Gyamfi‐Bannerman 2016.

Study characteristics
Methods	Type of study: double‐blind, RCT Method of treatment allocation: simple urn method of randomisation Stratification: yes, according to clinical site and gestational age (34‐35 weeks and 36 weeks) Placebo: yes, matching placebo Sample size calculation: yes Intention‐to‐treat analyses: yes Losses to follow‐up: yes, 4 (0.11%) lost to follow‐up; 2 in each treatment group
Participants	Location: 17 university‐based clinics in the USA. All centres affiliated with the Maternal–Fetal Medicine Units Network of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Eligibility criteria: women with singleton pregnancy 34 weeks + 0 d‐36 weeks + 5 d gestation at "high probability" of preterm delivery. Quote: "High probability was defined as either preterm labor with intact membranes and at least 3 cm dilation or 75% cervical effacement, or spontaneous rupture of the membranes. If neither of these criteria applied, a high probability was defined as expected preterm delivery for any other indication either through induction or cesarean section between 24 hours and 7 days after the planned randomisation, as determined by the obstetrical provider." Gestational age range: 34 weeks + 0 days‐36 weeks + 5 days Exclusion criteria: expected delivery < 12 hours for any reason, already received antenatal corticosteroids in current pregnancy, chorioamnionitis, 8 cm or more cervical dilation, non‐reassuring fetal status requiring immediate delivery, no gestational age dating by ultrasound before 32 weeks for women with known date for last menstrual period, women without ultrasound dating before 24 weeks' gestation with unknown date of last menstrual period Total recruited: 2831 women and 2831 infants; 1429 women and 1429 infants in the treatment arm and 1402 women and 1402 infants in the control arm
Interventions	Treatment group: (n = 1429 randomised) 2 IM injections of 12 mg betamethasone (equal parts betamethasone sodium phosphate and betamethasone acetate) administered 24 hors apart Control group received matching placebo "For those enrolled because of an indication for preterm delivery, labor inductions were expected to start by 36 weeks 5 d, and cesarean deliveries were to be scheduled by 36 weeks 6 days and not before 24 hours after randomization." Control: (n = 1402 randomised) placebo IM injections as above Follow up: to 28 d for oxygen dependency outcome
Outcomes	Maternal outcome (maternal death, chorioamnionitis, side effects of therapy in women), fetal/neonatal outcomes (perinatal death, fetal death, neonatal death, RDS, IVH, birthweight, necrotising enterocolitis, proven infection while in NICU, need for mechanical ventilation/CPAP, surfactant use, air leak syndrome, Apgar score < 7, small for gestation age, admission to NICU) We asked study authors to clarify the mechanical ventilation/CPAP data presented in Table 2 of the publication; we are unsure if outcome categories are exclusive or not. We have not included data from this trial in the meta‐analysis for 1.25 due to these concerns; data will be included at the next update if confirmed by study authors. Data from trial are available for following non‐review outcomes: maternal serious adverse events, infant serious adverse events, hypoglycaemia in infant. Length of stay (maternal and infant) reported as median with IQR only. Randomisation to delivery interval reported as median with IQR only
Notes	Supplementary appendix published online with data tables and additional information on trial methods relevant to risk of bias. Contact author confirmed no maternal deaths and blinding of researchers abstracting data from maternal and neonatal charts (24.2.2016 by email) ClinicalTrials.gov number, NCT01222247. Ruptured membranes occurred in 22.1% intervention and 21.7% controls No stillbirths or deaths within 72 hours Quote: "Adverse events that were reported after both injections were less common in the betamethasone group than in the placebo group (rate after first injection, 14.1% vs. 20.3%; P<0.001; rate after second injection, 5.5% vs. 9.5%; P<0.007). Almost all adverse events (95%) were local reactions at the injection site (Table S4 in the Supplementary Appendix)." These data were used for our review's side effects outcome Quote: "Serious maternal adverse events occurred in 10 women in the betamethasone group and 12 in the placebo group (Table S7 in the Supplementary Appendix). Apart from the neonatal deaths, only one serious neonatal adverse event occurred (a case of thrombocytopenia in the betamethasone group)." These data were reported narratively above. "A total of 860 of 1429 women (60.2%) in the betamethasone group and 826 of 1402 (58.9%) in the placebo group received the prespecified two doses of study medication. Of the 1145 women who did not receive a second dose, 1083 (94.6%) delivered before 24 hours; 6 women did not receive any of the assigned study medication. (In the placebo group, 3 women who consented to participate in the trial subsequently declined the injection, 1 woman delivered after randomization but before the first dose, and 1 received open label betamethasone. In the betamethasone group, 1 woman was in active labor with complete cervical dilation at the time of randomization)" Study dates: October 2010‐February 2015 Funding sources: National Heart, Lung, and Blood Institute, USA; Eunice Kennedy Shriver National Institute of Child Health and Human Development, USA; National Center for Advancing Translational Sciences, National Institutes of Health, USA Declarations of interest: "No potential conflict of interest relevant to this article was reported."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Independent data‐coordinating centre with the use of the simple urn method, with stratification according to clinical site and gestational age category (34 to 35 weeks vs. 36 weeks)"
Allocation concealment (selection bias)	Low risk	Remote centre performed randomisation and packaged intervention and placebo
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Identical treatment and placebo packs prepared remotely. Women and staff blinded
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Trained research staff extracted data from maternal and neonatal staff; authors confirmed by email that these researchers were blinded. Charts of babies admitted to special care were reviewed by blinded staff for respiratory outcomes
Incomplete outcome data (attrition bias) All outcomes	Low risk	Two women in each group lost to follow‐up. Data available for 2827 neonates
Selective reporting (reporting bias)	Low risk	Supplementary outcome data published online with paper
Other bias	Low risk	Few baseline imbalances apart from mean maternal age (28.6 versus 27.8 years) and Hispanic ethnic background (28.3 versus. 32%)