title: Vaginal progesterone decreases preterm birth and neonatal morbidity and mortality in women with a twin gestation and a short cervix: an updated meta-analysis of individual patient data.
abstract: OBJECTIVE
  To assess the efficacy of vaginal progesterone for the prevention of preterm birth and neonatal morbidity and mortality in asymptomatic women with a twin gestation and a sonographic short cervix (cervical length ≤ 25 mm) in the mid-trimester.
  
  
  METHODS
  This was an updated systematic review and meta-analysis of individual patient data (IPD) from randomized controlled trials comparing vaginal progesterone with placebo/no treatment in women with a twin gestation and a mid-trimester sonographic cervical length ≤ 25 mm. MEDLINE, EMBASE, POPLINE, CINAHL and LILACS (all from inception to 31 December 2016), the Cochrane Central Register of Controlled Trials, Research Registers of ongoing trials, Google Scholar, conference proceedings and reference lists of identified studies were searched. The primary outcome measure was preterm birth < 33 weeks' gestation. Two reviewers independently selected studies, assessed the risk of bias and extracted the data. Pooled relative risks (RRs) with 95% confidence intervals (CI) were calculated.
  
  
  RESULTS
  IPD were available for 303 women (159 assigned to vaginal progesterone and 144 assigned to placebo/no treatment) and their 606 fetuses/infants from six randomized controlled trials. One study, which included women with a cervical length between 20 and 25 mm, provided 74% of the total sample size of the IPD meta-analysis. Vaginal progesterone, compared with placebo/no treatment, was associated with a statistically significant reduction in the risk of preterm birth < 33 weeks' gestation (31.4% vs 43.1%; RR, 0.69 (95% CI, 0.51-0.93); moderate-quality evidence). Moreover, vaginal progesterone administration was associated with a significant decrease in the risk of preterm birth < 35, < 34, < 32 and < 30 weeks' gestation (RRs ranging from 0.47 to 0.83), neonatal death (RR, 0.53 (95% CI, 0.35-0.81)), respiratory distress syndrome (RR, 0.70 (95% CI, 0.56-0.89)), composite neonatal morbidity and mortality (RR, 0.61 (95% CI, 0.34-0.98)), use of mechanical ventilation (RR, 0.54 (95% CI, 0.36-0.81)) and birth weight < 1500 g (RR, 0.53 (95% CI, 0.35-0.80)) (all moderate-quality evidence). There were no significant differences in neurodevelopmental outcomes at 4-5 years of age between the vaginal progesterone and placebo groups.
  
  
  CONCLUSIONS
  Administration of vaginal progesterone to asymptomatic women with a twin gestation and a sonographic short cervix in the mid-trimester reduces the risk of preterm birth occurring at < 30 to < 35 gestational weeks, neonatal mortality and some measures of neonatal morbidity, without any demonstrable deleterious effects on childhood neurodevelopment. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.
authors.affiliation: Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD and Detroit, MI, USA.|Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA.|Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI, USA.|Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA.
authors.forename: R
authors.initials: R
authors.lastname: Romero
authors.affiliation: Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD and Detroit, MI, USA.|Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: A
authors.initials: A
authors.lastname: Conde-Agudelo
authors.affiliation: Department of Obstetrics and Gynecology, Mansoura University Hospitals, Mansoura University, Mansoura, Egypt.
authors.forename: W
authors.initials: W
authors.lastname: El-Refaie
authors.affiliation: Center of Fetal Medicine and Pregnancy, Department of Obstetrics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.|Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Herlev, Denmark.
authors.forename: L
authors.initials: L
authors.lastname: Rode
authors.affiliation: Department of Obstetrics and Gynecology, São Paulo University Medical School, São Paulo, Brazil.
authors.forename: M L
authors.initials: ML
authors.lastname: Brizot
authors.affiliation: Department of Obstetrics and Gynecology, Zeynep Kamil Women and Children Diseases Education and Research Hospital, Uskudar, Istanbul, Turkey.
authors.forename: E
authors.initials: E
authors.lastname: Cetingoz
authors.affiliation: Maternal-Fetal Medicine Unit, Instituto Valenciano de Infertilidad, University of Valencia, Valencia, Spain.|Department of Pediatrics, Obstetrics and Gynecology, University of Valencia, Valencia, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Serra
authors.affiliation: Departamento de Obstetrícia e Ginecologia, Hospital do Servidor Publico Estadual 'Francisco Morato de Oliveira' and School of Medicine, University of São Paulo, São Paulo, Brazil.
authors.forename: E
authors.initials: E
authors.lastname: Da Fonseca
authors.affiliation: Department of Obstetrics and Gynecology, Mansoura University Hospitals, Mansoura University, Mansoura, Egypt.
authors.forename: M S
authors.initials: MS
authors.lastname: Abdelhafez
authors.affiliation: Center of Fetal Medicine and Pregnancy, Department of Obstetrics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.|University of Copenhagen, Faculty of Health Sciences, Copenhagen, Denmark.
authors.forename: A
authors.initials: A
authors.lastname: Tabor
authors.affiliation: Department of Pediatrics, Obstetrics and Gynecology, University of Valencia, Valencia, Spain.|Department of Obstetrics, University Hospital La Fe, Valencia, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Perales
authors.affiliation: Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD and Detroit, MI, USA.|Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: S S
authors.initials: SS
authors.lastname: Hassan
authors.affiliation: Harris Birthright Research Centre for Fetal Medicine, King's College Hospital, London, UK.
authors.forename: K H
authors.initials: KH
authors.lastname: Nicolaides
mesh_terms: D000282:Administration, Intravaginal; D002584:Cervix Uteri / Q000187:drug effects* / Q000473:pathology; D005260:Female; D006801:Humans; D007223:Infant; D007226:Infant Mortality / Q000639:trends; D007231:Infant, Newborn; D063130:Maternal Death / Q000517:prevention & control*; D008428:Maternal Mortality / Q000639:trends; D066087:Perinatal Death / Q000517:prevention & control*; D011247:Pregnancy; D059285:Pregnancy, Twin; D047928:Premature Birth / Q000517:prevention & control*; D011374:Progesterone / Q000008:administration & dosage* / Q000494:pharmacology; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome
chemical_list: D011374:Progesterone
keywords: cervical length; prematurity; preterm delivery; progestins; progestogens; transvaginal ultrasound