Brizot 2015

Methods	Double‐blind, placebo‐controlled randomised trial conducted at the Multiple Pregnancy Unit of the Obstetrics Department at Sao Paulo University of Medicine, Brazil From June 2007 until October 2013
Participants	390 women with naturally‐conceived diamniotic twin pregnancies. Inclusion criteria: no history of preterm delivery (< 37 weeks’ gestation), gestational age of 18 to 21 weeks and 6 days at random assignment, absence of major fetal abnormalities (such as neural tube defects, abdominal wall defects, cardiac defects, hydrocephalus, and malformations that are associated with polyhydramnios) at the anomaly scan, no allergies to progesterone or peanuts (peanut oil is an excipient that is used in vaginal ovules), absence of hepatic dysfunction, porphyria, otosclerosis, malignant disease, severe depressive state, current or previous thromboembolic disease, uterine malformation, and prophylactic cerclage Exclusion criteria: subsequent diagnosis of major fetal abnormalities, the presence of ovular infection, or being lost to follow‐up
Interventions	Intervention group: vaginal progesterone ovules (200 mg of natural micronised progesterone that also contained excipients such as peanut oil, soybean lecithin, glycerol, and titanium dioxide). Control group: placebo ovules
Outcomes	Primary outcome: difference in mean gestational age at delivery Secondary outcomes included: spontaneous delivery at < 34 weeks’ gestation and the postnatal data until hospital discharge: birthweight, Apgar score < 7 at 5 minutes, hypoglycaemia, IVH grade 3, jaundice, NEC, PDA, retinopathy, septicaemia, admission to the NICU, RDS, the need for mechanical ventilation, death before hospital discharge, and composite neonatal outcome (defined as the occurrence of any of the following events: IVH, NEC, RDS, sepsis, and death before hospital discharge).
Notes	Agra 2016 reports secondary analysis Funding sources: none reported. Declarations of interest: the authors report no conflict of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random assignment was performed with a computer‐generated system with balanced blocks of 20 patients in each block
Allocation concealment (selection bias)	Low risk	The hospital's pharmacy department was responsible for packing and labelling the ovules (A and B); random assignment code was kept secret until data analysis
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Patients, researchers, and clinicians who were involved in clinical and ultrasonographic evaluations were blinded to the treatment assignment for the duration of the study
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Researchers blinded for duration of study. Code was kept secret until data analysis
Incomplete outcome data (attrition bias) All outcomes	High risk	Outcome data missing for > 20% of neonates as they were born at other hospitals
Selective reporting (reporting bias)	Low risk	The trial was registered prospectively and expected outcomes were reported. (ClinicalTrials.gov Identifier: NCT01031017)
Other bias	Low risk	Sample size calculation met. No baseline differences in characteristics ITT analysis undertaken Ethics approval obtained