TABLE 1.

Main characteristics of studies included in the systematic review

First author, year	Trial enrolment	Main inclusion/exclusion criteria	Interventions (No. of women with a singleton gestation and history of spontaneous preterm birth)	Compliance	Trial registration	Primary outcome
Da Fonseca,72 2003	Single Center in Brazil	•Inclusion: singleton gestation and history of spontaneous preterm birth, or prophylactic cervical cerclage because of cervical insufficiency, or uterine malformation •Exclusion: allergy to progesterone	•Vaginal progesterone suppository 100 mg/d from 24–34 weeks of gestation (n=65) •Placebo (n=68)	Unreported	Not registered	Preterm birth <37 weeks
O’Brien,73 2007	53 Centers in United States, India, South Africa, Czech Republic, Chile, and El Salvador	•Inclusion: singleton gestation and history of spontaneous preterm birth •Exclusion: planned cervical cerclage, preterm labor, preterm premature rupture of membranes, clinical chorioamnionitis or vaginal bleeding, placenta previa, history of adverse reaction to progesterone, treatment with progesterone within 4 weeks before enrollment, treatment for seizure disorder, psychiatric illness or chronic hypertension at time of enrollment, history of acute or chronic congestive heart failure, renal failure, uncontrolled diabetes mellitus, active liver disorder, HIV infection with CD4 count of <350 cells/mm3 and requiring multiple antiviral agents, history or suspicion of breast/genital tract malignancy or thromboembolic disease, Müllerian duct anomaly, major fetal anomaly or chromosomal disorder, or multiple gestation	•Vaginal progesterone gel 90 mg/d from 18–22 to 37+0 weeks of gestation, rupture of membranes or delivery, whichever occurred first (n=309) •Placebo (n=302)	96.2% for vaginal progesterone group and 96.4% for placebo group	NCT00086177	Preterm birth ≤32 weeks
Majhi,74 2009	Single center in India	•Inclusion: singleton gestation and history of spontaneous preterm birth •Exclusion: multifetal gestation, fetal congenital malformation, current or planned cervical cerclage, or any associated medical disorder	•Vaginal progesterone capsule 100 mg/d from 20–24 to 36 weeks of gestation or delivery, whichever occurred first (n=50) •Standard care (n=50)	100% for vaginal progesterone group	Not registered	Preterm birth <37 and <34 weeks
Akbari,75 2009	Single Center in Iran	•Inclusion: singleton gestation and history of spontaneous preterm birth, or previous cervical cerclage, or uterine malformation •Exclusion: preterm labor, preterm premature rupture of membranes, allergy to progesterone, fetal growth restriction, major fetal anomaly, unexplained vaginal bleeding, multiple gestation, chronic medical disorders, or cancer	•Vaginal progesterone suppository 100 mg/d from 24–34 weeks of gestation (n=65) •Standard care (n=67)	Unreported	Not registered	Mean gestational age at delivery
Cetingoz,76 2011	Single Center in Turkey	•Inclusion: singleton gestation with a history of spontaneous preterm birth or uterine malformation, or twin gestation •Exclusion: in-place or planned cervical cerclage, or serious fetal anomalies	•Vaginal progesterone suppository 100 mg/d from 24–34 weeks of gestation (n=37) •Placebo (n=34)	100% for both study groups	Not registered	Preterm birth <37 weeks
Modi,77 2014	Single Center in India	•Inclusion: singleton gestation and history of spontaneous preterm birth •Exclusion: allergy to progesterone, multiple gestation, preterm prelabor rupture of membranes, fetal congenital malformation, diabetes mellitus, chronic renal disease, chronic hypertension, heart disease, severe anemia, cervical incompetence (cervical length <25 mm or funneling on ultrasound), progesterone intake less than two weeks, or therapeutic preterm delivery	•Vaginal progesterone suppository 100 mg/d from 24–30 to 34 weeks of gestation (n=41) •Placebo (n=40)	41.5% for vaginal progesterone group and 70.0% for placebo group	CTRI/2008/091/00 0218	Preterm birth <37 weeks
Azargoon,78 2016	Single Center in Iran	•Inclusion: singleton gestation and history of spontaneous preterm birth, or history of spontaneous preterm birth and cervical length ≤28 mm plus cerclage, or uterine malformation, or uterine intramural myoma ≥7 cm •Exclusion: clinical chorioamnionitis, allergy to progesterone, serious fetal anomalies, multiple gestation, polyhydramnios, fetal growth restriction, hyperthyroidism, gestational diabetes, blood pressure ≥140/90 mm Hg, heart disease, epilepsy, or the use of anticonvulsants	•Vaginal progesterone suppository 400 mg/d from 16–22 to 36 weeks of gestation (n=28) •Placebo (n=25)	Unreported	IRCT2010122733 86N2	Preterm birth <37 weeks
Norman,79 2016	65 Centers in United Kingdom and one in Sweden	•Inclusion: singleton gestation and history of spontaneous preterm birth, or cervical length ≤25 mm, or positive fetal fibronectin test combined with other clinical risk factors for preterm birth •Exclusion: congenital structural or chromosomal fetal anomaly, known sensitivity, contraindications, or intolerance to progesterone or any excipient, rupture of membranes, or prescription or ingestion of medications known to interact with progesterone	•Vaginal progesterone capsule 200 mg/d from 22–24 to 34 weeks of gestation or delivery, whichever occurred first (n=457) •Placebo (n=455)	66.3% for vaginal progesterone group and 70.9% for placebo group	ISRCTN14568373	Fetal death or delivery occurring before 34 weeks of gestation, a composite of neonatal death, brain injury, or bronchopulmonary dysplasia, and the Bayley-III cognitive composite score at 2 years of age
Crowther,80 2017	32 Centers in Australia, 5 in New Zealand, and 2 in Canada	•Inclusion: singleton or twin gestation and history of spontaneous preterm birth in the preceding pregnancy •Exclusion: active vaginal bleeding requiring hospital admission at ≥18 weeks of gestation, preterm prelabor rupture of membranes, active labor, known lethal fetal anomaly or fetal demise, progesterone treatment after 16 weeks’ gestation, or any contraindication to continuation of the pregnancy or progesterone therapy	•Vaginal progesterone pessary 100 mg/d from 20-24 to 34 weeks of gestation or delivery, whichever occurred first (n=390) •Placebo (n=385)	91.6% for vaginal progesterone group and 90.8% for placebo group	ISRCTN20269066	Respiratory distress syndrome and severity of respiratory disease
Abdou,81 2018	Single Center in Egypt	•Inclusion: singleton gestation and history of spontaneous preterm birth •Exclusion: uterine malformation, prophylactic cervical cerclage, multiple gestation, fetal malformation, or premature prelabor rupture of membranes	•Vaginal progesterone suppository 200 mg/d from 20–24 to 36 weeks of gestation or delivery, whichever occurred first (n=45) •Standard care (n=45)	Unreported	Not registered	Preterm birth <37 weeks