Intervention Review

You have free access to this content

Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth

  1. Jodie M Dodd1,*,
  2. Leanne Jones2,
  3. Vicki Flenady3,
  4. Robert Cincotta4,
  5. Caroline A Crowther5,6

Editorial Group: Cochrane Pregnancy and Childbirth Group

Published Online: 31 JUL 2013

Assessed as up-to-date: 14 JAN 2013

DOI: 10.1002/14651858.CD004947.pub3


How to Cite

Dodd JM, Jones L, Flenady V, Cincotta R, Crowther CA. Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth. Cochrane Database of Systematic Reviews 2013, Issue 7. Art. No.: CD004947. DOI: 10.1002/14651858.CD004947.pub3.

Author Information

  1. 1

    The University of Adelaide, Women's and Children's Hospital, School of Paediatrics and Reproductive Health, Discipline of Obstetrics and Gynaecology, Adelaide, South Australia, Australia

  2. 2

    The University of Liverpool, Cochrane Pregnancy and Childbirth Group, Department of Women's and Children's Health, Liverpool, UK

  3. 3

    Mater Research Institute - The University of Queensland (MRI-UQ), Translating Research Into Practice (TRIP) Centre, Brisbane, Queensland, Australia

  4. 4

    Mater Mothers' Hospital, Department of Maternal Fetal Medicine, South Brisbane, Queensland, Australia

  5. 5

    The University of Auckland, Liggins Institute, Auckland, New Zealand

  6. 6

    The University of Adelaide, ARCH: Australian Research Centre for Health of Women and Babies, Robinson Research Institute, Discipline of Obstetrics and Gynaecology, Adelaide, South Australia, Australia

*Jodie M Dodd, School of Paediatrics and Reproductive Health, Discipline of Obstetrics and Gynaecology, The University of Adelaide, Women's and Children's Hospital, 72 King William Road, Adelaide, South Australia, 5006, Australia. jodie.dodd@adelaide.edu.au.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 31 JUL 2013

SEARCH

 
Characteristics of included studies [ordered by study ID]
Aboulghar 2012

MethodsSingle-centre prospective placebo-controlled randomised clinical trial.

IVF Center, Cairo, Egypt. 


Participants313 women at high risk of preterm birth with pregnancies conceived by IVF or ICSI.

Inclusion criteria: Healthy pregnant women who conceived after IVF/ICSI between 18-24 weeks of gestation, with a first pregnancy, singleton or dichorionic twins, normal uterine and cervical anatomy, and normal fetal anatomy.

Exclusion criteria: Previous pregnancy, serious fetal anomalies for which termination may be considered such as major heart anomaly or major CNS anomaly.

All women received progesterone injections as luteal phase support which they continued if pregnant until the day of the first ultrasound


InterventionsVaginal progesterone 200 mg twice daily from randomisation until delivery or 37 weeks’ gestation. Total number randomised: n = 161 women (161 analysed, 210 babies).

Placebo vaginal suppositories from randomisation until 37 weeks’ gestation. Total number randomised: n = 152 women (145 women analysed, 187 babies).


OutcomesPrimary outcomes were: preterm birth of singleton and twin pregnancies before 37 completed weeks and before 34 completed weeks.

 

Secondary outcomes: neonatal morbidity and mortality (live-born children who died < 28 days after delivery) and take-home baby rate (live-birth rate per patient). Birthweight > 2500 g; 1500-2500 g; < 1500 g; NICU admissions.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskStates, “Dark, sealed envelopes containing the intervention taken from a table of numbers” – not clear how the table of number generated – does not state “random number table”.

Allocation concealment (selection bias)Low riskRefers to “dark, sealed, sequentially numbered envelopes” and the envelopes were picked by a nurse not involved in the study.  The envelopes had been created by a third party not involved in the allocation process.

Incomplete outcome data (attrition bias)
All outcomes
Low riskStudy flow diagram clearly displays participant flow in the study.

410 women recruited, 313 randomised; none lost to follow-up in progesterone group and 6 lost to follow-up in placebo group and 1 excluded because of termination of pregnancy after diagnosis of trisomy 21. 

States “Intention–to-treat principle was followed during data analysis.”

Selective reporting (reporting bias)Low riskAll expected outcome results reported.

Other biasUnclear riskNone apparent, although baseline characteristics table not presented.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskStates “single blinding” and that “the patient was informed about the allocated arm” so presumably the clinician/personnel were blinded.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskNot clear, but probably low risk. Placebo-controlled trial.

Akbari 2009

MethodsRandomised.

Single centre, Lorestan.


Participants150 women randomised: 75 to each group.

Inclusion criteria: 1. Single child pregnancy with the exact age of conception based on LMP was determined and was verified by sonogram before reaching 20 weeks.  If the LMP was not available the exact age of pregnancy was based on 2 sonograms that were verified on at least 2 separate weeks; 2. Women with a history of 1 or 2 previous early childbirths before reaching 37 weeks of pregnancy or women with a history of prophylactic cervical cerclage or uterine anomalies (unicornuate uterus, bicornuate uterus, septate uterus, arcuate uterus, uterus didelphys); and 3. Older than 18 years, younger than 35 years.

Exclusion criteria: 1. Rupture of membranes PROM; 2. Large known fetal anomalies; 3 Cervix dilatation larger than 4 cm; 4. Contraindications for tocolysis including fetal distress, chorioamnionitis, pre-eclampsia, and haemodynamic instability; 5. Allergies to progesterone (dizziness, mygan, visual disturbances, depression, and increased blood sugar during previous consumption of this drug were considered allergic reactions to the hormone.); 6. Not following up with patients; 7. Multiple pregnancies; 8.The existence of an illness in the mother that necessitated medication, such as high blood pressure, cancer, tension, thromboembolic disease, Kennedy’s disease, illnesses that are treated for asthma with oral beta-adrenergic; 9. Age younger than 18 or older than 35; 10. Existence of IUGR fetuses; 11. Unwarranted vaginal bleeding.


InterventionsExperimental intervention: 100 mg of prophylactic vaginal progesterone daily between 24th and 34th week of gestation - Cyclogest.

Control/Comparison intervention: the other group received no treatment and were monitored.


OutcomesMean gestational age at time of delivery.

Preterm delivery before  37th week gestation.

Preterm delivery before 34th week gestation.

Respiratory distress syndrome.

Low birthweight.

Birthweight.

Need for oxygen.

Infant Apgar score.

Need for mechanical ventilator.

Hospitalisation in NICU.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot clear “150 women that had passed the entrance criterion to the study were divided randomly into two groups of 75.”

Allocation concealment (selection bias)Unclear riskNot reported.

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk3 individuals from the control group and 4 from the group receiving progesterone were excluded from the study – reasons for exclusion not clear – but in table of results – 6 people appear to be missing from denominator for the progesterone group (report 69) and not 4 as described?

Results presented for 69 women in progesterone group and 72 in control.

Selective reporting (reporting bias)Low riskAll expected outcomes appear to have been reported.

Other biasUnclear riskUnclear.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot reported.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported.

Borna 2008

MethodsMethod of randomisation: random number table.
Allocation concealment: unclear.
Blinded outcome assessment: no.
Completeness of follow-up: outcome data available for 70 women.


Participants70 women presenting between 24 and 34 weeks' gestation with symptoms and signs of threatened preterm labour, where acute symptoms were arrested following use of tocolytic medication.


InterventionsDaily intravaginal pessary (400 mg) versus no treatment.


OutcomesInterval from randomisation to birth.


NotesTrial conducted in Tehran, Iran.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom number table.

Allocation concealment (selection bias)Unclear riskUnclear.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete data available.

Selective reporting (reporting bias)Low riskAll prespecified outcomes reported in the abstract appear to have been reported upon (latency period until delivery; respiratory distress syndrome; low birthweight; birthweight; recurrent preterm birth; admission to intensive care unit; neonatal sepsis).

Other biasLow riskBaseline characteristics were similar (see table 1, page 61).

Blinding of participants and personnel (performance bias)
All outcomes
High riskNo blinding of care givers and women.

Blinding of outcome assessment (detection bias)
All outcomes
High riskNo blinding of outcome assessment.

Briery 2011

MethodsPlacebo-controlled double-blind randomised clinical trial.

Single site, USA.


Participants69 women randomised: 33 to 17-OH group and 36 to placebo.

Inclusion criteria: women who presented with singleton, vertex gestations to university’s obstetric emergency area with a diagnosis of PPROM at 20-30 weeks' gestation, typically dated by ultrasound, were eligible.

 

Exclusion criteria: severe fetal or placental disease that might bias neonatal outcomes such as intrauterine growth restriction (< 5th percentile), suspected placental abruption, and confirmed placenta previa. Also excluded were patients already taking 17P, and some with signs and symptoms of chorioamnionitis, non-reassuring fetal assessments or severe medical/obstetric diseases such as sickle cell disease with the crisis, insulin-dependent diabetes, and severe pre-eclampsia.


InterventionsExperimental intervention: weekly injections of 17P (250 mg) until 34 weeks or delivery, whichever came first.

Control/Comparison intervention: weekly injections of placebo until 34 weeks or delivery, whichever came first.


OutcomesGestational age at birth; route of delivery; indications for delivery; birthweight; 5-minute Apgar score; total NICU days; significant neonatal morbidity (sepsis, seizures); respiratory distress syndrome; patent ductus arteriosis; intraventricular haemorrhage; necrotising enterocolitis; bronchopulmonary dysplasia; death during neonatal period.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom number table.

Allocation concealment (selection bias)Low riskCentral allocation – pharmacy-controlled.

Incomplete outcome data (attrition bias)
All outcomes
Low risk2 patients lost – 1 person from 17P group who was previously enrolled in another study and 1 in placebo group refused the injection.                                             

 

“All 69 were analyzed (intention to treat).”

Selective reporting (reporting bias)Unclear riskAll expected outcomes, apart from intraventricular haemorrhage, are reported in tables – although number of seizures were recorded.

Other biasLow riskNo significant differences in demographic statistics between groups. 

Blinding of participants and personnel (performance bias)
All outcomes
Low risk“Patients, their families, research personnel, and physicians/nurses were not aware of the study group assignment”.  Also described as “double-blind”.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported.

Caritis 2009

MethodsRandomised, double-blinded, placebo-controlled trial.

14 centres, USA.


Participants134 women randomised: 71 to 17 alph-hydroxyprogesterone caproate; 63 to placebo

Inclusion criteria: pregnant women with triplets were eligible if their gestational age was at least 16 weeks and no more than 20 weeks.

Exclusion criteria: serious fetal anomalies, 2 or more fetuses in 1 amniotic sac, suspected twin-to-twin transfusion syndrome, marked ultrasonographic growth discordance, planned non study progesterone therapy after 16 weeks, in-place or planned cerclage, major uterine anomaly, unfractionated heparin therapy at any dose, and major chronic medical diseases.


InterventionsExperimental intervention: weekly injections of 17-OHPC* (250 mg in 1 mL castor oil) starting at 16-20 weeks and ending at delivery or 35 weeks' gestation.

*17 Alpha-Hydroxyprogesterone Caproate

Control/Comparison intervention: weekly injections of placebo (1mL castor oil) starting at 16-20 weeks and ending at delivery or 35 weeks' gestation.


OutcomesPrimary outcomes: composite of delivery or fetal loss before 35 completed weeks of gestation (245 days) – fetal loss included: miscarriage, termination, or stillbirth occurring any time after randomisation. 

 

Secondary outcomes: selected individual maternal and neonatal outcomes and a composite of serious neonatal outcomes. 

 

Composite serious adverse neonatal outcomes included: neonatal death, respiratory distress syndrome, culture-proven sepsis, necrotising enterocolitis stage II or III, bronchopulmonary dysplasia, intraventricular haemorrhage grade III or IV, or periventricular leucomalacia or severe retinopathy of prematurity stage III or higher.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk“The simple urn method of randomization with stratification according to clinical center, was used to create a randomization sequence for each center.”

Allocation concealment (selection bias)Low riskThe injections were prepared by a research pharmacy and boxes of 17-OHPC and placebo were packaged for each centre according to randomisation sequences – so appears to be central allocation – pharmacy-controlled.

Incomplete outcome data (attrition bias)
All outcomes
Low risk“Outcome data were available for 100% of the assigned women, and for all of the 402 fetuses.”

 

No exclusions apparent.

 

ITT stated in statistical methods.                        

Selective reporting (reporting bias)Low riskAll expected outcomes appear to have been reported.

Other biasLow riskThe baseline characteristics of the 2 study groups were similar (Table 1).

This study included women with multiple pregnancies (triplet) and there appears to be adjustment for neonatal binary outcomes - used log binomial regression to calculate relative risk.

Blinding of participants and personnel (performance bias)
All outcomes
Low risk“The participating women, their caregivers, and the research personnel were not aware of the study group assignment”.  Also described as “double-blinded”.

 

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported.

Cetingoz 2011

MethodsRandomised placebo-controlled double-blind study.

Department of Obstetrics and Gynecology, Istanbul.


Participants160 women randomised: 84 allocated to intervention and 76 allocated to placebo.

Inclusion criteria: high-risk pregnant women: twin pregnancies; pregnancies with at least 1 spontaneous preterm birth; uterine malformation.

Exclusion criteria: not stated.


InterventionsExperimental intervention: micronized progesterone (100 mg) administered daily by vaginal suppository between 24 and 34 weeks of gestation.

Control/Comparison intervention: placebo (100 mg) administered daily by vaginal suppository between 24 and 34 weeks of gestation.


OutcomesDelivery < 37 weeks.

Delivery < 34 weeks.

Preterm labour admission.

NICU admission.

Neonatal death.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated random-number list -  “Patients were allocated according to randomised number table".

Allocation concealment (selection bias)Low riskRandom-number list generated centrally by research hospital pharmacy.

Incomplete outcome data (attrition bias)
All outcomes
Low risk170 high-risk women were eligible – 10 women were excluded before randomisation due to abortion (n = 2), delivery between 20 and 24 weeks (n = 7) and application of cervical cerclage (n = 1). 

 

160 women were randomised – 10 lost during follow-up, 6 from the placebo group and 4 from intervention group.

150 women analysed (intervention group - n = 80 - prior preterm birth = 37; uterine malformation = 4; twin gestation = 39) and (placebo group - n = 70 - prior preterm birth = 34; uterine malformation = 8; twin gestation = 28).

Analysis was performed according to ITT principle.

Selective reporting (reporting bias)Low riskYes – all expected outcomes reported       

Other biasUnclear riskGroups were similar in regard to age, pregravid BMI, parity, abortion, and ratio of high-risk groups according to baseline characteristics table.  There were no statistically significant differences in demographics.

This study included singleton and twin pregnancies - Odd ratio presented, but does not state whether any adjustments made in the analysis.

Blinding of participants and personnel (performance bias)
All outcomes
Low risk“The participating women, their care-givers, and the research personnel were unaware of the woman’s study-group assignments.”

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported.

Combs 2010

MethodsDouble-blind, randomised clinical trial.

Multicentre, Obstetrix Collaborative Research Network, USA.


Participants81 women randomised: 56 allocated to 17P and 25 to placebo.

Inclusion criteria: mothers carrying trichorionic-triamniotic triplets – confirmed at 15-23 week detailed second-trimester ultrasound examination – showing normal amniotic fluid volume and no major fetal anomalies.

Exclusion criteria: women with symptomatic uterine contractions, rupture of fetal membranes, any contraindication to interventions intended to prolong the pregnancy, a pre-existing medical condition that might be worsened by progesterone, or a pre-existing medical condition carrying a high risk of preterm delivery.  Women less than 18 years of age, had an allergy to 17P or the oil vehicle, had taken any progesterone-derivative medication after 15 weeks of gestation, or had undergone placement of cervical cerclage for treatment of cervical change in the current pregnancy.


InterventionsExperimental intervention: 17 alpha-hydroxyprogesterone caproate (17P) (250 mg in 1 mL castor oil) – weekly injections starting at 16-22 weeks and continued until 34 weeks or delivery.  Weekly repeat injections were carried out at the site or at home with partner administering after training.  Injection diary for partner injections and measurement of unused medication returned by patient used to assess compliance with home administration.

Control/Comparison intervention: identical appearing placebo (in 1 mL castor oil). 


OutcomesPrimary outcomes: composite neonatal morbidity defined as 1 or more of: perinatal death (stillbirth, neonatal death, miscarriage); respiratory distress syndrome; use of oxygen therapy at 28 days of life; neonatal sepsis proven by blood culture; pneumonia; intraventricular haemorrhage (grade III or IV); periventricular leucomalacia; necrotising enterocolitis requiring surgery; retinopathy of prematurity; newborn asphyxia.

 

Secondary outcomes: individual neonatal morbidities listed above; gestational age at delivery; birthweight; maternal side effects.

 

Other outcomes reported:

Mean weeks of gestation.

Delivery before 28, 32 or 35 week.

Reason for delivery before 32 weeks (spontaneous; indicated).

Reason for delivery, all deliveries (spontaneous; indicated).

Caesarean delivery.

Tocolysis used.

Antenatal corticosteroids.

Maternal complications:

Pre-eclampsia or gestational hypertension.

Gestational diabetes.

Chorioamnionitis.

Sepsis.

Postpartum endometritis.

Neonatal outcomes:

Birthweight, g.

Head circumference, cm.

Total hospital stay, days.

NICU.

Intermediate care.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated scheme.

Allocation concealment (selection bias)Low riskRandom-number generated centrally by pharmacy.  “Progesterone or identical-appearing placebo was compounded by pharmacy and shipped in advance to each study site in coded prenumbered kits.  To randomise the research nurse contacted the central pharmacy by telephone or fax to obtain the code number for the kit assigned to that patient.”

Incomplete outcome data (attrition bias)
All outcomes
Low risk248 women identified with triplets, 147 eligible for trial inclusion, of these 89 gave consent (61%) and were given trial injection.  Of these, 81 (91%) returned for randomisation. 

No loss – 81 women randomised and outcome data available for all 81 mothers and 243 offspring.

“Analysis was by the “intention-to-treat” principle.  Accordingly, outcomes for each patient were tabulated according to the assigned group (17P vs placebo) regardless of her compliance.”

Selective reporting (reporting bias)Low riskYes – all expected outcomes reported.

Other biasLow riskBaseline characteristics of the participants were similar.  There were no significant difference between the groups in the percentage with cervix length less than  2.5 cm 17% in the 17P group versus 35% in the placebo group or with positive fibronectin, 11% versus 9%.

 

Mean compliance was 98.5% in the 17P group and 96.1% in the placebo group.  There was no significant difference between groups in the percentage of injections given by clinic staff (27% versus 30%), by patients themselves (13% versus 15%), or by their designated representatives (61% versus 56%).

Included multiple pregnancies (triplet) - adjustment made in analysis - used repeated measures model, where each infant was considered as a repeated measure.

Blinding of participants and personnel (performance bias)
All outcomes
Low risk“Subjects, physicians, and study personnel remained blinded as to group assignment until after completion of the trial.”

Blinding of outcome assessment (detection bias)
All outcomes
Low risk“Data were abstracted by study personnel who remained blinded to each subject’s group assignment.”

Combs 2011

MethodsDouble-blind, randomised clinical trial.

Multicentre – 18 sites, Obstetrix Collaborative Research Network, USA.


Participants240 women randomised: 160 allocated to 17Pc and 80 to placebo.

Inclusion criteria: women were eligible if they had a dichorionic-diamniotic twin pregnancy at 15-23 weeks' gestation and if they had completed a detailed ultrasound examination – showing no major fetal anomalies.   

Exclusion criteria: women were excluded if they were < 18 years old; had taken any progestins > 15 weeks of gestation; or had symptomatic uterine contractions, rupture of the fetal membranes, any contraindication to prolonging the pregnancy, any pre-existing condition that might be worsened by progesterone, or a pre-existing medical condition carrying a high risk of preterm delivery.


InterventionsExperimental intervention: 17 alpha-hydroxyprogesterone caproate (17P) (250 mg in 1 mL castor oil) – weekly injections starting at 16-24 weeks and continued until 34 weeks or delivery.  Weekly repeat injections were carried out at the site or at home with partner administering after training.  Injection diary for partner injections and measurement of unused medication returned by patient used to assess compliance with home administration.

Control/Comparison intervention: identical appearing placebo (in 1 mL castor oil). 


OutcomesPrimary outcomes: composite neonatal morbidity defined as 1 or more of: perinatal death (stillbirth, neonatal death, miscarriage); respiratory distress syndrome; use of oxygen therapy at 28 days of life; neonatal sepsis proven by blood culture; pneumonia; intraventricular haemorrhage (grade III or IV); periventricular leucomalacia; necrotising enterocolitis requiring surgery; retinopathy of prematurity; newborn asphyxia.

 

Secondary outcomes: individual neonatal morbidities listed above; gestational age at delivery; birthweight; maternal side effects.

 

Other outcomes reported:

Mean weeks of gestation.

Delivery before 28, 32 or 34 or 37 weeks.

Reason for delivery before 37 weeks (spontaneous; indicated).

Caesarean delivery.

Tocolysis used.

Antenatal corticosteroids.

Maternal complications:

Pre-eclampsia or gestational hypertension.

Gestational diabetes.

Chorioamnionitis.

Sepsis.

Postpartum endometritis.

Neonatal outcomes:

Birthweight, g.

Birthweight < 2500 g.

Birthweight < 1500 g.

Birthweight < 1000 g.

Small-for-gestational age.

All births.

Births < 2500 g.

Head circumference, cm.

Total hospital stay, days.

NICU.

Intermediate care.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated scheme.

Allocation concealment (selection bias)Low riskRandom-number generated centrally by pharmacy.  “Progesterone or identical-appearing placebo was compounded by pharmacy and shipped in advance to each study site in coded prenumbered kits.  To randomise the research nurse contacted the central pharmacy by telephone or fax to obtain the code number for the kit assigned to that patient.”

Incomplete outcome data (attrition bias)
All outcomes
Low risk1450 women identified with twin pregnancy, 254 eligible and consented and were given trial injection.  Of these, 240 returned for randomisation. 

 

No loss in progesterone group – 160 women allocated, 160 mothers delivered and 320 perinates with known outcome.  80 women allocated to placebo – 2 lost to follow-up – 78 women delivered and 156 perinates with known outcome.

“Outcomes for each patient were tabulated according to assigned group regardless of her compliance.”

Selective reporting (reporting bias)Low riskYes – all expected outcomes reported.

Other biasLow riskBaseline characteristics of the subjects were similar. 

 

Mean compliance was 96.4% in the 17P group and 98.7% in the placebo group.

Included multiple pregnancies (twin) - adjustment made in analysis - used repeated measures model, where each infant was considered as the repeated measure. 

Blinding of participants and personnel (performance bias)
All outcomes
Low risk“Subjects, physicians, and study personnel remained blinded as to group assignment until after completion of the trial.”

 

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported.

Combs 2011a

MethodsDouble-blind, placebo-controlled randomised clinical trial.

Multicentre – 18 sites, Obstetrix Collaborative Research Network, USA.


Participants12 women randomised: 4 allocated to 17P and 8 to placebo. The trial was terminated early because of 2 separate issues related to the supply of 17P.

Inclusion criteria:women were eligible if they were at least 18 years old, had a singleton pregnancy at 23.0 to 31.9 weeks of gestation and PROM.

 

Exclusion criteria: women were excluded with contraindications to expectant management; with known fetal abnormalities; with history of allergy to 17P or castor oil; with medical conditions that might adversely interact with 17P; with medical conditions treated with systemic steroid medications; or with a cervical cerclage present at the time of PROM. 


InterventionsExperimental intervention: 17 alpha-hydroxyprogesterone caproate (17P) (250 mg in 1 mL castor oil) – weekly intramuscular injections

Control/Comparison intervention: identical appearing placebo (in 1 mL castor oil).


OutcomesPrimary outcomes: prolongation of pregnancy until favourable gestational age. Composite neonatal morbidity defined as 1 or more of: stillbirth, neonatal death, infant death before hospital discharge; respiratory distress syndrome; intracranial haemorrhage grade III or IV; necrotising enterocolitis stage 2 or 3; culture proven sepsis within 72 hours of birth; periventricular leucomalacia.

 

Secondary outcomes: pregnancy prolongation (interval from randomisation to delivery). Individual neonatal morbidities listed above; gestational age at delivery; birthweight; maternal side effects.

 

Other outcomes reported:

Delivery at 34 weeks or more.

Delivery at 32-33.9 weeks with documented fetal lung maturity.

Mean gestational age at delivery.

Delivery before 32 or 34 weeks.

Pulmonary maturity testing.

Latency – randomisation to delivery.

Less than 1 week.

1.0  to 1.9 weeks.

2.0  2.0 weeks or more.

Reason for delivery before 34 weeks (spontaneous; chorioamnionitis; fetal indications).

Maternal complications:

Pre-eclampsia or gestational hypertension.

Gestational diabetes.

Chorioamnionitis.

Sepsis.

Caesarean delivery.

Tocolysis in first 48 hours.

Antenatal corticosteroids.

Neonatal outcomes:

Birthweight, g.

Total hospital stay, days.

NICU stay, days.

Newborns with congenital anomaly.

Adverse events not tabulated elsewhere.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated random number sequence was used by the trial statistician to generate a randomisation code.

Allocation concealment (selection bias)Low riskRandom-number generated by a statistician and held centrally at each site’s inpatient pharmacy.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss to follow-up – but only 12 patients were randomised – 8 to placebo and 4 to 17P

Appears to have been ITT.

Selective reporting (reporting bias)Low riskYes – all expected outcomes reported    .   

Other biasUnclear riskThe trial was stopped early due to 2 separate issues related to the supply of 17P.  Only 12 patients were randomised and because of the early termination, the trial was grossly under-powered to make conclusions as to the efficacy or safety of 17P in women with PROM.

 

Too few patients to assess baseline imbalance.

Blinding of participants and personnel (performance bias)
All outcomes
Low risk“Participants and research personnel were blinded to group assignment throughout.”

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported.

da Fonseca 2003

MethodsMethod of randomisation: random number table.
Allocation concealment: sequential sealed envelopes; allocation to either drug A or B; allocation of groups revealed after last woman birthed.
Blinded outcome assessment: yes.
Completeness of follow-up: outcome data available for 142 women (15 women excluded after randomisation).


Participants157 women considered to be at 'high risk' for preterm birth due to history of previous preterm birth, cervical suture, uterine malformation.


InterventionsNightly intravaginal pessary of either 100 mg progesterone or placebo from 24 weeks until 28 weeks' gestation, or birth if earlier.


OutcomesPreterm birth before 37 weeks' gestation; preterm birth before 34 weeks' gestation.


NotesTrial conducted in Sao Paulo, Brazil.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom number table.

Allocation concealment (selection bias)Low riskAdequate; sequential sealed opaque envelopes.

Incomplete outcome data (attrition bias)
All outcomes
Low risk15 women (less than 1%) post-randomisation exclusions.

Selective reporting (reporting bias)Low riskThe published report includes all expected outcomes (incidence of preterm delivery; frequency of uterine contractions).

Other biasLow risk"The two groups were found similar in regard to age, risk factors for preterm delivery, and obstetric history."

Blinding of participants and personnel (performance bias)
All outcomes
Low riskCaregivers and participants blinded.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcome assessor blinded.

Elsheikhah 2010

MethodsDescribed as “randomized controlled study” in abstract title.

Single centre, Cairo, Egypt.


Participants100 women: 50 allocated to progesterone group and 50 to placebo.

Inclusion criteria: women with twin pregnancy.

Exclusion criteria: patients with anomalies were excluded.


InterventionsExperimental intervention: vaginal progesterone 200 mg daily for 10 weeks from the 24th to the 34th week of gestation.

Control/Comparison intervention:  placebo for the same duration.


OutcomesMean cervical length.

Mean gestational age at delivery.

Fetal complications (not specified).

NICU admissions.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskData limited – only reported as an abstract.

Allocation concealment (selection bias)Unclear riskData limited – only reported as an abstract.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskData limited – only reported as an abstract.

Selective reporting (reporting bias)Unclear riskData limited – only reported as an abstract.

Other biasUnclear riskData limited – only reported as an abstract.

Multiple pregnancies - no adjustment apparent from abstract report.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskData limited – only reported as an abstract.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskData limited – only reported as an abstract.

Facchinetti 2007

MethodsMethod of randomisation: random number table.
Allocation concealment: randomisation list managed by senior midwife; allocation to either progesterone or placebo.
Blinding of outcome assessment: no.
Completeness of follow-up: outcome data available for 60 women.


Participants60 women presenting between 25 and 33 + 6 weeks' gestation with symptoms and signs of threatened preterm labour, where acute symptoms were arrested following use of tocolytic medication (atosiban).


Interventions341 mg intramuscular 17OHP administered every 4 days to 36 weeks' gestation.


OutcomesCervical length as assessed by transvaginal ultrasound. Secondary outcomes included preterm birth < 37 weeks, and infant birthweight.


NotesTrial conducted in Modena, Italy.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom number table.

Allocation concealment (selection bias)Unclear riskUnclear; list managed by "senior midwife" with allocation to either progesterone or placebo.

Incomplete outcome data (attrition bias)
All outcomes
Low riskOutcome data available for all women.

Selective reporting (reporting bias)High riskCervical length was measured by transvaginal ultrasound scanning at discharge and at day 7 and 21. Results for cervical length at discharge were not fully reported. All other outcomes appear to have been reported upon (cervical length at 7 and 21 days; preterm delivery < 37 weeks and < 35 weeks; birthweight).

Other biasLow riskNo differences were found between the 2 groups for baseline characteristics (see table, page 3).

Blinding of participants and personnel (performance bias)
All outcomes
High riskNo blinding - not possible "The study was not double blind because it was not sponsored; therefore, the preparation of true placebo (same vial, same oil without active compound) was not possible."

Blinding of outcome assessment (detection bias)
All outcomes
High riskNo blinding of outcome assessor.

Fonseca 2007

MethodsMethod of randomisation: not stated.
Allocation concealment: central randomisation process; identically appearing treatment packs.
Blinded outcome assessment: yes.
Completeness of follow-up: outcome data available for all 250 women randomised.


Participants250 women undergoing transvaginal ultrasound assessment of cervical length, where the cervical length was measured to be 15 mm or less. Women with both singleton and multiple pregnancies were eligible to participate (226 singleton and 24 with twin pregnancies).


InterventionsNightly intravaginal pessary of either 200 mg micronised progesterone or placebo from 24 weeks until 33 + 6 weeks' gestation, or birth if earlier.


OutcomesPrimary outcome: spontaneous preterm birth less than 34 weeks' gestation.
Secondary outcomes: infant birthweight, fetal death, neonatal death, major adverse outcomes (intraventricular haemorrhage, respiratory distress syndrome, retinopathy of prematurity, necrotising enterocolitis), need for neonatal special care (NICU, ventilation, phototherapy, treatment for proven or suspected sepsis, blood transfusion).


NotesTrial conducted in 5 maternity hospitals in London (UK), Santiago (Chile), Sao Paulo (Brazil), and Greece.

This data analysed in subgroup of women with short cervix - multiples only made up a small proportion of total group.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskMethod of randomisation generation not stated.

Allocation concealment (selection bias)Low riskAdequate; central randomisation; identical appearing treatment packs.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up.

Selective reporting (reporting bias)Low riskAll expected outcomes are reported (spontaneous delivery before 34 completed weeks; birthweight; fetal or neonatal death; major adverse outcomes before discharge; need for neonatal special care).

Other biasLow risk"There were no significant differences in baseline characteristics between the placebo and progesterone groups" (see Table 1, page 465).

Singleton and twin pregnancies - adjustment made for infant outcomes, “ the analyses of infant outcomes used robust standard errors and were clustered on a maternal identifier to account for the non-independence of twin pairs.”

Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinding of participants, caregivers, outcome assessors.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinding of participants, caregivers, outcome assessors.

Glover 2011

MethodsPilot, single-centre, randomised, double-blind, placebo-controlled trial.

Single centre, Miami Valley Hospital, Ohio, USA.


ParticipantsInclusion criteria: women < 20 weeks' gestation and had at least 1 prior spontaneous preterm birth of a live-born singleton infant between 200/7 weeks and 366/7 weeks' gestation.

 

Exclusion criteria: multiple gestations, the presence of major fetal anomalies, progesterone use in current pregnancy, the presence of a cervical cerclage and the presence of a placenta previa.


Interventions36 women randomised: 20 allocated to progesterone group and 16 allocated to placebo group.

Experimental intervention: 400 mg (2 200-mg capsules) of oral micronized progesterone MP.  Administration of the tables was initiated between 160/7 and 19 6/7weeks and was continued until the completion of the 33rd week of gestation.

Control/Comparison intervention: control group took 2 identical placebo capsules for the same time period.


OutcomesRate of recurrent spontaneous preterm birth.

Serum progesterone levels.

Neonatal morbidity and mortality:

birthweight (g) mean (SD);

male gender;

5-minute Apgar (mean);

ventilator use;

neonatal length of stay (mean), days.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk“Randomization was done by the hospital’s research pharmacy using a standard randomization table methodology for two groups.”

Allocation concealment (selection bias)Low riskCentral allocation – pharmacy controlled: “After subjects were randomized to their respective group, the research pharmacy dispensed a 1-month supply of either progesterone or placebo tablets in identical prescription bottles, which were labelled identically as “progesterone study medication.”

Incomplete outcome data (attrition bias)
All outcomes
Low risk45 patients were eligible for randomisation  –  9 women didn't complete the initial evaluation or failed to present to the pharmacy for randomisation and were excluded.

 

Appears that 36 were randomised, but only 33 analysed. 3 more participants were excluded – 1 from the MP group as became apparent that she had not had previous spontaneous preterm birth as she had been induced for severe eclampsia; 1 from the placebo group had a spontaneous abortion at 14 weeks; and another from placebo group did not complete her prenatal care at this centre and delivered elsewhere. 

 

3 appear to have been excluded after randomisation, see above.

  

Analysis appears to be ITT: 2 women ended their participation in the study – but both delivered at this institution and were included in their respective group for all analyses.

Selective reporting (reporting bias)Unclear riskIn methods reports that neonatal mortality will be reported – but was not reported.

Other biasLow riskSimilar baseline characteristics – no statistically significant differences between groups.

Blinding of participants and personnel (performance bias)
All outcomes
Low risk“The study subjects’ physicians were aware of the study participation but were blinded to the group assignment.”

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported.

Grobman 2012

MethodsMulticentre, randomised controlled trial.

Multicentre, Maternal-Fetal Units Network, USA.


Participants657 women recruited between April 2007 and May 2011 in various centres in the USA

 

657 women randomised: 327 to OHPc group and 330 to placebo.

Inclusion criteria: nulliparous women with a singleton gestation between 16 and 22 3/7 weeks with cervical length less than 30 mm.

Exclusion criteria: Women that had selective fetal reduction for multiple pregnancy, had evidence of additional fetal pole/embryo at 12 weeks or more, vaginal bleeding, prolapsed membranes, major fetal anomaly, current or planned cerclage, maternal medical condition associated with preterm delivery (e.g. hypertension) prior cervical surgery, or planned preterm delivery.


InterventionsExperimental intervention: 250 mg IM weekly 17 alpha hydroxyprogesterone caproate (17-OHPc) given by nurse until delivery or up to 36 weeks and 6 days gestation.

Control/Comparison intervention: An identical appearing placebo.Weekly IM injections of placebo (castor oil)  given by study nurse until delivery or up to 36 weeks and 6 days gestation.


OutcomesMaternal outcomes:

Preterm birth before 37 weeks

Birth before 35 weeks

Preterm rupture of membranes

Delivery < 28 weeks

Tocolytic therapy

Caesarean delivery

Side effects (any; injection site; urticaria; nausea)

 

Perinatal outcomes:

Fetal death

Neonatal death

Respiratory distress syndrome

Necrotising enterocolitis grade II or III

Intraventricular haemorrhage grade II or IV

Periventricular leucomalacia

Early-onset sepsis

Retinopathy of prematurity grade III or IV

Birthweight < 2500 g

5-minute Apgar < 7

NICU admission

Length of NICU stay, days


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskData co-ordinating centre to created the computer-generated randomisation sequence. Simple turn method of randomisation used.

Allocation concealment (selection bias)Low riskSimple randomisation method stratified by centre. Study treatments were research pharmacy prepared.

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll women randomised were accounted for in the analysis. Discontinuation of treatment was greater in the placebo group 33/330 vs 18/327 but there was an ITT analysis.

Selective reporting (reporting bias)Low riskAll expected outcomes reported upon.

Other biasUnclear riskGroups appeared balanced at baseline (slightly more white Hispanic in the placebo group and this group were slightly younger). The study was stopped early as the study monitoring committee decided that further recruitment after data for 591 available for interim analysis would be unlikely to show benefit (planned 1000 women , data for 657).

Blinding of participants and personnel (performance bias)
All outcomes
Low riskIt was stated that neither patients nor medical staff were aware of treatment group and the study was placebo controlled. It was stated that the IM injections appeared identical.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskIt was stated that the trial was blinded to research staff collecting outcome data. The trial was placebo controlled.

Hartikainen 1980

MethodsMethod of randomisation: stated to be "placebo controlled and double blind".
Allocation concealment: not stated.
Blinded outcome assessment: yes.
Completeness of follow-up: outcome data available for 77 women.


Participants77 women with a twin pregnancy.


InterventionsWeekly intramuscular injection of either 250 mg 17-hydroxyprogesterone caproate or placebo from 28 weeks' gestation until 37 weeks' gestation or birth if earlier.


OutcomesPerinatal death.


NotesTrial conducted in Finland.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskProcess of sequence generation not stated.

Allocation concealment (selection bias)Unclear riskUnclear.

Incomplete outcome data (attrition bias)
All outcomes
Low riskOutcome data available for all participants.

Selective reporting (reporting bias)Low riskAll expected outcomes are reported (duration of pregnancy; spontaneous delivery before 37 weeks; weights of neonates; perinatal mortality; neonatal morbidity (respiratory problems; omphalitis; pulmonary infection); maternal levels of progesterone; estradiol).

Other biasUnclear risk"The gestational age at the onset of medication, the gestational age at diagnosis of twin pregnancy and the patient's age were similar in both groups." (see table 1, page 693).

"The factors commonly regarded as risk factors for premature delivery showed no differences between groups." (see table 2, page 693).

Multiple pregnancies - abstract only available – limited data – no adjustment apparent.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskCaregivers and participants blinded.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinding of outcome assessors.

Hassan 2011

MethodsMulticentre randomised double-blind placebo-controlled trial.

Multicentre – 44 centres in 10 countries, USA.


Participants465 women randomised: 236 allocated to progesterone and 229 to placebo.

Inclusion criteria: singleton gestation; gestational age between 19 + 0 and 23 + 6 weeks; transvaginal sonographic cervical length between 10 and 20 mm; without signs and symptoms of preterm labour.

 

Exclusion criteria: planned cerclage; acute cervical dilation; allergic reaction to progesterone; current or recent progestogen treatment within 4 weeks; chronic medical conditions that would interfere with study participation or evaluation of the treatment; major fetal anomaly or known chromosomal abnormality; uterine anatomic malformation; vaginal bleeding; known or suspected clinical chorioamnionitis.


InterventionsExperimental intervention: daily micronised vaginal progesterone gel – women self-administered the study drug once daily in the morning.  Each applicator delivered 1.125 g gel containing 90 mg progesterone.

Control/Comparison intervention: an identical appearing placebo - each applicator delivered 1.125 g gel containing 90 mg placebo.


OutcomesPrimary outcome: preterm birth before 33 weeks.

 

Secondary outcomes: neonatal morbidity - respiratory distress syndrome; bronchopulmonary dysplasia; intraventricular haemorrhage grade III or IV; periventricular leucomalacia; proven sepsis; necrotising enterocolitis; perinatal mortality (fetal death or neonatal death) – composite scores were used to assess perinatal mortality and morbidity.  


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomisation allocation was 1:1 and was accomplished using a centralised interactive voice response system.  Randomisation was stratified according to centre and risk strata (previous preterm birth between 20 and 35 weeks or no  previous preterm birth) using a permuted blocks strategy with a block size of 4. 

Allocation concealment (selection bias)Low riskReported that allocation concealment accomplished in 3 ways:

1. participant study kits at each site were numbered independently from the treatment assignments in the randomisation blocks;

2. IVR system specified which kit number was to be dispensed to the subject;

3. the study drug packaging , applicators and contents were identical in appearance.

Incomplete outcome data (attrition bias)
All outcomes
Low risk733 women eligible, 268 declined, 465 randomised.

1 lost to follow-up from progesterone group and 6 from placebo group.

ITT analysis performed.

Selective reporting (reporting bias)Low riskAll expected outcomes reported upon.

Other biasLow riskBaseline characteristics were similar between groups.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDescribed as double blind.

 

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported.

Hauth 1983

MethodsMethod of randomisation: stated to be "randomised, double blind intervention".
Allocation concealment: not stated.
Blinded outcome assessment: yes.
Completeness of follow-up: outcome data available for all women randomised.


Participants168 women on active military duty.


InterventionsWeekly intramuscular injection of either 1000 mg 17-hydroxyprogesterone caproate or placebo from 16 to 20 weeks until 36 weeks' gestation, or birth if earlier.


OutcomesPreterm birth before 37 weeks' gestation; birthweight less than 2.5 kg; perinatal death.


NotesTrial conducted in Lackland Airforce Base, Texas, USA.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskSequence generation not stated.

Allocation concealment (selection bias)Unclear riskUnclear.

Incomplete outcome data (attrition bias)
All outcomes
Low riskOutcome data available for all women recruited.

Selective reporting (reporting bias)Low riskAll expected outcomes were reported (low birthweight; perinatal mortality; pregnancy-induced hypertension; premature labour).

Other biasLow riskThe groups were similar for parity, previous abortion, race, cigarette smoking, and marital status.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskCaregivers and participants blinded.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinding of outcome assessors.

Ibrahim 2010

MethodsRandomised placebo-controlled trial.

Ain Shams University Maternity Hospital, Cairo, Egypt.


Participants50 women randomised: 25 allocated to progesterone group and 25 to placebo group.

Inclusion criteria: singleton pregnant women in their second trimester with a history of preterm labour.

Exclusion criteria: women with a history medical disease during pregnancy, multiple pregnancy, abdominal or cervical cerclage, known fetal anomalies or scarred uterus.


InterventionsExperimental intervention: 17-α-hydoxy progesterone caproate – 1 dose of 250 mg intramuscular progesterone- weekly until 36 weeks.

Control/Comparison intervention: standard dose of placebo IM per week until 36 weeks.


OutcomesMean gestation age.

Birth < 37 weeks.

Birth  > 37 weeks.

Live neonates.

Need for NICU.

Neonatal death.

Birthweight < 2500 g.

Birthweight > 2500 g.

Apgar score < 7.

Apgar score > 7.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported – says women were divided into 2 groups –but no details of method of randomisation.

Allocation concealment (selection bias)Unclear risk“Randomisation was done by the use of sealed envelopes which were opened by the nurse responsible for giving the injections to all participants whether Cidolut depot or placebo” – unclear whether the envelopes were opaque and sequentially numbered – so nurse may have been able to foresee assignment.

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll women appear to be included in the results – 25 in each group.

Selective reporting (reporting bias)Low riskAll expected outcomes reported upon.

Other biasUnclear riskBaseline demographic characteristics not fully reported.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDescribed as double blind – but no details described.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported.

Johnson 1975

MethodsMethod of randomisation: stated to be "random double blind fashion".
Allocation concealment: next of identical drug packages.
Blinded outcome assessment: yes.
Completeness of follow-up: outcome data available for 43 women (7 women excluded after randomisation).


Participants50 women with a history of 2 previous spontaneous abortions or previous preterm birth before 36 weeks' gestation.


InterventionsWeekly intramuscular injection of either 250 mg 17-hydroxyprogesterone caproate or placebo from 'booking' until 24 weeks' gestation.


OutcomesPreterm birth before 37 weeks' gestation; birthweight less than 2.5 kg; perinatal death.


NotesTrial conducted in Baltimore, USA.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskGeneration of sequence not stated.

Allocation concealment (selection bias)Low riskAdequate; identical appearing treatment packs.

Incomplete outcome data (attrition bias)
All outcomes
Low risk7 women excluded post-randomisation (1%).

Selective reporting (reporting bias)Low riskAll expected outcomes reported (premature delivery; birthweight; perinatal mortality).

Other biasLow riskGroups were similar for baseline characteristics, (see table 2, page 678), although placebo group included fewer smokers and less heavy smokers than progesterone group.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskCaregivers and participants blinded.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcome assessors blinded.

Lim 2011

MethodsMulticentre, double-bind, placebo-controlled randomised trial.

Multicentre, 55 obstetric clinics in Netherland.


Participants671 women randomised: 336 allocated to progesterone and 326 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.


InterventionsExperimental intervention: 1 mL 17-α-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, in case the patient or a family member had a background in medical practice, at the patient’s home.

Control/Comparison intervention: 1 mL placebo (castor oil) – study medication and placebo were identical in packaging, colour and consistency.


OutcomesPrimary outcomes: composite adverse neonatal outcome – severe respiratory distress syndrome; bronchopulmonary dysplasia; intraventricular haemorrhage grade II B or worse;necrotising enterocolitis; 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


Risk of bias

BiasAuthors' judgementSupport 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 riskWeb-based randomisation – “Randomization was accessible through a website” and “Allocation code was known only to ACE Pharmaceuticals”

Incomplete outcome data (attrition bias)
All outcomes
Low risk1865 women eligible, 1194 declined participation, 671 women entered trial.

 

336 randomised to progesterone group and no women lost to follow-up/326 randomised to placebo and 4 lost to follow-up.

 

681 children born to 336 women in progesterone group/ 680 children born to 331 women in placebo group.

 

Neonatal outcome available for 681 in progesterone group and 674 in placebo group.

States that “all analyses were based on the intention-to-treat principle.”

 

Selective reporting (reporting bias)Low riskAll expected outcomes reported upon.

Other biasLow riskBaseline characteristics similar.

Multiple pregnancies (twin, triplet and 1 quadruplet) - adjustments made for all neonatal, delivery, pregnancy and side effect outcomes.

Blinding of participants and personnel (performance bias)
All outcomes
Low risk“Participants, caregivers, and data collectors were all blinded to allocation.”

Blinding of outcome assessment (detection bias)
All outcomes
Low riskParticipants, caregivers, and data collectors were all blinded to allocation.”

Majhi 2009

MethodsProspective randomised trial.

Department of Obstetrics and Gynaecology,  Postgraduate Instistute of Medical Education and Research (PGIMER), Chandigarh, India.


Participants50 women randomised: 50 allocated to progesterone and 50 allocate to no treatment.

Inclusion criteria:  women at high risk for preterm birth, having a singleton pregnancy and current gestation 16-24 weeks.  High risk was defined by history of at least once prior spontaneous preterm birth of a singleton infant > 20 and < 37 weeks due to spontaneous labour or preterm rupture of fetal membranes.

Exclusion criteria: women with multifetal gestation, congenital malformation in the fetus, current or planned cervical cerclage or with any associated medical disorder were excluded.


InterventionsExperimental intervention:  100 mg natural micronised progesterone capsule intravaginally once daily at bedtime from 20-24 weeks' gestation until 36 weeks.

Control/Comparison intervention:  no placebo – just managed according to the institute protocol.


OutcomesPrimary outcomes: 

Preterm birth < 37 weeks.

Preterm birth ≤ 34 weeks.

 

Secondary outcomes:

Maternal hospitalisation.

Vaginal delivery.

LSCS.

Birthweight (Mean SD).

NICU.

Sepsis.

Hyperbilirubinaemia.

Necrotising enterocolitis.

Cord pH (Mean SD).


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated random-number tables.

Allocation concealment (selection bias)Low riskSequentially numbered opaque sealed envelopes – provided centrally by Dept Biostatistics and investigators were not involved in the randomisation procedure.

Incomplete outcome data (attrition bias)
All outcomes
Low risk118 women met the inclusion criteria; 100 women consented and were included – 50 assigned to each group.

There was no attrition during follow-up.

Selective reporting (reporting bias)Low riskAll expected outcomes reported upon.

Other biasUnclear riskBoth groups were similar in all characteristics except BV, which was commoner in the study group.  It was treated in both groups.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot reported – no placebo used though – so participants would have been aware of assignment.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported.

Meis 2003

MethodsMethod of randomisation: computer-generated 2:1 random number schedule.
Allocation concealment: next of identical drug packages.
Blinded outcome assessment: yes.
Completeness of follow-up: outcome data available for 463 women.


Participants463 women with a history of previous spontaneous preterm birth; exclusion women with multiple pregnancy, known fetal anomaly, progesterone or heparin treatment during pregnancy, current or planned cervical cerclage, hypertension, seizure disorder.


InterventionsWeekly intramuscular injection of either 250 mg 17-hydroxyprogesterone caproate or placebo from 16 to 20 weeks until 36 weeks' gestation, or birth if earlier.


OutcomesPreterm birth before 37 weeks' gestation; birthweight less than 2.5 kg; stillbirth; neonatal death; intraventricular haemorrhage; respiratory distress syndrome; bronchopulmonary dysplasia; sepsis; necrotising enterocolitis; retinopathy of prematurity; patent ductus arteriosus.


NotesTrial conducted by the Maternal-Fetal Medicine Network, USA.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated sequence.

Allocation concealment (selection bias)Low riskAdequate; identical appearing treatment packs.

Incomplete outcome data (attrition bias)
All outcomes
Low riskOutcome data available for all 463 women recruited.

Selective reporting (reporting bias)Low riskAll expected outcomes reported (preterm delivery < 37, < 35, < 32 weeks; pregnancy outcomes (e.g. caesarean delivery; chorioamnionitis; fetal and neonatal outcomes (e.g. birthweight; neonatal death; ventilatory support; necrotizing enterocolitis; proven sepsis).

Other biasLow riskGroups were similar for baseline characteristics, (see table 1, page 2382), although the women in the placebo group had had more previous preterm deliveries.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskWomen, caregivers and outcome assessors blinded.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskWomen, caregivers and outcome assessors blinded.

Moghtadaei 2008

MethodsRandomised, double-blind, placebo-controlled trial.

Single site,  Iran.


Participants260 women randomised to treatment - number randomised to placebo not reported.

Inclusion criteria: women in advanced maternal age – primiparous aged 35 years or more.

Exclusion criteria: not reported.


InterventionsExperimental intervention: weekly injections of 17P (250 mg) starting at 16-20 weeks' gestation until 34 weeks.

Control/Comparison intervention: matching placebo.


OutcomesDelivery before 37 weeks.

Delivery before 35 weeks.

Delivery before 32 weeks.

Hypertension.

Diabetes.

Intrauterine growth restriction.

Side effects at injection site.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskOnly abstract available – data limited.

Allocation concealment (selection bias)Unclear riskOnly abstract available – data limited.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskOnly abstract available – data limited.

Selective reporting (reporting bias)Unclear riskOnly abstract available – data limited.

Other biasUnclear riskOnly abstract available – data limited.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskOnly abstract available – data limited – although states “double blind”.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskOnly abstract available – data limited.

Ndoni 2010

MethodsProspective randomised placebo-controlled study.

Single centre, Albania.


Participants121 women randomised into 3 groups: IM injection prontogest (n = 52); oral progesterone (n = 43); placebo (n = 26).

Inclusion criteria: 15-22 weeks' gestation at high risk for preterm labour, hospitalised in the pathology of pregnancy clinic.

Exclusion criteria: not stated.


InterventionsExperimental intervention:

Group 1: Daily intramuscular injection of 17 alpha-hydroxyprogesterone caproate (Prontogest) (n = 52).

Group 2: Oral progesterone (Utrogestan) (n = 43).

Control/Comparison intervention:  

Group 3: Identical-looking placebo (n = 26).


OutcomesNot reported.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskStates “The participants were separated in three groups..”

Allocation concealment (selection bias)Unclear riskData limited – only reported as an abstract.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskData limited – only reported as an abstract.

Selective reporting (reporting bias)Unclear riskNo outcome data was reported in the abstract.

Other biasUnclear riskData limited – only reported as an abstract.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskData limited – only reported as an abstract.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskData limited – only reported as an abstract.

Norman 2009

MethodsDouble-blind randomised placebo-controlled trial.

Multicentre, 9 UK NHS hospitals – STOPPIT study (Study Of Progesterone for the Prevention of Preterm Birth In Twins), UK.


Participants500 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.


InterventionsExperimental intervention: 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 intervention:  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 1.125 g of gel containing 8% excipients.


OutcomesPrimary:

Delivery or intrauterine death before 34 weeks.

 

Secondary:

Gestation at delivery.

Mode of delivery.

Duration of each stage of labour.

Safety outcomes:

Admission to neonatal unit.

Duration of neonatal unit stay.

Mother died.

Intrauterine death.

Neonatal death.

Involved or prolonged inpatient maternal hospital admission.

Involved persistent/significant maternal disability or incapacity.

Life threatening.

Chorioamnionitis or intrauterine infection.

Congenital anomaly or birth defect.

Maternal symptoms.

Maternal satisfaction.


Notes


Risk of bias

BiasAuthors' judgementSupport 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 riskCentral 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.

Incomplete outcome data (attrition bias)
All outcomes
Low risk1483 assessed for eligibility, 983 excluded (did not meet eligibility; declined participation), 500 enrolled and randomised.

  

250 randomised to each group, 3 lost to follow-up from both treatment and control groups (6 altogether) – because of withdrawal of consent or not traceable after moving out of study area. 3 therefore excluded from each analysis.

Analysis was by ITT. 494 mothers and 988 babies remained for the per-protocol analysis.

Selective reporting (reporting bias)Low riskAll expected outcomes appear to have been reported.

Other biasLow riskBaseline characteristics similar.

Multiple pregnancies - adjustment for some neonatal outcomes – give Odds Ratios: admission to neonatal unit;

duration of neonatal unit stay.

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
Unclear riskNot reported.

O'Brien 2007

MethodsMethod of randomisation: random number table.
Allocation concealment: identical appearing sequentially numbered treatment packs.
Blinded outcome assessment: yes.
Completeness of follow-up: outcome data available for 611 of 659 women randomised (48 (7.3%) women lost to follow-up).


Participants659 women with a history of prior spontaneous preterm birth.
Exclusions: adverse reaction to progesterone; progesterone treatment within 4 weeks of randomisation; medical conditions; suspected genital tract malignancy; thromboembolic disease; fetal anomaly; multiple pregnancy; planned cervical cerclage.


InterventionsNightly vaginal progesterone gel (90 mg) versus placebo.


OutcomesPreterm birth less than 32 weeks; Apgar scores, infant birthweight, NICU admission.

Secondary analysis of data from O'Brien 2012: infant weight, length and head circumference at 6, 12 and 24 months.


NotesTrial conducted in 53 centres worldwide.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom number table.

Allocation concealment (selection bias)Low riskAdequate; identical appearing treatment packs.

Incomplete outcome data (attrition bias)
All outcomes
Low riskOutcome data available for 611 of 659 women randomised (7.3% women lost to follow-up).

Selective reporting (reporting bias)Low riskAll expected outcomes reported (preterm birth; maternal, fetal and neonatal outcomes), detailed in table 2, page 692.

Other biasLow riskBaseline characteristics similar between groups (see table 1, page 691).

Blinding of participants and personnel (performance bias)
All outcomes
Low riskWomen, caregivers and outcome assessors blinded.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskWomen, caregivers and outcome assessors blinded.

Papiernik 1970

MethodsMethod of randomisation: unclear.
Allocation concealment: unclear.
Blinded outcome assessment: yes.
Completeness of follow-up: outcome data available for 99 women.


Participants99 women with a "high preterm risk score".


InterventionsEvery 3 days intramuscular injection of either 250 mg 17-hydroxyprogesterone caproate or placebo from 28 weeks' gestation until 32 weeks' gestation.


OutcomesPreterm birth before 37 weeks' gestation; birthweight less than 2.5 kg; perinatal death.


NotesTrial conducted in Paris, France.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported.

Allocation concealment (selection bias)Unclear riskUnclear.

Incomplete outcome data (attrition bias)
All outcomes
Low riskOutcome data available for 99 women randomised.

Selective reporting (reporting bias)Unclear riskNot possible to tell from translation.

Other biasLow riskFrom the translation of the paper "Each group studied was similar in age, the number of previous pregnancies, the onset of treatment and risk of preterm birth".

Blinding of participants and personnel (performance bias)
All outcomes
Low riskCaregivers and participants blinded.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcome assessor blinded.

Rai 2009

MethodsRandomised, double-blind, placebo-controlled trial.

Single centre, Dept Obstetrics & Gynaecology, University College of Medical Science and Guru Teg Bahadur Hospital, Delhi.


Participants150 women randomised: 75 allocated to progesterone and 75 allocated to placebo.

Inclusion criteria: asymptomatic women aged between 18 and 35 years who were between 18 and 24 weeks of pregnancy, with a history of at least 1 spontaneous preterm delivery (between 20 weeks and 36 weeks plus 6 days) and with a singleton live pregnancy.

 

Exclusion criteria: women with first trimester bleeding, PROM, multiple pregnancy, fetal anomalies or active liver disease were excluded.


InterventionsExperimental intervention: 100 mg oral micronised progesterone – twice a day from recruitment (18-24 weeks) until 36 weeks or delivery.

Control/Comparison intervention: placebo - twice a day from recruitment (18-24 weeks) until 36 weeks or delivery.


OutcomesPrimary:

Mean prolongation of pregnancy in weeks and days of gestation.

Gestational age at delivery:

< 28.

28-31 + 6.

32-33 + 6.

34-36 + 6.

 

Secondary:

Use of tocolysis.

Adverse drug effects.

 

Neonatal outcomes:

Neonatal age at delivery, week.

Birthweight, g.

NICU stay.

< 24 hours.

24 hours – 1 week.

> 1 week.

Apgar score at 1 minute.

< 6.

> 6.

Apgar score at 10 minute.

< 6.

> 6.

Neonatal deaths.

Respiratory distress syndrome.

RDS with septicaemia.

RDS with hyperbilirubinaemia.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk“computer-generated numbers table.”

Allocation concealment (selection bias)Low riskCentral allocation suggested -  random number table provided by the Department of Biostatistics. 

Incomplete outcome data (attrition bias)
All outcomes
Low risk150 assessed for eligibility, all enrolled and randomised.

 

75 randomised to each group – and 1 lost to follow-up from each group – 74 analysed in each group.

 

ITT not mentioned – but 74 from each group analysed.

Selective reporting (reporting bias)Low riskAll expected outcomes appear to have been reported  .  

Other biasLow riskBaseline characteristics similar.

 

Blinding of participants and personnel (performance bias)
All outcomes
Low risk“The patients and the medical staff were blinded to the study medication allocation until after the last patient had delivered and the study was complete.”

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported.

Rode 2011

MethodsRandomised, double-blind, placebo-controlled trial.

Multicentre, 17 centres in Denmark and Austria.


Participants677 women were randomised: 334 allocated to progesterone and 343 allocated to placebo

Inclusion criteria: women with a live, diamniotic twin pregnancy and chorionicity assessed by ultrasound before 16 weeks’ gestation were eligible for recruitment.

 

Exclusion criteria: age < 18 years; known allergy to progesterone or peanuts (active treatment contained peanuts); history of hormone-associated thromboembolic disorders; rupture of membranes; treatment for or signs of twin-to-twin transfusion syndrome; intentional fetal reduction; known major structural or chromosomal fetal abnormality; known or suspected malignancy in genitals or breasts; known liver disease; women with higher-order multiple pregnancies; women who did not speak and understand Danish or German.


InterventionsExperimental intervention: vaginal micronized progesterone pessaries (200 mg) – self-administered daily by participants – starting from 20-24 weeks until 34 weeks’ gestation.

Control/Comparison intervention: vaginal placebo pessaries (200 mg) – self-administered daily by participants – starting from 20-24 weeks until 34 weeks’ gestation.


OutcomesPrimary:

Incidence of delivery before 34 + 0 weeks’ gestation.

 

Secondary:

Delivery before 22, 28, 32, 37 weeks' gestation.

Delivery by caesarean section (emergency and planned).

Number of liveborn infants.

Miscarriage.

Intrauterine death.

Infant death during delivery.

Neonatal death.

Death after 28 days.

Sudden infant death.

Corticosteroids for fetal lung maturation.

Tocolytic therapy.

Maternal adverse outcomes (gestational diabetes; increased liver enzymes; pre-eclampsia; thromboembolic event).

Birthweight < 2500 g.

Birthweight < 1500 g.

Apgar score < 7 at 5 minutes.

Congenital or chromosomal anomalies.

Perinatal complication:

Hypoglycaemia.

Intraventricular haemorrhage.

Jaundice.

Necrotising enterocolitis.

Patent ductus arteriosis.

Respiratory distress syndrome.

Retinopathy of prematurity.

Septicemia.

Admission to NICU.

CPAP treatment of at least 24 hours.

Respirator treatment.

 

Neurophysiological development 6 and 18 months after estimated date of delivery (assessed via Ages and Stages Questionnaire (ASQ).


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk“The Perinatal Epidemiology Research Unit created a randomization sequence with a 1:1 ratio.” 

Allocation concealment (selection bias)Low riskCentral allocation suggested -  used an interactive voice-response randomisation system:

 

“We stratified by center and chorionicity using an interactive voice-response randomization system at the Perinatal Epidemiology Research Unit. Each local researcher telephoned the randomization system, was given a randomization number that corresponded to a specific treatment box from a given batch".

Incomplete outcome data (attrition bias)
All outcomes
Low risk1507 assessed for eligibility, 219 excluded, 1288 informed about the trial, 526 declined to participate/did not answer, 677 randomised – 343 to each group.

 

2 from placebo group lost to follow-up - 343 included in analysis for progesterone group and 341 in placebo group.

 

9 women in the progesterone group and 4 in the placebo group never started treatment because they changed their minds with respect to participation (n = 8), they miscarried or a fetus died in utero (n = 2) or they were withdrawn from the study (n = 3). Analyses based on 343 from progesterone group and 341 from placebo group.  

 

States that all analyses were performed according to the ITT principle.

Selective reporting (reporting bias)Low riskAll expected outcomes appear to have been reported.

Other biasLow riskBaseline characteristics were comparable for the groups but there were slightly more monochorionic gestations in the placebo group – but the difference was not statistically significant.

Multiple pregnancies - adjustments made for infant outcomes – present Relative Risks.

Blinding of participants and personnel (performance bias)
All outcomes
Low risk“All participants and study personnel were blinded to treatment assignment for the duration of the trial, and the randomization code was not broken before all data had been collected, including the infant follow-up at 18 months of age.”

Blinding of outcome assessment (detection bias)
All outcomes
Low riskAppears that outcome assessment was blinded – “Only the statistician and the independent Data Monitoring and Safety Committee had access to unblinded  data during the study period”.

Rouse 2007

MethodsMethod of randomisation: the "urn" method of randomisation.
Allocation concealment: next of identical appearing treatment injections.
Blinded outcome assessment: yes.
Completeness of follow-up: 661 women randomised with outcome data available for 655 women.


Participants661 women with a twin pregnancy; exclusion women with known fetal anomaly, spontaneous fetal death of a fetus after 12 weeks, presumed monoamnionic placenta, suspected twin-twin transfusion syndrome, marked ultrasonographic growth discordance, progesterone or heparin treatment during pregnancy, current or planned cervical cerclage, hypertension, insulin-dependent diabetes, and twin pregnancies that were the result of intentional fetal reduction.


InterventionsWeekly intramuscular injection of either 250 mg 17-hydroxyprogesterone caproate or placebo (castor oil) from 16 - 20 + 3 weeks until 34 completed weeks' gestation, or birth if earlier.


OutcomesPrimary outcome: composite of delivery or death prior to 35 weeks' gestation.
Secondary outcomes: randomisation to delivery interval; composite adverse outcomes (retinopathy of prematurity, respiratory distress syndrome, sepsis, necrotising enterocolitis, bronchopulmonary dysplasia, grade III or IV intraventricular haemorrhage, periventricular leucomalacia), birthweight (less than 2500 g and less than 1500 g), 5-minute Apgar score < 7, patent ductus arteriosus, pneumonia, mechanical ventilation, seizures.

Preterm birth before 37 weeks' gestation; birthweight less than 2.5 kg; stillbirth; neonatal death; intraventricular haemorrhage; respiratory distress syndrome; bronchopulmonary dysplasia; sepsis; necrotising enterocolitis; retinopathy of prematurity; patent ductus arteriosus.


NotesTrial conducted by the Maternal-Fetal Medicine Network, USA.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"The simple urn method of randomisation with stratification according to clinical center was used by the George Washington University Biostatistical Co-ordinating Center to create a randomization sequence for each center,..."

Allocation concealment (selection bias)Low riskAdequate; identical appearing treatment packs.

Incomplete outcome data (attrition bias)
All outcomes
Low riskOutcome data available for 655 of 661women (less than 1% loss to follow-up).

Selective reporting (reporting bias)Low riskAll expected outcomes reported (delivery or fetal death before 35 weeks' gestation; other obstetric and neonatal outcomes) see table 2 and 3.

Other biasUnclear risk"Baseline demographic data were similar in the two study groups" (see table 1).

Multiple pregnancies - no adjustment in analysis apparent.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskWomen, caregivers and outcome assessors blinded.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskWomen, caregivers and outcome assessors blinded.

Rozenberg 2012

MethodsOpen-label randomised controlled trial.

Multicentre, 13 French university hospitals.


Participants188 women randomised.

Inclusion criteria: women with singleton pregnancies admitted at 24 + 0 through 31 + 6 weeks of gestation with a cervical length < 25 mm for an episode of preterm labour that was then successfully arrested by tocolytic treatment.  A course of betamethasone 12 mg, repeated after 24 hours, was given intramuscularly in all patients. 

 

Exclusion criteria: cervical dilatation > 3cm, chorioamnionitis, fetal heart rate abnormalities, placenta previa, adruptio placentae, PROM, polyhydramnios, IUGR, pregnancy-related hypertension or pre-eclampsia, maternal or fetal condition requiring immediate delivery, anticonvulsive treatment or participation in any other trial.


InterventionsExperimental intervention: 500 mg of intramuscular 17 alpha-hydroxyprogesterone caproate (17 P) started after tocolysis ended and repeated twice weekly until 36 weeks or until preterm delivery. 

Control/Comparison intervention:  no treatment with 17P.  Additional management in the 2 arms was left to the discretion of the attending physician, except that  progesterone was not allowed in the control group.


OutcomesTime from randomisation to delivery, preterm delivery before 37, 34 and 32 weeks, readmissions for preterm labour, NICU, birthweight, respiratory distress, bronchopulmonary dysplasia, necrotising enterocolitis, periventricular leucomalacia, perinatal death, severe maternal or neonatal adverse effect.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskCentralised, computer-generated randomisation process in a 1:1 ratio.

Allocation concealment (selection bias)Unclear riskNot described.

Incomplete outcome data (attrition bias)
All outcomes
Low riskA total of 188 women were randomised.

 

Outcome data available for 184 women.

 

States “assessed according to the intention-to-treat principle”.

Selective reporting (reporting bias)Low riskAll expected outcome results reported.

Other biasUnclear riskA subsequent letter to the journal questioned the use of the study medication unless it had been tested for purity and many samples of the medication did not meet FDA specifications. The letter stated that this casts doubt on the findings of any study using 17Pc. The authors confirmed that the study medication was not of questionable quality.

 

Study groups appeared similar at baseline although 12% of the intervention group and 24% of controls had had a previous preterm delivery.

Blinding of participants and personnel (performance bias)
All outcomes
High riskNo blinding - trial is described as “open label”.

Blinding of outcome assessment (detection bias)
All outcomes
High riskNot mentioned.  High risk of bias (randomisation to the control group may have affected subsequent treatment and outcome assessment).

Saghafi 2011a

MethodsDescribed as an interventional study.

Obstetrics Clinic of Ghaem Hospital, Mashad University of Medical Sciences, Iran.


Participants100 women randomised: 50 allocated to progesterone and 50 allocated to placebo.

Inclusion criteria: pregnant women with a previous history of preterm delivery who had no contraindication for continuing pregnancy.

 

Exclusion criteria: women who had entered the active phase of delivery, cases of preterm PROM, pre-eclampsia, vaginal bleeding, maternal-fetal diseases for which continuation of the pregnancy was dangerous, symptoms of distress, and fetal anomalies.


InterventionsExperimental intervention: 250 mg of intramuscular 17 alpha-hydroxyprogesterone caproate (17 P) weekly from 16 weeks’ gestation up to a maximum of 37 weeks’ gestation. 

Control/Comparison intervention: routine perinatal care.


OutcomesPreterm delivery (< 37 weeks).

Apgar score at 1 and 5 minutes (mean values given).

Newborn weight (g) mean values.

Vaginal delivery (n).

Low birthweight neonates (%) – didn't specify what low birthweight was.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described - just says "They were randomly divided into two groups...".

Allocation concealment (selection bias)Unclear riskNot described.

Incomplete outcome data (attrition bias)
All outcomes
Low riskAppears to be no loss.

Outcome data available for all 100 women, 50 randomised to each group.

Selective reporting (reporting bias)Unclear riskData limited – only reported as an abstract.

Other biasLow riskStates that the 2 groups were similar for age, gravidity, abortions, previous preterm births - see table 1.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot described.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described.

Senat 2012

MethodsOpen-label multicentre, randomised controlled trial in France – 13 French university hospitals.


Participants165 women randomised and 161 followed up – it was not clear how many were randomised to each group.

Inclusion criteria: asymptomatic women with twin pregnancy and cervical length < 25 mm between 20 and 32 weeks of gestation.

Exclusion criteria: not reported in the abstract.


InterventionsExperimental intervention: 500 mg intramuscular 17 alpha-hydroxyprogesterone caproate (17P) – twice weekly until 36 weeks or until preterm delivery.

Control/Comparison intervention: no 17P.

 

Additional management in the 2 arms was left to the discretion of the attending physician, except that progesterone was not allowed in the control group.


OutcomesMedian time to delivery; delivery before 32 and 34 weeks' gestation.


NotesNot able to report any outcome data because the number randomised to each group is not stated.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomly assigned by computer-generated randomisation process in a 1:1 ratio.

Allocation concealment (selection bias)Low riskStates – central randomisation.  “A centralised, computer generated randomised process in a 1:1 ratio.”

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskUnclear – limited data reported as only an abstract.

Selective reporting (reporting bias)Unclear riskUnclear – limited data reported as only an abstract.

Other biasUnclear riskUnclear – limited data reported as only an abstract.

Blinding of participants and personnel (performance bias)
All outcomes
High riskDescribed as an "open label trial".

Blinding of outcome assessment (detection bias)
All outcomes
High riskDescribed as an "open label trial".

Serra 2013

Methods3-arm RCT in 5 centres in Spain, individual randomisation.


Participants294 women attending 1 of 5 university hospital centres in Spain between December 2005 and January 2008.

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, mono-chorionic 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.


InterventionsIntervention:

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.

Total number randomised: n = 294.


OutcomesPreterm 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 (respiratory distress syndrome; pneumonia; early onset sepsis; seizures; graded III-IV intraventricular haemorrhage; stage II-II necrotising enterocolitis; and/or patent duct arteriosus). 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


Risk of bias

BiasAuthors' judgementSupport 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 riskCentral 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."

Incomplete outcome data (attrition bias)
All outcomes
Low riskIt was stated that an ITT analysis was carried out. There was very little loss to follow-up.

294 randomised at 20 weeks.

290 analysed – analysed as ITT.

Placebo group – n = 98, n = 10 discontinued study, n = 2 lost to follow-up, 96 analysed

200 mg progesterone group = n = 98, n = 11 discontinued study, n = 1 lost to follow-up, 97 analysed.

400 mg progesterone group = n = 98, n = 10 discontinued study, n = 1 lost to follow-up, 97 analysed.

Selective reporting (reporting bias)Unclear riskMost expected outcomes reported upon. However – individual outcome results for short-term and long-term neonatal morbidity were not reported, e.g. respiratory distress syndrome, periventricular leucomalacia.

Other biasUnclear riskBaseline characteristics similar. Management may have differed in the 5 participating centres although this was not clear. Groups appeared similar at baseline.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskWomen and staff were blinded. Medication packs were coded and contained identical appearing pessaries.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskIt was reported that all study personnel were blind to treatment allocation for the duration of the project.

Sharami 2010

MethodsDescribed as placebo-controlled double-blind RCT. Alzhara Hospital, Iran. Recruitment between 2007 and 2009.


ParticipantsInclusion criteria:173 randomised. Women with singleton pregnancies, gestational age 28-36 weeks admitted with threatened preterm labour successfully treated with tocolysis with intact membranes and less than 2cm cervical dilatation.

Exclusion criteria: patients with intrauterine infection, vaginal bleeding, pre-eclampsia, urinary tract infection, intrauterine growth retardation, hypertension and heart disease, dilatation ≥ 2 cm, fetal distress and fetal abnormalities.


InterventionsIntervention: n = 86 women. 200 mg vaginal progesterone daily until 36 weeks’ gestation.

Control/comparison intervention: n = 87 women. Placebo vaginal suppositories until 36 weeks’ gestation.

All patients (in both groups) received 12 mg betamethasone and antibiotic prophylaxis and advised to restrict physical activity.


OutcomesPrimary:

Time until delivery (latency time)

PTB before 34 and 37 weeks of gestation

Secondary:

Selected maternal and neonatal outcomes including nausea, headache, pre-eclampsia, PROM, chorioamnionitis, post-partum haemorrhage for maternal complications and birth weight, Apgar score, admission to the NICU, fetal death, neonatal death, RDS, sepsis, and intraventricular haemorrhage (IVH).


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskJust states, “Random block allocation method” – no other details.

Allocation concealment (selection bias)Unclear riskNo details reported.

Incomplete outcome data (attrition bias)
All outcomes
Low risk270 eligible, 97 women delivered within 48 hours, a total of 173 randomised.

Placebo group – n = 87, n = 4 lost to follow-up, 83 completed follow-up – 83 included in analysis.

Progesterone group = n = 86, n = 6 lost to follow-up, 80 completed follow-up – 80 included in analysis.

Selective reporting (reporting bias)Unclear riskNot clear. Several outcomes stated as secondary outcomes in the methods were not reported (this may have been because there were no cases but this was not stated, e.g. fetal death, intraventricular haemorrhage).

Other biasLow riskBaseline characteristics similar.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskBoth patients and physician were blinded to the type of suppositories.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDescribed as double-blind. Not clear if outcome assessment was blind.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Abbott 2012RCT embedded in a longitudinal study, but comparison of progesterone versus cerclage, so not relevant to this review.

Arikan 2011Acute treatment – being used as a tocolytic.

Berghella 2010Women were randomised to cerclage versus no cerclage – not randomised to 17P use or not – stratified at randomisation to intent to use or not use 17P.

Breart 1979Progesterone administration for prevention of miscarriage.

Brenner 1962Progesterone administration for prevention of miscarriage.

Chandiramani 2012Not clear that this is an RCT and also compares progesterone with cerclage, so not relevant to this review.

Corrado 2002Progesterone administered after amniocentesis for the prevention of miscarriage.

Hobel 1986Compares an oral progesterone agent with placebo but the only outcome reported is the rate of preterm birth as a percentage (not able to determine n = in either progesterone or placebo group). Other results reported as experimental group versus control (this allocation is not randomised but based on risk assessment at first and second antenatal visit).

Ionescu 2012Progesterone versus cerclage – so not relevant to this review.

Keeler 2009Comparison with McDonald cerclage, not placebo – topic of  another review.

Le Vine 1964Quasi-randomised trial.

Rust 2006Progesterone versus cerclage – so not relevant to this review.

Suvonnakote 1986Quasi-randomised trial - women were 'divided' into 2 groups (trial group and control group).

Turner 1966Progesterone administration for prevention of miscarriage.

Walch 2005Progesterone administration for prevention of miscarriage.

Yemini 1985Quasi-randomised trial.

 
Characteristics of ongoing studies [ordered by study ID]
Coomarasamy 2012

Trial name or titleProgesterone in recurrent miscarriages (PROMISE) study.

Methods

Participants1. Women with unexplained recurrent miscarriages (3 or more consecutive first trimester miscarriages).
2. Age 18-39 years at randomisation (likelihood of miscarriages due to chromosomal aberrations is higher in older women; such miscarriages are unlikely to be prevented by progesterone therapy).
3. Spontaneous conception (as confirmed by urinary pregnancy tests).
4. Willing and able to give informed consent.

InterventionsIntervention group: progesterone pessaries (400 mg twice daily) started soon as possible after a positive pregnancy test (and no later than 6 weeks' gestation) and continued to 12 weeks of gestation.

Control group: placebo.

Total duration of follow-up per participant: 42 weeks.

OutcomesPrimary outcome: live births beyond 24 weeks.

Secondary outcomes:

1. Gestation at delivery.
2. Clinical pregnancy at 6-8 weeks.
3. On-going pregnancy at 12 weeks (range 11-13 weeks).
4. Miscarriage rate.
5. Survival at 28 days of neonatal life.
6. Congenital abnormalities with specific examination for genital anomalies.
7. Adverse events.

Starting date01/05/2009, anticipated end date 0105/2012.

Contact informationDr Arri Coomarasamy: a.coomarasamy@bham.ac.uk

Notes

Creasy 2008

Trial name or titleThe effect of vaginal progesterone administration in the prevention of preterm birth in women with a short cervix.
NCT00615550.

Methods

ParticipantsWomen with a singleton gestation and a short cervical length by transvaginal ultrasound defined as 10-20 mm.

InterventionsProgesterone 8% vaginal gel, 1.125 g once daily, beginning at 19 0/7 to 23 6/7 weeks' gestation through 36 6/7 weeks' gestation.

Placebo vaginal gel, 1.125 g once daily, beginning at 19 0/7 to 23 6/7 weeks' gestation through 36 6/7 weeks' gestation.

OutcomesReduction in the frequency of preterm birth (less than or equal to 32 6/7 weeks' gestation.

Starting dateMarch 2008.

Contact informationJoseph R Parella: jparella@columbialabs.com

Notes

Crowther 2007

Trial name or titleProgesterone for the prevention of neonatal respiratory distress syndrome (The PROGRESS Study).
ISRCTN20269066.

Methods

ParticipantsWomen with a history of previous spontaneous preterm birth.

InterventionsDaily vaginal progesterone vs placebo.

OutcomesNeonatal lung disease.

Starting dateOctober 2005.

Contact informationprogress@adelaide.edu.au
caroline.crowther@adelaide.edu.au

Notes

Martinez 2007

Trial name or titleVaginal progesterone to prevent preterm delivery in women with preterm labour.
NCT00536003.

Methods

ParticipantsWomen presenting with symptoms and signs of preterm labour, and evidence of cervical change or positive fetal fibronectin testing.

InterventionsVaginal progesterone vs placebo.

OutcomesPreterm birth less than 37 weeks.

Starting dateJuly 2006.

Contact informationBegona Martinez de Tejada: begona.mdt@bluewin.ch

Notes

Nassar 2007

Trial name or titlePrevention of preterm delivery in twin pregnancies by 17 alpha hydroxyprogesterone caproate.
NCT00141908.

Methods

ParticipantsWomen with a twin pregnancy.

InterventionsWeekly IM 17OHP vs placebo.

OutcomesPreterm birth.

Starting dateMarch 2006.

Contact informationAnwar Nassar: an21@aub.edu.lb

Notes

Norman 2012

Trial name or titleTrial protocol OPPTIMUM - Does progesterone prophylaxis for the prevention of preterm labour improve outcome?

ISRCTN14568373.

MethodsDouble-blind randomised placebo controlled trial.

ParticipantsWomen with singleton pregnancy and at high risk of preterm labour.

InterventionsProphylactice vaginal natural progesterone, 200 mg daily from 22-34 weeks' gestation vs placebo.

OutcomesIncidence of preterm delivery (before 34 weeks); neonatal outcome (composite of death and major morbidity); childhood cognitive and neurosensory outcomes at 2 years of age.

Starting dateRecruitment began in 2009 and is scheduled to close in Spring 2013.

Contact informationJane E Norman.

Notes

Perlitz 2007

Trial name or titlePrevention of recurrent preterm delivery by a natural progesterone agent.
NCT00329316.

Methods

ParticipantsWomen with preterm labour in a prior pregnancy.

InterventionsDaily vaginal progesterone gel vs placebo.

OutcomesNot specified.

Starting dateNot yet recruiting.

Contact informationYuri Perlitz: yperlitz@poria.health.gov.il

Notes

Starkey 2008

Trial name or titleComparing intramuscular versus vaginal progesterone for prevention of preterm birth.
NCT00579553.

Methods

ParticipantsWomen with singleton pregnancies and history of prior spontaneous preterm birth.

InterventionsWeekly intramuscular injection of 17 alpha hydroxylprogesterone caproate (250 mg) or daily vaginal progesterone (100 mg).

OutcomesMaternal, fetal and neonatal outcomes.

Starting dateOctober 2006.

Contact informationChristy Zornes: christina-zornes@ouhsc.edu

Notes

Swaby 2007

Trial name or titlePilot randomised controlled trial of vaginal progesterone to prevent preterm birth in multiple pregnancy.

Methods

ParticipantsWomen with a multiple pregnancy.

InterventionsVaginal progesterone (90 mg) or placebo gel.

OutcomesDuration of pregnancy.

Starting date

Contact informationC Swaby. University of Calgary, 1403-29 Street, Calgary, Canada.

Notes

van Os 2011

Trial name or titlePreventing preterm birth with progesterone: costs and effects of screening low risk women with a singleton pregnancy for short cervical length, the Triple P study.

Netherlands Trial Register (NTR): NTR207.

MethodsCohort study with a randomised placebo-controlled trial embedded.

Multicentre, Dutch Obstetric Consortium.

ParticipantsInclusion criteria: women with low risk singleton pregnancies at 18-22 weeks' gestation with a short cervix <= 30 mm.

InterventionsVaginal progesterone 200 mg-capsules of micronised progesterone - vs placebo, taken between 22 and 34 weeks.

OutcomesPrimary outcome: composite poor neonatal outcome (death or severe morbidity): severe respiratory distress syndrome; bronchopulmonary dysplasia; periventricular leucomalacia > grade 1; intracerebral haemorrhage > grade II; necrotising enterocolitis > stage 1; proven sepsis and death before discharge from the nursery.

Secondary outcomes: time to delivery; preterm birth rate before 32, 34 and 37 weeks; days of admission in neonatal intensive care unit; maternal morbidity; maternal admission days for preterm labour; costs; growth, physical condition (close examination of genital tract), neurodevelopmental outcome of child at 24 month age; cost-effectiveness of screening for short cervical length.

Starting dateOctober 2011 - not clear from paper.

Contact informationPaper reporting study protocol - Melanie A van Os first author - correspondence email: m.vanos@vumc.nl

Notes

Wood 2007

Trial name or titleVaginal progesterone versus placebo in multiple pregnancy.
NCT00343265.

Methods

ParticipantsWomen with a multiple pregnancy.

InterventionsDaily vaginal progesterone gel vs placebo.

OutcomesPrimary: gestational age.

Starting dateJune 2006.

Contact informationStephen Wood: stephen.wood@calgaryhealthregion.ca

Notes

 
Comparison 1. Progesterone versus placebo/no treatment: previous history spontaneous preterm birth (singletons)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Perinatal mortality61453Risk Ratio (M-H, Fixed, 95% CI)0.50 [0.33, 0.75]

    1.1 Intramuscular
3553Risk Ratio (M-H, Fixed, 95% CI)0.41 [0.23, 0.73]

    1.2 Vaginal
2752Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.34, 1.29]

    1.3 Oral
1148Risk Ratio (M-H, Fixed, 95% CI)0.43 [0.12, 1.59]

 2 Preterm birth less than 34 weeks5602Risk Ratio (M-H, Random, 95% CI)0.31 [0.14, 0.69]

   2.1 Intramuscular
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    2.2 Vaginal
4454Risk Ratio (M-H, Random, 95% CI)0.21 [0.10, 0.44]

    2.3 Oral
1148Risk Ratio (M-H, Random, 95% CI)0.59 [0.39, 0.90]

 3 Preterm birth less than 37 weeks101750Risk Ratio (M-H, Random, 95% CI)0.55 [0.42, 0.74]

    3.1 Intramuscular
4652Risk Ratio (M-H, Random, 95% CI)0.62 [0.52, 0.75]

    3.2 Vaginal
51065Risk Ratio (M-H, Random, 95% CI)0.52 [0.29, 0.92]

    3.3 Oral
133Risk Ratio (M-H, Random, 95% CI)0.46 [0.19, 1.11]

 4 Threatened preterm labour2601Risk Ratio (M-H, Random, 95% CI)0.87 [0.47, 1.62]

    4.1 Intramuscular
1459Risk Ratio (M-H, Random, 95% CI)1.17 [0.73, 1.87]

    4.2 Vaginal
1142Risk Ratio (M-H, Random, 95% CI)0.62 [0.35, 1.11]

 5 Spontaneous vaginal delivery2200Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.97, 1.18]

    5.1 Vaginal
2200Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.97, 1.18]

 6 Caesarean section31170Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.81, 1.20]

    6.1 Intramuscular
1459Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.68, 1.30]

    6.2 Vaginal
2711Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.79, 1.30]

 7 Antenatal corticosteroids21070Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.73, 1.16]

    7.1 Intramuscular
1459Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.58, 1.30]

    7.2 Vaginal
1611Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.72, 1.26]

 8 Antenatal tocolysis41262Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.78, 1.35]

    8.1 Intramuscular
2503Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.73, 1.72]

    8.2 Vaginal
1611Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.70, 1.74]

    8.3 Oral
1148Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.42, 1.35]

 9 Infant birthweight less than 2500 g4692Risk Ratio (M-H, Random, 95% CI)0.58 [0.42, 0.79]

    9.1 Intramuscular
3551Risk Ratio (M-H, Random, 95% CI)0.63 [0.49, 0.81]

    9.2 Vaginal
1141Risk Ratio (M-H, Random, 95% CI)0.22 [0.07, 0.74]

 10 Respiratory distress syndrome31217Risk Ratio (M-H, Random, 95% CI)0.45 [0.17, 1.16]

    10.1 Intramuscular
1458Risk Ratio (M-H, Random, 95% CI)0.63 [0.38, 1.04]

    10.2 Vaginal
1611Risk Ratio (M-H, Random, 95% CI)0.92 [0.59, 1.43]

    10.3 Oral
1148Risk Ratio (M-H, Random, 95% CI)0.10 [0.03, 0.30]

 11 Use of assisted ventilation3633Risk Ratio (M-H, Random, 95% CI)0.40 [0.18, 0.90]

    11.1 Intramuscular
1459Risk Ratio (M-H, Random, 95% CI)0.59 [0.35, 1.01]

    11.2 Oral
133Risk Ratio (M-H, Random, 95% CI)0.11 [0.01, 1.92]

    11.3 Vaginal
1141Risk Ratio (M-H, Random, 95% CI)0.24 [0.07, 0.81]

 12 Intraventricular haemorrhage - all grades31211Risk Ratio (M-H, Random, 95% CI)0.70 [0.20, 2.46]

    12.1 Intramuscular
1459Risk Ratio (M-H, Random, 95% CI)0.25 [0.08, 0.82]

    12.2 Vaginal
2752Risk Ratio (M-H, Random, 95% CI)1.31 [0.46, 3.77]

 13 Intraventricular haemorrhage - grade III or IV21069Risk Ratio (M-H, Fixed, 95% CI)1.59 [0.21, 11.75]

    13.1 Intramuscular
1458Risk Ratio (M-H, Fixed, 95% CI)2.52 [0.12, 52.09]

    13.2 Vaginal
1611Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.06, 15.55]

 14 Periventricular leucomalacia1141Risk Ratio (M-H, Fixed, 95% CI)3.13 [0.13, 75.52]

    14.1 Vaginal
1141Risk Ratio (M-H, Fixed, 95% CI)3.13 [0.13, 75.52]

 15 Retinopathy of prematurity1458Risk Ratio (M-H, Fixed, 95% CI)0.50 [0.15, 1.69]

    15.1 Intramuscular
1458Risk Ratio (M-H, Fixed, 95% CI)0.50 [0.15, 1.69]

 16 Necrotising enterocolitis31170Risk Ratio (M-H, Fixed, 95% CI)0.30 [0.10, 0.89]

    16.1 Intramuscular
1459Risk Ratio (M-H, Fixed, 95% CI)0.06 [0.00, 1.03]

    16.2 Vaginal
2711Risk Ratio (M-H, Fixed, 95% CI)0.53 [0.15, 1.92]

 17 Neonatal sepsis3700Risk Ratio (M-H, Random, 95% CI)0.42 [0.08, 2.23]

    17.1 Intramuscular
1459Risk Ratio (M-H, Random, 95% CI)1.13 [0.35, 3.59]

    17.2 Vaginal
2241Risk Ratio (M-H, Random, 95% CI)0.13 [0.02, 1.01]

 18 Patent ductus arteriosus1459Risk Ratio (M-H, Fixed, 95% CI)0.44 [0.16, 1.18]

    18.1 Intramuscular
1459Risk Ratio (M-H, Fixed, 95% CI)0.44 [0.16, 1.18]

 19 Intrauterine fetal death41164Risk Ratio (M-H, Random, 95% CI)0.66 [0.26, 1.69]

    19.1 Intramuscular
3553Risk Ratio (M-H, Random, 95% CI)0.49 [0.14, 1.69]

    19.2 Vaginal
1611Risk Ratio (M-H, Random, 95% CI)1.22 [0.33, 4.51]

 20 Neonatal death61453Risk Ratio (M-H, Fixed, 95% CI)0.45 [0.27, 0.76]

    20.1 Intramuscular
3553Risk Ratio (M-H, Fixed, 95% CI)0.38 [0.17, 0.87]

    20.2 Vaginal
2752Risk Ratio (M-H, Fixed, 95% CI)0.53 [0.24, 1.18]

    20.3 Oral
1148Risk Ratio (M-H, Fixed, 95% CI)0.43 [0.12, 1.59]

 21 Developmental delay1274Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.36, 2.04]

    21.1 Intramuscular
1274Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.36, 2.04]

 22 Intellectual impairment1274Risk Ratio (M-H, Fixed, 95% CI)1.29 [0.05, 31.34]

    22.1 Intramuscular
1274Risk Ratio (M-H, Fixed, 95% CI)1.29 [0.05, 31.34]

 23 Motor Impairment1274Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.11, 3.76]

    23.1 Intramuscular
1274Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.11, 3.76]

 24 Visual Impairment1274Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.16, 4.57]

    24.1 Intramuscular
1274Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.16, 4.57]

 25 Hearing Impairment1274Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.09, 1.24]

    25.1 Intramuscular
1274Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.09, 1.24]

 26 Cerebral palsy1274Risk Ratio (M-H, Fixed, 95% CI)0.14 [0.01, 3.48]

    26.1 Intramuscular
1274Risk Ratio (M-H, Fixed, 95% CI)0.14 [0.01, 3.48]

 27 Learning difficulties1274Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.38, 1.92]

    27.1 Intramuscular
1274Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.38, 1.92]

 28 Height less than 5th centile1270Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.23, 2.49]

    28.1 Intramuscular
1270Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.23, 2.49]

 29 Weight less than 5th centile1270Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.30, 2.05]

    29.1 Intramuscular
1270Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.30, 2.05]

 30 Adverse drug reaction1148Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.24, 2.15]

    30.1 Oral
1148Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.24, 2.15]

 31 Pregnancy prolongation (weeks)1148Mean Difference (IV, Fixed, 95% CI)4.47 [2.15, 6.79]

    31.1 Oral
1148Mean Difference (IV, Fixed, 95% CI)4.47 [2.15, 6.79]

 32 Apgar score < 7150Risk Ratio (M-H, Fixed, 95% CI)0.55 [0.24, 1.25]

    32.1 Intramuscular
150Risk Ratio (M-H, Fixed, 95% CI)0.55 [0.24, 1.25]

 33 Admission to neonatal intensive care unit3389Risk Ratio (M-H, Fixed, 95% CI)0.24 [0.14, 0.40]

    33.1 Oral
1148Risk Ratio (M-H, Fixed, 95% CI)0.26 [0.14, 0.49]

    33.2 Vaginal
2241Risk Ratio (M-H, Fixed, 95% CI)0.21 [0.09, 0.49]

 34 Neonatal length of hospital stay (days)133Mean Difference (IV, Fixed, 95% CI)-1.0 [-7.67, 5.67]

    34.1 Oral
133Mean Difference (IV, Fixed, 95% CI)-1.0 [-7.67, 5.67]

 35 Infant weight at 6 months follow-up (g)1436Mean Difference (IV, Fixed, 95% CI)29.0 [-209.62, 267.62]

    35.1 Vaginal
1436Mean Difference (IV, Fixed, 95% CI)29.0 [-209.62, 267.62]

 36 Infant weight at 12 months follow-up (g)1379Mean Difference (IV, Fixed, 95% CI)-88.0 [-381.48, 205.48]

    36.1 Vaginal
1379Mean Difference (IV, Fixed, 95% CI)-88.0 [-381.48, 205.48]

 37 Infant weight at 24 months follow-up (g)1287Mean Difference (IV, Fixed, 95% CI)-40.0 [-482.41, 402.41]

    37.1 Vaginal
1287Mean Difference (IV, Fixed, 95% CI)-40.0 [-482.41, 402.41]

 38 Infant length at 6 months follow-up (cm)1430Mean Difference (IV, Fixed, 95% CI)0.10 [-0.59, 0.79]

    38.1 Vaginal
1430Mean Difference (IV, Fixed, 95% CI)0.10 [-0.59, 0.79]

 39 Infant length at 12 months follow-up (cm)1376Mean Difference (IV, Fixed, 95% CI)-0.10 [-0.80, 0.60]

    39.1 Vaginal
1376Mean Difference (IV, Fixed, 95% CI)-0.10 [-0.80, 0.60]

 40 Infant length at 24 months follow-up (cm)1284Mean Difference (IV, Fixed, 95% CI)-0.20 [-1.23, 0.83]

    40.1 Vaginal
1284Mean Difference (IV, Fixed, 95% CI)-0.20 [-1.23, 0.83]

 41 Infant head circumference at 6 months follow-up (cm)1426Mean Difference (IV, Fixed, 95% CI)0.10 [-0.23, 0.43]

    41.1 Vaginal
1426Mean Difference (IV, Fixed, 95% CI)0.10 [-0.23, 0.43]

 42 Infant head circumference at 12 months follow-up (cm)1372Mean Difference (IV, Fixed, 95% CI)0.10 [-0.26, 0.46]

    42.1 Vaginal
1372Mean Difference (IV, Fixed, 95% CI)0.10 [-0.26, 0.46]

 43 Infant head circumference at 24 months follow-up (cm)1264Mean Difference (IV, Fixed, 95% CI)0.20 [-0.21, 0.61]

    43.1 Vaginal
1264Mean Difference (IV, Fixed, 95% CI)0.20 [-0.21, 0.61]

 
Comparison 2. Progesterone versus placebo/no treatment: previous history spontaneous preterm birth, by timing of commencement (< 20 wk v > 20 wk, singletons)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Preterm birth less than 37 weeks61360Risk Ratio (M-H, Random, 95% CI)0.63 [0.44, 0.89]

    1.1 Therapy commences before 20 weeks
41147Risk Ratio (M-H, Random, 95% CI)0.69 [0.46, 1.04]

    1.2 Therapy commences after 20 weeks
2213Risk Ratio (M-H, Random, 95% CI)0.49 [0.30, 0.78]

 
Comparison 3. Progesterone versus placebo/no treatment: previous history spontaneous preterm birth by cumulative weekly dose (< 500 mg v >= 500 mg, singletons)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Perinatal death51403Risk Ratio (M-H, Random, 95% CI)0.58 [0.35, 0.97]

    1.1 Dose < 500 mg per week
2503Risk Ratio (M-H, Random, 95% CI)0.38 [0.07, 2.18]

    1.2 Dose >= 500 mg per week
3900Risk Ratio (M-H, Random, 95% CI)0.59 [0.29, 1.21]

 2 Preterm birth less than 37 weeks91700Risk Ratio (M-H, Random, 95% CI)0.54 [0.40, 0.74]

    2.1 Dose < 500 mg per week
3602Risk Ratio (M-H, Random, 95% CI)0.59 [0.44, 0.80]

    2.2 Dose >= 500 mg per week
61098Risk Ratio (M-H, Random, 95% CI)0.51 [0.31, 0.85]

 3 Threatened preterm labour2601Risk Ratio (M-H, Random, 95% CI)0.87 [0.47, 1.62]

    3.1 Dose < 500 mg per week
1459Risk Ratio (M-H, Random, 95% CI)1.17 [0.73, 1.87]

    3.2 Dose >= 500 mg per week
1142Risk Ratio (M-H, Random, 95% CI)0.62 [0.35, 1.11]

 4 Caesarean section31170Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.72, 1.13]

    4.1 Dose < 500 mg per week
1459Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.58, 1.30]

    4.2 Dose >= 500 mg per week
2711Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.70, 1.21]

 5 Antenatal corticosteroids21070Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.73, 1.16]

    5.1 Dose < 500 mg per week
1459Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.58, 1.30]

    5.2 Dose >= 500 mg per week
1611Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.72, 1.26]

 6 Need for tocolysis31114Risk Ratio (M-H, Fixed, 95% CI)1.11 [0.81, 1.52]

    6.1 Dose < 500 mg per week
2503Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.73, 1.72]

    6.2 Dose >= 500 mg per week
1611Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.70, 1.74]

 7 Respiratory distress syndrome41359Risk Ratio (M-H, Random, 95% CI)0.38 [0.16, 0.89]

    7.1 Dose < 500 mg per week
1459Risk Ratio (M-H, Random, 95% CI)0.63 [0.38, 1.05]

    7.2 Dose >= 500 mg per week
3900Risk Ratio (M-H, Random, 95% CI)0.29 [0.07, 1.23]

 8 Intraventricular haemorrhage - all grades31211Risk Ratio (M-H, Random, 95% CI)0.70 [0.20, 2.46]

    8.1 Dose < 500 mg per week
1459Risk Ratio (M-H, Random, 95% CI)0.25 [0.08, 0.82]

    8.2 Dose >= 500 mg per week
2752Risk Ratio (M-H, Random, 95% CI)1.31 [0.46, 3.77]

 9 Intraventricular haemorrhage - grade III or IV21070Risk Ratio (M-H, Fixed, 95% CI)1.59 [0.21, 11.73]

    9.1 Dose < 500 mg per week
1459Risk Ratio (M-H, Fixed, 95% CI)2.51 [0.12, 51.92]

    9.2 Dose >= 500 mg per week
1611Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.06, 15.55]

 10 Necrotising enterocolitis31170Risk Ratio (M-H, Random, 95% CI)0.35 [0.10, 1.25]

    10.1 Dose < 500 mg per week
1459Risk Ratio (M-H, Random, 95% CI)0.06 [0.00, 1.03]

    10.2 Dose >= 500 mg per week
2711Risk Ratio (M-H, Random, 95% CI)0.53 [0.15, 1.95]

 11 Intrauterine fetal death31114Risk Ratio (M-H, Random, 95% CI)0.97 [0.32, 2.91]

    11.1 Dose < 500 mg per week
2503Risk Ratio (M-H, Random, 95% CI)0.58 [0.05, 6.51]

    11.2 Dose >= 500 mg per week
1611Risk Ratio (M-H, Random, 95% CI)1.22 [0.33, 4.51]

 12 Neonatal death51403Risk Ratio (M-H, Fixed, 95% CI)0.47 [0.28, 0.81]

    12.1 Dose < 500 mg per week
2503Risk Ratio (M-H, Fixed, 95% CI)0.42 [0.17, 1.03]

    12.2 Dose >= 500 mg per week
3900Risk Ratio (M-H, Fixed, 95% CI)0.50 [0.26, 0.99]

 
Comparison 4. Progesterone versus placebo: ultrasound identified short cervix, singletons

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Perinatal death31389Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.42, 1.29]

    1.1 Vaginal
2732Risk Ratio (M-H, Fixed, 95% CI)0.56 [0.27, 1.17]

    1.2 Intramuscular
1657Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.46, 2.72]

 2 Preterm birth less than 34 weeks2438Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.45, 0.90]

    2.1 Vaginal
1250Risk Ratio (M-H, Fixed, 95% CI)0.58 [0.38, 0.87]

    2.2 Intramuscular
1188Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.43, 1.46]

 3 Preterm labour1188Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.63, 1.74]

    3.1 Intramuscular
1188Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.63, 1.74]

 4 Prelabour spontaneous rupture of membranes2845Risk Ratio (M-H, Random, 95% CI)1.33 [0.68, 2.62]

    4.1 Intramuscular
2845Risk Ratio (M-H, Random, 95% CI)1.33 [0.68, 2.62]

 5 Side effects (any)2842Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.92, 1.13]

    5.1 Intramuscular
2842Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.92, 1.13]

 6 Side effects (injection site)1654Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.93, 1.17]

    6.1 Intramuscular
1654Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.93, 1.17]

 7 Side effects (urticaria)1654Risk Ratio (M-H, Fixed, 95% CI)5.03 [1.11, 22.78]

    7.1 Intramuscular
1654Risk Ratio (M-H, Fixed, 95% CI)5.03 [1.11, 22.78]

 8 Side effects (nausea)1654Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.27, 1.83]

    8.1 Intramuscular
1654Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.27, 1.83]

 9 Pregnancy prolongation (days)1188Mean Difference (IV, Fixed, 95% CI)-2.0 [-10.29, 6.29]

    9.1 Intramuscular
1188Mean Difference (IV, Fixed, 95% CI)-2.0 [-10.29, 6.29]

 10 Caesarean section2838Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.79, 1.40]

    10.1 Intramuscular
2838Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.79, 1.40]

 11 Antenatal tocolysis2828Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.60, 1.11]

    11.1 Intramuscular
2828Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.60, 1.11]

 12 Preterm birth less than 37 weeks31303Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.82, 1.15]

    12.1 Vaginal
1458Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.68, 1.16]

    12.2 Intramuscular
2845Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.83, 1.28]

 13 Preterm birth less than 28 weeks21115Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.37, 0.93]

    13.1 Vaginal
1458Risk Ratio (M-H, Fixed, 95% CI)0.50 [0.25, 0.97]

    13.2 Intramuscular
1657Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.36, 1.30]

 14 Infant birthweight less than 2500 g31379Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.78, 1.09]

    14.1 Vaginal
2728Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.73, 1.09]

    14.2 Intramuscular
1651Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.73, 1.30]

 15 Respiratory distress syndrome41556Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.48, 1.00]

    15.1 Vaginal
2732Risk Ratio (M-H, Fixed, 95% CI)0.49 [0.29, 0.85]

    15.2 Intramuscular
2824Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.58, 1.58]

 16 Apgar score < 71651Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.41, 1.55]

    16.1 Intramuscular
1651Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.41, 1.55]

 17 Need for assisted ventilation1274Risk Ratio (M-H, Fixed, 95% CI)0.65 [0.36, 1.16]

    17.1 Vaginal
1274Risk Ratio (M-H, Fixed, 95% CI)0.65 [0.36, 1.16]

 18 Intraventricular haemorrhage - all grades1274Risk Ratio (M-H, Fixed, 95% CI)0.51 [0.05, 5.53]

    18.1 Vaginal
1274Risk Ratio (M-H, Fixed, 95% CI)0.51 [0.05, 5.53]

 19 Intraventricular haemorrhage - grades III or IV21100Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.17, 5.60]

    19.1 Vaginal
1458Risk Ratio (M-H, Fixed, 95% CI)0.32 [0.01, 7.73]

    19.2 Intramuscular
1642Risk Ratio (M-H, Fixed, 95% CI)2.01 [0.18, 22.08]

 20 Periventricular leucomalacia31282Risk Ratio (M-H, Fixed, 95% CI)1.78 [0.38, 8.24]

    20.1 Vaginal
1458Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    20.2 Intramuscular
2824Risk Ratio (M-H, Fixed, 95% CI)1.78 [0.38, 8.24]

 21 Retinopathy of prematurity2916Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.23, 4.42]

    21.1 Vaginal
1274Risk Ratio (M-H, Fixed, 95% CI)5.07 [0.25, 104.70]

    21.2 Intramuscular
1642Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.04, 3.21]

 22 Necrotising enterocolitis31374Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.27, 1.78]

    22.1 Vaginal
2732Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.30, 3.11]

    22.2 Intramuscular
1642Risk Ratio (M-H, Fixed, 95% CI)0.40 [0.08, 2.06]

 23 Neonatal sepsis31374Risk Ratio (M-H, Random, 95% CI)0.46 [0.18, 1.20]

    23.1 Vaginal
2732Risk Ratio (M-H, Random, 95% CI)0.58 [0.15, 2.25]

    23.2 Intramuscular
1642Risk Ratio (M-H, Random, 95% CI)0.27 [0.08, 0.97]

 24 Intrauterine fetal death31389Risk Ratio (M-H, Fixed, 95% CI)1.21 [0.48, 3.04]

    24.1 Vaginal
2732Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.28, 2.42]

    24.2 Intramuscular
1657Risk Ratio (M-H, Fixed, 95% CI)4.04 [0.45, 35.92]

 25 Neonatal death41571Risk Ratio (M-H, Fixed, 95% CI)0.55 [0.26, 1.13]

    25.1 Vaginal
2732Risk Ratio (M-H, Fixed, 95% CI)0.41 [0.15, 1.15]

    25.2 Intramuscular
2839Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.27, 2.16]

 26 Admission to neonatal intensive care unit2834Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.79, 1.35]

    26.1 Intramuscular
2834Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.79, 1.35]

 
Comparison 5. Progesterone versus placebo: ultrasound identified short cervix, singletons by cumulative weekly dose (<500 mg v >=500 mg)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Periventricular leucomalacia2824Risk Ratio (M-H, Random, 95% CI)1.49 [0.13, 16.87]

    1.1 Dose < 500 mg per week
1642Risk Ratio (M-H, Random, 95% CI)4.03 [0.45, 35.81]

    1.2 Dose >= 500 mg per week
1182Risk Ratio (M-H, Random, 95% CI)0.32 [0.01, 7.73]

 2 Admission to neonatal intensive care unit2834Risk Ratio (M-H, Random, 95% CI)1.09 [0.72, 1.65]

    2.1 Dose < 500 mg per week
1651Risk Ratio (M-H, Random, 95% CI)0.93 [0.69, 1.27]

    2.2 Dose >= 500 mg per week
1183Risk Ratio (M-H, Random, 95% CI)1.45 [0.83, 2.55]

 
Comparison 6. Progesterone versus placebo: multiple pregnancy

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Perinatal death74136Risk Ratio (M-H, Random, 95% CI)0.93 [0.45, 1.94]

    1.1 Intramuscular
42228Risk Ratio (M-H, Random, 95% CI)1.06 [0.30, 3.71]

    1.2 Vaginal
31908Risk Ratio (M-H, Random, 95% CI)0.75 [0.24, 2.41]

 2 Preterm birth less than 34 weeks61758Risk Ratio (M-H, Random, 95% CI)0.97 [0.74, 1.27]

    2.1 Vaginal
51520Risk Ratio (M-H, Random, 95% CI)0.92 [0.69, 1.23]

    2.2 Intramuscular
1238Risk Ratio (M-H, Random, 95% CI)1.37 [0.73, 2.59]

 3 Preterm PROM3995Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.74, 1.70]

    3.1 Intramuscular
2802Risk Ratio (M-H, Fixed, 95% CI)1.11 [0.72, 1.71]

    3.2 Vaginal
1193Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.30, 5.74]

 4 Adverse drug reaction21162Risk Ratio (M-H, Random, 95% CI)0.88 [0.64, 1.19]

    4.1 Intramuscular
1668Risk Ratio (M-H, Random, 95% CI)0.74 [0.54, 1.01]

    4.2 Vaginal
1494Risk Ratio (M-H, Random, 95% CI)0.98 [0.89, 1.08]

 5 Caesarean section83136Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.91, 1.02]

    5.1 Intramuscular
51773Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.94, 1.09]

    5.2 Vaginal
31363Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.84, 0.98]

 6 Spontaneous birth21168Risk Ratio (M-H, Random, 95% CI)1.22 [0.62, 2.38]

    6.1 Intramuscular
1668Risk Ratio (M-H, Random, 95% CI)0.88 [0.75, 1.04]

    6.2 Vaginal
1500Risk Ratio (M-H, Random, 95% CI)1.74 [1.21, 2.49]

 7 Assisted birth21168Risk Ratio (M-H, Random, 95% CI)1.00 [0.57, 1.76]

    7.1 Intramuscular
1668Risk Ratio (M-H, Random, 95% CI)1.31 [0.86, 1.99]

    7.2 Vaginal
1500Risk Ratio (M-H, Random, 95% CI)0.73 [0.44, 1.24]

 8 Satisfaction with therapy1494Mean Difference (IV, Fixed, 95% CI)0.0 [-0.35, 0.35]

    8.1 Vaginal
1494Mean Difference (IV, Fixed, 95% CI)0.0 [-0.35, 0.35]

 9 Antenatal tocolysis72642Risk Ratio (M-H, Random, 95% CI)0.94 [0.80, 1.10]

    9.1 Intramuscular
51775Risk Ratio (M-H, Random, 95% CI)0.98 [0.82, 1.17]

    9.2 Vaginal
2867Risk Ratio (M-H, Random, 95% CI)0.75 [0.55, 1.03]

 10 Antenatal corticosteroids2847Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.77, 1.26]

    10.1 Intramuscular
1654Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.70, 1.17]

    10.2 Vaginal
1193Risk Ratio (M-H, Fixed, 95% CI)1.68 [0.81, 3.49]

 11 Preterm birth less than 37 weeks82674Risk Ratio (M-H, Random, 95% CI)1.04 [0.95, 1.14]

    11.1 Intramuscular
41638Risk Ratio (M-H, Random, 95% CI)1.09 [0.96, 1.22]

    11.2 Vaginal
41036Risk Ratio (M-H, Random, 95% CI)0.98 [0.85, 1.13]

 12 Preterm birth less than 28 weeks51855Risk Ratio (M-H, Fixed, 95% CI)1.21 [0.75, 1.95]

    12.1 Intramuscular
3987Risk Ratio (M-H, Fixed, 95% CI)1.19 [0.68, 2.07]

    12.2 Vaginal
2868Risk Ratio (M-H, Fixed, 95% CI)1.27 [0.51, 3.19]

 13 Infant birthweight less than 2500 g75404Risk Ratio (M-H, Random, 95% CI)0.95 [0.88, 1.03]

    13.1 Intramuscular
43502Risk Ratio (M-H, Random, 95% CI)1.02 [0.91, 1.14]

    13.2 Vaginal
31902Risk Ratio (M-H, Random, 95% CI)0.86 [0.80, 0.94]

 14 Apgar score < 7 at 5 minutes43451Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.66, 1.21]

    14.1 Intramuscular
21750Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.70, 1.38]

    14.2 Vaginal
21701Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.28, 1.23]

 15 Respiratory distress syndrome65065Risk Ratio (M-H, Random, 95% CI)1.13 [0.94, 1.35]

    15.1 Intramuscular
53732Risk Ratio (M-H, Random, 95% CI)1.13 [0.91, 1.42]

    15.2 Vaginal
11333Risk Ratio (M-H, Random, 95% CI)1.08 [0.79, 1.48]

 16 Use of assisted ventilation43392Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.78, 1.16]

    16.1 Intramuscular
21675Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.80, 1.22]

    16.2 Vaginal
21717Risk Ratio (M-H, Fixed, 95% CI)0.78 [0.45, 1.36]

 17 Intraventricular haemorrhage - grades III or IV42368Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.45, 1.92]

    17.1 Intramuscular
42368Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.45, 1.92]

 18 Intraventricular haemorrhage - all grades22688Risk Ratio (M-H, Fixed, 95% CI)1.77 [0.75, 4.21]

    18.1 Intramuscular
11355Risk Ratio (M-H, Fixed, 95% CI)1.98 [0.36, 10.77]

    18.2 Vaginal
11333Risk Ratio (M-H, Fixed, 95% CI)1.70 [0.62, 4.66]

 19 Periventricular leucomalacia31091Risk Ratio (M-H, Fixed, 95% CI)0.37 [0.05, 3.02]

    19.1 Intramuscular
31091Risk Ratio (M-H, Fixed, 95% CI)0.37 [0.05, 3.02]

 20 Retinopathy of prematurity53668Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.32, 1.91]

    20.1 Intramuscular
42335Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.20, 2.06]

    20.2 Vaginal
11333Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.26, 4.07]

 21 Chronic lung disease2681Risk Ratio (M-H, Random, 95% CI)1.91 [0.13, 27.80]

    21.1 Intramuscular
2681Risk Ratio (M-H, Random, 95% CI)1.91 [0.13, 27.80]

 22 Necrotising enterocolitis65059Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.50, 1.75]

    22.1 Intramuscular
53726Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.52, 1.88]

    22.2 Vaginal
11333Risk Ratio (M-H, Fixed, 95% CI)0.51 [0.05, 5.63]

 23 Neonatal sepsis65065Risk Ratio (M-H, Fixed, 95% CI)1.20 [0.89, 1.62]

    23.1 Intramuscular
53732Risk Ratio (M-H, Fixed, 95% CI)1.22 [0.87, 1.72]

    23.2 Vaginal
11333Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.61, 2.13]

 24 Fetal death64788Risk Ratio (M-H, Fixed, 95% CI)1.22 [0.71, 2.09]

    24.1 Intramuscular
32074Risk Ratio (M-H, Fixed, 95% CI)1.55 [0.77, 3.12]

    24.2 Vaginal
32714Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.35, 1.95]

 25 Neonatal death75170Risk Ratio (M-H, Random, 95% CI)1.01 [0.48, 2.10]

    25.1 Intramuscular
42456Risk Ratio (M-H, Random, 95% CI)0.81 [0.31, 2.10]

    25.2 Vaginal
32714Risk Ratio (M-H, Random, 95% CI)1.34 [0.36, 4.95]

 26 Admission to NICU54251Risk Ratio (M-H, Random, 95% CI)0.94 [0.76, 1.18]

    26.1 Vaginal
42896Risk Ratio (M-H, Random, 95% CI)0.87 [0.71, 1.07]

    26.2 Intramuscular
11355Risk Ratio (M-H, Random, 95% CI)1.31 [1.05, 1.62]

 27 Perinatal death74133Risk Ratio (M-H, Random, 95% CI)1.13 [0.61, 2.08]

    27.1 Intramuscular
42228Risk Ratio (M-H, Random, 95% CI)1.06 [0.30, 3.71]

    27.2 Vaginal
31905Risk Ratio (M-H, Random, 95% CI)1.25 [0.67, 2.35]

 28 Preterm birth less than 34 weeks61758Risk Ratio (M-H, Random, 95% CI)0.94 [0.71, 1.24]

    28.1 Vaginal
51520Risk Ratio (M-H, Random, 95% CI)0.88 [0.65, 1.19]

    28.2 Intramuscular
1238Risk Ratio (M-H, Random, 95% CI)1.37 [0.73, 2.59]

 29 Preterm PROM3995Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.69, 1.60]

    29.1 Intramuscular
2802Risk Ratio (M-H, Fixed, 95% CI)1.11 [0.72, 1.71]

    29.2 Vaginal
1193Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.03, 3.12]

 30 Caesarean section83136Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.91, 1.01]

    30.1 Intramuscular
51773Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.94, 1.09]

    30.2 Vaginal
31363Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.84, 0.98]

 31 Antenatal tocolysis72642Risk Ratio (M-H, Random, 95% CI)0.94 [0.80, 1.10]

    31.1 Intramuscular
51775Risk Ratio (M-H, Random, 95% CI)0.98 [0.82, 1.17]

    31.2 Vaginal
2867Risk Ratio (M-H, Random, 95% CI)0.77 [0.56, 1.05]

 32 Antenatal corticosteroids2847Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.76, 1.24]

    32.1 Intramuscular
1654Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.70, 1.17]

    32.2 Vaginal
1193Risk Ratio (M-H, Fixed, 95% CI)1.58 [0.76, 3.31]

 33 Preterm birth less than 37 weeks82674Risk Ratio (M-H, Random, 95% CI)1.04 [0.95, 1.13]

    33.1 Intramuscular
41638Risk Ratio (M-H, Random, 95% CI)1.09 [0.96, 1.22]

    33.2 Vaginal
41036Risk Ratio (M-H, Random, 95% CI)0.97 [0.84, 1.11]

 34 Preterm birth less than 28 weeks51855Risk Ratio (M-H, Fixed, 95% CI)1.28 [0.80, 2.04]

    34.1 Intramuscular
3987Risk Ratio (M-H, Fixed, 95% CI)1.19 [0.68, 2.07]

    34.2 Vaginal
2868Risk Ratio (M-H, Fixed, 95% CI)1.52 [0.63, 3.69]

 35 Infant birthweight less than 2500 g75401Risk Ratio (M-H, Random, 95% CI)0.96 [0.89, 1.04]

    35.1 Intramuscular
43502Risk Ratio (M-H, Random, 95% CI)1.02 [0.91, 1.14]

    35.2 Vaginal
31899Risk Ratio (M-H, Random, 95% CI)0.89 [0.82, 0.96]

 36 Apgar score < 7 at 5 minutes43448Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.70, 1.27]

    36.1 Intramuscular
21750Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.70, 1.38]

    36.2 Vaginal
21698Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.41, 1.58]

 37 Use of assisted ventilation43389Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.81, 1.19]

    37.1 Intramuscular
21675Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.80, 1.22]

    37.2 Vaginal
21714Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.55, 1.59]

 38 Fetal death64785Risk Ratio (M-H, Fixed, 95% CI)1.35 [0.79, 2.29]

    38.1 Intramuscular
32074Risk Ratio (M-H, Fixed, 95% CI)1.55 [0.77, 3.12]

    38.2 Vaginal
32711Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.49, 2.48]

 39 Neonatal death75167Risk Ratio (M-H, Random, 95% CI)1.17 [0.62, 2.21]

    39.1 Intramuscular
42456Risk Ratio (M-H, Random, 95% CI)0.81 [0.31, 2.10]

    39.2 Vaginal
32711Risk Ratio (M-H, Random, 95% CI)1.77 [0.84, 3.72]

 40 Admission to NICU54248Risk Ratio (M-H, Random, 95% CI)0.93 [0.75, 1.17]

    40.1 Vaginal
42893Risk Ratio (M-H, Random, 95% CI)0.86 [0.70, 1.07]

    40.2 Intramuscular
11355Risk Ratio (M-H, Random, 95% CI)1.31 [1.05, 1.62]

 41 Sensitivity analysis for perinatal death (assuming total non-independence)72068Risk Ratio (M-H, Random, 95% CI)0.84 [0.43, 1.65]

    41.1 Intramuscular
41114Risk Ratio (M-H, Random, 95% CI)0.99 [0.29, 3.36]

    41.2 Vaginal
3954Risk Ratio (M-H, Random, 95% CI)0.77 [0.28, 2.07]

 42 Sensitivity analysis for perinatal death (assuming 1% non-independence)74091Risk Ratio (M-H, Random, 95% CI)0.91 [0.44, 1.90]

    42.1 Intramuscular
42203Risk Ratio (M-H, Random, 95% CI)1.03 [0.29, 3.58]

    42.2 Vaginal
31888Risk Ratio (M-H, Random, 95% CI)0.75 [0.24, 2.41]

 
Comparison 7. Progesterone versus placebo: multiple pregnancy, by timing of commencement (< 20 wk v > 20 wk)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Preterm birth < 37 weeks41467Risk Ratio (M-H, Random, 95% CI)0.99 [0.82, 1.20]

    1.1 Supplementation commenced prior to 20 weeks' gestation
21323Risk Ratio (M-H, Random, 95% CI)1.04 [0.92, 1.17]

    1.2 Supplementation commenced after 20 weeks' gestation
2144Risk Ratio (M-H, Random, 95% CI)0.98 [0.38, 2.54]

 2 Neonatal death32738Risk Ratio (M-H, Random, 95% CI)0.95 [0.47, 1.93]

    2.1 Supplementation commenced prior to 20 weeks' gestation
21750Risk Ratio (M-H, Random, 95% CI)0.92 [0.29, 2.91]

    2.2 Supplementation commenced after 20 weeks' gestation
1988Risk Ratio (M-H, Random, 95% CI)1.33 [0.47, 3.81]

 3 Admission to NICU22343Risk Ratio (M-H, Random, 95% CI)1.16 [0.95, 1.43]

    3.1 Supplementation commenced prior to 20 weeks' gestation
1988Risk Ratio (M-H, Random, 95% CI)1.06 [0.88, 1.26]

    3.2 Supplementation commenced after 20 weeks' gestation
11355Risk Ratio (M-H, Random, 95% CI)1.31 [1.05, 1.62]

 
Comparison 8. Progesterone versus placebo: multiple pregnancy by cumulative weekly dose (< 500 mg v >= 500 mg)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Perinatal death74136Risk Ratio (M-H, Random, 95% CI)0.93 [0.45, 1.94]

    1.1 Dose < 500 mg per week
42228Risk Ratio (M-H, Random, 95% CI)1.06 [0.30, 3.71]

    1.2 Dose >= 500 mg per week
31908Risk Ratio (M-H, Random, 95% CI)0.75 [0.24, 2.41]

 2 Preterm birth less than 34 weeks61758Risk Ratio (M-H, Random, 95% CI)0.97 [0.74, 1.27]

    2.1 Dose < 500 mg per week
1238Risk Ratio (M-H, Random, 95% CI)1.37 [0.73, 2.59]

    2.2 Dose > 500 mg per week
51520Risk Ratio (M-H, Random, 95% CI)0.92 [0.69, 1.23]

 3 Antenatal tocolysis72642Risk Ratio (M-H, Random, 95% CI)0.94 [0.80, 1.10]

    3.1 Dose < 500 mg per week
51775Risk Ratio (M-H, Random, 95% CI)0.98 [0.82, 1.17]

    3.2 Dose >= 500 mg per week
2867Risk Ratio (M-H, Random, 95% CI)0.75 [0.55, 1.03]

 4 Preterm birth less than 37 weeks83489Risk Ratio (M-H, Random, 95% CI)0.97 [0.88, 1.06]

    4.1 Dose < 500 mg per week
62380Risk Ratio (M-H, Random, 95% CI)1.01 [0.88, 1.15]

    4.2 Dose >= 500 mg per week
41109Risk Ratio (M-H, Random, 95% CI)0.90 [0.80, 1.01]

 5 Infant birthweight less than 2500 g75404Risk Ratio (M-H, Random, 95% CI)0.95 [0.88, 1.03]

    5.1 Dose < 500 mg per week
43502Risk Ratio (M-H, Random, 95% CI)1.02 [0.91, 1.14]

    5.2 Dose >= 500 mg per week
31902Risk Ratio (M-H, Random, 95% CI)0.86 [0.80, 0.94]

 6 Respiratory distress syndrome65065Risk Ratio (M-H, Random, 95% CI)1.13 [0.94, 1.35]

    6.1 Dose < 500 mg per week
53732Risk Ratio (M-H, Random, 95% CI)1.13 [0.91, 1.42]

    6.2 Dose >= 500 mg per week
11333Risk Ratio (M-H, Random, 95% CI)1.08 [0.79, 1.48]

 7 Fetal death64788Risk Ratio (M-H, Random, 95% CI)1.07 [0.51, 2.23]

    7.1 Dose < 500 mg per week
32074Risk Ratio (M-H, Random, 95% CI)2.52 [0.19, 33.68]

    7.2 Dose >= 500 mg per week
32714Risk Ratio (M-H, Random, 95% CI)0.88 [0.36, 2.16]

 8 Admission to NICU54251Risk Ratio (M-H, Random, 95% CI)0.94 [0.76, 1.18]

    8.1 Dose < 500 mg per week
11355Risk Ratio (M-H, Random, 95% CI)1.31 [1.05, 1.62]

    8.2 Dose >= 500 mg per week
42896Risk Ratio (M-H, Random, 95% CI)0.87 [0.71, 1.07]

 
Comparison 9. Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Perinatal death112Risk Ratio (M-H, Random, 95% CI)2.0 [0.16, 24.33]

    1.1 Intramuscular
112Risk Ratio (M-H, Random, 95% CI)2.0 [0.16, 24.33]

 2 Preterm birth less than 34 weeks' gestation2175Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.55, 1.65]

    2.1 Intramuscular
112Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.72, 1.39]

    2.2 Vaginal
1163Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.37, 2.27]

 3 Pregnancy prolongation (days)2232Mean Difference (IV, Random, 95% CI)1.88 [-8.42, 12.17]

    3.1 Intramuscular
169Mean Difference (IV, Random, 95% CI)-3.30 [-7.41, 0.81]

    3.2 Vaginal
1163Mean Difference (IV, Random, 95% CI)7.21 [2.39, 12.03]

 4 Pregnancy prolongation - less than 1 week112Risk Ratio (M-H, Fixed, 95% CI)0.4 [0.07, 2.37]

    4.1 Intramuscular
112Risk Ratio (M-H, Fixed, 95% CI)0.4 [0.07, 2.37]

 5 Pregnancy prolongation - 1.0 to 1.9 weeks112Risk Ratio (M-H, Fixed, 95% CI)2.0 [0.16, 24.33]

    5.1 Intramuscular
112Risk Ratio (M-H, Fixed, 95% CI)2.0 [0.16, 24.33]

 6 Pregnancy prolongation - 2 weeks or more112Risk Ratio (M-H, Fixed, 95% CI)2.0 [0.42, 9.42]

    6.1 Intramuscular
112Risk Ratio (M-H, Fixed, 95% CI)2.0 [0.42, 9.42]

 7 Spontaneous birth169Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.80, 1.49]

    7.1 Intramuscular
169Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.80, 1.49]

 8 Caesarean section281Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.51, 1.60]

    8.1 Intramuscular
281Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.51, 1.60]

 9 Use of tocolysis2205Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.58, 1.65]

    9.1 Intramuscular
112Risk Ratio (M-H, Fixed, 95% CI)1.2 [0.55, 2.62]

    9.2 Vaginal
1193Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.50, 1.73]

 10 Preterm birth less than 37 weeks' gestation2223Risk Ratio (M-H, Random, 95% CI)0.51 [0.20, 1.31]

    10.1 Vaginal
1163Risk Ratio (M-H, Random, 95% CI)0.76 [0.55, 1.06]

    10.2 Intramuscular
160Risk Ratio (M-H, Random, 95% CI)0.29 [0.12, 0.69]

 11 Infant birthweight less than 2500 g170Risk Ratio (M-H, Fixed, 95% CI)0.52 [0.28, 0.98]

    11.1 Vaginal
170Risk Ratio (M-H, Fixed, 95% CI)0.52 [0.28, 0.98]

 12 Respiratory distress syndrome4314Risk Ratio (M-H, Random, 95% CI)0.74 [0.49, 1.10]

    12.1 Vaginal
2233Risk Ratio (M-H, Random, 95% CI)0.48 [0.20, 1.15]

    12.2 Intramuscular
281Risk Ratio (M-H, Random, 95% CI)0.86 [0.66, 1.12]

 13 Intraventricular haemorrhage grade III or IV112Risk Ratio (M-H, Fixed, 95% CI)9.0 [0.53, 152.93]

    13.1 Intramuscular
112Risk Ratio (M-H, Fixed, 95% CI)9.0 [0.53, 152.93]

 14 Periventricular leucomalacia112Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    14.1 Intramuscular
112Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 15 Use of assisted ventilation170Risk Ratio (M-H, Fixed, 95% CI)0.30 [0.06, 1.37]

    15.1 Vaginal
170Risk Ratio (M-H, Fixed, 95% CI)0.30 [0.06, 1.37]

 16 Necrotizing enterocolitis281Risk Ratio (M-H, Fixed, 95% CI)3.06 [0.50, 18.69]

    16.1 Intramuscular
281Risk Ratio (M-H, Fixed, 95% CI)3.06 [0.50, 18.69]

 17 Neonatal sepsis4314Risk Ratio (M-H, Random, 95% CI)0.54 [0.17, 1.68]

    17.1 Vaginal
2233Risk Ratio (M-H, Random, 95% CI)0.26 [0.07, 1.00]

    17.2 Intramuscular
281Risk Ratio (M-H, Random, 95% CI)1.09 [0.39, 3.05]

 18 Fetal death281Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.07, 16.75]

    18.1 Intramuscular
281Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.07, 16.75]

 19 Neonatal death2175Risk Ratio (M-H, Random, 95% CI)0.54 [0.05, 6.24]

    19.1 Intramuscular
112Risk Ratio (M-H, Random, 95% CI)2.0 [0.16, 24.33]

    19.2 Vaginal
1163Risk Ratio (M-H, Random, 95% CI)0.17 [0.02, 1.40]

 20 Neonatal length of hospital stay (days)281Mean Difference (IV, Fixed, 95% CI)-2.16 [-15.84, 11.53]

    20.1 Intramuscular
281Mean Difference (IV, Fixed, 95% CI)-2.16 [-15.84, 11.53]

 21 Apgar score less than seven at five minutes1163Risk Ratio (M-H, Fixed, 95% CI)0.26 [0.03, 2.27]

    21.1 Vaginal
1163Risk Ratio (M-H, Fixed, 95% CI)0.26 [0.03, 2.27]

 22 Prelabour spontaneous rupture of membranes1163Risk Ratio (M-H, Fixed, 95% CI)0.52 [0.19, 1.45]

    22.1 Vaginal
1163Risk Ratio (M-H, Fixed, 95% CI)0.52 [0.19, 1.45]

 23 Preterm birth less than 28 weeks' gestation1193Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.06, 15.60]

    23.1 Vaginal
1193Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.06, 15.60]

 24 Apgar score less than seven at five minutes1163Risk Ratio (M-H, Fixed, 95% CI)0.26 [0.03, 2.27]

    24.1 Vaginal
1163Risk Ratio (M-H, Fixed, 95% CI)0.26 [0.03, 2.27]

 25 Admission to neonatal intensive care unit1163Risk Ratio (M-H, Fixed, 95% CI)1.56 [0.27, 9.07]

    25.1 Vaginal
1163Risk Ratio (M-H, Fixed, 95% CI)1.56 [0.27, 9.07]

 
Comparison 10. Progesterone versus placebo/no treatment: prior threatened preterm labour, singletons, by cumulative weekly dose (< 500 mg v >= 500 mg)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Pregnancy prolongation (days)2232Mean Difference (IV, Random, 95% CI)1.88 [-8.42, 12.17]

    1.1 Dose < 500 mg per week
169Mean Difference (IV, Random, 95% CI)-3.30 [-7.41, 0.81]

    1.2 Dose >= 500 mg per week
1163Mean Difference (IV, Random, 95% CI)7.21 [2.39, 12.03]

 2 Preterm birth less than 37 weeks' gestation2223Risk Ratio (M-H, Random, 95% CI)0.51 [0.20, 1.31]

    2.1 Dose >=500 mg per week
1163Risk Ratio (M-H, Random, 95% CI)0.76 [0.55, 1.06]

    2.2 Dose <500 mg per week
160Risk Ratio (M-H, Random, 95% CI)0.29 [0.12, 0.69]

 3 Respiratory distress syndrome4314Risk Ratio (M-H, Random, 95% CI)0.74 [0.49, 1.10]

    3.1 Dose >=500 mg per week
2233Risk Ratio (M-H, Random, 95% CI)0.48 [0.20, 1.15]

    3.2 Dose <500 mg per week
281Risk Ratio (M-H, Random, 95% CI)0.86 [0.66, 1.12]

 4 Neonatal sepsis4314Risk Ratio (M-H, Random, 95% CI)0.54 [0.17, 1.68]

    4.1 Dose >=500 mg per week
2233Risk Ratio (M-H, Random, 95% CI)0.26 [0.07, 1.00]

    4.2 Dose <500 mg per week
281Risk Ratio (M-H, Random, 95% CI)1.09 [0.39, 3.05]

 5 Neonatal death2175Risk Ratio (M-H, Random, 95% CI)0.54 [0.05, 6.24]

    5.1 Dose <500 mg per week
112Risk Ratio (M-H, Random, 95% CI)2.0 [0.16, 24.33]

    5.2 Dose >=500 mg per week
1163Risk Ratio (M-H, Random, 95% CI)0.17 [0.02, 1.40]

 
Comparison 11. Progesterone versus placebo: other reason at risk of preterm birth, singletons

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Perinatal death3479Risk Ratio (M-H, Random, 95% CI)0.52 [0.09, 3.00]

    1.1 Intramuscular
2264Risk Ratio (M-H, Random, 95% CI)1.1 [0.23, 5.29]

    1.2 Vaginal
1215Risk Ratio (M-H, Random, 95% CI)0.18 [0.02, 1.55]

 2 Preterm birth less than 34 weeks1215Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.16, 3.01]

    2.1 Vaginal
1215Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.16, 3.01]

 3 Preterm birth less than 37 weeks3482Risk Ratio (M-H, Random, 95% CI)0.60 [0.32, 1.13]

    3.1 Intramuscular
2267Risk Ratio (M-H, Random, 95% CI)0.52 [0.11, 2.56]

    3.2 Vaginal
1215Risk Ratio (M-H, Random, 95% CI)0.63 [0.40, 0.98]

 4 Infant birthweight less than 2500 g3482Risk Ratio (M-H, Fixed, 95% CI)0.48 [0.25, 0.91]

    4.1 Intramuscular
2267Risk Ratio (M-H, Fixed, 95% CI)0.53 [0.23, 1.18]

    4.2 Vaginal
1215Risk Ratio (M-H, Fixed, 95% CI)0.42 [0.15, 1.16]

 5 Intrauterine fetal death1168Risk Ratio (M-H, Fixed, 95% CI)0.37 [0.04, 3.45]

    5.1 Intramuscular
1168Risk Ratio (M-H, Fixed, 95% CI)0.37 [0.04, 3.45]

 6 Neonatal death1168Risk Ratio (M-H, Fixed, 95% CI)5.49 [0.27, 112.73]

    6.1 Intramuscular
1168Risk Ratio (M-H, Fixed, 95% CI)5.49 [0.27, 112.73]

 7 Admission to neonatal intensive care unit1215Risk Ratio (M-H, Fixed, 95% CI)1.71 [0.71, 4.11]

    7.1 Vaginal
1215Risk Ratio (M-H, Fixed, 95% CI)1.71 [0.71, 4.11]

 
Comparison 12. Progesterone versus placebo: other reason at risk of preterm birth, by timing of commencement (< 20 wk v > 20 wk, singletons)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Perinatal death2264Risk Ratio (M-H, Fixed, 95% CI)1.1 [0.23, 5.29]

    1.1 Supplementation commenced prior to 20 weeks' gestation
1168Risk Ratio (M-H, Fixed, 95% CI)1.1 [0.23, 5.29]

    1.2 Supplementation commenced after 20 weeks' gestation
196Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 2 Preterm birth less than 37 weeks2267Risk Ratio (M-H, Random, 95% CI)0.52 [0.11, 2.56]

    2.1 Supplementation commenced prior to 20 weeks' gestation
1168Risk Ratio (M-H, Random, 95% CI)1.1 [0.33, 3.66]

    2.2 Supplementation commenced after 20 weeks' gestation
199Risk Ratio (M-H, Random, 95% CI)0.22 [0.05, 0.96]

 3 Infant birthweight less than 2500 g2267Risk Ratio (M-H, Random, 95% CI)0.51 [0.16, 1.65]

    3.1 Supplementation commenced prior to 20 weeks' gestation
1168Risk Ratio (M-H, Random, 95% CI)0.83 [0.30, 2.27]

    3.2 Supplementation commenced after 20 weeks' gestation
199Risk Ratio (M-H, Random, 95% CI)0.25 [0.05, 1.10]