MATERNAL-FETAL MEDICINE
Progestogens for preterm birth prevention: a systematic reviewand meta-analysis by drug route
Digna R. Velez Edwards • Frances E. Likis • Jeffrey C. Andrews •
Alison L. Woodworth • Rebecca N. Jerome • Christopher J. Fonnesbeck •
J. Nikki McKoy • Katherine E. Hartmann
Received: 14 December 2012 / Accepted: 5 March 2013 / Published online: 27 March 2013
� Springer-Verlag Berlin Heidelberg 2013
Abstract
Purpose Progestogen has been investigated as a pre-
ventive intervention among women with increased preterm
birth risk. Our objective was to systematically review the
effectiveness of intramuscular (IM), vaginal, and oral
progestogens for preterm birth and neonatal death
prevention.
Methods We included articles published from January
1966 to January 2013 and found 27 randomized trials with
data for Bayesian meta-analysis.
Results Across all studies, only vaginal and oral routes
were effective at reducing preterm births (IM risk ratio
[RR] 0.95, 95 % Bayesian credible interval [BCI]:
0.88–1.03; vaginal RR 0.87, 95 % BCI: 0.80–0.94; oral RR
0.64, 95 % BCI: 0.49–0.85). However, when analyses were
limited to only single births all routes were effective at
reducing preterm birth (IM RR 0.77, 95 % BCI: 0.69–0.87;
vaginal RR 0.80, 95 % BCI: 0.69–0.91; oral RR 0.66, 95 %
BCI: 0.47–0.84). Only IM progestogen was effective at
reducing neonatal deaths (IM RR 0.78, 95 % BCI:
0.56–0.99; vaginal RR 0.75, 95 % BCI: 0.45–1.09; oral RR
0.72, 95 % BCI: 0.09–1.74). Vaginal progestogen was
effective in reducing neonatal deaths when limited to sin-
gletons births.
Conclusions All progestogen routes reduce preterm births
but not neonatal deaths. Future studies are needed that
directly compare progestogen delivery routes.
Keywords Preterm birth � Meta-analysis � Review �Pregnancy � Progestogen
Electronic supplementary material The online version of thisarticle (doi:10.1007/s00404-013-2789-9) contains supplementarymaterial, which is available to authorized users.
D. R. Velez Edwards (&) � J. C. Andrews � K. E. Hartmann
Vanderbilt Epidemiology Center, Institute for Medicine and
Public Health, 2525 West End Ave., Suite 600 6th Floor,
Nashville, TN 37203, USA
e-mail: [email protected]
D. R. Velez Edwards � J. C. Andrews � K. E. Hartmann
Department of Obstetrics and Gynecology, Vanderbilt
University Medical Center, Nashville, TN, USA
F. E. Likis � K. E. Hartmann
Vanderbilt Evidence-based Practice Center, Institute for
Medicine and Public Health, Nashville, TN, USA
F. E. Likis � J. Nikki McKoy
Department of Medicine, Vanderbilt University Medical Center,
Nashville, TN, USA
A. L. Woodworth
Department of Pathology, Microbiology and Immunology,
Nashville, TN, USA
R. N. Jerome
Department of Biomedical Informatics, Nashville, TN, USA
R. N. Jerome
Eskind Biomedical Library, Vanderbilt University Medical
Center, Nashville, TN, USA
C. J. Fonnesbeck
Department of Biostatistics, Vanderbilt University Medical
Center, Nashville, TN, USA
123
Arch Gynecol Obstet (2013) 287:1059–1066
DOI 10.1007/s00404-013-2789-9
Purpose
Preterm birth is the predominant cause of perinatal mor-
tality in the United States [1]. Efforts to predict impending
preterm birth and delay its occurrence have experienced
limited success [2–4], thus a focus on primary intervention
has become a priority [5]. Attention has increasingly
focused on methods to prevent preterm birth using earlier
interventions to treat women based on risks rather than
symptoms.
Progestogen administration has been investigated as a
preventive intervention across several groups of women
with increased risk of preterm birth, such as those with
prior preterm birth, multiple gestation, a short cervix, or
symptoms of preterm labor. Progestogens, the encom-
passing term for natural progesterone, pharmacologic
agents that are chemically identical to endogenous pro-
gesterone, and synthetic progestins that are similar but not
identical in chemical structure [6], can be administered
orally, vaginally, or via injection. In February 2011, the US
Food and Drug Administration approved the Makena
(hydroxyprogesterone caproate) injection for the preven-
tion of preterm birth for women with a history of at least
one spontaneous preterm birth [7]. However, in January of
2012, the FDA did not approve progesterone gels for the
prevention of preterm birth among at-risk women with a
short cervix.
There is currently limited understanding about the
pharmaceutical mechanisms of action of progestogens and
there are no studies directly comparing progestogen drug
delivery routes. This is of concern to clinicians prescribing
progestogens for the prevention of preterm birth due to the
substantial expense of administering progestogens, the
poor understanding of the effects of sex hormones on
pregnant women and their fetuses, and the multiple for-
mulations and delivery routes that are available. In order to
build upon prior systematic reviews that have examined the
effectiveness of individual progestogen delivery routes
within subsets of women with specific indications for use,
we examined the effectiveness across the different pro-
gestogen delivery routes and formulations for preventing
preterm birth [8–12]. Our objective was to systematically
review the effectiveness of intramuscular, vaginal, and oral
administration of progestogens for prevention of preterm
birth.
Methods
Sources
We searched MEDLINE� and EMBASE for English lan-
guage articles published from January 1966 to January
2013. Controlled vocabulary terms served as the founda-
tion of our search, complemented by additional keyword
phrases to represent the myriad ways in which progesto-
gens and preterm labor are referred to in the clinical lit-
erature [13]. We also hand-searched references of included
articles to identify studies. This was a systematic review of
existing literature. No IRB approval is required for syn-
thesis of findings from existing literature.
Study selection
We included randomized controlled trials (RCTs) with 20
or more women in order to have adequate power for sta-
tistical analyses. We included all formulations and drug
delivery routes. Our searches were executed between
August 2009 and January 2013.
Two reviewers separately evaluated the abstracts for
inclusion or exclusion. If one reviewer concluded the
article could be eligible based on the abstract, we retained
it. Full publications were then independently reviewed for
final inclusion. All team members shared the task of
entering information into evidence tables [13]. After data
extraction, another member checked table entries for
accuracy, completeness, and consistency; inconsistencies
were adjudicated by team members. The team evaluating
the literature included two physicians, a certified nurse-
midwife and nurse practitioner, three biomedical
researchers, and two library scientists.
The primary outcomes extracted from articles were
preterm birth [less than 33 (singleton with short cervix), 34
(multiples and singleton with short cervix), 35 (multiples),
Non duplicate articles identified in search
n = 524Literature search: n = 433Hand-search: n = 91
Full text articles reviewedn = 204
Articles excluded:n = 320
Articles excluded:n = 177
• Not related to the use of progestogens to prevent PTB (n= 83)
• Did not address study question(n=19)
• Not original research (n=33)• Ineligible study size (n=53)• Ineligible study type/not RCT
(n=5)• Ineligible secondary analysis of
primary data already included (n=1)
Unique full text articles included
in reviewn = 27 RCTs
Fig. 1 Flow chart of study selection. The number of manuscripts
excluded based on the different criteria in the fourth box do not add
up to the articles excluded (n = 177) because manuscripts may have
met more than one exclusion criteria
1060 Arch Gynecol Obstet (2013) 287:1059–1066
123
and 37 (singleton) weeks’ gestation] and neonatal death.
We also limited analyses only to major indications for
progestogen treatment that include prior preterm births,
preterm labor, short cervix, and multiple gestations. From
among 524 abstracts, and the review yielded a total of 27
full publications including relevant data for meta-analysis
(Fig. 1).
We conducted a Bayesian meta-analysis [14, 15] to
provide aggregate estimates of the effectiveness of pro-
gestogen treatment for preventing preterm birth and
reducing neonatal death. We constructed mixed-effects
models grouping RCTs by fixed treatment effects for the
progestogen drug delivery route for which the progestogens
were administered in the study (prior preterm births, pre-
term labor, short cervix, and multiple gestations). Study-
level baseline variation was modeled using random effects.
A total of 27 studies were included in the meta-analyses: 13
studies used injected 17-hydroxyprogesterone (17OHP) as
the drug delivery route, 11 used vaginal, and three used
oral. Due to an insufficient number of studies (1) for oral
delivery, this delivery route was excluded from the neo-
natal death outcome analysis. Statistical models or preterm
birth outcome also included a covariate adjustment for the
gestational age cut-off used to define preterm birth status,
as well as indications for treatment. Finally, two additional
sub-analyses were performed limiting studies to singleton
births and multiple gestations in order to assess whether the
effectiveness of the drug delivery route varied by singleton
compared to multiple gestation.
Meta-analyses were implemented in PyMC version 2.1
[16], to fit Bayesian hierarchical models using Markov
chain Monte Carlo (MCMC) algorithms [14]. To check the
fit of the model, we conducted posterior predictive checks,
which generate simulated datasets based on the fitted
model. The distribution of simulated datasets was then
compared to the observed data from the studies in the meta-
analysis. The observed data for each study fell within the
2.5th and 97.5th quantiles of the distributions of datasets
simulated from our model, suggesting acceptable fit of the
model to the data, with the exception of two studies of
preterm birth that had poor fit [17, 18]. Posterior estimates
of risk ratios (RRs) with 95 % Bayesian credible intervals
(BCIs) are provided.
To assess quality, two reviewers independently used a
worksheet to capture key elements of study design and
conduct [19]. Inconsistencies were resolved through review
of the publications, discussion, and consensus with the
team. Assessment of internal validity included: randomized
allocation, method of randomization, use of masking,
description of inclusion criteria, loss to follow-up, dropout
rates, power calculation, and recognition and description of
statistical issues. Assessment of external validity included:
description of baseline population, clear specification of
intervention, description of the outcomes, length of follow-
up for infant, outcome measurement, and reliability of
outcome measurement. A composite quality score of good,
fair, or poor was calculated for both internal and external
validity, and the study as a whole [13]. Individual study
quality scores are provided in Supplemental Material
(Table 1S).
Extracted data were used to assess the strength of evi-
dence of the aggregate literature for assessing effectiveness
of the intervention in relation to specific outcomes.
Strength was assessed in four domains: risk of bias, con-
sistency, directness and precision [20]. The possible grades
were: (1) High confidence that the evidence reflects the true
effect. Further research is unlikely to change estimates;
(2) Moderate confidence that the evidence reflects the true
effect. Further research may change our confidence in the
estimate of effect and may change the estimate; (3) Low
confidence that the evidence reflects the true effect. Further
research is likely to change confidence in the estimate
of effect and is also likely to change the estimate; or
(4) Insufficient meaning evidence is either unavailable or
does not permit a conclusion [13].
Results
We identified 27 publications meeting the criteria for
inclusion in meta-analysis [3, 4, 17, 18, 21–43]. Studies
that were secondary analyses of the same datasets were
counted only once. The most common progestogen in these
studies was the synthetic progestin 17OHP. Other inject-
able forms of progesterone used include crystalline pro-
gesterone and natural progesterone. Vaginal progestogens
were administered via suppositories, gels, and capsules.
Oral progestogens included medroxyprogesterone acetate
(trade names Provera and Perlutex), allylestrenol, and oral
chlormadinone acetate. Of these oral formulations, only
medroxyprogesterone acetate is currently available in the
United States. Across all studies, the most common pro-
gestogens and doses, by route, were: 250 mg of 17OHP
injected intramuscularly weekly, 200 mg progesterone
vaginal suppository or gel daily, and 100 to 1,000 mg oral
micronized progestogen daily. RCTs making direct com-
parisons of one form of progestogen to another have not
been conducted with currently available progestogens. A
single 1979 study comparing intramuscular 17OHP injec-
tions and oral chlormadinone acetate was the only head-
to-head comparison; however, it did not meet criteria for
inclusion in meta-analysis [44]. Among the studies that
reported on intramuscular 17OHP, vaginal, and oral pro-
gestogen the majority of studies (n = 9) were conducted in
the US [22–25, 28–30, 34, 38], seven in Europe [3, 4, 18,
26, 32, 35, 39], six in Asia [21, 33, 37, 40–42], three from
Arch Gynecol Obstet (2013) 287:1059–1066 1061
123
Table 1 Summary of RCTs by progestogen drug delivery route
Study country Formulation Dosea Outcomeb Effectc Target EGA, start; end
(weeks’)
Injected 17OHP
Grobman et al. [30] US IM 250 mg q 7d \35
\37
ND
RR = 0.84 (0.58,
1.21)
RR = 1.03 (0.79,
1.35)
RR = 0.76 (0.27,
2.16)
16–20; 36 ? 6
Rozenberg et al. [40]
France
IM 500 mg b.i.w. \34
\37
ND
NR p = 0.69
NR p = 0.76
NR p [ 0.99
24-31 ? 6; 36
Tan et al. [43] Malaysia IM 250 mg (single dose) \34
\37
RR = 0.61 (0.30,
1.27)
RR = 0.85 (0.63,
1.45)
22-35; NR
Combs et al. [26] US IM 250 mg q 7d \34 RR = 1.4 (0.7, 2.6) 16–23; 34
Lim et al. [33]
Netherlands
IM 250 mg q 7d ND Only RR = 0.60 (0.25,
1.43)
16-20; 36
Ibrahim et al. [32] Egypt IM 250 mg q 7d \37 RR = 0.079 (0.021,
0.302)
[14; 36
Combs et al. [25] US IM 250 mg q 7d \ 35 NR p = 0.15 \21 (80.4 %); 36
Caritis et al. [24] US IM 250 mg q 7d \ 35 RR = 1.0 (0.9, 1.1) 16–21; 35
Briery et al. [23] US IM 250 mg q 7d \35 NR p = 0.117 20–30; NR
Facchinetti et al. [27] Italy IM 341 mg q 4d \ 37 NR p = 0.049 25–34; 36
Rouse et al. [39] US IM 250 mg q 7d \35 RR = 1.1 (0.09, 1.3) 16–20; 36
Facchinetti et al. [3] Italy IM 341 mg q 4d \37 NR p = 0.004 25–34; 36
Meis et al. [35] US IM 250 mg q 7d \37 RR = 0.66 (0.54,
0.81)
16–21; 36
Vaginal
Saleh Gargari et al. [41]
Iran
Vaginal suppository 400 mg qd ND only NR p = 0.08 24–34; 37
Wood et al. [44] Canada Vaginal gel 90 mg qd \35
\37
RR = 0.87 (0.47,
1.59)
RR = 0.93 (0.66,
1.30)
16-20; 35 ? 6
Serra et al. [18] Spain VaginalPessaries 200 mg qd \34 NR p = NS 20–34; 34
400 mg qd \37 ND NR p = NS
NR p = NS
Rode et al. [17]
Multinational
VaginalPessaries 200 mg qd \34
\37
ND
OR = 0.8 (0.5–1.2)
OR = 0.8 (0.6–1.1)
NR
20–23 ? 6; 33 ? 6
Arikan et al. [22] Turkey Vaginal (NR) 200 mg qd \37 NR p = NS 24–34; 37
Fonseca et al. [28]
Multinational
Vaginal capsule 200 mg qd \34 RR = 0.60 (0.35,
0.94)
24; 34
Sharami et al. [42] Iran VaginalSuppository 200 mg qd \37 NR p = 0.098 28–36; 36
Hassan et al. [31] US Vaginal gel 90 mg qd \33 RR = 0.55 (0.33,
0.92)
C24 (98.5 %); 34
Majhi et al. [34] India Vaginal capsule 100 mg qd \37 RR = 0.315 (0.137,
0.724)
20–24; 36
O’Brien et al. [37]
Multinational
Vaginal gel 90 mg qd \37 OR = 0.93 (0.66,
1.32)
16–23; 37
1062 Arch Gynecol Obstet (2013) 287:1059–1066
123
multiple countries [17, 27, 36], one from Canada [43], and
one form Africa [42].
Intramuscular 17OHP Injection
We identified thirteen RCTs in which intramuscular
17OHP injections were administered for prevention of
preterm birth [3, 22–26, 29, 31, 32, 34, 38, 39, 42]. Exact
combinations of dose, interval, and target gestational age
windows are included in Table 1. Three different indica-
tions were used for intramuscular 17OHP treatment
including prior preterm birth in one trial [34], preterm
labor in five [3, 26, 31, 39, 42], multiple gestation in six
[22–25, 32, 38], and short cervix in one [29]. Four of
thirteen demonstrated effectiveness of 17OHP [3, 26, 31,
34], nine had nonsignificant findings [22–25, 29, 32, 38,
39, 42], and none found significant advantage for the
placebo group. One study only had data for neonatal death
analyses [32]. Aggregate estimates indicated that intra-
muscular17OHP injections were effective at reducing risk
for neonatal death (meta-estimate RR 0.78, 95 % BCI 0.56
to 0.99) but not effective at reducing risk of preterm birth
(meta-estimate RR 0.95, 95 % BCI 0.88 to 1.03) (Fig. 2).
However, when limiting to only singleton births meta-
estimates for both neonatal death (meta-estimate RR 0.53,
95 % BCI 0.22 to 0.85) and preterm birth showed evi-
dence of protection (meta-estimate RR 0.77, 95 % BCI
0.69 to 0.87). Among multiple gestations intramuscular
17OHP was not effective at reducing risk or neonatal
deaths (meta-estimate RR 0.93, 95 % BCI 0.61 to 1.28) or
preterm births (meta-estimate RR 1.05, 95 % BCI 0.95 to
1.15).
Vaginal
We identified eleven publications that reported on a vaginal
gel, capsule, or suppository for administering progestogen
treatment (Table 1) [17, 18, 21, 27, 30, 33, 35, 36, 40, 41, 43].
These studies included two different doses. The indication
for treatment was history of prior preterm birth in two
studies [33, 36], preterm labor in three [21, 40, 41], multiple
gestation in three [17, 18, 35, 43], and short cervix in two
[27, 30]. Overall, three of eleven demonstrated effective-
ness of vaginal progestogens [27, 30, 33], eight had non-
significant findings [17, 18, 21, 35, 36, 40, 41, 43], and none
found significant advantage for the placebo group. One
study only had data for neonatal death analyses [40].
Aggregate estimates indicated that vaginal progestogens
was not effective at reducing risk for neonatal death (meta-
estimate RR 0.75, 95 % BCI 0.45 to 1.09), but was effective
at reducing risk of preterm birth (meta-estimate RR 0.87,
95 % BCI 0.80 to 0.94) (Fig. 2). The meta-estimates again
showed evidence for protection from neonatal death (meta-
estimate RR 0.47, 95 % BCI 0.20 to 0.0.75) and preterm
birth (meta-estimate RR 0.80, 95 % BCI 0.69 to 0.91)
outcomes after limiting analyses to singleton births. The
meta-estimates did not show evidence for protection from
neonatal deaths (meta-estimate RR 1.20, 95 % BCI 0.53
to 1.92) or preterm births among multiple gestations
(meta-estimate RR 0.93, 95 % BCI 0.83 to 1.03).
Table 1 continued
Study country Formulation Dosea Outcomeb Effectc Target EGA, start; end
(weeks’)
Norman et al. [36] UK Vaginal gel 90 mg qd \34 OR = 0.74 (0.48,
1.12)
24; 34
Oral
Glover et al. [29] US Progesterone
(Micronized)
400 mg qd \37 RR = 0.55 (0.26,
1.16)
16–19; 33.9
Rai et al. [38] India Progesterone
(Micronized)
100 mg b.i.d \37 NR p = 0.002 18–24; 36
Noblot et al. [4] France Progesterone
(Micronized)
4 9 100 mg q6 h for
24 h;
4 9 100 mg q8 h for
24 h; then
3 9 100 mg q8 h
\37 NR p = NS NR
EGA estimated gestational agea Dose reported in milligrams, q 7d and q 4d indicates every seven and every four days, b.i.d. twice per day, b.i.w. twice per week, q6 h once
every 6 h, q8 h once every 8 hb ND neonatal deathc NS not statistically significant, NR not reported, RR relative risk
Arch Gynecol Obstet (2013) 287:1059–1066 1063
123
Oral
Three RCTs used oral progestogens alone or in combination
with ritodrine in the treatment group [4, 28, 37]. The three
RCTs reported prematurity outcomes at less than 37 week’s
(Table 1). Each of the three RCTs used different doses. Two
had prior preterm birth as an indication for treatment [28,
37] and one had preterm labor [4]. One of three demon-
strated effectiveness of oral progestogens [37], two had
non-significant findings [4, 28], and none found significant
advantage for the placebo group. Aggregate estimates
indicated that oral progestogens were the most effective at
reducing risk of preterm birth relative to the meta-estimates
for 17OHP and vaginal progestogens (meta-estimate RR
0.64, 95 % BCI 0.49 to 0.85) (Fig. 2). There was not suf-
ficient data to analyze neonatal death outcome among oral
progestogen studies. None of the studies included multiple
gestations as an indication for treatment and therefore no
stratified analyses were performed.
Quality of evidence
Overall the strength of evidence was insufficient or low.
Deficiencies in the strength of evidence most often related to
a preponderance of study designs with high-risk of bias;
inconsistent findings across studies and inconsistencies
among outcomes that would be expected to show corre-
sponding benefit; use of intermediate outcomes; and small
studies with poor precision. The quality ratings of individual
studies are provided in Supplemental Material (Table 1S).
Conclusions
In this systematic review of progestogens for prevention of
preterm birth, we sought evidence that drug delivery route
might modify treatment response. No direct comparisons of
one progestogen drug delivery route to another were
identified that would allow us to directly compare the
effectiveness of the formulations and routes of the pro-
gestogen intervention. However, meta-analyses stratifying
studies by drug delivery routes indicated that all three drug
delivery routes (intramuscular 17OHP injection, oral, and
vaginal) were effective at reducing the number of preterm
births across studies. The meta-estimates for risk of neo-
natal death indicated that intramuscular 17OHP and vagi-
nal progestogen routes were effective at reducing neonatal
death among singleton births.
Fig. 2 Estimates of risk ratio
for each study (with 95 %
Bayesian credible interval),
along with meta-estimates for
the effectiveness of each
progestogen drug delivery route
for the prevention of preterm
birth. Results for meta-analyses
of RCTs by drug delivery route
are presented for: intramuscular
17OHP injection (IM); vaginal
progestogen; oral progestogen.
The solid line on the X axis
indicates where RR = 1 and the
bolded line indicates the overall
meta-estimate RR. Black circlesindicate the RR for each
individual RCT and the overall
meta-estimate RR, while
horizontal bounded black linesindicate the 95 % BCI. Effect
sizes for individual studies were
calculated from analyses of data
abstracted from the published
manuscripts
1064 Arch Gynecol Obstet (2013) 287:1059–1066
123
In order to make direct comparisons across drug for-
mulations and delivery route other factors of study design
would need to be fully comparable to allow isolation of the
factor of interest such as drug delivery route. Unfortu-
nately, no head-to-head trials of currently available pro-
gestogens have been conducted (one 1979 trial of poor
quality is the only publication) [44]. Although we were
able to assess the consistency of effect size estimates by
drug delivery routes through meta-analysis, we were not
able to directly compare and determine the effectiveness of
one route compared to another without a head-to-head
comparison. As an extension of the lack of direct com-
parisons, it is not possible to determine with confidence
whether acceptability, adherence, adverse effects, or safety
of progestogens vary by progestogen route. Without head-
to-head comparisons it is possible that differences in
effectiveness of progestogen treatments arise solely from
underlying differences in populations.
We found no direct comparator studies that allowed us to
assess how the gestational age timing of progestogen drug
delivery may be influenced by drug delivery route. Among
the studies examined, only two clinical care cohorts had
varied timing of initiation of treatment (for reasons other
than randomization) and showed no significant difference in
preterm birth rates based upon whether the progestogen was
initiated before or after 21 weeks gestation [45, 46]. No
RCTs directly addressed modification of effectiveness by
timing of initiation by drug delivery route. Given variation
in pharmaceutical agents being studied, it is not possible to
extrapolate from trends in study findings to determine an
optimal time for initiation of treatment.
Without direct comparisons of different progestogen
drug delivery routes we were unable to assess whether
benefit or risk of harm varies for different progestogen drug
delivery routes. However, a detailed description of known
harms and side effects of progestogen treatments has been
previously published [13]. Reported side effects varied
with route of administration, the most common being
injection site reactions and vaginal discharge. However,
more severe effects have been reported, but are much less
common [13]. Given lack of detailed reporting about harms
and lack of consistent definitions, it is not meaningful to
extrapolate among routes from what data are available.
Harms data were not uniformly collected so comparisons
across studies cannot provide meaningful data to inform
clinical decisions. Overall, there is no evidence to help
inform selection of the progestogen with the fewest side
effects and/or lowest risk of harms.
The overall strength of evidence was insufficient or low,
supporting the need for further research into progestogen
drug delivery route. This review is built upon prior reviews
of progestogen delivery route by comprehensively exam-
ining progestogen indications for use and delivery routes,
as well by providing a more updated assessment of the
literature. The findings of this systematic review indicate
that all routes of progestogen are effective at reducing
preterm birth risk and worthy of further investigation, as
route is likely to influence acceptability, adherence, and
costs. Head-to-head comparisons of benefits and harms are
needed to determine the ideal route.
Acknowledgments This project was supported by the Agency for
Healthcare Research and Quality (contract number: 290-2007-10065-I).
We are indebted to a tireless and exceptional group of colleagues who
made this report possible. Each step of a systematic review draws on
the skills and attention of an entire team. Additional members of our
team include Dr. Steven Fox, Dr. Melissa McPheeters, Ms. Rachel
Weaver, Mr. Jeffrey Seroogy, Ms. Allison Glasser, Ms. Cheena
Clermont, Dr. Chris Slaughter, and Ms. Tracy Shields.
Conflict of interest We declare that we have no conflict of
interest.
References
1. Behrman RE, Butler AS, Institute of Medicine (US) (2007)
Committee on understanding premature birth and assuring heal-
thy outcomes. Preterm birth: causes, consequences, and preven-
tion. National Academies Press, Washington, xvi, 772
2. Borna S, Sahabi N (2008) Progesterone for maintenance tocolytic
therapy after threatened preterm labour: a randomised controlled
trial. Aust N Z J Obstet Gynaecol 48:58–63
3. Facchinetti F, Paganelli S, Comitini G, Dante G, Volpe A (2007)
Cervical length changes during preterm cervical ripening: effects
of 17-alpha-hydroxyprogesterone caproate. Am J Obstet Gynecol
196:453
4. Noblot G, Audra P, Dargent D, Faguer B, Mellier G (1991) The
use of micronized progesterone in the treatment of menace of
preterm delivery. Eur J Obstet Gynecol Reprod Biol 40:203–209
5. Kauppila A, Hartikainen-Sorri AL, Janne O, Tuimala R, Jarvinen
PA (1980) Suppression of threatened premature labor by
administration of cortisol and 17 alpha-hydroxyprogesterone
caproate: a comparison with ritodrine. Am J Obstet Gynecol
138:404–408
6. Brucker MC, Likis FE (2011) Steroid hormones. Pharmacology
for Women’s Health
7. FDA approves drug to reduce risk of preterm birth in at-risk preg-
nant women (2011) United States Food and Drug Administration
8. Dodd JM, Flenady V, Cincotta R, Crowther CA (2006) Prenatal
administration of progesterone for preventing preterm birth.
Cochrane Database Syst Rev CD004947
9. Gallo MF, Grimes DA, Lopez LM, Schulz KF, d’Arcangues C
(2008) Combination injectable contraceptives for contraception.
Cochrane Database Syst Rev CD004568
10. Gallo MF, Nanda K, Grimes DA, Lopez LM, Schulz KF (2008)
20 lg versus [20 lg estrogen combined oral contraceptives for
contraception. Cochrane Database Syst Rev CD003989
11. Romero R, Nicolaides K, Conde-Agudelo A, Tabor A, O’Brien
JM, Cetingoz E et al (2012) Vaginal progesterone in women with
an asymptomatic sonographic short cervix in the midtrimester
decreases preterm delivery and neonatal morbidity: a systematic
review and metaanalysis of individual patient data. Am J Obstet
Gynecol 206:124
Arch Gynecol Obstet (2013) 287:1059–1066 1065
123
12. Smith V, Devane D, Begley CM, Clarke M, Higgins S (2009) A
systematic review and quality assessment of systematic reviews
of randomised trials of interventions for preventing and treating
preterm birth. Eur J Obstet Gynecol Reprod Biol 142:3–11
13. Likis FE, Andrews JC, Woodworth AL, Velez Edwards DR,
Jerome RN, Fonnesbeck CJ et al (2012) Progestogens for pre-
vention of preterm birth. Agency for Healthcare Research and
Quality, Rockville
14. Gelman A, Carlin J, Stern H, Rubin DB (2004) Bayesian Data
Analysis
15. Sutton A, Abrams K (2001) Bayesian methods in meta-analysis
and evidence synthesis
16. Patil A, Huard D, Fonnesbeck C (2010) Bayesian stochastic
modelling in python. J Stat Softw 35:1–80
17. Rode L, Klein K, Nicolaides KH, Krampl-Bettelheim E, Tabor A
(2011) Prevention of preterm delivery in twin gestations (PRE-
DICT): a multicenter, randomized, placebo-controlled trial on the
effect of vaginal micronized progesterone. Ultrasound Obstet
Gynecol 38:272–280
18. Serra V, Perales A, Meseguer J, Parrilla JJ, Lara C, Bellver J et al
(2013) Increased doses of vaginal progesterone for the prevention
of preterm birth in twin pregnancies: a randomised controlled
double-blind multicentre trial. BJOG Int J Obstet Gynaecol
120:50–57
19. Schulz KF, Chalmers I, Hayes RJ, Altman DG (1995) Empirical
evidence of bias. Dimensions of methodological quality associ-
ated with estimates of treatment effects in controlled trials.
JAMA 273:408–412
20. Hadjigeorgiou E, Malamitsi-Puchner A, Lolis D, Lazarides P,
Nicolopoulos D, Kaskarelis D (1982) Cardiovascular birth
defects and antenatal exposure to female sex hormones. Dev
Pharmacol Ther 5:61–67
21. Arikan I, Barut A, Harma M, Harma IM (2011) Effect of pro-
gesterone as a tocolytic and in maintenance therapy during pre-
term labor. Gynecol Obstet Invest 72:269–273
22. Briery CM, Veillon EW, Klauser CK, Martin RW, Chauhan SP,
Magann EF et al (2009) Progesterone does not prevent preterm
births in women with twins. South Med J 102:900–904
23. Caritis SN, Rouse DJ, Peaceman AM, Sciscione A, Momirova V,
Spong CY et al (2009) Prevention of preterm birth in triplets
using 17 alpha-hydroxyprogesterone caproate: a randomized
controlled trial. Obstet Gynecol 113:285–292
24. Combs CA, Garite T, Maurel K, Das A, Porto M (2010) Failure
of 17-hydroxyprogesterone to reduce neonatal morbidity or pro-
long triplet pregnancy: a double-blind, randomized clinical trial.
Am J Obstet Gynecol 203:248
25. Combs CA, Garite T, Maurel K, Das A, Porto M (2011)
17-hydroxyprogesterone caproate for twin pregnancy: a double-
blind, randomized clinical trial. Am J Obstet Gynecol 204:221
26. Facchinetti F, Dante G, Venturini P, Paganelli S, Volpe A (2008)
17alpha-hydroxy-progesterone effects on cervical proinflamma-
tory agents in women at risk for preterm delivery. Am J Perinatol
25:503–506
27. Fonseca EB, Celik E, Parra M, Singh M, Nicolaides KH (2007)
Progesterone and the risk of preterm birth among women with a
short cervix. N Engl J Med 357:462–469
28. Glover MM, McKenna DS, Downing CM, Smith DB, Croom CS,
Sonek JD (2011) A randomized trial of micronized progesterone
for the prevention of recurrent preterm birth. Am J Perinatol
28:377–381
29. Grobman WA, Thom EA, Spong CY, Iams JD, Saade GR,
Mercer BM et al (2012) 17 alpha-hydroxyprogesterone caproate
to prevent prematurity in nulliparas with cervical length less than
30 mm. Am J Obstet Gynecol 207:390
30. Hassan SS, Romero R, Vidyadhari D, Fusey S, Baxter JK,
Khandelwal M et al (2011) Vaginal progesterone reduces the rate
of preterm birth in women with a sonographic short cervix: a
multicenter, randomized, double-blind, placebo-controlled trial.
Ultrasound Obstet Gynecol 38:18–31
31. Ibrahim M, Mohamed Ramy AR, Younis MAF (2010) Proges-
terone supplementation for prevention of preterm labor: A ran-
domized controlled trial. 15 Middle East. Fertility Soc J 1:39–41
32. Lim AC, Schuit E, Bloemenkamp K, Bernardus RE, Duvekot JJ,
Erwich JJ et al (2011) 17alpha-hydroxyprogesterone caproate for
the prevention of adverse neonatal outcome in multiple pregnan-
cies: a randomized controlled trial. Obstet Gynecol 118:513–520
33. Majhi P, Bagga R, Kalra J, Sharma M (2009) Intravaginal use of
natural micronised progesterone to prevent pre-term birth: a
randomised trial in India. J Obstet Gynaecol 29:493–498
34. Meis PJ, Klebanoff M, Thom E, Dombrowski MP, Sibai B,
Moawad AH et al (2003) Prevention of recurrent preterm delivery
by 17 alpha-hydroxyprogesterone caproate. N Engl J Med 348:
2379–2385
35. Norman JE, Mackenzie F, Owen P, Mactier H, Hanretty K,
Cooper S et al (2009) Progesterone for the prevention of preterm
birth in twin pregnancy (STOPPIT): a randomised, double-blind,
placebo-controlled study and meta-analysis. Lancet 373:2034–
2040
36. O’Brien JM, Adair CD, Lewis DF, Hall DR, Defranco EA, Fusey
S et al (2007) Progesterone vaginal gel for the reduction of
recurrent preterm birth: primary results from a randomized,
double-blind, placebo-controlled trial. Ultrasound Obstet Gyne-
col 30:687–696
37. Rai P, Rajaram S, Goel N, Ayalur Gopalakrishnan R, Agarwal R,
Mehta S (2009) Oral micronized progesterone for prevention of
preterm birth. Int J Gynaecol Obstet 104:40–43
38. Rouse DJ, Caritis SN, Peaceman AM, Sciscione A, Thom EA,
Spong CY et al (2007) A trial of 17 alpha-hydroxyprogesterone
caproate to prevent prematurity in twins. N Engl J Med 357:454–461
39. Rozenberg P, Chauveaud A, Deruelle P, Capelle M, Winer N,
Desbriere R et al (2012) Prevention of preterm delivery after
successful tocolysis in preterm labor by 17 alpha-hydro-
xyprogesterone caproate: a randomized controlled trial. Am J
Obstet Gynecol 206:e1–9
40. Saleh Gargari S, Habibolahi M, Zonobi Z, Khani Z, Sarfjoo FS,
Kazemi Robati A et al (2012) Outcome of vaginal progesterone
as a tocolytic agent: Randomized clinical trial. ISRN Obstet
Gynecol 2012:607906
41. Sharami SH, Zahiri Z, Shakiba M, Milani F (2010) Maintenance
therapy by vaginal progesterone after threatened idiopathic pre-
term labor: a randomized placebo-controlled double-blind trial.
Int J Fert Steril 4:45–50
42. Tan PC, King AS, Vallikkannu N, Omar SZ (2012) Single dose
17 alpha-hydroxyprogesterone caproate in preterm labor: a ran-
domized trial. Arch Gynecol Obstet 285:585–590
43. Wood S, Ross S, Tang S, Miller L, Sauve R, Brant R (2012)
Vaginal progesterone to prevent preterm birth in multiple preg-
nancy: a randomized controlled trial. J Perinat Med 40:593–599
44. Breart G, Lanfranchi M, Chavigny C, Rumeau-Rouquette C,
Sureau C (1979) A comparative study of the efficiency of
hydroxyprogesterone caproate and of chlormadinone acetate in
the prevention of premature labor. Int J Gynaecol Obstet 16:
381–384
45. Gonzalez-Quintero VH, Istwan NB, Rhea DJ, Smarkusky L,
Hoffman MC, Stanziano GJ (2007) Gestational age at initiation
of 17-hydroxyprogesterone caproate (17P) and recurrent preterm
delivery. J Matern Fetal Neonatal Med 20:249–252
46. How HY, Barton JR, Istwan NB, Rhea DJ, Stanziano GJ (2007)
Prophylaxis with 17 alpha-hydroxyprogesterone caproate for
prevention of recurrent preterm delivery: does gestational age at
initiation of treatment matter? Am J Obstet Gynecol 197:260
1066 Arch Gynecol Obstet (2013) 287:1059–1066
123