Plain language summary
Introduction
Background
Current evidence and knowledge
Rationale for a new systematic review with IPD meta-analysis
Collaborative approach
Aims and objectives
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Twin pregnancy with previous preterm birth and maternal short cervix
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Twin pregnancy with previous spontaneous preterm birth (any cervical length)
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Twin pregnancy with maternal short cervix, but no previous preterm birth
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Twin pregnancy with no other risk factors
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Triplet pregnancy (likely to be too few trial participants to split further)
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Singleton gestation with previous preterm birth and maternal short cervix
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Singleton gestation with previous spontaneous preterm birth (any cervical length)
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Singleton gestation with maternal short cervix, but no previous preterm birth
Methods/design
Protocol development and registration
Inclusion and exclusion criteria
Population
Intervention
Comparators
Outcomes
Study design
Trial identification
Data provision and coding
Data storage and confidentiality
Critical appraisal, data checking, and quality assurance
Data description
Planned analyses
Main outcomes
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Preterm birth or fetal death (< =37, <= 34, <= 28 weeks)
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Serious neonatal complications or fetal/infant death(broncho-pulmonary dysplasia, severe intraventricular hemorrhage, nectrotizing enterocolitis, confirmed sepsis, patent ductus arteriosus, retinopathy of prematurity)
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Neurosensory disability (measured at 18 months or later) or infant/child death(cerebral palsy, visual impairment, hearing impairment, epilepsy, intellectual impairment, developmental delay)
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Important maternal morbidity or maternal death(gestational diabetes, gestational hypertension, preeclampsia, maternal infection)
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Fetal/infant death(fetal death occurring at any point after trial entry, stillbirth, or death of live born infant before hospital discharge following birth, or to 28 days, whichever is longer)
Additional outcomes
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Gestational age at birth
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Prolongation of pregnancy (interval between randomization and delivery)
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Prelabor spontaneous rupture of membranes (≤28, ≤34, ≤37 weeks and >37 weeks)
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Non-spontaneous onset of labor (medically induced or caesarian before labor)
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Mode of birth (vaginal/caesarian birth)
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Gestational diabetes
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Preeclampsia
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Gestational hypertension
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Maternal infection(chorioamnionitis during labor; intrapartum fever, postpartum fever requiring antibiotics)
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Adverse/side effects of treatment
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Maternal death
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Fetal death/stillbirth (death of fetus after randomization)
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Death of newborn (death of live born infant to hospital discharge following birth)
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Birth weight (adjusted for gestational age and sex)
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Admission to neonatal intensive or special care unit (NICU/SCU)
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Length of stay in NICU/SCU
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Respiratory distress syndrome (as defined in the trial)
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Use of respiratory support (mechanical, CPAP, high flow nasal cannula)
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Bronchopulmonary dysplasia (as defined in trial)
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Periventricular leukomalacia
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Necrotizing enterocolitis (grade II or III)
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Neonatal infection (antenatal, early, late; as defined in trial)
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Confirmed neonatal sepsis
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Patent ductus arteriosus (treated for)
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Severe intraventricular hemorrhage (grade III or IV)
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Retinopathy of prematurity (stage 3 or worse)
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Major congenital anomalies including cardiac malformation
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Death and cause of death after discharge (from hospital following birth)
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Cerebral palsy
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Visual impairment (visual acuity worse than 6/60, 20/200 in better eye)
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Hearing impairment (requiring amplification or worse)
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Epilepsy
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Intellectual impairment (as defined in trial)
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Developmental delay (mild, moderate, or severe on Bailey scale or equivalent)
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Growth outcomes (including height, weight, head circumference, if possible with reference to appropriate growth chart centiles)
Analysis of potential effect modifiers
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Intended dose (separately for each type of progestogen)
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Intended early co-intervention(s)
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Previous spontaneous preterm birth
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Gestational age at previous preterm birth
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Cervical length (continuous variable and using thresholds ≤15 mm, ≤20 mm, ≤25 mm, ≤30)
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Positive fetal fibronectin test(continuous variable and using thresholds ≥ 10 ng/ml, ≥ 50 ng/ml, ≥ 200 ng/ml)
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Singleton or multiple gestation pregnancy(singleton/multiple and singleton/twin/triplet gestation pregnancy)
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Chorionicity and amnionicity
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Gestational age at randomization/initiation of treatment
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Maternal age
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Ethnicity (within comparable geographical locations)
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Assisted conception
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Chronic hypertension
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Prepregnancy diabetes
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Smoking during pregnancy
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Maternal body mass index (categorized using WHO definitions)
Sensitivity and supplementary analyses
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Supplemented (where possible) with aggregate data from published reports of trials for which IPD is not available
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Restricted to trials at low risk of bias with respect to design features such as blinding
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Restricted to trials that have been prospectively registered
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Analysis of cervical length restricted to trials that used ultrasound measurement
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Separate analyses of trials measuring developmental outcomes directly and those that used questionnaires
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Separate analyses of trials measuring intellectual impairment based on health records and those that used parent reports
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Multivariable analysis including singleton and multiple gestation pregnancies
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Analysis of ethnicity across all trial locations
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Analyses of covariate treatment interaction for additional outcomes where analyses of main outcomes suggests that further analysis may be informative
Statistical methods
Outcome measures
Unit of analysis
One- and two-stage models
Two-stage models
One-stage models
Impact of trial and participant characteristics
Time to event analyses
Relative and absolute differences
Unavailable trials and missing data
Network meta-analysis
Software
Reporting
Data repository
Discussion
EPPPIC identifier | Trial setting | Recruitment years | Progestogen type, dose, intervention, period Comparator | Main indication(s) Gestation at randomization | Singleton/multiple pregnancy |
N
|
---|---|---|---|---|---|---|
A: Eligible trials comparing progestogen with standard care or placeboa
| ||||||
1 | Single center Egypt (Cairo) | 2008–2009 | Vaginal Micronized progesterone 400 mg suppository daily 18–24 to 37 weeks Placebo | First pregnancy by IVF/ICSI 18–24 weeks | SingletonTwin | 313 |
2 | Single center Iran (Khorramabad) | – | Vaginal Progesterone 100 mg daily 24 to 34 weeks Standard care | Previous SPTBProphylactic cerclage Uterine anomalies Gestation unclear | Singleton | 150 |
3 | Single center Lebanon (Beirut) | 2006–2012 | Intramuscular injection 17-OHPC 250 mg weekly 16–20 to 36 weeks Castor oil | Twin pregnancy 12–20 weeks | Twin | 293 |
4 | Multi center USA | 2004–2006 | Intramuscular injection 17-OHPC 250 mg weekly 16–20 to 35 weeks Castor oil | Triplet pregnancy 16–20 weeks | Triplet | 134 |
5 | Single center Turkey (Istanbul) | 2004–2007 | Vaginal Progesterone 100 mg suppository daily 24 to 34 weeks Placebo | Twin pregnancy Previous SPTB Uterine anomalies 24 weeks | Singleton Twin | 160 |
6 | Multi center USA | 2004–2008 | Intramuscular injection 17-OHPC 250 mg weekly 16–24 to 34 weeks Castor oil | Trichorionic-triamniotic triplet pregnancy 15–23 weeks | Triplet | 81 |
7 | Multi center USA | 2004–2009 | Intramuscular injection 17-OHPC 250 mg weekly 16–24 to 34 weeks Castor oil | Dichorionic-diamniotic twin pregnancy 15–23 weeks | Twin | 240 |
8 | Multi center Australia | 2005–2009 | Vaginal Progesterone 100 mg suppository nightly 20–24 to 34 weeks Placebo | SPTB preceding pregnancy 18–24 weeks | Singleton | 787 |
9 | Single center Brazil (São Paulo) | 1996–2001 | Vaginal Progesterone 100 mg suppository nightly 24 to 34 weeks Placebo | Previous SPTBPrevious cerclage Uterine anomalies Gestation not reported | Singleton | 157 |
10 | Single center Egypt (Cairo) | – | Vaginal Progesterone 200 mg daily 24 to 34 weeks Placebo | Twin pregnancy | Twin | 100 |
11 | Multi center International | 2003–2006 | Vaginal Progesterone 200 mg suppository nightly 24–25 to 34 weeks Safflower oil | Short cervix (≤15 mm) 20–25 weeks | Singleton twin | 250 |
12 | Single center Pilot USA (Ohio) | 2006–2009 | Oral Micronized progesterone 2 × 200 mg capsule daily 16–20 to 34 weeks Placebo | Previous live SPTB < 20 weeks | Singleton |
b33 |
13 | Multi center USA | 2007–2011 | Intramuscular injection 17-OHPC 250 mg weekly 16–23 to 37 weeks Castor oil | Nulliparous Short cervix (< 30 mm) 16–23 weeks | Singleton | 657 |
14 | Single center Finland (Oulu) | – | Intramuscular injection 17-OHPC 250 mg weekly 28–33 to 37 weeks Placebo | Twin pregnancy 28–33 weeks | Twin | 77 |
15 | Multi center International | 2008–2010 | Vaginal Progesterone 90 mg gel daily 20–24 to 37 weeks Placebo | Short cervix (10–20 mm) 19–24 weeks | Singleton | 465 |
16 | Single center Egypt (Cairo) | 2006–2008 | Intramuscular injection 17-OHPC 250 mg weekly Second trimester to 36 weeks Saline | Previous SPTB Second trimester | Singleton | 50 |
17 | Single center USA (Baltimore) | – | Intramuscular injection 17-OHPC 250 mg weekly Unclear to 37 weeks Castor oil + benzyl benzoate | 2 previous SPTB 2 SAs or (1 SPTB and 1 SA) in immediately preceding pregnancy < 24 weeks | Singleton Twin | 50 |
18 | Multi center Netherlands | 2006–2009 | Intramuscular injection 17-OHPC 250 mg weekly 16–20 to 36 weeks Castor oil | Multiple pregnancy 15–19 weeks | Twin Triplet Quadruplet | 671 |
19 | Single center India (Chandigarh) | 2004–2006 | Vaginal Micronized progesterone 100 mg capsule nightly 20–24 to 36 weeks Standard care | Previous singleton SPTB 16–24 weeks | Singleton | 100 |
20 | Multi center USA | 1999–2002 | Intramuscular injection 17-OHPC 250 mg weekly 16–20 to 36 weeks Castor oil | Previous SPTB 15–21 weeks | Singleton | 463 |
21 | Single center Albania (Tirana) | – | Intramuscular injection 17-OHPC Dose not reported, daily 15–22 to 34 weeks Oral Progesterone daily (dose not reported, daily 15–22 to 34 weeks Placebo | High risk of SPTB 15–22 weeks | – | 121 |
22 | Multi center UK | 2004–2008 | Vaginal Progesterone 90 mg gel daily 24 to 34 weeks Placebo | Twin pregnancy 22 weeks | Twin | 500 |
23 | Multi center UK | 2009–2013 | Vaginal Progesterone 200 mg suppository nightly 22–24 to 34 weeks Placebo | Previous SPTB Short cervix (≤ 25 mm) Positive FFT and other risk factors for SPTB | Singleton | 1228 |
24 | Multi center USA | 2004–2007 | Vaginal Progesterone 90 mg gel daily 18–23 to 37 weeks Vaginal moisturizer | Singleton SPTB in most recent pregnancy 16–23 weeks | Singleton | 659 |
25 | Single center Iran (Tehran) | Intramuscular injection 17-OHPC 250 mg weekly 16–20 to 34 weeks Placebo | Women ≥ 35 years | – | 260 | |
26 | Single center India (Delhi) | 2005–2006 | Oral Micronized progesterone 100 mg capsule twice daily 18–24 to 36 weeks Placebo | Previous SPTB 18–24 weeks | Singleton | 150 |
27 | Multi center Denmark and Austria | 2006–2008 | Vaginal Micronized progesterone 200 mg suppository daily 20–24 to 34 weeks Safflower oil, gelatine, glycerol, titanium dioxide (E171) | Diamniotic twin pregnancy Chorionicity <16 weeks 18–24 weeks | Multiple | 677 |
28 | Multi center USA | 2004–2006 | Intramuscular injection 17-OHPC 250 mg weekly 16–20 to 35 weeks Castor oil | Twin pregnancy 16–20 weeks | Twin | 661 |
29 | Single center Iran (Mashhad) | 2007–2008 | Intramuscular injection 17-OHPC 250 mg weekly 16 to 37 weeks Standard care | Previous SPTB Not reported | Singleton | 100 |
30 | Multi center France | 2006–2010 | Intramuscular injection 17-OHPC 500 mg twice weekly 24–32 to 36 weeks Standard care | Dichorionic diamniotic twin pregnancy Cervix ≤25 mm 24–32 weeks | Twin | 165 |
31 | Multi center Spain | 2006–2008 | Vaginal Progesterone (1) 2 × 200 mg suppository nightly (2) 1 × 200 mg + 1 × placebo suppository nightly 20 to 34 weeks (3) 2 x placebo suppository nighly Peanut oil + soy lecithin | Dichorionic diamniotic twin pregnancy 20 weeks | Twin | 294 |
32 | Two center Canada (Calgary) | 2006–2010 | Vaginal Progesterone 90 mg gel daily 16–21 to 36 weeks Placebo | Multiple gestation 16–21 weeks | Twin Triplet | 84 |
33 | Single center Brazil (São Paulo) | 2007–2013 | Vaginal Progesterone 200 mg suppository nightly 18–21 to 34 weeks Placebo | Naturally conceived diamniotic twin pregnancy 18–21 weeks | Twin | 390 |
34 | Single center Iran (Tehran) | 2010–2012 | Vaginal Progesterone 400 mg suppository nightly 16–22 to 36 weeks Placebo | Previous SPTB Cervix ≤ 28 mm + cerclage Uterine anomalies Uterine intramural myoma ≥ 7 cm 16–22 weeks | Singleton | 103 |
35 | Two center Egypt (Mansoura) | 2012–2014 | Vaginal Progesterone 400 mg suppository daily 20–24 to 37 weeks Standard care | Dichorionic twin pregnancy Cervix 20–25 mm 20–24 weeks | Twin | 250 |
36 | Multi center Netherlands | 2009–2013 | Vaginal Micronized progesterone 200 mg suppository daily 22 to 34 weeks Placebo | Nulliparous Multiparous without SPTB < 34 weeks gestation Cervix ≤30 mm 18–22 weeks | Singleton | 80 |
37 | Single center India (Shimla) | – | Vaginal Progesterone 100 mg suppository 24–28 to 34 weeks Placebo | Previous SPTB 24–28 weeks | Singleton | 80 |
38 | Single center Pakistan (Bahalwapur) | 2011 | Intramuscular injection 17P 250 mg weekly 16–20 to 36 weeks Placebo | Previous SPTB 16–20 weeks | Singleton | 60 |
45 | Single center USA (Jackson) | – | Intramuscular injection 17-OHCP 250mg weekly Up to 34 weeks or delivery Castor oil | Twin pregnancy 20–30 weeks | Twin | 30 |
B: Eligible trials comparing different types of progestogen | ||||||
21 | Single center Albania (Tirana) | – | Intramuscular injection 17-OHPC Dose not reported, daily 15–22 to 34 weeks Oral Progesterone daily (dose Dose not reported, daily 15–22 to 34 weeks Placebo | High risk of SPTB 15–22 weeks | – | 121 |
39 | Single center Egypt (Tanta) | 2010–2011 | Vaginal Micronized progesterone 200 mg suppository daily 20–24 to 34 weeks Intramuscular injection Progesterone 100 mg every 3rd day 20–24 to 34 weeks | Previous SPTB Cervix ≥ 15 mm 20–24 weeks | Singleton | 160 |
40 | Single center Iran (Yazd) | 2012–2015 | Vaginal Progesterone 200 mg suppository daily 16–20 to delivery Intramuscular injection 17-OHPC 250 mg weekly 16–20 weeks to delivery | Previous SPTB or Cervix < 25 mm (not both) 16–20 weeks | Singleton | 78 |
41 | Single center Saudi Arabia (Khamis Mushayt) | 2009–2011 | Vaginal Micronized progesterone 90 mg gel daily 14–18 to 36 weeks Intramuscular injection 17-OHPC 250 mg weekly 14–18 to 36 weeks | Previous mid-trimester SPTB Previous cerclage 14–18 weeks | Singleton | 518 |
42 | Single center Iran (Tehran) | 2012–2015 | Vaginal Progesterone 400 mg suppository daily 16–24 to 36 weeks 17-OHPC 250 mg weekly 16–24 to 36 weeks | Cervix < 25 mm 16–24 weeks | Singleton | 304 |
43 | Single center USA (Oklahoma) | 2007–2010 | Intramuscular injection 17-OHPC 250 mg weekly 16–21 to 37 weeks Vaginal Micronized progesterone 100 mg suppository daily 16–21 to 37 weeks | Previous live singleton SPTB 16–21 weeks | Singleton | 174 |
44 | Single center Iran (Yazd) | 2010–2011 | Intramuscular injection 17-OHPC 250 mg weekly 16 to 36 weeks Placebo | Assisted conception 16 weeks | Singleton | 106 |