Romero 2017
Romero 2017
Romero 2017
Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.17397. This is an open access article under the terms
of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided
the original work is properly cited and is not used for commercial purposes.
Genetics, Wayne State University, Detroit, MI, USA; 5 Department of Obstetrics and Gynecology, Wayne State University School of
Medicine, Detroit, MI, USA; 6 Department of Obstetrics and Gynecology, Mansoura University Hospitals, Mansoura University, Mansoura,
Egypt; 7 Center of Fetal Medicine and Pregnancy, Department of Obstetrics, Copenhagen University Hospital, Rigshospitalet, Copenhagen,
Denmark; 8 Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Herlev, Denmark; 9 Department of Obstetrics and
Gynecology, São Paulo University Medical School, São Paulo, Brazil; 10 Department of Obstetrics and Gynecology, Zeynep Kamil Women
and Children Diseases Education and Research Hospital, Uskudar, Istanbul, Turkey; 11 Maternal-Fetal Medicine Unit, Instituto Valenciano
de Infertilidad, University of Valencia, Valencia, Spain; 12 Department of Pediatrics, Obstetrics and Gynecology, University of Valencia,
Valencia, Spain; 13 Departamento de Obstetrı́cia e Ginecologia, Hospital do Servidor Publico Estadual ‘Francisco Morato de Oliveira’ and
School of Medicine, University of São Paulo, São Paulo, Brazil; 14 University of Copenhagen, Faculty of Health Sciences, Copenhagen,
Denmark; 15 Department of Obstetrics, University Hospital La Fe, Valencia, Spain; 16 Harris Birthright Research Centre for Fetal Medicine,
King’s College Hospital, London, UK
ABSTRACT of bias and extracted the data. Pooled relative risks (RRs)
with 95% confidence intervals (CI) were calculated.
Objective To assess the efficacy of vaginal progesterone
for the prevention of preterm birth and neonatal Results IPD were available for 303 women (159
morbidity and mortality in asymptomatic women with assigned to vaginal progesterone and 144 assigned
a twin gestation and a sonographic short cervix (cervical to placebo/no treatment) and their 606 fetuses/infants
length ≤ 25 mm) in the mid-trimester. from six randomized controlled trials. One study,
Methods This was an updated systematic review and which included women with a cervical length between
meta-analysis of individual patient data (IPD) from 20 and 25 mm, provided 74% of the total sample
randomized controlled trials comparing vaginal pro- size of the IPD meta-analysis. Vaginal progesterone,
gesterone with placebo/no treatment in women with a compared with placebo/no treatment, was associated
twin gestation and a mid-trimester sonographic cervi- with a statistically significant reduction in the risk
cal length ≤ 25 mm. MEDLINE, EMBASE, POPLINE, of preterm birth < 33 weeks’ gestation (31.4% vs
CINAHL and LILACS (all from inception to 31 Decem- 43.1%; RR, 0.69 (95% CI, 0.51–0.93); moderate-quality
ber 2016), the Cochrane Central Register of Controlled evidence). Moreover, vaginal progesterone administration
Trials, Research Registers of ongoing trials, Google was associated with a significant decrease in the risk of
Scholar, conference proceedings and reference lists of preterm birth < 35, < 34, < 32 and < 30 weeks’ gestation
identified studies were searched. The primary outcome (RRs ranging from 0.47 to 0.83), neonatal death (RR,
measure was preterm birth < 33 weeks’ gestation. Two 0.53 (95% CI, 0.35–0.81)), respiratory distress syndrome
reviewers independently selected studies, assessed the risk (RR, 0.70 (95% CI, 0.56–0.89)), composite neonatal
Correspondence to: Dr R. Romero, Perinatology Research Branch, Intramural Division, NICHD/NIH/DHHS, Hutzel Women’s Hospital,
Box #4, 3990 John R, Detroit, MI 48201, USA (e-mail: prbchiefstaff@med.wayne.edu)
The copyright line for this article was changed on 21 March 2017 after original online publication.
Accepted: 29 December 2016
Published 2017. This article is a U.S. Government work and is in the public domain in the USA. SYSTEMATIC REVIEW
Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.
304 Romero et al.
morbidity and mortality (RR, 0.61 (95% CI, 0.34–0.98)), progesterone in preventing preterm birth and neonatal
use of mechanical ventilation (RR, 0.54 (95% CI, morbidity and mortality in asymptomatic women with a
0.36–0.81)) and birth weight < 1500 g (RR, 0.53 (95% twin gestation and a CL ≤ 25 mm in the mid-trimester47 .
CI, 0.35–0.80)) (all moderate-quality evidence). There A total of 52 women (104 fetuses/infants) from three
were no significant differences in neurodevelopmental randomized controlled trials (RCTs) were included in the
outcomes at 4–5 years of age between the vaginal study. The use of vaginal progesterone was associated
progesterone and placebo groups. with a significant 44% reduction in the risk of composite
neonatal morbidity and mortality (relative risk (RR), 0.56
Conclusion Administration of vaginal progesterone to (95% CI, 0.30–0.97)) and a 30% non-significant reduc-
asymptomatic women with a twin gestation and a tion in the risk of preterm birth < 33 weeks’ gestation
sonographic short cervix in the mid-trimester reduces the (RR, 0.70 (95% CI, 0.34–1.44)). Since that time, addi-
risk of preterm birth occurring at < 30 to < 35 gestational tional RCTs evaluating the use of vaginal progesterone
weeks, neonatal mortality and some measures of neonatal in twin gestations have been published. Therefore, a
morbidity, without any demonstrable deleterious effects reassessment of the efficacy of this intervention in women
on childhood neurodevelopment. Published 2017. This with a twin gestation and a short cervix is justified.
article is a U.S. Government work and is in the The objective of this study was to update the previous
public domain in the USA. Ultrasound in Obstetrics IPD meta-analysis on the efficacy of vaginal progesterone
& Gynecology published by John Wiley & Sons Ltd in asymptomatic women with a twin gestation and a
on behalf of the International Society of Ultrasound in sonographic CL ≤ 25 mm in the mid-trimester for the
Obstetrics and Gynecology. prevention of preterm birth and neonatal morbidity and
mortality.
INTRODUCTION
METHODS
Twin births have become more prevalent in developed
countries over the last decades1–3 . In 2014, the twin birth The study was conducted according to a prospectively
rate in the USA was 33.9 per 1000 live births, the highest prepared protocol and reported in accordance with the
rate ever recorded4 . Twin gestations are at increased risk Preferred Reporting Items for Systematic reviews and
of maternal, perinatal and infant morbidity and mortality, Meta-Analyses statement48 . The review was registered
as well as long-term neurodevelopmental disability5–13 . with PROSPERO (number CRD42016039682).
Moreover, twin gestations also have a significant impact
on healthcare costs and quality of life for both the parents Data sources and searches
and the children7,14,15 .
Preterm birth is the most important factor determining We searched MEDLINE, EMBASE, POPLINE, CINAHL
neonatal morbidity and mortality among twins. The and LILACS (all from inception to 31 December 2016),
risk of preterm birth < 37 and < 32 weeks’ gestation the Cochrane Central Register of Controlled Trials and
is eight- to ninefold higher in twin than in singleton Research Registers of ongoing trials using a combination
gestations4 . Several interventions have been proposed of keywords and text words related to ‘progesterone’,
to reduce the rate of preterm birth in twin gestations, ‘preterm birth’, ‘randomized controlled trial’ and ‘twin
such as bed rest16 , prophylactic tocolysis17 , nutritional gestation’. Google Scholar, proceedings of congresses
advice18 , administration of 17α-hydroxyprogesterone on obstetrics, maternal-fetal medicine and ultrasound in
caproate19 , vaginal progesterone19 , cerclage20 and obstetrics, reference lists of identified studies, previously
cervical pessary21,22 . Unfortunately, these interventions published systematic reviews and review articles were also
have not been shown to reduce the risk of preterm birth searched. Experts in the field were contacted to identify
in unselected twin gestations. further studies. No language restrictions were applied.
A short cervix, traditionally defined as a transvagi-
nal sonographic cervical length (CL) ≤ 25 mm in the Study selection
mid-trimester of pregnancy, is an important risk fac-
tor for spontaneous preterm birth and has emerged as RCTs in which asymptomatic women with a twin
one of the strongest and most consistent predictors of gestation and a sonographic short cervix (CL ≤ 25 mm)
preterm birth in asymptomatic women with singleton23–29 in the mid-trimester were allocated randomly to receive
or twin gestations30–43 . Currently, there is compelling vaginal progesterone or placebo/no treatment for the
evidence that administration of vaginal progesterone to prevention of preterm birth and/or adverse perinatal
asymptomatic women with a singleton gestation and a outcomes were eligible for inclusion in the review. Trials
sonographic short cervix decreases the risk of preterm were included if the primary aim of the study was to
birth and neonatal morbidity and mortality44–46 . The prevent preterm birth in women with a twin gestation and
efficacy of vaginal progesterone in women with a twin a short cervix, or to prevent preterm birth in women with
gestation and a short cervix has been less studied. an unselected twin gestation but for whom outcomes were
A meta-analysis of individual patient data (IPD) available in those with a prerandomization CL ≤ 25 mm.
published in 2012 reported on the efficacy of vaginal We excluded quasirandomized trials, trials that evaluated
Published 2017. This article is a U.S. Government work and is in the public domain in the USA. Ultrasound Obstet Gynecol 2017; 49: 303–314.
Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.
Vaginal progesterone decreases preterm birth in twin gestation with short cervix 305
vaginal progesterone in women with preterm labor, (suspected or diagnosed developmental delay, cerebral
arrested preterm labor (as maintenance tocolysis), preterm palsy, intellectual disabilities, vision impairment, hearing
rupture of membranes or second-trimester bleeding, trials loss, cognitive and behavioral impairments and motor,
that assessed vaginal progesterone in the first trimester communication and learning disorders at any age in
only to prevent miscarriage and studies that did not report childhood).
clinical outcomes. Studies published only as abstracts were
excluded if additional information on methodological
Assessment of risk of bias
issues and results could not be obtained.
All of the potentially relevant studies were retrieved The risk of bias in each included trial was assessed
and reviewed independently by two authors to determine independently by two authors using the criteria outlined
inclusion. Disagreements were resolved by discussion in the Cochrane Handbook for Systematic Reviews of
amongst the reviewers. Interventions49 . This tool assesses seven domains related
to risk of bias (random sequence generation, allocation
Data collection concealment, blinding of participants and personnel,
blinding of outcome assessment, incomplete outcome
The corresponding author of each eligible trial was data, selective reporting and other bias) and categorizes
contacted and asked to provide anonymized data (without studies by low, unclear or high risk of bias in each
identifiers) about baseline characteristics and outcomes domain. Disagreements in risk of bias assessment were
for every randomly assigned patient, as well as data resolved through consensus.
on study characteristics and details of interventions and
co-interventions. All initial communications with authors
Statistical analysis
were based on a template explaining the study and the
data required. Data provided by the investigators were We included all randomized women and their fetuses/
merged into a master database specifically constructed for infants and performed all analyses on an intention-to-treat
the review. Data were checked for missing information, basis. For outcomes dealing with gestational age at
errors and inconsistencies by cross-referencing with the delivery, the unit of analysis was the pregnancy,
publications of the original trials. Quality and integrity of whereas for perinatal outcomes, the unit of analysis was
the randomization processes were assessed by reviewing the fetus/neonate. IPD were combined in a two-stage
the chronological randomization sequence and pattern approach in which outcomes were analyzed in the original
of assignment, as well as the balance of baseline trial and then summary statistics were generated using
characteristics across treatment groups. Inconsistencies standard summary data meta-analysis techniques to give
or missing data were discussed with the authors and an overall measure of effect (pooled RR with 95%
corrections were made when deemed necessary. CI)50 . Heterogeneity of the results among studies was
Informed consent was provided by the patients upon tested51 with the quantity I2 . We pooled results from
enrollment in each of the original trials. In the present individual studies using a fixed-effect model if substantial
study, the data were not used for any purposes other than statistical heterogeneity was not present (< 50%). If I2
those of the original trial and no new data were collected. values were ≥ 50%, a random-effects model was used to
Therefore, informed consent specifically for this project pool data across studies. For adverse perinatal outcomes,
was not considered necessary. This study was exempted we estimated pooled RRs using analytical methods that
from review by the Human Investigation Committee assumed independence between neonates. However, to
Administration Office of Wayne State University. avoid incorrect conclusions due to the non-independence
of newborns from twin gestations, we also used a
Outcome measures generalized linear model with generalized estimating
equations to estimate parameters while controlling for
The primary outcome measure was preterm birth cluster correlations52–54 . The number needed to treat
< 33 weeks’ gestation. Secondary outcome measures for benefit or harm, with a 95% CI, was calculated for
included: preterm birth < 37, < 36, < 35, < 34, < 32, outcomes for which there was a statistically significant
< 30 and < 28 weeks’ gestation; spontaneous preterm reduction or increase in risk difference based on control
birth < 33 and < 34 weeks’ gestation; respiratory distress event rates in the trials55 .
syndrome (RDS); necrotizing enterocolitis; intraventric- Subgroup analyses were performed to evaluate the effect
ular hemorrhage; proven neonatal sepsis; retinopathy of vaginal progesterone according to CL (<10, 10–20
of prematurity; fetal death; neonatal death; perinatal and 21–25 mm), daily dose of vaginal progesterone (100,
death; a composite outcome of neonatal morbidity 200 and 400 mg) and obstetric history (no previous
and mortality (defined as the occurrence of any of the spontaneous preterm birth < 37 weeks’ gestation and at
following events: RDS, intraventricular hemorrhage, least one previous spontaneous preterm birth < 37 weeks’
necrotizing enterocolitis, proven neonatal sepsis or neona- gestation). A test for interaction between the treatment
tal death); birth weight < 1500 g and < 2500 g; admission and subgroups was performed to examine whether
to the neonatal intensive care unit; use of mechanical treatment effects differed among subgroups56–58 . An
ventilation; and long-term neurodevelopmental outcomes interaction P-value ≥ 0.05 was considered to indicate
Published 2017. This article is a U.S. Government work and is in the public domain in the USA. Ultrasound Obstet Gynecol 2017; 49: 303–314.
Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.
306 Romero et al.
Identification
among subgroups. We planned to carry out sensitivity Records identified through Additional records identified
analyses to explore the effect of trial quality assessed by database search (n = 281) through other sources (n = 0)
allocation concealment and random sequence generation
(considering selection bias) and blinding (considering Records after duplicates removed (n = 213)
Screening
performance and detection biases), with studies rated as
‘high risk of bias’ or ‘unclear risk of bias’ for these domains
Records screened (n = 213) Records excluded (n = 204)
being excluded from the analyses in order to assess
whether this made any difference to the overall result.
Eligibility
Subgroup and sensitivity analyses were only performed Full-text articles assessed Full-text articles excluded (n = 3)
for the primary outcome of preterm birth < 33 weeks’ for eligibility (n = 9) • CL not measured or collected
before randomization (n = 2)
gestation and for the secondary outcome of neonatal • No data on women with CL
death. We also planned to explore potential sources of ≤ 25 mm at randomization (n = 1)
Included
but these analyses were not undertaken due to the limited
number of trials included in the review. Studies included in meta-analysis (n = 6)
Data are given as median (interquartile range) or n (%). *n = 41. †n = 36. CL, cervical length; GA, gestational age; PTB, preterm birth.
Published 2017. This article is a U.S. Government work and is in the public domain in the USA. Ultrasound Obstet Gynecol 2017; 49: 303–314.
Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.
Vaginal progesterone decreases preterm birth in twin gestation with short cervix 307
The individual characteristics of the studies included Effect of vaginal progesterone on preterm birth
in the meta-analysis are shown in Table 2. Five stud-
ies were double-blind, placebo-controlled trials64–68 . Women allocated to receive vaginal progesterone had
The remaining study compared vaginal progesterone a significantly lower risk of preterm birth < 33 weeks’
with no treatment69 . Three studies were performed in gestation (31.4% vs 43.1%; RR, 0.69 (95% CI, 0.51–
low/middle-income countries65,68,69 , two in high-income 0.93); P = 0.01; I2 = 0%; six studies, 303 women;
countries66,67 and one in both low/middle- and moderate-quality evidence) compared with those allo-
high-income countries64 . Two trials were specifically cated to placebo/no treatment (Figure 3). In addi-
designed to evaluate the use of vaginal progesterone in tion, vaginal progesterone was associated with a
women with a twin gestation and a sonographic short significant reduction in the risk of preterm birth
cervix (CL ≤ 15 mm64 and CL between 20 and 25 mm69 ). < 35 weeks’ gestation (RR, 0.83 (95% CI, 0.69–0.99);
The remaining four studies tested the effect of vaginal moderate-quality evidence), < 34 weeks’ gestation (RR,
progesterone in women with unselected twin gestations 0.71 (95% CI, 0.56–0.91); moderate-quality evidence),
and their authors provided data relevant to women < 32 weeks’ gestation (RR, 0.51 (95% CI, 0.34–0.77);
with a CL ≤ 25 mm before randomization65–68 . The trial moderate-quality evidence), < 30 weeks’ gestation (RR,
that assessed vaginal progesterone in women with a CL 0.47 (95% CI, 0.25–0.86); moderate-quality evidence),
between 20 and 25 mm69 provided data for 224 moth- and spontaneous preterm birth at < 33 weeks’ gestation
ers and their 448 fetuses/infants. The other five studies (RR, 0.67 (95% CI, 0.48–0.93); moderate-quality evi-
provided data for 79 women and 158 fetuses/infants. dence) and < 34 weeks’ gestation (RR, 0.71 (95% CI,
Three studies used vaginal progesterone 200 mg/day 0.54–0.93); moderate-quality evidence) (Table 3). The
(capsule64 , pessary66 or ovule68 ), one used vaginal pro- number needed to treat to prevent one case of preterm
gesterone suppositories 100 mg/day65 , one used vaginal birth occurring at < 30 to < 35 gestational weeks var-
progesterone suppositories 400 mg/day69 and the remain- ied from 6 to 12. There were no significant differences
ing study used vaginal progesterone suppositories 200 between the study groups in the risk of preterm birth
or 400 mg/day67 . Treatment was started between 20 and < 37 weeks’ (moderate-quality evidence), < 36 weeks’
24 weeks’ gestation in five trials64–67,69 , and between 18 (moderate-quality evidence) and < 28 weeks’ (low-quality
and 21 weeks’ gestation in the remaining trial68 . Five stud- evidence) gestation.
ies reported that participants received medication from
the time of enrollment until ∼34 weeks’ gestation64–68 , Effect of vaginal progesterone on adverse perinatal
and one study reported medication from enrollment until outcomes
37 weeks’ gestation69 . Two trials included only women
with a dichorionic twin gestation67,69 . Major fetal abnor- Infants whose mothers received vaginal progesterone
mality, cervical cerclage in place or planned, allergy had a significantly lower risk of neonatal death
to progesterone and hepatic dysfunction were reported (RR, 0.53 (95% CI, 0.35–0.81); moderate-quality evi-
as exclusion criteria in most studies. The primary out- dence), perinatal death (RR, 0.58 (95% CI, 0.39–0.84);
come measure was preterm birth < 34 weeks’ gestation moderate-quality evidence), RDS (RR, 0.70 (95%
in two trials66,69 , preterm birth < 37 weeks’ gestation in CI, 0.56–0.89); moderate-quality evidence), compos-
two trials65,67 , spontaneous preterm birth < 34 weeks’ ite neonatal morbidity and mortality (RR, 0.61
gestation in one trial64 and mean gestational age at deliv- (95% CI, 0.34–0.98); moderate-quality evidence), birth
ery in the remaining study68 . The study by El-Refaie weight < 1500 g (RR, 0.53 (95% CI, 0.35–0.80);
et al.69 did not collect data for some neonatal mor- moderate-quality evidence) and use of mechanical venti-
bidities, such as necrotizing enterocolitis, intraventricular lation (RR, 0.54 (95% CI, 0.36–0.81); moderate-quality
hemorrhage, proven neonatal sepsis and retinopathy of evidence) (Table 4). The number needed to treat to pre-
prematurity. vent one case of these adverse perinatal outcomes varied
The risk of bias in each included study is summarized in from 6 to 8. There was no evidence of an effect of vagi-
Figure 2. All studies had adequate generation of allocation nal progesterone on necrotizing enterocolitis (low-quality
sequence and concealment of allocation, and appeared evidence), intraventricular hemorrhage (low-quality evi-
to be free of selective outcome reporting and other dence), proven neonatal sepsis (low-quality evidence),
sources of bias. Five studies were considered to be at retinopathy of prematurity (low-quality evidence), fetal
low risk of selection, performance, detection, attrition death (very low-quality evidence), birth weight < 2500 g
and reporting biases64–68 . The study by El-Refaie et al.69 (moderate-quality evidence) and admission to the neona-
had a high risk of performance and detection biases tal intensive care unit (moderate-quality evidence).
because patients, clinical staff and outcome assessors were
not blinded to the allocated interventions. In addition, Subgroup and sensitivity analyses
this trial was judged to be at unclear risk of attrition
bias because the number of losses to follow-up was Subgroup analyses of the effect of vaginal progesterone on
not balanced across study groups (7.2% in the vaginal preterm birth < 33 weeks’ gestation and neonatal death,
progesterone group and 13.6% in the no treatment according to CL, daily dose of vaginal progesterone
group). and obstetric history, are shown in Table 5. There
Published 2017. This article is a U.S. Government work and is in the public domain in the USA. Ultrasound Obstet Gynecol 2017; 49: 303–314.
Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.
308
Women with
CL ≤ 25 mm
Primary target (n)/fetuses or Primary outcome
Study Country population Inclusion and exclusion criteria infants (n) Intervention measure
Fonseca (2007)64 UK, Chile, Women with Inclusion: women with singleton or twin gestation and transvaginal 24/48 Vaginal progesterone capsule Spontaneous
Brazil, Greece short cervix sonographic CL ≤ 15 mm (200 mg/day) or placebo from PTB < 34 weeks
Exclusion: major fetal abnormality, painful regular uterine contractions, 24 to 33 + 6 weeks
history of ruptured membranes or cervical cerclage
Cetingoz (2011)65 Turkey Women at high Inclusion: women with at least one previous spontaneous PTB, uterine 7/14 Vaginal progesterone suppository PTB < 37 weeks
risk of PTB malformation or twin gestation (100 mg/day) or placebo from
Exclusion: in-place or planned cervical cerclage or serious fetal anomaly 24 to 34 weeks
Rode (2011)66 Denmark, Women with Inclusion: women with a diamniotic twin gestation and chorionicity 21/42 Vaginal progesterone pessary PTB < 34 weeks
Austria twin gestation assessed by ultrasound before 16 weeks (200 mg/day) or placebo from
Exclusion: higher order multiple pregnancies, age < 18 years, known 20 to 23 + 6 up to
allergy to progesterone or peanuts as active treatment contained peanut 33 + 6 weeks
oil, history of hormone-associated thromboembolic disorders, rupture
of membranes, pregnancies treated for or with signs of TTTS,
intentional fetal reduction, known major structural or chromosomal
fetal abnormality, known or suspected malignancy in genitals or breasts
or known liver disease
Serra (2013)67 Spain Women with Inclusion: women with dichorionic diamniotic twin gestation 6/12 Vaginal progesterone pessary PTB < 37 weeks
twin gestation Exclusion: monochorionic twin gestation, triplet or higher order multiple (200 or 400 mg/day) or
gestation, elective cervical cerclage prior to 14 weeks, history of hepatic placebo from 20 to 34 weeks
problem or gestational cholestasis, abnormal liver enzymes, abnormal
kidney function, local allergy to micronized natural progesterone or
peanuts, recurrent vaginal bleeding, recurrent vaginal infection, fetal
Published 2017. This article is a U.S. Government work and is in the public domain in the USA.
anomaly, alcohol or illicit drug consumption or
smoking ≥ 10 cigarettes/day
Brizot (2015)68 Brazil Women with Inclusion: women with naturally conceived diamniotic twin gestation, no 21/42 Vaginal progesterone ovule Mean gestational
twin gestation previous PTB and gestational age between 18 + 0 and 21 + 6 weeks (200 mg/day) or placebo from age at delivery
Exclusion: major fetal abnormality, allergy to progesterone or peanuts, 18 to 21 + 6 up to
hepatic dysfunction, porphyria, otosclerosis, malignant disease, severe 34 + 6 weeks
depressive state, current or previous thromboembolic disease, uterine
malformation, prophylactic cerclage or ovular infection
El-Refaie (2016)69 Egypt Women with Inclusion: women with dichorionic twin gestation, gestational age 224/448 Vaginal progesterone suppository PTB < 34 weeks
twin gestation between 20 and 24 weeks, transvaginal sonographic CL between 20 and (400 mg/day) from 20 to 24 up
and short 25 mm, and without signs or symptoms of preterm labor to 37 weeks or no treatment
cervix Exclusion: known allergy or contraindication to progesterone therapy,
monochorionic twin gestation, known major fetal structural or
chromosomal abnormality, single fetal demise, fetal reduction in
current pregnancy, cervical cerclage in current pregnancy, medical
conditions that may lead to preterm labor, rupture of membranes or
vaginal bleeding
Only the first author of each study is given. CL, cervical length; PTB, preterm birth; TTTS, twin-to-twin transfusion syndrome.
Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.
Ultrasound Obstet Gynecol 2017; 49: 303–314.
Romero et al.
Vaginal progesterone decreases preterm birth in twin gestation with short cervix 309
6 ) 69
) 65
efa 07) 64
) 68
11
3) 67 gestation and neonatal death was non-significant (RR,
1) 66
tin (201
20
15
0
0.77 (95% CI, 0.48–1.24) and 0.56 (95% CI, 0.21–1.48),
01
Fo 201
z(
(2
20
ie
go
(2
t(
ec
e(
izo
rra
ns
-R
d
Ro
Ce
Br
Se
Vaginal Placebo/no
Relative risk (fixed) progesterone treatment Weight Relative risk
Study (95% CI) (n/N) (n/N) (%) (95% CI)
Figure 3 Forest plot of the effect of vaginal progesterone on the risk of preterm birth < 33 weeks’ gestation. CI, confidence interval.
Published 2017. This article is a U.S. Government work and is in the public domain in the USA. Ultrasound Obstet Gynecol 2017; 49: 303–314.
Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.
310 Romero et al.
CI, confidence interval; NNT, number needed to treat; refs, reference numbers; RR, relative risk.
Respiratory distress syndrome 664–69 102/311 131/280 0.67 (0.55–0.82) 0.70 (0.56–0.89) 0 6 (4–16)
Necrotizing enterocolitis 564–68 1/82 0/68 1.00 (0.04–22.43) 1.07 (0.05–22.25) NA —
Intraventricular hemorrhage 564–68 2/80 2/68 0.93 (0.15–5.75) 1.47 (0.22–9.63) 0 —
Proven neonatal sepsis 564–68 4/80 7/68 0.44 (0.13–1.46) 0.59 (0.18–1.93) 0 —
Retinopathy of prematurity 564–68 1/80 1/68 0.42 (0.07–2.56) 0.45 (0.08–2.59) 17 —
Fetal death 664–69 9/318 9/288 0.57 (0.23–1.42) 0.68 (0.26–1.84) 0 —
Neonatal death 664–69 34/318 63/288 0.50 (0.34–0.71) 0.53 (0.35–0.81) 25 8 (5–19)
Perinatal death 664–69 43/318 72/288 0.51 (0.36–0.70) 0.58 (0.39–0.84) 24 7 (5–20)
Composite neonatal 564–68 23/84 28/70 0.57 (0.36–0.93) 0.61 (0.34–0.98) 0 6 (3–109)
morbidity/mortality*
Birth weight < 1500 g 664–69 48/315 73/280 0.52 (0.38–0.72) 0.53 (0.35–0.80) 17 7 (5–17)
Birth weight < 2500 g 664–69 244/315 223/280 0.97 (0.89–1.06) 0.99 (0.89–1.10) 0 —
Admission to the NICU 664–69 211/315 209/282 0.92 (0.83–1.02) 0.95 (0.84–1.08) 0 —
Mechanical ventilation 664–69 49/311 76/280 0.52 (0.37–0.71) 0.54 (0.36–0.81) 0 7 (5–17)
*Occurrence of any of the following events: respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, proven
neonatal sepsis or neonatal death. CI, confidence interval; NA, not applicable; NICU, neonatal intensive care unit; NNT, number needed to
treat; refs, reference numbers; RR, relative risk.
exposed prenatally to vaginal progesterone had a signif- use of mechanical ventilation. Moreover, evidence from
icantly lower risk of having a low total ASQ score than two trials that assessed vaginal progesterone in unselected
those who were exposed to placebo (OR, 0.34 (95% CI, twin gestations showed that there were no significant
0.14–0.86)). differences in the risk of neurodevelopmental disability at
4–5 years of age between children exposed prenatally to
vaginal progesterone and those exposed to placebo.
DISCUSSION
Principal findings Quality of the evidence
The main finding in this updated IPD meta-analysis Evidence for most critical outcomes assessed with GRADE
is that the administration of vaginal progesterone methodology was considered to be of moderate quality
to asymptomatic women with a twin gestation and (Table S1). We downgraded the evidence from high
a mid-trimester sonographic short cervix significantly quality to moderate quality because most of the pooled
reduces the risk of preterm birth < 33 weeks’ gestation effect was provided by one study with moderate risk of
(primary outcome) by 31% and neonatal death by 47%. bias. A judgment of moderate quality means that we have
In addition, patients who received vaginal progesterone some confidence that our results approach the true impact
had a significantly decreased risk of preterm birth < 35, of vaginal progesterone on preterm birth and adverse
< 34, < 32 and < 30 weeks, spontaneous preterm birth neonatal outcomes in twin gestations with a short cervix;
< 33 and < 34 weeks, perinatal death, composite neonatal at the same time, we acknowledge that future trials may
morbidity and mortality, RDS, birth weight < 1500 g and change these results.
Published 2017. This article is a U.S. Government work and is in the public domain in the USA. Ultrasound Obstet Gynecol 2017; 49: 303–314.
Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.
Vaginal progesterone decreases preterm birth in twin gestation with short cervix 311
Table 5 Subgroup analyses of the effect of vaginal progesterone on preterm birth < 33 weeks’ gestation and neonatal death
*Adjusted for non-independence between twins. CI, confidence interval; RR, relative risk.
Published 2017. This article is a U.S. Government work and is in the public domain in the USA. Ultrasound Obstet Gynecol 2017; 49: 303–314.
Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.
312 Romero et al.
who were exposed prenatally to vaginal progesterone. Some potential limitations must also be considered.
However, these differences became non-significant after First, only two trials were specifically designed to assess
Bonferroni adjustment for multiple comparisons. In the efficacy of vaginal progesterone in women with a twin
conclusion, second- and third-trimester exposure to gestation and a sonographic short cervix. Second, 74%
vaginal progesterone does not seem to have harmful effects of the total sample size of the IPD meta-analysis was pro-
on the childhood health of twins. vided by one study69 , which included women with a CL
between 20 and 25 mm and was not placebo-controlled.
However, it should be highlighted that assessment
Lack of adverse maternal events
and measurement of most outcomes included in our
In our previous IPD meta-analysis47 , in which all included review are considered objective in nature, and therefore
studies used vaginal progesterone 90–200 mg/day, the not likely to be influenced by lack of blinding49 . It
rates of maternal adverse effects, such as vaginal is noteworthy that estimates of pooled RRs obtained
discharge, vaginal pruritus and discontinuation of after excluding this study were not significantly different
treatment because of adverse effects, were similar between from those obtained in the overall analyses. Moreover,
the vaginal progesterone and placebo groups. In 2013, the the significant 39% reduction in the risk of composite
three-armed trial by Serra et al.67 comparing placebo with neonatal morbidity and mortality associated with vaginal
two different daily doses of vaginal progesterone (200 progesterone administration was obtained without
and 400 mg) reported a dose-dependent, non-significant including data from the study by El-Refaie et al.69 in the
trend towards a higher rate of intrahepatic cholestasis of meta-analysis. Third, the larger study69 did not collect
pregnancy (0% in the placebo group, 1% in the group information about several neonatal morbidities, such as
receiving 200 mg and 5% in the group receiving 400 mg). necrotizing enterocolitis, intraventricular hemorrhage,
Nonetheless, the larger study by El-Refaie et al.69 reported proven neonatal sepsis and retinopathy of prematurity.
that there was no significant difference in the rate of Finally, some subgroup analyses included a small number
intrahepatic cholestasis of pregnancy between the group of patients, which limits the statistical power to estimate
using 400 mg of daily vaginal progesterone (1%) and the the effects within these subgroups.
no treatment group (0%). Moreover, this study found that
the rates of vaginal pruritus, vaginal discharge, headache,
skin rash and gastrointestinal symptoms did not differ Implications for practice and research
significantly between the study groups. Thus, it appears
This updated IPD meta-analysis indicates that vaginal
that a 400-mg daily dose of vaginal progesterone is not
progesterone reduces the risk of preterm birth and
associated with an increased risk of adverse maternal
neonatal morbidity and mortality in patients with a
effects as compared with a 200-mg daily dose of vaginal
twin gestation and a sonographic short cervix, without
progesterone or placebo/no treatment.
any deleterious effects on childhood neurodevelopment.
Although the results of our meta-analysis appear
Strengths and limitations promising, further research is required before conclusive
advice can be provided with regard to the benefits
The main strengths of our meta-analysis include: (i) the of using vaginal progesterone in women with a twin
use of patient-level data, which offer several advantages gestation and a short cervix. Evidence from this updated
over study-level analysis, including the ability to use IPD meta-analysis and three ongoing RCTs comparing
more appropriate statistical methods not always feasible vaginal progesterone with placebo (NCT02697331 and
using study-level analysis, define outcome measures NCT02518594) or no treatment (NCT02329535) in
consistently across studies, investigate subgroups in which ∼750 women with a twin gestation and a sonographic
treatment may be either more or less effective, address short cervix will help to determine whether vaginal
questions that have not been satisfactorily resolved by progesterone can be recommended to these patients
individual trials, minimize publication and reporting with the aim of preventing preterm birth and improving
biases and adjust for prognostic variables that may perinatal outcomes.
have confounded the original treatment comparisons;
(ii) the baseline balance in prognostic factors between
the two study groups, which reduces the possibility ACKNOWLEDGMENT
of causing bias in the intervention effect estimates;
(iii) the absence of substantial heterogeneity in most of This research was supported, in part, by the Peri-
the meta-analyses performed; indeed, all meta-analyses on natology Research Branch, Program for Perinatal
the effect of vaginal progesterone on preterm birth had no Research and Obstetrics, Division of Intramural Research,
observed heterogeneity (I2 = 0%), whereas the majority Eunice Kennedy Shriver National Institute of Child
of meta-analyses regarding adverse perinatal outcomes Health and Human Development, National Institutes
had low heterogeneity or no heterogeneity; and (iv) the of Health, Department of Health and Human Ser-
sensitivity analyses restricted to trials at low risk of bias vices (NICHD/NIH/DHHS); and, in part, with Federal
that were consistent with (and thus supportive of) the funds from NICHD/NIH/DHHS under Contract No.
overall findings. HHSN275201300006C.
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Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.
Vaginal progesterone decreases preterm birth in twin gestation with short cervix 313
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The following supporting information may be found in the online version of this article:
Table S1 Summary of findings of the quality of evidence for each outcome measure
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