Serra 2013

Methods	3‐arm randomised controlled trial 5 University hospital centres in Spain Between December 2005 and January 2008.
Participants	294 women Inclusion criteria: women were recruited at 11 ‐ 13 weeks’ gestation. If they had previously been treated with vaginal progesterone it was stopped. Women were 18 years or more, dichorionic, diamniotic twin pregnancy Exclusion criteria: singleton pregnancy; monochorionic twin pregnancies; triplets or higher multiple pregnancies; elective cervical cerclage before 14 weeks’ gestation; history of hepatic problems; pregnancy cholestasis; abnormal liver or kidney function; allergy to peanuts or study medication; recurrent vaginal bleeding or infection; fetal anomalies; alcohol or illicit drug use and smoking more than 10 cigarettes per day
Interventions	Intervention: 1. 200 mg vaginal progesterone self‐inserted daily at bedtime (98 women) 2. 400 mg vaginal progesterone self‐inserted daily at bedtime (98 women) 3. (control) placebo vaginal pessaries self‐inserted daily at bedtime (98 women) All women were provided with specially manufactured identical‐looking pessaries, 2 to be administered each evening from 20 weeks to 34 weeks of gestation or birth, whichever came first
Outcomes	Preterm birth rate < 37 weeks of gestation; early preterm birth rate < 34, 32, 28 weeks of gestation; need for tocolytic treatment; steroid treatment; rate of preterm premature rupture of membranes < 37 weeks of gestation; cervical length measurements at 20, 24, 28 weeks of gestation; perinatal mortality and morbidity; caesarean section. Local tolerance to the treatment; number of serious systemic adverse effects Perinatal outcomes: short‐term neonatal morbidity (RDS; pneumonia; early onset sepsis; seizures; graded III ‐ IV IVH; stage IIII NEC; and/or PDA). Long‐term neonatal morbidity included: broncho‐pulmonary dysplasia; periventricular leucomalacia; and/or severe retinopathy of prematurity, birthweight < 2500 g; 5 minute Apgar score; major congenital malformation; admission to NICU; mechanical ventilation; neonatal death
Notes	Funding sources: the trial was funded by grant EF489‐2004/1 from Laboratorios Effik S.A. (Madrid, Spain) Declarations of interest: the authors declare no conflict of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“Randomisation was performed by computer (SPSS Random Number Generator, using a randomisation sequence 1:1:1 ratio (blocks of nine, with no stratification).”
Allocation concealment (selection bias)	Low risk	Central allocation “An external monitoring centre provided a randomisation code number for each pregnant woman” “The medication was given at each visit by the hospital pharmacy department”.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Women and staff were blinded. Medication packs were coded and contained identical‐appearing pessaries
Blinding of outcome assessment (detection bias) All outcomes	Low risk	It was reported that all study personnel were blind to treatment allocation for the duration of the project
Incomplete outcome data (attrition bias) All outcomes	Low risk	There was very little loss to follow‐up It was stated that an ITT analysis was carried out
Selective reporting (reporting bias)	Unclear risk	Most expected outcomes reported upon. However ‐ individual outcome results for short‐term and long‐term neonatal morbidity were not reported, e.g. RDS, periventricular leucomalacia.
Other bias	Unclear risk	Other bias not apparent.