Methods	Type of study: MACS randomised controlled trial.
Participants	Location: 80 centres, 20 countries. Timeframe: April 2001 to August 2006. Included: single, twin or triplet pregnancy between 25 and 32 weeks’ gestation if women remained undelivered 14-21 days after an initial course of antenatal corticosteroids (either betamethasone or dexamethasone) and continued to be at high risk of preterm birth. Exclusion criteria: contraindication to corticosteroid use, needed chronic doses of these drugs, had evidence of chorioamnionitis, carried a fetus with a known lethal congenital abnormality, had an initial course of corticosteroids before 23 weeks’ gestation, previously participated in MACS, women with a multiple pregnancy with fetal death after 13 weeks’ gestation. Gestational age recruited up to less than 32 weeks. Total recruited 1858 women (2304 babies). 935 women in the antenatal corticosteroid group and 918 women in the placebo group
Interventions	Repeat steroid group: each course consisted of 2 intramuscular injections of betamethasone 12 mg (as 6 mg betamethasone sodium phosphate and 6 mg betamethasone acetate; Celestone Schering-Plough Corporation, Madison, NJ, USA)) 24 hours apart. Placebo group: similarly appearing intramuscular injection of dilute concentration of aluminium monostearate (an inert substance used as a filler in pharmaceutical preparations). Women who remained at risk of preterm birth after their first course of study medication continued to receive two doses of 12 mg betamethasone or placebo, 24 hours apart, every 14 days until 33 weeks’ gestation or birth, whichever happened first. For women with preterm rupture of the membranes the recommendation was to stop the study medication at 32 weeks’ gestation
Outcomes	Primary outcome: composite of perinatal or neonatal mortality and neonatal morbidity; one of the following: stillbirth or neonatal death (defined as death during the first 28 days of life or before hospital discharge); severe RDS (defined as needing assisted ventilation via endotracheal tube and supplemental oxygen within the first 24 hours of life and for 24 hours or more, and either a radiographic scan compatible with RDS or surfactant given between the first 2-24 hours of life); bronchopulmonary dysplasia (defined as needing oxygen at a postmenstrual age of 36 completed weeks and radiographic scan compatible with bronchopulmonary dysplasia); intraventricular haemorrhage grade III or IV; cystic periventricular leucomalacia, necrotising enterocolitis For the early childhood follow up at 2 years’ corrected age: primary outcome was death or the presence of a neurologic impairment at 18 to 24 months of age, corrected for gestational age at birth. Neurologic impairment was defined as the presence of cerebral palsy or a cognitive delay. Cerebral palsy was diagnosed if the child had a non-progressive motor impairment characterised by abnormal muscle tone and decreased range of movements. Cognitive delay were defined as Mental Developmental Index scores of 70 (2 SDs below the mean of 100) on the BSID-II or equivalent scores on another standardised assessment Secondary outcomes were anthropometric measurements (weight, height, and head circumference), general health, illnesses, and operations occurring after the primary hospitalisation was recorded, Psychomotor Developmental Index and the Behavior Rating Scale of the BSID-II
Funding Support	Funding: Canadian Institutes of Health Research (CIHR).
Notes	ISRCTN 72654148 Sample-size calculation: yes. A sample size of 1900 women (950 per group) was needed to have 80% probability of achieving a significant difference between the two groups (two-tailed type 1 error 0.05, if multiple courses of antenatal corticosteroids reduced the risk of RDS from 12% to 8%
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	“Randomisation was done with a 24-hour telephone service”. Information on the generation of the allocation sequence not pro-vided in the paper. Comment: probably done “The study was stratified by gestational age and centre.”
Allocation concealment (selection bias)	Low risk	“Randomisation was done with a 24-hour telephone service after patient eligibility and baseline information were recorded. A study number was assigned corresponding to a box of study medication at the participating centre.”
Blinding (performance bias and detection bias) All outcomes	Low risk	Placebo: yes. “Similarly appearing intramuscular injections”
Incomplete outcome data (attrition bias) All outcomes	Low risk	Intention-to-treat analyses: yes. Losses to follow-up to time of primary hospital discharge: 9 fetuses/infants (5 in the repeat antenatal corticosteroid group and 4 in the placebo group) were stillbirths within multiple pregnancies that took place before randomisation and were excluded from the analyses 5 women (0.3%) with 5 fetuses were lost to follow-up (2 women and 2 fetuses in the repeat antenatal corticosteroid group and 3 women and 3 fetuses in the placebo group)
Selective reporting (reporting bias)	Low risk	No obvious risk of selective reporting bias detected.
Other bias	Low risk	No obvious risk of other bias detected.