Liggins 1972b

Methods	Type of study: RCT Method of treatment allocation: random‐number table generated randomisation sequence by chief pharmacist. Pharmacy provided coded drug ampoules containing treatment or placebo Stratification: no Placebo: yes, of identical appearance Sample‐size calculation: no Intention‐to‐treat analyses: yes Losses to follow‐up: yes, 54 (18%) children in the follow‐up study at ages 4‐6 years (31 in the treatment arm and 23 in the control arm) and 412 (44%) adults in the follow‐up study at age 30 years (219 in the treatment arm and 193 in the control arm) Funding: Health Research Council of New Zealand, Auckland, New Zealand; Auckland Medical Research Foundation, Auckland, New Zealand; and New Zealand Lottery Grants Board, Wellington, New Zealand
Participants	Location: National Women's Hospital, Auckland, New Zealand Timeframe: December 1969 and February 1974 Eligibility criteria: women with threatened or planned preterm delivery Gestational age range: 24‐36 weeks Exclusion criteria: imminent delivery, contraindication to corticosteroids Total recruited: 1142 women and 1218 infants; 560 women and 601 infants in the treatment arm and 582 women and 617 infants in the control arm
Interventions	The treatment group 2 doses of 6 mg betamethasone phosphate and 6 mg betamethasone acetate IM 24 h apart. After the first 717 women had enrolled, the treatment intervention was doubled to 2 doses of 12 mg betamethasone phosphate and 12 mg betamethasone acetate IM 24 h apart. The control group received 6 mg cortisone acetate, which has 1/70th of the corticosteroid potency of the betamethasone.
Outcomes	Maternal outcome (chorioamnionitis), fetal/neonatal outcomes (fetal death, neonatal death, RDS, cerebroventricular haemorrhage, mean birthweight, Apgar score < 7, mean interval between trial entry and delivery, proven infection while in NICU), childhood outcomes (death, mean weight, mean height, mean head circumference, mean lung function, mean blood pressure, intellectual impairment, cerebral palsy) and adulthood outcomes were reported (death, mean weight, mean height, mean head circumference, mean skin fold thickness, mean blood pressure, glucose impairment, HPA axis function, mean cholesterol, educational achievement, visual impairment, hearing impairment, intellectual impairment)
Notes	Review includes new intention‐to‐treat analysis of the complete study and additional data due to the study authors providing individual participant study records
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random‐number table generated randomisation sequence by chief pharmacist
Allocation concealment (selection bias)	Low risk	Pharmacy provided coded drug ampoules containing treatment or placebo
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Blinding of study personnel was not described. It is likely that participants were blinded as placebo was of identical appearance to the corticosteroid.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	For the diagnosis of RDS, clinical records and chest radiographs were assessed separately and independently, by 1 of the study authors, and by a radiologist.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Incomplete outcome data for 54 (18%) children in the follow‐up study at ages 4‐6 (31 in the treatment arm and 23 in the control arm) and 412 (44%) adults in the follow‐up study at age 30 (219 in the treatment arm and 193 in the control arm)
Selective reporting (reporting bias)	Low risk	Study protocol not available, but appears to report on all pre‐specified outcomes
Other bias	Unclear risk	Insufficient information to asses if other sources of bias exist.