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Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and metaanalysis of individual patient data

Published:December 12, 2011DOI:https://doi.org/10.1016/j.ajog.2011.12.003

      Objective

      To determine whether the use of vaginal progesterone in asymptomatic women with a sonographic short cervix (≤25 mm) in the midtrimester reduces the risk of preterm birth and improves neonatal morbidity and mortality.

      Study Design

      Individual patient data metaanalysis of randomized controlled trials.

      Results

      Five trials of high quality were included with a total of 775 women and 827 infants. Treatment with vaginal progesterone was associated with a significant reduction in the rate of preterm birth <33 weeks (relative risk [RR], 0.58; 95% confidence interval [CI], 0.42–0.80), <35 weeks (RR, 0.69; 95% CI, 0.55–0.88), and <28 weeks (RR, 0.50; 95% CI, 0.30–0.81); respiratory distress syndrome (RR, 0.48; 95% CI, 0.30–0.76); composite neonatal morbidity and mortality (RR, 0.57; 95% CI, 0.40–0.81); birthweight <1500 g (RR, 0.55; 95% CI, 0.38–0.80); admission to neonatal intensive care unit (RR, 0.75; 95% CI, 0.59–0.94); and requirement for mechanical ventilation (RR, 0.66; 95% CI, 0.44–0.98). There were no significant differences between the vaginal progesterone and placebo groups in the rate of adverse maternal events or congenital anomalies.

      Conclusion

      Vaginal progesterone administration to asymptomatic women with a sonographic short cervix reduces the risk of preterm birth and neonatal morbidity and mortality.

      Key words

      Preterm birth is the leading cause of perinatal morbidity and mortality worldwide
      • Goldenberg R.L.
      • Culhane J.F.
      • Iams J.D.
      • Romero R.
      Epidemiology and causes of preterm birth.
      and contributes to 70% of neonatal mortality and approximately half of long-term neurodevelopmental disabilities.
      • Mathews T.J.
      • Menacker F.
      • MacDorman M.F.
      Infant mortality statistics from the 2002 period: linked birth/infant death data set.
      A recent systematic review has estimated that 12.9 million births, or 9.6% of all births worldwide, were preterm, of which approximately 11.9 million (92.3%) were in Africa, Asia, Latin America, and the Caribbean.
      • Beck S.
      • Wojdyla D.
      • Say L.
      • et al.
      The worldwide incidence of preterm birth: a systematic review of maternal mortality and morbidity.
      During the last 25 years, the preterm birth rate in the United States increased 36%, from 9.4% in 1981 to 12.8% in 2006.
      • Martin J.A.
      • Hamilton B.E.
      • Sutton P.D.
      • et al.
      Births: final data for 2007.
      This increase has been attributed to a higher frequency of “indicated” preterm births in singleton gestations and preterm delivery in multiple gestations resulting, in part, from the use of assisted reproductive technologies.
      • Ananth C.V.
      • Vintzileos A.M.
      Epidemiology of preterm birth and its clinical subtypes.
      • Ananth C.V.
      • Vintzileos A.M.
      Maternal-fetal conditions necessitating a medical intervention resulting in preterm birth.
      • Ananth C.V.
      • Joseph K.S.
      • Demissie K.
      • Vintzileos A.M.
      Trends in twin preterm birth subtypes in the United States, 1989 through 2000: impact on perinatal mortality.
      • Chauhan S.P.
      • Scardo J.A.
      • Hayes E.
      • Abuhamad A.Z.
      • Berghella V.
      Twins: prevalence, problems, and preterm births.
      • Stone J.
      • Ferrara L.
      • Kamrath J.
      • et al.
      Contemporary outcomes with the latest 1000 cases of multifetal pregnancy reduction (MPR).
      • Luke B.
      • Brown M.B.
      Maternal morbidity and infant death in twin vs triplet and quadruplet pregnancies.
      • Barri P.N.
      • Coroleu B.
      • Clua E.
      • Tur R.
      Prevention of prematurity by single embryo transfer.
      • Pandian Z.
      • Templeton A.
      • Bhattacharya S.
      Modification of assisted reproduction techniques to prevent preterm birth.
      • Adashi E.Y.
      • Ekins M.N.
      • Lacoursiere Y.
      On the discharge of Hippocratic obligations: challenges and opportunities.
      • Adashi E.Y.
      • Barri P.N.
      • Berkowitz R.
      • et al.
      Infertility therapy-associated multiple pregnancies (births): an ongoing epidemic.
      • Langhoff-Roos J.
      • Kesmodel U.
      • Jacobsson B.
      • Rasmussen S.
      • Vogel I.
      Spontaneous preterm delivery in primiparous women at low risk in Denmark: population based study.
      For Editors' Commentary, see Table of Contents
      See related editorial, page 101
      Spontaneous preterm labor/delivery is considered to be one of the “great obstetrical syndromes”,
      • Romero R.
      Prenatal medicine: the child is the father of the man 1996.
      • Di Renzo G.C.
      The great obstetrical syndromes.
      a term that emphasizes that obstetrical disorders with a similar phenotype are caused by multiple pathologic processes,
      • Romero R.
      • Mazor M.
      • Munoz H.
      • Gomez R.
      • Galasso M.
      • Sherer D.M.
      The preterm labor syndrome.
      have a long subclinical phase, and may result from complex gene-environment interactions.
      • Gomez R.
      • Romero R.
      • Nien J.K.
      • et al.
      Antibiotic administration to patients with preterm premature rupture of membranes does not eradicate intra-amniotic infection.
      • Ma S.
      • Yang L.
      • Romero R.
      • Cui Y.
      Varying coefficient model for gene-environment interaction: a non-linear look.
      • Macones G.A.
      • Parry S.
      • Elkousy M.
      • Clothier B.
      • Ural S.H.
      • Strauss III, J.F.
      A polymorphism in the promoter region of TNF and bacterial vaginosis: preliminary evidence of gene-environment interaction in the etiology of spontaneous preterm birth.
      • Parimi N.
      • Tromp G.
      • Kuivaniemi H.
      • et al.
      Analytical approaches to detect maternal/fetal genotype incompatibilities that increase risk of pre-eclampsia.
      Progesterone is considered a key hormone for pregnancy maintenance, and a decline of progesterone action is implicated in the onset of parturition.
      • Csapo A.I.
      The ‘see-saw’ theory of parturition.
      • Kerenyi T.
      Forgotten “father of progesterone.”.
      • Csapo A.
      The luteo-placental shift, the guardian of pre-natal life.
      • Csapo A.I.
      • Pulkkinen M.O.
      • Wiest W.G.
      Effects of luteectomy and progesterone replacement therapy in early pregnant patients.
      If such a decline occurs in the midtrimester, cervical shortening may occur, and this would predispose to preterm delivery. Therefore, an untimely decline in progesterone action has been proposed as a mechanism of disease in the “preterm parturition syndrome”.
      • Romero R.
      Prevention of spontaneous preterm birth: the role of sonographic cervical length in identifying patients who may benefit from progesterone treatment.
      Progesterone actions are mediated by genomic and nongenomic effects which have been studied in the uterine cervix, myometrium, sperm, etc.
      • Romero R.
      • Espinoza J.
      • Kusanovic J.P.
      • et al.
      The preterm parturition syndrome.
      • Elovitz M.A.
      • Mrinalini C.
      The use of progestational agents for preterm birth: lessons from a mouse model.
      • Carbonne B.
      • Dallot E.
      • Haddad B.
      • Ferré F.
      • Cabrol D.
      Effects of progesterone on prostaglandin E(2)-induced changes in glycosaminoglycan synthesis by human cervical fibroblasts in culture.
      • Facchinetti F.
      • Paganelli S.
      • Comitini G.
      • Dante G.
      • Volpe A.
      Cervical length changes during preterm cervical ripening: effects of 17-alpha-hydroxyprogesterone caproate.
      • Denison F.C.
      • Calder A.A.
      • Kelly R.W.
      The action of prostaglandin E2 on the human cervix: stimulation of interleukin 8 and inhibition of secretory leukocyte protease inhibitor.
      • Kelly R.W.
      • Leask R.
      • Calder A.A.
      Choriodecidual production of interleukin-8 and mechanism of parturition.
      • Rajabi M.
      • Solomon S.
      • Poole A.R.
      Hormonal regulation of interstitial collagenase in the uterine cervix of the pregnant guinea pig.
      • Rodriguez H.A.
      • Kass L.
      • Varayoud J.
      • et al.
      Collagen remodeling in the guinea-pig uterine cervix at term is associated with a decrease in progesterone receptor expression.
      • Sato T.
      • Ito A.
      • Mori Y.
      • Yamashita K.
      • Hayakawa T.
      • Nagase H.
      Hormonal regulation of collagenolysis in uterine cervical fibroblasts: modulation of synthesis of procollagenase, prostromelysin and tissue inhibitor of metalloproteinases (TIMP) by progesterone and oestradiol-17 beta.
      • Uldbjerg N.
      • Ekman G.
      • Malmstrom A.
      • Olsson K.
      • Ulmsten U.
      Ripening of the human uterine cervix related to changes in collagen, glycosaminoglycans, and collagenolytic activity.
      • Stjernholm Y.
      • Sahlin L.
      • Akerberg S.
      • et al.
      Cervical ripening in humans: potential roles of estrogen, progesterone, and insulin-like growth factor-I.
      • Naftolin F.
      • Stubblefield P.
      Dilatation of the uterine cervix: connective tissue biology and clinical management.
      • Chwalisz K.
      • Benson M.
      • Scholz P.
      • Daum J.
      • Beier H.M.
      • Hegele-Hartung C.
      Cervical ripening with the cytokines interleukin 8, interleukin 1 beta and tumor necrosis factor alpha in guinea-pigs.
      • Chwalisz K.
      • Garfield R.E.
      Regulation of the uterus and cervix during pregnancy and labor: role of progesterone and nitric oxide.
      • Chwalisz K.
      • Garfield R.E.
      Nitric oxide as the final metabolic mediator of cervical ripening.
      • Mahendroo M.S.
      • Cala K.M.
      • Russell D.W.
      5 Alpha-reduced androgens play a key role in murine parturition.
      • Mahendroo M.S.
      • Porter A.
      • Russell D.W.
      • Word R.A.
      The parturition defect in steroid 5 alpha-reductase type 1 knockout mice is due to impaired cervical ripening.
      • Word R.A.
      • Li X.H.
      • Hnat M.
      • Carrick K.
      Dynamics of cervical remodeling during pregnancy and parturition: mechanisms and current concepts.
      • Garfield R.E.
      • Puri C.P.
      • Csapo A.I.
      Endocrine, structural, and functional changes in the uterus during premature labor.
      • Saito Y.
      • Takahashi S.
      • Maki M.
      Effects of some drugs on ripening of uterine cervix in nonpregnant castrated and pregnant rats.
      • Elovitz M.
      • Wang Z.
      Medroxyprogesterone acetate, but not progesterone, protects against inflammation-induced parturition and intrauterine fetal demise.
      • Ito A.
      • Imada K.
      • Sato T.
      • Kubo T.
      • Matsushima K.
      • Mori Y.
      Suppression of interleukin 8 production by progesterone in rabbit uterine cervix.
      • Marx S.G.
      • Wentz M.J.
      • Mackay L.B.
      • et al.
      Effects of progesterone on iNOS, COX-2, and collagen expression in the cervix.
      • Stiemer B.
      • Elger W.
      Cervical ripening of the rat in dependence on endocrine milieu; effects of antigestagens.
      • Zuidema L.J.
      • Khan-Dawood F.
      • Dawood M.Y.
      • Work Jr, B.A.
      Hormones and cervical ripening: dehydroepiandrosterone sulfate, estradiol, estriol, and progesterone.
      • Chwalisz K.
      • Shi Shao O.
      • Neff G.
      • Elger J.
      The effect of antigestagen ZK 98, 199 on the uterine cervix.
      • Elliott C.L.
      • Brennand J.E.
      • Calder A.A.
      The effects of mifepristone on cervical ripening and labor induction in primigravidae.
      • Norman J.
      Antiprogesterones.
      • Giacalone P.L.
      • Daures J.P.
      • Faure J.M.
      • Boulot P.
      • Hedon B.
      • Laffargue F.
      The effects of mifepristone on uterine sensitivity to oxytocin and on fetal heart rate patterns.
      • Hegele-Hartung C.
      • Chwalisz K.
      • Beier H.M.
      • Elger W.
      Ripening of the uterine cervix of the guinea-pig after treatment with the progesterone antagonist onapristone (ZK 98.299): an electron microscopic study.
      • Stenlund P.M.
      • Ekman G.
      • Aedo A.R.
      • Bygdeman M.
      Induction of labor with mifepristone–a randomized, double-blind study versus placebo.
      • Stys S.J.
      • Clewell W.H.
      • Meschia G.
      Changes in cervical compliance at parturition independent of uterine activity.
      • Wolf J.P.
      • Sinosich M.
      • Anderson T.L.
      • Ulmann A.
      • Baulieu E.E.
      • Hodgen G.D.
      Progesterone antagonist (RU 486) for cervical dilation, labor induction, and delivery in monkeys: effectiveness in combination with oxytocin.
      • Allan G.F.
      • Tsai S.Y.
      • Tsai M.J.
      • O'Malley B.W.
      Ligand-dependent conformational changes in the progesterone receptor are necessary for events that follow DNA binding.
      • Beato M.
      Gene regulation by steroid hormones.
      • Brosens J.J.
      • Tullet J.
      • Varshochi R.
      • Lam E.W.
      Steroid receptor action.
      • Henderson D.
      • Wilson T.
      Reduced binding of progesterone receptor to its nuclear response element after human labor onset.
      • Merlino A.A.
      • Welsh T.N.
      • Tan H.
      • et al.
      Nuclear progesterone receptors in the human pregnancy myometrium: evidence that parturition involves functional progesterone withdrawal mediated by increased expression of progesterone receptor-A.
      • Oh S.Y.
      • Kim C.J.
      • Park I.
      • et al.
      Progesterone receptor isoform (A/B) ratio of human fetal membranes increases during term parturition.
      • Power R.F.
      • Conneely O.M.
      • O'Malley B.W.
      New insights into activation of the steroid hormone receptor superfamily.
      • Cabrol D.
      • Carbonne B.
      • Bienkiewicz A.
      • Dallot E.
      • Alj A.E.
      • Cedard L.
      Induction of labor and cervical maturation using mifepristone (RU 486) in the late pregnant rat Influence of a cyclooxygenase inhibitor (Diclofenac).
      • Tsai M.J.
      • O'Malley B.W.
      Molecular mechanisms of action of steroid/thyroid receptor superfamily members.
      • Vegeto E.
      • Shahbaz M.M.
      • Wen D.X.
      • Goldman M.E.
      • O'Malley B.W.
      • McDonnell D.P.
      Human progesterone receptor A form is a cell- and promoter-specific repressor of human progesterone receptor B function.
      • Denner L.A.
      • Weigel N.L.
      • Maxwell B.L.
      • Schrader W.T.
      • O'Malley B.W.
      Regulation of progesterone receptor-mediated transcription by phosphorylation.
      • Fomin V.P.
      • Cox B.E.
      • Word R.A.
      Effect of progesterone on intracellular Ca2+ homeostasis in human myometrial smooth muscle cells.
      • McEwen B.S.
      Non-genomic and genomic effects of steroids on neural activity.
      • Meizel S.
      • Turner K.O.
      Progesterone acts at the plasma membrane of human sperm.
      • Mesiano S.
      • Chan E.C.
      • Fitter J.T.
      • Kwek K.
      • Yeo G.
      • Smith R.
      Progesterone withdrawal and estrogen activation in human parturition are coordinated by progesterone receptor A expression in the myometrium.
      • Schumacher M.
      Rapid membrane effects of steroid hormones: an emerging concept in neuroendocrinology.
      • Condon J.C.
      • Jeyasuria P.
      • Faust J.M.
      • Wilson J.W.
      • Mendelson C.R.
      A decline in the levels of progesterone receptor coactivators in the pregnant uterus at term may antagonize progesterone receptor function and contribute to the initiation of parturition.
      • Chapman N.R.
      • Kennelly M.M.
      • Harper K.A.
      • Europe-Finner G.N.
      • Robson S.C.
      Examining the spatio-temporal expression of mRNA encoding the membrane-bound progesterone receptor-alpha isoform in human cervix and myometrium during pregnancy and labor.
      • Madsen G.
      • Zakar T.
      • Ku C.Y.
      • Sanborn B.M.
      • Smith R.
      • Mesiano S.
      Prostaglandins differentially modulate progesterone receptor-A and -B expression in human myometrial cells: evidence for prostaglandin-induced functional progesterone withdrawal.
      • Condon J.C.
      • Hardy D.B.
      • Kovaric K.
      • Mendelson C.R.
      Upregulation of the progesterone receptor (PR)-C isoform in laboring myometrium by activation of nuclear factor-kappaB may contribute to the onset of labor through inhibition of PR function.
      • Falkenstein E.
      • Norman A.W.
      • Wehling M.
      Mannheim classification of nongenomically initiated (rapid) steroid action(s).
      • Bennett P.
      • Allport V.
      • Loudon J.
      • Elliott C.
      Prostaglandins, the fetal membranes and the cervix.
      • Kofinas A.D.
      • Rose J.C.
      • Koritnik D.R.
      • Meis P.J.
      Progesterone and estradiol concentrations in nonpregnant and pregnant human myometrium: effect of progesterone and estradiol on cyclic adenosine monophosphate-phosphodiesterase activity.
      • Losel R.
      • Wehling M.
      Nongenomic actions of steroid hormones.
      • Losel R.M.
      • Falkenstein E.
      • Feuring M.
      • et al.
      Nongenomic steroid action: controversies, questions, and answers.
      • Perusquia M.
      • Garcia-Yanez E.
      • Ibanez R.
      • Kubli-Garfias C.
      Non-genomic mechanism of action of delta-4 and 5-reduced androgens and progestins on the contractility of the isolated rat myometrium.
      • Sager G.
      • Orbo A.
      • Jaeger R.
      • Engstrom C.
      Non-genomic effects of progestins–inhibition of cell growth and increased intracellular levels of cyclic nucleotides.
      • Ekman-Ordeberg G.
      • Stjernholm Y.
      • Wang H.
      • Stygar D.
      • Sahlin L.
      Endocrine regulation of cervical ripening in humans – potential roles for gonadal steroids and insulin-like growth factor-I.
      • Blackmore P.F.
      • Neulen J.
      • Lattanzio F.
      • Beebe S.J.
      Cell surface-binding sites for progesterone mediate calcium uptake in human sperm.
      • Fernandes M.S.
      • Pierron V.
      • Michalovich D.
      • et al.
      Regulated expression of putative membrane progestin receptor homologues in human endometrium and gestational tissues.
      • Grazzini E.
      • Guillon G.
      • Mouillac B.
      • Zingg H.H.
      Inhibition of oxytocin receptor function by direct binding of progesterone.
      • Haukkamaa M.
      High affinity progesterone binding sites of human uterine microsomal membranes.
      • Karteris E.
      • Zervou S.
      • Pang Y.
      • et al.
      Progesterone signaling in human myometrium through two novel membrane G protein-coupled receptors: potential role in functional progesterone withdrawal at term.
      • Lye S.J.
      • Porter D.G.
      Demonstration that progesterone ‘blocks’ uterine activity in the ewe in vivo by a direct action on the myometrium.
      • Challis J.R.
      • Patel F.A.
      • Pomini F.
      Prostaglandin dehydrogenase and the initiation of labor [Review].
      • Modi D.N.
      • Shah C.
      • Puri C.P.
      Non-genomic membrane progesterone receptors on human spermatozoa.
      • Andersson S.
      • Minjarez D.
      • Yost N.P.
      • Word R.A.
      Estrogen and progesterone metabolism in the cervix during pregnancy and parturition.
      • Yellon S.M.
      • Ebner C.A.
      • Elovitz M.A.
      Medroxyprogesterone acetate modulates remodeling, immune cell census, and nerve fibers in the cervix of a mouse model for inflammation-induced preterm birth.
      • Cicinelli E.
      • de Ziegler D.
      Transvaginal progesterone: evidence for a new functional 'portal system' flowing from the vagina to the uterus.
      • Romero R.
      • Scoccia B.
      • Mazor M.
      • Wu Y.K.
      • Benveniste R.
      Evidence for a local change in the progesterone/estrogen ratio in human parturition at term.
      • Mitchell B.F.
      • Mitchell J.M.
      • Chowdhury J.
      • Tougas M.
      • Engelen S.M.
      • Senff N.
      • et al.
      Metabolites of progesterone and the pregnane X receptor: a novel pathway regulating uterine contractility in pregnancy?.
      A blockade of progesterone action can lead to the clinical, biochemical, and morphologic changes associated with cervical ripening.
      • Romero R.
      • Espinoza J.
      • Kusanovic J.P.
      • et al.
      The preterm parturition syndrome.
      • Elovitz M.A.
      • Mrinalini C.
      The use of progestational agents for preterm birth: lessons from a mouse model.
      • Carbonne B.
      • Dallot E.
      • Haddad B.
      • Ferré F.
      • Cabrol D.
      Effects of progesterone on prostaglandin E(2)-induced changes in glycosaminoglycan synthesis by human cervical fibroblasts in culture.
      • Facchinetti F.
      • Paganelli S.
      • Comitini G.
      • Dante G.
      • Volpe A.
      Cervical length changes during preterm cervical ripening: effects of 17-alpha-hydroxyprogesterone caproate.
      • Denison F.C.
      • Calder A.A.
      • Kelly R.W.
      The action of prostaglandin E2 on the human cervix: stimulation of interleukin 8 and inhibition of secretory leukocyte protease inhibitor.
      • Kelly R.W.
      • Leask R.
      • Calder A.A.
      Choriodecidual production of interleukin-8 and mechanism of parturition.
      • Rajabi M.
      • Solomon S.
      • Poole A.R.
      Hormonal regulation of interstitial collagenase in the uterine cervix of the pregnant guinea pig.
      • Rodriguez H.A.
      • Kass L.
      • Varayoud J.
      • et al.
      Collagen remodeling in the guinea-pig uterine cervix at term is associated with a decrease in progesterone receptor expression.
      • Sato T.
      • Ito A.
      • Mori Y.
      • Yamashita K.
      • Hayakawa T.
      • Nagase H.
      Hormonal regulation of collagenolysis in uterine cervical fibroblasts: modulation of synthesis of procollagenase, prostromelysin and tissue inhibitor of metalloproteinases (TIMP) by progesterone and oestradiol-17 beta.
      • Uldbjerg N.
      • Ekman G.
      • Malmstrom A.
      • Olsson K.
      • Ulmsten U.
      Ripening of the human uterine cervix related to changes in collagen, glycosaminoglycans, and collagenolytic activity.
      • Stjernholm Y.
      • Sahlin L.
      • Akerberg S.
      • et al.
      Cervical ripening in humans: potential roles of estrogen, progesterone, and insulin-like growth factor-I.
      • Naftolin F.
      • Stubblefield P.
      Dilatation of the uterine cervix: connective tissue biology and clinical management.
      • Chwalisz K.
      • Benson M.
      • Scholz P.
      • Daum J.
      • Beier H.M.
      • Hegele-Hartung C.
      Cervical ripening with the cytokines interleukin 8, interleukin 1 beta and tumor necrosis factor alpha in guinea-pigs.
      • Chwalisz K.
      • Garfield R.E.
      Regulation of the uterus and cervix during pregnancy and labor: role of progesterone and nitric oxide.
      • Chwalisz K.
      • Garfield R.E.
      Nitric oxide as the final metabolic mediator of cervical ripening.
      • Mahendroo M.S.
      • Cala K.M.
      • Russell D.W.
      5 Alpha-reduced androgens play a key role in murine parturition.
      • Mahendroo M.S.
      • Porter A.
      • Russell D.W.
      • Word R.A.
      The parturition defect in steroid 5 alpha-reductase type 1 knockout mice is due to impaired cervical ripening.
      • Word R.A.
      • Li X.H.
      • Hnat M.
      • Carrick K.
      Dynamics of cervical remodeling during pregnancy and parturition: mechanisms and current concepts.
      • Garfield R.E.
      • Puri C.P.
      • Csapo A.I.
      Endocrine, structural, and functional changes in the uterus during premature labor.
      • Saito Y.
      • Takahashi S.
      • Maki M.
      Effects of some drugs on ripening of uterine cervix in nonpregnant castrated and pregnant rats.
      • Elovitz M.
      • Wang Z.
      Medroxyprogesterone acetate, but not progesterone, protects against inflammation-induced parturition and intrauterine fetal demise.
      • Ito A.
      • Imada K.
      • Sato T.
      • Kubo T.
      • Matsushima K.
      • Mori Y.
      Suppression of interleukin 8 production by progesterone in rabbit uterine cervix.
      • Marx S.G.
      • Wentz M.J.
      • Mackay L.B.
      • et al.
      Effects of progesterone on iNOS, COX-2, and collagen expression in the cervix.
      • Stiemer B.
      • Elger W.
      Cervical ripening of the rat in dependence on endocrine milieu; effects of antigestagens.
      • Zuidema L.J.
      • Khan-Dawood F.
      • Dawood M.Y.
      • Work Jr, B.A.
      Hormones and cervical ripening: dehydroepiandrosterone sulfate, estradiol, estriol, and progesterone.
      • Chwalisz K.
      • Shi Shao O.
      • Neff G.
      • Elger J.
      The effect of antigestagen ZK 98, 199 on the uterine cervix.
      • Elliott C.L.
      • Brennand J.E.
      • Calder A.A.
      The effects of mifepristone on cervical ripening and labor induction in primigravidae.
      • Norman J.
      Antiprogesterones.
      • Giacalone P.L.
      • Daures J.P.
      • Faure J.M.
      • Boulot P.
      • Hedon B.
      • Laffargue F.
      The effects of mifepristone on uterine sensitivity to oxytocin and on fetal heart rate patterns.
      • Hegele-Hartung C.
      • Chwalisz K.
      • Beier H.M.
      • Elger W.
      Ripening of the uterine cervix of the guinea-pig after treatment with the progesterone antagonist onapristone (ZK 98.299): an electron microscopic study.
      • Stenlund P.M.
      • Ekman G.
      • Aedo A.R.
      • Bygdeman M.
      Induction of labor with mifepristone–a randomized, double-blind study versus placebo.
      • Stys S.J.
      • Clewell W.H.
      • Meschia G.
      Changes in cervical compliance at parturition independent of uterine activity.
      • Wolf J.P.
      • Sinosich M.
      • Anderson T.L.
      • Ulmann A.
      • Baulieu E.E.
      • Hodgen G.D.
      Progesterone antagonist (RU 486) for cervical dilation, labor induction, and delivery in monkeys: effectiveness in combination with oxytocin.
      • Allan G.F.
      • Tsai S.Y.
      • Tsai M.J.
      • O'Malley B.W.
      Ligand-dependent conformational changes in the progesterone receptor are necessary for events that follow DNA binding.
      • Beato M.
      Gene regulation by steroid hormones.
      • Brosens J.J.
      • Tullet J.
      • Varshochi R.
      • Lam E.W.
      Steroid receptor action.
      • Henderson D.
      • Wilson T.
      Reduced binding of progesterone receptor to its nuclear response element after human labor onset.
      • Merlino A.A.
      • Welsh T.N.
      • Tan H.
      • et al.
      Nuclear progesterone receptors in the human pregnancy myometrium: evidence that parturition involves functional progesterone withdrawal mediated by increased expression of progesterone receptor-A.
      • Oh S.Y.
      • Kim C.J.
      • Park I.
      • et al.
      Progesterone receptor isoform (A/B) ratio of human fetal membranes increases during term parturition.
      • Power R.F.
      • Conneely O.M.
      • O'Malley B.W.
      New insights into activation of the steroid hormone receptor superfamily.
      • Cabrol D.
      • Carbonne B.
      • Bienkiewicz A.
      • Dallot E.
      • Alj A.E.
      • Cedard L.
      Induction of labor and cervical maturation using mifepristone (RU 486) in the late pregnant rat Influence of a cyclooxygenase inhibitor (Diclofenac).
      • Tsai M.J.
      • O'Malley B.W.
      Molecular mechanisms of action of steroid/thyroid receptor superfamily members.
      • Vegeto E.
      • Shahbaz M.M.
      • Wen D.X.
      • Goldman M.E.
      • O'Malley B.W.
      • McDonnell D.P.
      Human progesterone receptor A form is a cell- and promoter-specific repressor of human progesterone receptor B function.
      • Denner L.A.
      • Weigel N.L.
      • Maxwell B.L.
      • Schrader W.T.
      • O'Malley B.W.
      Regulation of progesterone receptor-mediated transcription by phosphorylation.
      • Fomin V.P.
      • Cox B.E.
      • Word R.A.
      Effect of progesterone on intracellular Ca2+ homeostasis in human myometrial smooth muscle cells.
      • McEwen B.S.
      Non-genomic and genomic effects of steroids on neural activity.
      • Meizel S.
      • Turner K.O.
      Progesterone acts at the plasma membrane of human sperm.
      • Mesiano S.
      • Chan E.C.
      • Fitter J.T.
      • Kwek K.
      • Yeo G.
      • Smith R.
      Progesterone withdrawal and estrogen activation in human parturition are coordinated by progesterone receptor A expression in the myometrium.
      • Schumacher M.
      Rapid membrane effects of steroid hormones: an emerging concept in neuroendocrinology.
      • Condon J.C.
      • Jeyasuria P.
      • Faust J.M.
      • Wilson J.W.
      • Mendelson C.R.
      A decline in the levels of progesterone receptor coactivators in the pregnant uterus at term may antagonize progesterone receptor function and contribute to the initiation of parturition.
      • Chapman N.R.
      • Kennelly M.M.
      • Harper K.A.
      • Europe-Finner G.N.
      • Robson S.C.
      Examining the spatio-temporal expression of mRNA encoding the membrane-bound progesterone receptor-alpha isoform in human cervix and myometrium during pregnancy and labor.
      • Madsen G.
      • Zakar T.
      • Ku C.Y.
      • Sanborn B.M.
      • Smith R.
      • Mesiano S.
      Prostaglandins differentially modulate progesterone receptor-A and -B expression in human myometrial cells: evidence for prostaglandin-induced functional progesterone withdrawal.
      • Condon J.C.
      • Hardy D.B.
      • Kovaric K.
      • Mendelson C.R.
      Upregulation of the progesterone receptor (PR)-C isoform in laboring myometrium by activation of nuclear factor-kappaB may contribute to the onset of labor through inhibition of PR function.
      • Falkenstein E.
      • Norman A.W.
      • Wehling M.
      Mannheim classification of nongenomically initiated (rapid) steroid action(s).
      • Bennett P.
      • Allport V.
      • Loudon J.
      • Elliott C.
      Prostaglandins, the fetal membranes and the cervix.
      • Kofinas A.D.
      • Rose J.C.
      • Koritnik D.R.
      • Meis P.J.
      Progesterone and estradiol concentrations in nonpregnant and pregnant human myometrium: effect of progesterone and estradiol on cyclic adenosine monophosphate-phosphodiesterase activity.
      • Losel R.
      • Wehling M.
      Nongenomic actions of steroid hormones.
      • Losel R.M.
      • Falkenstein E.
      • Feuring M.
      • et al.
      Nongenomic steroid action: controversies, questions, and answers.
      • Perusquia M.
      • Garcia-Yanez E.
      • Ibanez R.
      • Kubli-Garfias C.
      Non-genomic mechanism of action of delta-4 and 5-reduced androgens and progestins on the contractility of the isolated rat myometrium.
      • Sager G.
      • Orbo A.
      • Jaeger R.
      • Engstrom C.
      Non-genomic effects of progestins–inhibition of cell growth and increased intracellular levels of cyclic nucleotides.
      • Ekman-Ordeberg G.
      • Stjernholm Y.
      • Wang H.
      • Stygar D.
      • Sahlin L.
      Endocrine regulation of cervical ripening in humans – potential roles for gonadal steroids and insulin-like growth factor-I.
      • Blackmore P.F.
      • Neulen J.
      • Lattanzio F.
      • Beebe S.J.
      Cell surface-binding sites for progesterone mediate calcium uptake in human sperm.
      • Fernandes M.S.
      • Pierron V.
      • Michalovich D.
      • et al.
      Regulated expression of putative membrane progestin receptor homologues in human endometrium and gestational tissues.
      • Grazzini E.
      • Guillon G.
      • Mouillac B.
      • Zingg H.H.
      Inhibition of oxytocin receptor function by direct binding of progesterone.
      • Haukkamaa M.
      High affinity progesterone binding sites of human uterine microsomal membranes.
      • Karteris E.
      • Zervou S.
      • Pang Y.
      • et al.
      Progesterone signaling in human myometrium through two novel membrane G protein-coupled receptors: potential role in functional progesterone withdrawal at term.
      • Lye S.J.
      • Porter D.G.
      Demonstration that progesterone ‘blocks’ uterine activity in the ewe in vivo by a direct action on the myometrium.
      • Challis J.R.
      • Patel F.A.
      • Pomini F.
      Prostaglandin dehydrogenase and the initiation of labor [Review].
      • Modi D.N.
      • Shah C.
      • Puri C.P.
      Non-genomic membrane progesterone receptors on human spermatozoa.
      • Andersson S.
      • Minjarez D.
      • Yost N.P.
      • Word R.A.
      Estrogen and progesterone metabolism in the cervix during pregnancy and parturition.
      • Yellon S.M.
      • Ebner C.A.
      • Elovitz M.A.
      Medroxyprogesterone acetate modulates remodeling, immune cell census, and nerve fibers in the cervix of a mouse model for inflammation-induced preterm birth.
      • Cicinelli E.
      • de Ziegler D.
      Transvaginal progesterone: evidence for a new functional 'portal system' flowing from the vagina to the uterus.
      • Romero R.
      • Scoccia B.
      • Mazor M.
      • Wu Y.K.
      • Benveniste R.
      Evidence for a local change in the progesterone/estrogen ratio in human parturition at term.
      • Mitchell B.F.
      • Mitchell J.M.
      • Chowdhury J.
      • Tougas M.
      • Engelen S.M.
      • Senff N.
      • et al.
      Metabolites of progesterone and the pregnane X receptor: a novel pathway regulating uterine contractility in pregnancy?.
      A short cervix detected with transvaginal ultrasound is a powerful predictor of preterm birth in women with singleton and twin gestations.
      • Romero R.
      Prevention of spontaneous preterm birth: the role of sonographic cervical length in identifying patients who may benefit from progesterone treatment.
      • Andersen H.F.
      • Nugent C.E.
      • Wanty S.D.
      • Hayashi R.H.
      Prediction of risk for preterm delivery by ultrasonographic measurement of cervical length.
      • Iams J.D.
      • Goldenberg R.L.
      • Meis P.J.
      • et al.
      The length of the cervix and the risk of spontaneous premature delivery.
      • Hassan S.S.
      • Romero R.
      • Berry S.M.
      • et al.
      Patients with an ultrasonographic cervical length < or = 15 mm have nearly a 50% risk of early spontaneous preterm delivery.
      • To M.S.
      • Skentou C.
      • Liao A.W.
      • Cacho A.
      • Nicolaides K.H.
      Cervical length and funneling at 23 weeks of gestation in the prediction of spontaneous early preterm delivery.
      • Celik E.
      • To M.
      • Gajewska K.
      • Smith G.C.
      • Nicolaides K.H.
      Cervical length and obstetric history predict spontaneous preterm birth: development and validation of a model to provide individualized risk assessment.
      • Crane J.M.
      • Hutchens D.
      Transvaginal sonographic measurement of cervical length to predict preterm birth in asymptomatic women at increased risk: a systematic review.
      • Conde-Agudelo A.
      • Romero R.
      • Hassan S.S.
      • Yeo L.
      Transvaginal sonographic cervical length for the prediction of spontaneous preterm birth in twin pregnancies: a systematic review and metaanalysis.
      • Vaisbuch E.
      • Romero R.
      • Erez O.
      • et al.
      Clinical significance of early (<20 weeks) vs late (20-24 weeks) detection of sonographic short cervix in asymptomatic women in the mid-trimester.
      The shorter the sonographic cervical length, the higher the risk of spontaneous preterm birth.
      • Andersen H.F.
      • Nugent C.E.
      • Wanty S.D.
      • Hayashi R.H.
      Prediction of risk for preterm delivery by ultrasonographic measurement of cervical length.
      • Iams J.D.
      • Goldenberg R.L.
      • Meis P.J.
      • et al.
      The length of the cervix and the risk of spontaneous premature delivery.
      • Hassan S.S.
      • Romero R.
      • Berry S.M.
      • et al.
      Patients with an ultrasonographic cervical length < or = 15 mm have nearly a 50% risk of early spontaneous preterm delivery.
      • To M.S.
      • Skentou C.
      • Liao A.W.
      • Cacho A.
      • Nicolaides K.H.
      Cervical length and funneling at 23 weeks of gestation in the prediction of spontaneous early preterm delivery.
      • Heath V.C.
      • Southall T.R.
      • Souka A.P.
      • Elisseou A.
      • Nicolaides K.H.
      Cervical length at 23 weeks of gestation: prediction of spontaneous preterm delivery.
      • Taipale P.
      • Hiilesmaa V.
      Sonographic measurement of uterine cervix at 18-22 weeks' gestation and the risk of preterm delivery.
      • Heath V.C.
      • Daskalakis G.
      • Zagaliki A.
      • Carvalho M.
      • Nicolaides K.H.
      Cervicovaginal fibronectin and cervical length at 23 weeks of gestation: relative risk of early preterm delivery.
      • To M.S.
      • Alfirevic Z.
      • Heath V.C.
      • et al.
      Cervical cerclage for prevention of preterm delivery in women with short cervix: randomized controlled trial.
      • To M.S.
      • Palaniappan V.
      • Skentou C.
      • Gibb D.
      • Nicolaides K.H.
      Elective cerclage vs ultrasound-indicated cerclage in high-risk pregnancies.
      • Alfirevic Z.
      • Allen-Coward H.
      • Molina F.
      • Vinuesa C.P.
      • Nicolaides K.
      Targeted therapy for threatened preterm labor based on sonographic measurement of the cervical length: a randomized controlled trial.
      • Gomez R.
      • Romero R.
      • Medina L.
      • et al.
      Cervicovaginal fibronectin improves the prediction of preterm delivery based on sonographic cervical length in patients with preterm uterine contractions and intact membranes.
      • Gomez R.
      • Romero R.
      • Nien J.K.
      • et al.
      A short cervix in women with preterm labor and intact membranes: a risk factor for microbial invasion of the amniotic cavity.
      • Hassan S.
      • Romero R.
      • Hendler I.
      • et al.
      A sonographic short cervix as the only clinical manifestation of intra-amniotic infection.
      • Kusanovic J.P.
      • Espinoza J.
      • Romero R.
      • et al.
      Clinical significance of the presence of amniotic fluid 'sludge' in asymptomatic patients at high risk for spontaneous preterm delivery.
      • Palma-Dias R.S.
      • Fonseca M.M.
      • Stein N.R.
      • Schmidt A.P.
      • Magalhaes J.A.
      Relation of cervical length at 22-24 weeks of gestation to demographic characteristics and obstetric history.
      • Tekesin I.
      • Eberhart L.H.
      • Schaefer V.
      • Wallwiener D.
      • Schmidt S.
      Evaluation and validation of a new risk score (CLEOPATRA score) to predict the probability of premature delivery for patients with threatened preterm labor.
      • To M.S.
      • Skentou C.A.
      • Royston P.
      • Yu C.K.
      • Nicolaides K.H.
      Prediction of patient-specific risk of early preterm delivery using maternal history and sonographic measurement of cervical length: a population-based prospective study.
      • Owen J.
      • Yost N.
      • Berghella V.
      • et al.
      Mid-trimester endovaginal sonography in women at high risk for spontaneous preterm birth.
      Moreover, a short cervix is associated with intraamniotic infection and inflammation, and this may modify the response to interventions.
      An interest in the role of progestogens (natural and synthetic) for the prevention of preterm birth has existed for decades.
      • Keirse M.J.
      Progesterone and preterm: seventy years of “deja vu” or “still to be seen”?.
      • da Fonseca E.B.
      • Bittar R.E.
      • Carvalho M.H.
      • Zugaib M.
      Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study.
      • Hartikainen-Sorri A.L.
      • Kauppila A.
      • Tuimala R.
      Inefficacy of 17 alpha-hydroxyprogesterone caproate in the prevention of prematurity in twin pregnancy.
      • Hauth J.C.
      • Gilstrap III, L.C.
      • Brekken A.L.
      • Hauth J.M.
      The effect of 17 alpha-hydroxyprogesterone caproate on pregnancy outcome in an active-duty military population.
      • Johnson J.W.
      • Austin K.L.
      • Jones G.S.
      • Davis G.H.
      • King T.M.
      Efficacy of 17alpha-hydroxyprogesterone caproate in the prevention of premature labor.
      • Meis P.J.
      • Klebanoff M.
      • Thom E.
      • et al.
      Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.
      • Yemini M.
      • Borenstein R.
      • Dreazen E.
      • et al.
      Prevention of premature labor by 17 alpha-hydroxyprogesterone caproate.
      Recently, the administration of vaginal progesterone was proposed for the prevention of preterm birth in women with a sonographic short cervix in the midtrimester based on its biologic effects on the cervix, myometrium, and chorioamniotic membranes. In 2007, Fonseca et al,
      • Fonseca E.B.
      • Celik E.
      • Parra M.
      • Singh M.
      • Nicolaides K.H.
      Progesterone and the risk of preterm birth among women with a short cervix.
      on behalf of the Fetal Medicine Foundation of the United Kingdom, reported that the administration of vaginal progesterone in women with a cervical length ≤15 mm was associated with a significant 44% reduction in the rate of spontaneous preterm birth <34 weeks of gestation. Similar findings were reported by DeFranco et al
      • DeFranco E.A.
      • O'Brien J.M.
      • Adair C.D.
      • et al.
      Vaginal progesterone is associated with a decrease in risk for early preterm birth and improved neonatal outcome in women with a short cervix: a secondary analysis from a randomized, double-blind, placebo-controlled trial.
      in a secondary analysis of a randomized clinical trial of vaginal progesterone in women with a history of preterm birth in which the cervix was measured. Hassan et al
      • Hassan S.S.
      • Romero R.
      • Vidyadhari D.
      • et al.
      Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
      reported the largest randomized clinical trial to date, indicating that vaginal progesterone, when administered to women with a cervical length of 10-20 mm, reduces the rate of preterm birth at <33, <28, and <35 weeks, and this was associated with a significant 61% reduction in the rate of respiratory distress syndrome (RDS).
      • Hassan S.S.
      • Romero R.
      • Vidyadhari D.
      • et al.
      Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
      Since the publication of the trial of Hassan et al,
      • Hassan S.S.
      • Romero R.
      • Vidyadhari D.
      • et al.
      Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
      several trials evaluating vaginal progesterone in women at high risk of spontaneous preterm birth,
      • Rode L.
      • Klein K.
      • Nicolaides K.
      • Krampl-Bettelheim E.
      • Tabor A.
      Prevention of preterm delivery in twin gestations (PREDICT): a multicenter randomized placebo-controlled trial on the effect of vaginal micronized progesterone.
      • Klein K.
      • Rode L.
      • Nicolaides K.
      • Krampl-Bettelheim E.
      • Tabor A.
      Vaginal micronized progesterone and the risk of preterm delivery in high-risk twin pregnancies–secondary analysis of a placebo-controlled randomized trial and meta-analysis.
      • Cetingoz E.
      • Cam C.
      • Sakalli M.
      • Karateke A.
      • Celik C.
      • Sancak A.
      Progesterone effects on preterm birth in high-risk pregnancies: a randomized placebo-controlled trial.
      including a subset of women with a short cervix, have been published.
      An individual patient data (IPD) metaanalysis is a specific type of systematic review in which the original research data for each participant in a study are sought directly from the investigators responsible for that trial.
      • Higgins J.P.T.
      • Altman D.G.
      • Sterne J.A.C.
      Chapter 8: assessing risk of bias in included studies.
      Such an approach has been considered the gold standard for summarizing evidence across clinical studies since it offers several advantages, both statistically and clinically, over conventional metaanalyses, which are based on published aggregate data.
      • Stewart L.A.
      • Parmar M.K.
      Meta-analysis of the literature or of individual patient data: is there a difference?.
      These advantages include standardizing and updating of data sets, the ability to verify the quality of the data and the appropriateness of the analyses, the improvement of consistency across trials (eg, definition of outcomes), the performance of subgroup analyses that could effectively identify groups of patients who might benefit from an intervention, the investigation of interaction between patient-level covariates and treatment effects, and the performance of time-to-event analyses.
      • Thompson S.G.
      • Higgins J.P.
      Treating individuals 4: can meta-analysis help target interventions at individuals most likely to benefit?.
      • Sutton A.J.
      • Kendrick D.
      • Coupland C.A.
      Meta-analysis of individual- and aggregate-level data.
      • Riley R.D.
      • Lambert P.C.
      • Abo-Zaid G.
      Meta-analysis of individual participant data: rationale, conduct, and reporting.
      Using IPD from randomized controlled trials, we performed a metaanalysis to evaluate the efficacy and safety of vaginal progesterone for the prevention of preterm birth and neonatal morbidity and mortality in asymptomatic women with a sonographic short cervix in the midtrimester. We also sought to determine whether there were clinical benefits associated with the administration of vaginal progesterone in singleton and twin pregnancies.

      Materials and Methods

      The study was conducted based on a prospectively prepared protocol, and is reported using the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines for metaanalyses of randomized controlled trials
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration.
      and suggested guidelines for IPD metaanalyses.
      • Riley R.D.
      • Lambert P.C.
      • Abo-Zaid G.
      Meta-analysis of individual participant data: rationale, conduct, and reporting.

      Literature search

      We searched MEDLINE, EMBASE, CINAHL, and LILACS (all from inception through December 31, 2011); the Cochrane Central Register of Controlled Trials (www.mrw.interscience.wiley.com/cochrane/cochrane_clcentral_articles_fs.html) (1960 through December 31, 2011); ISI Web of Science (www.isiknowledge.com) (1960 through December 31, 2011); Research Registers of ongoing trials (www.clinicaltrials.gov, www.controlled-trials.com, www.centerwatch.com, www.anzctr.org.au, www.nihr.ac.uk, and www.umin.ac.jp/ctr); and Google Scholar using a combination of key words and text words related to progesterone (“progesterone,” “progestins,” “progestogen,” “progestagen,” “progestational agent”) and preterm birth (“preterm,” “premature”). Proceedings of the Society for Maternal-Fetal Medicine and international meetings on preterm birth, reference lists of identified studies, textbooks, previously published systematic reviews, and review articles were also searched. Experts in the field were contacted to identify further studies. No language restriction was used.

      Study selection

      We included randomized controlled trials in which asymptomatic women with a sonographic short cervix (cervical length of ≤25 mm) in the midtrimester were randomly allocated to receive vaginal progesterone or placebo/no treatment for the prevention of preterm birth. Trials were included if the primary aim of the study was to prevent preterm birth in women with a sonographic short cervix, or if the primary aim was to prevent preterm birth in women with risk factors other than a short cervix, but outcomes were available for patients with a prerandomization cervical length of ≤25 mm. Trials were excluded if they: (1) were quasirandomized; (2) evaluated vaginal progesterone in women with threatened preterm labor, second trimester bleeding, or premature rupture of membranes; (3) evaluated the administration of vaginal progesterone in the first trimester only to prevent miscarriage; or (4) did not report clinical outcomes. Although there is no agreement on what is a sonographic short cervix, we chose 25 mm as the cutoff because this value corresponds approximately to the 10th percentile for cervical length in the midtrimester.
      • Iams J.D.
      • Goldenberg R.L.
      • Meis P.J.
      • et al.
      The length of the cervix and the risk of spontaneous premature delivery.
      • Heath V.C.
      • Southall T.R.
      • Souka A.P.
      • Elisseou A.
      • Nicolaides K.H.
      Cervical length at 23 weeks of gestation: prediction of spontaneous preterm delivery.
      In addition, this cervical length is the most commonly used in studies evaluating the predictive accuracy of cervical length for preterm birth.
      • Crane J.M.
      • Hutchens D.
      Transvaginal sonographic measurement of cervical length to predict preterm birth in asymptomatic women at increased risk: a systematic review.
      • Honest H.
      • Bachmann L.M.
      • Coomarasamy A.
      • Gupta J.K.
      • Kleijnen J.
      • Khan K.S.
      Accuracy of cervical transvaginal sonography in predicting preterm birth: a systematic review.
      Two investigators (R.R. and A.C.-A.) independently reviewed all potentially relevant articles for eligibility. Disagreements regarding trial eligibility were resolved by consensus.

      Data collection

      We contacted the corresponding authors to request access to the data. Authors were asked to supply anonymized data (without identifiers) about patient baseline characteristics, experimental intervention, control intervention, cointerventions, and prespecified outcome measures for every randomly assigned subject and were invited to become part of the collaborative group with joint authorship of the final publication. Data provided by the investigators were merged into a master database specifically constructed for the review. Data were checked for missing information, errors, and inconsistencies by cross-referencing the publications of the original trials. Quality and integrity of the randomization processes were assessed by reviewing the chronological randomization sequence and pattern of assignment, as well as the balance of baseline characteristics across treatment groups. Inconsistencies or missing data were discussed with the authors and corrections were made when deemed necessary.

      Outcome measures

      The prespecified primary outcome measure was preterm birth <33 weeks of gestation. Secondary outcome measures included preterm birth <37, <36, <35, <34, <30, and <28 weeks of gestation; spontaneous preterm birth <33 and <34 weeks of gestation; RDS; necrotizing enterocolitis; intraventricular hemorrhage (all grades); proven neonatal sepsis; retinopathy of prematurity; bronchopulmonary dysplasia; periventricular leukomalacia; fetal death; neonatal death; perinatal mortality, a composite neonatal morbidity and mortality outcome (defined as the occurrence of any of the following events: RDS, intraventricular hemorrhage, necrotizing enterocolitis, proven neonatal sepsis, or neonatal death); Apgar score <7 at 5 minutes; birthweight <1500 g and <2500 g; admission to the neonatal intensive care unit (NICU); use of mechanical ventilation; congenital anomaly; any maternal adverse event; vaginal discharge; vaginal pruritus; discontinuation of treatment because of adverse events; threatened preterm labor; and neurodevelopmental disability at 18-24 months of age. Neonatal morbidities were defined as in the original study.
      • Fonseca E.B.
      • Celik E.
      • Parra M.
      • Singh M.
      • Nicolaides K.H.
      Progesterone and the risk of preterm birth among women with a short cervix.
      • Hassan S.S.
      • Romero R.
      • Vidyadhari D.
      • et al.
      Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
      • Rode L.
      • Klein K.
      • Nicolaides K.
      • Krampl-Bettelheim E.
      • Tabor A.
      Prevention of preterm delivery in twin gestations (PREDICT): a multicenter randomized placebo-controlled trial on the effect of vaginal micronized progesterone.
      • Cetingoz E.
      • Cam C.
      • Sakalli M.
      • Karateke A.
      • Celik C.
      • Sancak A.
      Progesterone effects on preterm birth in high-risk pregnancies: a randomized placebo-controlled trial.
      • O'Brien J.M.
      • Adair C.D.
      • Lewis D.F.
      • et al.
      Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial.

      Assessment of risk of bias

      We assessed the risk of bias using the criteria recently outlined in the Cochrane Handbook for Systematic Reviews of Interventions.
      • Higgins J.P.T.
      • Altman D.G.
      • Sterne J.A.C.
      Chapter 8: assessing risk of bias in included studies.
      Seven domains related to risk of bias were assessed in each included trial since there is evidence that these issues are associated with biased estimates of treatment effect: (1) random sequence generation; (2) allocation concealment; (3) blinding of participants and personnel; (4) blinding of outcome assessment; (5) incomplete outcome data; (6) selective reporting; and (7) other bias. Review authors' judgments were categorized as “low”, “high”, or “unclear” risk of bias. The assessments considered the risk of material bias rather than any bias. “Material bias” is defined as a bias of sufficient magnitude to have a notable impact on the results or conclusions of the trial.
      • Higgins J.P.T.
      • Altman D.G.
      • Sterne J.A.C.
      Chapter 8: assessing risk of bias in included studies.
      The risk of bias in each trial included was assessed individually by 2 reviewers (R.R. and A.C.-A.). In addition, methods of random sequence generation, allocation concealment, and blinding were confirmed with the authors of the trials. Any differences of opinion regarding assessment of risk of bias were resolved by discussion.

      Statistical analysis

      Statistical analyses were based on an intent-to-treat basis and included all randomized women and their fetuses/infants. For baseline data, maternal outcomes, and gestational age at birth-related outcomes, the unit of analysis was the pregnancy, whereas for neonatal outcomes, the unit of analysis was the neonate. To assess safety of vaginal progesterone, all patients exposed to progesterone were included. This included all studies and patients, even those in which the cervical length was not measured. IPD were combined in a 2-stage approach in which outcomes were analyzed in the original trial and then summary statistics were generated using standard summary data metaanalysis techniques to give an overall measure of effect (summary relative risk [RR] with 95% confidence interval [CI]).
      • Simmonds M.C.
      • Higgins J.P.
      • Stewart L.A.
      • Tierney J.F.
      • Clarke M.J.
      • Thompson S.G.
      Meta-analysis of individual patient data from randomized trials: a review of methods used in practice.
      Heterogeneity of the results among studies was tested with the quantity I2, which describes the percentage of total variation across studies that can be attributed to heterogeneity rather than chance.
      • Higgins J.P.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analyses.
      A value of 0% indicates no observed heterogeneity, whereas I2 values of ≥50% indicate a substantial level of heterogeneity.
      • Higgins J.P.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analyses.
      We planned to use a fixed effects model if substantial statistical heterogeneity was not present. Random effects models were also used to test the robustness of results. The number needed to treat (NNT) for benefit or harm with the 95% CI was calculated for outcomes for which there was a statistically significant reduction or increase in risk difference based on control event rates in the trials.
      • Altman D.G.
      Confidence intervals for the number needed to treat.
      Publication and related biases were assessed visually by examining the symmetry of funnel plots and statistically by using the Egger test.
      • Egger M.
      • Davey Smith G.
      • Schneider M.
      • Minder C.
      Bias in meta-analysis detected by a simple, graphical test.
      A P value < .1 was considered to indicate significant asymmetry.
      Access to data from individual patients also allowed the performance of subgroup analyses to examine whether the administration of vaginal progesterone was more effective in some subgroups than in others. Specifically, we assessed the effect of vaginal progesterone in singleton and twin gestations separately. Also, to explore treatment effects according to other patient characteristics, subgroup analyses were prespecified on the basis of sonographic cervical length (<10, 10-20, and 21-25 mm), obstetrical history (no previous spontaneous preterm birth and at least 1 previous spontaneous preterm birth <37 weeks), maternal age (<20, 20-34, and ≥35 years), race/ethnicity (Caucasian, Black, Asian, and other), and body mass index (<18.5, 18.5-24.9, 25.0-29.9, ≥30 kg/m2). To explore effects by trial characteristics, prespecified subgroup analyses were planned according to the daily dose of vaginal progesterone (90-100 vs 200 mg). Definitions and subgroup analyses were specified before any data were obtained or analyzed. Treatment effects in these subgroups were assessed by simple logistic regression models (which included a subgroup-allocated treatment interaction term), with adjustment for between-trial outcome differences. A test for interaction between treatment and subgroup is the standard method to examine whether treatment effects differ between subgroups.
      • Rothwell P.M.
      Treating individuals 2 Subgroup analysis in randomized controlled trials: importance, indications, and interpretation.
      • Klebanoff M.A.
      Subgroup analysis in obstetrics clinical trials.
      This approach tests and estimates the difference between treatment effects across subgroups directly. It involves one statistical test regardless of the number of subgroups. An interaction P value > .05 was considered to indicate that the effect of treatment did not differ significantly between subgroups. Adjustment for predictive baseline characteristics, even when largely balanced, can lead to different estimates of treatment effects.
      • Berlin J.A.
      • Santanna J.
      • Schmid C.H.
      • Szczech L.A.
      • Feldman H.I.
      Individual patient- versus group-level data meta-regressions for the investigation of treatment effect modifiers: ecological bias rears its ugly head.
      Therefore, multivariable logistic regression models were employed to estimate adjusted treatment effects. In the twin pregnancy subgroup, the lack of independence of twins may have influenced the outcome of the analysis. Thus, for adverse perinatal outcomes in twins, we used analytical methods assuming independence between neonates as well as methods recommended to take into account nonindependence of newborns from twin gestations.
      • Higgins J.P.T.
      • Altman D.G.
      • Sterne J.A.C.
      Chapter 8: assessing risk of bias in included studies.
      • Gates S.
      • Brocklehurst P.
      How should randomized trials including multiple pregnancies be analyzed?.
      We planned sensitivity analyses to test the robustness of the results by excluding trials with any risk of bias and including only studies for which the primary aim was to assess the effects of vaginal progesterone in women with a short cervix. Subgroup and sensitivity analyses were only performed for the primary outcome of preterm birth <33 weeks of gestation and for the secondary outcome of composite neonatal morbidity and mortality. Analyses were performed with the Review Manager (RevMan) version 5.1 (Nordic Cochrane Centre, Copenhagen, Denmark), and SAS version 9.2 (SAS Institute, Cary, NC) software.
      Informed consent was provided by the patients upon enrollment in each of the original trials. In this study, the data were not used for any purposes other than those of the original trial, and no new data were collected. Therefore, informed consent specifically for this project was not considered necessary. No patient identifiers were provided by any investigator. This study was exempted for review by the Human Investigations Committee of Wayne State University's Institutional Review Board, Detroit, MI.

      Results

      Study selection, details, and quality

      The searches yielded 2611 citations, of which 10 were considered for potential inclusion (Figure 1) . Five studies were excluded.
      • da Fonseca E.B.
      • Bittar R.E.
      • Carvalho M.H.
      • Zugaib M.
      Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study.
      • Borna S.
      • Sahabi N.
      Progesterone for maintenance tocolytic therapy after threatened preterm labor: a randomized controlled trial.
      • Majhi P.
      • Bagga R.
      • Kalra J.
      • Sharma M.
      Intravaginal use of natural micronized progesterone to prevent pre-term birth: a randomized trial in India.
      • Norman J.E.
      • Mackenzie F.
      • Owen P.
      • et al.
      Progesterone for the prevention of preterm birth in twin pregnancy (STOPPIT): a randomized, double-blind, placebo-controlled study and meta-analysis.
      • Sharami S.H.
      • Zahiri Z.
      • Shakiba M.
      • Milani F.
      Maintenance therapy by vaginal progesterone after threatened idiopathic preterm labor: a randomized placebo-controlled double-blind trial.
      Three of these studies evaluated vaginal progesterone in women at high risk for preterm birth (previous preterm birth,
      • da Fonseca E.B.
      • Bittar R.E.
      • Carvalho M.H.
      • Zugaib M.
      Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study.
      • Majhi P.
      • Bagga R.
      • Kalra J.
      • Sharma M.
      Intravaginal use of natural micronized progesterone to prevent pre-term birth: a randomized trial in India.
      uterine malformation,
      • da Fonseca E.B.
      • Bittar R.E.
      • Carvalho M.H.
      • Zugaib M.
      Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study.
      cervical insufficiency,
      • da Fonseca E.B.
      • Bittar R.E.
      • Carvalho M.H.
      • Zugaib M.
      Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study.
      and twins
      • Norman J.E.
      • Mackenzie F.
      • Owen P.
      • et al.
      Progesterone for the prevention of preterm birth in twin pregnancy (STOPPIT): a randomized, double-blind, placebo-controlled study and meta-analysis.
      ) but none of them measured or collected data on cervical length. Two of these studies
      • da Fonseca E.B.
      • Bittar R.E.
      • Carvalho M.H.
      • Zugaib M.
      Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study.
      • Majhi P.
      • Bagga R.
      • Kalra J.
      • Sharma M.
      Intravaginal use of natural micronized progesterone to prevent pre-term birth: a randomized trial in India.
      reported that prophylactic administration of vaginal progesterone reduced the risk of preterm birth in women with a previous preterm birth, whereas the study by Norman et al
      • Norman J.E.
      • Mackenzie F.
      • Owen P.
      • et al.
      Progesterone for the prevention of preterm birth in twin pregnancy (STOPPIT): a randomized, double-blind, placebo-controlled study and meta-analysis.
      found that vaginal progesterone did not reduce the risk of the composite outcome delivery or fetal death <34 weeks of gestation in women with a twin gestation. The 2 remaining studies evaluated vaginal progesterone as an adjunct to tocolytic therapy after threatened preterm labor.
      • Borna S.
      • Sahabi N.
      Progesterone for maintenance tocolytic therapy after threatened preterm labor: a randomized controlled trial.
      • Sharami S.H.
      • Zahiri Z.
      • Shakiba M.
      • Milani F.
      Maintenance therapy by vaginal progesterone after threatened idiopathic preterm labor: a randomized placebo-controlled double-blind trial.
      Five studies, which provided data for 775 women (723 [93.3%] with singleton pregnancies and 52 [6.7%] with twin pregnancies) and 827 fetuses/infants (723 [87.4%] from singleton pregnancies and 104 [12.6%] from twin pregnancies), met the inclusion criteria.
      • Fonseca E.B.
      • Celik E.
      • Parra M.
      • Singh M.
      • Nicolaides K.H.
      Progesterone and the risk of preterm birth among women with a short cervix.
      • Hassan S.S.
      • Romero R.
      • Vidyadhari D.
      • et al.
      Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
      • Rode L.
      • Klein K.
      • Nicolaides K.
      • Krampl-Bettelheim E.
      • Tabor A.
      Prevention of preterm delivery in twin gestations (PREDICT): a multicenter randomized placebo-controlled trial on the effect of vaginal micronized progesterone.
      • Cetingoz E.
      • Cam C.
      • Sakalli M.
      • Karateke A.
      • Celik C.
      • Sancak A.
      Progesterone effects on preterm birth in high-risk pregnancies: a randomized placebo-controlled trial.
      • O'Brien J.M.
      • Adair C.D.
      • Lewis D.F.
      • et al.
      Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial.
      Figure thumbnail gr1
      FIGURE 1Flow of study identification
      Romero. Vaginal progesterone to prevent preterm birth in women with a short cervix: an IPD metaanalysis. Am J Obstet Gynecol 2012.
      The main characteristics of studies included in this IPD metaanalysis are shown in Table 1. All studies were double-blind, placebo-controlled trials, of which 4 were multicenter, conducted in sites from both developed and developing countries. Two trials were specifically designed to evaluate the administration of vaginal progesterone in women with a sonographic short cervix,
      • Fonseca E.B.
      • Celik E.
      • Parra M.
      • Singh M.
      • Nicolaides K.H.
      Progesterone and the risk of preterm birth among women with a short cervix.
      • Hassan S.S.
      • Romero R.
      • Vidyadhari D.
      • et al.
      Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
      one evaluated the use of vaginal progesterone in women with a history of spontaneous preterm birth,
      • O'Brien J.M.
      • Adair C.D.
      • Lewis D.F.
      • et al.
      Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial.
      another assessed vaginal progesterone in women with a twin gestation,
      • Rode L.
      • Klein K.
      • Nicolaides K.
      • Krampl-Bettelheim E.
      • Tabor A.
      Prevention of preterm delivery in twin gestations (PREDICT): a multicenter randomized placebo-controlled trial on the effect of vaginal micronized progesterone.
      and the remaining trial examined the use of progesterone in women with a prior spontaneous preterm birth, uterine malformations, or twin gestations.
      • Cetingoz E.
      • Cam C.
      • Sakalli M.
      • Karateke A.
      • Celik C.
      • Sancak A.
      Progesterone effects on preterm birth in high-risk pregnancies: a randomized placebo-controlled trial.
      Two of these studies
      • Rode L.
      • Klein K.
      • Nicolaides K.
      • Krampl-Bettelheim E.
      • Tabor A.
      Prevention of preterm delivery in twin gestations (PREDICT): a multicenter randomized placebo-controlled trial on the effect of vaginal micronized progesterone.
      • O'Brien J.M.
      • Adair C.D.
      • Lewis D.F.
      • et al.
      Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial.
      reported data of planned secondary analyses for women with a short cervix in additional reports.
      • DeFranco E.A.
      • O'Brien J.M.
      • Adair C.D.
      • et al.
      Vaginal progesterone is associated with a decrease in risk for early preterm birth and improved neonatal outcome in women with a short cervix: a secondary analysis from a randomized, double-blind, placebo-controlled trial.
      • Klein K.
      • Rode L.
      • Nicolaides K.
      • Krampl-Bettelheim E.
      • Tabor A.
      Vaginal micronized progesterone and the risk of preterm delivery in high-risk twin pregnancies–secondary analysis of a placebo-controlled randomized trial and meta-analysis.
      Data from the trials by O'Brien et al,
      • O'Brien J.M.
      • Adair C.D.
      • Lewis D.F.
      • et al.
      Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial.
      Cetingoz et al,
      • Cetingoz E.
      • Cam C.
      • Sakalli M.
      • Karateke A.
      • Celik C.
      • Sancak A.
      Progesterone effects on preterm birth in high-risk pregnancies: a randomized placebo-controlled trial.
      and Rode et al
      • Rode L.
      • Klein K.
      • Nicolaides K.
      • Krampl-Bettelheim E.
      • Tabor A.
      Prevention of preterm delivery in twin gestations (PREDICT): a multicenter randomized placebo-controlled trial on the effect of vaginal micronized progesterone.
      relevant to women with a cervical length of ≤25 mm before randomization were provided by the authors for inclusion in this review. The 2 trials
      • Fonseca E.B.
      • Celik E.
      • Parra M.
      • Singh M.
      • Nicolaides K.H.
      Progesterone and the risk of preterm birth among women with a short cervix.
      • Hassan S.S.
      • Romero R.
      • Vidyadhari D.
      • et al.
      Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
      specifically designed to evaluate the use of vaginal progesterone in women with a short cervix screened a total of 56,711 women, of which 1146 (2.0%) had a sonographic short cervix as defined by the authors for the purposes of each study. Of these women, 715 (62.4%) were randomized; 708 mothers with their 732 infants provided data for the metaanalysis (∼90% of total sample size of the IPD metaanalysis). The other 3 studies provided data for 67 women and 95 infants.
      TABLE 1Characteristics of studies included
      StudyParticipating countriesPrimary target populationInclusion/exclusion criteriaNo of women with CL ≤25 mm/fetuses or infantsInterventionCointerventionsPrimary outcome
      Vaginal progesterone groupPlacebo group
      Fonseca et al,
      • Fonseca E.B.
      • Celik E.
      • Parra M.
      • Singh M.
      • Nicolaides K.H.
      Progesterone and the risk of preterm birth among women with a short cervix.
      2007
      United Kingdom, Chile, Brazil, GreeceWomen with a short cervixInclusion: women with a singleton or twin pregnancy and sonographic CL ≤15 mm

      Exclusion: major fetal abnormalities, painful regular uterine contractions, history of ruptured membranes, and cervical cerclage
      125/136125/138Vaginal progesterone capsule (200 mg/d) or placebo from 24-33 6/7 wk of gestationCervical cerclage (1 [0.8%] in vaginal progesterone group and 0 [0.0%] in placebo group)Spontaneous preterm birth <34 wk
      O'Brien et al,
      • O'Brien J.M.
      • Adair C.D.
      • Lewis D.F.
      • et al.
      Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial.
      2007
      United States, South Africa, India, Czech Republic, Chile, El SalvadorWomen with a history of spontaneous preterm birthInclusion: women with a singleton pregnancy, gestational age between 16 0/7-22 6/7 wk, and a history of spontaneous singleton preterm birth at 20-35 wk of gestation in the immediately preceding pregnancy

      Exclusion: planned cervical cerclage, history of adverse reaction to progesterone, treatment with progesterone within 4 wk before enrollment, treatment for seizure disorder, psychiatric illness or chronic hypertension at time of enrollment, history of acute or chronic congestive heart failure, renal failure, uncontrolled diabetes mellitus, active liver disorder, HIV infection with CD4 count of <350 cells/mm3 and requiring multiple antiviral agents, placenta previa, history or suspicion of breast or genital tract malignancy, history or suspicion of thromboembolic disease, müllerian duct anomaly, major fetal anomaly or chromosomal disorder, or multifetal gestation
      12/1219/19Vaginal progesterone gel (90 mg/d) or placebo from 18-22 to 37 0/7 wk of gestation, rupture of membranes or preterm delivery, whichever occurred firstNonePreterm birth ≤32 wk
      Cetingoz et al,
      • Cetingoz E.
      • Cam C.
      • Sakalli M.
      • Karateke A.
      • Celik C.
      • Sancak A.
      Progesterone effects on preterm birth in high-risk pregnancies: a randomized placebo-controlled trial.
      2011
      TurkeyWomen at high risk of preterm birthInclusion: women with at least 1 previous spontaneous preterm birth, uterine malformation, or twin pregnancy

      Exclusion: in-place or planned cervical cerclage, serious fetal anomalies
      9/146/8Vaginal progesterone suppository (100 mg/d) or placebo from 24-34 wk of gestationNonePreterm birth <37 wk
      Hassan et al,
      • Hassan S.S.
      • Romero R.
      • Vidyadhari D.
      • et al.
      Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
      2011
      United States, Republic of Belarus, Chile, Czech Republic, India, Israel, Italy, Russia, South Africa, UkraineWomen with a short cervixInclusion: women with a singleton pregnancy, gestational age between 19 0/7-23 6/7 wk, transvaginal sonographic CL between 10-20 mm, and without signs or symptoms of preterm labor

      Exclusion: planned cerclage, acute cervical dilation, allergic reaction to progesterone, current or recent progestogen treatment within previous 4 wk, chronic medical conditions that would interfere with study participation or evaluation of treatment, major fetal anomaly or known chromosomal abnormality, uterine anatomic malformation, vaginal bleeding, known or suspected clinical chorioamnionitis
      235/235223/223Vaginal progesterone gel (90 mg/d) or placebo from 20-23 6/7 to 36 6/7 wk of gestation, rupture of membranes or preterm delivery, whichever occurred firstEmergency cervical cerclage (10 [4.3%] in vaginal progesterone group and 6 [2.7%] in placebo group)Preterm birth <33 wk
      Rode et al,
      • Rode L.
      • Klein K.
      • Nicolaides K.
      • Krampl-Bettelheim E.
      • Tabor A.
      Prevention of preterm delivery in twin gestations (PREDICT): a multicenter randomized placebo-controlled trial on the effect of vaginal micronized progesterone.
      2011
      Denmark, AustriaWomen with a twin pregnancyInclusion: women with a diamniotic twin pregnancy and chorionicity assessed by ultrasound <16 wk of gestation

      Exclusion: higher order multiple pregnancies, known allergy to progesterone or peanuts as active treatment contained peanut oil, history of hormone-associated thromboembolic disorders, rupture of membranes, pregnancies treated for or with signs of twin-to-twin transfusion syndrome, intentional fetal reduction, known major structural or chromosomal fetal abnormality, known or suspected malignancy in genitals or breasts, known liver disease
      7/1414/28Vaginal progesterone pessary (200 mg/d) or placebo from 20-23 6/7 to 33 6/7 wk of gestationCervical cerclage (2 [28.6%] in vaginal progesterone group and 2 [14.3%] in placebo group)Preterm birth <34 wk
      CL, cervical length; HIV, human immunodeficiency virus.
      Romero. Vaginal progesterone to prevent preterm birth in women with a short cervix: an IPD metaanalysis. Am J Obstet Gynecol 2012.
      Two studies used vaginal progesterone capsules or pessaries 200 mg/d,
      • Fonseca E.B.
      • Celik E.
      • Parra M.
      • Singh M.
      • Nicolaides K.H.
      Progesterone and the risk of preterm birth among women with a short cervix.
      • Rode L.
      • Klein K.
      • Nicolaides K.
      • Krampl-Bettelheim E.
      • Tabor A.
      Prevention of preterm delivery in twin gestations (PREDICT): a multicenter randomized placebo-controlled trial on the effect of vaginal micronized progesterone.
      2 used vaginal progesterone gel 90 mg/d,
      • Hassan S.S.
      • Romero R.
      • Vidyadhari D.
      • et al.
      Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
      • O'Brien J.M.
      • Adair C.D.
      • Lewis D.F.
      • et al.
      Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial.
      and the other used vaginal progesterone suppositories 100 mg/d.
      • Cetingoz E.
      • Cam C.
      • Sakalli M.
      • Karateke A.
      • Celik C.
      • Sancak A.
      Progesterone effects on preterm birth in high-risk pregnancies: a randomized placebo-controlled trial.
      The treatment was initiated at 24 weeks of gestation in 2 trials,
      • Fonseca E.B.
      • Celik E.
      • Parra M.
      • Singh M.
      • Nicolaides K.H.
      Progesterone and the risk of preterm birth among women with a short cervix.
      • Cetingoz E.
      • Cam C.
      • Sakalli M.
      • Karateke A.
      • Celik C.
      • Sancak A.
      Progesterone effects on preterm birth in high-risk pregnancies: a randomized placebo-controlled trial.
      between 20-23 weeks of gestation in 2 trials,
      • Hassan S.S.
      • Romero R.
      • Vidyadhari D.
      • et al.
      Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
      • Rode L.
      • Klein K.
      • Nicolaides K.
      • Krampl-Bettelheim E.
      • Tabor A.
      Prevention of preterm delivery in twin gestations (PREDICT): a multicenter randomized placebo-controlled trial on the effect of vaginal micronized progesterone.
      and between 18-22 weeks of gestation in 1 trial.
      • O'Brien J.M.
      • Adair C.D.
      • Lewis D.F.
      • et al.
      Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial.
      Three studies
      • Fonseca E.B.
      • Celik E.
      • Parra M.
      • Singh M.
      • Nicolaides K.H.
      Progesterone and the risk of preterm birth among women with a short cervix.
      • Rode L.
      • Klein K.
      • Nicolaides K.
      • Krampl-Bettelheim E.
      • Tabor A.
      Prevention of preterm delivery in twin gestations (PREDICT): a multicenter randomized placebo-controlled trial on the effect of vaginal micronized progesterone.
      • Cetingoz E.
      • Cam C.
      • Sakalli M.
      • Karateke A.
      • Celik C.
      • Sancak A.
      Progesterone effects on preterm birth in high-risk pregnancies: a randomized placebo-controlled trial.
      reported that participating women received study medication from enrollment until 34 weeks of gestation, and 2 studies
      • Hassan S.S.
      • Romero R.
      • Vidyadhari D.
      • et al.
      Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
      • O'Brien J.M.
      • Adair C.D.
      • Lewis D.F.
      • et al.
      Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial.
      from enrollment until 36 6/7 weeks of gestation. In 3 studies,
      • Fonseca E.B.
      • Celik E.
      • Parra M.
      • Singh M.
      • Nicolaides K.H.
      Progesterone and the risk of preterm birth among women with a short cervix.
      • Hassan S.S.
      • Romero R.
      • Vidyadhari D.
      • et al.
      Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
      • Rode L.
      • Klein K.
      • Nicolaides K.
      • Krampl-Bettelheim E.
      • Tabor A.
      Prevention of preterm delivery in twin gestations (PREDICT): a multicenter randomized placebo-controlled trial on the effect of vaginal micronized progesterone.
      cervical cerclage was allowed after randomization. In the study by Cetingoz et al,
      • Cetingoz E.
      • Cam C.
      • Sakalli M.
      • Karateke A.
      • Celik C.
      • Sancak A.
      Progesterone effects on preterm birth in high-risk pregnancies: a randomized placebo-controlled trial.
      cervical cerclage was not performed in any women. The primary outcome was preterm birth <33 weeks of gestation for 1 trial,
      • Hassan S.S.
      • Romero R.
      • Vidyadhari D.
      • et al.
      Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
      ≤32 weeks of gestation for 1 trial,
      • O'Brien J.M.
      • Adair C.D.
      • Lewis D.F.
      • et al.
      Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial.
      <34 weeks for 1 trial,
      • Rode L.
      • Klein K.
      • Nicolaides K.
      • Krampl-Bettelheim E.
      • Tabor A.
      Prevention of preterm delivery in twin gestations (PREDICT): a multicenter randomized placebo-controlled trial on the effect of vaginal micronized progesterone.
      <37 weeks for 1 trial,
      • Cetingoz E.
      • Cam C.
      • Sakalli M.
      • Karateke A.
      • Celik C.
      • Sancak A.
      Progesterone effects on preterm birth in high-risk pregnancies: a randomized placebo-controlled trial.
      and spontaneous preterm birth <34 weeks for the remaining study.
      • Fonseca E.B.
      • Celik E.
      • Parra M.
      • Singh M.
      • Nicolaides K.H.
      Progesterone and the risk of preterm birth among women with a short cervix.
      All of the 5 studies included in this IPD metaanalysis had high methodological quality and were considered to be at low risk of bias (Figure 2) . One study did not report the method of random sequence generation in the article but reported, upon request, having used a table of random numbers.
      • Fonseca E.B.
      • Celik E.
      • Parra M.
      • Singh M.
      • Nicolaides K.H.
      Progesterone and the risk of preterm birth among women with a short cervix.
      All 5 studies had adequate allocation concealment and used identical placebo to blind patients and clinical staff to treatment allocation. There was blinding of outcome assessment and adequate handling of incomplete outcome data in all studies. One study
      • Cetingoz E.
      • Cam C.
      • Sakalli M.
      • Karateke A.
      • Celik C.
      • Sancak A.
      Progesterone effects on preterm birth in high-risk pregnancies: a randomized placebo-controlled trial.
      did not report several secondary neonatal outcomes of interest to the present study, but they were provided to the investigators (R.R. and A.C.-A.) with the database and included into the metaanalyses. Overall, there was no obvious risk of other biases for the 5 trials.
      Figure thumbnail gr2
      FIGURE 2Methodological quality summary: risk of biases for each included study
      Romero. Vaginal progesterone to prevent preterm birth in women with a short cervix: an IPD metaanalysis. Am J Obstet Gynecol 2012.

      Primary outcome

      Treatment with vaginal progesterone in patients with a sonographic short cervix was associated with a significant reduction in the risk of preterm birth <33 weeks of gestation (12.4% vs 22.0%; RR, 0.58; 95% CI, 0.42–0.80; I2 = 0%; 775 women) (Figure 3) . The number of patients with a short cervix who needed to be treated with vaginal progesterone rather than with placebo to prevent 1 case of preterm birth <33 weeks of gestation was 11 (95% CI, 8–23).
      Figure thumbnail gr3
      FIGURE 3Effect of vaginal progesterone on preterm birth <33 weeks of gestation
      Romero. Vaginal progesterone to prevent preterm birth in women with a short cervix: an IPD metaanalysis. Am J Obstet Gynecol 2012.

      Secondary outcomes

      Patients allocated to receive vaginal progesterone had a significantly lower risk of preterm birth <35 weeks of gestation (20.4% vs 30.5%; RR, 0.69; 95% CI, 0.55–0.88; I2 = 0%; NNT for benefit 11; 95% CI, 7–27), <34 weeks (16.0% vs 27.1%; RR, 0.61; 95% CI, 0.47–0.81; I2 = 0%; NNT for benefit 9; 95% CI, 7–19), <30 weeks (7.5% vs 13.2%; RR, 0.58; 95% CI, 0.38–0.89; I2 = 0%; NNT for benefit 18; 95% CI, 12–69), and <28 weeks (5.4% vs 11.1%; RR, 0.50; 95% CI, 0.30–0.81; I2 = 0%; NNT for benefit 18; 95% CI, 13–47) compared to those allocated to placebo (Table 2). Moreover, vaginal progesterone administration was associated with a significantly reduced risk of spontaneous preterm birth <33 and <34 weeks of gestation. The reduction in the risk of preterm birth <36 weeks of gestation was marginally significant (RR, 0.82; 95% CI, 0.67–1.00). Treatment with vaginal progesterone was associated with an overall nonsignificant reduction in the risk of perinatal mortality (3.4% vs 5.3%; RR, 0.63; 95% CI, 0.34–1.18; I2 = 41%). This reduction appeared to be attributable to a reduction in neonatal death (1.9% vs 3.6%; RR, 0.55; 95% CI, 0.26–1.19; I2 = 43%) rather than fetal death (1.5% vs 1.7%; RR, 0.82; 95% CI, 0.28–2.42; I2 = 0%).
      TABLE 2Effect of vaginal progesterone on secondary outcome measures
      Occurrence of any of the following events: respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, proven neonatal sepsis, or neonatal death;
      OutcomeNo. of trialsNo. of events/total no.Pooled RR (95% CI)I2 (%)NNT (95% CI)
      Vaginal progesteronePlacebo
      Preterm birth <37 wk5144/388165/3870.89 (0.75–1.06)0
      Preterm birth <36 wk5108/388136/3870.82 (0.67–1.00)0
      Preterm birth <35 wk579/388118/3870.69 (0.55–0.88)011 (7–27)
      Preterm birth <34 wk562/388105/3870.61 (0.47–0.81)09 (7–19)
      Preterm birth <30 wk529/38851/3870.58 (0.38–0.89)018 (12–69)
      Preterm birth <28 wk521/38843/3870.50 (0.30–0.81)018 (13–47)
      Spontaneous preterm birth <33 wk539/38871/3870.57 (0.40–0.81)013 (9–29)
      Spontaneous preterm birth <34 wk551/38887/3870.62 (0.46–0.84)012 (8–28)
      Respiratory distress syndrome525/41152/4160.48 (0.30–0.76)015 (11–33)
      Necrotizing enterocolitis55/4116/4160.88 (0.30–2.64)0
      Intraventricular hemorrhage56/4119/4160.74 (0.27–2.05)0
      Proven neonatal sepsis512/41120/4160.64 (0.32–1.29)13
      Retinopathy of prematurity56/4113/4161.56 (0.46–5.28)0
      Bronchopulmonary dysplasia24/2495/2310.76 (0.21–2.79)NA
      Periventricular leukomalacia20/2490/231Not estimableNA
      Fetal death56/4117/4160.82 (0.28–2.42)0
      Neonatal death58/41115/4160.55 (0.26–1.19)43
      Perinatal death514/41122/4160.63 (0.34–1.18)41
      Composite neonatal morbidity/mortality
      Occurrence of any of the following events: respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, proven neonatal sepsis, or neonatal death;
      540/41172/4160.57 (0.40–0.81)013 (10–30)
      Apgar score <7 at 5 min515/40827/4120.57 (0.32–1.02)16
      Birthweight <1500 g536/41068/4130.55 (0.38–0.80)613 (10–30)
      Birthweight <2500 g5140/410162/4130.91 (0.76–1.08)0
      Admission to NICU585/411121/4160.75 (0.59–0.94)014 (8–57)
      Mechanical ventilation535/41151/4160.66 (0.44–0.98)024 (15–408)
      Congenital anomaly730/196734/19540.89 (0.55–1.44)0
      Any maternal adverse event386/62480/5951.04 (0.79–1.38)0
      Vaginal discharge4244/1065248/10571.00 (0.87–1.15)33
      Vaginal pruritus454/106550/10571.08 (0.74–1.57)0
      Discontinuation of treatment because of adverse events528/108328/10611.01 (0.61–1.69)0
      Threatened preterm labor5115/384139/3830.83 (0.68–1.02)16
      Low ASQ developmental and socioemotional score at 18 mo of age
      ASQ score <115 points.
      119/50318/4881.02 (0.54–1.93)NA
      ASQ, Ages and Stages Questionnaire; CI, confidence interval; NA, not applicable; NICU, neonatal intensive care unit; NNT, number needed to treat; RR, relative risk.
      Romero. Vaginal progesterone to prevent preterm birth in women with a short cervix: an IPD metaanalysis. Am J Obstet Gynecol 2012.
      a Occurrence of any of the following events: respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, proven neonatal sepsis, or neonatal death;
      b ASQ score <115 points.
      Infants whose mothers received vaginal progesterone also had a significantly lower risk of RDS (6.1% vs 12.5%; RR, 0.48; 95% CI, 0.30–0.76; I2 = 0%; NNT for benefit 15; 95% CI, 11–33), composite neonatal morbidity and mortality (9.7% vs 17.3%; RR, 0.57; 95% CI, 0.40–0.81; I2 = 0%; NNT for benefit 13; 95% CI, 10–30), birthweight <1500 g (8.8% vs 16.5%; RR, 0.55; 95% CI, 0.38–0.80; I2 = 6%; NNT for benefit 13; 95% CI, 10–30), admission to NICU (20.7% vs 29.1%; RR, 0.75; 95% CI, 0.59–0.94; I2 = 0%; NNT for benefit 14; 95% CI, 8–57), and mechanical ventilation (8.5% vs 12.3%; RR, 0.66; 95% CI, 0.44–0.98; I2 = 0%; NNT for benefit 24; 95% CI, 15–408) than infants whose mothers had received placebo.
      There was no evidence of an effect of vaginal progesterone on necrotizing enterocolitis, intraventricular hemorrhage, proven neonatal sepsis, retinopathy of prematurity, bronchopulmonary dysplasia, periventricular leukomalacia, Apgar score <7 at 5 minutes, birthweight <2500 g, or threatened preterm labor.
      In addition, the rates of maternal adverse effects, discontinuation of treatment because of adverse effects, and congenital anomalies did not differ significantly between the vaginal progesterone and placebo groups. One study
      • Rode L.
      • Klein K.
      • Nicolaides K.
      • Krampl-Bettelheim E.
      • Tabor A.
      Prevention of preterm delivery in twin gestations (PREDICT): a multicenter randomized placebo-controlled trial on the effect of vaginal micronized progesterone.
      reported that the mean Ages and Stages Questionnaire scores (a tool that measures neurodevelopmental disability) at 18 months of age were 193 ± 42.6 for infants in the progesterone group and 194 ± 40.6 for infants in the placebo group (P = .89).

      Effect of vaginal progesterone in singleton and twin gestations

      Table 3 shows the effect of vaginal progesterone on the risk of preterm birth and perinatal outcomes in singleton and twin gestations separately. According to the interaction P values (all > .10), there was no evidence that women with singleton pregnancies benefit more or less from the use of vaginal progesterone than women with twin pregnancies.
      TABLE 3Effect of vaginal progesterone on preterm birth and perinatal outcomes in singleton and twin gestations
      Singleton pregnancyTwin pregnancy
      No. of events/total No.No. of events/total No.
      OutcomeNo. of trialsVaginal progesteronePlaceboPooled RR (95% CI)No. of trialsVaginal progesteronePlaceboPooled RR (95% CI)Interaction P value
      Primary outcome
       Preterm birth <33 wk441/36572/3580.56 (0.40–0.80)37/2313/290.70 (0.34–1.44).55
      Secondary outcomes
       Preterm birth <37 wk4127/365141/3580.91 (0.75–1.10)317/2324/290.91 (0.68–1.23).88
       Preterm birth <35 wk467/365100/3580.67 (0.51–0.87)312/2318/290.91 (0.57–1.46).24
       Preterm birth <28 wk420/36539/3580.51 (0.31–0.85)31/234/290.44 (0.11–1.85).83
       Respiratory distress syndrome417/36537/3580.47 (0.27–0.81)38/4615/580.48 (0.21–1.09).68
       Necrotizing enterocolitis45/3656/3580.88 (0.29–2.62)30/460/58Not estimableNA
       Intraventricular hemorrhage45/3657/3580.68 (0.22–2.13)31/462/581.00 (0.10–10.11).74
       Proven neonatal sepsis411/36514/3580.80 (0.37–1.74)31/466/580.33 (0.06–1.67).30
       Retinopathy of prematurity45/3653/3581.51 (0.40–5.69)31/460/581.42 (0.05–42.22).91
       Fetal death46/3657/3580.82 (0.28–2.40)30/460/58Not estimableNA
       Neonatal death46/36511/3580.53 (0.20–1.39)32/464/580.68 (0.23–2.02).69
       Perinatal death412/36518/3580.64 (0.31–1.31)32/464/580.68 (0.23–2.02).90
       Composite neonatal morbidity/mortality
      Occurrence of any of the following events: respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, proven neonatal sepsis, or neonatal death.
      429/36549/3580.59 (0.38–0.91)311/4623/580.52(0.29–0.93).69
       Apgar score <7 at 5 min411/36223/3540.48 (0.24–0.95)34/464/581.03 (0.38–2.81).20
       Birthweight <1500 g428/36453/3550.52 (0.34–0.81)38/4615/580.69 (0.34–1.39).47
       Birthweight <2500 g4102/364117/3550.86 (0.69–1.07)338/4645/581.11 (0.92–1.35).11
       Admission to NICU459/36587/3580.67 (0.50–0.91)326/4634/580.98 (0.70–1.35).12
       Mechanical ventilation428/36543/3580.65 (0.41–1.01)37/468/580.68 (0.30–1.56).88
      CI, confidence interval; NA, not applicable; NICU, neonatal intensive care unit; RR, relative risk.
      Romero. Vaginal progesterone to prevent preterm birth in women with a short cervix: an IPD metaanalysis. Am J Obstet Gynecol 2012.
      a Occurrence of any of the following events: respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, proven neonatal sepsis, or neonatal death.
      Among singleton gestations, the administration of vaginal progesterone was associated with a statistically significant reduction in the risk of preterm birth <33, <35, and <28 weeks of gestation; RDS; composite neonatal morbidity and mortality; Apgar score <7 at 5 minutes; birthweight <1500 g; and admission to the NICU.
      Among twin gestations, the administration of progesterone did not significantly reduce the risk of preterm birth <33 weeks of gestation (RR, 0.70; 95% CI, 0.34–1.44). However, it significantly decreased the risk of composite neonatal morbidity and mortality (RR, 0.52; 95% CI, 0.29–0.93). There were no significant differences in other outcome measures among the vaginal progesterone and placebo groups. The effects of vaginal progesterone on adverse perinatal outcome in twins were tested with 2 methods: one that assumed independence of the twins, and another that did not make such assumption. The results of both analyses were similar, with a slightly wider CI when the method which assumed nonindependence was employed (Table 4). The beneficial effects on composite neonatal morbidity and mortality in twins remained statistically significant (RR, 0.56; 95% CI, 0.30–0.97).
      TABLE 4Effect of vaginal progesterone on adverse perinatal outcomes in twins according to analytical method used
      Pooled RR (95% CI)
      OutcomeAssuming independence of newbornsAdjustment for the lack of independence of newborns
      Respiratory distress syndrome0.48 (0.21–1.09)0.58 (0.25–1.39)
      Necrotizing enterocolitisNot estimableNot estimable
      Intraventricular hemorrhage1.00 (0.10–10.11)1.00 (0.05–18.19)
      Proven neonatal sepsis0.33 (0.06–1.67)0.44 (0.04–4.67)
      Retinopathy of prematurity1.42 (0.05–42.22)1.36 (0.03–58.74)
      Fetal deathNot estimableNot estimable
      Neonatal death0.68 (0.23–2.02)0.48 (0.06–3.74)
      Perinatal death0.68 (0.23–2.02)0.48 (0.06–3.74)
      Composite neonatal morbidity/mortality
      Occurrence of any of the following events: respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, proven neonatal sepsis, or neonatal death.
      0.52 (0.29–0.93)0.56 (0.30–0.97)
      Apgar score <7 at 5 min1.03 (0.38–2.81)0.88 (0.16–4.75)
      Birthweight <1500 g0.69 (0.34–1.39)0.73 (0.29–1.83)
      Birthweight <2500 g1.11 (0.92–1.35)1.13 (0.91–1.40)
      Admission to NICU0.98 (0.70–1.35)0.89 (0.60–1.31)
      Mechanical ventilation0.68 (0.30–1.56)0.60 (0.22–1.65)
      CI, confidence interval; NICU, neonatal intensive care unit; RR, relative risk.
      Romero. Vaginal progesterone to prevent preterm birth in women with a short cervix: an IPD metaanalysis. Am J Obstet Gynecol 2012.
      a Occurrence of any of the following events: respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, proven neonatal sepsis, or neonatal death.
      Importantly, vaginal progesterone was associated with a significant reduction in the risk of preterm birth <33 weeks of gestation in both women with a singleton gestation with no previous preterm birth (RR, 0.60; 95% CI, 0.39–0.92) as well as in women with a singleton gestation and at least 1 previous spontaneous preterm birth <37 weeks of gestation (RR, 0.54; 95% CI, 0.30–0.98). Moreover, vaginal progesterone significantly decreased the risk of composite neonatal morbidity and mortality in women with a singleton gestation and at least 1 previous spontaneous preterm birth <37 weeks of gestation (RR, 0.41; 95% CI, 0.17–0.98), and in women with a twin gestation and no previous preterm birth (RR, 0.52; 95% CI, 0.29–0.93).

      Subgroup and sensitivity analyses

      Subgroup analyses of the effect of vaginal progesterone on primary outcomes are presented in Table 5. There was no evidence that women in any one of the prespecified subgroups benefit more or less from the use of vaginal progesterone than those in any other subgroup (all P for interaction > .30). However, the use of vaginal progesterone was associated with a statistically significant reduction in the risk of preterm birth <33 weeks and composite neonatal morbidity and mortality in both women with no previous spontaneous preterm birth and women with at least 1 previous spontaneous preterm birth <37 weeks of gestation, women with a sonographic cervical length between 10-20 mm, women aged 20-34 years, and Caucasian women.
      TABLE 5Subgroup analyses of effect of vaginal progesterone on preterm birth <33 weeks of gestation and composite neonatal morbidity/mortality
      Occurrence of any of the following events: respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, proven neonatal sepsis, or neonatal death.
      Preterm birth <33 wk of gestationComposite neonatal morbidity/mortality
      Occurrence of any of the following events: respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, proven neonatal sepsis, or neonatal death.
      SubgroupnRR (95% CI)Interaction P valuenRR (95% CI)Interaction P value
      Patient characteristics
       Cervical length, mm.32.93
        <10790.83 (0.49–1.41)900.62 (0.28–1.38)
        10-206530.52 (0.35–0.76)6800.54 (0.35–0.84)
        21-25430.50 (0.10–2.41).68570.55 (0.26–1.19).40
       Obstetric history
        With no previous preterm birth6060.61 (0.42–0.89)6580.62 (0.43–0.91)
        With ≥1 previous preterm birth1690.54 (0.30–0.98)1690.41 (0.17–0.96)
       Maternal age, y.85.31
        <20630.66 (0.21–2.14)661.05 (0.25–4.37)
        20-346200.58 (0.41–0.84)6590.48 (0.31–0.73)
        ≥35920.49 (0.20–1.15)1020.89 (0.33–2.36)
       Race/ethnicity.44.68
        Caucasian2690.39 (0.22–0.69)2910.57 (0.35–0.93)
        Black2870.74 (0.46–1.19)2930.60 (0.32–1.12)
        Asian1570.53 (0.21–1.34)1590.87 (0.20–3.78)
        Other410.60 (0.19–1.92)420.20 (0.03–1.57)
       Body mass index, kg/m2.70.58
        <18.5580.35 (0.10–1.20)620.26 (0.05–1.34)
        18.5-24.93590.63 (0.36–1.10)3900.62 (0.37–1.03)
        25.0-29.91870.68 (0.39–1.19)2000.76 (0.39–1.47)
        ≥301590.49 (0.26–0.92)1630.46 (0.21–1.03)
      Trial characteristics
       Daily dose of vaginal progesterone, mg.57.92
        90-1005040.53 (0.33–0.85)5110.58 (0.35–0.95)
        2002710.63 (0.41–0.96)3160.56 (0.34–0.94)
      CI, confidence interval; RR, relative risk.
      Romero. Vaginal progesterone to prevent preterm birth in women with a short cervix: an IPD metaanalysis. Am J Obstet Gynecol 2012.
      a Occurrence of any of the following events: respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, proven neonatal sepsis, or neonatal death.
      No significant differences were noted for preterm birth <33 weeks of gestation and composite neonatal morbidity and mortality between subgroups based on the daily dose of progesterone. A significant decrease in the risk of preterm birth <33 weeks of gestation and composite neonatal morbidity and mortality was found in women who received either 90-100 or 200 mg/d of vaginal progesterone.
      The effect of vaginal progesterone on the risk of preterm birth <33 weeks of gestation and composite neonatal morbidity/mortality did not change when sensitivity analysis was limited to the 2 trials
      • Fonseca E.B.
      • Celik E.
      • Parra M.
      • Singh M.
      • Nicolaides K.H.
      Progesterone and the risk of preterm birth among women with a short cervix.
      • Hassan S.S.
      • Romero R.
      • Vidyadhari D.
      • et al.
      Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
      in which the primary aim was to evaluate the effect of vaginal progesterone in women with a short cervix (pooled RR, 0.57; 95% CI, 0.40–0.80 for preterm birth <33 weeks and pooled RR, 0.54; 95% CI, 0.35–0.82 for composite neonatal morbidity/mortality). In addition, the results of the metaanalyses did not change significantly when random effects models were used for preterm birth <33 weeks (RR, 0.59; 95% CI, 0.43–0.81) or for composite neonatal morbidity/mortality (RR, 0.59; 95% CI, 0.41–0.83). Sensitivity analyses based on trial quality were not performed because all trials were considered at low risk for biases. No funnel plots showed asymmetry, either visually or in terms of statistical significance (P > .10 for all, by Egger test).

      Comment

      Principal findings of this study

      Vaginal progesterone administration to asymptomatic women with a sonographic short cervix in the midtrimester was associated with: (1) a significant 42% reduction in the rate of preterm birth <33 weeks (primary outcome); (2) a significant reduction in the risk of preterm birth <35, <34, <30, and <28 weeks and a trend for a reduction in the rate of preterm birth <36 weeks; (3) a significant reduction in the risk of spontaneous preterm birth <33 and <34 weeks; (4) a significantly lower rate of RDS (6.1% vs 12.5% in the placebo group); (5) a significant 43% decrease in composite neonatal morbidity and mortality; (6) a significantly lower rate of admission to NICU (20.7% vs 29.1%) and use of mechanical ventilation (8.5% vs 12.3%); (7) a significantly lower rate of neonates with a birthweight <1500 g (8.8% vs 16.5%); and (8) a nonsignificant difference in the rate of maternal adverse events (13.8% vs 13.4%), discontinuation of therapy because of adverse events (2.6% vs 2.6%), congenital anomalies (1.5% vs 1.7%), and neurodevelopmental disability at 18 months of age (3.8% vs 3.7%). Furthermore, most results remained significant when the analyses were restricted to patients with a singleton gestation. In patients with a twin gestation, there was a nonsignificant trend toward reduction of the rate of preterm birth <33 weeks of gestation. However, there was a significant reduction in the risk of composite neonatal morbidity/mortality (pooled RR, 0.52; 95% CI, 0.29–0.93). Importantly, the reduction in the rates of preterm birth <33 weeks of gestation and composite neonatal morbidity and mortality was observed in both women with no previous spontaneous preterm birth and women with a history of spontaneous preterm birth. Finally, there was no difference in efficacy when a dose of either 90-100 or 200 mg/d of vaginal progesterone was used.
      The major effect of vaginal progesterone was to reduce the rate of early preterm birth; however, our results indicate that a fraction of late preterm births (34-36 6/7 weeks) can also be prevented with the administration of vaginal progesterone. Further studies are required to explore the reasons for the differential effect in early vs late preterm births. One possibility is that vaginal progesterone was stopped at 36 6/7 weeks of gestation in the largest trial, but at 34 weeks of gestation in the trial of Fonseca et al.
      • Fonseca E.B.
      • Celik E.
      • Parra M.
      • Singh M.
      • Nicolaides K.H.
      Progesterone and the risk of preterm birth among women with a short cervix.
      Nonetheless, the importance of preventing early preterm birth stems from their disproportionate contribution to serious perinatal morbidity and long-term neurodevelopmental disability.
      A decrease in the rate of preterm birth has been considered a surrogate endpoint for neonatal morbidity and mortality, and indeed, in some trials, a reduction in the rate of preterm birth has not been accompanied by a demonstrable reduction in the frequency of neonatal morbid events. It has been argued that a preventive strategy for preterm birth should accomplish both a reduction in preterm birth and neonatal morbidity. Hassan et al
      • Hassan S.S.
      • Romero R.
      • Vidyadhari D.
      • et al.
      Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
      demonstrated that the significant reduction in the rate of preterm birth at <33 weeks was associated with a significant reduction in the rate of RDS by 61%, whereas Fonseca et al
      • Fonseca E.B.
      • Celik E.
      • Parra M.
      • Singh M.
      • Nicolaides K.H.
      Progesterone and the risk of preterm birth among women with a short cervix.
      reported a nonsignificant reduction in the risk of RDS by 41%. However, in this IPD metaanalysis, we found that vaginal progesterone significantly decreased the risk of RDS by 52%.
      There was no significant difference in the risk of adverse maternal events, discontinuation of treatment because of adverse events, and congenital anomalies between vaginal progesterone and placebo groups. Only 1 study of twin gestations
      • Rode L.
      • Klein K.
      • Nicolaides K.
      • Krampl-Bettelheim E.
      • Tabor A.
      Prevention of preterm delivery in twin gestations (PREDICT): a multicenter randomized placebo-controlled trial on the effect of vaginal micronized progesterone.
      examined developmental and socioemotional scores at 18 months of age, and found that there was no difference between infants exposed to vaginal progesterone and those exposed to placebo. These results are consistent with those of an unpublished observation in a trial of singleton gestations exposed to vaginal progesterone.
      • O'Brien J.M.
      • Steichen J.J.
      • Phillips J.A.
      • Creasy G.W.
      Two year infant outcomes for children exposed to supplemental intravaginal progesterone gel in utero: secondary analysis of a multicenter, randomized, double-blind, placebo-controlled trial.

      Subgroup analyses

      Subgroup analyses did not indicate that vaginal progesterone has differential efficacy in the main clinical subgroups of interest. For example, patients with a sonographic short cervix with or without a history of preterm birth seem to benefit from vaginal progesterone for the reduction of preterm birth. On the other hand, there was some suggestion that patients with a singleton gestation, sonographic cervical length between 10-20 mm, history of preterm birth, age 20-34 years, Caucasian, and body mass index ≥30 kg/m2 might derive a larger benefit from the use of vaginal progesterone than those with other characteristics. Although such analysis was prespecified, subgroup analyses should, of course, be interpreted cautiously because of the risk for false-positive and false-negative results.
      • Rothwell P.M.
      Treating individuals 2 Subgroup analysis in randomized controlled trials: importance, indications, and interpretation.
      • Klebanoff M.A.
      Subgroup analysis in obstetrics clinical trials.
      An important question is the range of cervical length in which vaginal progesterone is effective. Fonseca et al
      • Fonseca E.B.
      • Celik E.
      • Parra M.
      • Singh M.
      • Nicolaides K.H.
      Progesterone and the risk of preterm birth among women with a short cervix.
      noted that vaginal progesterone reduced the rate of spontaneous preterm delivery at <34 weeks of gestation by only 15% in women with a cervical length of 1-5 mm and 25% in patients with a cervical length of 6-10 mm, but the effect size was 75% in patients with a cervical length between 11-15 mm. One possible explanation for this observation is that women with a very short cervix are more likely to have intraamniotic inflammation and may be less responsive to progesterone.
      • Kiefer D.G.
      • Keeler S.M.
      • Rust O.A.
      • Wayock C.P.
      • Vintzileos A.M.
      • Hanna N.
      Is midtrimester short cervix a sign of intraamniotic inflammation?.
      • Vaisbuch E.
      • Hassan S.S.
      • Mazaki-Tovi S.
      • et al.
      Patients with an asymptomatic short cervix (< or =15 mm) have a high rate of subclinical intraamniotic inflammation: implications for patient counseling.
      These observations are in keeping with the rationale for excluding patients with a cervical length of <10 mm in the study reported by Hassan et al.
      • Hassan S.S.
      • Romero R.
      • Vidyadhari D.
      • et al.
      Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
      A subgroup analysis of this IPD metaanalysis suggests that progesterone might be less effective in patients with a cervical length of <10 mm. However, there was no statistically significant differential effect according to cervical length (interaction P value of .32 for preterm birth <33 weeks of gestation and .93 for composite neonatal morbidity/mortality). Therefore, this result is subject to all limitations of analysis of subgroups.
      • Rothwell P.M.
      Treating individuals 2 Subgroup analysis in randomized controlled trials: importance, indications, and interpretation.
      • Klebanoff M.A.
      Subgroup analysis in obstetrics clinical trials.
      Fonseca et al
      • Fonseca E.B.
      • Celik E.
      • Parra M.
      • Singh M.
      • Nicolaides K.H.
      Progesterone and the risk of preterm birth among women with a short cervix.
      and Hassan et al
      • Hassan S.S.
      • Romero R.
      • Vidyadhari D.
      • et al.
      Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
      reported that vaginal progesterone was associated with a nonstatistically significant reduction in the rate of preterm birth <34 weeks and preterm birth <33 weeks, respectively, in patients with a short cervix and history of spontaneous preterm birth. Some have interpreted such findings as suggesting that vaginal progesterone does not reduce the rate of preterm birth in these women. This is not a correct interpretation of the results of the trials, because the number of patients with a prior preterm birth in each individual trial was small. Indeed, patients with a history of preterm birth <37 weeks of gestation represented only 15% and 21% of those enrolled in the trials of Fonseca et al
      • Fonseca E.B.
      • Celik E.
      • Parra M.
      • Singh M.
      • Nicolaides K.H.
      Progesterone and the risk of preterm birth among women with a short cervix.
      and Hassan et al,
      • Hassan S.S.
      • Romero R.
      • Vidyadhari D.
      • et al.
      Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
      respectively. Moreover, the primary objective of both trials was to test whether vaginal progesterone would reduce the rate of preterm birth in women with a sonographic short cervix, and not in a particular subgroup. Although the inclusion of patients with a history of spontaneous preterm birth was not a central focus in the design of these trials, this IPD metaanalysis sheds light on this question, because with the increased statistical power afforded by the larger sample size, we were able to show that patients with a short cervix and a history of preterm birth benefitted to the same extent as patients with a short cervix without a history of preterm birth. There is no biological explanation as to why patients with a history of spontaneous preterm birth would not benefit from progesterone administration if they have a short cervix.
      The results reported herein have clinical implications because they extend the indication of vaginal progesterone to women with a history of spontaneous preterm birth with a short cervix. Some have claimed that 17α-hydroxyprogesterone caproate is the only therapeutic intervention effective in reducing the rate of preterm birth in women with a history of preterm birth
      • Lockwood C.
      The real progesterone story.
      –such conclusion is contradicted by the results of this IPD metaanalysis. In addition, a recent metaanalysis reported that cervical cerclage (compared with no cervical cerclage) significantly reduces the risk of preterm birth <35 weeks of gestation by 30% (RR, 0.70; 95% CI, 0.55–0.89) and composite perinatal morbidity and mortality by 36% (RR, 0.64; 95% CI, 0.45–0.91) in women with a singleton gestation, previous spontaneous preterm birth, and cervical length <25 mm.
      • Berghella V.
      • Rafael T.J.
      • Szychowski J.M.
      • Rust O.A.
      • Owen J.
      Cerclage for short cervix on ultrasonography in women with singleton gestations and previous preterm birth: a meta-analysis.
      In the present IPD metaanalysis, vaginal progesterone significantly decreased the risk of preterm birth <33 weeks of gestation by 46% (RR, 0.54; 95% CI, 0.30–0.98) in patients with a singleton gestation, prior preterm birth, and sonographic short cervix. Therefore, it appears that administration of vaginal progesterone could be an alternative treatment to cervical cerclage in patients with a singleton pregnancy, short cervix, and history of spontaneous preterm birth for preventing preterm birth and neonatal morbidity and mortality. Vaginal progesterone administration does not carry the risks of anesthesia, the surgical procedure per se, or some of the complications attributed to cerclage (ie, rupture of membranes).
      • Gupta M.
      • Emary K.
      • Impey L.
      Emergency cervical cerclage: predictors of success.
      • Owen J.
      • Hankins G.
      • Iams J.D.
      • et al.
      Multicenter randomized trial of cerclage for preterm birth prevention in high-risk women with shortened midtrimester cervical length.
      • Fox N.S.
      • Chervenak F.A.
      Cervical cerclage: a review of the evidence.
      • Vidaeff A.C.
      • Ramin S.M.
      Management strategies for the prevention of preterm birth: part II–update on cervical cerclage.
      • Abenhaim H.A.
      • Tulandi T.
      Cervical insufficiency: re-evaluating the prophylactic cervical cerclage.
      • Zaveri V.
      • Aghajafari F.
      • Amankwah K.
      • Hannah M.
      Abdominal versus vaginal cerclage after a failed transvaginal cerclage: a systematic review.
      • Romero R.
      • Espinoza J.
      • Erez O.
      • Hassan S.
      The role of cervical cerclage in obstetric practice: can the patient who could benefit from this procedure be identified?.
      • Hassan S.S.
      • Romero R.
      • Maymon E.
      • et al.
      Does cervical cerclage prevent preterm delivery in patients with a short cervix?.