Accepted Manuscript Vaginal progesterone for maintenance tocolysis: a systematic review and metaanalysis of randomized trials Anju Suhag, MD, Gabriele Saccone, MD, Vincenzo Berghella, MD PII:

S0002-9378(15)00261-6

DOI:

10.1016/j.ajog.2015.03.031

Reference:

YMOB 10319

To appear in:

American Journal of Obstetrics and Gynecology

Received Date: 20 December 2014 Revised Date:

5 March 2015

Accepted Date: 17 March 2015

Please cite this article as: Suhag A, Saccone G, Berghella V, Vaginal progesterone for maintenance tocolysis: a systematic review and meta-analysis of randomized trials, American Journal of Obstetrics and Gynecology (2015), doi: 10.1016/j.ajog.2015.03.031. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

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Vaginal progesterone for maintenance tocolysis: a systematic review and meta-analysis of

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randomized trials

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Anju Suhag MD,1 Gabriele Saccone MD,2 Vincenzo Berghella MD1

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Jefferson University Hospital, Philadelphia, PA, USA

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University of Naples Federico II, Naples, Italy

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Correspondence: Vincenzo Berghella, MD, Department of Obstetrics and Gynecology, Division

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of Maternal-Fetal Medicine, Thomas Jefferson University, 833 Chestnut Street, First Floor,

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Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Thomas

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Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine,

Philadelphia, PA 19107, USA.

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E-mail: [email protected]

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Disclosure: The authors report no conflict of interest

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Financial Support: No financial support was received for this study

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Level of evidence: IA

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Word count: Abstract 274; Text 1705; Tables 2; Figures 4

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Obstetrics

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Condensation

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Maintenance tocolysis with vaginal progesterone prevents preterm birth

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Short titles

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Vaginal progesterone for maintenance tocolysis

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Abstract

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Objective: To evaluate the efficacy of maintenance tocolysis with vaginal progesterone

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compared to placebo in singleton gestations with arrested preterm labor (PTL) in a meta-analysis

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of randomized controlled trials (RCTs).

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Data Source: Searches were performed in MEDLINE, OVID, Scopus, ClinicalTrials.gov and

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the Cochrane Central Register of Controlled Trials with the use of a combination of keywords

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and text words related to “progesterone,” “tocolysis” and “preterm labor” from 1966 until

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November 2014.

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Study eligibility criteria: We included all randomized trials of singleton gestations that had

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arrested preterm labor and then were randomized to maintenance tocolysis treatment with either

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vaginal progesterone or control (either placebo or no treatment). All published randomized

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studies on progesterone tocolysis were carefully reviewed. Exclusion criteria included

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maintenance tocolysis in women with preterm premature rupture of membrane, maintenance

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tocolysis with 17-alpha-hydroxyprogesterone caproate and maintenance tocolysis with oral

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progesterone.

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Study appraisal and synthesis methods: The summary measures were reported as risk ratios

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(RR), with 95% confidence interval (95% CI). The primary outcome was preterm birth less than

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37 weeks.

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Results: Five randomized trials, including 441 singleton gestations, were analyzed. Women who

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received vaginal progesterone maintenance tocolysis for arrested preterm labor had a

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significantly lower rate of preterm birth less than 37 weeks (42% vs 58%; RR 0.71, 95% CI 0.57,

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0.90; three trials, 298 women). Women who received vaginal progesterone had significantly

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longer latency (mean difference 13.80 days, 95% CI 3.97, 23.63; four trials, 368 women), later

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gestational age at delivery (mean difference 1.29 weeks, 95% CI 0.43, 2.15; four trials, 368

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women), lower rate of recurrent PTL (24% vs 46%; RR 0.51, 95% CI 0.31, 0.84; two trials, 122

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women) and lower rate of neonatal sepsis (2% vs 7%; RR 0.34, 95% CI 0.12, 0.98; four trials,

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368 women).

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Conclusions: Maintenance tocolysis with vaginal progesterone is associated with prevention of

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preterm birth, significant prolongation of pregnancy, and lower neonatal sepsis. However, given

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the frequent lack of blinding and the generally poor quality of the trials, we do not currently

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suggest a change in clinical care of women with arrested PTL. We suggest instead well-designed

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placebo-controlled randomized trials to confirm the findings of our meta-analysis.

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Key words: preterm labor; preterm birth; tocolysis; progesterone

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Introduction

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Preterm birth (PTB), defined as birth between 20 and 36 6/7 weeks, is responsible for the

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majority of the neonatal morbidity and mortality in the United States,1,2,3 and 35% of all U.S.

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healthcare spending on infants.4 Globally, about 28% of the 4 million annual neonatal deaths are

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directly attributable to PTB.5

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Preterm labor (PTL) is the final pathway for about 50% of all PTB. Tocolytic agents are drugs

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that can slow or stop labor contractions in the attempt to delay births preceded by PTL. Primary

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tocolysis is defined as tocolysis given on initial presentation of women with PTL. In most of

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these women, PTL stops, but as their risk of PTB remains high, some have advocated use of

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maintenance tocolysis, i.e. tocolysis after arrested PTL. So far, no maintenance tocolytic agent

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has been shown to be beneficial in preventing PTB.1 Recently, progesterone has been used

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successfully for prevention of PTB, in particular in asymptomatic singleton gestations with either

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short CL6,7 or with prior spontaneous PTB.8 The efficacy of vaginal progesterone in preventing

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PTB in women with arrested PTL is not clear.

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Objective

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The aim of this study was to evaluate the efficacy of maintenance tocolysis with vaginal

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progesterone compared to placebo in singleton gestations with arrested PTL in a meta-analysis of

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randomized trials.

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Methods

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Study design

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The research protocol was designed a priori, defining methods for searching the literature,

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including and examining articles, and extracting and analyzing data. Searches were performed in

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MEDLINE, OVID, Scopus, ClinicalTrials.gov and the Cochrane Central Register of Controlled

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Trials with the use of a combination of keywords and text words: “progesterone,” “tocolysis”

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and “preterm labor” from 1966 until November 2014. To locate additional publications, we

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reviewed proceedings of international society meetings on PTB and tocolysis and bibliographies

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of identified studies and reviews articles. No restrictions for language or geographic location

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were applied.

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We included randomized trials of singleton gestations that had arrested PTL and then were

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randomized to maintenance tocolysis treatment with either vaginal progesterone or control

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(either placebo or no treatment). All published randomized studies on progesterone tocolysis

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were carefully reviewed. Exclusion criteria included quasi-randomized trials (i.e. trials in which

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allocation was done on the basis of a pseudo-random sequence, e.g. odd/even hospital number or

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date of birth, alternation), maintenance tocolysis in women with preterm premature rupture of

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membrane (PPROM), maintenance tocolysis with 17-alpha-hydroxyprogesterone caproate (17P)

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and maintenance tocolysis with oral progesterone.

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Before data extraction, the protocol was registered with PROSPERO (Registration number:

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CRD42014013706).9 The meta-analysis was reported following the Preferred Reporting Item for

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Systematic Reviews and Meta-analyses (PRISMA) statement.10,11

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Data abstraction was completed by three independent investigators (GS, AS, VB). Each

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investigator independently abstracted data from each study and analyzed data separately.

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Differences were reviewed, and further resolved by common review of the entire data. All

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authors were contacted for missing data.

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The risk of bias in each included study was assessed by using the criteria outlined in the

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Cochrane Handbook for Systematic Reviews of Interventions.10 Seven domains related to risk of

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bias were assessed in each included trial since there is evidence that these issues are associated

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with biased estimates of treatment effect: 1) random sequence generation; 2) allocation

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concealment; 3) blinding of participants and personnel; 4) blinding of outcome assessment; 5)

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incomplete outcome data; 6) selective reporting; and 7) other bias. Review authors’ judgments

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were categorized as “low risk”, “high risk” or “unclear risk” of bias.10 Risk of bias was assessed

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by two investigators (AS, GS). Disagreements were resolved by consensus with a third reviewer

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(VB).

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The primary outcome was PTB

Vaginal progesterone for maintenance tocolysis: a systematic review and metaanalysis of randomized trials.

We sought to evaluate the efficacy of maintenance tocolysis with vaginal progesterone compared to control (placebo or no treatment) in singleton gesta...
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