Prematurity: Review
Progestogens as Maintenance Treatment in
Arrested Preterm Labor
A Systematic Review and Meta-analysis
Montse Palacio, MD, PhD, Stefania Ronzoni, MD, PhD,
and Kellie E. Murphy, MD, MSc
OBJECTIVE: To evaluate the efficacy of maintenance
tocolysis with progestogens compared with placebo or
no treatment in women with singleton pregnancies and
arrested preterm labor.
DATA SOURCES: Studies without language restrictions
were identified from MEDLINE, EMBASE, PubMed, Sco-
pus, the Cochrane Pregnancy and Childbirth Groups Tri-
als Register, the Cochrane Central Register of Controlled
Trials, and ClinicalTrials.gov from inception to June 2015.
MeSH headings for progestogens were combined with
terms regarding labor, tocolysis, or preterm birth. Refer-
ence lists of included studies and GoogleSearch were
also reviewed.
METHODS OF STUDY SELECTION: Randomized con-
trolled trials that compared progestogens as a mainte-
nance treatment after arrested preterm labor in singleton
pregnancies with placebo or no treatment were identi-
fied. Selected studies evaluated delivery before 37 or 34
weeks of gestation or the latency period from random-
From the BCNatalBarcelona Center for Maternal-Fetal and Neonatal Medicine
(Hospital Clnic and Hospital Sant Joan de Deu), Fetal i+D Fetal Medicine
Research Center, IDIBAPS, University of Barcelona, Barcelona, and the Centre
for Biomedical Research on Rare Diseases (CIBER-ER), Spain; the Department
of Obstetrics and Gynaecology, Mount Sinai Hospital, University of Toronto,
Toronto, Ontario, Canada; and the Department of Obstetrics and Gynecology,
Division of Maternal-Fetal Medicine, University of Florida Health Science
Center, Jacksonville, Florida.
Montse Palacio was supported by Instituto de Salud Carlos III (BA15/00028
and EC07/90023) and Ministerio de Sanidad y Poltica Social (TRA-096).
The authors thank Daphne Horn, Research Librarian at Mount Sinai Hospital,
for help with the literature search, and Josie Chundamala, Scientific Grant
Editor in the Department of Obstetrics and Gynaecology at Mount Sinai Hos-
pital, for editorial assistance.
Corresponding author: Montse Palacio, MD, PhD, BCNatal, Barcelona Centre for
Maternal-Fetal and Neonatal Medicine, Hospital Clnic, Sabino de Arana 1, 08028
Barcelona, Spain; e-mail: mpalacio@clinic.cat.
Financial Disclosure
The authors did not report any potential conflicts of interest.
2016 by The American College of Obstetricians and Gynecologists. Published
by Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 0029-7844/16
VOL. 128, NO. 5, NOVEMBER 2016
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Luis Snchez-Ramos, MD,
ization to delivery. Excluded studies used progestogens
as prevention in asymptomatic women at risk. Risk of
bias assessment, subgroup analysis on type of proges-
togens used, and sensitivity analysis by high-quality
studies were performed.
TABULATION, INTEGRATION, AND RESULTS: Sixteen
randomized controlled trials consisting of 1,917 partic-
ipants were included. Study characteristics and quality
were recorded. Preterm delivery at less than 37 weeks of
gestation was decreased (38.2% compared with 44.3%;
relative risk 0.79, 95% confidence interval [CI] 0.650.97)
and pregnancy was prolonged (mean difference 8.1 days;
95% CI 3.812.4) when women treated with progesto-
gens were compared with placebo or no treatment.
There were no differences in the outcome of delivery
at less than 34 weeks of gestation (15.6% compared with
18.3%; relative risk 0.77, 95% CI 0.531.12). However,
sensitivity analysis including five high-quality studies
showed no significant differences for preterm delivery
at less than 37 weeks of gestation (37.2% compared with
36.9%; relative risk 0.91, 95% CI 0.671.25) or latency
period (mean difference 0.6 days; 95% CI 23.7 to 4.9).
CONCLUSION: There is insufficient high-quality data to
inform clinicians and patients about the use of proges-
togens as maintenance treatment after arrested preterm
labor to reduce the incidence of preterm birth or
pregnancy prolongation.
(Obstet Gynecol 2016;128:9891000)
DOI: 10.1097/AOG.0000000000001676
M
ore than 1 in 10 of the worlds children born in
2010 were born preterm, defined as before 37
weeks of gestation.1 Current tocolytic agents appear to
be superior to placebo at delaying delivery at both 48
hours and 7 days but do not reduce the incidence of
preterm birth or improve perinatal outcome.2 Main-
tenance tocolytic therapy has not been proven to
improve the outcomes in women treated because of
OBSTETRICS & GYNECOLOGY 989
preterm labor and the risk of preterm birth in these
patients remains high.3,4
Progestogens have been shown to reduce the
spontaneous preterm birth rate, especially in women
at risk for preterm birth,5 with a history of prior pre-
term birth,6,7 or with an asymptomatic short cervix.810
It is reasonable to hypothesize that progestogens, with
their inhibitory effect on uterine contractility11 and role
in maintaining pregnancy until term,12 would be a good
intervention in arrested preterm labor. As such, both
17-hydroxyprogesterone13,14 and vaginal natural
progesterone1520 have been studied as maintenance
treatment for women with arrested preterm labor
with conflicting results. The authors of two recent
meta-analyses21,22 on the topic were cautious with
their conclusions because of the limited quality of
the studies included. Given that recent data from
additional large studies were not included20,23 and
other small studies were missed, a review of the topic
at this time is warranted.
The objective of this systematic review and meta-
analysis was to examine whether progestogens are an
effective maintenance treatment for women after
arrested preterm labor.
SOURCES
A systematic review was conducted according to the
protocol as outlined subsequently and reported fol-
lowing Preferred Reporting Items for Systematic Re-
views and Meta-Analyses guidelines.24 The following
sources were searched from inception to June 2015:
MEDLINE, EMBASE, the Cochrane Central Regis-
ter of Systematic Reviews, the Cochrane Central Reg-
ister of Controlled Trials, Web of Science, and
ClinicalTrials.gov database. The full search strategy
can be found in Appendix 1, available online at
http://links.lww.com/AOG/A869. The reference lists
of all included primary and review articles and Goo-
gleSearch were also examined to identify articles not
captured by the electronic searches. No language re-
strictions were applied.
STUDY SELECTION
All articles were screened by two authors (M.P., S.R.)
and articles likely to meet selection criteria were
reviewed. Three reviewers (M.P., S.R., K.E.M.) made
the final inclusion and exclusion decisions according
to adherence to the following: 1) population: pregnant
women with singleton pregnancies who received
progestational agents for maintenance of pregnancy
after arrested preterm labor; 2) progestogen: use of
any kind of progestogen and by any route (ie,
intramuscular, vaginal, or oral) had to be tested; 3)
990 Palacio et al Progestogens as Maintenance Treatment
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main outcome: delivery at less than 37 weeks of
gestation, delivery at less than 34 weeks of gestation,
and latency period to delivery; and 4) study design:
randomized clinical trials in which progestational
agents were compared with a nontreatment arm or
to placebo. Trials that included women with ruptured
membranes, trials without a placebo or a no treat-
ment arm, and other studies were excluded.
All articles were assessed independently and data
abstracted by two reviewers (M.P., S.R.). A third
reviewer (K.E.M. or L.S.-R.) resolved by consensus or
through arbitration in case of disagreement. In case of
duplicate publications or those with overlapping data
sets, only data from the most complete study were
included.
All included papers were assessed for methodo-
logic quality and risk of bias by two investigators
(M.P., S.R.) using Jadads criteria25 and the Cochrane
Risk of Bias tool.26 Disagreements were resolved by
consensus with a third reviewer (K.E.M.). Trials that
met all of Jadads criteria were considered high
quality.
Data were extracted for the main outcomes:
preterm birth at less than 37 weeks of gestation, less
than 34 weeks of gestation, and latency period from
randomization to delivery. Secondary outcomes such
as gestational age at delivery, recurrence of preterm
labor, neonatal outcomes as admissions to the neo-
natal intensive care unit, and neonatal respiratory
distress syndrome were also explored. Studies report-
ing continuous variables as medians and interquartile
ranges were converted to means and standard devia-
tions as per Hozos method.27
Data analysis was completed independently by
two authors (M.P., L.S.-R.) using Review Manager
5.3. Any differences between the analyses were
resolved by independent analysis by the coauthors.
A random-effects meta-analysis model of
DerSimonian and Laird was chosen for each test to
obtain the pooled relative risks (RRs) estimate when
there was evidence of statistical heterogeneity between
studies (P value of the Cochrane Q statistic ,.1). Oth-
erwise, a fixed-effects model was selected. Statistical
heterogeneity between studies was assessed using the
Cochrane Q statistic and I2 statistics of Higgins et al.26
The summary measures were reported as RRs with
95% confidence interval (CI) for binary outcomes
and weighted mean difference for continuous variables.
A P value ,.05 was considered statistically significant.
To explore potential sources of heterogeneity, we per-
formed planned a priori subgroup analysis to deter-
mine whether the type of progestogen used would
affect the results. An a priori sensitivity analysis was
OBSTETRICS & GYNECOLOGY
Fig. 1. Flowchart of included
studies. PROM, prelabor rupture of
membranes; RCT, randomized
controlled trial.
Palacio. Progestogens as Maintenance
Treatment. Obstet Gynecol 2016.

also performed consisting of high-quality trials based
on Jadads criteria.25
To test for the presence of publication bias,
a visual inspection of the funnel plots displaying
individual study log RR with the standard error RR
for binary outcomes and mean difference with stan-
dard error of mean difference for continuous out-
comes was performed. Asymmetry in such funnel
plots is usually caused by small trials that report
greater effects, on average, than large trials, which
suggests publication or other biases.28 To assess pub-
lication bias statistically, Beggs test for small study
effects was used (P,.05).
All analyses were conducted and summary results
generated as forest plots using Review Manager
(RevMan) 5.3.
RESULTS
Sixteen randomized controlled trials met the inclu-
sion criteria and were included in this meta-analysis
(Fig. 1).1318,20,2936 One trial32 had three arms: one using
progesterone, one using 17-hydroxyporgesterone, and

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992
Palacio et al

Table 1. Descriptive Data for Each Trial and Primary Outcomes

Preterm
Labor When GA Range at
Author, Year, S or Total Patients (Progestogen Dose (mg), Starting Randomization
Progestogens as Maintenance Treatment

Country Years M vs Control) Route Control Primary Tocolytic Agent Medication (wk)

Borna and Sahabi,17 20042005 S 70 (37 vs 33) 400 OD, VAG No T MgSO4 Arrested, tocolysis discontinued 2434 6/7
2008, Iran
El-Abidin et al,35 20072008 S 40 (20 vs 20) 200 BID, VAG No T MgSO4 Arrested, tocolysis discontinued 2434
2009, Egypt
Sharami et al,33 2010, 20072009 S 163 (80 vs 83) 200 OD, VAG Placebo MgSO4 Arrested, tocolysis not specified 2834 6/7
Iran
Arikan et al,18 2011, NA S 83 (43 vs 40) 200 OD, VAG No T Ritodrine Acute preterm labor 2434 6/7
Turkey
Saleh Gargari et al,30 20072010 S 144 (72 vs 72) 400 OD, VAG No T MgSO4 Arrested, tocolysis not specified 2434 6/7
2012, Iran
Areia et al,15 2013, 20082010 S 52 (26 vs 26) 200 OD, VAG No T Atosiban Arrested, tocolysis discontinued 2434 6/7
Portugal
Lotfakizadeh et al,32 2010 S 73 (37 vs 36) 400 OD, VAG No T MgSO4 or nifedipine Arrested, on tocolysis 2636 6/7
2013, Iran
Mishra and Inamdar,36 20122014 S 100 (50 vs 50) 400 OD, VAG No T Isoxsuprine hydrochloride Arrested, tocolysis discontinued 2836
2014, India
Martinez de Tejada 20062012 M 379 (193 vs 186) 200 OD, VAG Placebo B-mimetic, atosiban, or Ca+ Arrested, tocolysis not specified 2433 6/7
et al,20 2015, channel blockers
Switzerland and
Argentina
Palacio et al,23 2016, 20082012 M 258 (126 vs 132) 200 OD, VAG Placebo B-mimetic, atosiban, nifedipine Arrested, tocolysis discontinued 2433 6/7
Spain
Noblot et al,29 1991, 1987 S 44 (22 vs 22) 300 TID, PO Placebo Ritrodrine Acute preterm labor ,35
France
Choudhary et al,16 20102012 S 90 (45 vs 45) 200 OD, PO Placebo Nifedipine Arrested, on tocolysis 2434 6/7
2014, India
Facchinetti et al,31 20042006 S 60 (30 vs 30) 341 bwk, IM No T Atosiban Not specified if arrested, on tocolysis 2533 6/7
2007, Italy
Rozenberg et al,13 20062008 M 188 (94 vs 94) 500 bwk, IM No T Nifedipine, nicardipine Arrested, tocolysis not specified 2431 6/7
OBSTETRICS & GYNECOLOGY

2012, France salbutamol

Regmi et al,34 2012, 20092010 S 60 (29 vs 31) 250 wk, IM No T Nifedipine Arrested, tocolysis discontinued 2834 6/7
Nepal
Lotfakizadeh et al,32 2010 S 73 (37 vs 36) 250 wk, IM No T MgSO4 or nifedipine Arrested, still on tocolysis 2636 6/7
2013, Iran
Briery et al,14 2014, 39 mo S 45 (22 vs 23) 250 wk, IM Placebo MgSO4 or Ca+ channel blockers Arrested, tocolysis discontinued 2030 6/7
United States or anti-PGE
S, single center; M, multicenter; GA, gestational age; PTL, preterm labor; PTB, preterm birth; OD, once a day; VAG, vaginal; No T, no treatment; MgSO4, magnesium sulphate; ctxs,
contractions; NA, not available; BID, twice a day; TID, every 8 hours; bwk, biweekly; PO, per os; IM, intramuscular; anti-PGE, antiprostaglandins.

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VOL. 128, NO. 5, NOVEMBER 2016

Mean GA at
Randomization Definition Prior PTB Progestogens vs PTB at Less Than 37 Wk of PTB at Less Than 34 Wk Latency (d;
(wk) of PTL Control (%) Study Primary Outcomes Gestation, n (%) of Gestation, n (%) mean)

31/32 .6 ctxs/309+cervical changes 5/37 (13.5) vs 4/33 (12.1) Latency period, recurrent PTL NA NA 36.1 vs 24.5
(manual)
27/28 .2 ctxs/109+cervical changes 9/20 (45) vs 7/20 (35) Latency period and recurrent NA 2/20 (10), 11/20 (55) 8.3 vs 5.0
(manual) PTL
33/34 $6 ctxs/309 for 30sec+cervical 1/80 (1.3) vs 3/83 (3.6) Latency period and PTB less 33/80 (41), 45/83 (54) 8/80 (10), 9/83 (11) 23.9 vs 16.7
changes (manual) than 37 and 34 wk of
gestation
32/32 .6 ctxs/309+cervical changes 4/43 (9.3) vs 3/40 (7.5) Latency period, GA at delivery 20/43 (47), 28/40 (70) 20/43 (47), 28/40 (70) 32.1 vs 21.2
(manual) and PTB less than 37 wk of
gestation
32/32 $4 ctxs/209 or $8 ctxs/ NA Latency period, GA at delivery NA NA 28.0 vs 9.8
609+cervical changes
(manual)
28/29 4 ctxs/209 or 8 ctxs/609 9/26 (34.6) vs 9/26 (34.6) Latency period 9/26 (35), 13/26 (50) 3/26 (12), 6/26 (23) 55 vs 38
+cervical changes (TVUS or
fFN+)
34/33 4 ctxs/209+2 cm cervical NA Rate of recurrent PTL NA NA 31 vs 26
dilatation or progressive
cervical changes (manual)
Stratified for 4 ctxs/209 or 8 ctxs/609 Latency, birth weight, NICU 17/50 (34), 34/50 (68) 4/50 (8), 13/50 (26) 23.4 vs 11.7
+cervical dilatation .1 cm
Palacio et al

range of GA admission
and eff .80%
29/29 $2 ctxs/109 for 309+cervical 46/193 (23.8) vs 39/186 (21.0) PTB less than 37 wk of 82/193 (43), 66/186 (36) 38/193 (20), 24/186 (13) 45 vs 52
changes (TVUS or manual, gestation
or fFN+)
32/32 $2 ctxs/109 for 309+cervical 11.9 vs 12.1 PTB less than 37 and 34 wk of 36/126 (29), 29/132 (22) 9/126 (7), 10/132 (8) NA
changes (TVUS and manual) gestation
32/31 Regular ctxs /109 for 1h NA NA 8/22 (36), 6/22 (27) 44 vs 42
Progestogens as Maintenance Treatment

+cervical change (manual)

32/32 4 ctxs/209 or 8 ctxs/609 6/45 (13.3) vs 2/45 (4.4) Latency period 15/45 (33), 26/45 (58) 8/45 (18), 9/45 (20) 33.3 vs 23.1
+cervical dilatation .1 cm
and eff .80%
30/30 .6 ctxs/309 for 30sec+cervical 1/30 (3.3) vs 2/30 (6.6) Cervical shortening 5/30 (16), 17/30 (57) 3/30 (10), 7/30 (23) 35.3 vs 25.5
changes (manual)
28/28 $2 ctxs/109 for 609+TVUS 11/94 (11.7) vs 22/92 (23.9) Latency period 37/94 (35), 36/94 (38) 15/94 (16), 19/94 (20) 61 vs 63
33/33 .6 ctxs/309 for 30sec+cervical 11/29 (37.9) vs 20/31 (64.5) Latency period and rate of NA NA 25 vs 16
changes (manual) recurrent PTL within 48 h
34/33 4 ctxs/min+2 cm cervical NA Rate of recurrent PTL NA NA 36 vs 26
dilatation or progressive
cervical changes (manual)
29/27 Painful ctx every 5 min and 8/22 (36.4) vs 7/23 (30.4) PTB less than 37 wk of 19/22 (86), 22/23 (96) 14/22 (63), 21/23 (91) 23 vs 16
cervical dilatation (manual) gestation
993

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Fig. 2. Risk of bias summary: review authors judgments
about each risk of bias item for each included study.
Palacio. Progestogens as Maintenance Treatment. Obstet Gynecol
2016.
the other received no treatment. Another29 included
a small number of multiple pregnancies (four in total),
but all authors agreed to include these data because the
effect on the overall data was considered to be negligible.
994 Palacio et al Progestogens as Maintenance Treatment
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Overall, 1,917 women were included in this systematic
review. Descriptive characteristics of the studies included
and primary outcomes are shown in Table 1. The trials
were relatively small with only two studies recruiting 200
or more participants20,23 and six trials used placebo in the
control arm.14,16,20,23,29,33 Five trials fulfilled all of Jadads
criteria and thus were considered to be high qual-
ity.16,20,23,29,33 The risk of bias for the included studies is
detailed in Figure 2. Of the 16 included trials, 7 failed in
at least half of the Cochrane Risk of Bias tool criteria.
The rate of preterm birth at less than 37 weeks of
gestation in the placebo or no treatment arms in the
included studies ranged from 22%23 to 96%,14
although the rate was reduced to 22%23 to 58%16 when
only high-quality studies were considered. All but
three studies20,23,29 reported a rate of preterm birth
at less than 37 weeks of gestation of 50% or more
and five13,14,16,35,36 out of eight that reported the results
of preterm birth at less than 34 weeks of gestation
reported a rate from 20% to 91.3% for this outcome
in the placebo or no treatment arm.
Five trials reported the use of magnesium sul-
phate as a tocolytic agent.17,30,32,33,35 Other trials were
using betamimetics, calcium channel blockers, atosi-
ban, or antiprostaglandin drugs (Table 1).
Twelve trials tested natural progesterone either
by the vaginal 15,17,18,20,23,30,32,33,35,36 or oral16,29
route and five trials used intramuscular 17-
hydroxyprogesterone.13,14,31,32,34 Nine trials reported the
use of a standard dose of progesterone (ie, 200 mg per
day)15,16,18,20,23,33 or 17-hydroxyprogesterone (ie, 250 mg
intramuscularly weekly).14,32,34 Eight other trials
used higher doses of progesterone17,29,30,32,35,36 or
17-hydroprogesterone.13,31
In one study,23 women were randomized once the
decision to discharge was taken and medication was
started the first day at home. In all the other trials,
women were randomized and started on study treat-
ment while in the hospital. However, the rate of pre-
term delivery before hospital discharge was not stated
in any study. In two trials,18,29 study medication was
started together with the acute tocolysis or this was not
specified31 and was prolonged as a maintenance treat-
ment. In six trials, study medication was started after
cessation of uterine contractions but concomitant to
tocolysis16,32 or the latter was not specified.13,20,30,33 In
seven trials, study medication was administered after
a contraction-free period after discontinuation of acute
tocolysis.14,15,17,23,3436
Secondary outcomes of the included studies are
shown in Appendix 2, available online at http://links.
lww.com/AOG/A869. Preterm delivery at less than
37 weeks of gestation, less than 34 weeks of gestation,
OBSTETRICS & GYNECOLOGY
Fig. 3. A. Forest plot comparison (progestational agents compared with nontreatment or placebo) for outcome: preterm birth at
less than 37 weeks of gestation. B. Forest plot comparison (progestational agents compared with nontreatment or placebo) for
outcome: preterm birth at less than 37 weeks of gestation (high-quality studies). IV, inverse-variance; CI, confidence interval.
Palacio. Progestogens as Maintenance Treatment. Obstet Gynecol 2016.

and latency to delivery was reported in 11, 8, and 16
out of 16 studies, respectively.
The forest plots in Figures 35 provide study-
specific details regarding evaluation of pooled pre-
term delivery at less than 37 weeks of gestation, less
than 34 weeks of gestation, and latency period
between preterm labor and delivery. Preterm delivery
at less than 37 weeks of gestation was decreased
(38.2% compared with 44.3%; RR 0.79, 95% CI
0.650.97) and pregnancy was prolonged (mean dif-
ference 8.1 days; 95% CI 3.812.4) when women trea-
ted with progestogens were compared with women
who received placebo or no treatment. There were
no differences in the outcome of delivery at less than
34 weeks of gestation (15.6% compared with 18.3%;
RR 0.77, 95% CI 0.531.12). Significant heterogeneity
among studies was noted for preterm delivery at less
than 37 weeks of gestation (I2 65%, P5.001), less than
34 weeks of gestation (I2 56%, P5.03), and latency
period (I2 96%, P,.001).
Only five studies fulfilled all of Jadads criteria.
Sensitivity analysis of these studies showed no signif-
icant differences in preterm delivery at less than 37
weeks of gestation (36.9% compared with 37.2%; RR
0.91, 95% CI 0.671.25), preterm delivery at less than
34 weeks of gestation (14.2% compared with 11.7%;

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Fig. 4. A. Forest plot comparison (progestational agents compared with nontreatment or placebo) for outcome: preterm birth at
less than 34 weeks of gestation. B. Forest plot comparison (progestational agents compared with nontreatment or placebo) for
outcome: preterm birth at less than 34 weeks of gestation (high-quality studies). IV, inverse-variance; CI, confidence interval.
Palacio. Progestogens as Maintenance Treatment. Obstet Gynecol 2016.

RR 1.20, 95% CI 0.861.69), or for latency period
(mean difference 0.6 days; 95% CI 23.7 to 4.9). Sen-
sitivity analysis did not explain the source of hetero-
geneity for preterm delivery at less than 37 weeks of
gestation (I2 65%, P5.02) or the latency period (I2
86%, P,.001), but did explain the heterogeneity for
preterm delivery at less than 34 weeks of gestation (I2
0%, P5.55).
There were limited data reporting on the second-
ary outcomes of gestational age at delivery (13 of 16
studies), recurrence of preterm labor (8 of 16 studies),
neonatal admission to the neonatal intensive care unit
(12 of 16 studies), or neonatal respiratory distress
syndrome (10 of 16 studies). Other outcomes related
to neonatal morbidity (intraventricular hemorrhage,
necrotizing enterocholitis, or sepsis) were inconsis-
tently reported (Appendix 2, http://links.lww.com/
AOG/A869).
Table 2 summarizes the overall results and the
results of the sensitivity analysis on the five high-
quality studies (Jadad score of 5) for all outcomes.
Use of progestogens did not improve the primary or
secondary outcomes. Appendix 3, available online at
http://links.lww.com/AOG/A869, summarizes the re-
sults for the secondary outcomes of the subgroup anal-
ysis when the type of progestogen used was
considered. Subgroup analysis did not show addi-
tional benefit for any of the progestogens used.
Analysis of publication bias based on Eggers test
showed publication bias for the outcome of latency to

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Fig. 5. A. Forest plot comparison (progestational agents compared with nontreatment or placebo) for outcome: latency to
delivery. B. Forest plot comparison (progestational agents compared with nontreatment or placebo) for outcome: latency to
delivery (high-quality studies). SD, standard deviation; IV, inverse-variance; CI, confidence interval.
Palacio. Progestogens as Maintenance Treatment. Obstet Gynecol 2016.

delivery (17 studies, P5.010) (Fig. 6) and suggests bias
for preterm birth at less than 37 weeks of gestation (11
studies, P5.095) (Appendix 4, available online at
http://links.lww.com/AOG/A869).
DISCUSSION
There is insufficient high-quality evidence to eval-
uate the use of progestogens as maintenance treat-
ment after arrested preterm labor to either reduce
preterm birth or increase latency to delivery.
Studies included in this meta-analysis were variable
in both quality and design because they varied in
size, type of progestogen, route of administration,
and whether they included a placebo arm.
Although differences in the primary outcomes were
found when all trials were included, sensitivity
analysis performed on high-quality trials showed
no differences in preterm birth at less than 37 weeks
of gestation, less than 34 weeks of gestation, or in
the latency period to delivery between the pro-
gestogen and placebo arms.
Two recent meta-analyses21,22 have shown that
progestogens, when used after arrested preterm labor,
might be of some benefit. However, the authors were
cautious with their conclusions because of the limited
quality of the studies published (ie, small sample size
or lack of blinding). Since that publication, a subse-
quent meta-analysis showed conflicting results,37
recent data have been published,23 and additional
studies in which progestogen was introduced shortly
after preterm labor was arrested were not included in
the earlier meta-analyses20; a review of the topic at this
time is timely. Furthermore, previous systematic re-
views21,22,37 did not include small trials not cited in

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Table 2. Summary of the Overall Results and the Sensitivity Analysis (High-Quality Studies Jadads Score 5)

Overall Analysis Sensitivity Analysis (High-Quality Studies)

Effect Estimate Effect Estimate

(Progestogens vs (Progestogens vs
No. of No. of Nontreatment or No. of No. of Nontreatment or
Outcomes Studies Participants I2 (%) P Placebo) Studies Participants I2 (%) P Placebo)

PTB at less than 37 11 1,462 65 .001 0.79 (0.650.97)* 5 934 65 .02 0.91 (0.671.25)*
wk of gestation
PTB at less than 34 8 1,263 56 .03 0.77 (0.531.12) 4 890 0 .55 1.20 (0.861.69)
wk of gestation
Latency to delivery (d) 16 1,917 96 ,.001 8.1 (3.812.4)* 5 929 86 ,.001 0.6 (23.74.9)*
GA at delivery 13 1,672 87 ,.001 1.31 (0.801.81) 4 890 69 .02 0.14 (20.510.78)
Recurrent preterm 8 1,047 0 .56 0.63 (0.520.78) 3 725 20 .29 0.74 (0.531.02)
labor
Admission to NICU 12 1,672 33 .13 0.91 (0.751.10) 4 882 0 .98 1.15 (0.871.52)
Respiratory distress 10 1,057 7 .38 0.70 (0.500.97) 3 506 0 .97 0.75 (0.431.31)
syndrome
PTB, preterm birth; GA, gestational age; NICU, neonatal intensive care unit; CI, confidence interval.
* Risk ratio (IV, random, 95% CI).

Risk ratio (M-H, fixed, 95% CI).

Mean difference (IV, random, 95% CI).

PubMed.35,36 This systematic review also addresses
this deficiency.
The strengths of this systematic review included
its comprehensive search strategy, methodologic
design, and statistical analysis. In particular, it synthe-
sized the results of existing studies in which pro-
gestational agents were used as a maintenance
treatment after arrested preterm labor whether or
not the treatment was initiated together with acute
tocolysis. The inclusion of a range of outcomes such
as preterm birth, latency period from randomization
to delivery, recurrence of preterm labor, gestational
age at delivery, admissions to the neonatal intensive
Fig. 6. Funnel plot of studies (comparing progestational
agents and nontreatment or placebo) for outcome: latency
to delivery.
Palacio. Progestogens as Maintenance Treatment. Obstet Gynecol
2016.
care unit, and neonatal distress syndrome ensured
a complete evaluation of the intervention. In addition,
a subgroup analysis was performed and allowed the
comparison of the estimated effect of different proges-
togens, which is relevant for different clinical practices
and sensitivity analysis showed results derived from
inclusion of high-quality studies.
The studies heterogeneity was this systematic
reviews most obvious limitation and limits the val-
idity of the combined results, especially because
findings from larger and low risk of bias trials con-
flicted with those from smaller trials. The potential
for selection bias exists in randomized studies when
there is no blinding or inadequate concealment,
which happened in 10 of 16 studies (Fig. 2), limiting
the quality of the data. Indeed, heterogeneity might
also be explained by the fact that inclusion criteria
among studies were very different. Evidence for that
is the high rate of preterm birth in some studies
compared with others. On the other hand, some out-
comes (ie, preterm delivery at less than 34 weeks of
gestation) were reported in some studies but not in
others. The inclusion of core outcome sets for pre-
term delivery in future research may avoid hetero-
geneity resulting from this fact.
In addition, the risk of publication bias was
assessed by visual inspection of the funnel and
asymmetric plots and suggested publication bias. This
suggests underreporting of negative trials. Thus, this
comprehensive systematic review provides data to
evaluate these limitations and forms the basis for
future studies.

998 Palacio et al Progestogens as Maintenance Treatment OBSTETRICS & GYNECOLOGY

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and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.
 The findings from this meta-analysis suggest that
there is insufficient high-quality data to inform clini-
cians and patients about the use of progestogens as
maintenance treatment after arrested preterm labor to
reduce preterm birth or prolong pregnancy. There-
fore, the use of progestogens for this indication should
be limited to research protocols until results from
additional large and well-designed randomized trials
become available.
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Copyright by The American College of Obstetricians

and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.