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Prematurity: Review
Progestogens as Maintenance Treatment inArrested Preterm LaborA
Systematic Review and Meta-analysis
Montse Palacio, MD, PhD, Stefania Ronzoni, MD, PhD, Luis
Sánchez-Ramos, MD,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 Group’s 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-
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] 0.65–0.97)
and pregnancy was prolonged (mean difference 8.1 days;
95% CI 3.8–12.4) 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 0.53–1.12). 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 0.67–1.25) 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;128:989–1000)
DOI: 10.1097/AOG.0000000000001676
More than 1 in 10 of the world’s children born in2010 were born
preterm, defined as before 37weeks of gestation.1 Current tocolytic
agents appear tobe superior to placebo at delaying delivery at both
48hours and 7 days but do not reduce the incidence ofpreterm birth
or improve perinatal outcome.2 Main-tenance tocolytic therapy has
not been proven toimprove the outcomes in women treated because
of
From the BCNatal–Barcelona Center for Maternal-Fetal and
Neonatal Medicine(Hospital Clínic and Hospital Sant Joan de Deu),
Fetal i+D Fetal MedicineResearch Center, IDIBAPS, University of
Barcelona, Barcelona, and the Centrefor Biomedical Research on Rare
Diseases (CIBER-ER), Spain; the Departmentof 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 ScienceCenter, Jacksonville, Florida.
Montse Palacio was supported by Instituto de Salud Carlos III
(BA15/00028and EC07/90023) and Ministerio de Sanidad y Política
Social (TRA-096).
The authors thank Daphne Horn, Research Librarian at Mount Sinai
Hospital,for help with the literature search, and Josie Chundamala,
Scientific GrantEditor in the Department of Obstetrics and
Gynaecology at Mount Sinai Hos-pital, for editorial assistance.
Corresponding author: Montse Palacio, MD, PhD, BCNatal,
Barcelona Centre forMaternal-Fetal and Neonatal Medicine, Hospital
Clínic, Sabino de Arana 1, 08028Barcelona, Spain; e-mail:
[email protected].
Financial DisclosureThe authors did not report any potential
conflicts of interest.
© 2016 by The American College of Obstetricians and
Gynecologists. Publishedby Wolters Kluwer Health, Inc. All rights
reserved.ISSN: 0029-7844/16
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http://ClinicalTrials.govRichardResaltado
RichardResaltado
RichardResaltado
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preterm labor and the risk of preterm birth in thesepatients
remains high.3,4
Progestogens have been shown to reduce thespontaneous preterm
birth rate, especially in womenat risk for preterm birth,5 with a
history of prior pre-term birth,6,7 or with an asymptomatic short
cervix.8–10
It is reasonable to hypothesize that progestogens, withtheir
inhibitory effect on uterine contractility11 and rolein maintaining
pregnancy until term,12 would be a goodintervention in arrested
preterm labor. As such, both17-hydroxyprogesterone13,14 and vaginal
naturalprogesterone15–20 have been studied as maintenancetreatment
for women with arrested preterm laborwith conflicting results. The
authors of two recentmeta-analyses21,22 on the topic were cautious
withtheir conclusions because of the limited quality ofthe studies
included. Given that recent data fromadditional large studies were
not included20,23 andother small studies were missed, a review of
the topicat this time is warranted.
The objective of this systematic review and meta-analysis was to
examine whether progestogens are aneffective maintenance treatment
for women afterarrested preterm labor.
SOURCES
A systematic review was conducted according to theprotocol as
outlined subsequently and reported fol-lowing Preferred Reporting
Items for Systematic Re-views and Meta-Analyses guidelines.24 The
followingsources 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,
andClinicalTrials.gov database. The full search strategycan be
found in Appendix 1, available online
athttp://links.lww.com/AOG/A869. The reference listsof all included
primary and review articles and Goo-gleSearch were also examined to
identify articles notcaptured 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 werereviewed. Three
reviewers (M.P., S.R., K.E.M.) madethe final inclusion and
exclusion decisions accordingto adherence to the following: 1)
population: pregnantwomen with singleton pregnancies who
receivedprogestational agents for maintenance of pregnancyafter
arrested preterm labor; 2) progestogen: use ofany kind of
progestogen and by any route (ie,intramuscular, vaginal, or oral)
had to be tested; 3)
main outcome: delivery at less than 37 weeks ofgestation,
delivery at less than 34 weeks of gestation,and latency period to
delivery; and 4) study design:randomized clinical trials in which
progestationalagents were compared with a nontreatment arm orto
placebo. Trials that included women with rupturedmembranes, trials
without a placebo or a “no treat-ment” arm, and other studies were
excluded.
All articles were assessed independently and dataabstracted by
two reviewers (M.P., S.R.). A thirdreviewer (K.E.M. or L.S.-R.)
resolved by consensus orthrough arbitration in case of
disagreement. In case ofduplicate publications or those with
overlapping datasets, only data from the most complete study
wereincluded.
All included papers were assessed for methodo-logic quality and
risk of bias by two investigators(M.P., S.R.) using Jadad’s
criteria25 and the CochraneRisk of Bias tool.26 Disagreements were
resolved byconsensus with a third reviewer (K.E.M.). Trials thatmet
all of Jadad’s criteria were considered highquality.
Data were extracted for the main outcomes:preterm birth at less
than 37 weeks of gestation, lessthan 34 weeks of gestation, and
latency period fromrandomization to delivery. Secondary outcomes
suchas gestational age at delivery, recurrence of pretermlabor,
neonatal outcomes as admissions to the neo-natal intensive care
unit, and neonatal respiratorydistress syndrome were also explored.
Studies report-ing continuous variables as medians and
interquartileranges were converted to means and standard
devia-tions as per Hozo’s method.27
Data analysis was completed independently bytwo authors (M.P.,
L.S.-R.) using Review Manager5.3. Any differences between the
analyses wereresolved by independent analysis by the coauthors.
A random-effects meta-analysis model ofDerSimonian and Laird was
chosen for each test toobtain the pooled relative risks (RRs)
estimate whenthere was evidence of statistical heterogeneity
betweenstudies (P value of the Cochrane Q statistic ,.1).
Oth-erwise, a fixed-effects model was selected.
Statisticalheterogeneity between studies was assessed using
theCochrane Q statistic and I2 statistics of Higgins et al.26
The summary measures were reported as RRs with95% confidence
interval (CI) for binary outcomesand 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 wouldaffect the results. An a priori
sensitivity analysis was
990 Palacio et al Progestogens as Maintenance Treatment
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also performed consisting of high-quality trials basedon Jadad’s
criteria.25
To test for the presence of publication bias,a visual inspection
of the funnel plots displayingindividual study log RR with the
standard error RRfor binary outcomes and mean difference with
stan-dard error of mean difference for continuous out-comes was
performed. Asymmetry in such funnelplots is usually caused by small
trials that reportgreater effects, on average, than large trials,
whichsuggests publication or other biases.28 To assess pub-
lication bias statistically, Beggs’ test for small studyeffects
was used (P,.05).
All analyses were conducted and summary resultsgenerated 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).13–18,20,29–36 One
trial32 had three arms: one usingprogesterone, one using
17-hydroxyporgesterone, and
Fig. 1. Flowchart of includedstudies. PROM, prelabor rupture
ofmembranes; RCT, randomizedcontrolled trial.
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Table 1. Descriptive Data for Each Trial and Primary
Outcomes
Author, Year,Country Years
S orM
Total Patients (Progestogenvs Control)
Dose (mg),Route Control Primary Tocolytic Agent
PretermLabor When
StartingMedication
GA Range atRandomization
(wk)
Borna and Sahabi,17
2008, Iran2004–2005 S 70 (37 vs 33) 400 OD, VAG No T MgSO4
Arrested, tocolysis discontinued 24–34 6/7
El-Abidin et al,35
2009, Egypt2007–2008 S 40 (20 vs 20) 200 BID, VAG No T MgSO4
Arrested, tocolysis discontinued 24–34
Sharami et al,33 2010,Iran
2007–2009 S 163 (80 vs 83) 200 OD, VAG Placebo MgSO4 Arrested,
tocolysis not specified 28–34 6/7
Arikan et al,18 2011,Turkey
NA S 83 (43 vs 40) 200 OD, VAG No T Ritodrine Acute preterm
labor 24–34 6/7
Saleh Gargari et al,30
2012, Iran2007–2010 S 144 (72 vs 72) 400 OD, VAG No T MgSO4
Arrested, tocolysis not specified 24–34 6/7
Areia et al,15 2013,Portugal
2008–2010 S 52 (26 vs 26) 200 OD, VAG No T Atosiban Arrested,
tocolysis discontinued 24–34 6/7
Lotfakizadeh et al,32
2013, Iran2010 S 73 (37 vs 36) 400 OD, VAG No T MgSO4 or
nifedipine Arrested, on tocolysis 26–36 6/7
Mishra and Inamdar,36
2014, India2012–2014 S 100 (50 vs 50) 400 OD, VAG No T
Isoxsuprine hydrochloride Arrested, tocolysis discontinued
28–36
Martinez de Tejadaet al,20 2015,Switzerland andArgentina
2006–2012 M 379 (193 vs 186) 200 OD, VAG Placebo B-mimetic,
atosiban, or Ca+channel blockers
Arrested, tocolysis not specified 24–33 6/7
Palacio et al,23 2016,Spain
2008–2012 M 258 (126 vs 132) 200 OD, VAG Placebo B-mimetic,
atosiban, nifedipine Arrested, tocolysis discontinued 24–33 6/7
Noblot et al,29 1991,France
1987 S 44 (22 vs 22) 300 TID, PO Placebo Ritrodrine Acute
preterm labor ,35
Choudhary et al,16
2014, India2010–2012 S 90 (45 vs 45) 200 OD, PO Placebo
Nifedipine Arrested, on tocolysis 24–34 6/7
Facchinetti et al,31
2007, Italy2004–2006 S 60 (30 vs 30) 341 bwk, IM No T Atosiban
Not specified if arrested, on tocolysis 25–33 6/7
Rozenberg et al,13
2012, France2006–2008 M 188 (94 vs 94) 500 bwk, IM No T
Nifedipine, nicardipine
salbutamolArrested, tocolysis not specified 24–31 6/7
Regmi et al,34 2012,Nepal
2009–2010 S 60 (29 vs 31) 250 wk, IM No T Nifedipine Arrested,
tocolysis discontinued 28–34 6/7
Lotfakizadeh et al,32
2013, Iran2010 S 73 (37 vs 36) 250 wk, IM No T MgSO4 or
nifedipine Arrested, still on tocolysis 26–36 6/7
Briery et al,14 2014,United States
39 mo S 45 (22 vs 23) 250 wk, IM Placebo MgSO4 or Ca+ channel
blockersor anti-PGE
Arrested, tocolysis discontinued 20–30 6/7
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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Mean GA atRandomization
(wk)Definitionof PTL
Prior PTB Progestogens vsControl (%) Study Primary Outcomes
PTB at Less Than 37 Wk ofGestation, n (%)
PTB at Less Than 34 Wkof Gestation, n (%)
Latency (d;mean)
31/32 .6 ctxs/309+cervical changes(manual)
5/37 (13.5) vs 4/33 (12.1) Latency period, recurrent PTL NA NA
36.1 vs 24.5
27/28 .2 ctxs/109+cervical changes(manual)
9/20 (45) vs 7/20 (35) Latency period and recurrentPTL
NA 2/20 (10), 11/20 (55) 8.3 vs 5.0
33/34 $6 ctxs/309 for 30sec+cervicalchanges (manual)
1/80 (1.3) vs 3/83 (3.6) Latency period and PTB lessthan 37 and
34 wk ofgestation
33/80 (41), 45/83 (54) 8/80 (10), 9/83 (11) 23.9 vs 16.7
32/32 .6 ctxs/309+cervical changes(manual)
4/43 (9.3) vs 3/40 (7.5) Latency period, GA at deliveryand PTB
less than 37 wk ofgestation
20/43 (47), 28/40 (70) 20/43 (47), 28/40 (70) 32.1 vs 21.2
32/32 $4 ctxs/209 or $8 ctxs/609+cervical changes(manual)
NA Latency period, GA at delivery NA NA 28.0 vs 9.8
28/29 4 ctxs/209 or 8 ctxs/609+cervical changes (TVUS
orfFN+)
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
34/33 4 ctxs/209+2 cm cervicaldilatation or progressivecervical
changes (manual)
NA Rate of recurrent PTL NA NA 31 vs 26
Stratified forrange of GA
4 ctxs/209 or 8 ctxs/609+cervical dilatation .1 cmand eff
.80%
Latency, birth weight, NICUadmission
17/50 (34), 34/50 (68) 4/50 (8), 13/50 (26) 23.4 vs 11.7
29/29 $2 ctxs/109 for 309+cervicalchanges (TVUS or manual,or
fFN+)
46/193 (23.8) vs 39/186 (21.0) PTB less than 37 wk
ofgestation
82/193 (43), 66/186 (36) 38/193 (20), 24/186 (13) 45 vs 52
32/32 $2 ctxs/109 for 309+cervicalchanges (TVUS and manual)
11.9 vs 12.1 PTB less than 37 and 34 wk ofgestation
36/126 (29), 29/132 (22) 9/126 (7), 10/132 (8) NA
32/31 Regular ctxs /109 for 1h+cervical change (manual)
NA NA 8/22 (36), 6/22 (27) 44 vs 42
32/32 4 ctxs/209 or 8 ctxs/609+cervical dilatation .1 cmand eff
.80%
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
30/30 .6 ctxs/309 for 30sec+cervicalchanges (manual)
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
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
6333/33 .6 ctxs/309 for 30sec+cervical
changes (manual)11/29 (37.9) vs 20/31 (64.5) Latency period and
rate of
recurrent PTL within 48 hNA NA 25 vs 16
34/33 4 ctxs/min+2 cm cervicaldilatation or progressivecervical
changes (manual)
NA Rate of recurrent PTL NA NA 36 vs 26
29/27 Painful ctx every 5 min andcervical dilatation
(manual)
8/22 (36.4) vs 7/23 (30.4) PTB less than 37 wk ofgestation
19/22 (86), 22/23 (96) 14/22 (63), 21/23 (91) 23 vs 16
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the other received no treatment. Another29 includeda small
number of multiple pregnancies (four in total),but all authors
agreed to include these data because theeffect on the overall data
was considered to be negligible.
Overall, 1,917 women were included in this systematicreview.
Descriptive characteristics of the studies includedand primary
outcomes are shown in Table 1. The trialswere relatively small with
only two studies recruiting 200or more participants20,23 and six
trials used placebo in thecontrol arm.14,16,20,23,29,33 Five trials
fulfilled all of Jadad’scriteria and thus were considered to be
high qual-ity.16,20,23,29,33 The risk of bias for the included
studies isdetailed in Figure 2. Of the 16 included trials, 7 failed
inat least half of the Cochrane Risk of Bias tool criteria.
The rate of preterm birth at less than 37 weeks ofgestation in
the placebo or no treatment arms in theincluded studies ranged from
22%23 to 96%,14
although the rate was reduced to 22%23 to 58%16 whenonly
high-quality studies were considered. All butthree studies20,23,29
reported a rate of preterm birthat less than 37 weeks of gestation
of 50% or moreand five13,14,16,35,36 out of eight that reported the
resultsof preterm birth at less than 34 weeks of gestationreported
a rate from 20% to 91.3% for this outcomein 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 wereusing betamimetics,
calcium channel blockers, atosi-ban, or antiprostaglandin drugs
(Table 1).
Twelve trials tested natural progesterone eitherby the
vaginal15,17,18,20,23,30,32,33,35,36 or oral16,29
route and five trials used intramuscular
17-hydroxyprogesterone.13,14,31,32,34 Nine trials reported theuse
of a standard dose of progesterone (ie, 200 mg
perday)15,16,18,20,23,33 or 17-hydroxyprogesterone (ie, 250
mgintramuscularly weekly).14,32,34 Eight other trialsused higher
doses of progesterone17,29,30,32,35,36
or17-hydroprogesterone.13,31
In one study,23 women were randomized once thedecision to
discharge was taken and medication wasstarted 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 statedin any
study. In two trials,18,29 study medication wasstarted together
with the acute tocolysis or this was notspecified31 and was
prolonged as a maintenance treat-ment. In six trials, study
medication was started aftercessation of uterine contractions but
concomitant totocolysis16,32 or the latter was not
specified.13,20,30,33 Inseven trials, study medication was
administered aftera contraction-free period after discontinuation
of acutetocolysis.14,15,17,23,34–36
Secondary outcomes of the included studies areshown in Appendix
2, available online at http://links.lww.com/AOG/A869. Preterm
delivery at less than37 weeks of gestation, less than 34 weeks of
gestation,
Fig. 2. Risk of bias summary: review authors’ judgmentsabout
each risk of bias item for each included study.
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Gynecol2016.
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and latency to delivery was reported in 11, 8, and 16out of 16
studies, respectively.
The forest plots in Figures 3–5 provide study-specific details
regarding evaluation of pooled pre-term delivery at less than 37
weeks of gestation, lessthan 34 weeks of gestation, and latency
periodbetween preterm labor and delivery. Preterm deliveryat less
than 37 weeks of gestation was decreased(38.2% compared with 44.3%;
RR 0.79, 95% CI0.65–0.97) and pregnancy was prolonged (mean
dif-ference 8.1 days; 95% CI 3.8–12.4) when women trea-ted with
progestogens were compared with womenwho received placebo or no
treatment. There were
no differences in the outcome of delivery at less than34 weeks
of gestation (15.6% compared with 18.3%;RR 0.77, 95% CI 0.53–1.12).
Significant heterogeneityamong studies was noted for preterm
delivery at lessthan 37 weeks of gestation (I2 65%, P5.001), less
than34 weeks of gestation (I2 56%, P5.03), and latencyperiod (I2
96%, P,.001).
Only five studies fulfilled all of Jadad’s criteria.Sensitivity
analysis of these studies showed no signif-icant differences in
preterm delivery at less than 37weeks of gestation (36.9% compared
with 37.2%; RR0.91, 95% CI 0.67–1.25), preterm delivery at less
than34 weeks of gestation (14.2% compared with 11.7%;
Fig. 3. A. Forest plot comparison (progestational agents
compared with nontreatment or placebo) for outcome: preterm birth
atless than 37 weeks of gestation. B. Forest plot comparison
(progestational agents compared with nontreatment or placebo)
foroutcome: preterm birth at less than 37 weeks of gestation
(high-quality studies). IV, inverse-variance; CI, confidence
interval.
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RR 1.20, 95% CI 0.86–1.69), 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 ofgestation (I2 65%, P5.02) or the latency
period (I2
86%, P,.001), but did explain the heterogeneity forpreterm
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 16studies),
recurrence of preterm labor (8 of 16 studies),neonatal admission to
the neonatal intensive care unit(12 of 16 studies), or neonatal
respiratory distresssyndrome (10 of 16 studies). Other outcomes
relatedto 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 theresults 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 orsecondary outcomes. Appendix 3, available online
athttp://links.lww.com/AOG/A869, summarizes the re-sults for the
secondary outcomes of the subgroup anal-ysis when the type of
progestogen used wasconsidered. Subgroup analysis did not show
addi-tional benefit for any of the progestogens used.
Analysis of publication bias based on Egger’s testshowed
publication bias for the outcome of latency to
Fig. 4. A. Forest plot comparison (progestational agents
compared with nontreatment or placebo) for outcome: preterm birth
atless than 34 weeks of gestation. B. Forest plot comparison
(progestational agents compared with nontreatment or placebo)
foroutcome: 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
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delivery (17 studies, P5.010) (Fig. 6) and suggests biasfor
preterm birth at less than 37 weeks of gestation (11studies,
P5.095) (Appendix 4, available online
athttp://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 reducepreterm birth or increase latency to
delivery.Studies included in this meta-analysis were variablein
both quality and design because they varied insize, type of
progestogen, route of administration,and whether they included a
placebo arm.Although differences in the primary outcomes werefound
when all trials were included, sensitivityanalysis performed on
high-quality trials showed
no differences in preterm birth at less than 37 weeksof
gestation, less than 34 weeks of gestation, or inthe latency period
to delivery between the pro-gestogen and placebo arms.
Two recent meta-analyses21,22 have shown thatprogestogens, when
used after arrested preterm labor,might be of some benefit.
However, the authors werecautious with their conclusions because of
the limitedquality of the studies published (ie, small sample
sizeor lack of blinding). Since that publication, a subse-quent
meta-analysis showed conflicting results,37
recent data have been published,23 and additionalstudies in
which progestogen was introduced shortlyafter preterm labor was
arrested were not included inthe earlier meta-analyses20; a review
of the topic at thistime is timely. Furthermore, previous
systematic re-views21,22,37 did not include small trials not cited
in
Fig. 5. A. Forest plot comparison (progestational agents
compared with nontreatment or placebo) for outcome: latency
todelivery. B. Forest plot comparison (progestational agents
compared with nontreatment or placebo) for outcome: latency
todelivery (high-quality studies). SD, standard deviation; IV,
inverse-variance; CI, confidence interval.
Palacio. Progestogens as Maintenance Treatment. Obstet Gynecol
2016.
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-
PubMed.35,36 This systematic review also addressesthis
deficiency.
The strengths of this systematic review includedits
comprehensive search strategy, methodologicdesign, and statistical
analysis. In particular, it synthe-sized the results of existing
studies in which pro-gestational agents were used as a
maintenancetreatment after arrested preterm labor whether ornot the
treatment was initiated together with acutetocolysis. The inclusion
of a range of outcomes suchas preterm birth, latency period from
randomizationto delivery, recurrence of preterm labor,
gestationalage at delivery, admissions to the neonatal
intensive
care unit, and neonatal distress syndrome ensureda complete
evaluation of the intervention. In addition,a subgroup analysis was
performed and allowed thecomparison of the estimated effect of
different proges-togens, which is relevant for different clinical
practicesand sensitivity analysis showed results derived
frominclusion of high-quality studies.
The studies’ heterogeneity was this systematicreview’s most
obvious limitation and limits the val-idity of the combined
results, especially becausefindings from larger and low risk of
bias trials con-flicted with those from smaller trials. The
potentialfor selection bias exists in randomized studies whenthere
is no blinding or inadequate concealment,which happened in 10 of 16
studies (Fig. 2), limitingthe quality of the data. Indeed,
heterogeneity mightalso be explained by the fact that inclusion
criteriaamong studies were very different. Evidence for thatis the
high rate of preterm birth in some studiescompared with others. On
the other hand, some out-comes (ie, preterm delivery at less than
34 weeks ofgestation) were reported in some studies but not
inothers. 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 wasassessed by visual
inspection of the funnel andasymmetric plots and suggested
publication bias. Thissuggests underreporting of negative trials.
Thus, thiscomprehensive systematic review provides data toevaluate
these limitations and forms the basis forfuture studies.
Table 2. Summary of the Overall Results and the Sensitivity
Analysis (High-Quality Studies Jadad’s Score 5)
Outcomes
Overall Analysis Sensitivity Analysis (High-Quality Studies)
No. ofStudies
No. ofParticipants I2 (%) P
Effect Estimate(Progestogens vsNontreatment or
Placebo)No. ofStudies
No. ofParticipants I2 (%) P
Effect Estimate(Progestogens vsNontreatment or
Placebo)
PTB at less than 37wk of gestation
11 1,462 65 .001 0.79 (0.65–0.97)* 5 934 65 .02 0.91
(0.67–1.25)*
PTB at less than 34wk of gestation
8 1,263 56 .03 0.77 (0.53–1.12)† 4 890 0 .55 1.20
(0.86–1.69)†
Latency to delivery (d) 16 1,917 96 ,.001 8.1 (3.8–12.4)* 5 929
86 ,.001 0.6 (23.7–4.9)*GA at delivery 13 1,672 87 ,.001 1.31
(0.80–1.81)‡ 4 890 69 .02 0.14 (20.51–0.78)‡
Recurrent pretermlabor
8 1,047 0 .56 0.63 (0.52–0.78)† 3 725 20 .29 0.74
(0.53–1.02)†
Admission to NICU 12 1,672 33 .13 0.91 (0.75–1.10)† 4 882 0 .98
1.15 (0.87–1.52)†
Respiratory distresssyndrome
10 1,057 7 .38 0.70 (0.50–0.97)† 3 506 0 .97 0.75
(0.43–1.31)†
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).
Fig. 6. Funnel plot of studies (comparing progestationalagents
and nontreatment or placebo) for outcome: latencyto delivery.
Palacio. Progestogens as Maintenance Treatment. Obstet
Gynecol2016.
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-
The findings from this meta-analysis suggest thatthere is
insufficient high-quality data to inform clini-cians and patients
about the use of progestogens asmaintenance treatment after
arrested preterm labor toreduce preterm birth or prolong pregnancy.
There-fore, the use of progestogens for this indication shouldbe
limited to research protocols until results fromadditional large
and well-designed randomized trialsbecome available.
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