Types of studies

Types of participants

Types of interventions

Types of outcome measures

Randomised controlled trials of postnatal corticosteroid therapy were sought from the Cochrane Controlled Trials Register, MEDLINE, 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.

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 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.

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 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 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 24 - 48 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 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 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 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 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 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 mechanical 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 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 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 controlled 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. 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 501 - 1000 g needing mechanical ventilation before 12 hours of age were eligible 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 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 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 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 500-999 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 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.

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 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 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. Follow-up 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 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 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 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 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 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: 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): Survivors 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 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: 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 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 non-ambulant 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. Follow-up 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 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 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 a sample size estimate of 1200 the trial was halted. Outcome measures 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 developmental observers blinded to treatment group allocation. The follow-up rate of survivors was 87% (143/164). Criteria for the diagnosis 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 neurological exam, blindness, deafness, or an MDI or PDI <-2 SD.

Subhedar 1997: Block randomisation was performed using computer 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 paediatrician 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 Development. Major neurosensory disability comprised any of cerebral 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 random lots and the envelopes were drawn by a neutral, uninvolved person. This was considered a pilot trial before starting a multicentre 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 cooperation and coordination at the beginning of the study, nine infants were not randomised. Four infants were excluded after randomisation 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 ampoules of dexamethasone and saline prepared in the hospital pharmacy 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 malformation 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 treatment 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 constant block design with four patients per block to minimise bias over time. Separate randomisation tables were used for infants exposed to antenatal corticosteroids. The hydrocortisone doses and the placebo of normal saline were prepared by the hospital pharmacies. 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 prematurity, by a neonatologist and a physiotherapist, with observers blinded to treatment group allocation. The follow-up rate of survivors 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 disability was not defined.

Watterberg 2004: Randomisation was performed centrally, stratified for birthweight (500 - 749 g, and 750 - 999 g) and centre, with permuted block sizes of six within each stratum. Only the pharmacists at individual sites preparing the drug were aware of the group assignment. All other personnel were masked. Twins were randomised together to the same study arm. Mortality was reported for all infants enrolled, but other short-term outcomes were reported 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 neurodevelopmental (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 measurement 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 presented for all 262 infants enrolled. The study is described as double-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 treatment 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 dysfunction (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 corrected 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.

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 requirement, need for assisted ventilation or survival was demonstrated 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, severe 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 mortality, 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 infants who survived (68/99 vs. 81/98; P = 0.01). Intestinal perforation was more common, but not significantly so, in the dexamethasone 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 dexamethasone treated infants (P = 0.007).

Halac 1990: There were no substantial or statistically significant effects of dexamethasone on neonatal mortality, mortality to hospital 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. Dexamethasone 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 dexamethasone group and two in the control group. None of the infants developed BPD (definition not given). Four infants in the dexamethasone 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 mortality. 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, cystic 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% confidence 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 period 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 pressures, 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 dexamethasone 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, blindness, 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, hypertension and hyperglycaemia were more common in treated infants, but no life threatening complications, such as gastrointestinal perforation, 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 examination, 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 survival (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 differences 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 differences 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 insulin 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), required oxygen at 28 days (78% vs. 94%; P < 0.05) or had subsequent 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% respectively 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 without NEC (P < 0.05). Spontaneous perforation was also associated with indomethacin treatment ( P = 0.005) and there was an interaction between indomethacin and corticosteroid therapy (P = 0.04). There were no significant differences in the rates of cerebral 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 incidence of CLD and/or death before discharge from hospital between 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, developmental 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 supplemental oxygen (4.2 d vs. 12.5 d; P < 0.02); pulmonary complications 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' postmenstrual 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 independent variables showed that study treatment was the only variable 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 inspired 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 survived 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 significant 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 treatment the rates of hyponatraemia, hypernatraemia, hyperkalaemia, hyperglycaemia, hypertension and GI bleeding were similar between 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, rehospitalisation, 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 ventilation, 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 evidence 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, probably attributable to infection. There was no difference between the groups for duration of oxygen therapy and hospitalisation. Significantly more infants in the dexamethasone group had either bacteraemia or clinical sepsis (44/132 vs. 27/130, P < 0.05). Other immediate but transient side effects observed in the dexamethasone group were hyperglycaemia, hypertension, cardiac hypertrophy, hyperparathyroidism and delay in growth rate. At 25 months of age there were no significant differences in the rates of blindness, developmental delay, major neurosensory disability, the combined 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 significantly 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 corticosteroid 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 revealed 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, 95% CI 0.68, 1.16; 8 studies and 880 infants).

• 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 studies and 2484 infants; hydrocortisone 0.96, 95% CI 0.82, 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, 95% CI 0.86, 1.06; 7 studies and 836 infants).

• 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 studies and 1729 infants; hydrocortisone 1.53, 95% CI 0.27, 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; dexamethasone 1.75, 95% CI 1.20, 2.55; typical risk difference 0.05, 95%CI 0.01, 0.09; 7 studies and 921 infants; hydrocortisone 0.97, 95% CI 0.55, 1.69; 5 studies and 531 infants; death or cerebral palsy; typical relative risk; dexamethasone 1.17, 95% CI 1.00, 1.37; typical risk difference 0.07, 95%CI 0.00, 0.13; 7 studies and 921 infants; hydrocortisone 0.91, 95% CI 0.70, 1.19; 5 studies and 531 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.

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 neurological examination and cerebral palsy. However, the methodological quality of the studies determining the long-term outcome was limited 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 effects vs. the potential short-term benefits, it appears appropriate to curtail early corticosteroid treatment for prevention of chronic lung disease.

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. 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 include long-term neurological follow-up. Studies comparing different types, doses and durations of corticosteroid treatment, and examining the effects of inhaled corticosteroids, are urgently needed.

Risk of bias table

Item	Judgement	Description
Allocation concealment?	Yes	A - Adequate

Risk of bias table

Item	Judgement	Description
Allocation concealment?	Yes	A - Adequate

Risk of bias table

Item	Judgement	Description
Allocation concealment?	Yes	A - Adequate

Risk of bias table

Item	Judgement	Description
Allocation concealment?	Yes	A - Adequate

Risk of bias table

Item	Judgement	Description
Allocation concealment?	Yes	A - Adequate

Risk of bias table

Item	Judgement	Description
Allocation concealment?	Yes	A - Adequate

Risk of bias table

Item	Judgement	Description
Allocation concealment?	Yes	A - Adequate

Risk of bias table

Item	Judgement	Description
Allocation concealment?	Yes	A - Adequate

Risk of bias table

Item	Judgement	Description
Allocation concealment?	Yes	A - Adequate

Risk of bias table

Item	Judgement	Description
Allocation concealment?	Unclear	B - Unclear

Risk of bias table

Item	Judgement	Description
Allocation concealment?	Yes	A - Adequate

Risk of bias table

Item	Judgement	Description
Allocation concealment?	Yes	A - Adequate

Risk of bias table

Item	Judgement	Description
Allocation concealment?	Yes	A - Adequate

Risk of bias table

Item	Judgement	Description
Allocation concealment?	Yes	A - Adequate

Risk of bias table

Item	Judgement	Description
Allocation concealment?	Yes	A - Adequate

Risk of bias table

Item	Judgement	Description
Allocation concealment?	Yes	A - Adequate

Risk of bias table

Item	Judgement	Description
Allocation concealment?	Yes	A - Adequate

Risk of bias table

Item	Judgement	Description
Allocation concealment?	Yes	A - Adequate

Risk of bias table

Item	Judgement	Description
Allocation concealment?	Yes	A - Adequate

Risk of bias table

Item	Judgement	Description
Allocation concealment?	Yes	A - Adequate

Risk of bias table

Item	Judgement	Description
Allocation concealment?	Yes	A - Adequate

Risk of bias table

Item	Judgement	Description
Allocation concealment?	Yes	A - Adequate

Risk of bias table

Item	Judgement	Description
Allocation concealment?	Unclear	B - Uncertain

Risk of bias table

Item	Judgement	Description
Allocation concealment?	Yes	A - Adequate

Risk of bias table

Item	Judgement	Description
Allocation concealment?	Yes	A - Adequate

Risk of bias table

Item	Judgement	Description
Allocation concealment?	Yes	A - Adequate

Risk of bias table

Item	Judgement	Description
Allocation concealment?	Yes	A - Adequate

Risk of bias table

Item	Judgement	Description
Allocation concealment?	Yes	A - Adequate