Combs 2010.

Study characteristics
Methods	Double‐blind, randomised clinical trial Multicentre, Obstetrix Collaborative Research Network, USA Recruitment took place from November 2004 through June 2008
Participants	81 women randomised: 56 allocated to 17‐OHPC and 25 to placebo. Inclusion criteria: mothers carrying trichorionic‐triamniotic triplets ‐ confirmed at 15 ‐ 23 weeks detailed second‐trimester ultrasound examination, showing normal amniotic fluid volume and no major fetal anomalies Exclusion criteria: women with symptomatic uterine contractions, rupture of fetal membranes, any contraindication to interventions intended to prolong the pregnancy, a pre‐existing medical condition that might be worsened by progesterone, or a pre‐existing medical condition carrying a high risk of preterm delivery. Women less than 18 years of age, had an allergy to 17‐OHPC or the oil vehicle, had taken any progesterone‐derivative medication after 15 weeks of gestation, or had undergone placement of cervical cerclage for treatment of cervical change in the current pregnancy
Interventions	Intervention group: 17‐alpha‐hydroxyprogesterone caproate (250 mg in 1 mL castor oil) ‐ weekly injections starting at 16 ‐ 22 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 35 weeks of gestation; reason for delivery before 32 weeks (spontaneous; indicated); reason for delivery, all deliveries (spontaneous; indicated); caesarean delivery; tocolysis used; antenatal corticosteroids; maternal complications; pre‐eclampsia or gestational hypertension; gestational diabetes; chorioamnionitis; sepsis; postpartum endometritis Neonatal outcomes include: birthweight; head circumference; total hospital stay; NICU admission and intermediate care
Notes	The trial was conducted under Investigational New Drug (IND) approval Number 69‐536, assigned by the United States Food and Drug Administration (FDA). Clinicaltrials.gov: NCT00163020 An independent Data and Safety Monitoring Board (DSMB) supervised the trial, reviewed adverse event reports, and conducted an interim analysis of efficacy Funding sources: supported by a grant from the Center for Research and Education, Pediatrix Medical Group, Sunrise, FL 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	“Data were abstracted by study personnel who remained blinded to each subject’s group assignment.”
Incomplete outcome data (attrition bias) All outcomes	Low risk	248 women identified with triplets, 147 eligible for trial inclusion. Of these 89 gave consent (61%) and were given trial injection. 81 (91%) returned for randomisation No loss ‐ 81 women randomised and outcome data available for all 81 mothers and 243 offspring. “Analysis was by the “intention‐to‐treat” principle. Accordingly, outcomes for each patient were tabulated according to the assigned group (17P vs placebo) regardless of her compliance.”
Selective reporting (reporting bias)	Low risk	Yes ‐ all expected outcomes reported
Other bias	Low risk	Sample size calculation undertaken, but power based on number of neonates and so underpowered to detect differences in maternal outcomes. No baseline group differences. ITT analysis undertaken