Wapner 2006.

Methods	Type of study: randomised controlled trial.
Participants	Location: 18 US hospitals (NICHD MFMU network centres). Timeframe: March 2000 to April 2003. Eligibility criteria: pregnant women with intact membranes between 23 weeks 0 days and 31 weeks and 6 days if they had received a single full course of betamethasone or dexamethasone between 7 and 10 days earlier and were at high risk for spontaneous preterm birth, or had the diagnosis of placenta praevia or chronic abruption Exclusions: preterm premature rupture of the membranes prior to randomisation, confirmed fetal lung maturity, chorioamnionitis, a major fetal anomaly, non‐reassuring fetal status, systemic corticosteroid use during the current pregnancy, or insulin‐dependent diabetes. Gestational age was determined from the last menstrual period provided that ultrasonography confirmed the estimate. When there was discordance, the duration of gestation at randomisation was determined from the first sonogram performed. Gestational age range: 23 weeks 0 days to 31 weeks 6 days gestation. Total recruited: 495 women (planned for 2400) = 591 fetuses/infants. 252 to the repeat corticosteroid arm and 243 to the placebo.
Interventions	Repeat corticosteroid group: each course consisted of 2 injections of betamethasone 12 mg (as 6 mg betamethasone sodium phosphate and 6 mg betamethasone acetate) repeated once in 24 hours. Placebo group: 'matching placebo' ‐ no other details of preparation given. Initially women received courses until birth or 33 weeks 6 days' gestation, whichever was sooner. After 67 women had been enrolled, the number of courses (not including the qualifying course) was limited to 4 because of difficulty in recruitment and published literature suggesting possible harmful effects of multiple courses. 63.4% of women received 4 or more study courses.
Outcomes	To time of primary hospital discharge: the primary outcome was a composite endpoint of 1 of the following: severe RDS (defined as clinical features of RDS with the need for oxygen and respiratory support from 6 to 24 hours or more of age, an abnormal chest x‐ray, and either administration of a full course of surfactant or a fraction of inspired oxygen (FiO2 of at least 60%); grade 3 or 3 IVH; PVL; chronic lung disease (defined as the need for supplemental oxygen at 36 weeks' corrected age in infants born before 34 weeks' gestation); or stillbirth or neonatal death. Secondary outcomes not stated in the paper. For the early childhood follow‐up at 2 years' corrected age: the pre‐specified developmental outcome was the Bayley Mental Developmental Index Score. Other outcomes included Bayley Psychomotor Developmental Index Score; measurements of weight, height and head circumference; and the occurrence of cerebral palsy.
Funding Support	Funding: National Institute of Child Health and Human Development.
Notes	Sample‐size calculation: yes. Planned sample size was 2400 women. "A primary outcome rate of 11.5% was anticipated for patients assigned to placebo. Detection of a 30% reduction for patients assigned to repeat corticosteroids required a sample of 1200 patients in each group" (80% power and type 1 error rate of 5% (2‐sided). Recruitment was stopped early based on safety concerns (because of a tendency towards decreased birthweight in the repeat corticosteroid group without any reduction in the primary morbidity outcome and also because of difficulties in recruitment).
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Method of treatment allocation: numbered kits were prepared using randomisation sequences created by an independent data co‐ordinating centre. Sequences were generated using the urn design and were stratified by clinical centre, type of qualifying course, and inpatient/outpatient. Woman was assigned to the next sequentially‐numbered kit ‐ betamethasone or identical looking placebo prepared by a centralised research pharmacy.
Allocation concealment (selection bias)	Low risk	Assessed as adequate. Women were assigned to the next sequentially‐numbered kit ‐ betamethasone or identical looking placebo prepared by a centralised research pharmacy.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants are likely to be blinded due to the use of a matching placebo.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	At early childhood follow‐up the assessments were performed by centrally trained and certified study personnel who were unaware of the treatment assignment.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Intention‐to‐treat analyses: yes. "For categorical infant outcomes the statistical unit was pregnancy rather than infant, because of the correlation between twins." Continuous variables were compared with an adjustment for the correlation between twins, for infants. Losses to follow‐up to time of primary hospital discharge: 3 (< 1%) women lost to follow‐up (2 in the repeat group and 1 in the placebo group). Losses to follow‐up to time of 2‐year corrected age assessment: There were 582 known survivors. Of the survivors, 96 (16.5%) were not able to be seen, 46 in the repeat corticosteroid group and 50 in the placebo group; 117 (20.1%) did not have a Bayley assessment performed, 59 in the repeat corticosteroid group and 58 in the placebo group. Intention‐to‐treat analyses: yes.
Selective reporting (reporting bias)	Low risk	No obvious risk of selective reporting bias detected.
Other bias	High risk	Recruitment was stopped early based on safety concerns after the recruitment of 495 women. "At the second interim analysis the Data Safety Monitoring Committee recommended that enrolment be halted because of a tendency towards decreased birthweight in the repeat corticosteroid group without evident reduction in the primary morbidity outcome and also because of difficulties with recruitment."

ACTH: adrenocorticotropic hormone
 BPD: bronchopulmonary dysplasia
 IVH: intraventricular haemorrhageMFMU: Maternal Fetal Medicine Units
 NICHD: National Institute of Child Health and Human Development
 PVL: periventricular leukomalacia
 RDS: respiratory distress syndrome
 SD: standard deviation