Norman 2009

Methods	Double‐blind randomised placebo‐controlled trial Multicentre, 9 UK NHS hospitals ‐ STOPPIT study (Study Of Progesterone for the Prevention of Preterm Birth In Twins), UK. Protocol states trial planned to run November 2004 to October 2007; actual study dates unclear
Participants	500 women randomised: 250 allocated to progesterone and 250 allocated to placebo Inclusion criteria: women with twin pregnancy, with gestation and chorionicity established by scan before 20 weeks’ gestation and attending the antenatal clinic during the recruitment period Exclusion criteria: pregnancy complicated by a recognised structural or chromosomal fetal abnormality at the time of recruitment, or if they had contraindications to progesterone, planned cervical suture, planned elective delivery before 34 weeks’ gestation, or planned intervention for twin‐to‐twin transfusion before 22 weeks’ gestation. Women with higher multiple pregnancy were also excluded
Interventions	Intervention group: daily vaginal progesterone gel 90 mg starting at 24 weeks and 0 days of gestation. Each applicator of intervention contained 1.45 g of gel and delivered 1.125 g of gel containing 8% progesterone Control/Comparison group: placebo gel ‐ administered in the same way as active treatment, daily from 24 weeks’ gestation. Each applicator of intervention contained 1.45 g of gel and delivered 1.125g of gel containing 8% excipients
Outcomes	Primary outcome: delivery or intrauterine death before 34 weeks and 0 days of gestation. Delivery of the first twin was used to define the time of delivery. If 1 twin died in utero before 34 weeks and the other was born alive after 34 weeks, intrauterine fetal death was defined as occurring before 34 weeks. The gestational age was calculated from ultrasound scan done before 20 weeks Maternal secondary outcomes: gestation at delivery, method of delivery (spontaneous vaginal delivery, vaginal breech, forceps or ventouse, or caesarean section), duration of each stage of labour, and safety outcomes such as duration of stay in hospital. Neonatal secondary outcomes were neonatal unit admission and duration of neonatal unit care. Maternal satisfaction by questionnaire
Notes	Funding sources: the authors disclosed receipt of the following financial support for the research and/or authorship of this article: grants CZB/4/408 from Chief Scientist Office (www.cso.scot.nhs.uk), Scottish Government; grant SP4068 from Action Medical Research (www.action.org.uk) and grants from Wellcome ‘‘Value in People’’ (www.wellcome.ac.uk) and the Jennifer Brown Research Laboratory (www.piggybankkids. org). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the article Declarations of interest: the authors do not declare any conflicts of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“We used a randomisation schedule with permuted blocks of randomly mixed sizes to make up treatment packs (either active or placebo) for every patient, which were held in individual hospital pharmacies until use.”
Allocation concealment (selection bias)	Low risk	Central allocation from research network ‐ local researcher telephoned the interactive voice response randomisation application at the UK Clinical Research Network registered trials unit to be given a participant number that corresponded to a specific treatment pack
Blinding of participants and personnel (performance bias) All outcomes	Low risk	“All study personnel and participants were masked to treatment assignment for the duration of the study.”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Study personnel masked to treatment
Incomplete outcome data (attrition bias) All outcomes	Low risk	Only 6 women of 500 (3 from each treatment group) lost to follow‐up from 500 randomised participants. Analysis was ITT
Selective reporting (reporting bias)	Low risk	Expected outcomes reported
Other bias	Unclear risk	Other bias not apparent