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

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1 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 2009, Issue 1

2 T A B L E O F C O N T E N T S HEADER ABSTRACT PLAIN LANGUAGE SUMMARY BACKGROUND OBJECTIVES METHODS RESULTS DISCUSSION AUTHORS CONCLUSIONS REFERENCES CHARACTERISTICS OF STUDIES DATA AND ANALYSES Analysis 1.1. Comparison 1 Mortality, Outcome 1 Neonatal mortality (up to 28 days) Analysis 1.2. Comparison 1 Mortality, Outcome 2 Mortality to hospital discharge Analysis 1.3. Comparison 1 Mortality, Outcome 3 Mortality at latest reported age Analysis 2.1. Comparison 2 Chronic lung disease (CLD)/bronchopulmonary dysplasia (BPD), Outcome 1 CLD (28 days) Analysis 2.2. Comparison 2 Chronic lung disease (CLD)/bronchopulmonary dysplasia (BPD), Outcome 2 CLD (36 weeks) Analysis 2.3. Comparison 2 Chronic lung disease (CLD)/bronchopulmonary dysplasia (BPD), Outcome 3 CLD at 36 weeks in survivors Analysis 2.4. Comparison 2 Chronic lung disease (CLD)/bronchopulmonary dysplasia (BPD), Outcome 4 Late rescue with corticosteroids Analysis 2.5. Comparison 2 Chronic lung disease (CLD)/bronchopulmonary dysplasia (BPD), Outcome 5 Survivors who had late rescue with corticosteroids Analysis 2.6. Comparison 2 Chronic lung disease (CLD)/bronchopulmonary dysplasia (BPD), Outcome 6 Survivors discharged home on oxygen Analysis 3.1. Comparison 3 Death or CLD, Outcome 1 Death or CLD at 28 days Analysis 3.2. Comparison 3 Death or CLD, Outcome 2 Death or CLD at 36 weeks Analysis 4.1. Comparison 4 Failure to extubate, Outcome 1 Failure to extubate by 3rd day Analysis 4.2. Comparison 4 Failure to extubate, Outcome 2 Failure to extubate by 7th day Analysis 4.3. Comparison 4 Failure to extubate, Outcome 3 Failure to extubate by 14th day Analysis 4.4. Comparison 4 Failure to extubate, Outcome 4 Failure to extubate by 28th day Analysis 5.1. Comparison 5 Complications during primary hospitalisation, Outcome 1 Infection Analysis 5.2. Comparison 5 Complications during primary hospitalisation, Outcome 2 Hyperglycaemia Analysis 5.3. Comparison 5 Complications during primary hospitalisation, Outcome 3 Hypertension Analysis 5.4. Comparison 5 Complications during primary hospitalisation, Outcome 4 Hypertrophic cardiomyopathy. 87 Analysis 5.5. Comparison 5 Complications during primary hospitalisation, Outcome 5 Growth failure Analysis 5.6. Comparison 5 Complications during primary hospitalisation, Outcome 6 Pulmonary air leak Analysis 5.7. Comparison 5 Complications during primary hospitalisation, Outcome 7 PDA Analysis 5.8. Comparison 5 Complications during primary hospitalisation, Outcome 8 Severe IVH Analysis 5.9. Comparison 5 Complications during primary hospitalisation, Outcome 9 Severe IVH in infants examined. 97 Analysis Comparison 5 Complications during primary hospitalisation, Outcome 10 PVL Analysis Comparison 5 Complications during primary hospitalisation, Outcome 11 PVL in infants with cranial ultrasound scans Analysis Comparison 5 Complications during primary hospitalisation, Outcome 12 PVL in survivors seen at followup Analysis Comparison 5 Complications during primary hospitalisation, Outcome 13 NEC Analysis Comparison 5 Complications during primary hospitalisation, Outcome 14 Gastro-intestinal bleeding. 105 Analysis Comparison 5 Complications during primary hospitalisation, Outcome 15 Intestinal perforation Analysis Comparison 5 Complications during primary hospitalisation, Outcome 16 Pulmonary haemorrhage i

3 Analysis Comparison 5 Complications during primary hospitalisation, Outcome 17 Any ROP Analysis Comparison 5 Complications during primary hospitalisation, Outcome 18 Severe ROP Analysis Comparison 5 Complications during primary hospitalisation, Outcome 19 Severe ROP in survivors Analysis 6.1. Comparison 6 Long-term follow-up, Outcome 1 Bayley MDI <-2SD Analysis 6.2. Comparison 6 Long-term follow-up, Outcome 2 Bayley MDI <-2SD in tested survivors Analysis 6.3. Comparison 6 Long-term follow-up, Outcome 3 Bayley PDI <-2SD Analysis 6.4. Comparison 6 Long-term follow-up, Outcome 4 Bayley PDI <-2SD in tested survivors Analysis 6.5. Comparison 6 Long-term follow-up, Outcome 5 Developmental delay (criteria not specified) Analysis 6.6. Comparison 6 Long-term follow-up, Outcome 6 Developmental delay (criteria not specified) in tested survivors Analysis 6.7. Comparison 6 Long-term follow-up, Outcome 7 Blindness Analysis 6.8. Comparison 6 Long-term follow-up, Outcome 8 Blindness in survivors assessed Analysis 6.9. Comparison 6 Long-term follow-up, Outcome 9 Deafness Analysis Comparison 6 Long-term follow-up, Outcome 10 Deafness in survivors assessed Analysis Comparison 6 Long-term follow-up, Outcome 11 Cerebral palsy Analysis Comparison 6 Long-term follow-up, Outcome 12 Death before follow-up in trials assessing cerebral palsy Analysis Comparison 6 Long-term follow-up, Outcome 13 Death or cerebral palsy Analysis Comparison 6 Long-term follow-up, Outcome 14 Cerebral palsy in survivors assessed Analysis Comparison 6 Long-term follow-up, Outcome 15 Major neurosensory disability (variable criteria - see individual studies) Analysis Comparison 6 Long-term follow-up, Outcome 16 Death before follow-up in trials assessing major neurosensory disability (variable criteria) Analysis Comparison 6 Long-term follow-up, Outcome 17 Death or major neurosensory disability (variable criteria) Analysis Comparison 6 Long-term follow-up, Outcome 18 Major neurosensory disability (variable criteria) in survivors examined Analysis Comparison 6 Long-term follow-up, Outcome 19 Abnormal neurological exam (variable criteria - see individual studies) Analysis Comparison 6 Long-term follow-up, Outcome 20 Death before follow-up in trials assessing abnormal neurological exam (variable criteria) Analysis Comparison 6 Long-term follow-up, Outcome 21 Death or abnormal neurological exam (variable criteria) Analysis Comparison 6 Long-term follow-up, Outcome 22 Abnormal neurological exam (variable criteria) in tested survivors Analysis Comparison 6 Long-term follow-up, Outcome 23 Intellectual impairment (IQ < 70) Analysis Comparison 6 Long-term follow-up, Outcome 24 Intellectual impairment (IQ < 70) in survivors assessed. 151 Analysis Comparison 6 Long-term follow-up, Outcome 25 Major neurosensory impairment - blindness or deafness Analysis Comparison 6 Long-term follow-up, Outcome 26 Major neurosensory impairment - blindness or deafness - in survivors assessed Analysis Comparison 6 Long-term follow-up, Outcome 27 Behavior abnormalities Analysis Comparison 6 Long-term follow-up, Outcome 28 Behavior abnormalities in 3 yr old survivors assessed. 153 Analysis Comparison 6 Long-term follow-up, Outcome 29 Abnormal EEG Analysis Comparison 6 Long-term follow-up, Outcome 30 Abnormal EEG in tested survivors Analysis Comparison 6 Long-term follow-up, Outcome 31 Re-hospitalisation in infancy Analysis Comparison 6 Long-term follow-up, Outcome 32 Re-hospitalisation in infancy in survivors WHAT S NEW HISTORY CONTRIBUTIONS OF AUTHORS DECLARATIONS OF INTEREST SOURCES OF SUPPORT INDEX TERMS ii

4 [Intervention Review] Early (< 8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants Henry L Halliday 1, Richard A Ehrenkranz 2, Lex W Doyle 3 1 Perinatal Room, Royal-Jubilee Maternity Service, Belfast, UK. 2 Department of Pediatrics, Yale University, New Haven, USA. 3 Department 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. h.halliday@qub.ac.uk. (Editorial group: Cochrane Neonatal Group.) Cochrane Database of Systematic Reviews, Issue 1, 2009 (Status in this issue: New search for studies completed, conclusions not changed) DOI: / CD pub2 This version first published online: 21 January 2009 in Issue 1, Last assessed as up-to-date: 9 September (Help document - Dates and Statuses explained) This record should be cited as: Halliday HL, Ehrenkranz RA, Doyle LW. Early (< 8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD DOI: / CD pub2. Background A B S T R A C T 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 strategy Randomised controlled trials (RCTs) of postnatal corticosteroid therapy were sought from the Cochrane Controlled Trials Register, MEDLINE ( 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 leucomalacia (PVL), necrotising enterocolitis (NEC), gastrointestinal bleeding, intestinal perforation, severe retinopathy of prematurity 1

5 (ROP), and long-term outcome (including blindness, deafness, cerebral palsy and major neurosensory disability) were abstracted and analysed using RevMan 5. 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 followup 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. 2

6 B A C K G R O U N D Advances in neonatal care, including the use of antenatal corticosteroids and surfactant therapy, have improved the outcome of preterm infants with RDS, but the risk of chronic lung disease (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 dependency at either 28 days of life or 36 weeks PMA. More infants with CLD are being cared for in neonatal units and their management is both time consuming and costly. Postnatal corticosteroid treatment has been shown to have some beneficial acute effects on lung function in infants with established CLD, especially those that are ventilator dependent (Mammel 1983; CDTG 1991). Recently, there has been concern that the benefits of corticosteroids 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 previous 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 (Halliday 2003c). 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 treatment). 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 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 leucomalacia (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, examining previous review articles and information received from practising neonatologists. MEDLINE was searched from 1966 through May 2008 using the terms adrenal cortex hormones or dexamethasone or betamethasone or hydrocortisone or steroids or corticosteroids, 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 randomisation, blinding, stratification, reporting of the outcome of all the infants enrolled and whether the trial was single or multicentred. 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, infection, 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 neurosensory disability. Meta-analysis of the included trials was performed 3

7 using RevMan 5, including subgroup analyses by the type of corticosteroid 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 assessment. 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, however, 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 management 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 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 syndrome, mild hypoxia and hypercapnia and a chest radiograph compatible with RDS. They were randomised to receive either hydrocortisone 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 ventilated 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 hydrocortisone 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 ventilator-dependent after surfactant treatment were recruited. Exclusion ctiteria were cardiopulmonary malformations, perinatal asphyxia, 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 specified), gestational age (not specified) and antenatal steroid exposure. 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 reports 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 comparing a three day course of dexamethasone therapy beginning at hours of life with placebo. 241 preterm infants (dexamethasone 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 corticosteroid 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 infants 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 involving infants of g. Infants were stratified by birth weight into three groups: g, g and g. Within each group equal numbers of dexamethasone-treated or 4

8 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 administered 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 controls. The method of randomisation was not described. Treated infants 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 hypotension. 48 infants of birth weight < 1500 grams were randomised 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 hydrocortisone (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 H 2 O mean airway pressure (MAP), a/a PO 2 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 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 untreated controls. Entry criteria were: birth weight < 1251 g, gestational 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 mg/kg/d for 1 d. Sanders 1994 enrolled 40 infants < 30 weeks gestation who had RDS diagnosed by clinical and radiographic signs, required mechanical ventilation at 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 exchange 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 contraindications to corticosteroid treatment, such as a bleeding tendency, hypertension, 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 intravenous 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 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 controlled trial comparing dexamethasone given at 12 hours of age with selective late dexamethasone therapy in premature infants weighing 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. Intravenous 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 ventilation with supplemental oxygen > 30%. Stark 2001a was a randomised multicentre controlled trial to compare a tapering course of stress dose corticosteroid started on the first day with placebo. Infants with birth weight g needing mechanical ventilation before 12 hours of age were eligible for the study. Infants with birth weight > 750 g also needed 5

9 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 inhaled 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 developing CLD using a scoring system (Ryan et al 1996). Exclusion criteria included major congenital anomaly, structural cardiac defect, significant ductus shunting, culture positive sepsis, IVH with parenchymal involvement, pulmonary or gastrointestinal haemorrhage, disordered coagulation or platelet count < 50,000. Dexamethasone 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, haemodynamically relevant cardiac anomalies except for PDA, or malformations of the lung or central nervous system (CNS) were excluded. 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-dependent 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 mg/kg/d for one day (total dose 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 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, 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 controlled pilot study to compare early treatment with low dose hydrocortisone (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 g and who were mechanically ventilated 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 ventilated 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 dexamethasone 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 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 coordinating centre using coded vials with blinding of the study investigators. Open label dexamethasone was allowed when deemed necessary by the attending neonatologist but its use was discouraged. Intention to treat analysis was performed. There was no followup 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. 6

10 Follow-up component (Fitzhardinge 1974): Survivors were seen at 12 months of age, corrected for prematurity, by one paediatrician 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 assessment included the Griffiths scales. Major neurosensory disability 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 regard to birth weight, gestation and antenatal corticosteroid administration. 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. Followup data were reported for 92% (33/36) of survivors to hospital discharge. Efird 2005: Randomisation was by opening sequentially numbered, opaque envelopes containing preassigned treatment designations. Infants of multiple gestations were randomised as separate subjects. Clinicians were blinded to treatment identity. If hypotension 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 dexamethasone group. After adjusting for severity of illness the difference was not of statistical significance to stop enrolment. However, to ensure patient safety the data monitoring committee recommended reducing the dexamethasone dose. The dosing schedule was changed to 4 doses of 0.25 mg/kg/dose every 12 hours begun at 24 to 48 hours, followed by doses of 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 therapy 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 provided 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 measures were reported for these 19 infants. There was no follow-up component. Ng 2006: Randomisation used computer generated random numbers and opening of sequentially numbered sealed opaque envelopes 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 followup component. Peltoniemi 2005: Randomisation was performed centrally by nonclinical 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 pharmacy 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 prohibited; 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 infants enrolled. Follow-up component (Peltoniemi 2008): Surviving children were assessed at 24 months of age, corrected for prematurity, by paediatricians, paediatric neurologists and psychologists at individual study sites who were blinded to treatment group 7

11 allocation. Children were considered to have a major neurosensory 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 period 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: g, g and 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): Survivors were seen at 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 criteria for blindness or deafness. Psychological assessment included the Stanford-Binet - 3rd Revision; intellectual impairment comprised an IQ <70. Major neurosensory impairment comprised either blindness or deafness. Sanders 1994: Randomisation occurred in the pharmacy after opening a sealed envelopes. Dexamethasone or placebo were dispensed 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 numbered sets of syringes containing either dexamethasone or physiological saline. Syringes containing dexamethasone were not distinguishable from those containing saline. Syringe sets were numbered according to a random number list and randomisation was stratified by centre and by two birth weight groups: g and 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 abnormalities (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 component (Shinwell 2002): Survivors were seen at a mean age of 53 (SD 18; range 24-71) months, presumably not corrected for prematurity. 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 nonambulant cerebral palsy, global retardation (not specified), blindness or deafness. Further follow-up is planned at school age. Sinkin 2000: Randomisation with stratification by centre was performed using a set of sealed envelopes in the pharmacy. Outcome data appear to have been provided for all infants enrolled. Followup component (Sinkin 2002): Data were obtained from one of the four original centres in the study, from follow-up clinic appointments, and from questionnaires to parents and paediatricians. Survivors 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 followup 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 opening 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 pharmacies 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 8