Lim 2011

Methods	Multicentre, double‐bind, placebo‐controlled randomised trial 55 obstetric clinics in Netherland Between July 2006 and August 2009
Participants	671 women randomised: 336 allocated to progesterone and 335 allocated to placebo. Inclusion criteria: women with a multiple pregnancy and gestational age between 15 and 19 weeks Exclusion criteria: women with a previous spontaneous preterm birth before 34 weeks, serious congenital defects or death of 1 or more fetuses, early signs of twin‐to‐twin transfusion syndrome, or primary cerclage were excluded from participation
Interventions	Intervention group: 1 mL 17‐hydoxyprogesterone caproate (250 mg/mL in castor oil) ‐ starting between 16 and 20 weeks and continuing to 36 weeks. Injections were administered at the clinic, by a general practitioner or, if the participant or a family member had a background in medical practice, at the participant’s home Control/Comparison group: 1 mL placebo (castor oil) ‐ study medication and placebo were identical in packaging, colour and consistency
Outcomes	Primary outcomes: composite adverse neonatal outcome ‐ severe RDS; bronchopulmonary dysplasia; IVH grade II B or worse; NEC; proven sepsis; death before discharge Secondary outcomes: side effects (soreness, itching, and swelling; gestational age at delivery; preterm birth before 28, 32 and 37 weeks; length of admission to the NICU; maternal morbidity; hospitalisation of the mother due to (threatened) preterm labour; costs
Notes	Funding sources: Funded by ZonMw, the Netherlands organization for health research and development (grant number 62200019) Declarations of interest: The authors did not report any potential conflicts of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“An independent data manager rendered a computer‐generated list that was stratified by chorionicity, parity, and number of multiples, using random blocks of maximum block size.”
Allocation concealment (selection bias)	Low risk	Web‐based randomisation ‐ “Randomization was accessible through a website” and “Allocation code was known only to ACE Pharmaceuticals"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	“The participants, caregivers, and data collectors were all blinded to allocation."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Data collectors were blinded.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Only 4 infants lost to follow‐up States that “all analyses were based on the intention‐to‐treat principle”
Selective reporting (reporting bias)	Low risk	All expected outcomes reported
Other bias	Unclear risk	Other bias not apparent