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Vaginal progesterone vs cervical cerclage for the prevention of preterm birth in women with a sonographic short cervix, previous preterm birth, and singleton gestation: a systematic review and indirect comparison metaanalysis

Published:November 19, 2012DOI:https://doi.org/10.1016/j.ajog.2012.10.877

      Objective

      No randomized controlled trial has compared vaginal progesterone and cervical cerclage directly for the prevention of preterm birth in women with a sonographic short cervix in the mid trimester, singleton gestation, and previous spontaneous preterm birth. We performed an indirect comparison of vaginal progesterone vs cerclage using placebo/no cerclage as the common comparator.

      Study Design

      Adjusted indirect metaanalysis of randomized controlled trials.

      Results

      Four studies that evaluated vaginal progesterone vs placebo (158 patients) and 5 studies that evaluated cerclage vs no cerclage (504 patients) were included. Both interventions were associated with a statistically significant reduction in the risk of preterm birth at <32 weeks of gestation and composite perinatal morbidity and mortality compared with placebo/no cerclage. Adjusted indirect metaanalyses did not show statistically significant differences between vaginal progesterone and cerclage in the reduction of preterm birth or adverse perinatal outcomes.

      Conclusion

      Based on state-of-the-art methods for indirect comparisons, either vaginal progesterone or cerclage are equally efficacious in the prevention of preterm birth in women with a sonographic short cervix in the mid trimester, singleton gestation, and previous preterm birth. Selection of the optimal treatment needs to consider adverse events, cost and patient/clinician preferences.

      Key words

      Most of the efforts to prevent preterm birth have been focused on the treatment of symptoms or signs of activation of the common pathway of parturition
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      For Editors' Commentary, see Contents
      See related editorial, page 1
      A sonographic short cervix has emerged as a powerful predictor of preterm birth.
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      Vaginal ultrasonographic assessment of cervical length changes during normal pregnancy.
      • Okitsu O.
      • Mimura T.
      • Nakayama T.
      • Aono T.
      Early prediction of preterm delivery by transvaginal ultrasonography.
      It is unlikely that this condition is due to a single cause; a multiple causation model of a sonographic short cervix has been proposed (eg, a short cervix is syndromic in nature).
      • 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?.
      • Romero R.
      Prenatal medicine: the child is the father of the man.
      • Di Renzo G.C.
      The great obstetrical syndromes.
      Such model would have biologic, diagnostic, prognostic, and therapeutic implications.
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      • et al.
      The preterm parturition syndrome and its implications for understanding the biology, risk assessment, diagnosis, treatment and prevention of preterm birth.
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      • Erez O.
      • Hassan S.
      The role of cervical cerclage in obstetric practice: can the patient who could benefit from this procedure be identified?.
      Indeed, patients may have a short cervix after diethylstilbestrol exposure in utero,
      • Levine R.U.
      • Berkowitz K.M.
      Conservative management and pregnancy outcome in diethylstilbestrol-exposed women with and without gross genital tract abnormalities.
      • Ludmir J.
      • Landon M.B.
      • Gabbe S.G.
      • Samuels P.
      • Mennuti M.T.
      Management of the diethylstilbestrol-exposed pregnant patient: a prospective study.
      • Mangan C.E.
      • Borow L.
      • Burtnett-Rubin M.M.
      • Egan V.
      • Giuntoli R.L.
      • Mikuta J.J.
      Pregnancy outcome in 98 women exposed to diethylstilbestrol in utero, their mothers, and unexposed siblings.
      a cervical conization,
      • Raio L.
      • Ghezzi F.
      • Di Naro E.
      • Gomez R.
      • Luscher K.P.
      Duration of pregnancy after carbon dioxide laser conization of the cervix: influence of cone height.
      • Bruinsma F.J.
      • Quinn M.A.
      The risk of preterm birth following treatment for precancerous changes in the cervix: a systematic review and meta-analysis.
      • Bevis K.S.
      • Biggio J.R.
      Cervical conization and the risk of preterm delivery.
      • Armarnik S.
      • Sheiner E.
      • Piura B.
      • Meirovitz M.
      • Zlotnik A.
      • Levy A.
      Obstetric outcome following cervical conization.
      • Nam K.H.
      • Kwon J.Y.
      • Kim Y.H.
      • Park Y.W.
      Pregnancy outcome after cervical conization: risk factors for preterm delivery and the efficacy of prophylactic cerclage.
      • Andia D.
      • Mozo de Rosales F.
      • Villasante A.
      • Rivero B.
      • Diez J.
      • Perez C.
      Pregnancy outcome in patients treated with cervical conization for cervical intraepithelial neoplasia.
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      • Poppe W.
      • Verguts J.
      • Arbyn M.
      Pregnancy outcome after cervical conisation: a retrospective cohort study in the Leuven University Hospital.
      • Ortoft G.
      • Henriksen T.
      • Hansen E.
      • Petersen L.
      After conisation of the cervix, the perinatal mortality as a result of preterm delivery increases in subsequent pregnancy.
      • Masamoto H.
      • Nagai Y.
      • Inamine M.
      • et al.
      Outcome of pregnancy after laser conization: implications for infection as a causal link with preterm birth.
      • Albrechtsen S.
      • Rasmussen S.
      • Thoresen S.
      • Irgens L.M.
      • Iversen O.E.
      Pregnancy outcome in women before and after cervical conisation: population based cohort study.
      • Patrelli T.S.
      • Anfuso S.
      • Vandi F.
      • et al.
      Preterm delivery and premature rupture of membranes after conization in 80 women: preliminary data.
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      • Vistad I.
      • Myhr S.S.
      • et al.
      Pregnancy outcome after cervical cone excision: a case-control study.
      • Klaritsch P.
      • Reich O.
      • Giuliani A.
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      • Haas J.
      • Winter R.
      Delivery outcome after cold-knife conization of the uterine cervix.
      • Kristensen J.
      • Langhoff-Roos J.
      • Wittrup M.
      • Bock J.E.
      Cervical conization and preterm delivery/low birth weight; a systematic review of the literature.
      • Hagen B.
      • Skjeldestad F.E.
      The outcome of pregnancy after CO2 laser conisation of the cervix.
      • Kristensen G.B.
      The outcome of pregnancy and preterm delivery after conization of the cervix.
      • Leiman G.
      • Harrison N.A.
      • Rubin A.
      Pregnancy following conization of the cervix: complications related to cone size.
      • Moinian M.
      • Andersch B.
      Does cervix conization increase the risk of complications in subsequent pregnancies?.
      a loop electrosurgical excision procedure,
      • Arbyn M.
      • Kyrgiou M.
      • Simoens C.
      • et al.
      Perinatal mortality and other severe adverse pregnancy outcomes associated with treatment of cervical intraepithelial neoplasia: meta-analysis.
      • Sadler L.
      • Saftlas A.
      Cervical surgery and preterm birth.
      • Jakobsson M.
      • Gissler M.
      • Paavonen J.
      • Tapper A.M.
      Loop electrosurgical excision procedure and the risk for preterm birth.
      • Fischer R.L.
      • Sveinbjornsson G.
      • Hansen C.
      Cervical sonography in pregnant women with a prior cone biopsy or loop electrosurgical excision procedure.
      • Shin M.Y.
      • Seo E.S.
      • Choi S.J.
      • et al.
      The role of prophylactic cerclage in preventing preterm delivery after electrosurgical conization.
      intrauterine infection/inflammation,
      • Romero R.
      • Gonzalez R.
      • Sepulveda W.
      • et al.
      Infection and labor: VIII, microbial invasion of the amniotic cavity in patients with suspected cervical incompetence: prevalence and clinical significance.
      • Mays J.K.
      • Figueroa R.
      • Shah J.
      • Khakoo H.
      • Kaminsky S.
      • Tejani N.
      Amniocentesis for selection before rescue cerclage.
      • 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.
      • 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 (≤15 mm) have a high rate of subclinical intraamniotic inflammation: implications for patient counseling.
      • Holst R.M.
      • Jacobsson B.
      • Hagberg H.
      • Wennerholm U.B.
      Cervical length in women in preterm labor with intact membranes: relationship to intra-amniotic inflammation/microbial invasion, cervical inflammation and preterm delivery.
      • Lee S.E.
      • Romero R.
      • Park C.W.
      • Jun J.K.
      • Yoon B.H.
      The frequency and significance of intraamniotic inflammation in patients with cervical insufficiency.
      • 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.
      • Rizzo G.
      • Capponi A.
      • Vlachopoulou A.
      • Angelini E.
      • Grassi C.
      • Romanini C.
      Ultrasonographic assessment of the uterine cervix and interleukin-8 concentrations in cervical secretions predict intrauterine infection in patients with preterm labor and intact membranes.
      • Vaisbuch E.
      • Romero R.
      • Mazaki-Tovi S.
      • et al.
      The risk of impending preterm delivery in asymptomatic patients with a nonmeasurable cervical length in the second trimester.
      a decline in progesterone action,
      • Straach K.J.
      • Shelton J.M.
      • Richardson J.A.
      • Hascall V.C.
      • Mahendroo M.S.
      Regulation of hyaluronan expression during cervical ripening.
      • Roberson A.E.
      • Hyatt K.
      • Kenkel C.
      • Hanson K.
      • Myers D.A.
      Interleukin 1beta regulates progesterone metabolism in human cervical fibroblasts.
      • Yellon S.M.
      • Ebner C.A.
      • Sugimoto Y.
      Parturition and recruitment of macrophages in cervix of mice lacking the prostaglandin F receptor.
      • Ledger W.L.
      • Webster M.A.
      • Anderson A.B.
      • Turnbull A.C.
      Effect of inhibition of prostaglandin synthesis on cervical softening and uterine activity during ovine parturition resulting from progesterone withdrawal induced by epostane.
      and the challenging condition clinically referred to as idiopathic cervical insufficiency.
      • Danforth D.N.
      The distribution and functional activity of the cervical musculature.
      • Danforth D.N.
      • Buckingham J.C.
      Cervical incompetence: a re-evaluation.
      • Danforth D.N.
      • Buckingham J.C.
      • Roddick Jr, J.W.
      Connective tissue changes incident to cervical effacement.
      • Danforth D.N.
      • Veis A.
      • Breen M.
      • Weinstein H.G.
      • Buckingham J.C.
      • Manalo P.
      The effect of pregnancy and labor on the human cervix: changes in collagen, glycoproteins, and glycosaminoglycans.
      • Uldbjerg N.
      Cervical connective tissue in relation to pregnancy, labour, and treatment with prostaglandin E2.
      • Uldbjerg N.
      Preterm delivery.
      • 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.
      • Sundtoft I.
      • Sommer S.
      • Uldbjerg N.
      Cervical collagen concentration within 15 months after delivery.
      Three interventions have been proposed to treat patients with a sonographic short cervix: (1) vaginal progesterone administration,
      • 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.
      • 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.
      • O'Brien J.M.
      • Defranco E.A.
      • Adair C.D.
      • et al.
      Effect of progesterone on cervical shortening in women at risk for preterm birth: secondary analysis from a multinational, randomized, double-blind, placebo-controlled 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.
      • Romero R.
      • Nicolaides K.
      • Conde-Agudelo A.
      • et al.
      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.
      (2) cervical cerclage for patients with a history of preterm birth,
      • 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.
      • Berghella V.
      • Haas S.
      • Chervoneva I.
      • Hyslop T.
      Patients with prior second-trimester loss: prophylactic cerclage or serial transvaginal sonograms?.
      • Berghella V.
      • Odibo A.O.
      • To M.S.
      • Rust O.A.
      • Althuisius S.M.
      Cerclage for short cervix on ultrasonography: meta-analysis of trials using individual patient-level data.
      • 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.
      and (3) vaginal pessary.
      • Arabin B.
      • Halbesma J.R.
      • Vork F.
      • Hubener M.
      • van Eyck J.
      Is treatment with vaginal pessaries an option in patients with a sonographically detected short cervix?.
      • Kimber-Trojnar Z.
      • Patro-Malysza J.
      • Leszczynska-Gorzelak B.
      • Marciniak B.
      • Oleszczuk J.
      Pessary use for the treatment of cervical incompetence and prevention of preterm labour.
      • Goya M.
      • Pratcorona L.
      • Merced C.
      • et al.
      Cervical pessary in pregnant women with a short cervix (PECEP): an open-label randomised controlled trial.
      Recently, a combination of vaginal progesterone and a pessary has been reported to be a successful method to reduce the rate of preterm delivery in twin gestations with a cervix of <25 mm.
      • Zacharakis D.
      • Daskalakis G.
      • Papantoniou N.
      • et al.
      Is treatment with cervical pessaries an option in pregnant women with a mid-trimester short cervix?.
      Two independent randomized clinical 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.
      and an individual patient data (IPD) metaanalysis showed that vaginal progesterone decreases the rate of preterm delivery and neonatal morbidity/mortality in women with a sonographic short cervix.
      • Romero R.
      • Nicolaides K.
      • Conde-Agudelo A.
      • et al.
      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.
      This is the case for patients with or without a history of preterm birth.
      • Romero R.
      • Nicolaides K.
      • Conde-Agudelo A.
      • et al.
      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.
      The placement of a cervical cerclage appears to be indicated in patients with acute cervical insufficiency,
      • Althuisius S.M.
      • Dekker G.A.
      • Hummel P.
      • van Geijn H.P.
      Cervical incompetence prevention randomized cerclage trial: emergency cerclage with bed rest vs bed rest alone.
      • Daskalakis G.
      • Papantoniou N.
      • Mesogitis S.
      • Antsaklis A.
      Management of cervical insufficiency and bulging fetal membranes.
      • Stupin J.H.
      • David M.
      • Siedentopf J.P.
      • Dudenhausen J.W.
      Emergency cerclage versus bed rest for amniotic sac prolapse before 27 gestational weeks: a retrospective, comparative study of 161 women.
      • Ventolini G.
      • Genrich T.J.
      • Roth J.
      • Neiger R.
      Pregnancy outcome after placement of 'rescue' Shirodkar cerclage.
      • Cockwell H.A.
      • Smith G.N.
      Cervical incompetence and the role of emergency cerclage.
      • Matijevic R.
      • Olujic B.
      • Tumbri J.
      • Kurjak A.
      Cervical incompetence: the use of selective and emergency cerclage.
      • Novy M.J.
      • Gupta A.
      • Wothe D.D.
      • Gupta S.
      • Kennedy K.A.
      • Gravett M.G.
      Cervical cerclage in the second trimester of pregnancy: a historical cohort study.
      • Novy M.J.
      • Haymond J.
      • Nichols M.
      Shirodkar cerclage in a multifactorial approach to the patient with advanced cervical changes.
      and perhaps, in some with a history of preterm birth and a sonographic short cervix of <25 mm.
      • 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.
      • Berghella V.
      • Haas S.
      • Chervoneva I.
      • Hyslop T.
      Patients with prior second-trimester loss: prophylactic cerclage or serial transvaginal sonograms?.
      • Berghella V.
      • Odibo A.O.
      • To M.S.
      • Rust O.A.
      • Althuisius S.M.
      Cerclage for short cervix on ultrasonography: meta-analysis of trials using individual patient-level data.
      • 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.
      Thus, there appear to be 2 interventions that may reduce the rate of preterm delivery in patients with a history of preterm birth and a cervix of <25 mm: vaginal progesterone administration or a cervical cerclage.
      Recently, 2 professional organizations have recommended that cerclage may be considered for the treatment of women with a singleton gestation, previous spontaneous preterm birth, and a cervical length <25 mm at <24 weeks of gestation.
      American College of Obstetricians and Gynecologists
      Committee opinion no. 522: incidentally detected short cervical length.
      Progesterone and preterm birth prevention: translating clinical trials data into clinical practice.
      This recommendation was based mainly on an IPD metaanalysis of randomized controlled trials that show that cerclage is associated with a statistically significant reduction in the risk of preterm birth at <37, <35, <32, <28, and <24 weeks of gestation, and composite perinatal morbidity and mortality when compared with no cerclage.
      • Berghella V.
      • Odibo A.O.
      • To M.S.
      • Rust O.A.
      • Althuisius S.M.
      Cerclage for short cervix on ultrasonography: meta-analysis of trials using individual patient-level data.
      However, another IPD metaanalysis demonstrated that vaginal progesterone administration to women with a sonographic short cervix (≤25 mm) in the mid trimester significantly decreased the risk of preterm birth at <35, <34, <33, <30, and <28 weeks of gestation and composite neonatal morbidity and mortality when compared with placebo.
      • Althuisius S.M.
      • Dekker G.A.
      • Hummel P.
      • van Geijn H.P.
      Cervical incompetence prevention randomized cerclage trial: emergency cerclage with bed rest vs bed rest alone.
      In addition, a subgroup analysis showed that vaginal progesterone was associated with a significant reduction in the risk of preterm birth at <33 weeks of gestation and composite neonatal morbidity and mortality in women with a short cervix (≤25 mm), singleton gestation, and previous spontaneous preterm birth.
      • Romero R.
      • Nicolaides K.
      • Conde-Agudelo A.
      • et al.
      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.
      The availability of vaginal progesterone and cerclage for the prevention of preterm birth in women with a short cervix, singleton gestation, and previous spontaneous preterm birth could create a dilemma for physicians and patients about the optimal choice of treatment.
      • Parry S.
      • Simhan H.
      • Elovitz M.
      • Iams J.
      Universal maternal cervical length screening during the second trimester: pros and cons of a strategy to identify women at risk of spontaneous preterm delivery.
      Thus far, there are no randomized controlled trials comparing vaginal progesterone and cerclage directly. In the absence of this evidence, indirect metaanalysis has emerged as an accepted and valid method for the comparison of competing interventions with the use of a common comparator.
      • Song F.
      • Altman D.G.
      • Glenny A.M.
      • Deeks J.J.
      Validity of indirect comparison for estimating efficacy of competing interventions: empirical evidence from published meta-analyses.
      • Sutton A.
      • Ades A.E.
      • Cooper N.
      • Abrams K.
      Use of indirect and mixed treatment comparisons for technology assessment.
      • Wells G.A.
      • Sultan A.
      • Chen L.
      • Khan M.
      • Coyle D.
      Indirect evidence: indirect treatment comparisons in meta-analysis.
      • Edwards S.J.
      • Clarke M.J.
      • Wordsworth S.
      • Borrill J.
      Indirect comparisons of treatments based on systematic reviews of randomised controlled trials.
      We performed an adjusted indirect metaanalysis to compare the treatment effects of vaginal progesterone vs cerclage in asymptomatic women with a cervical length <25 mm in the mid trimester, singleton gestation and previous spontaneous preterm birth for the prevention of preterm birth. Previously, we had conducted an IPD metaanalysis to evaluate the efficacy of vaginal progesterone vs placebo in patients with such characteristics. Then, the summary estimates and measures of uncertainty were used together with those reported in the IPD metaanalysis that evaluated cerclage vs no cerclage
      • 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.
      to perform the adjusted indirect comparison metaanalysis.

      Materials and Methods

      The study was conducted based on a prospectively prepared protocol and is reported with the use of the Preferred Reporting Items for Systematic reviews and Metaanalyses (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
      • Riley R.D.
      • Lambert P.C.
      • Abo-Zaid G.
      Meta-analysis of individual participant data: rationale, conduct, and reporting.
      and indirect metaanalyses.
      • Donegan S.
      • Williamson P.
      • Gamble C.
      • Tudur-Smith C.
      Indirect comparisons: a review of reporting and methodological quality.

      Literature search

      We searched MEDLINE, EMBASE, CINAHL, and LILACS (all from inception to October 31, 2012), the Cochrane Central Register of Controlled Trials (1960 to October 31, 2012; http://www.mrw.interscience.wiley.com/cochrane/cochrane_clcentral_articles_fs.html), ISI Web of Science (1960 to October 31, 2012; http://www.isiknowledge.com), research registers of ongoing trials (www.clinicaltrials.gov, www.controlled-trials.com, www.centerwatch.com, www.anzctr.org.au, http://www.nihr.ac.uk, and www.umin.ac.jp/ctr), and Google scholar using a combination of keywords and text words related to progesterone (progesterone, progestins, progestogen, progestagen, progestational agent), cervical cerclage (cerclage, cervical stitch, cervical suture, cervical ligation, Shirodkar suture, Shirodkar operation, Shirodkar stitch, Shirodkar procedure, McDonald suture, McDonald procedure, McDonald method, McDonald technique), short cervix (short cervical length, short cervix, cervical shortening), and preterm birth (preterm, premature). Congress proceedings of international society meetings of maternal-fetal and reproductive 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 restrictions were applied.

      Study selection

      We included randomized controlled trials in which asymptomatic women with a sonographic short cervix (cervical length, <25 mm) in the mid trimester, singleton gestation, and previous spontaneous preterm birth at <37 weeks of gestation were allocated randomly to receive vaginal progesterone vs placebo/no treatment or cerclage vs no cerclage for the prevention of preterm birth. Trials were included if the primary aim of the study was to (1) prevent preterm birth in women with such characteristics; or (2) prevent preterm birth in women with other characteristics, but outcomes were available for patients with a prerandomization cervical length <25 mm in the mid trimester, singleton gestation, and previous preterm birth. Trials were excluded if they (1) were quasirandomized, (2) evaluated the interventions in women with only multiple gestations, (3) evaluated vaginal progesterone in women with actual or threatened preterm labor, second trimester bleeding, or premature rupture of membranes, (4) evaluated the administration of progesterone in the first trimester only to prevent miscarriage, (5) assessed history-indicated cerclage (placed for the sole indication of poor obstetric history), physical examination–indicated cerclage (placed for second trimester cervical dilation), or compared different cerclage techniques or outpatient cerclage vs inpatient cerclage, (6) compared cerclage with 17α-hydroxyprogesterone caproate, or (7) did not provide data for women with a cervical length <25 mm in the mid trimester, singleton gestation, and previous preterm birth.
      All published studies that were deemed suitable were retrieved and reviewed independently by 2 authors (A.C-A. and R.R.) to determine inclusion. Disagreements were resolved through consensus.

      Data collection

      For the IPD metaanalysis that evaluated vaginal progesterone vs placebo, 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 that were provided by the investigators were merged into a master database that had been constructed specifically 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 a review of the chronologic randomization sequence and pattern of assignment and the balance of baseline characteristics across treatment groups. Inconsistencies or missing data were discussed with the authors and corrections were made when deemed necessary. Finally, data were extracted for women with a cervical length <25 mm in the mid trimester, singleton gestation, and previous preterm births. A similar approach was used in the IPD metaanalysis by Berghella et al
      • 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.
      that evaluated cerclage vs no cerclage.

      Outcome measures

      The prespecified primary outcome measures were preterm birth <32 weeks of gestation and composite perinatal morbidity and mortality (defined as the occurrence of any of the following events: respiratory distress syndrome, grade III/IV intraventricular hemorrhage, necrotizing enterocolitis, neonatal sepsis, bronchopulmonary dysplasia, or perinatal mortality). Secondary outcome measures included preterm birth at <37, <35, and <28 weeks of gestation, respiratory distress syndrome, necrotizing enterocolitis, grade III/IV intraventricular hemorrhage, neonatal sepsis, bronchopulmonary dysplasia, perinatal mortality, a composite neonatal morbidity outcome (defined as the occurrence of any of the above mentioned neonatal morbidities), birthweight <1500 g and <2500 g, and admission to the neonatal intensive care unit (NICU).

      Assessment of risk of bias

      The risk of bias in each included study was assessed by the use of 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 that are related to the risk of bias were assessed in each included trial because 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 risk” of bias, “high risk” of bias, or “unclear risk” of bias. The assessments considered the risk of material bias rather than any bias. Material bias was defined as a bias of sufficient magnitude to have a notable impact on the results or conclusions of the trial. The risk of bias in each included trial was assessed individually by 2 reviewers (A.C-A. and R.R.). Any differences of opinion regarding assessment of risk of bias were resolved by discussion.

      Data extraction

      Two authors (A.C-A. and R.R.) extracted data from each study on participants (inclusion and exclusion criteria, number of women and fetuses/infants in randomized groups, baseline characteristics, and country and date of recruitment), study characteristics (randomization procedure, concealment allocation method, blinding of clinicians, women and outcome assessors, completeness of outcome data for each outcome, which included attrition and exclusions from the analysis, and intention-to-treat analysis), details of interventions (aim, gestational age at trial entry, daily dose of vaginal progesterone and duration of treatment, cerclage type and suture used, and cointerventions), and outcomes (number of outcome events/total number in women with a cervical length <25 mm, singleton gestation, and previous spontaneous preterm birth). Women with multiple gestations, no previous spontaneous preterm birth, or cervical length ≥25 mm were excluded. For studies that assessed cerclage, data on proportions and relative risks (RRs) with 95% confidence intervals (CIs) for each outcome measure were extracted from the IPD metaanalysis by Berghella et al.
      • 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.
      Disagreements in extracted data were resolved by discussion among reviewers.

      Statistical analysis

      Statistical analyses were based on an intent-to-treat basis and included all randomly assigned women and their fetuses/infants. For studies that assessed vaginal progesterone, IPD were combined in a 2-stage approach in which outcomes were analyzed in their original trial, then summary statistics were combined with the use of standard summary data metaanalysis techniques to give an overall measure of effect (summary RR with 95% 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.
      A similar approach was used in the IPD metaanalysis of trials that evaluated cerclage vs no cerclage.
      • 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.
      Heterogeneity of the results among studies was tested with the quantity I2 in the IPD metaanalysis of vaginal progesterone vs placebo
      • Higgins J.P.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analyses.
      and the Mantel-Haenszel Q statistics in the IPD metaanalysis of cerclage vs no cerclage. I2 values of ≥50% or a probability value of < .10 for Mantel-Haenszel Q statistics indicated a substantial level of heterogeneity. Fixed-effects models were used if substantial statistical heterogeneity was not present. Otherwise, random-effects models were used.
      The number needed to treat for benefit or harm (with their 95% CIs) were calculated for the primary outcomes for which there was a statistically significant reduction or increase in risk difference based on control event rates in the included trials.
      • Altman D.G.
      Confidence intervals for the number needed to treat.
      Publication and related biases were assessed visually by an examination of the symmetry of funnel plots and statistically by the use of the Egger test.
      • Egger M.
      • Davey Smith G.
      • Schneider M.
      • Minder C.
      Bias in meta-analysis detected by a simple, graphical test.
      A probability value of < .1 was considered to indicate significant asymmetry.
      The adjusted indirect comparison metaanalysis of vaginal progesterone vs cerclage was performed according to the most widely applied indirect comparison method by Bucher et al.
      • Bucher H.C.
      • Guyatt G.H.
      • Griffith L.E.
      • Walter S.D.
      The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials.
      The Canadian Agency for Drugs and Technologies in Health
      • Wells G.A.
      • Sultan A.
      • Chen L.
      • Khan M.
      • Coyle D.
      Indirect evidence: indirect treatment comparisons in meta-analysis.
      and others
      • Song F.
      • Altman D.G.
      • Glenny A.M.
      • Deeks J.J.
      Validity of indirect comparison for estimating efficacy of competing interventions: empirical evidence from published meta-analyses.
      • Edwards S.J.
      • Clarke M.J.
      • Wordsworth S.
      • Borrill J.
      Indirect comparisons of treatments based on systematic reviews of randomised controlled trials.
      • Glenny A.M.
      • Altman D.G.
      • Song F.
      • et al.
      Indirect comparisons of competing interventions.
      have identified this method as the most suitable approach for performing indirect treatment comparisons of randomized controlled trials. In this method, the randomization of each trial is maintained, and the direct comparisons A vs B and C vs B with the common comparator link B are used to yield an indirect comparison of A vs C. Because vaginal progesterone and cerclage have been compared with placebo and no cerclage, respectively, indirect comparison was enabled by the “common” placebo/no cerclage arms. An extension of the Bucher approach was used to convert the summary estimates (lnRRs) and measures of uncertainty (variances) from the 2 metaanalyses into a RR (95% CI) that represented the difference between vaginal progesterone (p) and cerclage (c) as in the following equations:
      • Wells G.A.
      • Sultan A.
      • Chen L.
      • Khan M.
      • Coyle D.
      Indirect evidence: indirect treatment comparisons in meta-analysis.
      ln(RRpc Indirect)=Σln(RRpc)


      95% CI of ln(RRpc Indirect) =  Σln(RRpc)±Zα/2ΣVar(ln(RRpc))


      where Var indicates the square of the standard error (variance) and Zα/2 is the upper 95% percentile of the standard normal distribution. All values were back transformed to give the estimate of RRpc with a 95% CI.
      To examine the assumption of similarity of treatment effects, we investigated the effect of patient and trial characteristics on both direct and indirect comparison results with the use of sensitivity analyses. A predefined sensitivity analysis was conducted by excluding patients who received progesterone in trials that evaluated cerclage vs no cerclage and patients who received a cerclage in studies that compared vaginal progesterone with placebo to explore the impact of these cointerventions on the effect size for preterm birth and perinatal mortality. This analysis was performed because it is unclear whether the effects of progesterone and cerclage are additive in women with a short cervix, singleton gestation, and previous spontaneous preterm birth. An additional sensitivity analysis was planned to evaluate the effect of study quality on the main outcomes by the exclusion of trials with high risk of bias.
      One author (A.C-A.) conducted all statistical analyses using Review Manager software (version 5.1.6; Nordic Cochrane Centre, Copenhagen, Denmark) for performing direct metaanalyses and Indirect Treatment Comparison software (version 1.0; Canadian Agency for Drugs and Technologies in Health, Ottawa, Canada) to perform adjusted indirect comparison metaanalyses.
      Informed consent was provided by the patients on enrollment in the each of the original trials. In this study, the data were not used for any other purpose other than those of the original trial, and no new data were collected. Therefore, informed consent specifically for this project was not considered necessary. This study was exempted for review by the Human Investigations Committee of Wayne State University. No patient identifiers were provided by any investigator.

      Results

      Of the 5606 relevant citations that were identified, the abstracts were reviewed, and 32 studies were retrieved because they were considered potentially relevant to this indirect metaanalysis. Twenty-three 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.
      • Majhi P.
      • Bagga R.
      • Kalra J.
      • Sharma M.
      Intravaginal use of natural micronised progesterone to prevent pre-term birth: a randomised trial in India.
      • Norman J.E.
      • Mackenzie F.
      • Owen P.
      • et al.
      Progesterone for the prevention of preterm birth in twin pregnancy (STOPPIT): a randomised, double-blind, placebo-controlled study and meta-analysis.
      • Rode L.
      • Klein K.
      • Nicolaides K.
      • Krampl-Bettelheim E.
      • Tabor A.
      Prevention of preterm delivery in twin gestations (PREDICT): a multicentre randomised placebo-controlled trial on the effect of vaginal micronised progesterone.
      • Borna S.
      • Sahabi N.
      Progesterone for maintenance tocolytic therapy after threatened preterm labour: a randomised 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.
      • Arikan I.
      • Barut A.
      • Harma M.
      • Harma I.M.
      Effect of progesterone as a tocolytic and in maintenance therapy during preterm labor.
      • Rush R.W.
      • Isaacs S.
      • McPherson K.
      • Jones L.
      • Chalmers I.
      • Grant A.
      A randomized controlled trial of cervical cerclage in women at high risk of spontaneous preterm delivery.
      • Lazar P.
      • Gueguen S.
      • Dreyfus J.
      • Renaud R.
      • Pontonnier G.
      • Papiernik E.
      Multicentred controlled trial of cervical cerclage in women at moderate risk of preterm delivery.
      • Szeverenyi M.
      • Chalmels J.
      • Grant A.
      • et al.
      [Surgical cerclage in the treatment of cervical incompetence during pregnancy (determining the legitimacy of the procedure)].
      MRC/RCOG Working Party on Cervical Cerclage
      Final report of the Medical Research Council/Royal College of Obstetricians and Gynaecologists multicentre randomised trial of cervical cerclage.
      • Ezechi O.C.
      • Kalu B.K.
      • Nwokoro C.A.
      Prophylactic cerclage for the prevention of preterm delivery.
      • Kassanos D.
      • Salamalekis E.
      • Vitoratos N.
      • Panayotopoulos N.
      • Loghis C.
      • Creatsas C.
      The value of transvaginal ultrasonography in diagnosis and management of cervical incompetence.
      • Beigi A.Z.F.
      Elective versus ultrasound-indicated cervical cerclage in women at risk for cervical incompetence.
      • Simcox R.
      • Seed P.T.
      • Bennett P.
      • Teoh T.G.
      • Poston L.
      • Shennan A.H.
      A randomized controlled trial of cervical scanning vs history to determine cerclage in women at high risk of preterm birth (CIRCLE trial).
      • Caspi E.
      • Schneider D.
      • Sadovsky G.
      • Weinraub Z.
      • Bukovsky I.
      Diameter of cervical internal os after induction of early abortion by laminaria or rigid dilatation.
      • Tsai Y.L.
      • Lin Y.H.
      • Chong K.M.
      • Huang L.W.
      • Hwang J.L.
      • Seow K.M.
      Effectiveness of double cervical cerclage in women with at least one previous pregnancy loss in the second trimester: a randomized controlled trial.
      • Broumand F.
      • Bahadori F.
      • Behrouzilak T.
      • Yekta Z.
      • Ashrafi F.
      Viable extreme preterm birth and some neonatal outcomes in double cerclage versus traditional cerclage: a randomized clinical trial.
      • Dor J.
      • Shalev J.
      • Mashiach S.
      • Blankstein J.
      • Serr D.M.
      Elective cervical suture of twin pregnancies diagnosed ultrasonically in the first trimester following induced ovulation.
      • Rust O.
      • Atlas R.
      • Wells M.
      • Rawlinson K.
      Cerclage in multiple gestation with midtrimester dilation of the internal os.
      • Forster F.D.R.
      • Schwarzlos G.
      [Therapy of cervix insufficiency: cerclage or support pessary?].
      • Blair O.
      • Fletcher H.
      • Kulkarni S.
      A randomised controlled trial of outpatient versus inpatient cervical cerclage.
      • Keeler S.M.
      • Kiefer D.
      • Rochon M.
      • Quinones J.N.
      • Novetsky A.P.
      • Rust O.
      A randomized trial of cerclage vs 17 alpha-hydroxyprogesterone caproate for treatment of short cervix.
      (Figure). The remaining 9 trials met the inclusion criteria and provided data for 662 women with a cervical length of <25 mm at mid trimester, singleton gestation, and previous spontaneous preterm birth at <37 weeks of gestation.
      • 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.
      • Berghella V.
      • Odibo A.O.
      • Tolosa J.E.
      Cerclage for prevention of preterm birth in women with a short cervix found on transvaginal ultrasound examination: a randomized trial.
      • Althuisius S.M.
      • Dekker G.A.
      • Hummel P.
      • Bekedam D.J.
      • van Geijn H.P.
      Final results of the Cervical Incompetence Prevention Randomized Cerclage Trial (CIPRACT): therapeutic cerclage with bed rest vs bed rest alone.
      • 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.
      • 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 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.
      • Rust O.A.
      • Atlas R.O.
      • Reed J.
      • van Gaalen J.
      • Balducci J.
      Revisiting the short cervix detected by transvaginal ultrasound in the second trimester: why cerclage therapy may not help.
      • To M.S.
      • Alfirevic Z.
      • Heath V.C.
      • et al.
      Cervical cerclage for prevention of preterm delivery in women with short cervix: randomised controlled trial.
      Four studies evaluated vaginal progesterone vs placebo (158 women),
      • 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.
      • 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 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 5 studies evaluated cerclage vs no cerclage (504 women).
      • Berghella V.
      • Odibo A.O.
      • Tolosa J.E.
      Cerclage for prevention of preterm birth in women with a short cervix found on transvaginal ultrasound examination: a randomized trial.
      • Althuisius S.M.
      • Dekker G.A.
      • Hummel P.
      • Bekedam D.J.
      • van Geijn H.P.
      Final results of the Cervical Incompetence Prevention Randomized Cerclage Trial (CIPRACT): therapeutic cerclage with bed rest vs bed rest alone.
      • 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.
      • Rust O.A.
      • Atlas R.O.
      • Reed J.
      • van Gaalen J.
      • Balducci J.
      Revisiting the short cervix detected by transvaginal ultrasound in the second trimester: why cerclage therapy may not help.
      • To M.S.
      • Alfirevic Z.
      • Heath V.C.
      • et al.
      Cervical cerclage for prevention of preterm delivery in women with short cervix: randomised controlled trial.
      Figure thumbnail gr1
      FIGUREStudy selection process
      Conde-Agudelo. Vaginal progesterone vs cervical cerclage. Am J Obstet Gynecol 2013.
      The main characteristics of studies that were included in this indirect comparison metaanalysis are presented in Table 1. All 4 studies that evaluated vaginal progesterone were double-blind, placebo-controlled 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.
      • 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 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.
      None of the studies that assessed cerclage were double-blind. Seven trials (2 that evaluated vaginal progesterone
      • 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.
      and all 5 that evaluated cerclage
      • Berghella V.
      • Odibo A.O.
      • Tolosa J.E.
      Cerclage for prevention of preterm birth in women with a short cervix found on transvaginal ultrasound examination: a randomized trial.
      • Althuisius S.M.
      • Dekker G.A.
      • Hummel P.
      • Bekedam D.J.
      • van Geijn H.P.
      Final results of the Cervical Incompetence Prevention Randomized Cerclage Trial (CIPRACT): therapeutic cerclage with bed rest vs bed rest alone.
      • 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.
      • Rust O.A.
      • Atlas R.O.
      • Reed J.
      • van Gaalen J.
      • Balducci J.
      Revisiting the short cervix detected by transvaginal ultrasound in the second trimester: why cerclage therapy may not help.
      • To M.S.
      • Alfirevic Z.
      • Heath V.C.
      • et al.
      Cervical cerclage for prevention of preterm delivery in women with short cervix: randomised controlled trial.
      ) examined the interventions in women with a sonographic short cervix, 1 study 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.
      and the remaining study evaluated the use of vaginal progesterone in women with a previous spontaneous preterm birth, uterine malformations, or twin gestation.
      • 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.
      Only 1 trial was designed specifically to evaluate the use of cerclage in women with a cervical length of <25 mm in the mid trimester, singleton gestation, and previous spontaneous preterm birth.
      • 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.
      The primary outcome was preterm birth at <37 weeks of gestation 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.
      <35 weeks of gestation for 2 trials,
      • Berghella V.
      • Odibo A.O.
      • Tolosa J.E.
      Cerclage for prevention of preterm birth in women with a short cervix found on transvaginal ultrasound examination: a randomized trial.
      • 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.
      <34 weeks of gestation for 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.
      • Althuisius S.M.
      • Dekker G.A.
      • Hummel P.
      • Bekedam D.J.
      • van Geijn H.P.
      Final results of the Cervical Incompetence Prevention Randomized Cerclage Trial (CIPRACT): therapeutic cerclage with bed rest vs bed rest alone.
      <33 weeks of gestation for 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.
      • To M.S.
      • Alfirevic Z.
      • Heath V.C.
      • et al.
      Cervical cerclage for prevention of preterm delivery in women with short cervix: randomised 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.
      and gestational age at delivery for the remaining study.
      • Rust O.A.
      • Atlas R.O.
      • Reed J.
      • van Gaalen J.
      • Balducci J.
      Revisiting the short cervix detected by transvaginal ultrasound in the second trimester: why cerclage therapy may not help.
      TABLE 1Characteristics of studies included in this systematic review
      StudyParticipating countriesPrimary target populationInclusion/exclusion criteriaWomen with cervical length <25 mm, singleton gestation, and previous preterm birth, nGestational age at screening, wkInterventionCointerventionsPrimary outcome
      Intervention groupControl group
      Vaginal progesterone compared with placebo
      Fonseca et al, 2007
      • 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.
      United Kingdom, Chile, Brazil, GreeceWomen with a short cervixInclusion: women with a singleton or twin pregnancy and a sonographic cervical length ≤15 mm152320-25Vaginal progesterone capsule (200 mg/d) or placebo from 24-33 6/7 weeks of gestationNoSpontaneous preterm birth <34 wk
      Exclusion: major fetal abnormalities, painful regular uterine contractions, a history of ruptured membranes, or cervical cerclage
      O'Brien et al, 2007
      • 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.
      United States, South Africa, India, Czech Republic, Chile, El SalvadorWomen with a history of spontaneous preterm birthInclusion: women with a singleton pregnancy, 18-45 years old, and a history of spontaneous singleton preterm birth at 20-35 wk of gestation in the immediately preceding pregnancy91316-22Vaginal progesterone gel (90 mg/d) or placebo from 18-22 to 37 0/7 weeks of gestation, rupture of membranes or preterm delivery, whichever occurred firstNoPreterm birth ≤32 wk
      Exclusion: planned cervical cerclage, history of adverse reaction to progesterone, treatment with progesterone within 4 wk before enrollment, treatment for a seizure disorder, a psychiatric illness or chronic hypertension at the time of enrolment, history of acute or chronic congestive heart failure, renal failure, uncontrolled diabetes mellitus, active liver disorder, HIV infection with a CD4 count of <350 cells/mm3 that require 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
      Cetingoz et al, 2011
      • 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.
      TurkeyWomen at high risk of preterm birthInclusion: women with a least 1 previous spontaneous preterm birth, uterine malformation or twin pregnancy3320-24Vaginal progesterone suppository (100 mg/d) or placebo from 24-34 wk of gestationNoPreterm birth <37 wk
      Exclusion: in-place or planned cervical cerclage or serious fetal anomalies
      Hassan et al, 2011
      • 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.
      United States, Republic of Belarus, Chile, Czech Republic, India, Israel, Italy, Russia, South Africa, UkraineWomen with a short cervixInclusion: women with a singleton pregnancy, transvaginal sonographic cervical length of 10-20 mm, and no signs or symptoms of preterm labor484419-23Vaginal progesterone gel (90 mg/d) or placebo from 20-23 to 36 6/7 weeks of gestation, rupture of membranes or preterm delivery, whichever occurred firstEmergency cervical cerclage (4 in vaginal progesterone group [8.3%] and 1 [2.3%] in placebo group)Preterm birth <33 wk
      Exclusion: planned cerclage, acute cervical dilation, allergic reaction to progesterone, current or recent progestogen treatment within the previous 4 wk, chronic medical conditions that would interfere with study participation or evaluation of the treatment, major fetal anomaly or known chromosomal abnormality, uterine anatomic malformation, vaginal bleeding, or known or suspected clinical chorioamnionitis
      Rust et al, 2001
      • Rust O.A.
      • Atlas R.O.
      • Reed J.
      • van Gaalen J.
      • Balducci J.
      Revisiting the short cervix detected by transvaginal ultrasound in the second trimester: why cerclage therapy may not help.
      United StatesWomen with a short cervixInclusion: women with a singleton or multiple gestation and transvaginal sonographic dilation of the internal os with either membrane prolapse into the endocervical canal at least 25% of the total cervical length but not beyond the external os or a cervical length <25 mm534916-24McDonald procedure with a single stitch of permanent monofilament or no cerclageClindamycin and indomethacin that were discontinued at approximately 24 hr after random assignment (both groups); rescue cerclage (both groups)Gestational age at delivery and neonatal morbidity
      Exclusion: membrane prolapse beyond the external os, any fetal lethal congenital or chromosomal anomaly, abruption placenta, unexplained vaginal bleeding, chorioamnionitis, persistent uterine activity with cervical change, or any other contraindication to a cerclage procedure
      Althuisius et al, 2001
      • Althuisius S.M.
      • Dekker G.A.
      • Hummel P.
      • Bekedam D.J.
      • van Geijn H.P.
      Final results of the Cervical Incompetence Prevention Randomized Cerclage Trial (CIPRACT): therapeutic cerclage with bed rest vs bed rest alone.
      The NetherlandsWomen with a short cervixInclusion: women with a singleton gestation, risk factors and/or symptoms of cervical incompetence, and a cervical length <25 mm141214-23McDonald procedure with braided polyester thread or no cerclageAmoxicillin/clavulanic acid for 7 days and bed rest (both groups); two 100-mg suppositories of indomethacin (cerclage group); rescue cerclage (no cerclage group)Preterm birth <34 wk and neonatal morbidity and mortality
      Exclusion: fetal congenital/chromosomal anomalies, preterm rupture of membranes, membranes bulging into the vagina, or intrauterine infection
      To et al, 2004
      • To M.S.
      • Alfirevic Z.
      • Heath V.C.
      • et al.
      Cervical cerclage for prevention of preterm delivery in women with short cervix: randomised controlled trial.
      United Kingdom, Brazil, South Africa, Slovenia, Greece, ChileWomen with a short cervixInclusion: women with a singleton gestation and cervical length ≤15 mm212322-24Shirodkar suture with Mersilene tape or no cerclageProphylactic corticosteroids for fetal lung maturation (both groups); single dose of erythromycin (cerclage group)Preterm birth <33 wk
      Exclusion: major fetal abnormalities, painful regular uterine contractions, history of ruptured membranes and cervical cerclage in situ, and dilated cervix during transvaginal sonography
      Berghella et al, 2004
      • Berghella V.
      • Odibo A.O.
      • Tolosa J.E.
      Cerclage for prevention of preterm birth in women with a short cervix found on transvaginal ultrasound examination: a randomized trial.
      United StatesWomen with a short cervixInclusion: women with a singleton or twin gestation and cervical length <25 mm or significant funneling (>25%)141714-23McDonald procedure with Mersilene tape or no cerclageBed rest (both groups)Preterm birth <35 wk
      Exclusion: history indicated prophylactic cerclage, last pregnancy delivered at term, major fetal anomaly, triplets or higher order pregnancy, previous inclusion in another trial, current drug abuse, or regular contractions leading to preterm labor after identification of abnormal cervix by ultrasonography
      Owen et al, 2009
      • Owen J.
      • Yost N.
      • Berghella V.
      • et al.
      Mid-trimester endovaginal sonography in women at high risk for spontaneous preterm birth.
      United StatesWomen with a short cervix, singleton gestation, and previous spontaneous preterm birthInclusion: women with a singleton gestation, at least 1 previous spontaneous preterm birth between 17-33 weeks of gestation, and mid trimester cervical length <25 mm14815316-22McDonald procedure with nonabsorbable suture (braided tape) or no cerclage17α-hydroxyprogesterone caproate (47 [31.8%] in cerclage group and 52 [34.0%] in no cerclage group); vaginal progesterone (1 [0.7%] in no cerclage group); rescue cerclage (no cerclage group)Preterm birth <35 wk
      Exclusion: fetal anomaly, planned history indicated cerclage for a clinical diagnosis of cervical insufficiency, and clinically significant maternal/fetal complications (eg, fetal red cell isoimmunization, treated chronic hypertension, insulin-dependent diabetes mellitus) and cervical insufficiency that indicated cerclage in a previous pregnancy.
      Conde-Agudelo. Vaginal progesterone vs cervical cerclage. Am J Obstet Gynecol 2013.
      Gestational age at cervical length screening varied between 14 and 25 weeks of gestation, although most studies performed screening at <25 weeks of gestation.
      • 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.
      • Berghella V.
      • Odibo A.O.
      • Tolosa J.E.
      Cerclage for prevention of preterm birth in women with a short cervix found on transvaginal ultrasound examination: a randomized trial.
      • Althuisius S.M.
      • Dekker G.A.
      • Hummel P.
      • Bekedam D.J.
      • van Geijn H.P.
      Final results of the Cervical Incompetence Prevention Randomized Cerclage Trial (CIPRACT): therapeutic cerclage with bed rest vs bed rest alone.
      • 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.
      • 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 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.
      • Rust O.A.
      • Atlas R.O.
      • Reed J.
      • van Gaalen J.
      • Balducci J.
      Revisiting the short cervix detected by transvaginal ultrasound in the second trimester: why cerclage therapy may not help.
      • To M.S.
      • Alfirevic Z.
      • Heath V.C.
      • et al.
      Cervical cerclage for prevention of preterm delivery in women with short cervix: randomised controlled trial.
      Of the 4 trials that evaluated vaginal progesterone, 2 used 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.
      1 used capsules (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.
      and the other used 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 and 23 weeks of gestation in 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.
      and between 18 and 22 weeks of gestation in the remaining study.
      • 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.
      Two studies reported that participating women received study medication from enrollment until 34 weeks of gestation,
      • 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.
      and 2 studies reported that medication was given from enrollment until 36 6/7 weeks of gestation.
      • 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.
      In the study 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.
      5 women received an emergency cerclage. Among the 5 trials that evaluated cerclage, 4 used the McDonald procedure,
      • Berghella V.
      • Odibo A.O.
      • Tolosa J.E.
      Cerclage for prevention of preterm birth in women with a short cervix found on transvaginal ultrasound examination: a randomized trial.
      • Althuisius S.M.
      • Dekker G.A.
      • Hummel P.
      • Bekedam D.J.
      • van Geijn H.P.
      Final results of the Cervical Incompetence Prevention Randomized Cerclage Trial (CIPRACT): therapeutic cerclage with bed rest vs bed rest alone.
      • 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.
      • Rust O.A.
      • Atlas R.O.
      • Reed J.
      • van Gaalen J.
      • Balducci J.
      Revisiting the short cervix detected by transvaginal ultrasound in the second trimester: why cerclage therapy may not help.