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  • Ultrasound Obstet Gynecol 2017; 49: 303314Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.17397. This is an open access article under the termsof the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, providedthe original work is properly cited and is not used for commercial purposes.

    Vaginal progesterone decreases preterm birth and neonatalmorbidity and mortality in women with a twin gestation anda short cervix: an updated meta-analysis of individualpatient dataR. ROMERO1,2,3,4, A. CONDE-AGUDELO1,5, W. EL-REFAIE6, L. RODE7,8, M. L. BRIZOT9,E. CETINGOZ10, V. SERRA11,12, E. DA FONSECA13, M. S. ABDELHAFEZ6, A. TABOR7,14,A. PERALES12,15, S. S. HASSAN1,5 and K. H. NICOLAIDES16

    1Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy ShriverNational Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services,Bethesda, MD and Detroit, MI, USA; 2Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA;3Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI, USA; 4Center for Molecular Medicine andGenetics, Wayne State University, Detroit, MI, USA; 5Department of Obstetrics and Gynecology, Wayne State University School ofMedicine, Detroit, MI, USA; 6Department of Obstetrics and Gynecology, Mansoura University Hospitals, Mansoura University, Mansoura,Egypt; 7Center of Fetal Medicine and Pregnancy, Department of Obstetrics, Copenhagen University Hospital, Rigshospitalet, Copenhagen,Denmark; 8Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Herlev, Denmark; 9Department of Obstetrics andGynecology, Sao Paulo University Medical School, Sao Paulo, Brazil; 10Department of Obstetrics and Gynecology, Zeynep Kamil Womenand Children Diseases Education and Research Hospital, Uskudar, Istanbul, Turkey; 11Maternal-Fetal Medicine Unit, Instituto Valencianode Infertilidad, University of Valencia, Valencia, Spain; 12Department of Pediatrics, Obstetrics and Gynecology, University of Valencia,Valencia, Spain; 13Departamento de Obstetrcia e Ginecologia, Hospital do Servidor Publico Estadual Francisco Morato de Oliveira andSchool of Medicine, University of Sao Paulo, Sao Paulo, Brazil; 14University of Copenhagen, Faculty of Health Sciences, Copenhagen,Denmark; 15Department of Obstetrics, University Hospital La Fe, Valencia, Spain; 16Harris Birthright Research Centre for Fetal Medicine,Kings College Hospital, London, UK

    KEYWORDS: cervical length; prematurity; preterm delivery; progestins; progestogens; transvaginal ultrasound

    ABSTRACT

    Objective To assess the efficacy of vaginal progesteronefor the prevention of preterm birth and neonatalmorbidity and mortality in asymptomatic women witha twin gestation and a sonographic short cervix (cervicallength 25 mm) in the mid-trimester.Methods This was an updated systematic review andmeta-analysis of individual patient data (IPD) fromrandomized controlled trials comparing vaginal pro-gesterone with placebo/no treatment in women with atwin gestation and a mid-trimester sonographic cervi-cal length 25 mm. MEDLINE, EMBASE, POPLINE,CINAHL and LILACS (all from inception to 31 Decem-ber 2016), the Cochrane Central Register of ControlledTrials, Research Registers of ongoing trials, GoogleScholar, conference proceedings and reference lists ofidentified studies were searched. The primary outcomemeasure was preterm birth < 33 weeks gestation. Tworeviewers independently selected studies, assessed the risk

    Correspondence to: Dr R. Romero, Perinatology Research Branch, Intramural Division, NICHD/NIH/DHHS, Hutzel Womens Hospital,Box #4, 3990 John R, Detroit, MI 48201, USA (e-mail: prbchiefstaff@med.wayne.edu)

    The copyright line for this article was changed on 21 March 2017 after original online publication.

    Accepted: 29 December 2016

    of bias and extracted the data. Pooled relative risks (RRs)with 95% confidence intervals (CI) were calculated.

    Results IPD were available for 303 women (159assigned to vaginal progesterone and 144 assignedto placebo/no treatment) and their 606 fetuses/infantsfrom six randomized controlled trials. One study,which included women with a cervical length between20 and 25 mm, provided 74% of the total samplesize of the IPD meta-analysis. Vaginal progesterone,compared with placebo/no treatment, was associatedwith a statistically significant reduction in the riskof preterm birth < 33 weeks gestation (31.4% vs43.1%; RR, 0.69 (95% CI, 0.510.93); moderate-qualityevidence). Moreover, vaginal progesterone administrationwas associated with a significant decrease in the risk ofpreterm birth < 35, < 34, < 32 and < 30 weeks gestation(RRs ranging from 0.47 to 0.83), neonatal death (RR,0.53 (95% CI, 0.350.81)), respiratory distress syndrome(RR, 0.70 (95% CI, 0.560.89)), composite neonatal

    Published 2017. This article is a U.S. Government work and is in the public domain in the USA. SYSTEMATIC REVIEWUltrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

  • 304 Romero et al.

    morbidity and mortality (RR, 0.61 (95% CI, 0.340.98)),use of mechanical ventilation (RR, 0.54 (95% CI,0.360.81)) and birth weight < 1500 g (RR, 0.53 (95%CI, 0.350.80)) (all moderate-quality evidence). Therewere no significant differences in neurodevelopmentaloutcomes at 45 years of age between the vaginalprogesterone and placebo groups.

    Conclusion Administration of vaginal progesterone toasymptomatic women with a twin gestation and asonographic short cervix in the mid-trimester reduces therisk of preterm birth occurring at < 30 to < 35 gestationalweeks, neonatal mortality and some measures of neonatalmorbidity, without any demonstrable deleterious effectson childhood neurodevelopment. Published 2017. Thisarticle is a U.S. Government work and is in thepublic domain in the USA. Ultrasound in Obstetrics& Gynecology published by John Wiley & Sons Ltdon behalf of the International Society of Ultrasound inObstetrics and Gynecology.

    INTRODUCTION

    Twin births have become more prevalent in developedcountries over the last decades13. In 2014, the twin birthrate in the USA was 33.9 per 1000 live births, the highestrate ever recorded4. Twin gestations are at increased riskof maternal, perinatal and infant morbidity and mortality,as well as long-term neurodevelopmental disability513.Moreover, twin gestations also have a significant impacton healthcare costs and quality of life for both the parentsand the children7,14,15.

    Preterm birth is the most important factor determiningneonatal morbidity and mortality among twins. Therisk of preterm birth < 37 and < 32 weeks gestationis eight- to ninefold higher in twin than in singletongestations4. Several interventions have been proposedto reduce the rate of preterm birth in twin gestations,such as bed rest16, prophylactic tocolysis17, nutritionaladvice18, administration of 17-hydroxyprogesteronecaproate19, vaginal progesterone19, cerclage20 andcervical pessary21,22. Unfortunately, these interventionshave not been shown to reduce the risk of preterm birthin unselected twin gestations.

    A short cervix, traditionally defined as a transvagi-nal sonographic cervical length (CL) 25 mm in themid-trimester of pregnancy, is an important risk fac-tor for spontaneous preterm birth and has emerged asone of the strongest and most consistent predictors ofpreterm birth in asymptomatic women with singleton2329

    or twin gestations3043. Currently, there is compellingevidence that administration of vaginal progesterone toasymptomatic women with a singleton gestation and asonographic short cervix decreases the risk of pretermbirth and neonatal morbidity and mortality4446. Theefficacy of vaginal progesterone in women with a twingestation and a short cervix has been less studied.

    A meta-analysis of individual patient data (IPD)published in 2012 reported on the efficacy of vaginal

    progesterone in preventing preterm birth and neonatalmorbidity and mortality in asymptomatic women with atwin gestation and a CL 25 mm in the mid-trimester47.A total of 52 women (104 fetuses/infants) from threerandomized controlled trials (RCTs) were included in thestudy. The use of vaginal progesterone was associatedwith a significant 44% reduction in the risk of compositeneonatal morbidity and mortality (relative risk (RR), 0.56(95% CI, 0.300.97)) and a 30% non-significant reduc-tion in the risk of preterm birth < 33 weeks gestation(RR, 0.70 (95% CI, 0.341.44)). Since that time, addi-tional RCTs evaluating the use of vaginal progesteronein twin gestations have been published. Therefore, areassessment of the efficacy of this intervention in womenwith a twin gestation and a short cervix is justified.

    The objective of this study was to update the previousIPD meta-analysis on the efficacy of vaginal progesteronein asymptomatic women with a twin gestation and asonographic CL 25 mm in the mid-trimester for theprevention of preterm birth and neonatal morbidity andmortality.

    METHODS

    The study was conducted according to a prospectivelyprepared protocol and reported in accordance with thePreferred Reporting Items for Systematic reviews andMeta-Analyses statement48. The review was registeredwith PROSPERO (number CRD42016039682).

    Data sources and searches

    We searched MEDLINE, EMBASE, POPLINE, CINAHLand LILACS (all from inception to 31 December 2016),the Cochrane Central Register of Controlled Trials andResearch Registers of ongoing trials using a combinationof keywords and text words related to progesterone,preterm birth, randomized co

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