . . . . 68

Analysis 5.8. Comparison 5 Complications during primary hospitalisation, Outcome 8 Severe IVH. . . . . . . 69

Analysis 5.9. Comparison 5 Complications during primary hospitalisation, Outcome 9 Severe IVH in infants examined. 71

Analysis 5.10. Comparison 5 Complications during primary hospitalisation, Outcome 10 PVL. . . . . . . . . 72

Analysis 5.11. Comparison 5 Complications during primary hospitalisation, Outcome 11 PVL in infants with cranial

ultrasound scans. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73

Analysis 5.12. Comparison 5 Complications during primary hospitalisation, Outcome 12 PVL in survivors seen at follow-

up. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74

Analysis 5.13. Comparison 5 Complications during primary hospitalisation, Outcome 13 NEC. . . . . . . . 75

Analysis 5.14. Comparison 5 Complications during primary hospitalisation, Outcome 14 Gastro-intestinal bleeding. 76

Analysis 5.15. Comparison 5 Complications during primary hospitalisation, Outcome 15 Intestinal perforation. . . 78

Analysis 5.16. Comparison 5 Complications during primary hospitalisation, Outcome 16 Pulmonary haemorrhage. . 79

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


Analysis 5.17. Comparison 5 Complications during primary hospitalisation, Outcome 17 Any ROP. . . . . . . 80

Analysis 5.18. Comparison 5 Complications during primary hospitalisation, Outcome 18 Severe ROP. . . . . . 81

Analysis 5.19. Comparison 5 Complications during primary hospitalisation, Outcome 19 Severe ROP in survivors. . 82

Analysis 6.1. Comparison 6 Long-term follow-up, Outcome 1 Bayley MDI <-2SD. . . . . . . . . . . . . 83

Analysis 6.2. Comparison 6 Long-term follow-up, Outcome 2 Bayley MDI <-2SD in tested survivors. . . . . . 83

Analysis 6.3. Comparison 6 Long-term follow-up, Outcome 3 Bayley PDI <-2SD. . . . . . . . . . . . . 84

Analysis 6.4. Comparison 6 Long-term follow-up, Outcome 4 Bayley PDI <-2SD in tested survivors. . . . . . . 85

Analysis 6.5. Comparison 6 Long-term follow-up, Outcome 5 Developmental delay (criteria not specified). . . . 85

Analysis 6.6. Comparison 6 Long-term follow-up, Outcome 6 Developmental delay (criteria not specified) in tested

survivors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86

Analysis 6.7. Comparison 6 Long-term follow-up, Outcome 7 Blindness. . . . . . . . . . . . . . . . 86

Analysis 6.8. Comparison 6 Long-term follow-up, Outcome 8 Blindness in survivors assessed. . . . . . . . . 87

Analysis 6.9. Comparison 6 Long-term follow-up, Outcome 9 Deafness. . . . . . . . . . . . . . . . . 88

Analysis 6.10. Comparison 6 Long-term follow-up, Outcome 10 Deafness in survivors assessed. . . . . . . . 89

Analysis 6.11. Comparison 6 Long-term follow-up, Outcome 11 Cerebral palsy. . . . . . . . . . . . . . 90

Analysis 6.12. Comparison 6 Long-term follow-up, Outcome 12 Death before follow-up in trials assessing cerebral palsy. 91

Analysis 6.13. Comparison 6 Long-term follow-up, Outcome 13 Death or cerebral palsy. . . . . . . . . . . 92

Analysis 6.14. Comparison 6 Long-term follow-up, Outcome 14 Cerebral palsy in survivors assessed. . . . . . . 93

Analysis 6.15. Comparison 6 Long-term follow-up, Outcome 15 Major neurosensory disability (variable criteria - see

individual studies). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94

Analysis 6.16. Comparison 6 Long-term follow-up, Outcome 16 Death before follow-up in trials assessing major

neurosensory disability (variable criteria). . . . . . . . . . . . . . . . . . . . . . . . . 95

Analysis 6.17. Comparison 6 Long-term follow-up, Outcome 17 Death or major neurosensory disability (variable

criteria). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

Analysis 6.18. Comparison 6 Long-term follow-up, Outcome 18 Major neurosensory disability (variable criteria) in

survivors examined. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

Analysis 6.19. Comparison 6 Long-term follow-up, Outcome 19 Abnormal neurological exam (variable criteria - see

individual studies). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98

Analysis 6.20. Comparison 6 Long-term follow-up, Outcome 20 Death before follow-up in trials assessing abnormal

neurological exam (variable criteria). . . . . . . . . . . . . . . . . . . . . . . . . . . 99

Analysis 6.21. Comparison 6 Long-term follow-up, Outcome 21 Death or abnormal neurological exam (variable

criteria). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100

Analysis 6.22. Comparison 6 Long-term follow-up, Outcome 22 Abnormal neurological exam (variable criteria) in tested

survivors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101

Analysis 6.23. Comparison 6 Long-term follow-up, Outcome 23 Intellectual impairment (IQ < 70). . . . . . . 101

Analysis 6.24. Comparison 6 Long-term follow-up, Outcome 24 Intellectual impairment (IQ < 70) in survivors assessed. 102

Analysis 6.25. Comparison 6 Long-term follow-up, Outcome 25 “Major neurosensory impairment” - blindness or

deafness. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103

Analysis 6.26. Comparison 6 Long-term follow-up, Outcome 26 “Major neurosensory impairment” - blindness or deafness

- in survivors assessed. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103

Analysis 6.27. Comparison 6 Long-term follow-up, Outcome 27 Behavior abnormalities. . . . . . . . . . . 104

Analysis 6.28. Comparison 6 Long-term follow-up, Outcome 28 Behavior abnormalities in 3 yr old survivors assessed. 104

Analysis 6.29. Comparison 6 Long-term follow-up, Outcome 29 Abnormal EEG. . . . . . . . . . . . . 105

Analysis 6.30. Comparison 6 Long-term follow-up, Outcome 30 Abnormal EEG in tested survivors. . . . . . . 105

Analysis 6.31. Comparison 6 Long-term follow-up, Outcome 31 Re-hospitalisation in infancy. . . . . . . . . 106

Analysis 6.32. Comparison 6 Long-term follow-up, Outcome 32 Re-hospitalisation in infancy in survivors. . . . . 106

107WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

107HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

108CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

108DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

108SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

108INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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


[Intervention Review]

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

Henry L Halliday1, Richard A Ehrenkranz2, Lex W Doyle3

1Perinatal Room, Royal-Jubilee Maternity Service, Belfast, UK. 2Department of Pediatrics, Yale University, New Haven, Connecticut,

USA. 3Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Australia

Contact address: Henry L Halliday, Perinatal Room, Royal-Jubilee Maternity Service, Royal Maternity Hospital, Grosvenor Road,

Belfast, Northern Ireland, BT12 6BA, UK. [email protected].

Editorial group: Cochrane Neonatal Group.

Publication status and date: Edited (no change to conclusions), published in Issue 1, 2010.

Review content assessed as up-to-date: 9 September 2008.

Citation: Halliday HL, Ehrenkranz RA, Doyle LW. Early (< 8 days) postnatal corticosteroids for preventing chronic

lung disease in preterm infants. Cochrane Database of Systematic Reviews 2010, Issue 1. Art. No.: CD001146. DOI:

10.1002/14651858.CD001146.pub3.


A B S T R A C T

Background

Chronic lung disease (CLD) remains a major problem in neonatal intensive care units. Persistent inflammation in the lungs is the most

likely underlying pathogenesis. Corticosteroids have been used to either prevent or treat CLD because of their potent anti-inflammatory

effects.

Objectives

To determine if postnatal corticosteroid treatment is of benefit in the prevention of chronic lung disease (CLD) in preterm infants.

This review examines the outcome of trials where preterm infants at risk of CLD were given postnatal corticosteroids within the first

seven days of life.

Search methods

Randomised controlled trials (RCTs) of postnatal corticosteroid therapy were sought from the Cochrane Controlled Trials Register,

MEDLINE (1966 - May 2008), hand searching paediatric and perinatal journals, examining previous review articles and information

received from practising neonatologists. Authors of all studies were contacted, where possible, to confirm details of reported follow-up

studies, or to obtain any information about long-term follow-up where none had been reported.

Selection criteria

Randomised controlled trials of postnatal corticosteroid treatment within the first 7 days of life (early) in high risk preterm infants were

selected for this review. Most studies evaluated the use of dexamethasone but we also included studies that assessed hydrocortisone,

even if it was used to manage hypotension.

Data collection and analysis

Data regarding clinical outcomes including mortality, CLD (including late rescue with corticosteroids, and need for home oxygen

therapy), death or CLD, failure to extubate, complications during the primary hospitalisation (including infection, hyperglycaemia,

hypertension, pulmonary air leak, patent ductus arteriosus (PDA), severe intraventricular haemorrhage (IVH), periventricular leu-

comalacia (PVL), necrotising enterocolitis (NEC), gastrointestinal bleeding, intestinal perforation, severe retinopathy of prematurity

(ROP), and long-term outcome (including blindness, deafness, cerebral palsy and major neurosensory disability) were abstracted and

analysed using RevMan 5.

1Early (< 8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants (Review)


mailto:[email protected]

Main results

Twenty-eight RCTs enrolling a total of 3740 participants were eligible for inclusion in this review. A meta-analysis of these trials

demonstrated significant benefits as regards earlier extubation and decreased risks of CLD at both 28 days and 36 weeks’ postmenstrual

age (PMA), death or CLD at 28 days and 36 weeks’ PMA, PDA and ROP, including severe ROP. There were no significant differences in

the rates of neonatal or subsequent mortality, infection, severe IVH, PVL, NEC or pulmonary haemorrhage. Gastrointestinal bleeding

and intestinal perforation were important adverse effects and the risks of hyperglycaemia, hypertension, hypertrophic cardiomyopathy

and growth failure were also increased. In the twelve trials that reported late outcomes, several adverse neurological effects were found at

follow-up examinations including developmental delay (not defined), cerebral palsy and abnormal neurological examination. However,

major neurosensory disability was not significantly increased, either overall in the seven studies where this outcome could be determined,

or in the two individual studies where the rates of cerebral palsy or abnormal neurological examination were significantly increased.

Moreover, the rates of the combined outcomes of death or cerebral palsy, or of death or major neurosensory disability were not

significantly increased. Dexamethasone was the drug used in most studies (n = 20); only eight studies used hydrocortisone. In subgroup

analyses by type of corticosteroid, most of the beneficial and harmful effects were attributable to dexamethasone; hydrocortisone had

little effect on any outcomes except for an increase in intestinal perforation and a borderline reduction in PDA.

Authors’ conclusions

The benefits of early postnatal corticosteroid treatment (≤ 7 days), particularly dexamethasone, may not outweigh the known or

potential adverse effects of this treatment. Although early corticosteroid treatment facilitates extubation and reduces the risk of chronic

lung disease and patent ductus arteriosus, it causes short-term adverse effects including gastrointestinal bleeding, intestinal perforation,

hyperglycaemia, hypertension, hypertrophic cardiomyopathy and growth failure. Long-term follow-up studies report an increased risk

of abnormal neurological examination and cerebral palsy. However, the methodological quality of the studies determining long-term

outcomes is limited in some cases; the surviving children have been assessed predominantly before school age, and no study has been

sufficiently powered to detect important adverse long-term neurosensory outcomes. There is a compelling need for the long-term follow-

up and reporting of late outcomes, especially neurological and developmental outcomes, among surviving infants who participated in

all randomised trials of early postnatal corticosteroid treatment. Hydrocortisone in the doses and regimens used in the reported RCTs

has few beneficial or harmful effects and cannot be recommended for prevention of CLD.

P L A I N L A N G U A G E S U M M A R Y

Early (≤ 7 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants

Corticosteroids can reduce lung inflammation in newborns with chronic lung disease (CLD) but there are major adverse effects of the

drugs. CLD is a major problem for newborn babies in neonatal intensive care units. Persistent inflammation of the lungs is the most

likely cause. Corticosteroid drugs have been used to either prevent or treat CLD because of their strong anti-inflammatory effects.

This review of trials found that the benefits of giving corticosteroids to infants up to seven days of age may not outweigh the known

adverse effects. The beneficial effects were shorter time on the ventilator and less CLD but the adverse effects included high blood

pressure, bleeding from the stomach or bowel, perforation of the bowel, an excess of glucose in the bloodstream and an increased risk

of cerebral palsy at follow-up. Use of early corticosteroids, especially dexamethasone, to treat or prevent CLD should be curtailed until

more research has been performed.

B A C K G R O U N D

Advances in neonatal care, including the use of antenatal cor-

ticosteroids and surfactant therapy, have improved the outcome

of preterm infants with RDS, but the risk of chronic lung dis-

ease (CLD) or bronchopulmonary dysplasia (BPD) has been only

modestly reduced (Egberts 1997). The terms CLD and BPD are

often used interchangeably; for the purposes of this review we

have decided to use CLD to describe infants with oxygen depen-

dency at either 28 days of life or 36 weeks’ PMA. More infants

with CLD are being cared for in neonatal units and their man-



agement is both time consuming and costly. Postnatal corticos-

teroid treatment has been shown to have some beneficial acute

effects on lung function in infants with established CLD, espe-

cially those that are ventilator dependent (Mammel 1983; CDTG

1991). Recently, there has been concern that the benefits of corti-

costeroids might not outweigh the adverse effects, which include

hypertension, hyperglycaemia, intestinal perforation and extreme

catabolism (Anonymous 1991; Ng 1993).

Corticosteroids have been used to try to prevent CLD by treating

at risk preterm infants within the first four days of life. It is not

clear if early use of corticosteroids provides long-term benefits.

Nor is it clear that adverse neurological outcomes found in animal

studies do not apply to the immature human newborn infant.

In total, at least 47 randomised trials of postnatal corticosteroids

have been conducted in infants at risk of, or with CLD (see pre-

vious reviews by Halliday 1997; Halliday 1999; Arias-Camison

1999; Bhuta 1998; Doyle 2000b and Tarnow-Mordi 1999). There

are three existing Cochrane reviews, which review separately the

trials in which postnatal corticosteroids were started within 96

hours of birth (Halliday 2003a), 7 - 14 days after birth (Halliday

2003b), or predominantly after three weeks (Halliday2003c). This

review examines the outcome of trials where preterm infants have

been treated with corticosteroids up to seven days after birth. It is

an update of previous Cochrane reviews (Halliday 2000; Halliday

2003a) and it includes long-term outcome data from 12 trials.

O B J E C T I V E S

To examine the relative benefits and adverse effects of postnatal

corticosteroids administered within the first seven days of life to

preterm infants at risk of developing CLD.

M E T H O D S

Criteria for considering studies for this review

Types of studies

Randomised controlled trials of postnatal corticosteroid therapy

in preterm infants at risk of developing CLD who were enrolled

within the first seven days of life (early postnatal corticosteroids).

Trials using hydrocortisone in the first days of life were included

even if it had been used to treat or prevent hypotension.

Types of participants

Preterm infants at risk of developing CLD including those who

are ventilator dependent.

Types of interventions

Intravenous or oral corticosteroid vs. control (placebo or no treat-

ment). Trials of inhaled corticosteroids are not included in this

review.

Types of outcome measures

Clinical outcome measures including mortality, CLD (including

late rescue with corticosteroids, and need for home oxygen ther-

apy), death or CLD, failure to extubate, complications during the

primary hospitalisation (including infection, hyperglycaemia, hy-

pertension, pulmonary air leak, patent ductus arteriosus (PDA),

severe intraventricular haemorrhage (IVH), periventricular leuco-

malacia (PVL), necrotising enterocolitis (NEC), gastrointestinal

bleeding, intestinal perforation, severe retinopathy of prematurity

(ROP), and long-term outcomes (including blindness, deafness,

cerebral palsy and major neurosensory disability).

Search methods for identification of studies

Randomised controlled trials of postnatal corticosteroid therapy

were sought from the Cochrane Controlled Trials Register, MED-

LINE, hand searching paediatric and perinatal journals, examin-

ing previous review articles and information received from practis-

ing neonatologists. MEDLINE was searched from 1966 through

May 2008 using the terms adrenal cortex hormones or dexam-

ethasone or betamethasone or hydrocortisone or steroids or corti-

costeroids, limits randomised controlled trials, human, all infant:

birth - 23 months. Authors of all studies were contacted, when

possible, to confirm details of reported follow-up studies, or to

obtain any information about long-term follow-up where none

had been reported.

Data collection and analysis

For each trial information was sought regarding the method of ran-

domisation, blinding, stratification, reporting of the outcome of

all the infants enrolled and whether the trial was single or multicen-

tred. Information on the trial participants included birth weight,

gestational age, severity of RDS, need for mechanical ventilation

and surfactant, and gender. Information on clinical outcomes was

analysed for mortality, survival without CLD, CLD defined at 28

days and 36 weeks’ PMA, failure to extubate, pneumothorax, in-

fection, hyperglycaemia, hypertension, severe ROP, PDA, severe

IVH, PVL, NEC, gastrointestinal bleeding, intestinal perforation,

need for late corticosteroid treatment, and long-term outcome,

including blindness, deafness, cerebral palsy and major neurosen-

sory disability. Meta-analysis of the included trials was performed

using RevMan 5, including subgroup analyses by the type of cor-

ticosteroid used (dexamethasone or hydrocortisone) where there



were sufficient numbers of trials to make such subgroup analyses

meaningful.

R E S U L T S

Description of studies

See: Characteristics of included studies; Characteristics of excluded

studies; Characteristics of studies awaiting classification.

Twenty-eight trials qualified for inclusion in this review. Most of

the trials enrolled low birth weight infants with RDS who were

receiving mechanical ventilation.

The corticosteroid administered was usually dexamethasone and

the commonest treatment regimen was 0.50 mg/kg/day for three

days followed by 0.25 mg/kg/day for three days, 0.12 mg/kg/day

for three days and 0.05 mg/kg/day for three days. There was, how-

ever, considerable variation with treatment regimens including

short courses of 1 - 2 days and longer courses of up to four weeks.

Eight studies used hydrocortisone (Baden 1972; Watterberg 1999;

Biswas 2003; Watterberg 2004; Efird 2005; Peltoniemi 2005; Ng

2006; Bonsante 2007) and in some cases the indication was man-

agement of hypotension when low (almost physiological) doses

were used (see under Description of Studies).

Anttila 2005 was a multicentre, double-blind, placebo-controlled

trial of infants with birth weight 500 - 999 grams, gestation < 32

weeks and respiratory failure by four hours of age. 109 infants were

randomised to receive either four doses of dexamethasone (0.25

mg/kg at 12 hour intervals) or saline placebo.

Baden 1972 included 44 infants with respiratory distress syn-

drome, mild hypoxia and hypercapnia and a chest radiograph com-

patible with RDS. They were randomised to receive either hydro-

cortisone 15 mg/kg on admission and 12 hours later intravenously

or a placebo. Their birth weights ranged from 800 to 2805 g and

gestational ages from 26 to 36 weeks.

Biswas 2003 was a multicentre randomised trial of 253 infants <

30 weeks’ gestational age. The infants were mechanically venti-

lated and were entered within nine hours of birth. All were given

surfactant in the first 24 hours of life. Those in the treatment

group (n = 125) were randomised to receive an infusion of hydro-

cortisone 1 mg/kg/day and tri-iodothyronine (T3) 6 microgram/

kg/day for five days, then hydrocortisone 0.5 mg/kg/day and T3

3 microgram/kg/day for two days. The placebo group (n = 128)

received an equal volume of 5% dextrose.

Bonsante 2007 enrolled a total of 50 infants either < 1250 g birth

weight or gestation 24 to 30 wk who were < 48 h old and were ven-

tilator-dependent after surfactant treatment were recruited. Exclu-

sion ctiteria were cardiopulmonary malformations, perinatal as-

phyxia, death < 12 h after recruitment, or use of steroids for any

reason < 12 days after birth. No infants were excluded for these

latter two reasons. Stratification was by birth weight (not speci-

fied), gestational age (not specified) and antenatal steroid expo-

sure. Infants were randomly allocated to either a 12-day course

of hydrocortisone (1.0 mg/kg for nine days, then 0.5 mg/kg/day

for three days) (n = 25) or an equivalent volume of 0.9% saline

placebo (n = 25). The sample size calculation was based on results

of Watterberg 1999 with an estimate of 138 infants to be recruited.

The study was stopped early at 50 infants enrolled because of re-

ports from other trials of spontaneous intestinal perforation with

early hydrocortisone treatment.

Efird 2005 was a randomised controlled trial of hydrocortisone to

prevent hypotension in infants of < 1000 grams birth weight and

gestation 24 to 28 weeks. 34 infants were randomised to receive

either 1 mg/kg of intravenous hydrocortisone 12 hourly for two

days, followed by 0.3 mg/kg 12 hourly for three days or a normal

saline placebo.

Garland 1999 was a prospective multicentre randomised trial com-

paring a three day course of dexamethasone therapy beginning at

24 - 48 hours of life with placebo. 241 preterm infants (dexam-

ethasone n = 118, placebo n = 123) who weighed between 500 g

and 1500 g, had received surfactant therapy and were at significant

risk for CLD or death using a predictive model at 24 hours were

enrolled. Dexamethasone was given in a three day tapering course

at 12 hour intervals. The first two doses were 0.4 mg/kg, the 3rd

and 4th doses were 0.2 mg/kg and the 5th and 6th doses were 0.1

mg/kg and 0.05 mg/kg respectively. A similar volume of normal

saline was given to placebo treated infants at similar time intervals.

Halac 1990 was a randomised trial to determine if prenatal cor-

ticosteroid therapy would reduce the incidence of NEC. Women

were randomised to prenatal betamethasone or placebo when they

were admitted in preterm labor and expected to deliver within

24 hours. Infants of mothers who had received placebo were then

randomised to postnatal dexamethasone or placebo; only the in-

fants randomised to postnatal therapy are included in this review.

Study infants were < 1501 g birth weight or < 34 weeks’ gestation

and had evidence of “birth asphyxia” (1 minute Apgar score < 5,

prolonged resuscitation and metabolic acidosis [bicarbonate <15

mmol/L within 1 h of birth]). Treatment group was assigned by a

table of random numbers. The treatment group (n = 130) received

2 mg/kg/day of dexamethasone phosphate intravenously for seven

days; the control group (n = 118) received an equal volume of

10% dextrose. The major endpoint of the study was NEC.

Kopelman 1999 was a prospective blinded randomised controlled

trial of 70 infants of less than 28 weeks’ gestation who required

mechanical ventilation. 37 infants received dexamethasone 0.20

mg/kg at delivery and 33 infants received a placebo of an equal

volume of saline.

Lin 1999 was a randomised trial with a sequential design involv-

ing infants of 500 - 1999 g. Infants were stratified by birth weight

into three groups: 500 - 999 g, 1000 - 1500 g and 1501 - 1999

g. Within each group equal numbers of dexamethasone-treated or

control cards were placed in envelopes for random selection of the



first infant of each pair. The next infant of the appropriate birth

weight stratum was enrolled for the match. A pharmacist opened

the envelope and the dexamethasone or saline placebo was admin-

istered blind. Entry criteria were: presence of severe radiographic

RDS, need for assisted ventilation within 6 h of birth, and given

1 dose of surfactant. Treated infants were given dexamethasone

starting within 12 h of birth at 0.25 mg/kg/dose 12 hourly for 7

d, 0.12 mg/kg/dose 12 hourly for 7 d, 0.05 mg/kg/dose 12 hourly

for 7 d and 0.02 mg/kg/dose 12 hourly for 7 d giving a total of

4 weeks treatment. Results are presented for 20 treated and 20

control infants.

Mukhopadhyay 1998 was a randomised trial with untreated con-

trols. The method of randomisation was not described. Treated in-

fants received dexamethasone 0.5 mg/kg/dose 12 hourly for three

days beginning within six hours of birth. 19 infants of < 34 wk

and < 2000 g who could be provided with mechanical ventilation

were included in the study. These infants had severe RDS but were

not given surfactant.

Ng 2006 was a double-blind, randomised controlled trial of a

“stress dose” of hydrocortisone for treatment of refractory hy-

potension. 48 infants of birth weight < 1500 grams were ran-

domised to have either hydrocortisone 1 mg/kg 8 hourly for five

days or an equivalent volume of isotonic saline.

Peltoniemi 2005 enrolled a total of 51 infants either < 1251 grams

birth weight or < 31 weeks’ gestation who were < 36 hours old

and who were ventilator-dependent. There were 3 collaborating

centres in Finland. Stratification was by centre and birth weight

(501 to 749 g, 750 to 999 g and 1000 to 1250 g). Infants were

randomly allocated to either a 10 day tapering course of hydro-

cortisone (2 mg/kg/day for two days, 1.5 mg/kg/day for 2 days,

0.75 mg/kg/day for six days) (n = 25) or an equivalent volume

of 0.9% saline placebo (n = 26). The sample size calculation was

based on detecting an increase in survival without CLD from 50%

to 70% and required 160 patients per study arm (alpha and beta

error 0.05 and 0.20 respectively). The study was stopped early at

51 infants because two of the hydrocortisone treated infants had

intestinal perforation and because of reports from other RCTs of

early hydrocortisone of the same complication.

Rastogi 1996 recruited 70 infants with birth weights 700 to 1500

g who had severe RDS (assisted ventilation with at least 40%

oxygen and/or 7 cm H2O mean airway pressure (MAP), a/A PO2

ratio of 0.24 or less) and had been treated with surfactant before

entry. The infants were < 12 hours old. Infants were excluded

if they had major malformations, chromosome abnormalities, 5

minute Apgar scores < 3 or severe infection. The intervention

group had dexamethasone intravenously every 12 hours according

to the following schedule: 0.50 mg/kg/d on days 1 - 3, 0.30 mg/

kg/d on days 4 - 6, 0.20 mg/kg/d on days 7 - 9 and finally 0.10

mg/kg/d on days 10 - 12. A saline placebo was given intravenously

to the control group.

Romagnoli 1999 was a randomised trial using numbered sealed

envelopes involving 25 dexamethasone treated infants and 25 un-

treated controls. Entry criteria were: birth weight < 1251 g, gesta-

tional age < 33 wk, ventilator and oxygen dependent at 72 h and

at high risk of CLD using a local scoring system that predicted

a 90% risk. Treated infants were given dexamethasone beginning

on the 4th day at a dose of 0.5 mg/kg/d for 3 d, 0.25 mg/kg/d for

3 d and 0.125 mg/kg/d for 1 d.

Sanders 1994 enrolled 40 infants < 30 weeks’ gestation who had

RDS diagnosed by clinical and radiographic signs, required me-

chanical ventilation at 12 - 18 hours of age, and had received at

least one dose of surfactant. Exclusion criteria at entry included a

strong suspicion of sepsis or pneumonia, congenital heart disease,

chromosome abnormalities and those infants who received an ex-

change transfusion. The infants were randomised to receive either

dexamethasone 0.50 mg/kg between 12 and 18 hours of age and

a second dose 12 hours later, or a saline placebo. Both treatments

were given intravenously.

Shinwell 1996 was a multicentre trial that randomised 248 infants

of birth weight 500 to 2000 g if they had clinical and radiographic

evidence of RDS, required mechanical ventilation with more than

40% oxygen, were less than 12 hours old and had no contraindica-

tions to corticosteroid treatment, such as a bleeding tendency, hy-

pertension, hyperglycaemia or active infection. Infantswith lethal

congenital malformations were also excluded. The intervention

group received dexamethasone 0.25 mg/kg intravenously every 12

hours for a total of six doses. The control group received intra-

venous saline.

Sinkin 2000 was a multicentre randomised double-blind trial of

384 infants of less than 30 weeks’ gestation with RDS. 189 infants

received dexamethasone 0.50 mg/kg at 12 - 18 hours of age and

with a second dose 12 hours later, and 195 infants had an equal

volume of saline placebo.

Soll 1999 was a multicentre randomised double-blinded con-

trolled trial comparing dexamethasone given at 12 hours of age

with selective late dexamethasone therapy in premature infants

weighing 501 - 1000 g (early dexamethasone n = 272, late selective

therapy n = 270). The infants required assisted ventilation, had

received surfactant therapy, were physiologically stable, had no

obvious life threatening congenital anomaly, had blood cultures

obtained and antibiotic therapy started. Infants were randomly

assigned to early dexamethasone therapy or saline placebo. Intra-

venous dexamethasone was administered for 12 days according to

the following schedule: 0.5 mg/kg/day for 3 days, 0.25 mg/kg/day

for three days, 0.1 mg/kg/day for three days and 0.05 mg/kg/day

for three days. Infants in either group could receive late postnatal

corticosteroids beginning on day 14 if they needed assisted venti-

lation with supplemental oxygen > 30%.

Stark 2001a was a randomised multicentre controlled trial to com-

pare a tapering course of stress dose corticosteroid started on the

first day with placebo. Infants with birth weight 501 - 1000 g

needing mechanical ventilation before 12 hours of age were eligi-

ble for the study. Infants with birth weight > 750 g also needed to

have received surfactant and required an oxygen concentration of



30% or greater. The initial dose of dexamethasone was 0.15 mg/

kg/day for three days, then tapered over seven days. After enrolling

220 infants (sample size was 1200), the trial was halted because of

an excess of intestinal perforations in the dexamethasone treated

group. 111 infants had been randomised to receive dexamethasone

and 109 placebo.

Subhedar 1997 was a randomised trial which enrolled infants into

one of four treatment groups using a factorial design. Both in-

haled nitric oxide (iNO) and early dexamethasone were compared

separately with controls. 42 infants were randomised: 10 receiving

iNO alone; 11 dexamethasone alone; 10 both treatments; and 11

neither treatment. The 21 infants receiving dexamethasone were

compared with 21 controls. Infants were eligible for entry into the

trial at 96 hours of age if they met the following criteria: gestational

age < 32 weeks, mechanical ventilation from birth, had received

surfactant therapy and were thought to be at high risk of devel-

oping CLD using a scoring system (Ryan et al 1996). Exclusion

criteria included major congenital anomaly, structural cardiac de-

fect, significant ductus shunting, culture positive sepsis, IVH with

parenchymal involvement, pulmonary or gastrointestinal haem-

orrhage, disordered coagulation or platelet count < 50,000. Dex-

amethasone was given intravenously at 12 hourly intervals for six

days: 0.50 mg/kg/dose for six doses, and 0.25 mg/kg/dose for a

further six doses. Control infants were not given a placebo.

Suske 1996 randomised 26 infants with gestational ages 24 to 34

weeks who had RDS that had been treated with surfactant. Infants

with known septicaemia during the first week of life, haemody-

namically relevant cardiac anomalies except for PDA, or malfor-

mations of the lung or central nervous system (CNS) were ex-

cluded. Randomisation was by drawing lots prior to the age of

two hours. The intervention group received dexamethasone 0.50

mg/kg intravenously in two divided doses for five days and the

controls received no placebo.

Tapia 1998 was a multicentre double-blind placebo controlled

trial of 109 preterm infants with RDS and birth weights between

700 and 1600 g who were treated with mechanical ventilation and

surfactant. 55 infants were randomised to receive dexamethasone

0.50 mg/kg/d for three days, followed by 0.25 mg/kg/d for 3 days,

followed by 0.12 mg/kg/d for three days and then 0.06 mg/kg/

d for three days. 54 control infants received an equal volume of

saline.

Vento 2004 enrolled 20 neonates with birth weight < 1251 grams

and gestation < 33 weeks who were oxygen and ventilator-depen-

dent on the fourth day of life were randomised to receive either

dexamethasone 0.50 mg/kg/d for 3 days, 0.25 mg/kg/d for 3 days

and 0.125 mg/kg/d for one day (total dose 2.375 mg/kg) or no

corticosteroid treatment.

Wang 1996 was a randomised trial of a 21 day course of either

dexamethasone or saline placebo given in a double-blind fashion.

Method of randomisation not stated. Entry criteria: birth weight

1000 - 1999 g, appropriate for gestational age (AGA), clinical

and radiological severe RDS, mechanical ventilation and age < 12

h. Surfactant was not given as it was not commercially available

in Taiwan at the time of the study. Treated infants were given

dexamethasone 0.25 mg/kg/dose 12 hourly for 7 d, 0.125 mg/kg/

dose 12 hourly for 7 d, 0.05 mg/kg/dose 12 hourly for 7 d making

a total course of 21 days. The first dose of dexamethasone was

given during the first 12 h of life. There were 34 infants in the

dexamethasone group and 29 in the placebo control group.

Watterberg 1999 was a randomised double-masked placebo con-

trolled pilot study to compare early treatment with low dose hy-

drocortisone (1.0 mg/kg/d for nine days, then 0.5 mg/kg/d for

three days) begun before 48 hours of age with placebo. 40 infants

weighing between 500-999 g and who were mechanically venti-

lated were enrolled at two centres, 20 hydrocortisone treated and

20 placebo controls.

Watterberg 2004 was a multicentre masked, randomised trial of

hydrocortisone to prevent early adrenal insufficiency. 360 infants

with birth weights 500 to 999 grams who were mechanically ven-

tilated were randomised to receive either hydrocortisone 1 mg/kg/

d for 12 days, then 0.5 mg/kg/d for three days or saline placebo.

infants were enrolled between 12 and 48 hours of life. The trial

was stopped because of an increase of spontaneous gastrointestinal

perforation in the hydrocortisone group.

Yeh 1990 enrolled 57 infants whose birth weights were < 2000 g

and who had severe RDS based upon the appearances on a chest

radiograph and the need for mechanical ventilation within four

hours after birth. The absence of infection was also required for

inclusion. The infants were randomly assigned to receive dexam-

ethasone 0.50 mg/kg per dose every 12 hours from days 1 - 3, then

0.25 mg/kg per dose 12 hourly from days 4 - 6, then 0.12 mg/kg

per dose 12 hourly from days 7 - 9 and finally 0.05 mg/kg per dose

12 hourly from days 10 - 12. All doses were given intravenously.

A saline solution was used in the placebo group.

Yeh 1997 was a multicentre randomised double-blind clinical trial

of 262 preterm infants (< 2000 g) who had RDS and required

mechanical ventilation from shortly after birth. The treated group

had dexamethasone 0.25 mg/kg/dose every 12 hours i.v. from day

1 to 7; 0.12 mg/kg/dose every 12 hours i.v. from day 8 - 14; 0.05

mg/kg/dose every 12 hours i.v. from days 15 - 21; and 0.02 mg/

kg/dose every 12 hours i.v. from day 22 to 28. Control infants had

a saline placebo.

Risk of bias in included studies

Anttila 2005: Randomisation was in the pharmacy of the coordi-

nating centre using coded vials with blinding of the study investi-

gators. Open label dexamethasone was allowed when deemed nec-

essary by the attending neonatologist but its use was discouraged.

Intention to treat analysis was performed. There was no follow-

up component.

Baden 1972: Randomisation was by vials and a table of random

numbers. The clinical personnel were not aware of the content

of any vial. Outcomes were given for all of the infants enrolled.



Follow-up component (Fitzhardinge 1974): Survivors were seen

at 12 months of age, corrected for prematurity, by one paedia-

trician and one psychologist. A neurologist saw all children with

abnormal neurological signs. Observers were blind to treatment

group allocation. The follow-up rate of survivors was 93% (25/

27). Criteria for the diagnosis of cerebral palsy were not specified,

nor were there specific criteria for blindness or deafness (children

were tested by free-field pure tone audiometry). Psychological as-

sessment included the Griffiths scales. Major neurosensory dis-

ability was not specified.

Biswas 2003: Randomisation was conducted by the Perinatal Trials

Unit in Oxford, with stratification for centre and gender, and the

code held by the study pharmacist. Controls received an equal

infusion rate of 5% dextrose. Syringes were made in one pharmacy

and transported to individual study centres. Short-term outcomes

were reported for all infants enrolled. There was no follow-up

component.

Bonsante 2007: Randomisation was centralised using a computer

generated random number sequence. There was stratification into

6 risk groups to ensure a homogeneous number of infants with re-

gard to birth weight, gestation and antenatal corticosteroid admin-

istration. The drugs were prepared each day in the pharmacy and

the care team, parents and the personnel collecting the data had

no knowledge of the random assignment at any time. Follow-up

component: Results of follow-up at two years of age are reported in

conjunction with data from another study (Peltoniemi 2008), but

clinical criteria for various outcomes were not described. Follow-

up data were reported for 92% (33/36) of survivors to hospital

discharge.

Efird 2005: Randomisation was by opening sequentially num-

bered, opaque envelopes containing preassigned treatment desig-

nations. Infants of multiple gestations were randomised as separate

subjects. Clinicians were blinded to treatment identity. If hypoten-

sion persisted the randomisation assignment could be unblinded

and hydrocortisone administered if the infant had been assigned

to the placebo group. There was no follow-up component.

Garland 1999: Infants were randomised at each centre within each

of four strata based on birth weight (≤ 1000 g, > 1000 g) and

arterial/alveolar (a/A) ratio before surfactant (≤ 0.15, > 0.15).

Randomisation codes were maintained by the study pharmacists

at each centre. Investigators, caregivers and parents were blinded

to treatment allocation. At the first interim analysis (n = 75), an

increased risk of gastrointestinal perforation was noted in the dex-

amethasone group. After adjusting for severity of illness the dif-

ference was not of statistical significance to stop enrolment. How-

ever, to ensure patient safety the data monitoring committee rec-

ommended reducing the dexamethasone dose. The dosing sched-

ule was changed to 4 doses of 0.25 mg/kg/dose every 12 hours

begun at 24 to 48 hours, followed by doses of 0.125 mg/kg and

0.05 mg/kg at the next two 12 hour periods respectively. After the

first interim analysis all enrolled infants received ranitidine ther-

apy during the first three days of the study. Outcome measures

appear to have been reported for all 241 infants enrolled in the

study. There was no follow-up component.

Halac 1990: Randomisation was by means of a table of random

numbers, with placebo blinding. It was stated that deaths before

10 days of age were excluded from the study; there were a total

of five early deaths from sepsis, but it was not clear how often

this occurred in each group. Apart from these infants, outcome

data were provided for all remaining infants enrolled. There was

limited follow-up to six months of age, but no results were given

(apart from a statement that “growth and development were not

hampered in any of these patients”).

Kopelman 1999: Randomisation was performed in the pharmacy

after stratification for treatment with antenatal corticosteroids.

The blinded clinical team provided care. Outcome data were pro-

vided for all infants enrolled. There was no follow-up component.

Lin 1999: Randomisation was by opening sealed envelopes in the

pharmacy. The study had a sequential analysis design with 12

infants being paired successfully. Outcome measures were given

for all 40 infants enrolled including those who remained unpaired.

There was no follow-up component.

Mukhopadhyay 1998: Method of randomisation not stated. Only

28 of 43 eligible infants could be provided with ventilation. Eight

infants were subsequently excluded due to non-availability of

blood gases due to a technical fault and one baby was excluded

because of congenital heart block. This left 19 infants for study;

10 received intravenous dexamethasone and nine were not treated

with any drug. There is no mention of placebo. Outcome mea-

sures were reported for these 19 infants. There was no follow-up

component.

Ng 2006: Randomisation used computer generated random num-

bers and opening of sequentially numbered sealed opaque en-

velopes in the pharmacy. Assignment was in blocks of six and once

an envelope was opened an infant would be irrevocably entered

into the trial. To ensure effective blinding of the medications both

types of trial drug were colourless, odourless and made up to the

same volume before being sent to the ward. There was no follow-

up component.

Peltoniemi 2005: Randomisation was performed centrally by non-

clinical staff independent of the chief investigators, with random

variation in block sizes of two to eight, and separately for each

centre. Syringes were prepared and labelled identically in the phar-

macy department of the centre, concealing allocation from the

study site’s investigators and the infant’s caregivers. Open-label

corticosteroids were discouraged after randomisation, but not pro-

hibited; some infants may have received both a second course of

their initially allocated study drug and open-label corticosteroids.

No one apart from the pharmacist at study sites had access to the

treatment codes. Short-term outcomes were reported for all in-

fants enrolled. Follow-up component (Peltoniemi 2008): Surviv-

ing children were assessed at 24 months of age, corrected for pre-

maturity, by paediatricians, paediatric neurologists and psycholo-

gists at individual study sites who were blinded to treatment group



allocation. Children were considered to have a major neurosen-

sory impairment if they had cerebral palsy, blindness (inability to

see any objects, with the exception of light), deafness (failure to

pass an evoked otoacoustic emission test during the neonatal pe-

riod and no response in brainstem auditory evoked potentials), or

developmental delay (defined as a Mental Developmental Index

(MDI) on the Bayley Scales of Infant Development < 70 [<-2 SD]

, or a DQ < 70 on the Griffiths Cognitive Scales). The follow-up

rate of survivors at two years was 98% (45/46).

Rastogi 1996: Randomisation occurred in the pharmacy using a

random number list after stratifying for birth weight into three

groups: 700 - 999 g, 1000 - 1249 g and 1250 - 1500 g. The clinical

team and other study personnel were blinded to the assignments

until the study was completed and all outcome variables were

recorded for all infants. There was no follow-up component.

Romagnoli 1999: Randomisation, obtained by random number

allocation, was achieved by opening numbered sealed envelopes.

Infants with prenatal infections, congenital malformations and

evidence of sepsis at randomisation were excluded. There is no

mention of placebo. Outcome measures were reported for all 50

infants enrolled. Follow-up component (Romagnoli 2002a): Sur-

vivors were seen at 34 - 42 months of age, corrected for prematurity,

by one paediatrician and one neurologist, with observers blinded

to treatment group allocation. The follow-up rate of survivors was

100% (45/45). Cerebral palsy was diagnosed by the neurologist,

but the criteria were not specified, neither were there specific cri-

teria for blindness or deafness. Psychological assessment included

the Stanford-Binet - 3rd Revision; intellectual impairment com-

prised an IQ <70. Major neurosensory impairment comprised ei-

ther blindness or deafness.

Sanders 1994: Randomisation occurred in the pharmacy after

opening a sealed envelopes. Dexamethasone or placebo were dis-

pensed in labelled syringes. Clinical personnel were not aware of

the assignment of the intervention. Outcomes are given for all 40

infants enrolled. Follow-up component (Sinkin 2002): Survivors

were seen at mean ages of 64 (SD 8) months (dexamethasone) and

61 (SD 4) months (controls), not corrected for prematurity, by

a paediatrician, a neurologist and a psychologist, with observers

blinded to treatment group allocation. Additional data were sought

from parents and teachers. The follow-up rate of survivors was

100% (31/31). The criterion for the diagnosis of cerebral palsy

was a fixed motor deficit diagnosed by the neurologist. Blindness

comprised visual acuity < 6/60 in the better eye. Deafness was

defined as the need for a hearing aid. Psychological assessment

included the Wechsler Scales (WISC and WPPSI) - intellectual

impairment comprised a Full Scale IQ < 70. Major neurosensory

disability was not specified. Further follow-up at 15 years of age

is planned.

Shinwell 1996: Each participating unit was supplied with num-

bered sets of syringes containing either dexamethasone or physi-

ological saline. Syringes containing dexamethasone were not dis-

tinguishable from those containing saline. Syringe sets were num-

bered according to a random number list and randomisation was

stratified by centre and by two birth weight groups: 500 - 1000 g

and 1001 - 2000 g. The drug assignment was not known to any

of the investigators until after the three month observation period

of the last enrolled infant. Outcomes are reported for 248 of the

255 infants who were enrolled. The seven infants subsequently

excluded from analysis included three with major congenital ab-

normalities (two with myotonic dystrophy and one with cyanotic

congenital heart disease), three with errors in drug administration

and one randomised after the age of 12 hours. Follow-up com-

ponent (Shinwell 2002): Survivors were seen at a mean age of 53

(SD 18; range 24-71) months, presumably not corrected for pre-

maturity. These children were seen in multiple follow-up clinics

by multiple paediatricians, with observers blinded to treatment

group allocation. The follow-up rate of survivors was 83% (159/

190). Criteria for the diagnosis of cerebral palsy were not specified,

but the diagnosis was made by neurologists in all cases. There were

no specified criteria for blindness. Deafness comprised the need

for hearing aids. There were no formal psychological assessments;

developmental delay was assigned by judgement of the multiple

assessors. Major neurosensory disability comprised any of non-

ambulant cerebral palsy, global retardation (not specified), blind-

ness or deafness. Further follow-up is planned at school age.

Sinkin 2000: Randomisation with stratification by centre was per-

formed using a set of sealed envelopes in the pharmacy. Outcome

data appear to have been provided for all infants enrolled. Follow-

up component (Sinkin 2002): Data were obtained from one of the

four original centres in the study, from follow-up clinic appoint-

ments, and from questionnaires to parents and paediatricians. Sur-

vivors were seen at approximately 12 months of age, corrected for

prematurity, by a paediatrician, a neurologist and a psychologist,

with observers blinded to treatment group allocation. The follow-

up rate of survivors was 13% (41/311) of survivors at 36 weeks’

PMA overall, but was confined to one of four individual study

centres, within which the follow-up rate was 100% (41/41). The

criterion for the diagnosis of cerebral palsy was a fixed motor deficit

diagnosed by the neurologist. Blindness comprised visual acuity <

6/60 in the better eye. Deafness comprised the need for a hearing

aid. Psychological assessment included the Bayley Scales of Infant

Development. Major neurosensory disability was not specified.

Soll 1999: Randomisation was in hospital pharmacies after open-

ing opaque sealed envelopes supplied by the Vermont Oxford

Neonatal Network. The study was stopped prior to completion of

sample size goals due to concern regarding adverse effects in the

early corticosteroid therapy group. Outcome measures appear to

have been reported for most of the 542 infants enrolled. There

was no follow-up component.

Stark 2001a: Random allocation was performed in hospital phar-

macies using a random number scheme. The study had a factorial

design so that infants were also randomised to routine ventilator

management or a strategy of minimal ventilator support aimed at

reducing mechanical lung injury. After enrolling 220 infants from



a sample size estimate of 1200 the trial was halted. Outcome mea-

sures seem to have been reported for all 220 patients enrolled in the

trial. Follow-up component (Stark 2001b): Survivors were seen at

18 - 22 months of age, corrected for prematurity, by trained de-

velopmental observers blinded to treatment group allocation. The

follow-up rate of survivors was 87% (143/164). Criteria for the di-

agnosis of cerebral palsy were not specified, and rates of blindness

or deafness were not reported. Psychological assessment included

the MDI and the PDI of the Bayley Scales of Infant Development.

Major neurosensory disability comprised any of abnormal neuro-

logical exam, blindness, deafness, or an MDI or PDI <-2 SD.

Subhedar 1997: Block randomisation was performed using com-

puter generated random numbers and sealed envelopes. No

placebo was used. There was no evidence of blinding of clinicians.

Outcome measures were reported for all infants enrolled. Follow-

up component (Subhedar 2002): Survivors were seen at 30 months

of age, corrected for prematurity, by one developmental paediatri-

cian who was blinded to treatment group allocation. The follow-

up rate of survivors was 95% (21/22). Criteria for the diagnosis

of cerebral palsy were specified, but not for deafness; blindness

was diagnosed by an ophthalmologist. Psychological assessment

included the MDI and the PDI of the Bayley Scales of Infant De-

velopment. Major neurosensory disability comprised any of cere-

bral palsy, an MDI or PDI <71, blindness or deafness.

Suske 1996: Randomisation was by drawing lots; the lot numbers

corresponded to numbers on non-transparent envelopes. The ran-

dom lots and the envelopes were drawn by a neutral, uninvolved

person. This was considered a pilot trial before starting a multi-

centre study and it was planned that the trial would be stopped if

a statistically significant difference was found between the groups.

The inclusion criteria were met by 41 infants. Due to lack of co-

operation and coordination at the beginning of the study, nine

infants were not randomised. Four infants were excluded after ran-

domisation because of definite signs of septicaemia. Results are

given for 26 of the 28 remaining infants. There was no follow-up

component.

Tapia 1998: Random assignment was at each centre using am-

poules of dexamethasone and saline prepared in the hospital phar-

macy of one of the centres. Outcomes were reported for 109 of the

113 infants enrolled. Two infants from the dexamethasone group

were excluded, one because of congenital cystic adenomatoid mal-

formation and one because of early sepsis. Two patients from the

placebo group were excluded, one because of early sepsis and the

other was transferred to another hospital at two weeks of age and

further data on outcome could not be obtained. There was no

follow-up component.

Vento 2004: Method of randomisation was not stated. It is not

clear if the clinicians caring for the infants were blinded to treat-

ment allocation. Control infants did not receive a placebo. There

was no follow-up component.

Wang 1996: Random allocation was said to have been double-

blind but the exact method was not described. Outcome measures

were reported for all 63 infants enrolled in the study. There was

no follow-up component.

Watterberg 1999: Infants were randomised at each centre by con-

stant block design with four patients per block to minimise bias

over time. Separate randomisation tables were used for infants ex-

posed to antenatal corticosteroids. The hydrocortisone doses and

the placebo of normal saline were prepared by the hospital phar-

macies. Outcome measures were reported for all of the 40 infants

enrolled in the trial. Follow-up component (Watterberg 2002):

Survivors were seen in a regular follow-up clinic for one of the two

study sites at a mean age of 11 (SD 2) months, corrected for pre-

maturity, by a neonatologist and a physiotherapist, with observers

blinded to treatment group allocation. The follow-up rate of sur-

vivors was 53% (18/34) for the study overall, but 86% (18/21)

for the study centre with follow-up data. Criteria for the diagnosis

of cerebral palsy were specified and comprised abnormal tone and

movement. Blindness was diagnosed by an ophthalmologist, and

deafness was screened for in early infancy and at follow-up. There

was no formal psychological testing. Major neurosensory disabil-

ity was not defined.

Watterberg 2004: Randomisation was performed centrally, strati-

fied for birthweight (500 - 749 g, and 750 - 999 g) and centre, with

permuted block sizes of six within each stratum. Only the pharma-

cists at individual sites preparing the drug were aware of the group

assignment. All other personnel were masked. Twins were ran-

domised together to the same study arm. Mortality was reported

for all infants enrolled, but other short-term outcomes were re-

ported for all but three infants who were withdrawn from the study.

Follow-up component (Watterberg 2007):surviving children were

assessed at 18 - 22 months of age, corrected for prematurity, by

assessors at individual study sites who were blinded to treatment

group allocation. Children were considered to have a neurode-

velopmental (neurosensory) impairment if they had cerebral palsy

(criteria included abnormalities of tone, movement and posture),

functional blindness (inability to complete the Bayley Scales of

Infant Development - Second Edition [BSID-II] because of visual

impairment), functional deafness (inability to complete BSID-II

because of hearing impairment), developmental delay (defined as

a Mental Developmental Index [MDI] on the BSID-II <70 [<-

2 SD] Bayley 1993) or motor delay (defined as a Psychomotor

Developmental Index on the BSID-II <70 [<-2 SD]). The follow-

up rate of survivors at 18-22 months was 86% (252/294), or 87%

(252/291) excluding three children whose families had withdrawn

consent.

Yeh 1990: Randomisation was performed in the pharmacy using

balanced blocks of 10. The vials were labelled in the pharmacy and

the clinical staff were unaware of the assignment. Sixty infants were

included in the study and three were subsequently withdrawn:

one because of death from Haemophilus influenzae septicaemia

six hours after enrolment, and two because of an error in the mea-

surement of birth weight (581 and 2200 g). Outcomes for these

three infants are not given. There was no follow-up component.



Yeh 1997: The method of randomisation was by an assignment

list in the central pharmacy. The sample size was calculated on the

basis of an expected 50% reduction in the incidence of CLD with

early dexamethasone, allowing a 5% chance of a type I error and

a 10% chance of a type II error. Short-term outcome data are pre-

sented for all 262 infants enrolled. The study is described as dou-

ble-blind. Follow-up components: a) (Yeh 1998) Survivors were

seen at a mean age of 25 months, corrected for prematurity, by one

neurologist and one psychologist, with observers blinded to treat-

ment group allocation. The follow-up rate of survivors was 81%

(133/164). Criteria for the diagnosis of cerebral palsy, blindness

or deafness were not specified. Psychological assessment included

the MDI and the PDI of the Bayley Scales of Infant Development.

Major neurosensory disability comprised severe motor dysfunc-

tion (child non-ambulant), or an MDI or PDI <-2 SD. b). (Yeh

2004) Survivors were reassessed at 7 - 9 years of age. The follow-

up rate of survivors was 92% (146/159). Assessors were blind to

treatment allocation. A paediatric neurologist assessed the children

for cerebral palsy. Motor skills were assessed with the Movement

ABC. IQ was measured with the WISC-III. Vision and hearing

were formally evaluated. Major neurological disability comprised

any of cerebral palsy, vision worse than 20/60, deafness requiring

hearing aids, or an IQ <5th centile. It was unclear if age was cor-

rected for prematurity. Data for cerebral palsy at eight years were

used in the meta-analysis as the diagnosis of cererbal palsy is more

certain at eight years than at two years of age, and because the

follow-up rate was higher when the subjects were eight years of

age. Blood pressure, height, weight and head circumference were

measured at 8 years of age but not reported as standardised scores

(SD or Z-scores) to enable pooling of data for meta-analysis.

Effects of interventions

Results of Individual Trials

Anttila 2005: The primary outcome was survival without BPD,

IVH (grade 3 or 4) or PVL and although this tended to be greater

in the dexamethasone group the differences compared to controls

were not statistically significant. The relative risk for death or BPD

at 36 weeks’ PMA was 0.78 (95%CI 0.54 to 1.13) overall and 0.61

(95%CI 0.33 to 1.11) in the subgroup with birth weight 750 to

999 grams. There were no detectable trends in mortality, severe

IVH or PVL. The rates of PDA, ROP or sepsis did not differ

between groups. Mean arterial blood pressures were increased in

the dexamethasone group during the first week (P = 0.015) and

the dexamethasone group tended to need more insulin therapy

(49% vs. 39%; P = 0.25).

Baden 1972: No significant effect on blood gases, pH, oxygen re-

quirement, need for assisted ventilation or survival was demon-

strated in this study. There were no significant differences in the

rates of cerebral palsy or deafness in survivors, or in mean scores

on the Griffiths scales, or in the combined rate of death or cerebral

palsy (Fitzhardinge 1974).

Biswas 2003: There were no significant effects of the infusion of

hydrocortisone and T3 on the primary endpoint of death or failure

to extubate by seven days, or death or oxygen dependency at 14

days. PDA was significantly reduced in the treatment group (41/

125 vs. 60/128; relative risk 0.70, 95% CI 0.51, 0.96), but there

were no other significant differences in secondary outcomes.

Bonsante 2007: Oxygen-free survival was significantly greater in

the hydrocortisone group than in controls (64% vs. 32%; P =

0.023). The effect of hydrocortisone was particularly evident in

the subgroup not exposed to prenatal corticosteroids. Four infants

in the hydrocortisone group died compared to 10 in the control

group (16% vs. 40%; P = 0.05). Duration of ventilation, PDA, se-

vere ROP, severe IVH and PVL were not different between groups.

Efird 2005: Vasopressor use was lower in the hydrocortisone

treated group, significantly so on the second day of life. There

were no significant differences in cortisol levels between groups

at any time point. There were no significant differences in mor-

tality, duration of ventilation, BPD (oxygen at 36 weeks’ PMA),

nosocomial infections, NEC, spontaneous intestinal perforations

or IVH. No infants were treated or removed from the study as a

result of hypertension. There was no difference in rate of glucose

intolerance between groups but 2 infants in the hydrocortisone

group received insulin for five days.

Garland 1999: Early dexamethasone treated infants were more

likely to survive without CLD (83/118 vs. 71/123; P = 0.03) than

placebo treated controls. They were also less likely to develop CLD

if they survived to 28 days (16/99 vs. 27/98; P = 0.042). Mortality

rates were not significantly different. Subsequent dexamethasone

therapy was used less often in the early dexamethasone treated in-

fants who survived (68/99 vs. 81/98; P = 0.01). Intestinal perfo-

ration was more common, but not significantly so, in the dexam-

ethasone treated infants (12/118 vs. 7/122; P = 0.20); during the

first week of life the difference was significant (9/118 vs. 1/122;

P = 0.009). Infants in the dexamethasone group also spent less

time in oxygen (median days 43 vs. 50; P = 0.04). Any grade of

IVH (36% vs. 52%; P = 0.02) and PDA ligation (14% vs. 28%;

P = 0.01) were also less common in the dexamethasone group.

Hypertension and insulin therapy occurred more often in the dex-

amethasone treated infants (P = 0.007).

Halac 1990: There were no substantial or statistically significant

effects of dexamethasone on neonatal mortality, mortality to hos-

pital discharge, NEC, sepsis, PDA or severe IVH.

Kopelman 1999: IMV rate and ventilation index improved more

rapidly in the dexamethasone treated group. Mean blood pressure

was higher after the first day in the dexamethasone group. Dex-

amethasone treated infants had fewer PDAs (13/37 vs. 19/33; P

= 0.08), and fewer received indomethacin (8/37 vs. 15/33; P =

0.03). At the study hospital where early extubation was practised,

more dexamethasone treated infants were extubated during the

first week (10/22 vs. 2/16, P < 0.03). There was no difference in

IVH. No adverse effects occurred.

Lin 1999: For the end-point of CLD at 28 d statistical significance



favouring dexamethasone was reached when 12 consecutive pairs

in which one infant had CLD and the other did not showed that

10 pairs favoured dexamethasone and two pairs favoured control.

Data presented for 40 infants (20 in each group) show a lower

incidence of CLD at 28 d in the dexamethasone group (n = 3)

compared to nine in the control group (P < 0.05). Duration of

oxygen therapy was also shorter in the dexamethasone group, 7+/

- 6 d vs. 13 +/- 12 d (P < 0.05). Among survivors 12/15 were

extubated in the dexamethasone group compared to 9/16 in the

control group at the end of the study. Infants in the treated group

had transient hyperglycaemia and hypertension, but there were no

differences between the groups for mortality, incidence of sepsis

or intraventricular haemorrhage.

Mukhopadhyay 1998: Oxygen requirement was lower in the

treated group on days three, four and five compared to the control

group, although the differences were not statistically significant.

Mean duration of ventilation was shorter in the dexamethasone

group (87 +/- 42 h) vs. control group (120+/- 46 h); P value not

given. There was one case of culture positive sepsis in the dexam-

ethasone group and two in the control group. None of the infants

developed BPD (definition not given). Four infants in the dex-

amethasone group developed a pneumothorax versus three in the

control group. Survival was 60% in the treated group and 55% in

the control group.

Ng 2006: 19 (79%) infants in the hydrocortisone group were

weaned from vasopressor support within 72 hours compared with

8 (33%) controls (P < 0.001). The cumulative doses of dopamine

and dobutamine after randomisation were significantly lower in

the hydrocortisone group. Duration of ventilation, duration of

oxygen and incidence of BPD (oxygen at 36 weeks’ PMA) were not

significantly different between groups. There were no differences

between groups for highest serum glucose, culture-proven sepsis,

NEC, intestinal perforation, duration of hospitalisation and mor-

tality. However, significantly more hydrocortisone treated infants

had glycosuria (P = 0.029).

Peltoniemi 2005: Hydrocortisone treated infants did not have

a significant increase in survival without BPD (64% vs. 54%

placebo) or a significant decrease in BPD in survivors (OR 0.53;

95%CI 0.17 to 1.71). However, the study enrolled only 16% of

its intended sample size. Two infants in the hydrocortisone group

died and three in the placebo group. During the first week of life,

infants in the hydrocortisone group needed lower mean airway

pressures compared to the placebo group (P = 0.03). PDA (36%

vs. 73%; P = 0.01) and duration of oxygen therapy (34 vs. 62 days;

P = 0.02) were lower in the hydrocortisone group but IVH, cys-

tic PVL, ROP, sepsis, NEC, GI haemorrhage, open corticosteroid

treatment and durations of intubation and hospitalisation were

not different between groups. There was an increased risk of GI

perforation in the hydrocortisone group (16% vs. 0%; P = 0.05).

There were no differences in the rate of hyperglycaemia needing

insulin or blood pressures (diastolic and systolic).

Rastogi 1996: Ventilator variables at 5 - 14 days were significantly

improved in those infants who received dexamethasone compared

to those who received placebo. The effect seemed to be more

marked in infants weighing < 1250 g at birth. Significantly more

infants could be extubated by 14 days in the dexamethasone group

(26/32 vs. 14/32; P = 0.004). Dexamethasone therapy reduced

the incidence of CLD at 28 days (odds ratio, 0.10, 95% confi-

dence interval, 0.03 - 0.30) and eliminated CLD at 36 weeks’ post-

menstrual age. Dexamethasone treated infants were more likely

to show weight loss at 14 days (12.9% vs. 3.7%; P = 0.01) and

higher blood pressures from days 3 - 10. However, no differences

were seen in time to regain birth weight, hypertension (one infant

in each group), or incidence of IVH.

Romagnoli 1999: The incidences of CLD at 28 d and 36 weeks’

PMA were significantly lower in the dexamethasone group than

the control group ( P < 0.001). Infants in the dexamethasone group

remained intubated and required oxygen therapy for a shorter pe-

riod than those in the control group (P < 0.001). Hyperglycaemia,

hypertension, growth failure and hypertrophy of the left ventricle

were transient side effects of early corticosteroid administration.

There were no significant differences in the rates of cerebral palsy,

blindness, deafness, or intellectual impairment, or in mean IQ, or

in the combined rate of death or cerebral palsy (Romagnoli 2002).

Sanders 1994: The dexamethasone group required less ventilatory

support (mean airway, peak inspiratory and end-expiratory pres-

sures, and IMV) and supplemental oxygen after study day four (all

P < 0.05). Improved tidal volume in the dexamethasone group, as

assessed by pulmonary function testing of infants who remained

intubated, was seen on study day seven (P = 0.02). The dexam-

ethasone group required a shorter time in hospital (median 95 days

vs. 106 days, P = 0.01). Survival in the dexamethasone group was

89% vs. 67% in the placebo group (P = 0.08). Survival without

CLD was 68% in the dexamethasone vs. 43% in the placebo group

(P = 0.14). Mean blood pressure was elevated on study day four to

seven. No differences in the rate of hyperglycaemia, incidence or

severity of IVH, or days to regain birth weight were seen. There

were no significant differences in the rates of cerebral palsy, blind-

ness, deafness, or intellectual impairment, or in the combined rate

of death or cerebral palsy (Sinkin 2002).

Shinwell 1996: No differences were found in any outcome variable

except for a reduction in the need for mechanical ventilation at

three days in dexamethasone treated infants (54/122, 44% vs. 71/

106, 67%; P = 0.001). Gastrointestinal haemorrhage, hyperten-

sion and hyperglycaemia were more common in treated infants,

but no life threatening complications, such as gastrointestinal per-

foration, were encountered. Follow-up of survivors at two to six

years showed no significant differences in the rates of blindness,

deafness, major neurosensory disability, or in the combined rate

of death or major neurosensory disability. However, there were

significant increases in the rates of abnormal neurological exami-

nation, developmental delay, and cerebral palsy. There was also a

significant increase in the combined rate of death or cerebral palsy

(Shinwell 2000).



Sinkin 2000: No differences were found in the dexamethasone

and placebo groups respectively for the primary outcomes of sur-

vival (79% vs. 83%), survival without oxygen at 36 weeks’ PMA

(both 59%), and survival without oxygen at 36 weeks’ PMA and

without late corticosteroids (46% vs. 44%). No significant differ-

ences between the groups were found for median time in oxygen

(50 vs. 56 days), ventilation (20 vs. 27 days), time to regain birth

weight (15.5 vs. 15.0 days), nor length or stay (88 vs. 89 days).

Infants given early dexamethasone were less likely to receive late

corticosteroids for BPD during their hospital stay (25 vs. 35%, P

= 0.042). No clinically significant side-effects were noted in the

dexamethasone group although there were transient elevations in

blood glucose and blood pressure with return to baseline by study

day 10. Among infants who died (40 vs. 33), there were no dif-

ferences in the median days on oxygen, ventilation or length of

hospital stay. However, in survivors (149 vs. 162), the following

were observed: median days on oxygen 37 vs. 45, ventilation 14 vs.

19 d, and length of stay 79 vs. 81 d, for the dexamethasone versus

placebo groups, respectively. There were no significant differences

in the rates of cerebral palsy, or in the combined rate of death or

cerebral palsy, or in mean Bayley scores (Sinkin 2002).

Soll 1999: There were no differences in the primary outcome of

CLD or death at 36 weeks’ PMA (early therapy 136/272 vs. 143/

270; P = 0.50). Infants who received early corticosteroid therapy

were less likely to need late treatment (114/272 vs. 165/270; P <

0.001). They also had a lower risk of PDA: 92/272 vs. 116/270; P

< 0.05) and were less likely to receive indomethacin therapy (131/

272 vs. 178/270; P < 0.001). However, infants who received early

corticosteroid therapy were more likely to have complications such

as gastrointestinal haemorrhage, (33/272 vs. 19/270; P < 0.05),

hyperglycaemia (201/272 vs. 154/270; P < 0.001), and use of in-

sulin therapy (169/272 vs. 103/270; P < 0.001). There was a trend

toward increased gastrointestinal perforation (30/272 vs. 19/270;

P < 0.01 ). In infants who had cranial ultrasound scans there was

an increase in PVL in the early corticosteroid group (7% vs. 3%;

P < 0.05). Infants who received early corticosteroid therapy had

fewer days in supplemental oxygen but they experienced poorer

weight gain.

Stark 2001a: Corticosteroid treated infants had a lower incidence

of the primary outcome, death or CLD at 36 weeks’ PMA (63%

vs. 69%; P < 0.05). Fewer infants in the corticosteroid group had

pulmonary interstitial emphysema (9% vs. 23%; P < 0.05), re-

quired oxygen at 28 days (78% vs. 94%; P < 0.05) or had sub-

sequent corticosteroid treatment (34% vs. 51%; P < 0.05). The

rates of severe IVH, PVL, ROP and nosocomial infection were

similar. Hypertension and hyperglycaemia were more frequent in

the corticosteroid group (27% vs. 4% and 23% vs. 12% respec-

tively with both P < 0.05). During the first 14 days 14/111 (13%)

infants in the corticosteroid group and 3/109 (3%) infants in the

placebo group had spontaneous gastrointestinal perforation with-

out NEC (P < 0.05). Spontaneous perforation was also associated

with indomethacin treatment ( P = 0.005) and there was an in-

teraction between indomethacin and corticosteroid therapy (P =

0.04). There were no significant differences in the rates of cere-

bral palsy, developmental delay, major neurosensory disability, the

combined rate of death or cerebral palsy, or the combined rate of

death or major neurosensory disability (Stark 2001).

Subhedar 1997: There was no difference in the combined inci-

dence of CLD and/or death before discharge from hospital be-

tween either infants treated with dexamethasone and controls (RR

0.95, 95% CI 0.79 -1.18) or those treated with inhaled NO and

controls (RR 1.05, 95% CI 0.84 -1.25). There were no significant

differences in the rates of cerebral palsy, blindness, deafness, de-

velopmental delay, the combined rate of death or cerebral palsy,

or the combined rate of death or major neurosensory disability

(Subhedar 2000, Subhedar 2002).

Suske 1996: Infants in the dexamethasone group were extubated

earlier (6.6 d vs. 14.2 d; P < 0.02) and required less time in sup-

plemental oxygen (4.2 d vs. 12.5 d; P < 0.02); pulmonary com-

plications tended to be lower in the dexamethasone group (1/14

vs. 4/12), as was the frequency of ROP (2/14 vs. 6/12; P < 0.05).

Tapia 1998: There were no significant differences in mortality and/

or CLD between the groups. There was a significant reduction

in the number of infants requiring oxygen at 36 weeks’ postmen-

strual age in the dexamethasone group (8% vs. 33%; P < 0.05).

Stepwise logistic regression analysis with oxygen dependency at 36

weeks as the dependent variable and birth weight, gestational age,

gender, prenatal corticosteroids and study treatment as the inde-

pendent variables showed that study treatment was the only vari-

able significantly associated with oxygen dependency at 36 weeks.

There were no differences in the number of days of mechanical

ventilation and oxygen treatment between the groups. There were

no differences in the incidences of major morbidity and possible

complications related to corticosteroid administration, except for

a lower incidence of NEC in the dexamethasone group.

Vento 2004: Seven dexamethasone treated infants and two control

infants were extubated during the study period of seven days. There

were no differences between groups for RDS, PDA or severe IVH

(grade 3 or 4). Dexamethasone treated infants had lower absolute

cell count and proportion of polymorphs in tracheal aspirate fluid

compared to control infants as early as day 1 of treatment. They

also had significantly higher dynamic compliance values compared

to control infants (P < 0.01) as early as day 2 of treatment. There

were also significantly lower inspired oxygen concentrations on

day 2 (0.24 vs. 0.31; P < 0.05) and MAP on day 5 (4.8 vs. 7.2 cm

H2O; P < 0.05).

Wang 1996: Dexamethasone treatment decreased fractional in-

spired oxygen concentration, arterial carbon dioxide tension, MAP

and facilitated successful weaning from mechanical ventilation.

SP-A concentrations in tracheal aspirates were increased at day 7

and 14, and SP-D concentrations were increased during the period

from days 3 - 14 in the dexamethasone treated group, compared

with the control group.

Watterberg 1999: More infants treated with hydrocortisone sur-



vived without supplemental oxygen at 36 weeks’ PMA (12/20 vs.

7/20; P = 0.023). Hydrocortisone treatment was also associated

with a reduction in duration of oxygen > 40% (7 vs. 28 days; P

= 0.06), duration of oxygen > 25% (48 vs. 69 days; P = 0.02)

and duration of mechanical ventilation (25 vs. 32 days; P = 0.03).

There were no differences in the rates of death, sepsis, PDA, NEC,

gastrointestinal perforation, IVH or ROP. There were no signifi-

cant differences in the rates of cerebral palsy, blindness, deafness,

or the combined rate of death or cerebral palsy (Watterberg 2002).

Watterberg 2004: There were no differences in primary outcomes

between groups (hydrocortisone vs. placebo): survival without

BPD (35% vs. 34%), death before 36 weeks’ PMA (15% vs. 16%)

and death before discharge (16% vs. 17%). In a subgroup of infants

exposed to chorioamnionitis the hydrocortisone treated group had

significantly improved survival without BPD (38% vs. 24%; P =

0.005) and lower mortality at 36 weeks’ PMA (10% vs. 18%; P =

0.02) and before discharge (12% vs. 21%; P = 0.02). During treat-

ment the rates of hyponatraemia, hypernatraemia, hyperkalaemia,

hyperglycaemia, hypertension and GI bleeding were similar be-

tween groups. 74 (41%) infants in the hydrocortisone group were

treated with insulin vs. 62 (34%) in the placebo group (P = 0.19).

Serum sodium and mean arterial blood pressure were significantly

higher in hydrocortisone treated infants (P< 0.001 and P = 0.022,

respectively). Other outcomes included no differences in weight

gain nor head circumference, durations of oxygen and ventilation,

pulmonary air leaks, pulmonary haemorrhage, PDA, sepsis, IVH,

PVL, ROP and NEC. However, hydrocortisone treated infants

were less likely to receive open label corticosteroids during the

treatment period (18% vs. 28%; P = 0.02) and more likely to have

a spontaneous GI perforation (9% vs. 2%; P = 0.01). At follow-up

there were no significant differences in the rates of cerebral palsy,

major neurological disability, developmental delay, rehospitalisa-

tion, or the combined rates of death or cerebral palsy, or death or

major neurological disability (Watterberg 2007).

Yeh 1990: Infants in the dexamethasone group had significantly

higher pulmonary compliance, tidal volume and minute ventila-

tion, and required lower MAP for ventilation than infants in the

placebo group. The endotracheal tube was successfully removed

from more infants in the dexamethasone group (16/28 vs. 8/29;

P < 0.025) at two weeks of age. Nineteen infants (65%) in the

placebo group and 11 (39%) in the dexamethasone group (P <

0.05) had lung injuries characterised by:

1. surviving infants with CLD

2. infants who died of intractable respiratory failure and had evi-

dence of CLD at autopsy

3. infants who died of intractable respiratory failure with clinical

evidence of CLD

Dexamethasone therapy was associated with a temporary increase

in blood pressure and plasma glucose concentration and a delay

in somatic growth.

Yeh 1997: Infants in the dexamethasone group had a significantly

lower incidence of CLD than those in the placebo group judged

either at 28 postnatal days (21/132 vs. 40/130, P < 0.05) or at

36 weeks postmenstrual age (20/132 vs. 37/130, P < 0.05). More

infants in the dexamethasone group were extubated during the

study. There was no difference between the groups for mortality

(39/130 vs. 44/132); however, a higher proportion of infants in

the dexamethasone group died in the late study period, proba-

bly attributable to infection. There was no difference between the

groups for duration of oxygen therapy and hospitalisation. Signif-

icantly more infants in the dexamethasone group had either bac-

teraemia or clinical sepsis (44/132 vs. 27/130, P < 0.05). Other

immediate but transient side effects observed in the dexametha-

sone group were hyperglycaemia, hypertension, cardiac hypertro-

phy, hyperparathyroidism and delay in growth rate. At 25 months

of age there were no significant differences in the rates of blind-

ness, developmental delay, major neurosensory disability, the com-

bined rate of death or cerebral palsy, or the combined rate of death

or major neurosensory disability. However, there were significant

increases in the rates of abnormal neurological examination and

cerebral palsy among survivors (Yeh 1998).The follow-up rate of

survivors at 8 years was 92% (146/159). Although rates of cerebral

palsy were not significantly higher in the dexamethasone group,

their overall motor performance on the Movement ABC was worse

than in controls. IQ and other cognitive performance was signifi-

cantly worse in the dexamethasone group. Overall the survivors in

the dexamethasone group had more major neurological disability.

Results of Meta-analysis

Meta-analysis of these twenty-eight studies of early post-natal cor-

ticosteroid treatment shows the following results:

• Mortality - There was no evidence that early postnatal

corticosteroid treatment reduced mortality either at 28 days

(typical relative risk 1.02, 95% CI 0.88, 1.19; 19 studies and

2950 infants), before discharge (typical relative risk 1.00, 95%

CI 0.89, 1.13; 27 studies and 3720 infants), or at the latest age

possible to determine the outcome (typical relative risk 0.99,

95% CI 0.89, 1.12; 27 studies and 3720 infants).

• Chronic lung disease - Early corticosteroids reduced the

incidence of CLD defined as needing oxygen supplementation at

either 28 days (typical relative risk 0.87, 95% CI 0.81, 0.93;

typical risk difference -0.07, 95% CI -0.10, -0.03; 17 studies and

2874 infants) or 36 weeks’ PMA (typical relative risk 0.79, 95%

CI 0.71, 0.88; typical risk difference -0.07, 95% CI -0.10, -0.04;

21 studies and 3286 infants). There was also a reduction in CLD

at 36 weeks’ PMA in survivors (typical relative risk 0.82, 95% CI

0.74, 0.90; typical risk difference -0.08, 95% CI -0.11, -0.04; 18

studies and 2462 infants). However, there was no significant

reduction in the proportion of survivors discharged home on

oxygen, although there were fewer studies where this outcome

could be determined (typical relative risk 0.72, 95% CI 0.51,

1.03; 6 studies and 691 infants). Early corticosteroids reduced

the need for later corticosteroid treatment overall (typical relative

risk 0.75, 95% CI 0.68, 0.82; typical risk difference -0.11, 95%

CI -0.15, -0.07; 14 studies and 2483 infants) and in survivors



(typical relative risk 0.77, 95%CI 0.67 - 0.89; typical risk

difference -0.11, 95%CI -0.77, -0.05; 7 studies and 895 infants).

• Death or chronic lung disease - Early corticosteroids

reduced the incidence of death or CLD defined as needing

oxygen supplementation at either 28 days (typical relative risk

0.92, 95% CI 0.88, 0.96; typical risk difference -0.06, 95% CI -

0.09, -0.03; 16 studies and 2548 infants) or 36 weeks’ PMA

(typical relative risk 0.89, 95% CI 0.84, 0.95; typical risk

difference -0.06, 95% CI -0.09, -0.02; 22 studies and 3320

infants).

• Failure to extubate - Early corticosteroids reduced the rates

of failure to extubate at three days (typical relative risk 0.73, 95%

CI 0.62, 0.86; typical risk difference -0.19, 95% CI -0.28, -0.10;

3 studies and 381 infants), 7 days (typical relative risk 0.75, 95%

CI 0.65, 0.86; typical risk difference -0.13, 95% CI - 0.19, -

0.07; 7 studies and 956 infants), 14 days (typical relative risk

0.77, 95% CI 0.62, 0.97; typical risk difference -0.10, 95% CI -

0.19, -0.02; 4 studies and 443 infants) and at 28 days (typical

relative risk 0.84, 95% CI 0.72, 0.98; typical risk difference -

0.07, 95% CI -0.13, -0.01, 7 studies and 902 infants).

Complications during the primary hospitalisation were as follows:

• Metabolic complications - Early corticosteroids increased

the risk of hyperglycaemia (typical relative risk 1.34, 95% CI

1.21, 1.48; typical risk difference 0.11, 95% CI 0.07, 0.15; 13

studies and 2175 infants), and hypertension (typical relative risk

1.85, 95% CI 1.55, 2.22; typical risk difference 0.10, 95% CI

0.07, 0.13; 11 studies and 1996 infants).

• Gastrointestinal complications - Early corticosteroids

increased the risks of GI bleeding (typical relative risk 1.86, 95%

CI 1.35, 2.55; typical risk difference 0.05, 95% CI 0.03, 0.08;

12 studies and 1820 infants) and GI perforation (typical relative

risk 1.81, 95% CI 1.33, 2.48, typical risk difference 0.04, 95%

CI 0.02, 0.06; 15 studies and 2523 infants) but there was no

evidence of effect on the incidence of NEC (typical relative risk

0.87, 95% CI 0.70, 1.08; 22 studies and 3497 infants).

• Other effects - Early corticosteroids increased the risk of

hypertrophic cardiomyopathy (relative risk 4.33, 95% CI 1.40,

13.4; risk difference 0.40, 95% CI 0.17, 0.63; 1 study and 50

infants) and growth failure (relative risk 6.67, 95% CI 2.27,

19.6; risk difference 0.68, 95% CI 0.48, 0.88; 1 study and 50

infants) in one study where these were reported. Early

corticosteroids reduced the risk of PDA (typical relative risk 0.78,

95% CI 0.72, 0.85; typical risk difference -0.09, 95% CI -0.12, -

0.06; 23 studies and 3493 infants), but there was no significant

effect on pulmonary air leaks (typical relative risk 0.93, 95% CI

0.75, 1.15; 14 studies and 2604 infants), severe IVH (typical

relative risk 0.95, 95% CI, 0.82, 1.11; 24 studies and 3572

infants), pulmonary haemorrhage (typical relative risk 1.16, 95%

CI 0.85, 1.59; 9 studies and 1299 infants), PVL (typical relative

risk 1.20, 95% CI 0.85, 1.68; 12 studies and 2176 infants) or

infection (typical relative risk 1.02, 95% CI 0.93, 1.13; 23

studies and 3558 infants). Any ROP (typical relative risk 0.88,

95%CI 0.80, 0.97; 10 studies and 1345 infants) and both severe

ROP (typical relative risk 0.79, 95% CI 0.65, 0.97; risk

difference -0.04, 95% CI -0.07, -0.01; 13 studies and 2056

infants) and severe ROP in survivors (typical relative risk 0.77,

95%CI 0.64, 0.94; risk difference -0.05, 95% CI -0.09, 0.01; 12

studies and 1575 infants) were reduced by early corticosteroids.

Follow-up data were as follows:

• Follow-up studies are limited in number relative to the total

number of studies - 12 with follow-up data out of a total of 28.

• Developmental delay was increased with corticosteroids in

one study with the criteria for the diagnosis not explicit (relative

risk 1.68, 95% CI 1.08, 2.61; risk difference 0.14, 95% CI 0.03,

0.24; 1 study and 248 infants).

• Cerebral palsy was increased with corticosteroids (typical

relative risk 1.45, 95% CI 1.06, 1.98; typical risk difference

0.03, 95% CI 0.00, 0.06; 12 studies and 1452 infants), but there

was a non-significant increase in the combined outcome, death

or cerebral palsy (typical relative risk 1.09, 95% CI 0.95, 1.25;

12 studies and 1452 infants).

• There were non-significant effects on major neurosensory

disability (typical relative risk 1.13 95% CI 0.92, 1.38; 7 studies

and 1233 infants) and the combined outcome of death or major

neurosensory disability (typical relative risk 1.04, 95% CI 0.93,

1.16; 7 studies and 1233 infants).

• There was a significant increase in the rate of abnormal

neurological examination (typical relative risk 1.81, 95% CI

1.33, 2.47; typical risk difference 0.10, 95%CI 0.05, 0.15; 5

studies and 829 infants) and in the combined outcome of death

or abnormal neurological examination (typical relative risk 1.23,

95% CI 1.06, 1.42; typical risk difference 0.10, 95%CI 0.03,

0.16; 5 studies and 829 infants). Although the criteria for this

diagnosis were vague and varied between studies, the size of the

difference in this outcome in the trials where data were available

was similar to the size of the difference in cerebral palsy in the

corresponding study. In the study of Yeh et al (Yeh 1997), the

data for cerbral palsy were obtained at age 8-9 years, whereas the

abnormal examination data were obtained from earlier in

childhood, at 2 years of age.

• There were no significant effects on other long-term

outcomes of blindness, deafness, formal psychometric testing,

abnormal EEG, behaviour problems, or rehospitalisation.

Subgroup analysis by type of corticosteroid used in the trials re-

vealed the following main results:

• Mortality - There was little difference in the effects of either

dexamethasone or hydrocortisone on mortality at 28 days

(typical relative risk; dexamethasone 1.06, 95% CI 0.90, 1.24;

16 studies and 2603 infants; hydrocortisone 0.78, 95% CI 0.50,



1.23; 3 studies and 347 infants), before discharge (typical relative

risk; dexamethasone 1.03, 95% CI 0.90, 1.18; 19 studies and

2840 infants; hydrocortisone 0.88, 95% CI 0.67, 1.17; 8 studies

and 880 infants), or at the latest age possible to determine the

outcome (typical relative risk; dexamethasone 1.02, 95% CI

0.90, 1.17; 19 studies and 2840 infants; hydrocortisone 0.89,


• Chronic lung disease - Most of the benefit of early

corticosteroids in reducing the incidence of CLD came from

dexamethasone, with little effect of hydrocortisone, regardless of

the definition of CLD; needing oxygen supplementation at 28

days (typical relative risk; dexamethasone 0.85, 95% CI 0.79,

0.92; typical risk difference -0.07, 95%CI -0.11, -0.04; 16

studies and 2621 infants; hydrocortisone 1.00, 95% CI 0.85,

1.18; 1 study and 253 infants), needing oxygen at 36 weeks’

PMA (typical relative risk; dexamethasone 0.70, 95% CI 0.61,

0.81; typical risk difference -0.08, 95%CI -0.12, -0.05; 15


1.12; 6 studies and 802 infants). The benefit in reducing the

need for late rescue with postnatal corticosteroids was also largely

confined to the dexamethasone group (typical relative risk;

dexamethasone 0.70, 95% CI 0.63, 0.78; typical risk difference -

0.14, 95%CI -0.19, -0.10; 9 studies and 1865 infants;

hydrocortisone 1.17, 95% CI 0.78, 1.73; 2 studies and 410

infants).

• Death or chronic lung disease - Most of the benefit of early

corticosteroids in reducing the incidence of the combined

outcome of death or CLD came from dexamethasone, with little

effect of hydrocortisone; death or CLD defined as needing

oxygen supplementation at 28 days (typical relative risk;

dexamethasone 0.91, 95% CI 0.86, 0.96; typical risk difference -

0.07, 95%CI -0.10, -0.03; 14 studies and 2293 infants;

hydrocortisone 1.00, 95% CI 0.90, 1.12; 1 study and 253

infants) or 36 weeks’ PMA (typical relative risk;dexamethasone

0.87, 95% CI 0.80, 0.94; typical risk difference -0.07, 95%CI -

0.10, -0.03; 15 studies and 2484 infants; hydrocortisone 0.95,


• Some of the short-term complications observed with

corticosteroids were related more to dexamethasone than to

hydrocortisone, including hyperglycaemia (typical relative risk;

dexamethasone 1.36, 95% CI 1.22, 1.50; typical risk difference

0.11, 95%CI 0.08, 0.15; 12 studies and 2125 infants;

hydrocortisone 0.92, 95% CI 0.50, 1.67; 1 study and 50

infants), hypertension (typical relative risk; dexamethasone 1.84,

95% CI 1.54, 2.21; typical risk difference 0.10, 95%CI 0.07,

0.13; 10 studies and 1946 infants; hydrocortisone 3.00, 95% CI

0.33, 26.92; 1 study and 50 infants), and gastrointesinal

haemorrhage (typical relative risk; dexamethasone 1.87, 95% CI

1.35, 2.58; typical risk difference 0.05, 95%CI 0.03, 0.08; 10


8.74; 2 studies and 91 infants). However, both types of

corticosteroid were associated with more GI perforation (typical

relative risk; dexamethasone 1.73, 95% CI 1.20, 2.51; typical

risk difference 0.03, 95%CI 0.01, 0.05; 9 studies and 1340

infants; hydrocortisone 2.02, 95% CI 1.13, 3.59; typical risk

difference 0.06, 95%CI 0.01, 0.10; 6 studies and 583 infants)

and lower rates of PDA (typical relative risk; dexamethasone

0.76, 95% CI 0.69, 0.84; typical risk difference -0.10, 95%CI -

0.13, -0.06; 17 studies and 2707 infants; hydrocortisone 0.85,

95% CI 0.73, 0,99; typical risk difference -0.09, 95%CI -0.12, -

0.06; 6 studies and 786 infants).

• Cerebral palsy and the combined outcome of death or

cerebral palsy were more common with dexamethasone but not

hydrocortisone (cerebral palsy; typical relative risk;




infants; death or cerebral palsy; typical relative risk;




infants)

It was noted that in some of the subgroup analyses there were few

studies and small sample sizes for the hydrocortisone subgroup,

and hence to power to detect either beneficial or harmful effects

of hydrocortisone was limited under these circumstances.

D I S C U S S I O N

Corticosteroids are potent drugs which may improve lung function

in infants with CLD by a number of different mechanisms. It

has been suggested that they might have a role to play in the

prevention of CLD by suppressing the inflammatory response in

the lung of infants at risk (Groneck 1995). It has also been shown

that infants who develop CLD have low cortisol levels following

ACTH stimulation during the first week of life (Watterberg 1999).

To be effective in preventing CLD corticosteroids may have to be

given within the first few days of life.

This review has demonstrated that early corticosteroid treatment

facilitates weaning from the ventilator. Additional advantages are

increased survival without CLD at 28 days and 36 weeks’ PMA,

reductions in the risk of CLD at 28 days and at 36 weeks’ PMA,

the need for late treatment with corticosteroids, and PDA. On the

other hand, there are increases in the risk of gastrointestinal bleed-

ing, intestinal perforation, hyperglycaemia, hypertension, hyper-

trophic cardiomyopathy and growth failure.

There are other potential hazards of corticosteroid treatment in the

neonate including retardation of growth (Gibson 1993), protein

breakdown (van Goudoever 1994), cardiac hypertrophy (Werner

et al 1992) and possible adverse effects on development of the



central nervous system (Weichsel 1977; Gramsbergen 1998) and

lungs (Tschanz 1995). One study has shown a significant decline in

the growth of head circumference with early corticosteroid treat-

ment (Papile 1996). Long-term follow-up results show that early

dexamethasone treatment is associated with a significant increase

in the risk of developmental delay and cerebral palsy, but no signif-

icant effects on the combined outcome of death or cerebral palsy

except in the subgroup of infants treated with dexamethasone.

One study where the rate of cerebral palsy was significantly higher

at 2 years of age used a four week tapering course of dexametha-

sone (Yeh 1997) and so is similar in duration to the six week ta-

pering course of late corticosteroids reported by O’Shea 1999 and

included in the systematic review of late corticosteroids (Halliday

2008). However, in the the Yeh study (Yeh 1997) the numbers of

surviving children with cerebral palsy declined between two and

eight to nine years of age, and the difference became statistically

non-signiifcant. In the follow-up study of Shinwell 1996 (Shinwell

2000) adverse long-term neurological outcomes were reported in

children treated with only a three day course of early dexametha-

sone starting within 12 hours of birth. This finding is of extreme

importance and concern as there was about a three-fold increased

risk of cerebral palsy in survivors including children with spastic

diplegia, spastic quadriplegia and hemiplegia. Why dexametha-

sone given early for a short course should have such devastating ef-

fects is unknown. Certainly some infants would have been treated

with repeat courses of dexamethasone but this would have been

more likely in the control infants. Periventricular leucomalacia

(PVL) is an obvious cause of cerebral palsy, but studies have shown

no excess of PVL in corticosteroid-treated infants compared with

controls. Despite the increase in the diagnosis of cerebral palsy, it

is important to note that this does not necessarily translate into

major functional disability for the children concerned.

This systematic review found that early (≤ 7 days) postnatal corti-

costeroids for preventing chronic lung disease in preterm infants,

in the regimens used, have significant short and long-term effects,

both beneficial and harmful. A significant problem in interpreting

the late follow-up data is that only twelve of the 28 trials of early

postnatal corticosteroids have reported follow-up results; there-

fore, the possibility of follow-up bias and publication bias must

be considered. Potential limitations of the study with a significant

increase in the rate of cerebral palsy (Shinwell 1996) are that only

84% of surviving infants were examined, and the age of assess-

ment was in early childhood. It is important to remember that

cerebral palsy had been diagnosed before the children were five

years of age in most cases; diagnosing cerebral palsy with certainty

before five years of age is problematic (Stanley 1982). In the other

study where the rate of cerebral palsy was significantly worse at

two years of age with 81% follow-up, the difference became non-

significant at eight to nine years, an age when the diagnosis of

cerebral palsy is more certain, and where the follow-up rate was

much better (92%), illustrating the importance of age of assess-

ment and high follow-up rates. No study was designed primarily

to test the effect of postnatal corticosteroids on adverse long-term

neurosensory outcome, and all were underpowered to detect clin-

ically important differences in long-term neurosensory outcome.

In the subgroup analyses by type of corticosteroid, most of the

beneficial and harmful effects were attributable to dexamethasone,

with hydrocortisone having little effect, but the power to detect

beneficial or harmful effects of hydrocortisone was low in most

comparisons.

In an observational study of infants born after antenatal corti-

costeroid therapy there appeared to be an excess of periventric-

ular leucomalacia in those whose mothers had received dexam-

ethasone rather than betamethasone (Baud 1999). Most studies

of postnatal corticosteroids used dexamethasone in high doses of

0.5 - 1.0 mg/kg/day. Other corticosteroids or lower doses of dex-

amethasone may prove to be safer, but there is little evidence to

support the use of hydrocortisone as prophylaxis for CLD in the

dose regimes employed in the studies reviewed. Further studies are

needed comparing lower doses of corticosteroids, other corticos-

teroids and alternative routes of administration, e.g. by inhalation

(see Cochrane Review by Shah 2000).

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

The benefits of early postnatal corticosteroids in preterm infants

at risk of developing CLD may not outweigh the real or potential

adverse effects. Early postnatal corticosteroid treatment resulted

in short-term benefits, including earlier extubation and decreased

risks of CLD and of death or CLD at 28 days and 36 weeks’

PMA, but was also associated with significant short and long-

term adverse effects. Adverse effects included the short-term risk

of gastrointestinal bleeding, intestinal perforation, hyperglycemia,

and hypertension, and the long-term risks of abnormal neurolog-

ical examination and cerebral palsy. However, the methodological

quality of the studies determining the long-term outcome was lim-

ited in some cases; the children have been assessed predominantly

before school age and no study was sufficiently powered to detect

important adverse long-term neurosensory outcomes. Therefore,

given the risks of potential short-term and long-term adverse ef-

fects vs. the potential short-term benefits, it appears appropriate

to curtail early corticosteroid treatment for prevention of chronic

lung disease.

Implications for research

There is a compelling need for the long-term follow-up and re-

porting of late outcomes, especially neurological and developmen-

tal outcomes, among surviving infants who participated in all ran-

domised trials of early postnatal corticosteroid treatment. Tests of

gross motor function, cognitive functioning, hearing and visual

acuity should be included in these follow-up studies.



Future studies are also needed to accurately identify those infants

most at risk of developing CLD. Any future placebo-controlled

trials of postnatal corticosteroids in preterm infants should in-

clude long-term neurological follow-up. Studies comparing differ-

ent types, doses and durations of corticosteroid treatment, and ex-

amining the effects of inhaled corticosteroids, are urgently needed.

R E F E R E N C E S

References to studies included in this review

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neonatal dexamethasone treatment for prevention of

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Stern L. A controlled trial of hydrocortisone therapy in

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Fitzhardinge PM, Eisen A, Lejtenyi C, Metrakos K, Ramsay

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Biswas S. Personal communication. 2002.∗ Biswas S, Buffery J, Enoch H, Bland M, Markiewicz M,

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Efird MM, Heerens AT, Gordon PV, et al.A randomized-

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Kopelman AE, Moise AA, Holbert D, Hegemier SE. A

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Mukhopadhyay 1998 {published data only}

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Shinwell 1996 {published data only}

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therapy is associated with increased incidence of cerebral

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postnatal dexamethasone to prevent chronic lung disease

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Sinkin 2000 {published data only}

D’Angio CT, Maniscalco WM, Ryan RM, et al.Vascular

endothelial growth factor in pulmonary lavage fluid

from premature infants: effects of age and postnatal

dexamethasone. Biology of the Neonate 1999;76:266–73.

Sinkin RA. Personal communication. 2002.∗ Sinkin RA, Dweck HS, Horgan MJ, Gallaher KJ, Cox

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Soll 1999 {published data only}

Soll RF for the Vermont Oxford Network Steroid Study

Group. Early postnatal dexamethasone therapy for the

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Stark 2001a {published data only}

Stark AR, Carlo W, Vohr BR, Papile L, Bauer C, Donovan

E, Oh W, Shankaran S, Tyson JE, Wright LL, Saha

S, Poole K. National Institute of Child Health and

Human Development Neonatal Research Network.

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Shankaran S, Donovan EF, Oh W, Bauer CR, Saha S,

Poole WK, Stoll BJ. National Institute of Child Health and

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Suske 1996 {published data only}

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Tapia 1998 {published data only}

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dexamethasone therapy may lessen lung inflammation in

premature infants with respiratory distress syndrome on

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Watterberg KL, Shaffer ML, Mishefske MJ, Leach

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C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Anttila 2005

Methods Random allocation by use of coded vials prepared in the pharmacy of each centre. Blinding of randomi-

sation: yes. Blinding of intervention: yes. Complete follow-up: yes. Blinding of outcome measurements:

yes

Participants 109 infants with birth weight 500-999 g, gestation < 32 weeks, need for mechanical ventilation and

supplemental oxygen by 4 hours of age. Stratified by weight (500-749 g vs. 750-999 g). Exclusions: life-

threatening congenital anomalies or known chromosomal anomaly

Interventions Four doses of dexamethasone 0.25 mg/kg each at 12 hourly intervals or normal saline as placebo. First dose

was given before 6 hours. Open-label dexamethasone was allowed when deemed necessary by attending

physician, but its use was discouraged

Outcomes Survival to 36 weeks without IVH (grade III-IV), PVL (echodensities after 1st week or periventricular

cysts on ultrasound) or BPD (oxygen at 36 weeks), growth, duration of assisted ventilation and oxygen,

late corticosteroid treatment, infection, hyperglycaemia, hypertension, ROP, PDA, GI bleeding and per-

foration and NEC

Notes This paper also reported a meta-analysis of early short vs. early prolonged dexamethasone treatment

Risk of bias

Item Authors’ judgement Description

Allocation concealment? Yes A - Adequate

Baden 1972

Methods Random allocation using random numbers and sealed envelopes. Blinding of randomisation: yes. Blinding

of intervention: yes. Complete follow-up: yes. Blinding of outcome measurements: yes

Participants 44 preterm infants < 24 hours old with respiratory distress both clinically and radiologically

Interventions Hydrocortisone 25 mg/kg on admission and 12 hours later intravenously. Control group given placebo

Outcomes Death, FiO2, cortisol levels and blood gases.

Notes The oldest study, carried out 1972. Used hydrocortisone in a very short course of treatment

Risk of bias




Baden 1972 (Continued)


Biswas 2003

Methods Randomisation by Oxford Perinatal Trials Unit. Blinding of randomisation: yes. Blinding of intervention:

yes. Blinding of outcome measurements: yes. Complete follow-up: yes

Participants 253 infants < 30 weeks’ gestation, within 9 hours of birth at entry; all mechanically ventilated

Interventions Hydrocortisone 1mg/kg/day as continuous infusion for 5 days, then 0.5 mg/kg/day for 2 days. Also given

tri-iodothyronine 6 micrograms/kg/day for 5 days, halving to 3 micrograms/kg/day for 2 days. Controls

given equal volume infusion of 5% dextrose

Outcomes The primary outcome was death or ventilator dependence at 7 days, or death or oxygen dependence at

14 days. Secondary outcomes included durations of ventilation, oxygen dependence and hospitalisation,

oxygen dependency at 36 weeks, IVH, PVL, PDA and NEC

Notes Hydrocortisone combined with T3 infusion

Risk of bias



Bonsante 2007

Methods Computer-generated randomisation centrally. Blinding of randomisation: yes. Blinding of intervention:

yes. Complete follow-up reporting: yes for outcomes during primary hospital stay - 98% of surviving

infants traced to 2 years of age. Outcome assesment blind: yes

Participants 70 infants either < 1000 grams birth weight or < 28 weeks’ gestation, ventilator-dependent after 7 days of

age and considered to be a candidate for corticosteroids. Exclusions: major anomaly likely to affect long-

term neurological outcome

Interventions Active treatment - total dose of dexamethasone 0.89 mg/kg over 10 days. Placebo group - equal volume

of 0.9% saline

Outcomes Primary outcomes: survival free of disability at 2 years of age, mortality up to 2 years of age and neurological

outcome after discharge. Secondary outcomes: rate of CLD, death or CLD, failure to extubate, other

complications during primary hospital stay including GI perforation, severe IVH (grade 3 or 4) and cystic

PVL, long-term neurosensory impairment (blindness, deafness, developmental delay assessed by MDI

on Bayley scales, cerebral palsy) and disabilities (severe - any of severe cerebral palsy [not likely to walk],

blindness or severe developmental delay [MDI < 55], moderate - moderate cerebral palsy [not walking

at 2 years but likely to do so], deafness, moderate developmental delay [MDI 55 to < 70], mild - mild

cerebral palsy [walking at 2 years] or mild developmental delay [MDI 70 to < 85]



Bonsante 2007 (Continued)

Notes

Risk of bias



Efird 2005

Methods Random allocation using numbered sealed, opaque envelopes. Blinding of randomisation: yes. Blinding

of Intervention: yes. Complete follow-up: yes. Blinding of outcome measurements: yes

Participants 34 infants inborn with gestation > 23 weeks and < 29 weeks, and birth weight > 500 g and < 1000 g

enrolled by 2 hours of age. Exclusions: major malformations, chromosomal abnormalities and congenital

heart disease

Interventions Hydrocortisone intravenously at dose of 1 mg/kg every 12 hours for 2 days, followed by 0.3 mg/kg every

12 hours for 3 days. Control infants received an equivalent volume of normal saline as placebo

Outcomes Blood pressure, urine output, hyperglycaemia, mortality, durations of mechanical ventilation and hospital

stay, CLD (oxygen at 36 weeks), infection, NEC, intestinal perforation, PDA, IVH, PVL, and cortisol

levels

Notes

Risk of bias



Garland 1999

Methods Randomisation by study pharmacists at each centre. Blinding of randomisation: yes. Blinding of inter-

vention: yes. Blinding of outcome measurements: yes. Complete follow-up: yes

Participants 241 infants weighing between 500 and 1500 g, received surfactant, at significant risk for CLD or death

using a model to predict at 24 hours

Interventions 3 day course of dexamethasone beginning at 24-48 hours. The first 2 doses were 0.4 mg/kg, 3rd and 4th

doses 0.2 mg/kg and the 5th and 6th doses 0.1 mg/kg and 0.05 mg/kg respectively. Dexamethasone dose

reduced slightly after first interim analysis (see Notes). A similar volume of normal saline was given to

control infants



Garland 1999 (Continued)

Outcomes The primary outcomes were survival without CLD defined as oxygen therapy at 36 weeks to maintain

SaO2 above 91% and mortality. Secondary outcomes included duration of ventilation and supplemental

oxygen, respiratory support at 28 days, length of stay for survivors, use of subsequent dexamethasone

therapy and usual complications of prematurity

Notes At the first interim analysis (n = 75) an increased risk of GI perforation was noted in the dexamethasone

group. The data monitoring committee recommended reducing the dexamethasone dose to: 4 doses of

0.25 mg/kg/dose every 12 hours begun at 24 - 48 hours followed by doses of 0.125 mg/kg and 0.05 mg/

kg at the next two 12 hour periods respectively

Risk of bias



Halac 1990

Methods Random allocation using list of random numbers. Blinding of randomisation: yes. Blinding of interven-

tion: yes. Complete follow-up: yes. Blinding of outcome measurement: yes

Participants 248 infants, birthweight ≤1500 g, gestation <34 wk, with evidence of “birth asphyxia” (1 minute Apgar

score <5, prolonged resuscitation and metabolic acidosis [HCO3 <15 mmol/l within 1 hour of birth]).

Interventions 7 day course of dexamethasone 1 mg/kg 12 hourly beginning on first day of life

Outcomes Neonatal mortality, mortality to discharge, NEC, PDA, sepsis and severe IVH

Notes Possible exclusion of 5 deaths after randomisation but not clear which group they came from

Risk of bias



Kopelman 1999

Methods Random allocation in the hospital pharmacy stratified by use of antenatal corticosteroids. Blinding of

randomisation: yes. Blinding of intervention: yes. Complete follow-up: yes. Blinding of outcome mea-

surement: yes

Participants 70 infants of < 28 weeks’ gestation requiring intermittent mandatory ventilation and arterial catheterisation

Interventions Dexamethasone 0.2 mg/kg within 2 hours of delivery. Control infants given an equal volume of saline



Kopelman 1999 (Continued)

Outcomes Ventilation Index (VI), IMV rate, mean blood pressure, incidence of PDA, need for indomethacin and

number extubated during the first week and usual complications of RDS

Notes After an interim analysis showed that the incidence of IVH was much lower than expected, enrollment

was stopped and the analysis was limited to a comparison of ventilator settings, blood pressure and pressor

use during the first 7 days.

The outcome of successful extubation was available at only one hospital where 38 infants were enrolled

Risk of bias



Lin 1999

Methods Random allocation in a paired sequential trial. Assignment determined by pharmacist and groups stratified

by birthweight: 500-999 g, 1000 - 1500 g and 1501 - 1999 g. Blinding of randomisation: yes. Blinding

of intervention: yes. Blinding of outcome measurement: yes. Complete follow-up: yes

Participants 40 infants of 500-1999 g with severe RDS, needing IPPV within 6 h of birth

Interventions Dexamethasone 0.25 mg/kg 12 hourly from 1 - 7 d, 0.12 mg/kg 12 hourly from 8 - 14 d, 0.05 mg/kg 12

hourly from 15-21 d, 0.02 mg/kg 12 hourly from 22 - 28 d. Saline placebo was given to controls

Outcomes Mortality at 28 d and discharge, failure to extubate (during study), death or CLD (36 wk), CLD (28 d

and 36 wk), infection (clinical), severe IVH, plasma glucose and mean blood pressure on d 2, 5, 7 and

16, weight at 2 wk

Notes Sequential analysis for 12 pairs. Data given for 40 infants as randomised into the 2 groups

Risk of bias



Mukhopadhyay 1998

Methods Random allocation, method not stated. Blinding of randomisation: not sure. Blinding of intervention:

not sure. Blinding of outcome measurement: not sure. Complete follow-up: yes

Participants 19 infants < 34 weeks and < 2000 g who could be provided with ventilation. Clinical and radiographic

evidence of RDS, IPPV with oxygen > 30%



Mukhopadhyay 1998 (Continued)

Interventions Dexamethasone 0.5 mg/kg per dose 12 hourly for 3 days starting within 6 hours of birth. The control

group did not receive any drug

Outcomes Changes in oxygen requirements, mean duration of ventilation, culture positive sepsis, PDA, BPD (not

defined), pneumothorax, mortality

Notes Infants were only entered into the trial if a ventilator was available. Surfactant was not given

Risk of bias


Allocation concealment? Unclear B - Unclear

Ng 2006

Methods Random allocation in blocks of 6 by computer-generated random numbers and opening numbered sealed

opaque envelopes. Blinding of randomisation: yes. Blinding of intervention: yes. Complete follow-up:

yes. Blinding of outcome measurements: yes

Participants 48 infants of gestation < 32 weeks and birth weight < 1500 g who had systemic hypotension despite

treatment with volume expanders and dopamine within the first 7 days of life. Infants also had to have an

indwelling arterial catheter for continuous BP monitoring. Exclusions: major or lethal congenital or chro-

mosomal abnormalities, congenital heart defects, previous postnatal systemic or inhaled corticosteroids,

proven infection or NEC

Interventions Hydrocortisone 1 mg/kg every 8 hours for 5 days. Control infants received isotonic saline as a placebo for

5 days

Outcomes BP, use of vasopressors, durations of ventilation, oxygen and hospital stay, PIE, pulmonary haemorrhage,

pneumothorax, hyperglycaemia, glycosuria, IVH (grades III or IV), PVL, NEC, GI perforation, sepsis,

ROP (> stage II) and mortality

Notes

Risk of bias





Peltoniemi 2005

Methods Random allocation in each centre using identical coded syringes. Stratified by birth weight (501 to 750

g vs. 750 to 999 g vs. 1000 to 1250 g). Blinding of randomisation: yes. Blinding of intervention: yes.

Complete follow-up: yes. Blinding of outcome measurements: yes

Participants 51 infants with birth weight 501 to 1250 g, gestation 23 to 29 weeks, needing mechanical ventilation

before age of 24 hours. The subgroup 1000 to 1250 g had to need supplemental oxygen and mechanical

ventilation > 24 hours despite surfactant. Exclusions: lethal malformations or suspected chromosomal

abnormalities

Interventions Hydrocortisone 2.0 mg/kg/day intravenously 8 hourly for 2 days, 1.5 mg/kg/day 8 hourly for 2 days, 0.

75 mg/kg/day 12 hourly for 6 days. Control infants received isotonic saline as placebo. The first dose was

given before 36 hours. Use of open-label corticosteroids was discouraged

Outcomes Survival without BPD (oxygen at 36 weeks), IVH (grades III or IV), cystic PVL, durations of ventila-

tion, oxygen and hospital stay, sepsis, hyperglycaemia, hypertension, PDA, GI bleeding, GI perforation,

NEC, ROP and cortisol levels. Long-term outcomes: neurosensory impairments (blindness, deafness,

developmental delay assessed by MDI on Bayley scales, cerebral palsy) and disabilities (severe - any of

severe cerebral palsy [not likely to walk], blindness or severe developmental delay [MDI < 55, moderaste

- moderate cerebral palsy [not walking at 2 yeards but likely to do so], deafness, moderate developmental

delay [MDI 55 to < 70], mild - mild cerebral palsy [walking at 2 years] or mild developmental delay [MDI

70 to < 85]

Notes

Risk of bias



Rastogi 1996

Methods Random allocation: using a pharmacy list, stratified for birthweight. Blinding of randomisation: yes.

Blinding of intervention: yes. Complete follow-up: yes. Blinding of outcome measurement: yes

Participants 70 preterm infants < 12 h old, weighing 700 - 1500 g with RDS clinically and radiologically, infants

needed mechanical ventilation > 30% O2 and / or MAP 7 cmH2O a/A < 0.25 after surfactant treatment.

Exclusions for major malformations, chromosome abnormalities, severe infection, Apgar < 3 at 5 minutes

Interventions Intravenous dexamethasone 0.5 mg/kg/day for 3 days, 0.25 mg/kg/day for 3 days, 0.15 mg/kg/day for 3

days, 0.05 mg/kg/day for 3 days. Control group given saline placebo

Outcomes FiO2, MAP, BPD (28 days and CXR), severe BPD (36 weeks), duration O2, infections, deaths, pneu-

mothorax, pulmonary haemorrhage, PDA, IVH, NEC, hyperglycemia, insulin use, hypertension, ROP

Notes

Risk of bias



Rastogi 1996 (Continued)



Romagnoli 1999

Methods Random allocation using random numbers concealed in numbered sealed envelopes. Blinding of ran-

domisation: yes. Blinding of intervention: probably no. Blinding of outcome measurements: not sure.

Complete follow-up: yes

Participants 50 infants < 1251 g or < 33 weeks, oxygen dependent at 72 h and at high risk of CLD according to a

scoring system predicting 90% risk of CLD

Interventions Dexamethasone 0.5 mg/kg/day for 3 days, 0.25 mg/kg/day for 3 days and 0.125 mg/kg/day for 1 day.

Control group: no mention of placebo

Outcomes Survival to 28 days, survival to discharge, PDA, IVH (grades 3 and 4), PVL, sepsis, NEC, ROP (stages III

and above), requiring ventilation at 28 d, CLD at 28 d & 36 wk, hyperglycaemia, hypertension, needed

late corticosteroids, growth failure and left ventricular hypertrophy

Notes

Risk of bias



Sanders 1994

Methods Random allocation in the Pharmacy using sealed envelopes. Blinding of randomisation: yes. Blinding of

intervention: yes. Complete follow-up: yes. Blinding of outcome measurement: yes

Participants 40 infants < 30 weeks’ gestation and 12-18 hours old with RDS, both clinical and radiological. The infants

were being treated with mechanical ventilation and surfactant and exclusions comprised sepsis, congenital

heart disease, chromosome abnormalities or need for exchange transfusion

Interventions Dexamethsone 0.5 mg/kg twice intravenously. Control group given saline placebo

Outcomes MAP, FiO2, mortality, extubation < 7 days, pulmonary function tests, duration IPPV, O2, hospital,

mortality, BPD (36 weeks O2), late corticosteroids.

Notes

Risk of bias



Sanders 1994 (Continued)



Shinwell 1996

Methods Random allocation, stratified by centre and birthweight, from random numbers list in Pharmacy. Blinding

of randomisation: yes. Blinding of intervention: yes. Complete follow-up: yes for short term; 84% for

long term. Blinding of outcome measurement: yes

Participants 248 preterm infants with birthweight 500 - 2000 g, 1-3 days old, requiring mechanical ventilation with

more than 40% oxygen. Exclusions for active bleeding, hypertension, hyperglycaemia, active infection

and lethal congenital anomalies

Interventions Intravenous dexamethasone 0.25 mg/kg every 12 h six times. Controls given saline placebo

Outcomes Mortality, survival with no O2, mechanical ventilation at 3 and 7 days, CLD, duration hospital, IVH,

PVL, pneumothorax, PIE, PDA, sepsis, hypertension, hyperglycaemia

Notes

Risk of bias



Sinkin 2000

Methods Random allocation in the pharmacy with labelled syringes. Stratification by centre. Blinding of randomi-

sation: yes. Blinding of intervention: yes. Complete follow-up: yes. Blinding of outcome measurement:

yes

Participants 384 infants < 30 weeks’ gestation with RDS by clinical and radiographic signs, needing IPPV at 12-18 h

of age and had received at least 1 dose of surfactant

Interventions Dexamethsone 0.5 mg/kg at 12-18 hours of age and second dose 12 hours later. Control group given an

equal volume of placebo

Outcomes Primary outcomes were survival, survival without oxygen at 28 d or 36 wk, and survival without oxygen

at 28 d or 36 wk and without late corticosteroids. Length of time in oxygen, on ventilation, to regain

birthweight and in hospital. Hyperglycaemia, hypertension, IVH, PDA, sepsis, NEC, isolated GI perfo-

ration, ROP, air leak, discharged home on oxygen

Notes



Sinkin 2000 (Continued)

Risk of bias



Soll 1999

Methods Random allocation in hospital pharmacies by opening opaque sealed envelopes. Blinding of randomisation:

yes. Blinding of intervention: yes. Complete follow-up: yes. Blinding of outcome measurement: yes

Participants 542 infants weighing 501 - 1000 g who required assisted ventilation < 12 h, had received surfactant by

12 hours, were physiologically stable and had no life threatening congenital anomalies

Interventions Dexamethasone 0.5 mg/kg/day for 3 days. 0.25 mg/kg /day for 3 days, 0.10 mg/kg/day for 3 days and 0.

05 mg/kg/day for 3 days. Control infants received a similar volume of normal saline.

Infants in either group could receive late post-natal corticosteroids beginning on day 14 if they were on

assisted ventilation with supplemental oxygen > 30%

Outcomes Primary outcome was CLD or death at 36 weeks adjusted age. Secondary outcome measures included

clinical status at 14 days and 28 days, duration of assisted ventilation, supplemental oxygen and hospital

stay, treatment with late postnatal corticosteroids, proven sepsis, hypertension and hyperglycaemia requir-

ing therapy, weight at 36 weeks and the usual complications of prematurity

Notes Published as an extended abstract and presented at a clinical meeting

Risk of bias



Stark 2001a

Methods Random allocation using random numbers list supplied to pharmacy, stratified by birth weight. Blinding

of randomisation: yes. Blinding of intervention: yes. Complete follow-up: yes. Blinding of outcome

measurements: yes

Participants 220 infants with birthweight 501 - 1000 g, mechanically ventilated < 12 h. Infants > 750 g also needed

to receive surfactant and have FiO2 > 0.29.

Interventions Dexamethasone 0.15 mg/kg/day for 3 days, then tapered over 7 days or saline placebo

Outcomes Death or CLD, oxygen at 28 d, PIE, late corticosteroid treatment, hypertension, hyperglycaemia, GI

perforation



Stark 2001a (Continued)

Notes Factorial design, infants also randomised to routine ventilator management or a strategy of minimal

ventilator support to reduce mechanical lung injury. After enrolling 220 infants (sample size estimate was

1200) the trial was halted for unanticipated adverse events

Risk of bias



Subhedar 1997

Methods Random allocation by computer generated random numbers and sealed envelopes. Factorial design pro-

vided 4 groups: early dexamethasone, inhaled NO, both drugs together and neither drug. Blinding of ran-

domisation: yes. Blinding of intervention: probably not. Complete follow-up: yes. Blinding of outcome

measurements: probably not

Participants 42 preterm infants, entry at 96 hours if gestation < 32 weeks, mechanical ventilation from birth, surfactant

treatment and high risk of developing CLD by a score (Ryan et al 1996). Exclusion criteria: major

congenital anomaly, structural cardiac defect, significant ductus shunting, culture positive sepsis, IVH with

parenchymal involvement, pulmonary or GI haemorrhage, abnormal coagulation, or thrombocytopenia

(platelets < 50,000)

Interventions Intravenous dexamethasone at 12 hourly intervals for 6 days; 0.5 mg/kg/dose for 6 doses and 0.25 mg/kg/

dose for a further 6 doses. Inhaled NO 5-20 ppm for 72 hours. Control groups were not given a placebo

Outcomes Mortality, CLD at 28 days and > 36 weeks with abnormal chest radiograph. Duration of ventilation, time to

extubation, duration of hospitalisation, maximum grade of IVH, pulmonary haemorrhage, pneumothorax,

severe PDA, NEC, ROP (Stages 3 or 4). Complications including ileal perforation, upper GI haemorrhage,

hyperglycaemia, hypertension, septicaemia

Notes Note factorial design which means that half of the treated and half of the control infants also received 72

hours of inhaled NO

Risk of bias





Suske 1996

Methods Random allocation using sealed envelopes. Blinding of randomisation: yes. Blinding of intervention:

probably not. Complete follow-up: yes. Blinding of outcome measurement: probably not

Participants 26 preterm infants < 2 h old, with birthweight < 1500 g if FiO2 > 0.50, or > 1500 g birthweight with

FiO2 >0.70, exclusion for known sepsis, cardiac anomalies, malformations of lung or CNS

Interventions Intravenous dexamethasone 0.5 mg/kg/day for 5 days. Controls were not given a placebo

Outcomes Blood gases, ventilator settings, mortality IVH, BPD (O2 28 days), NEC, late sepsis, PDA, ROP, air leak,

duration in hospital

Notes

Risk of bias



Tapia 1998

Methods Random allocation using ampoules of dexamethasone and saline prepared in the hospital pharmacy.

Blinding of randomisation: yes. Blinding of intervention: yes. Complete follow-up: almost (109/113).

Blinding of outcome measurement: yes

Participants 113 (4 exclusions for congenital abnormality, early sepsis and failure to obtain follow-up data) infants with

birthweight between 700 and 1600 g, clinical and radiological diagnosis of RDS, needing mechanical

ventilation and < 36 hours of age. Exclusion criteria were life-threatening congenital malformation or

chromosome abnormality, a strong suspicion of infection at birth (maternal chorioamnionitis), or early

sepsis (positive blood culture in the first 36 hours of life)

Interventions Intravenous dexamethasone 0.5 mg/kg/day for 3 days, 0.25 mg/kg for 3 days, 0.12 mg/kg/day for 3 days

and 0.06 mg/kg/day for 3 days. The placebo group received an equivalent volume of saline solution

Outcomes The primary outcomes were death before hospital discharge, BPD (oxygen need at 28 days and x-ray

changes), death or BPD and oxygen need at 36 weeks. Other outcomes included time on ventilator, time

in over 40% oxygen and time in oxygen. Major morbidity and complications included pneumothorax,

PIE, PDA, pulmonary haemorrhage, pneumonia, sepsis, NEC, ROP, hypertension, hyperglycaemia and

IVH (grades I-II, and III-IV)

Notes

Risk of bias





Vento 2004

Methods Random allocation but method not stated. Blinding of randomisation: uncertain. Blinding of intervention:

uncertain. Complete follow-up: yes. Blinding of outcome measurement: uncertain

Participants 20 infants with birth weight < 1251 g and gestation < 33 weeks who were oxygen- and ventilator-dependent

on 4th day of life and who were at high risk of CLD by authors’ own scoring system. Exclusions: none

stated

Interventions Intravenous dexamethasone 0.5 mg/kg/day for 3 days, 0.25 mg/kg/day for 3 days, and 0.125 mg/kg/day

for 1 day (total dose 2.375 mg/kg). The control group received no corticosteroid treatment

Outcomes Tracheal aspirates for cell counts, pulmonary mechanics, PDA, IVH (grades III and IV), extubation during

study period

Notes

Risk of bias


Allocation concealment? Unclear B - Uncertain

Wang 1996

Methods Random allocation in a double-blind fashion, method not stated. Blinding of randomisation: yes; blinding

of intervention: yes; blinding of outcome measurements: yes; complete follow-up: yes

Participants 63 infants with birthweights from 1000 to 1999 g, AGA, clinical and radiographic RDS, IPPV (0-12 age

after birth),

Interventions Dexamethasone 0.25 mg/kg 12 hourly from 1 to 7 d, 0.125 mg/kg 12 hourly from 8 to 14 d, 0.05 mg/

kg, 12 hourly from 15 to 21 d. First dose administered < 12 h. Controls received saline placebo

Outcomes Oxygen requirements, PCO2, MAP, SP-A and SP-D in tracheal aspirate, failure to extubate by 3rd d, 7th

d, 14th d and 28th d, mortality before discharge, sepsis, CLD at 28 d

Notes

Risk of bias





Watterberg 1999

Methods Random allocation at each centre by constant block design with 4 patients per block to minimse bias

over time. Separate randomisation tables were used for infants exposed to antenatal corticosteroids. Ran-

domisation was probably performed in hospital pharmacies. Blinding of randomisation: yes. Blinding of

intervention: yes. Complete follow-up: yes. Blinding of outcome measurement: yes

Participants 40 infants weighing between 500 and 999 g who were AGA and needed mechanical ventilation < 48

hours of age. Exclusion criteria included maternal diabetes, congenital sepsis and SGA

Interventions Hydrocortisone 1.0 mg/kg/day every 12 hours for 9 days, 0.5 mg/kg/day for 3 days. Control infants were

given an equal volume of normal saline

Outcomes The primary outcome was survival without supplemental oxygen at 36 weeks’ post-conception. Secondary

outcomes included in survivors: CLD at 36 weeks, duration of mechanical ventilation, > 40% oxygen, >

25% oxygen, hospital stay, and weight and head circumference at 36 weeks

Notes

Risk of bias



Watterberg 2004

Methods Random allocation, stratified by centre and birth weight (500-749 g vs. 750-999 g) using a permuted-

blocks scheme with blocks of 6 in each stratum. Randomisation lists in each pharmacy in a sealed envelope.

Blinding of randomisation: yes. Blinding of intervention: yes. Complete follow-up: yes. Blinding of

outcome measurements: yes

Participants 360 infants of 500 - 999 g birth weight, needing mechanical ventilation and aged 12 to 48 hours.

Exclusions: major congenital anomaly, congenital sepsis, postnatal corticosteroids, triplet or higher order

gestation

Interventions Hydrocortisone 1 mg/kg/day 12 hourly for 12 days, then 0.5 mg/kg/day for 3 days. Control group infants

received an equal volume of normal saline placebo

Outcomes Survival without BPD (oxygen at 36 weeks), physiological BPD, death before 36 weeks, death before

discharge, BPD in survivors, durations of mechanical ventilation, oxygen and hospital stay, weight and

OFC at 36 weeks, PDA, infection, NEC, GI perforation, major IVH (grades 3 or 4), cystic PVL, ROP,

and open-label corticosteroid therapy. Longer-term outcomes included neurosensory impairments (any

of cerebral palsy, blindness, deafness, or developmental or motor delay assessed by the Bayley Scales [MDI

or PDI, respectively])

Notes The sample size estimate was 712 but the study was stopped early because on an increased incidence of

apparently spontaneous GI perforation in the hydrocortisone group

Risk of bias



Watterberg 2004 (Continued)



Yeh 1990

Methods Random allocation in blocks of ten using a Pharmacy list. Blinding of randomisation: yes. Blinding of

intervention: yes. Complete follow-up: almost. Blinding of outcome measurements: yes

Participants 57 preterm infants weighing between 700 and 1999 g, < 13 hours old with severe RDS both clinically

and radiologically. They needed mechanical ventilation < 4 h and were excluded if they had infection

Interventions Intravenous dexamethasone 0.50 mg/kg/day for 3 days, 0.25 mg/kg/day for 3 days, 0.12 mg/kg/day for

3 days, 0.05 mg/kg/day for 3 days. Control infants were given saline placebo

Outcomes MAP, FiO2, pulmonary function tests, BP, glucose, mortality, CLD, duration O2, hospital, weight loss,

sepsis, PDA, IVH (> grade I), ROP.

Notes

Risk of bias



Yeh 1997

Methods Random allocation by central pharmacy random number list. Blinding of randomisation: yes. Blinding of

intervention: yes. Complete follow-up: almost for short term; 81% for long-term. Blinding of outcome

measurement: yes

Participants 262 infants of birthweight < 2000 g with RDS and requiring mechanical ventilation after birth

Interventions Dexamethasone 0.25 mg/kg/dose every 12 hours intravenously on days 1-7; 0.12 mg/kg/dose every 12

hours intravenously from 8-14 days; 0.05 mg/kg/dose every 12 hours intravenously from day 15 to 21;

and 0.02 mg/kg/dose every 12 hours intravenously from days 22 to 28. Control infants were given saline

placebo

Outcomes CLD either judged at 28 d or at 36 wk. Extubation during the study, mortality, bacteraemia or clinical

sepsis, and side effects of hyperglycaemia, hypertension, cardiac hypertrophy, hyperparathyroidism and

growth failure

Notes

Risk of bias



Yeh 1997 (Continued)



Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Gaissmaier 1999 Primary outcome was need for an epinephrine infusion 12 hours after treatment. No longterm outcomes reported

Tsukahara 1999 Not a RCT; 26 study infants and 12 historical controls.

Characteristics of studies awaiting assessment [ordered by study ID]

Yaseen 1999

Methods Not known

Participants Not known

Interventions Not known

Outcomes Not known

Notes



D A T A A N D A N A L Y S E S

Comparison 1. Mortality

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Neonatal mortality (up to 28

days)

19 2950 Risk Ratio (M-H, Fixed, 95% CI) 1.02 [0.88, 1.19]

1.1 dexamethasone 16 2603 Risk Ratio (M-H, Fixed, 95% CI) 1.06 [0.90, 1.24]

1.2 hydrocortisone 3 347 Risk Ratio (M-H, Fixed, 95% CI) 0.78 [0.50, 1.23]

2 Mortality to hospital discharge 27 3720 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.89, 1.13]



3 Mortality at latest reported age 27 3720 Risk Ratio (M-H, Fixed, 95% CI) 0.99 [0.89, 1.12]



Comparison 2. Chronic lung disease (CLD)/bronchopulmonary dysplasia (BPD)


studies

No. of


1 CLD (28 days) 17 2874 Risk Ratio (M-H, Fixed, 95% CI) 0.87 [0.81, 0.93]



2 CLD (36 weeks) 21 3286 Risk Ratio (M-H, Fixed, 95% CI) 0.79 [0.71, 0.88]



3 CLD at 36 weeks in survivors 18 2462 Risk Ratio (M-H, Fixed, 95% CI) 0.82 [0.74, 0.90]



4 Late rescue with corticosteroids 14 2483 Risk Ratio (M-H, Fixed, 95% CI) 0.75 [0.68, 0.82]



5 Survivors who had late rescue

with corticosteroids




6 Survivors discharged home on

oxygen






Comparison 3. Death or CLD


studies

No. of


1 Death or CLD at 28 days 15 2546 Risk Ratio (M-H, Fixed, 95% CI) 0.92 [0.88, 0.96]



2 Death or CLD at 36 weeks 22 3320 Risk Ratio (M-H, Fixed, 95% CI) 0.89 [0.84, 0.95]



Comparison 4. Failure to extubate


studies

No. of


1 Failure to extubate by 3rd day 3 381 Risk Ratio (M-H, Fixed, 95% CI) 0.73 [0.62, 0.86]

2 Failure to extubate by 7th day 7 956 Risk Ratio (M-H, Fixed, 95% CI) 0.75 [0.65, 0.86]



Comparison 5. Complications during primary hospitalisation


studies

No. of


1 Infection 23 3558 Risk Ratio (M-H, Fixed, 95% CI) 1.02 [0.93, 1.13]



2 Hyperglycaemia 13 2175 Risk Ratio (M-H, Fixed, 95% CI) 1.34 [1.21, 1.48]



3 Hypertension 11 1996 Risk Ratio (M-H, Fixed, 95% CI) 1.85 [1.55, 2.22]



4 Hypertrophic cardiomyopathy 1 50 Risk Ratio (M-H, Fixed, 95% CI) 4.33 [1.40, 13.37]

5 Growth failure 1 50 Risk Ratio (M-H, Fixed, 95% CI) 6.67 [2.27, 19.62]

6 Pulmonary air leak 14 2604 Risk Ratio (M-H, Fixed, 95% CI) 0.93 [0.75, 1.15]



7 PDA 23 3493 Risk Ratio (M-H, Fixed, 95% CI) 0.78 [0.72, 0.85]



8 Severe IVH 24 3572 Risk Ratio (M-H, Fixed, 95% CI) 0.95 [0.82, 1.11]





9 Severe IVH in infants examined 6 1388 Risk Ratio (M-H, Fixed, 95% CI) 0.86 [0.68, 1.09]

10 PVL 12 2176 Risk Ratio (M-H, Fixed, 95% CI) 1.20 [0.85, 1.68]



11 PVL in infants with cranial

ultrasound scans


12 PVL in survivors seen at

follow-up


13 NEC 22 3497 Risk Ratio (M-H, Fixed, 95% CI) 0.87 [0.70, 1.08]


13.2 hydorcortisone 7 836 Risk Ratio (M-H, Fixed, 95% CI) 0.84 [0.54, 1.30]

14 Gastro-intestinal bleeding 12 1820 Risk Ratio (M-H, Fixed, 95% CI) 1.86 [1.35, 2.55]



15 Intestinal perforation 15 2523 Risk Ratio (M-H, Fixed, 95% CI) 1.81 [1.33, 2.48]



16 Pulmonary haemorrhage 9 1299 Risk Ratio (M-H, Fixed, 95% CI) 1.16 [0.85, 1.59]



17 Any ROP 9 1345 Risk Ratio (M-H, Fixed, 95% CI) 0.88 [0.80, 0.97]



18 Severe ROP 13 2056 Risk Ratio (M-H, Fixed, 95% CI) 0.79 [0.65, 0.97]



19 Severe ROP in survivors 12 1575 Risk Ratio (M-H, Fixed, 95% CI) 0.77 [0.64, 0.94]



Comparison 6. Long-term follow-up


studies

No. of


1 Bayley MDI <-2SD 3 842 Risk Ratio (M-H, Fixed, 95% CI) 0.99 [0.77, 1.27]

2 Bayley MDI <-2SD in tested

survivors


3 Bayley PDI <-2SD 3 842 Risk Ratio (M-H, Fixed, 95% CI) 1.16 [0.86, 1.58]

4 Bayley PDI <-2SD in tested

survivors


5 Developmental delay (criteria

not specified)


6 Developmental delay (criteria

not specified) in tested

survivors


7 Blindness 6 668 Risk Ratio (M-H, Fixed, 95% CI) 1.92 [0.66, 5.54]

8 Blindness in survivors assessed 6 407 Risk Ratio (M-H, Fixed, 95% CI) 2.11 [0.74, 6.02]



9 Deafness 6 450 Risk Ratio (M-H, Fixed, 95% CI) 0.96 [0.22, 4.22]

10 Deafness in survivors assessed 6 299 Risk Ratio (M-H, Fixed, 95% CI) 1.01 [0.24, 4.24]

11 Cerebral palsy 12 1452 Risk Ratio (IV, Fixed, 95% CI) 1.45 [1.06, 1.98]

11.1 dexamethasone 7 921 Risk Ratio (IV, Fixed, 95% CI) 1.75 [1.20, 2.55]

11.2 hydrocortisone 5 531 Risk Ratio (IV, Fixed, 95% CI) 0.97 [0.55, 1.69]

12 Death before follow-up in trials

assessing cerebral palsy




13 Death or cerebral palsy 12 1452 Risk Ratio (M-H, Fixed, 95% CI) 1.09 [0.95, 1.25]



14 Cerebral palsy in survivors

assessed




15 Major neurosensory disability

(variable criteria - see individual

studies)





assessing major neurosensory

disability (variable criteria)




17 Death or major neurosensory

disability (variable criteria)




18 Major neurosensory disability

(variable criteria) in survivors

examined




19 Abnormal neurological exam

(variable criteria - see individual

studies)



assessing abnormal neurological

exam (variable criteria)


21 Death or abnormal neurological

exam (variable criteria)


22 Abnormal neurological exam

(variable criteria) in tested

survivors


23 Intellectual impairment (IQ <

70)


24 Intellectual impairment (IQ <

70) in survivors assessed




25 ”Major neurosensory

impairment” - blindness or

deafness


26 ”Major neurosensory

impairment” - blindness or

deafness - in survivors assessed


27 Behavior abnormalities 1 50 Risk Ratio (M-H, Fixed, 95% CI) 0.6 [0.16, 2.25]

28 Behavior abnormalities in 3 yr

old survivors assessed


29 Abnormal EEG 2 306 Risk Ratio (M-H, Fixed, 95% CI) 1.24 [0.66, 2.33]

30 Abnormal EEG in tested

survivors


31 Re-hospitalisation in infancy 3 672 Risk Ratio (M-H, Fixed, 95% CI) 0.86 [0.68, 1.08]

32 Re-hospitalisation in infancy in

survivors


Analysis 1.1. Comparison 1 Mortality, Outcome 1 Neonatal mortality (up to 28 days).

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

Comparison: 1 Mortality

Outcome: 1 Neonatal mortality (up to 28 days)

Study or subgroup Steroid Control Risk Ratio Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 dexamethasone

Garland 1999 12/118 20/123 0.63 [ 0.32, 1.22 ]

Halac 1990 17/130 21/118 0.73 [ 0.41, 1.32 ]

Kopelman 1999 8/37 3/33 2.38 [ 0.69, 8.23 ]

Lin 1999 5/20 4/20 1.25 [ 0.39, 3.99 ]

Rastogi 1996 4/36 2/34 1.89 [ 0.37, 9.65 ]

Romagnoli 1999 0/25 0/25 0.0 [ 0.0, 0.0 ]

Sanders 1994 2/19 3/21 0.74 [ 0.14, 3.95 ]

Shinwell 1996 31/132 22/116 1.24 [ 0.76, 2.01 ]

Sinkin 2000 31/189 25/195 1.28 [ 0.79, 2.08 ]

Soll 1999 65/273 50/269 1.28 [ 0.92, 1.78 ]

Stark 2001a 20/111 22/109 0.89 [ 0.52, 1.54 ]

Subhedar 1997 9/21 8/21 1.13 [ 0.54, 2.35 ]

Suske 1996 1/14 1/12 0.86 [ 0.06, 12.28 ]

0.05 0.2 1 5 20

Favours steroid Favours control

(Continued . . . )



(. . . Continued)Study or subgroup Steroid Control Risk Ratio Risk Ratio


Wang 1996 3/34 6/29 0.43 [ 0.12, 1.56 ]

Yeh 1990 3/28 8/29 0.39 [ 0.11, 1.32 ]

Yeh 1997 44/132 39/130 1.11 [ 0.78, 1.59 ]

Subtotal (95% CI) 1319 1284 1.06 [ 0.90, 1.24 ]

Total events: 255 (Steroid), 234 (Control)

Heterogeneity: Chi2 = 13.48, df = 14 (P = 0.49); I2 =0.0%

Test for overall effect: Z = 0.72 (P = 0.47)

2 hydrocortisone

Baden 1972 6/22 7/22 0.86 [ 0.34, 2.14 ]

Biswas 2003 19/125 19/128 1.02 [ 0.57, 1.84 ]

Bonsante 2007 2/25 9/25 0.22 [ 0.05, 0.93 ]

Subtotal (95% CI) 172 175 0.78 [ 0.50, 1.23 ]


Heterogeneity: Chi2 = 3.83, df = 2 (P = 0.15); I2 =48%


Total (95% CI) 1491 1459 1.02 [ 0.88, 1.19 ]




0.05 0.2 1 5 20




Analysis 1.2. Comparison 1 Mortality, Outcome 2 Mortality to hospital discharge.



Outcome: 2 Mortality to hospital discharge

Study or subgroup Steroid Control Risk Ratio Weight Risk Ratio


1 dexamethasone

Anttila 2005 11/53 12/56 2.9 % 0.97 [ 0.47, 2.00 ]

Garland 1999 19/118 25/123 6.0 % 0.79 [ 0.46, 1.36 ]

Halac 1990 22/130 24/118 6.2 % 0.83 [ 0.49, 1.40 ]

Kopelman 1999 10/37 5/33 1.3 % 1.78 [ 0.68, 4.68 ]

Lin 1999 5/20 4/20 1.0 % 1.25 [ 0.39, 3.99 ]

Mukhopadhyay 1998 6/10 6/9 1.6 % 0.90 [ 0.45, 1.79 ]

Rastogi 1996 4/36 2/34 0.5 % 1.89 [ 0.37, 9.65 ]

Romagnoli 1999 2/25 3/25 0.7 % 0.67 [ 0.12, 3.65 ]

Sanders 1994 2/19 7/21 1.6 % 0.32 [ 0.07, 1.34 ]

Shinwell 1996 31/132 22/116 5.8 % 1.24 [ 0.76, 2.01 ]

Sinkin 2000 40/189 33/195 8.0 % 1.25 [ 0.83, 1.89 ]

Soll 1999 76/273 62/269 15.4 % 1.21 [ 0.90, 1.61 ]

Stark 2001a 23/111 28/109 7.0 % 0.81 [ 0.50, 1.31 ]

Subhedar 1997 9/21 8/21 2.0 % 1.13 [ 0.54, 2.35 ]

Suske 1996 1/14 1/12 0.3 % 0.86 [ 0.06, 12.28 ]

Tapia 1998 17/55 18/54 4.5 % 0.93 [ 0.54, 1.60 ]

Wang 1996 7/34 6/29 1.6 % 1.00 [ 0.38, 2.63 ]

Yeh 1990 3/28 8/29 1.9 % 0.39 [ 0.11, 1.32 ]

Yeh 1997 46/132 42/130 10.4 % 1.08 [ 0.77, 1.52 ]

Subtotal (95% CI) 1437 1403 78.7 % 1.03 [ 0.90, 1.18 ]




2 hydrocortisone

Baden 1972 7/22 8/22 2.0 % 0.88 [ 0.38, 2.00 ]

Biswas 2003 23/125 25/128 6.1 % 0.94 [ 0.57, 1.57 ]

0.1 0.2 0.5 1 2 5 10


(Continued . . . )



(. . . Continued)Study or subgroup Steroid Control Risk Ratio Weight Risk Ratio


Bonsante 2007 4/25 10/25 2.5 % 0.40 [ 0.14, 1.11 ]

Efird 2005 2/16 3/18 0.7 % 0.75 [ 0.14, 3.94 ]

Ng 2006 4/24 3/24 0.7 % 1.33 [ 0.33, 5.33 ]

Peltoniemi 2005 2/25 3/26 0.7 % 0.69 [ 0.13, 3.81 ]

Watterberg 1999 3/20 3/20 0.7 % 1.00 [ 0.23, 4.37 ]

Watterberg 2004 31/180 32/180 7.9 % 0.97 [ 0.62, 1.52 ]

Subtotal (95% CI) 437 443 21.3 % 0.88 [ 0.67, 1.17 ]




Total (95% CI) 1874 1846 100.0 % 1.00 [ 0.89, 1.13 ]




0.1 0.2 0.5 1 2 5 10




Analysis 1.3. Comparison 1 Mortality, Outcome 3 Mortality at latest reported age.



Outcome: 3 Mortality at latest reported age



1 dexamethasone

Anttila 2005 11/53 12/56 2.8 % 0.97 [ 0.47, 2.00 ]

Garland 1999 19/118 25/123 5.8 % 0.79 [ 0.46, 1.36 ]

Halac 1990 22/130 24/118 5.9 % 0.83 [ 0.49, 1.40 ]

Kopelman 1999 10/37 5/33 1.2 % 1.78 [ 0.68, 4.68 ]

Lin 1999 5/20 4/20 0.9 % 1.25 [ 0.39, 3.99 ]

Mukhopadhyay 1998 6/10 6/9 1.5 % 0.90 [ 0.45, 1.79 ]

Rastogi 1996 4/36 2/34 0.5 % 1.89 [ 0.37, 9.65 ]

Romagnoli 1999 2/25 3/25 0.7 % 0.67 [ 0.12, 3.65 ]

Sanders 1994 2/19 7/21 1.6 % 0.32 [ 0.07, 1.34 ]

Shinwell 1996 32/132 26/116 6.5 % 1.08 [ 0.69, 1.70 ]

Sinkin 2000 40/189 33/195 7.7 % 1.25 [ 0.83, 1.89 ]

Soll 1999 76/273 62/269 14.7 % 1.21 [ 0.90, 1.61 ]

Stark 2001a 26/111 30/109 7.1 % 0.85 [ 0.54, 1.34 ]

Subhedar 1997 11/21 9/21 2.1 % 1.22 [ 0.64, 2.32 ]

Suske 1996 1/14 1/12 0.3 % 0.86 [ 0.06, 12.28 ]

Tapia 1998 17/55 18/54 4.3 % 0.93 [ 0.54, 1.60 ]

Wang 1996 7/34 6/29 1.5 % 1.00 [ 0.38, 2.63 ]

Yeh 1990 3/28 8/29 1.9 % 0.39 [ 0.11, 1.32 ]

Yeh 1997 53/132 50/130 11.9 % 1.04 [ 0.77, 1.41 ]

Subtotal (95% CI) 1437 1403 78.9 % 1.02 [ 0.90, 1.17 ]




2 hydrocortisone

Baden 1972 8/22 9/22 2.1 % 0.89 [ 0.42, 1.88 ]

Biswas 2003 23/125 26/128 6.1 % 0.91 [ 0.55, 1.50 ]

0.1 0.2 0.5 1 2 5 10


(Continued . . . )





Bonsante 2007 4/25 10/25 2.4 % 0.40 [ 0.14, 1.11 ]

Efird 2005 2/16 3/18 0.7 % 0.75 [ 0.14, 3.94 ]

Ng 2006 4/24 3/24 0.7 % 1.33 [ 0.33, 5.33 ]

Peltoniemi 2005 2/25 3/26 0.7 % 0.69 [ 0.13, 3.81 ]

Watterberg 1999 3/20 3/20 0.7 % 1.00 [ 0.23, 4.37 ]

Watterberg 2004 33/180 33/180 7.8 % 1.00 [ 0.65, 1.55 ]

Subtotal (95% CI) 437 443 21.1 % 0.89 [ 0.68, 1.16 ]




Total (95% CI) 1874 1846 100.0 % 0.99 [ 0.89, 1.12 ]




0.1 0.2 0.5 1 2 5 10




Analysis 2.1. Comparison 2 Chronic lung disease (CLD)/bronchopulmonary dysplasia (BPD), Outcome 1

CLD (28 days).


Comparison: 2 Chronic lung disease (CLD)/bronchopulmonary dysplasia (BPD)

Outcome: 1 CLD (28 days)



1 dexamethasone

Garland 1999 73/118 76/123 1.00 [ 0.82, 1.22 ]

Halac 1990 15/130 10/118 1.36 [ 0.64, 2.91 ]

Lin 1999 4/20 11/20 0.36 [ 0.14, 0.95 ]

Mukhopadhyay 1998 0/10 0/9 0.0 [ 0.0, 0.0 ]

Rastogi 1996 5/36 21/34 0.22 [ 0.10, 0.53 ]

Romagnoli 1999 11/25 24/25 0.46 [ 0.29, 0.72 ]

Shinwell 1996 29/132 23/116 1.11 [ 0.68, 1.80 ]

Sinkin 2000 93/189 103/195 0.93 [ 0.77, 1.13 ]

Soll 1999 181/273 186/269 0.96 [ 0.85, 1.08 ]

Stark 2001a 71/111 82/109 0.85 [ 0.71, 1.01 ]

Subhedar 1997 11/21 13/21 0.85 [ 0.50, 1.43 ]

Suske 1996 1/14 3/12 0.29 [ 0.03, 2.40 ]

Tapia 1998 11/55 16/54 0.68 [ 0.35, 1.32 ]

Wang 1996 5/34 9/29 0.47 [ 0.18, 1.26 ]

Yeh 1990 8/28 12/29 0.69 [ 0.33, 1.43 ]

Yeh 1997 21/132 40/130 0.52 [ 0.32, 0.83 ]

Subtotal (95% CI) 1328 1293 0.85 [ 0.79, 0.92 ]




2 hydrocortisone

Biswas 2003 86/125 88/128 1.00 [ 0.85, 1.18 ]

Subtotal (95% CI) 125 128 1.00 [ 0.85, 1.18 ]


Heterogeneity: not applicable


Total (95% CI) 1453 1421 0.87 [ 0.81, 0.93 ]

0.05 0.2 1 5 20

Favors steroid Favors control

(Continued . . . )








0.05 0.2 1 5 20



CLD (36 weeks).



Outcome: 2 CLD (36 weeks)



1 dexamethasone

Anttila 2005 11/53 15/56 2.7 % 0.77 [ 0.39, 1.53 ]

Garland 1999 16/118 27/123 4.9 % 0.62 [ 0.35, 1.09 ]

Kopelman 1999 6/37 5/33 1.0 % 1.07 [ 0.36, 3.18 ]

Lin 1999 3/20 9/20 1.7 % 0.33 [ 0.11, 1.05 ]

Rastogi 1996 0/36 6/34 1.2 % 0.07 [ 0.00, 1.24 ]

Romagnoli 1999 3/25 17/25 3.2 % 0.18 [ 0.06, 0.53 ]

Sanders 1994 4/19 5/21 0.9 % 0.88 [ 0.28, 2.82 ]

Shinwell 1996 15/132 11/116 2.2 % 1.20 [ 0.57, 2.50 ]

Sinkin 2000 38/189 48/195 8.8 % 0.82 [ 0.56, 1.19 ]

Soll 1999 62/273 84/269 15.8 % 0.73 [ 0.55, 0.96 ]

Stark 2001a 47/111 49/109 9.2 % 0.94 [ 0.70, 1.27 ]

Subhedar 1997 11/21 13/21 2.4 % 0.85 [ 0.50, 1.43 ]

Tapia 1998 3/55 12/54 2.3 % 0.25 [ 0.07, 0.82 ]

0.005 0.1 1 10 200


(Continued . . . )





Yeh 1990 8/28 12/29 2.2 % 0.69 [ 0.33, 1.43 ]

Yeh 1997 20/132 37/130 7.0 % 0.53 [ 0.33, 0.87 ]

Subtotal (95% CI) 1249 1235 65.6 % 0.70 [ 0.61, 0.81 ]



Test for overall effect: Z = 4.95 (P < 0.00001)

2 hydrocortisone

Biswas 2003 59/125 56/128 10.3 % 1.08 [ 0.82, 1.41 ]

Bonsante 2007 6/25 8/25 1.5 % 0.75 [ 0.30, 1.85 ]

Ng 2006 9/24 8/24 1.5 % 1.13 [ 0.52, 2.42 ]

Peltoniemi 2005 7/25 11/26 2.0 % 0.66 [ 0.31, 1.43 ]

Watterberg 1999 5/20 10/20 1.9 % 0.50 [ 0.21, 1.20 ]

Watterberg 2004 90/180 92/180 17.2 % 0.98 [ 0.80, 1.20 ]

Subtotal (95% CI) 399 403 34.4 % 0.96 [ 0.82, 1.12 ]




Total (95% CI) 1648 1638 100.0 % 0.79 [ 0.71, 0.88 ]




0.005 0.1 1 10 200





CLD at 36 weeks in survivors.



Outcome: 3 CLD at 36 weeks in survivors



1 dexamethasone

Anttila 2005 11/42 15/44 2.9 % 0.77 [ 0.40, 1.48 ]

Garland 1999 16/99 27/98 5.4 % 0.59 [ 0.34, 1.02 ]

Kopelman 1999 6/27 5/28 1.0 % 1.24 [ 0.43, 3.60 ]

Rastogi 1996 0/32 6/32 1.3 % 0.08 [ 0.00, 1.31 ]

Romagnoli 1999 3/23 17/23 3.4 % 0.18 [ 0.06, 0.52 ]

Sanders 1994 4/17 5/14 1.1 % 0.66 [ 0.22, 2.00 ]

Shinwell 1996 15/101 11/94 2.3 % 1.27 [ 0.61, 2.62 ]

Sinkin 2000 38/149 47/162 9.0 % 0.88 [ 0.61, 1.27 ]

Soll 1999 62/199 84/208 16.4 % 0.77 [ 0.59, 1.00 ]

Stark 2001a 47/88 49/83 10.1 % 0.90 [ 0.69, 1.18 ]

Subhedar 1997 11/12 13/13 2.6 % 0.92 [ 0.74, 1.14 ]

Tapia 1998 3/38 12/36 2.5 % 0.24 [ 0.07, 0.77 ]

Yeh 1997 20/88 37/91 7.3 % 0.56 [ 0.35, 0.88 ]

Subtotal (95% CI) 915 926 65.2 % 0.73 [ 0.64, 0.84 ]




2 hydrocortisone

Biswas 2003 59/106 56/109 11.0 % 1.08 [ 0.84, 1.39 ]

Bonsante 2007 6/22 8/17 1.8 % 0.58 [ 0.25, 1.35 ]

Efird 2005 9/13 8/15 1.5 % 1.30 [ 0.72, 2.36 ]

Watterberg 1999 5/17 10/17 2.0 % 0.50 [ 0.22, 1.15 ]

Watterberg 2004 90/153 92/152 18.4 % 0.97 [ 0.81, 1.17 ]

Subtotal (95% CI) 311 310 34.8 % 0.97 [ 0.85, 1.12 ]




0.005 0.1 1 10 200


(Continued . . . )





Total (95% CI) 1226 1236 100.0 % 0.82 [ 0.74, 0.90 ]




0.005 0.1 1 10 200



Late rescue with corticosteroids.



Outcome: 4 Late rescue with corticosteroids



1 dexamethasone

Anttila 2005 35/53 41/56 7.3 % 0.90 [ 0.70, 1.16 ]

Garland 1999 68/118 81/123 14.6 % 0.88 [ 0.72, 1.07 ]

Kopelman 1999 16/37 17/33 3.3 % 0.84 [ 0.51, 1.38 ]

Rastogi 1996 4/36 15/34 2.8 % 0.25 [ 0.09, 0.68 ]

Romagnoli 1999 3/25 13/25 2.4 % 0.23 [ 0.07, 0.71 ]

Sanders 1994 3/19 3/21 0.5 % 1.11 [ 0.25, 4.83 ]

Shinwell 1996 24/132 30/116 5.9 % 0.70 [ 0.44, 1.13 ]

Sinkin 2000 48/189 69/195 12.5 % 0.72 [ 0.53, 0.98 ]

Soll 1999 114/273 164/269 30.3 % 0.68 [ 0.58, 0.81 ]

Stark 2001a 38/111 56/109 10.4 % 0.67 [ 0.49, 0.91 ]

Subtotal (95% CI) 993 981 89.9 % 0.72 [ 0.65, 0.80 ]



0.1 0.2 0.5 1 2 5 10


(Continued . . . )






2 hydrocortisone

Bonsante 2007 7/25 12/25 2.2 % 0.58 [ 0.28, 1.23 ]

Ng 2006 6/24 7/24 1.3 % 0.86 [ 0.34, 2.18 ]

Peltoniemi 2005 7/25 12/26 2.2 % 0.61 [ 0.29, 1.29 ]

Watterberg 2004 35/180 24/180 4.4 % 1.46 [ 0.91, 2.35 ]

Subtotal (95% CI) 254 255 10.1 % 1.01 [ 0.73, 1.40 ]




Total (95% CI) 1247 1236 100.0 % 0.75 [ 0.68, 0.82 ]




0.1 0.2 0.5 1 2 5 10





Survivors who had late rescue with corticosteroids.



Outcome: 5 Survivors who had late rescue with corticosteroids



1 dexamethasone

Rastogi 1996 4/32 15/32 6.8 % 0.27 [ 0.10, 0.72 ]

Shinwell 1996 24/101 30/94 14.1 % 0.74 [ 0.47, 1.18 ]

Sinkin 2000 47/149 64/162 27.9 % 0.80 [ 0.59, 1.08 ]

Garland 1999 68/99 81/98 37.0 % 0.83 [ 0.71, 0.98 ]

Kopelman 1999 16/27 17/28 7.6 % 0.98 [ 0.63, 1.50 ]

Sanders 1994 3/17 1/14 0.5 % 2.47 [ 0.29, 21.21 ]

Subtotal (95% CI) 425 428 94.0 % 0.79 [ 0.68, 0.91 ]




2 hydrocortisone

Bonsante 2007 7/23 12/19 6.0 % 0.48 [ 0.24, 0.98 ]

Subtotal (95% CI) 23 19 6.0 % 0.48 [ 0.24, 0.98 ]




Total (95% CI) 448 447 100.0 % 0.77 [ 0.67, 0.89 ]




0.05 0.2 1 5 20





Survivors discharged home on oxygen.



Outcome: 6 Survivors discharged home on oxygen



1 dexamethasone

Rastogi 1996 0/32 1/32 2.4 % 0.33 [ 0.01, 7.89 ]

Sanders 1994 2/17 1/14 1.8 % 1.65 [ 0.17, 16.33 ]

Sinkin 2000 22/149 31/162 48.0 % 0.77 [ 0.47, 1.27 ]

Subtotal (95% CI) 198 208 52.2 % 0.78 [ 0.48, 1.26 ]




2 hydrocortisone

Biswas 2003 15/106 19/109 30.3 % 0.81 [ 0.44, 1.51 ]

Bonsante 2007 0/21 2/15 4.7 % 0.15 [ 0.01, 2.83 ]

Watterberg 1999 4/17 8/17 12.9 % 0.50 [ 0.18, 1.35 ]

Subtotal (95% CI) 144 141 47.8 % 0.66 [ 0.40, 1.11 ]




Total (95% CI) 342 349 100.0 % 0.72 [ 0.51, 1.03 ]




0.01 0.1 1 10 100




Analysis 3.1. Comparison 3 Death or CLD, Outcome 1 Death or CLD at 28 days.


Comparison: 3 Death or CLD

Outcome: 1 Death or CLD at 28 days



1 dexamethasone

Garland 1999 85/118 96/123 0.92 [ 0.80, 1.07 ]

Kopelman 1999 0/1 0/1 0.0 [ 0.0, 0.0 ]

Lin 1999 9/20 15/20 0.60 [ 0.35, 1.04 ]

Rastogi 1996 9/36 23/34 0.37 [ 0.20, 0.68 ]

Romagnoli 1999 11/25 24/25 0.46 [ 0.29, 0.72 ]

Shinwell 1996 60/132 45/116 1.17 [ 0.87, 1.57 ]

Sinkin 2000 115/189 120/195 0.99 [ 0.84, 1.16 ]

Soll 1999 246/273 236/269 1.03 [ 0.97, 1.09 ]

Stark 2001a 91/111 104/109 0.86 [ 0.78, 0.95 ]

Subhedar 1997 20/21 21/21 0.95 [ 0.84, 1.09 ]

Suske 1996 2/14 4/12 0.43 [ 0.09, 1.94 ]

Tapia 1998 28/55 34/54 0.81 [ 0.58, 1.13 ]

Yeh 1990 11/28 19/29 0.60 [ 0.35, 1.02 ]

Yeh 1997 65/132 79/130 0.81 [ 0.65, 1.01 ]

Subtotal (95% CI) 1155 1138 0.91 [ 0.86, 0.96 ]


Heterogeneity: Chi2 = 46.31, df = 12 (P<0.00001); I2 =74%


2 hydrocortisone

Biswas 2003 105/125 107/128 1.00 [ 0.90, 1.12 ]

Subtotal (95% CI) 125 128 1.00 [ 0.90, 1.12 ]




Total (95% CI) 1280 1266 0.92 [ 0.88, 0.96 ]




0.1 0.2 0.5 1 2 5 10




Analysis 3.2. Comparison 3 Death or CLD, Outcome 2 Death or CLD at 36 weeks.


Comparison: 3 Death or CLD

Outcome: 2 Death or CLD at 36 weeks



1 dexamethasone

Anttila 2005 22/53 27/56 3.0 % 0.86 [ 0.57, 1.31 ]

Garland 1999 35/118 52/123 5.8 % 0.70 [ 0.50, 0.99 ]

Kopelman 1999 16/37 10/33 1.2 % 1.43 [ 0.76, 2.69 ]

Lin 1999 8/20 13/20 1.5 % 0.62 [ 0.33, 1.15 ]

Rastogi 1996 4/36 8/34 0.9 % 0.47 [ 0.16, 1.43 ]

Romagnoli 1999 5/25 19/25 2.2 % 0.26 [ 0.12, 0.59 ]

Sanders 1994 6/19 12/21 1.3 % 0.55 [ 0.26, 1.18 ]

Shinwell 1996 46/132 33/116 4.0 % 1.22 [ 0.85, 1.78 ]

Sinkin 2000 76/189 77/195 8.6 % 1.02 [ 0.80, 1.30 ]

Soll 1999 135/273 143/269 16.4 % 0.93 [ 0.79, 1.10 ]

Stark 2001a 70/111 75/109 8.6 % 0.92 [ 0.76, 1.11 ]

Subhedar 1997 20/21 21/21 2.4 % 0.95 [ 0.84, 1.09 ]

Tapia 1998 20/55 30/54 3.4 % 0.65 [ 0.43, 1.00 ]

Yeh 1990 11/28 19/29 2.1 % 0.60 [ 0.35, 1.02 ]

Yeh 1997 64/132 76/130 8.7 % 0.83 [ 0.66, 1.04 ]

Subtotal (95% CI) 1249 1235 70.1 % 0.87 [ 0.80, 0.94 ]




2 hydrocortisone

Biswas 2003 82/125 81/128 9.1 % 1.04 [ 0.86, 1.24 ]

Bonsante 2007 9/25 17/25 1.9 % 0.53 [ 0.29, 0.95 ]

Efird 2005 11/16 11/18 1.2 % 1.13 [ 0.69, 1.85 ]

Ng 2006 13/24 11/24 1.2 % 1.18 [ 0.67, 2.09 ]

Peltoniemi 2005 9/25 12/26 1.3 % 0.78 [ 0.40, 1.52 ]

Watterberg 1999 8/20 13/20 1.5 % 0.62 [ 0.33, 1.15 ]

0.2 0.5 1 2 5


(Continued . . . )





Watterberg 2004 117/180 120/180 13.6 % 0.98 [ 0.84, 1.13 ]

Subtotal (95% CI) 415 421 29.9 % 0.95 [ 0.86, 1.06 ]




Total (95% CI) 1664 1656 100.0 % 0.89 [ 0.84, 0.95 ]




0.2 0.5 1 2 5


Analysis 4.1. Comparison 4 Failure to extubate, Outcome 1 Failure to extubate by 3rd day.


Comparison: 4 Failure to extubate

Outcome: 1 Failure to extubate by 3rd day



Rastogi 1996 20/36 27/34 21.0 % 0.70 [ 0.50, 0.98 ]

Shinwell 1996 54/132 71/116 57.0 % 0.67 [ 0.52, 0.86 ]

Wang 1996 29/34 27/29 22.0 % 0.92 [ 0.77, 1.09 ]

Total (95% CI) 202 179 100.0 % 0.73 [ 0.62, 0.86 ]




0.5 0.7 1 1.5 2




Analysis 4.2. Comparison 4 Failure to extubate, Outcome 2 Failure to extubate by 7th day.



Outcome: 2 Failure to extubate by 7th day



Biswas 2003 49/125 59/128 24.4 % 0.85 [ 0.64, 1.13 ]

Rastogi 1996 11/36 22/34 9.5 % 0.47 [ 0.27, 0.82 ]

Sanders 1994 15/19 14/21 5.6 % 1.18 [ 0.81, 1.73 ]

Shinwell 1996 27/132 34/116 15.2 % 0.70 [ 0.45, 1.08 ]

Vento 2004 3/10 8/10 3.3 % 0.38 [ 0.14, 1.02 ]

Wang 1996 22/34 23/29 10.4 % 0.82 [ 0.60, 1.11 ]

Yeh 1997 54/132 75/130 31.6 % 0.71 [ 0.55, 0.91 ]

Total (95% CI) 488 468 100.0 % 0.75 [ 0.65, 0.86 ]




0.2 0.5 1 2 5










Biswas 2003 40/125 40/128 39.0 % 1.02 [ 0.71, 1.47 ]

Rastogi 1996 10/36 20/34 20.3 % 0.47 [ 0.26, 0.86 ]

Wang 1996 17/34 19/29 20.3 % 0.76 [ 0.50, 1.17 ]

Yeh 1990 12/28 21/29 20.4 % 0.59 [ 0.37, 0.96 ]

Total (95% CI) 223 220 100.0 % 0.77 [ 0.62, 0.97 ]




0.5 0.7 1 1.5 2










Garland 1999 50/118 53/123 26.2 % 0.98 [ 0.73, 1.32 ]

Lin 1999 8/20 11/20 5.6 % 0.73 [ 0.37, 1.42 ]

Romagnoli 1999 4/25 13/25 6.6 % 0.31 [ 0.12, 0.81 ]

Stark 2001a 43/111 44/109 22.5 % 0.96 [ 0.69, 1.33 ]

Suske 1996 1/14 3/12 1.6 % 0.29 [ 0.03, 2.40 ]

Wang 1996 5/34 9/29 4.9 % 0.47 [ 0.18, 1.26 ]

Yeh 1997 55/132 64/130 32.6 % 0.85 [ 0.65, 1.11 ]

Total (95% CI) 454 448 100.0 % 0.84 [ 0.72, 0.98 ]




0.05 0.2 1 5 20




Analysis 5.1. Comparison 5 Complications during primary hospitalisation, Outcome 1 Infection.


Comparison: 5 Complications during primary hospitalisation

Outcome: 1 Infection



1 dexamethasone

Anttila 2005 22/53 20/56 3.8 % 1.16 [ 0.72, 1.87 ]

Garland 1999 47/118 44/123 8.3 % 1.11 [ 0.80, 1.54 ]

Halac 1990 15/130 18/118 3.7 % 0.76 [ 0.40, 1.43 ]

Kopelman 1999 24/37 19/33 3.9 % 1.13 [ 0.77, 1.64 ]

Lin 1999 6/20 4/20 0.8 % 1.50 [ 0.50, 4.52 ]

Rastogi 1996 1/36 3/34 0.6 % 0.31 [ 0.03, 2.88 ]

Romagnoli 1999 8/25 7/25 1.4 % 1.14 [ 0.49, 2.67 ]

Sanders 1994 1/19 1/21 0.2 % 1.11 [ 0.07, 16.47 ]

Shinwell 1996 32/132 37/116 7.6 % 0.76 [ 0.51, 1.14 ]

Sinkin 2000 13/189 11/195 2.1 % 1.22 [ 0.56, 2.65 ]

Soll 1999 109/273 107/269 20.9 % 1.00 [ 0.82, 1.23 ]

Stark 2001a 51/111 48/109 9.4 % 1.04 [ 0.78, 1.40 ]

Subhedar 1997 2/21 1/21 0.2 % 2.00 [ 0.20, 20.41 ]

Suske 1996 5/14 1/12 0.2 % 4.29 [ 0.58, 31.79 ]

Tapia 1998 14/55 15/54 2.9 % 0.92 [ 0.49, 1.71 ]

Wang 1996 5/34 6/29 1.3 % 0.71 [ 0.24, 2.09 ]

Yeh 1990 1/28 1/29 0.2 % 1.04 [ 0.07, 15.77 ]

Yeh 1997 17/132 12/130 2.3 % 1.40 [ 0.69, 2.80 ]

Subtotal (95% CI) 1427 1394 69.6 % 1.02 [ 0.91, 1.15 ]




2 hydrocortisone

Biswas 2003 63/125 64/128 12.2 % 1.01 [ 0.79, 1.29 ]

Bonsante 2007 9/25 7/25 1.4 % 1.29 [ 0.57, 2.91 ]

Efird 2005 3/16 6/18 1.1 % 0.56 [ 0.17, 1.89 ]

0.05 0.2 1 5 20


(Continued . . . )





Watterberg 1999 5/20 6/20 1.2 % 0.83 [ 0.30, 2.29 ]

Watterberg 2004 80/180 75/180 14.5 % 1.07 [ 0.84, 1.35 ]

Subtotal (95% CI) 366 371 30.4 % 1.03 [ 0.87, 1.21 ]




Total (95% CI) 1793 1765 100.0 % 1.02 [ 0.93, 1.13 ]




0.05 0.2 1 5 20


Analysis 5.2. Comparison 5 Complications during primary hospitalisation, Outcome 2 Hyperglycaemia.



Outcome: 2 Hyperglycaemia



1 dexamethasone

Anttila 2005 26/53 22/56 6.1 % 1.25 [ 0.82, 1.91 ]

Garland 1999 39/118 22/123 6.2 % 1.85 [ 1.17, 2.92 ]

Kopelman 1999 19/37 11/33 3.3 % 1.54 [ 0.87, 2.74 ]

Rastogi 1996 24/36 18/34 5.3 % 1.26 [ 0.85, 1.86 ]

Romagnoli 1999 7/25 0/25 0.1 % 15.00 [ 0.90, 249.30 ]

Sanders 1994 8/19 6/21 1.6 % 1.47 [ 0.63, 3.47 ]

Shinwell 1996 16/132 9/116 2.7 % 1.56 [ 0.72, 3.40 ]

Sinkin 2000 55/189 39/195 11.0 % 1.46 [ 1.02, 2.08 ]

0.005 0.1 1 10 200


(Continued . . . )





Soll 1999 200/273 151/269 43.6 % 1.31 [ 1.15, 1.48 ]

Stark 2001a 52/111 44/109 12.7 % 1.16 [ 0.86, 1.57 ]

Subhedar 1997 3/21 6/21 1.7 % 0.50 [ 0.14, 1.74 ]

Tapia 1998 9/55 7/54 2.0 % 1.26 [ 0.51, 3.15 ]

Subtotal (95% CI) 1069 1056 96.6 % 1.36 [ 1.22, 1.50 ]




2 hydrocortisone

Bonsante 2007 11/25 12/25 3.4 % 0.92 [ 0.50, 1.67 ]

Subtotal (95% CI) 25 25 3.4 % 0.92 [ 0.50, 1.67 ]




Total (95% CI) 1094 1081 100.0 % 1.34 [ 1.21, 1.48 ]




0.005 0.1 1 10 200




Analysis 5.3. Comparison 5 Complications during primary hospitalisation, Outcome 3 Hypertension.



Outcome: 3 Hypertension



1 dexamethasone

Garland 1999 95/118 56/123 1.77 [ 1.43, 2.19 ]

Rastogi 1996 1/36 1/34 0.94 [ 0.06, 14.51 ]

Romagnoli 1999 2/25 0/25 5.00 [ 0.25, 99.16 ]

Sanders 1994 0/19 0/21 0.0 [ 0.0, 0.0 ]

Shinwell 1996 8/132 2/116 3.52 [ 0.76, 16.22 ]

Sinkin 2000 4/189 0/195 9.28 [ 0.50, 171.27 ]

Soll 1999 68/273 50/269 1.34 [ 0.97, 1.85 ]

Stark 2001a 30/111 4/109 7.36 [ 2.68, 20.21 ]

Subhedar 1997 0/21 0/21 0.0 [ 0.0, 0.0 ]

Tapia 1998 3/55 2/54 1.47 [ 0.26, 8.47 ]

Subtotal (95% CI) 979 967 1.84 [ 1.54, 2.21 ]




2 hydrocortisone

Bonsante 2007 3/25 1/25 3.00 [ 0.33, 26.92 ]

Subtotal (95% CI) 25 25 3.00 [ 0.33, 26.92 ]




Total (95% CI) 1004 992 1.85 [ 1.55, 2.22 ]




0.005 0.1 1 10 200




Analysis 5.4. Comparison 5 Complications during primary hospitalisation, Outcome 4 Hypertrophic

cardiomyopathy.



Outcome: 4 Hypertrophic cardiomyopathy



Romagnoli 1999 13/25 3/25 100.0 % 4.33 [ 1.40, 13.37 ]

Total (95% CI) 25 25 100.0 % 4.33 [ 1.40, 13.37 ]




0.1 0.2 0.5 1 2 5 10


Analysis 5.5. Comparison 5 Complications during primary hospitalisation, Outcome 5 Growth failure.



Outcome: 5 Growth failure



Romagnoli 1999 20/25 3/25 100.0 % 6.67 [ 2.27, 19.62 ]

Total (95% CI) 25 25 100.0 % 6.67 [ 2.27, 19.62 ]




0.05 0.2 1 5 20




Analysis 5.6. Comparison 5 Complications during primary hospitalisation, Outcome 6 Pulmonary air leak.



Outcome: 6 Pulmonary air leak



1 dexamethasone

Garland 1999 6/118 13/123 8.2 % 0.48 [ 0.19, 1.22 ]

Mukhopadhyay 1998 4/10 3/9 2.0 % 1.20 [ 0.36, 3.97 ]

Rastogi 1996 2/36 3/34 2.0 % 0.63 [ 0.11, 3.54 ]

Sanders 1994 1/19 4/21 2.5 % 0.28 [ 0.03, 2.26 ]

Shinwell 1996 9/132 13/116 8.9 % 0.61 [ 0.27, 1.37 ]

Sinkin 2000 29/189 25/195 15.9 % 1.20 [ 0.73, 1.97 ]

Soll 1999 34/273 24/269 15.6 % 1.40 [ 0.85, 2.29 ]

Stark 2001a 10/111 25/109 16.3 % 0.39 [ 0.20, 0.78 ]

Subhedar 1997 3/21 1/21 0.6 % 3.00 [ 0.34, 26.56 ]

Suske 1996 1/14 4/12 2.8 % 0.21 [ 0.03, 1.67 ]

Tapia 1998 4/55 4/54 2.6 % 0.98 [ 0.26, 3.73 ]

Subtotal (95% CI) 978 963 77.5 % 0.85 [ 0.67, 1.09 ]




2 hydrocortisone

Biswas 2003 16/125 13/128 8.3 % 1.26 [ 0.63, 2.51 ]

Bonsante 2007 2/25 4/25 2.6 % 0.50 [ 0.10, 2.49 ]

Watterberg 2004 23/180 18/180 11.6 % 1.28 [ 0.71, 2.28 ]

Subtotal (95% CI) 330 333 22.5 % 1.18 [ 0.77, 1.81 ]




Total (95% CI) 1308 1296 100.0 % 0.93 [ 0.75, 1.15 ]




0.05 0.2 1 5 20




Analysis 5.7. Comparison 5 Complications during primary hospitalisation, Outcome 7 PDA.



Outcome: 7 PDA



1 dexamethasone

Anttila 2005 21/47 29/52 3.7 % 0.80 [ 0.54, 1.19 ]

Garland 1999 17/118 34/123 4.5 % 0.52 [ 0.31, 0.88 ]

Halac 1990 52/130 46/118 6.5 % 1.03 [ 0.75, 1.40 ]

Kopelman 1999 13/37 18/33 2.6 % 0.64 [ 0.38, 1.10 ]

Mukhopadhyay 1998 3/10 1/9 0.1 % 2.70 [ 0.34, 21.53 ]

Rastogi 1996 9/36 13/34 1.8 % 0.65 [ 0.32, 1.33 ]

Romagnoli 1999 13/25 17/25 2.3 % 0.76 [ 0.48, 1.21 ]

Shinwell 1996 25/132 32/116 4.6 % 0.69 [ 0.43, 1.09 ]

Sinkin 2000 89/189 109/195 14.6 % 0.84 [ 0.69, 1.02 ]

Soll 1999 92/273 117/269 16.0 % 0.77 [ 0.62, 0.96 ]

Stark 2001a 38/111 49/109 6.7 % 0.76 [ 0.55, 1.06 ]

Subhedar 1997 3/21 4/21 0.5 % 0.75 [ 0.19, 2.95 ]

Suske 1996 4/14 6/12 0.9 % 0.57 [ 0.21, 1.56 ]

Tapia 1998 13/55 18/54 2.5 % 0.71 [ 0.39, 1.30 ]

Vento 2004 2/10 2/10 0.3 % 1.00 [ 0.17, 5.77 ]

Yeh 1990 9/28 10/29 1.3 % 0.93 [ 0.45, 1.95 ]

Yeh 1997 14/132 34/130 4.6 % 0.41 [ 0.23, 0.72 ]

Subtotal (95% CI) 1368 1339 73.7 % 0.76 [ 0.69, 0.84 ]




2 hydrocortisone

Biswas 2003 41/125 60/128 8.0 % 0.70 [ 0.51, 0.96 ]

Bonsante 2007 8/25 9/25 1.2 % 0.89 [ 0.41, 1.93 ]

Efird 2005 4/14 6/18 0.7 % 0.86 [ 0.30, 2.46 ]

Peltoniemi 2005 9/25 19/26 2.5 % 0.49 [ 0.28, 0.87 ]

0.05 0.2 1 5 20


(Continued . . . )





Watterberg 1999 8/20 13/20 1.8 % 0.62 [ 0.33, 1.15 ]

Watterberg 2004 94/180 89/180 12.1 % 1.06 [ 0.86, 1.29 ]

Subtotal (95% CI) 389 397 26.3 % 0.85 [ 0.73, 0.99 ]




Total (95% CI) 1757 1736 100.0 % 0.78 [ 0.72, 0.85 ]




0.05 0.2 1 5 20


Analysis 5.8. Comparison 5 Complications during primary hospitalisation, Outcome 8 Severe IVH.



Outcome: 8 Severe IVH



1 dexamethasone

Anttila 2005 8/53 8/56 2.7 % 1.06 [ 0.43, 2.61 ]

Garland 1999 17/118 26/123 8.9 % 0.68 [ 0.39, 1.19 ]

Halac 1990 31/130 20/118 7.3 % 1.41 [ 0.85, 2.33 ]

Kopelman 1999 8/37 4/33 1.5 % 1.78 [ 0.59, 5.38 ]

Lin 1999 4/20 3/20 1.1 % 1.33 [ 0.34, 5.21 ]

Rastogi 1996 2/36 4/34 1.4 % 0.47 [ 0.09, 2.41 ]

Romagnoli 1999 5/25 6/25 2.1 % 0.83 [ 0.29, 2.38 ]

Sanders 1994 6/19 5/21 1.7 % 1.33 [ 0.48, 3.65 ]

0.02 0.1 1 10 50


(Continued . . . )





Shinwell 1996 7/132 10/116 3.7 % 0.62 [ 0.24, 1.56 ]

Sinkin 2000 22/189 21/195 7.2 % 1.08 [ 0.62, 1.90 ]

Soll 1999 38/273 50/269 17.7 % 0.75 [ 0.51, 1.10 ]

Stark 2001a 24/111 26/109 9.2 % 0.91 [ 0.56, 1.48 ]

Suske 1996 0/14 1/12 0.6 % 0.29 [ 0.01, 6.50 ]

Tapia 1998 6/55 8/54 2.8 % 0.74 [ 0.27, 1.98 ]

Vento 2004 2/10 1/10 0.4 % 2.00 [ 0.21, 18.69 ]

Yeh 1990 9/28 6/29 2.1 % 1.55 [ 0.64, 3.79 ]

Yeh 1997 25/132 20/130 7.1 % 1.23 [ 0.72, 2.10 ]

Subtotal (95% CI) 1382 1354 77.4 % 0.96 [ 0.81, 1.14 ]




2 hydrocortisone

Biswas 2003 15/125 19/128 6.6 % 0.81 [ 0.43, 1.52 ]

Bonsante 2007 1/25 2/25 0.7 % 0.50 [ 0.05, 5.17 ]

Efird 2005 2/16 5/18 1.6 % 0.45 [ 0.10, 2.01 ]

Ng 2006 3/24 5/24 1.8 % 0.60 [ 0.16, 2.23 ]

Peltoniemi 2005 3/25 4/26 1.4 % 0.78 [ 0.19, 3.14 ]

Watterberg 1999 2/20 1/20 0.4 % 2.00 [ 0.20, 20.33 ]

Watterberg 2004 33/180 29/180 10.2 % 1.14 [ 0.72, 1.79 ]

Subtotal (95% CI) 415 421 22.6 % 0.92 [ 0.67, 1.28 ]




Total (95% CI) 1797 1775 100.0 % 0.95 [ 0.82, 1.11 ]




0.02 0.1 1 10 50




Analysis 5.9. Comparison 5 Complications during primary hospitalisation, Outcome 9 Severe IVH in infants

examined.



Outcome: 9 Severe IVH in infants examined



Bonsante 2007 1/25 2/21 1.7 % 0.42 [ 0.04, 4.31 ]

Shinwell 1996 7/88 10/76 8.5 % 0.60 [ 0.24, 1.51 ]

Soll 1999 38/257 50/255 39.9 % 0.75 [ 0.51, 1.11 ]

Stark 2001a 24/111 26/109 20.8 % 0.91 [ 0.56, 1.48 ]

Tapia 1998 6/48 8/50 6.2 % 0.78 [ 0.29, 2.08 ]

Watterberg 2004 33/172 29/176 22.8 % 1.16 [ 0.74, 1.83 ]

Total (95% CI) 701 687 100.0 % 0.86 [ 0.68, 1.09 ]




0.05 0.2 1 5 20




Analysis 5.10. Comparison 5 Complications during primary hospitalisation, Outcome 10 PVL.



Outcome: 10 PVL



1 dexamethasone

Anttila 2005 4/53 3/56 5.0 % 1.41 [ 0.33, 6.00 ]

Efird 2005 0/16 3/18 5.7 % 0.16 [ 0.01, 2.87 ]

Garland 1999 6/118 7/123 11.8 % 0.89 [ 0.31, 2.58 ]

Romagnoli 1999 2/25 2/25 3.4 % 1.00 [ 0.15, 6.55 ]

Shinwell 1996 16/132 9/116 16.5 % 1.56 [ 0.72, 3.40 ]

Soll 1999 18/273 8/269 13.9 % 2.22 [ 0.98, 5.01 ]

Stark 2001a 8/111 8/79 16.1 % 0.71 [ 0.28, 1.82 ]

Subtotal (95% CI) 728 686 72.5 % 1.24 [ 0.84, 1.84 ]




2 hydrocortisone

Biswas 2003 4/125 2/128 3.4 % 2.05 [ 0.38, 10.98 ]

Bonsante 2007 1/25 2/25 3.4 % 0.50 [ 0.05, 5.17 ]

Ng 2006 1/24 1/24 1.7 % 1.00 [ 0.07, 15.08 ]

Peltoniemi 2005 3/25 2/26 3.4 % 1.56 [ 0.28, 8.56 ]

Watterberg 2004 8/180 9/180 15.5 % 0.89 [ 0.35, 2.25 ]

Subtotal (95% CI) 379 383 27.5 % 1.07 [ 0.55, 2.09 ]




Total (95% CI) 1107 1069 100.0 % 1.20 [ 0.85, 1.68 ]




0.01 0.1 1 10 100




Analysis 5.11. Comparison 5 Complications during primary hospitalisation, Outcome 11 PVL in infants with

cranial ultrasound scans.



Outcome: 11 PVL in infants with cranial ultrasound scans



Bonsante 2007 1/23 2/20 4.9 % 0.43 [ 0.04, 4.44 ]

Garland 1999 6/107 7/112 15.7 % 0.90 [ 0.31, 2.58 ]

Shinwell 1996 16/88 9/76 22.2 % 1.54 [ 0.72, 3.27 ]

Soll 1999 18/252 8/250 18.4 % 2.23 [ 0.99, 5.04 ]

Stark 2001a 8/82 8/79 18.7 % 0.96 [ 0.38, 2.44 ]

Watterberg 2004 8/112 9/119 20.0 % 0.94 [ 0.38, 2.36 ]

Total (95% CI) 664 656 100.0 % 1.28 [ 0.88, 1.88 ]




0.05 0.2 1 5 20




Analysis 5.12. Comparison 5 Complications during primary hospitalisation, Outcome 12 PVL in survivors

seen at follow-up.



Outcome: 12 PVL in survivors seen at follow-up



Romagnoli 1999 1/23 1/1 25.6 % 0.08 [ 0.01, 0.48 ]

Shinwell 1996 13/80 8/79 74.4 % 1.60 [ 0.70, 3.66 ]

Total (95% CI) 103 80 100.0 % 1.22 [ 0.60, 2.48 ]




0.02 0.1 1 10 50




Analysis 5.13. Comparison 5 Complications during primary hospitalisation, Outcome 13 NEC.



Outcome: 13 NEC



1 dexamethasone

Anttila 2005 8/53 8/56 4.8 % 1.06 [ 0.43, 2.61 ]

Garland 1999 6/118 8/123 4.8 % 0.78 [ 0.28, 2.19 ]

Halac 1990 9/130 17/118 10.9 % 0.48 [ 0.22, 1.04 ]

Kopelman 1999 5/37 3/33 1.9 % 1.49 [ 0.38, 5.75 ]

Rastogi 1996 2/36 2/34 1.3 % 0.94 [ 0.14, 6.33 ]

Romagnoli 1999 2/25 3/25 1.8 % 0.67 [ 0.12, 3.65 ]

Sanders 1994 0/19 3/21 2.0 % 0.16 [ 0.01, 2.86 ]

Shinwell 1996 10/132 10/116 6.5 % 0.88 [ 0.38, 2.04 ]

Sinkin 2000 16/189 13/195 7.8 % 1.27 [ 0.63, 2.57 ]

Soll 1999 24/273 25/269 15.4 % 0.95 [ 0.55, 1.61 ]

Stark 2001a 14/111 10/109 6.2 % 1.37 [ 0.64, 2.96 ]

Subhedar 1997 2/21 1/21 0.6 % 2.00 [ 0.20, 20.41 ]

Suske 1996 1/14 2/12 1.3 % 0.43 [ 0.04, 4.16 ]

Tapia 1998 0/55 5/54 3.4 % 0.09 [ 0.01, 1.58 ]

Yeh 1997 11/132 12/130 7.4 % 0.90 [ 0.41, 1.97 ]

Subtotal (95% CI) 1345 1316 76.3 % 0.88 [ 0.69, 1.13 ]




2 hydorcortisone

Biswas 2003 16/125 15/128 9.1 % 1.09 [ 0.56, 2.11 ]

Bonsante 2007 1/25 2/25 1.2 % 0.50 [ 0.05, 5.17 ]

Efird 2005 2/16 2/18 1.2 % 1.13 [ 0.18, 7.09 ]

Ng 2006 2/24 3/24 1.8 % 0.67 [ 0.12, 3.64 ]

Peltoniemi 2005 2/25 1/26 0.6 % 2.08 [ 0.20, 21.52 ]

Watterberg 1999 2/20 2/20 1.2 % 1.00 [ 0.16, 6.42 ]

0.005 0.1 1 10 200


(Continued . . . )





Watterberg 2004 7/180 14/180 8.6 % 0.50 [ 0.21, 1.21 ]

Subtotal (95% CI) 415 421 23.7 % 0.84 [ 0.54, 1.30 ]




Total (95% CI) 1760 1737 100.0 % 0.87 [ 0.70, 1.08 ]




0.005 0.1 1 10 200


Analysis 5.14. Comparison 5 Complications during primary hospitalisation, Outcome 14 Gastro-intestinal

bleeding.



Outcome: 14 Gastro-intestinal bleeding



1 dexamethasone

Anttila 2005 2/53 1/56 2.11 [ 0.20, 22.63 ]

Kopelman 1999 2/37 1/33 1.78 [ 0.17, 18.78 ]

Rastogi 1996 0/36 0/34 0.0 [ 0.0, 0.0 ]

Shinwell 1996 28/132 12/116 2.05 [ 1.09, 3.84 ]

Soll 1999 33/273 21/269 1.55 [ 0.92, 2.61 ]

Stark 2001a 6/111 2/109 2.95 [ 0.61, 14.28 ]

Subhedar 1997 2/21 0/21 5.00 [ 0.25, 98.27 ]

Tapia 1998 0/55 0/54 0.0 [ 0.0, 0.0 ]

0.01 0.1 1 10 100


(Continued . . . )





Yeh 1990 4/28 3/29 1.38 [ 0.34, 5.62 ]

Yeh 1997 21/132 10/130 2.07 [ 1.01, 4.22 ]

Subtotal (95% CI) 878 851 1.87 [ 1.35, 2.58 ]




2 hydrocortisone

Peltoniemi 2005 2/25 1/26 2.08 [ 0.20, 21.52 ]

Watterberg 1999 1/20 1/20 1.00 [ 0.07, 14.90 ]

Subtotal (95% CI) 45 46 1.53 [ 0.27, 8.74 ]




Total (95% CI) 923 897 1.86 [ 1.35, 2.55 ]




0.01 0.1 1 10 100




Analysis 5.15. Comparison 5 Complications during primary hospitalisation, Outcome 15 Intestinal

perforation.



Outcome: 15 Intestinal perforation



1 dexamethasone

Anttila 2005 3/53 1/56 3.17 [ 0.34, 29.53 ]

Garland 1999 12/118 7/123 1.79 [ 0.73, 4.38 ]

Kopelman 1999 3/37 0/33 6.26 [ 0.34, 116.92 ]

Rastogi 1996 0/36 0/34 0.0 [ 0.0, 0.0 ]

Sinkin 2000 3/189 2/195 1.55 [ 0.26, 9.16 ]

Soll 1999 31/273 20/269 1.53 [ 0.89, 2.61 ]

Stark 2001a 15/111 8/109 1.84 [ 0.81, 4.17 ]

Subhedar 1997 2/21 1/21 2.00 [ 0.20, 20.41 ]

Yeh 1997 1/132 1/130 0.98 [ 0.06, 15.58 ]

Subtotal (95% CI) 970 970 1.73 [ 1.20, 2.51 ]




2 hydrocortisone

Bonsante 2007 2/25 1/25 2.00 [ 0.19, 20.67 ]

Efird 2005 1/16 0/18 3.35 [ 0.15, 76.93 ]

Ng 2006 1/24 2/24 0.50 [ 0.05, 5.15 ]

Peltoniemi 2005 4/25 0/26 9.35 [ 0.53, 165.12 ]

Watterberg 1999 1/20 1/20 1.00 [ 0.07, 14.90 ]

Watterberg 2004 22/180 11/180 2.00 [ 1.00, 4.00 ]

Subtotal (95% CI) 290 293 2.02 [ 1.13, 3.59 ]




Total (95% CI) 1260 1263 1.81 [ 1.33, 2.48 ]




0.01 0.1 1 10 100




Analysis 5.16. Comparison 5 Complications during primary hospitalisation, Outcome 16 Pulmonary

haemorrhage.



Outcome: 16 Pulmonary haemorrhage



1 dexamethasone

Garland 1999 9/118 12/123 0.78 [ 0.34, 1.79 ]

Rastogi 1996 2/36 3/34 0.63 [ 0.11, 3.54 ]

Sanders 1994 0/1 0/1 0.0 [ 0.0, 0.0 ]

Shinwell 1996 0/1 0/1 0.0 [ 0.0, 0.0 ]

Stark 2001a 18/111 18/109 0.98 [ 0.54, 1.78 ]

Subhedar 1997 2/21 2/21 1.00 [ 0.16, 6.45 ]

Tapia 1998 10/55 7/54 1.40 [ 0.58, 3.42 ]

Subtotal (95% CI) 343 343 0.97 [ 0.65, 1.45 ]




2 hydrocortisone

Biswas 2003 15/125 9/128 1.71 [ 0.78, 3.76 ]

Watterberg 2004 18/180 13/180 1.38 [ 0.70, 2.74 ]

Subtotal (95% CI) 305 308 1.52 [ 0.90, 2.54 ]




Total (95% CI) 648 651 1.16 [ 0.85, 1.59 ]




0.1 0.2 0.5 1 2 5 10




Analysis 5.17. Comparison 5 Complications during primary hospitalisation, Outcome 17 Any ROP.



Outcome: 17 Any ROP



1 dexamethasone

Anttila 2005 14/45 22/49 6.5 % 0.69 [ 0.41, 1.18 ]

Rastogi 1996 5/36 8/34 2.5 % 0.59 [ 0.21, 1.63 ]

Sanders 1994 10/19 11/21 3.2 % 1.00 [ 0.56, 1.81 ]

Sinkin 2000 96/189 116/195 35.3 % 0.85 [ 0.71, 1.02 ]

Suske 1996 2/14 6/12 2.0 % 0.29 [ 0.07, 1.16 ]

Tapia 1998 7/55 8/54 2.5 % 0.86 [ 0.33, 2.20 ]

Yeh 1990 5/28 4/29 1.2 % 1.29 [ 0.39, 4.33 ]

Yeh 1997 23/132 22/130 6.8 % 1.03 [ 0.60, 1.75 ]

Subtotal (95% CI) 518 524 60.1 % 0.84 [ 0.72, 0.99 ]




2 hydrocortisone

Watterberg 2004 122/153 128/150 39.9 % 0.93 [ 0.84, 1.04 ]

Subtotal (95% CI) 153 150 39.9 % 0.93 [ 0.84, 1.04 ]




Total (95% CI) 671 674 100.0 % 0.88 [ 0.80, 0.97 ]




0.1 0.2 0.5 1 2 5 10




Analysis 5.18. Comparison 5 Complications during primary hospitalisation, Outcome 18 Severe ROP.



Outcome: 18 Severe ROP



1 dexamethasone

Anttila 2005 3/45 4/49 2.2 % 0.82 [ 0.19, 3.45 ]

Garland 1999 12/118 17/123 9.4 % 0.74 [ 0.37, 1.47 ]

Kopelman 1999 4/37 5/33 3.0 % 0.71 [ 0.21, 2.44 ]

Romagnoli 1999 9/25 8/25 4.5 % 1.13 [ 0.52, 2.44 ]

Shinwell 1996 10/132 8/116 4.8 % 1.10 [ 0.45, 2.69 ]

Soll 1999 32/273 49/269 28.0 % 0.64 [ 0.43, 0.97 ]

Stark 2001a 18/111 24/109 13.7 % 0.74 [ 0.42, 1.28 ]

Subhedar 1997 2/21 0/21 0.3 % 5.00 [ 0.25, 98.27 ]

Subtotal (95% CI) 762 745 66.0 % 0.77 [ 0.60, 0.99 ]




2 hydrocortisone

Bonsante 2007 3/25 4/25 2.3 % 0.75 [ 0.19, 3.01 ]

Ng 2006 1/24 2/24 1.1 % 0.50 [ 0.05, 5.15 ]

Peltoniemi 2005 1/25 1/26 0.6 % 1.04 [ 0.07, 15.74 ]

Watterberg 1999 4/20 6/20 3.4 % 0.67 [ 0.22, 2.01 ]

Watterberg 2004 41/180 47/180 26.7 % 0.87 [ 0.61, 1.26 ]

Subtotal (95% CI) 274 275 34.0 % 0.83 [ 0.60, 1.16 ]




Total (95% CI) 1036 1020 100.0 % 0.79 [ 0.65, 0.97 ]




0.01 0.1 1 10 100




Analysis 5.19. Comparison 5 Complications during primary hospitalisation, Outcome 19 Severe ROP in

survivors.



Outcome: 19 Severe ROP in survivors



1 dexamethasone

Garland 1999 12/99 17/98 9.3 % 0.70 [ 0.35, 1.39 ]

Kopelman 1999 4/27 5/28 2.7 % 0.83 [ 0.25, 2.77 ]

Rastogi 1996 5/32 8/32 4.4 % 0.63 [ 0.23, 1.71 ]

Shinwell 1996 10/101 8/94 4.5 % 1.16 [ 0.48, 2.82 ]

Soll 1999 32/194 49/204 26.1 % 0.69 [ 0.46, 1.02 ]

Stark 2001a 18/80 24/80 13.1 % 0.75 [ 0.44, 1.27 ]

Subhedar 1997 2/12 0/13 0.3 % 5.38 [ 0.28, 101.96 ]

Suske 1996 2/13 6/11 3.6 % 0.28 [ 0.07, 1.13 ]

Tapia 1998 7/38 8/36 4.5 % 0.83 [ 0.33, 2.05 ]

Yeh 1990 5/25 4/21 2.4 % 1.05 [ 0.32, 3.42 ]

Subtotal (95% CI) 621 617 70.8 % 0.75 [ 0.59, 0.95 ]




2 hydrocortisone

Watterberg 1999 4/17 6/17 3.3 % 0.67 [ 0.23, 1.95 ]

Watterberg 2004 41/153 47/150 25.9 % 0.86 [ 0.60, 1.22 ]

Subtotal (95% CI) 170 167 29.2 % 0.83 [ 0.60, 1.17 ]




Total (95% CI) 791 784 100.0 % 0.77 [ 0.64, 0.94 ]




0.01 0.1 1 10 100




Analysis 6.1. Comparison 6 Long-term follow-up, Outcome 1 Bayley MDI <-2SD.


Comparison: 6 Long-term follow-up

Outcome: 1 Bayley MDI <-2SD



Stark 2001a 37/111 28/109 29.0 % 1.30 [ 0.86, 1.96 ]

Watterberg 2004 34/180 47/180 48.2 % 0.72 [ 0.49, 1.07 ]

Yeh 1997 26/132 22/130 22.8 % 1.16 [ 0.70, 1.95 ]

Total (95% CI) 423 419 100.0 % 0.99 [ 0.77, 1.27 ]




0.5 0.7 1 1.5 2


Analysis 6.2. Comparison 6 Long-term follow-up, Outcome 2 Bayley MDI <-2SD in tested survivors.



Outcome: 2 Bayley MDI <-2SD in tested survivors



Stark 2001a 37/76 28/67 30.5 % 1.16 [ 0.81, 1.68 ]

Watterberg 2004 34/126 47/126 48.2 % 0.72 [ 0.50, 1.04 ]

Yeh 1997 26/63 22/70 21.4 % 1.31 [ 0.83, 2.07 ]

Total (95% CI) 265 263 100.0 % 0.98 [ 0.79, 1.23 ]




0.5 0.7 1 1.5 2




Analysis 6.3. Comparison 6 Long-term follow-up, Outcome 3 Bayley PDI <-2SD.



Outcome: 3 Bayley PDI <-2SD



Stark 2001a 23/111 24/109 38.2 % 0.94 [ 0.57, 1.56 ]

Watterberg 2004 26/180 23/180 36.3 % 1.13 [ 0.67, 1.90 ]

Yeh 1997 25/132 16/130 25.5 % 1.54 [ 0.86, 2.75 ]

Total (95% CI) 423 419 100.0 % 1.16 [ 0.86, 1.58 ]




0.5 0.7 1 1.5 2




Analysis 6.4. Comparison 6 Long-term follow-up, Outcome 4 Bayley PDI <-2SD in tested survivors.



Outcome: 4 Bayley PDI <-2SD in tested survivors



Stark 2001a 23/76 24/67 40.1 % 0.84 [ 0.53, 1.35 ]

Watterberg 2004 26/126 23/126 36.1 % 1.13 [ 0.68, 1.87 ]

Yeh 1997 25/63 16/70 23.8 % 1.74 [ 1.02, 2.94 ]

Total (95% CI) 265 263 100.0 % 1.16 [ 0.87, 1.54 ]




0.5 0.7 1 1.5 2


Analysis 6.5. Comparison 6 Long-term follow-up, Outcome 5 Developmental delay (criteria not specified).



Outcome: 5 Developmental delay (criteria not specified)



Shinwell 1996 44/132 23/116 100.0 % 1.68 [ 1.08, 2.61 ]

Total (95% CI) 132 116 100.0 % 1.68 [ 1.08, 2.61 ]




0.5 0.7 1 1.5 2




Analysis 6.6. Comparison 6 Long-term follow-up, Outcome 6 Developmental delay (criteria not specified)

in tested survivors.



Outcome: 6 Developmental delay (criteria not specified) in tested survivors



Shinwell 1996 44/79 23/80 100.0 % 1.94 [ 1.30, 2.88 ]

Total (95% CI) 79 80 100.0 % 1.94 [ 1.30, 2.88 ]




0.5 0.7 1 1.5 2


Analysis 6.7. Comparison 6 Long-term follow-up, Outcome 7 Blindness.



Outcome: 7 Blindness



Romagnoli 1999 2/25 1/25 2.00 [ 0.19, 20.67 ]

Sanders 1994 0/19 0/21 0.0 [ 0.0, 0.0 ]

Shinwell 1996 3/132 1/116 2.64 [ 0.28, 25.00 ]

Subhedar 1997 0/21 0/21 0.0 [ 0.0, 0.0 ]

Watterberg 1999 0/13 0/13 0.0 [ 0.0, 0.0 ]

Yeh 1997 5/132 3/130 1.64 [ 0.40, 6.73 ]

Total (95% CI) 342 326 1.92 [ 0.66, 5.54 ]




0.05 0.2 1 5 20




Analysis 6.8. Comparison 6 Long-term follow-up, Outcome 8 Blindness in survivors assessed.



Outcome: 8 Blindness in survivors assessed



Romagnoli 1999 2/23 1/22 1.91 [ 0.19, 19.63 ]

Sanders 1994 0/17 0/14 0.0 [ 0.0, 0.0 ]

Shinwell 1996 3/79 1/80 3.04 [ 0.32, 28.59 ]

Subhedar 1997 0/10 0/11 0.0 [ 0.0, 0.0 ]

Watterberg 1999 0/10 0/8 0.0 [ 0.0, 0.0 ]

Yeh 1997 5/63 3/70 1.85 [ 0.46, 7.44 ]

Total (95% CI) 202 205 2.11 [ 0.74, 6.02 ]




0.05 0.2 1 5 20




Analysis 6.9. Comparison 6 Long-term follow-up, Outcome 9 Deafness.



Outcome: 9 Deafness



Baden 1972 0/22 0/22 0.0 [ 0.0, 0.0 ]

Romagnoli 1999 0/25 2/25 0.20 [ 0.01, 3.97 ]

Sanders 1994 0/19 0/21 0.0 [ 0.0, 0.0 ]

Shinwell 1996 1/132 0/116 2.64 [ 0.11, 64.16 ]

Subhedar 1997 1/21 0/21 3.00 [ 0.13, 69.70 ]

Watterberg 1999 0/13 0/13 0.0 [ 0.0, 0.0 ]

Total (95% CI) 232 218 0.96 [ 0.22, 4.22 ]




0.01 0.1 1 10 100




Analysis 6.10. Comparison 6 Long-term follow-up, Outcome 10 Deafness in survivors assessed.



Outcome: 10 Deafness in survivors assessed



Baden 1972 0/13 0/12 0.0 [ 0.0, 0.0 ]

Romagnoli 1999 0/23 2/22 0.19 [ 0.01, 3.78 ]

Sanders 1994 0/17 0/14 0.0 [ 0.0, 0.0 ]

Shinwell 1996 1/79 0/80 3.04 [ 0.13, 73.46 ]

Subhedar 1997 1/10 0/11 3.27 [ 0.15, 72.23 ]

Watterberg 1999 0/10 0/8 0.0 [ 0.0, 0.0 ]

Total (95% CI) 152 147 1.01 [ 0.24, 4.24 ]




0.01 0.1 1 10 100




Analysis 6.11. Comparison 6 Long-term follow-up, Outcome 11 Cerebral palsy.



Outcome: 11 Cerebral palsy


n/N n/N IV,Fixed,95% CI IV,Fixed,95% CI

1 dexamethasone

Romagnoli 1999 2/25 3/25 3.4 % 0.67 [ 0.12, 3.65 ]

Sanders 1994 3/19 1/21 2.1 % 3.32 [ 0.38, 29.23 ]

Shinwell 1996 38/132 12/116 27.2 % 2.78 [ 1.53, 5.07 ]

Sinkin 2000 4/32 1/27 2.2 % 3.38 [ 0.40, 28.42 ]

Stark 2001a 11/111 12/109 16.3 % 0.90 [ 0.42, 1.95 ]

Subhedar 1997 0/21 2/21 1.1 % 0.20 [ 0.01, 3.93 ]

Yeh 1997 17/132 9/130 16.4 % 1.86 [ 0.86, 4.02 ]

Subtotal (95% CI) 472 449 68.7 % 1.75 [ 1.20, 2.55 ]




2 hydrocortisone

Baden 1972 2/22 1/22 1.8 % 2.00 [ 0.20, 20.49 ]

Bonsante 2007 2/25 2/25 2.8 % 1.00 [ 0.15, 6.55 ]

Peltoniemi 2005 2/25 0/26 1.1 % 5.19 [ 0.26, 103.07 ]

Watterberg 1999 1/13 2/13 1.9 % 0.50 [ 0.05, 4.86 ]

Watterberg 2004 16/180 18/180 23.8 % 0.89 [ 0.47, 1.69 ]

Subtotal (95% CI) 265 266 31.3 % 0.97 [ 0.55, 1.69 ]




Total (95% CI) 737 715 100.0 % 1.45 [ 1.06, 1.98 ]




Test for subgroup differences: Chi2 = 2.96, df = 1 (P = 0.09), I2 =66%

0.01 0.1 1 10 100




Analysis 6.12. Comparison 6 Long-term follow-up, Outcome 12 Death before follow-up in trials assessing

cerebral palsy.



Outcome: 12 Death before follow-up in trials assessing cerebral palsy



1 dexamethasone

Romagnoli 1999 2/25 3/25 1.6 % 0.67 [ 0.12, 3.65 ]

Sanders 1994 2/19 7/21 3.5 % 0.32 [ 0.07, 1.34 ]

Shinwell 1996 32/132 26/116 14.5 % 1.08 [ 0.69, 1.70 ]

Sinkin 2000 11/32 7/27 4.0 % 1.33 [ 0.60, 2.94 ]

Stark 2001a 26/111 30/109 15.8 % 0.85 [ 0.54, 1.34 ]

Subhedar 1997 11/21 9/21 4.7 % 1.22 [ 0.64, 2.32 ]

Watterberg 2004 33/180 33/180 17.2 % 1.00 [ 0.65, 1.55 ]

Yeh 1997 53/132 50/130 26.3 % 1.04 [ 0.77, 1.41 ]

Subtotal (95% CI) 652 629 87.5 % 0.99 [ 0.83, 1.19 ]




2 hydrocortisone

Baden 1972 8/22 9/22 4.7 % 0.89 [ 0.42, 1.88 ]

Bonsante 2007 4/25 10/25 5.2 % 0.40 [ 0.14, 1.11 ]

Peltoniemi 2005 2/25 3/26 1.5 % 0.69 [ 0.13, 3.81 ]

Watterberg 1999 3/13 2/13 1.0 % 1.50 [ 0.30, 7.55 ]

Subtotal (95% CI) 85 86 12.5 % 0.71 [ 0.42, 1.21 ]




Total (95% CI) 737 715 100.0 % 0.96 [ 0.81, 1.14 ]




0.1 0.2 0.5 1 2 5 10




Analysis 6.13. Comparison 6 Long-term follow-up, Outcome 13 Death or cerebral palsy.



Outcome: 13 Death or cerebral palsy



1 dexamethasone

Romagnoli 1999 4/25 6/25 2.3 % 0.67 [ 0.21, 2.08 ]

Sanders 1994 5/19 8/21 3.0 % 0.69 [ 0.27, 1.75 ]

Shinwell 1996 70/132 38/116 15.8 % 1.62 [ 1.19, 2.20 ]

Sinkin 2000 15/32 8/27 3.4 % 1.58 [ 0.79, 3.15 ]

Stark 2001a 37/111 42/109 16.6 % 0.87 [ 0.61, 1.23 ]

Subhedar 1997 11/21 11/21 4.3 % 1.00 [ 0.56, 1.78 ]

Yeh 1997 70/132 59/130 23.3 % 1.17 [ 0.91, 1.50 ]

Subtotal (95% CI) 472 449 68.7 % 1.17 [ 1.00, 1.37 ]




2 hydrocortisone

Baden 1972 10/22 10/22 3.9 % 1.00 [ 0.52, 1.91 ]

Bonsante 2007 6/25 12/25 4.7 % 0.50 [ 0.22, 1.12 ]

Peltoniemi 2005 4/25 3/26 1.2 % 1.39 [ 0.34, 5.58 ]

Watterberg 1999 4/13 4/13 1.6 % 1.00 [ 0.32, 3.17 ]

Watterberg 2004 49/180 51/180 20.0 % 0.96 [ 0.69, 1.34 ]

Subtotal (95% CI) 265 266 31.3 % 0.91 [ 0.70, 1.19 ]




Total (95% CI) 737 715 100.0 % 1.09 [ 0.95, 1.25 ]




0.2 0.5 1 2 5




Analysis 6.14. Comparison 6 Long-term follow-up, Outcome 14 Cerebral palsy in survivors assessed.



Outcome: 14 Cerebral palsy in survivors assessed



1 dexamethasone

Romagnoli 1999 2/23 3/22 4.7 % 0.64 [ 0.12, 3.46 ]

Sanders 1994 3/17 1/14 1.7 % 2.47 [ 0.29, 21.21 ]

Shinwell 1996 38/79 12/80 18.3 % 3.21 [ 1.81, 5.67 ]

Sinkin 2000 4/21 1/20 1.6 % 3.81 [ 0.46, 31.23 ]

Stark 2001a 11/76 12/67 19.6 % 0.81 [ 0.38, 1.71 ]

Subhedar 1997 0/10 2/11 3.7 % 0.22 [ 0.01, 4.06 ]

Yeh 1997 17/72 9/74 13.6 % 1.94 [ 0.93, 4.07 ]

Subtotal (95% CI) 298 288 63.1 % 1.82 [ 1.29, 2.57 ]




2 hydrocortisone

Baden 1972 2/13 1/12 1.6 % 1.85 [ 0.19, 17.84 ]

Bonsante 2007 2/19 2/14 3.5 % 0.74 [ 0.12, 4.61 ]

Peltoniemi 2005 2/23 0/22 0.8 % 4.79 [ 0.24, 94.53 ]

Watterberg 1999 1/10 2/8 3.4 % 0.40 [ 0.04, 3.66 ]

Watterberg 2004 16/126 18/126 27.6 % 0.89 [ 0.48, 1.66 ]

Subtotal (95% CI) 191 182 36.9 % 0.95 [ 0.56, 1.63 ]




Total (95% CI) 489 470 100.0 % 1.50 [ 1.13, 2.00 ]




0.01 0.1 1 10 100




Analysis 6.15. Comparison 6 Long-term follow-up, Outcome 15 Major neurosensory disability (variable

criteria - see individual studies).



Outcome: 15 Major neurosensory disability (variable criteria - see individual studies)



1 dexamethasone

Shinwell 1996 18/132 11/116 9.1 % 1.44 [ 0.71, 2.92 ]

Stark 2001a 43/111 36/109 28.4 % 1.17 [ 0.82, 1.67 ]

Subhedar 1997 1/21 4/21 3.1 % 0.25 [ 0.03, 2.05 ]

Yeh 1997 28/132 16/130 12.6 % 1.72 [ 0.98, 3.03 ]

Subtotal (95% CI) 396 376 53.2 % 1.29 [ 0.98, 1.70 ]




2 hydrocortisone

Bonsante 2007 4/25 3/25 2.3 % 1.33 [ 0.33, 5.36 ]

Peltoniemi 2005 3/25 2/26 1.5 % 1.56 [ 0.28, 8.56 ]

Watterberg 2004 49/180 55/180 42.9 % 0.89 [ 0.64, 1.23 ]

Subtotal (95% CI) 230 231 46.8 % 0.93 [ 0.69, 1.28 ]




Total (95% CI) 626 607 100.0 % 1.13 [ 0.92, 1.38 ]




0.05 0.2 1 5 20





major neurosensory disability (variable criteria).



Outcome: 16 Death before follow-up in trials assessing major neurosensory disability (variable criteria)



1 dexamethasone

Shinwell 1996 32/132 26/116 17.0 % 1.08 [ 0.69, 1.70 ]

Stark 2001a 26/111 30/109 18.5 % 0.85 [ 0.54, 1.34 ]

Subhedar 1997 11/21 9/21 5.5 % 1.22 [ 0.64, 2.32 ]

Yeh 1997 53/132 50/130 30.9 % 1.04 [ 0.77, 1.41 ]

Subtotal (95% CI) 396 376 71.9 % 1.02 [ 0.82, 1.25 ]




2 hydrocortisone

Bonsante 2007 4/25 10/25 6.1 % 0.40 [ 0.14, 1.11 ]

Peltoniemi 2005 2/25 3/26 1.8 % 0.69 [ 0.13, 3.81 ]

Watterberg 2004 33/180 33/180 20.2 % 1.00 [ 0.65, 1.55 ]

Subtotal (95% CI) 230 231 28.1 % 0.85 [ 0.58, 1.25 ]




Total (95% CI) 626 607 100.0 % 0.97 [ 0.81, 1.17 ]




0.2 0.5 1 2 5




Analysis 6.17. Comparison 6 Long-term follow-up, Outcome 17 Death or major neurosensory disability

(variable criteria).



Outcome: 17 Death or major neurosensory disability (variable criteria)



1 dexamethasone

Shinwell 1996 50/132 37/116 13.5 % 1.19 [ 0.84, 1.68 ]

Stark 2001a 69/111 66/109 22.9 % 1.03 [ 0.83, 1.27 ]

Subhedar 1997 12/21 13/21 4.5 % 0.92 [ 0.56, 1.52 ]

Yeh 1997 81/132 66/130 22.8 % 1.21 [ 0.97, 1.50 ]

Subtotal (95% CI) 396 376 63.7 % 1.12 [ 0.98, 1.28 ]




2 hydrocortisone

Bonsante 2007 8/25 13/25 4.5 % 0.62 [ 0.31, 1.22 ]

Peltoniemi 2005 5/25 5/26 1.7 % 1.04 [ 0.34, 3.16 ]

Watterberg 2004 82/180 88/180 30.2 % 0.93 [ 0.75, 1.16 ]

Subtotal (95% CI) 230 231 36.3 % 0.90 [ 0.73, 1.10 ]




Total (95% CI) 626 607 100.0 % 1.04 [ 0.93, 1.16 ]




0.5 0.7 1 1.5 2




Analysis 6.18. Comparison 6 Long-term follow-up, Outcome 18 Major neurosensory disability (variable

criteria) in survivors examined.



Outcome: 18 Major neurosensory disability (variable criteria) in survivors examined



1 dexamethasone

Shinwell 1996 18/79 11/80 8.5 % 1.66 [ 0.84, 3.28 ]

Stark 2001a 43/76 36/67 29.6 % 1.05 [ 0.78, 1.42 ]

Subhedar 1997 1/10 4/11 2.9 % 0.28 [ 0.04, 2.07 ]

Yeh 1997 28/72 16/74 12.2 % 1.80 [ 1.07, 3.03 ]

Subtotal (95% CI) 237 232 53.2 % 1.28 [ 1.00, 1.63 ]




2 hydrocortisone

Bonsante 2007 4/19 3/14 2.7 % 0.98 [ 0.26, 3.71 ]

Peltoniemi 2005 3/23 2/22 1.6 % 1.43 [ 0.26, 7.78 ]

Watterberg 2004 49/126 55/126 42.5 % 0.89 [ 0.66, 1.20 ]

Subtotal (95% CI) 168 162 46.8 % 0.91 [ 0.69, 1.22 ]




Total (95% CI) 405 394 100.0 % 1.11 [ 0.92, 1.33 ]




0.05 0.2 1 5 20




Analysis 6.19. Comparison 6 Long-term follow-up, Outcome 19 Abnormal neurological exam (variable

criteria - see individual studies).



Outcome: 19 Abnormal neurological exam (variable criteria - see individual studies)



Sanders 1994 7/19 4/21 7.3 % 1.93 [ 0.67, 5.58 ]

Shinwell 1996 39/132 12/116 24.4 % 2.86 [ 1.57, 5.19 ]

Sinkin 2000 7/32 6/27 12.4 % 0.98 [ 0.38, 2.58 ]

Stark 2001a 20/111 17/109 32.8 % 1.16 [ 0.64, 2.08 ]

Yeh 1997 25/132 12/130 23.1 % 2.05 [ 1.08, 3.91 ]

Total (95% CI) 426 403 100.0 % 1.81 [ 1.33, 2.47 ]




0.2 0.5 1 2 5





abnormal neurological exam (variable criteria).



Outcome: 20 Death before follow-up in trials assessing abnormal neurological exam (variable criteria)



Sanders 1994 2/19 7/21 5.5 % 0.32 [ 0.07, 1.34 ]

Shinwell 1996 32/132 26/116 23.0 % 1.08 [ 0.69, 1.70 ]

Sinkin 2000 11/32 7/27 6.3 % 1.33 [ 0.60, 2.94 ]

Stark 2001a 26/111 30/109 25.1 % 0.85 [ 0.54, 1.34 ]

Yeh 1997 50/132 48/130 40.1 % 1.03 [ 0.75, 1.40 ]

Total (95% CI) 426 403 100.0 % 0.97 [ 0.79, 1.21 ]




0.1 0.2 0.5 1 2 5 10




Analysis 6.21. Comparison 6 Long-term follow-up, Outcome 21 Death or abnormal neurological exam

(variable criteria).



Outcome: 21 Death or abnormal neurological exam (variable criteria)



Sanders 1994 9/19 11/21 6.0 % 0.90 [ 0.48, 1.69 ]

Shinwell 1996 71/132 38/116 23.4 % 1.64 [ 1.21, 2.23 ]

Sinkin 2000 18/32 13/27 8.2 % 1.17 [ 0.71, 1.92 ]

Stark 2001a 46/111 47/109 27.4 % 0.96 [ 0.71, 1.31 ]

Yeh 1997 75/132 60/130 35.0 % 1.23 [ 0.97, 1.56 ]

Total (95% CI) 426 403 100.0 % 1.23 [ 1.06, 1.42 ]




0.5 0.7 1 1.5 2




Analysis 6.22. Comparison 6 Long-term follow-up, Outcome 22 Abnormal neurological exam (variable

criteria) in tested survivors.



Outcome: 22 Abnormal neurological exam (variable criteria) in tested survivors



Sanders 1994 7/17 4/14 8.5 % 1.44 [ 0.53, 3.93 ]

Shinwell 1996 39/79 12/80 23.0 % 3.29 [ 1.87, 5.80 ]

Sinkin 2000 7/21 6/20 11.8 % 1.11 [ 0.45, 2.74 ]

Stark 2001a 20/76 17/67 34.8 % 1.04 [ 0.59, 1.81 ]

Yeh 1997 25/63 12/70 21.9 % 2.31 [ 1.27, 4.21 ]

Total (95% CI) 256 251 100.0 % 1.88 [ 1.41, 2.51 ]




0.2 0.5 1 2 5


Analysis 6.23. Comparison 6 Long-term follow-up, Outcome 23 Intellectual impairment (IQ < 70).



Outcome: 23 Intellectual impairment (IQ < 70)



Romagnoli 1999 3/25 3/25 44.1 % 1.00 [ 0.22, 4.49 ]

Sanders 1994 6/19 4/21 55.9 % 1.66 [ 0.55, 4.99 ]

Total (95% CI) 44 46 100.0 % 1.37 [ 0.57, 3.31 ]




0.2 0.5 1 2 5




Analysis 6.24. Comparison 6 Long-term follow-up, Outcome 24 Intellectual impairment (IQ < 70) in

survivors assessed.



Outcome: 24 Intellectual impairment (IQ < 70) in survivors assessed



Romagnoli 1999 3/23 3/22 41.1 % 0.96 [ 0.22, 4.24 ]

Sanders 1994 6/17 4/14 58.9 % 1.24 [ 0.43, 3.53 ]

Total (95% CI) 40 36 100.0 % 1.12 [ 0.47, 2.65 ]




0.2 0.5 1 2 5




Analysis 6.25. Comparison 6 Long-term follow-up, Outcome 25 “Major neurosensory impairment” -

blindness or deafness.



Outcome: 25 ”Major neurosensory impairment” - blindness or deafness



Romagnoli 1999 3/25 5/25 100.0 % 0.60 [ 0.16, 2.25 ]

Total (95% CI) 25 25 100.0 % 0.60 [ 0.16, 2.25 ]




0.2 0.5 1 2 5


Analysis 6.26. Comparison 6 Long-term follow-up, Outcome 26 “Major neurosensory impairment” -

blindness or deafness - in survivors assessed.



Outcome: 26 ”Major neurosensory impairment” - blindness or deafness - in survivors assessed



Romagnoli 1999 3/23 5/22 100.0 % 0.57 [ 0.16, 2.12 ]

Total (95% CI) 23 22 100.0 % 0.57 [ 0.16, 2.12 ]




0.2 0.5 1 2 5




Analysis 6.27. Comparison 6 Long-term follow-up, Outcome 27 Behavior abnormalities.



Outcome: 27 Behavior abnormalities



Romagnoli 1999 3/25 5/25 100.0 % 0.60 [ 0.16, 2.25 ]

Total (95% CI) 25 25 100.0 % 0.60 [ 0.16, 2.25 ]




0.2 0.5 1 2 5


Analysis 6.28. Comparison 6 Long-term follow-up, Outcome 28 Behavior abnormalities in 3 yr old survivors

assessed.



Outcome: 28 Behavior abnormalities in 3 yr old survivors assessed



Romagnoli 1999 3/23 5/23 100.0 % 0.60 [ 0.16, 2.22 ]

Total (95% CI) 23 23 100.0 % 0.60 [ 0.16, 2.22 ]




0.2 0.5 1 2 5




Analysis 6.29. Comparison 6 Long-term follow-up, Outcome 29 Abnormal EEG.



Outcome: 29 Abnormal EEG



Baden 1972 4/22 0/22 3.2 % 9.00 [ 0.51, 157.78 ]

Yeh 1997 15/132 15/130 96.8 % 0.98 [ 0.50, 1.93 ]

Total (95% CI) 154 152 100.0 % 1.24 [ 0.66, 2.33 ]




0.005 0.1 1 10 200


Analysis 6.30. Comparison 6 Long-term follow-up, Outcome 30 Abnormal EEG in tested survivors.



Outcome: 30 Abnormal EEG in tested survivors



Baden 1972 4/12 0/1 5.7 % 1.38 [ 0.11, 17.11 ]

Yeh 1997 15/63 15/70 94.3 % 1.11 [ 0.59, 2.09 ]

Total (95% CI) 75 71 100.0 % 1.13 [ 0.61, 2.08 ]




0.1 0.2 0.5 1 2 5 10




Analysis 6.31. Comparison 6 Long-term follow-up, Outcome 31 Re-hospitalisation in infancy.



Outcome: 31 Re-hospitalisation in infancy



Romagnoli 1999 10/25 15/25 14.8 % 0.67 [ 0.37, 1.19 ]

Watterberg 2004 65/180 67/180 66.2 % 0.97 [ 0.74, 1.27 ]

Yeh 1997 12/132 19/130 18.9 % 0.62 [ 0.31, 1.23 ]

Total (95% CI) 337 335 100.0 % 0.86 [ 0.68, 1.08 ]




0.5 0.7 1 1.5 2


Analysis 6.32. Comparison 6 Long-term follow-up, Outcome 32 Re-hospitalisation in infancy in survivors.



Outcome: 32 Re-hospitalisation in infancy in survivors



Romagnoli 1999 10/23 15/22 15.3 % 0.64 [ 0.37, 1.10 ]

Watterberg 2004 65/126 67/126 66.8 % 0.97 [ 0.77, 1.23 ]

Yeh 1997 12/63 19/70 17.9 % 0.70 [ 0.37, 1.33 ]

Total (95% CI) 212 218 100.0 % 0.87 [ 0.71, 1.07 ]




0.5 0.7 1 1.5 2




W H A T ’ S N E W

Last assessed as up-to-date: 9 September 2008.

Date Event Description

5 November 2009 Amended Peltoniemi reference citation edit

10 November 2008 New citation required but conclusions have not

changed

Substantive update

H I S T O R Y

Protocol first published: Issue 3, 1998

Review first published: Issue 3, 1998

Date Event Description

10 September 2008 New search has been performed This review updates the existing review of “Early

postnatal (<96 hours) corticosteroids for preventing

chronic lung disease in preterm infants” published in

The Cochrane Library, Issue 1, 2003

This update contains data from a total of 28 trials, 12

of which have long-term follow-up data

10 April 2008 Amended Converted to new review format.

11 November 2002 New citation required and conclusions have changed Substantive amendment

11 November 2002 New search has been performed The review updates the existing review of “Early

postnatal (<96 hours) corticosteroids for preventing

chronic lung disease in preterm infants” published in

The Cochrane Library, Issue 1, 2001.

Additional long-term neurodevelopmental follow-up

data have been included in this update from 7 trials;

data for Baden 1972 and Romagnoli 1999 were pub-

lished in full reports, data for Subhedar 1997 were pub-

lished as a letter to the editor, data for Stark 2001 were

obtained from a presented and published abstract, and

data for Sanders 1994, Sinkin 2000 and Watterberg

1999 were provided by the investigators. Two trials

reporting short-term outcome data are also newly in-

cluded; Halac 1990 and Biswas 2003.

Although early steroid treatment facilitates extubation



(Continued)

and reduces the risk of chronic lung disease, long-term

follow-up studies indicate a possible increased risk of

adverse neurosensory outcome. Furthermore, short-

term complications such as gastrointestinal bleeding,

intestinal perforation, hyperglycaemia, hypertension,

hypertrophic cardiomyopathy and growth failure are

increased by early steroid treatment

C O N T R I B U T I O N S O F A U T H O R S

Lex Doyle collated the data concerning long term neurosensory outcomes

D E C L A R A T I O N S O F I N T E R E S T

Dr Doyle was Chief Investigator of the DART study, a randomised controlled trial of low-dose, short-course dexamethasone in ventilator

dependent infants, funded by the National Health and Medical Research Council of Australia.

S O U R C E S O F S U P P O R T

Internal sources

• Action Research UK Grant to study the effects of postnatal steroids, UK.

• Action Research UK Grant to study longterm follow-up, UK.

External sources

• National Health and Medical Research Council, Australia.

I N D E X T E R M S

Medical Subject Headings (MeSH)

Administration, Inhalation; Anti-Inflammatory Agents [adverse effects; ∗therapeutic use]; Bronchopulmonary Dysplasia [∗prevention

& control]; Dexamethasone [adverse effects; therapeutic use]; Drug Administration Schedule; Glucocorticoids [adverse effects;∗therapeutic use]; Hydrocortisone [adverse effects; therapeutic use]; Infant, Low Birth Weight; Infant, Newborn; Randomized Con-

trolled Trials as Topic; Respiratory Distress Syndrome, Newborn [∗prevention & control]



MeSH check words

Humans



Documents

Cochrane Database of Systematic Reviews (Reviews) || Early (< 8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants