Caritis 2009

Methods	Randomised, double‐blinded, placebo‐controlled trial 14 centres, USA Starting in April 2004 and completed in September 2006
Participants	134 women with multiple pregnancies Inclusion criteria: < 21 weeks of gestation when randomised, pregnant women with triplets were eligible if their gestational age was at least 16 weeks and no more than 20 weeks Exclusion criteria: serious fetal anomalies, 2 or more fetuses in 1 amniotic sac, suspected twin‐to‐twin transfusion syndrome, marked ultrasonographic growth discordance, planned non‐study progesterone therapy after 16 weeks, in‐place or planned cerclage, major uterine anomaly, unfractionated heparin therapy at any dose, and major chronic medical diseases
Interventions	Intervention group: weekly injections of 17‐OHPC (250 mg in 1 mL castor oil) starting at 16 ‐ 20 + 6 weeks and ending at delivery or 35 weeks’ gestation Control/Comparison group: weekly injections of placebo (1 mL castor oil) starting at 16 ‐ 20 + 6 weeks and ending at delivery or 35 weeks’ gestation
Outcomes	Primary outcomes: composite of delivery or fetal loss before 35 completed weeks of gestation (245 days) ‐ fetal loss included:miscarriage, termination, or stillbirth occurring any time after randomisation. Secondary outcomes: selected individual maternal and neonatal outcomes and a composite of serious adverse neonatal outcomes, including: neonatal death, RDS, culture‐proven sepsis, NEC stage II or III, bronchopulmonary dysplasia, IVH grade III or IV, or periventricular leucomalacia or severe retinopathy of prematurity stage III or higher
Notes	ClincialTrials.gov: NCT00099164 Funding sources: supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, (HD21410; HD27869; HD40512; HD27915; HD40485; HD34208; HD40500; HD34116; HD40560; HD40544; HD27917; HD27860; HD40545; HD53097; HD36801; HD34136) Declarations of interest: the authors disclosed no potential conflicts of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“The simple urn‐method of randomization with stratification according to clinical center, was used to create a randomization sequence for each center.”
Allocation concealment (selection bias)	Low risk	The injections were prepared by a research pharmacy and boxes of 17‐OHPC and placebo were packaged for each centre according to randomisation sequences ‐ so appears to be central allocation ‐ pharmacy controlled
Blinding of participants and personnel (performance bias) All outcomes	Low risk	“The participating women, their caregivers, and the research personnel were not aware of the study group assignment”. Also described as “double‐blinded”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Not reported
Incomplete outcome data (attrition bias) All outcomes	Low risk	“Outcome data were available for 100% of the assigned women, and for all of the 402 fetuses.” No exclusions apparent ITT stated in statistical methods
Selective reporting (reporting bias)	Low risk	All expected outcomes appear to have been reported
Other bias	Low risk	No group differences in baseline characteristics. Sample size calculation met. ITT analysis undertaken