Combs 2011

Methods	Double‐blind, randomised clinical trial Multicentre ‐ 18 sites, Obstetrix Collaborative Research Network, USA Recruitment from November 2004 through August 2009.
Participants	240 women randomised: 160 allocated to 17‐hp and 80 to placebo. Inclusion criteria: women were eligible if they had a dichorionic‐diamniotic twin pregnancy at 15 ‐ 23 weeks’ gestation and if they had completed a detailed ultrasound examination, showing no major fetal anomalies Exclusion criteria: women < 18 years old, taken any progestins > 15 weeks of gestation, had symptomatic uterine contractions, rupture of the fetal membranes, any contraindication to prolonging the pregnancy, any pre‐existing condition that might be worsened by progesterone, or a pre‐existing medical condition carrying a high risk of preterm delivery
Interventions	Intervention group: 17 alpha‐hydroxyprogesterone caproate (250 mg in 1 mL castor oil) ‐ weekly injections starting at 16 ‐ 24 weeks and continued until 34 weeks or delivery. Weekly repeat injections were carried out at the site or at home with partner administering after training. Injection diary for partner injections and measurement of unused medication returned by participant used to assess compliance with home administration Control/Comparison group: identical‐appearing placebo (in 1 mL castor oil)
Outcomes	Primary outcomes: composite neonatal morbidity defined as 1 or more of: perinatal death (stillbirth, neonatal death, miscarriage); RDS; use of oxygen therapy at 28 days of life; neonatal sepsis proven by blood culture; pneumonia; IVH (grade III or IV); periventricular leucomalacia; NEC requiring surgery; retinopathy of prematurity; newborn asphyxia Secondary outcomes: individual neonatal morbidities listed above; gestational age at delivery; birthweight; maternal side effects. Other outcomes reported: mean weeks of gestation; delivery before 28, 32 or 34 or 37 weeks; reason for delivery before 37 weeks (spontaneous; indicated); caesarean delivery; tocolysis used; antenatal corticosteroids. Maternal complications: pre‐eclampsia or gestational hypertension; gestational diabetes; chorioamnionitis; sepsis; postpartum endometritis. Neonatal outcomes: birthweight; birthweight < 2500 g, < 1500 g and birthweight < 1000 g; small‐for‐gestational age
Notes	Funding sources: supported by a grant from the Center for Research, Education, and Quality, Pediatrix Medical Group, Mednax Inc, Sunrise, FL (groups of clinicians) Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated scheme. Random‐number generated centrally by pharmacy
Allocation concealment (selection bias)	Low risk	Random‐number generated centrally by pharmacy. “Progesterone or identical‐appearing placebo was compounded by pharmacy and shipped in advance to each study site in coded pre‐numbered kits. To randomise the research nurse contacted the central pharmacy by telephone or fax to obtain the code number for the kit assigned to that patient.”
Blinding of participants and personnel (performance bias) All outcomes	Low risk	“Subjects, physicians, and study personnel remained blinded as to group assignment until after completion of the trial.”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Study personnel remained blinded until after completion of the trial
Incomplete outcome data (attrition bias) All outcomes	Low risk	No loss in progesterone group ‐ 160 women allocated, 160 mothers delivered and 320 perinates with known outcome. 80 women allocated to placebo ‐ 2 lost to follow‐up ‐ 78 women delivered and 156 perinates with known outcome “Outcomes for each patient were tabulated according to assigned group regardless of her compliance.”
Selective reporting (reporting bias)	High risk	Trial was not registered and no published protocol
Other bias	Low risk	Sample size calculation met. Interim analysis undertaken when 50% of data collected; primary outcome adjusted for this. No baseline group differences. Compliance 96.4% in the 17‐ph group and 98.7% in the placebo group (P .07)