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The role of cervical cerclage in obstetric practice: Can the patient who could benefit from this procedure be identified?

  • Roberto Romero
    Affiliations
    Perinatology Research Branch, National Institute of Child Health and Human Development, National Institute of Health, Department of Health and Human Services, Bethesda, MD and Detroit, MI
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  • Jimmy Espinoza
    Affiliations
    Perinatology Research Branch, National Institute of Child Health and Human Development, National Institute of Health, Department of Health and Human Services, Bethesda, MD and Detroit, MI

    Wayne State University, Department of Obstetrics and Gynecology, Detroit, MI
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  • Offer Erez
    Affiliations
    Perinatology Research Branch, National Institute of Child Health and Human Development, National Institute of Health, Department of Health and Human Services, Bethesda, MD and Detroit, MI

    Wayne State University, Department of Obstetrics and Gynecology, Detroit, MI
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  • Sonia Hassan
    Affiliations
    Wayne State University, Department of Obstetrics and Gynecology, Detroit, MI
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      This editorial critically examines the definition of “cervical insufficiency.” The definition, the clinical ascertainment, efforts to develop an objective method of diagnosis, as well as the nature of cervical disease leading to spontaneous mid-trimester spontaneous abortion and preterm delivery are reviewed. The value and limitations of cervical sonography as a risk assessment tool for spontaneous preterm delivery are appraised. The main focus is on the role of cervical cerclage to prevent an adverse pregnancy outcome. The value of assessing the presence or absence of endocervical inflammation in the outcome of cerclage placement is discussed.

      Key words

      When and how cervical cerclage was introduced into obstetric practice

      Cervical cerclage was introduced in 1955 by V.N. Shirodkar, Professor of Midwifery and Gynecology at the Grant Medical College in Bombay, India.
      • Shirodkar V.N.
      • et al.
      A new method of operative treatment for habitual abortions in the second trimester of pregnancy.
      The procedure was developed in response to his observation that “some women abort repeatedly between the fourth and seventh months and no amount of rest and treatment with hormones seemed to help them in retaining the product of conception.”
      • Shirodkar V.N.
      • et al.
      A new method of operative treatment for habitual abortions in the second trimester of pregnancy.
      Shirodkar referred to a group of 30 women who had had at least 4 abortions (some between 9 and 11). He stated that in his opinion, “95% of cases were due to a weak cervical sphincter and the other few to an underdeveloped or malformed uterus, etc.”
      • Shirodkar V.N.
      • et al.
      A new method of operative treatment for habitual abortions in the second trimester of pregnancy.
      Shirodkar emphasized that his work was confined to women in whom he could prove the existence of weakness of the internal os by “repeated internal examinations.”
      • Shirodkar V.N.
      • et al.
      A new method of operative treatment for habitual abortions in the second trimester of pregnancy.
      Ian McDonald, from the Royal Melbourne Hospital, reported in 1957 his experience with 70 patients who had a suture of the cervix for inevitable miscarriage.
      • McDonald I.A.
      Suture of the cervix for inevitable miscarriage.
      Since the publication of these reports, the ability of cerclage to prevent mid-trimester pregnancy loss has become part of obstetric dogma. The history of cerclage is relevant because 50 years after its introduction it is being used for indications different from those originally intended, and there is conflicting evidence about its efficacy for the new indications (eg, prevention of preterm birth in women with a sonographic short cervix).
      • Quinn M.J.
      Vaginal ultrasound and cervical cerclage: a prospective study.
      • Guzman E.R.
      • Forster J.K.
      • Vintzileos A.M.
      • Ananth C.V.
      • Walters C.
      • Gipson K.
      Pregnancy outcomes in women treated with elective versus ultrasound-indicated cervical cerclage.
      • Heath V.C.
      • Souka A.P.
      • Erasmus I.
      • Gibb D.M.
      • Nicolaides K.H.
      Cervical length at 23 weeks of gestation: the value of Shirodkar suture for the short cervix.
      • Berghella V.
      • Daly S.F.
      • Tolosa J.E.
      • DiVito M.M.
      • Chalmers R.
      • Garg N.
      • et al.
      Prediction of preterm delivery with transvaginal ultrasonography of the cervix in patients with high-risk pregnancies: does cerclage prevent prematurity?.
      • Althuisius S.M.
      • Dekker G.A.
      • van Geijn H.P.
      • Bekedam D.J.
      • Hummel P.
      Cervical incompetence prevention randomized cerclage trial (CIPRACT): study design and preliminary results.
      • Hibbard J.U.
      • Snow J.
      • Moawad A.H.
      Short cervical length by ultrasound and cerclage.
      • Rust O.A.
      • Atlas R.O.
      • Jones K.J.
      • Benham B.N.
      • Balducci J.
      A randomized trial of cerclage versus no cerclage among patients with ultrasonographically detected second-trimester preterm dilatation of the internal os.
      • Hassan S.S.
      • Romero R.
      • Maymon E.
      • Berry S.M.
      • Blackwell S.C.
      • Treadwell M.C.
      • et al.
      Does cervical cerclage prevent preterm delivery in patients with a short cervix?.
      • 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.
      • Althuisius S.
      • Dekker G.
      • Hummel P.
      • Bekedam D.
      • Kuik D.
      • van Geijn H.
      Cervical Incompetence Prevention Randomized Cerclage Trial (CIPRACT): effect of therapeutic cerclage with bed rest vs. bed rest only on cervical length.
      • Berghella V.
      • Haas S.
      • Chervoneva I.
      • Hyslop T.
      Patients with prior second-trimester loss: prophylactic cerclage or serial transvaginal sonograms?.
      • Blair O.
      • Fletcher H.
      • Kulkarni S.
      A randomised controlled trial of outpatient versus inpatient cervical cerclage.
      • Groom K.M.
      • Shennan A.H.
      • Bennett P.R.
      Ultrasound-indicated cervical cerclage: outcome depends on preoperative cervical length and presence of visible membranes at time of cerclage.
      • Harger J.H.
      Cerclage and “cervical insufficiency”: an evidence-based analysis.
      • To M.S.
      • Palaniappan V.
      • Skentou C.
      • Gibb D.
      • Nicolaides K.H.
      Elective cerclage vs. ultrasound-indicated cerclage in high-risk pregnancies.
      • Belej-Rak T.
      • Okun N.
      • Windrim R.
      • Ross S.
      • Hannah M.E.
      Effectiveness of cervical cerclage for a sonographically shortened cervix: a systematic review and meta-analysis.
      • Drakeley A.J.
      • Roberts D.
      • Alfirevic Z.
      Cervical cerclage for prevention of preterm delivery: meta-analysis of randomized trials.
      • Drakeley A.J.
      • Roberts D.
      • Alfirevic Z.
      Cervical stitch (cerclage) for preventing pregnancy loss in women.
      • Odibo A.O.
      • Elkousy M.
      • Ural S.H.
      • Macones G.A.
      Prevention of preterm birth by cervical cerclage compared with expectant management: a systematic review.
      • Owen J.
      • Iams J.D.
      • Hauth J.C.
      Vaginal sonography and cervical incompetence.
      • 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.
      • Groom K.M.
      • Bennett P.R.
      • Golara M.
      • Thalon A.
      • Shennan A.H.
      Elective cervical cerclage versus serial ultrasound surveillance of cervical length in a population at high risk for preterm delivery.
      • Higgins S.P.
      • Kornman L.H.
      • Bell R.J.
      • Brennecke S.P.
      Cervical surveillance as an alternative to elective cervical cerclage for pregnancy management of suspected cervical incompetence.
      • Pramod R.
      • Okun N.
      • McKay D.
      • Kiehn L.
      • Hewson S.
      • Ross S.
      • et al.
      Cerclage for the short cervix demonstrated by transvaginal ultrasound: current practice and opinion.
      • To M.S.
      • Alfirevic Z.
      • Heath V.C.
      • Cicero S.
      • Cacho A.M.
      • Williamson P.R.
      • et al.
      Cervical cerclage for prevention of preterm delivery in women with short cervix: randomised controlled trial.
      • Williams M.
      • Iams J.D.
      Cervical length measurement and cervical cerclage to prevent preterm birth.
      • Althuisius S.M.
      The short and funneling cervix: when to use cerclage?.
      • Baxter J.K.
      • Airoldi J.
      • Berghella V.
      Short cervical length after history-indicated cerclage: is a reinforcing cerclage beneficial?.
      • 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.

      The initial recognition of cervical incompetence as a mechanism for pregnancy loss

      Cole, Culpepper, and Rowland are credited with the first description of cervical incompetence.
      • Anonymous
      In the “Practice of Physick,” published in 1658, they wrote, “the second fault in women which hindered conception is when the seed is not retained or the orifice of the womb is so slack that it cannot rightly contract itself to keep in the seed; which is chiefly caused by abortion or hard labor and childbirth, whereby the fibers of the womb are broken in pieces one from another and the inner orifice of the womb overmuch slackened.”
      • Anonymous
      The term “cervical incompetence” was mentioned by Gream in an article published in the Lancet in 1865.
      • Grant A.
      Cervical cerclage to prolong pregnancy.
      It took nearly 300 years from the first description for a surgical treatment to be developed. The biology of cervical ripening, a term that describes the changes in cervical dilatation, effacement, and consistency, which generally precede the onset of spontaneous labor, is complex and involves degradation of extracellular matrix, as well as inflammation.
      • Liggins G.C.
      Ripening of the cervix.
      • Naftolin F.
      • Stubblefield P.G.
      Dilatation of the uterine cervix: connective tissue biology and clinical management.
      • Leppert P.C.
      • Yu S.Y.
      • Keller S.
      • Cerreta J.
      • Mandl I.
      Decreased elastic fibers and desmosine content in incompetent cervix.
      • Leppert P.C.
      • Woessner J.F.
      The extracellular matrix of the uterus, cervix and fetal membranes: Synthesis, degradation and hormonal regulation.
      • Osmers R.
      • Rath W.
      • Adelmann-Grill B.C.
      • Fittkow C.
      • Krieg T.
      • Severenyi M.
      • et al.
      Collagenase activity in the human cervix during parturition: the role of polymorphonuclear leukocytes.
      • Romero R.
      • Mazor M.
      • Gomez R.
      • Gonzalez R.
      • Galasso M.
      • Cotton D.
      Cervix, incompetence and premature labor.
      • 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 tumour necrosis factor alpha in guinea-pigs.
      • Leppert P.C.
      Anatomy and physiology of cervical ripening.
      • Sennstrom M.K.
      • Brauner A.
      • Lu Y.
      • Granstrom L.M.
      • Malmstrom A.L.
      • Ekman G.E.
      Interleukin-8 is a mediator of the final cervical ripening in humans.
      • Chwalisz K.
      • Garfield R.E.
      Role of nitric oxide in the uterus and cervix: implications for the management of labor.
      • Leppert P.C.
      Proliferation and apoptosis of fibroblasts and smooth muscle cells in rat uterine cervix throughout gestation and the effect of the antiprogesterone onapristone.
      • Uldbjerg N.
      • Forman A.
      Biomechanical and biochemical changes of the uterus and cervix during pregnancy.
      • Mackler A.M.
      • Lezza G.
      • Akin M.R.
      • McMillian P.
      • Yellon S.M.
      Macrophage trafficking in the uterus and cervix precedes parturition in the mouse.
      • Winkler M.
      • Rath W.
      Changes in the cervical extracellular matrix during pregnancy and parturition.
      • Word R.A.
      • Landrum C.P.
      • Timmons B.C.
      • Young S.G.
      • Mahendroo M.S.
      Transgene insertion on mouse chromosome 6 impairs function of the uterine cervix and causes failure of parturition.

      Word A, Li X. Transcriptional regulation of cervical ripening. Scientific Program and Abstracts 1st International Summit in Preterm Birth, abstract 197, November 10-12, 2005.

      These changes are aimed at increasing cervical compliance so that the conceptus can pass through the birth canal.

      Cervical incompetence/“cervical insufficiency”

      Authors have repeated, often uncritically, definitions of cervical incompetence proposed by others. Such definitions need to be examined, particularly in light of recent observations and results of clinical trials. For example, the expectation that pregnancy loss and/or preterm delivery can be prevented with a “prophylactic cerclage” is now open to question based upon the results of randomized controlled trials
      • Althuisius S.M.
      • Dekker G.A.
      • van Geijn H.P.
      • Bekedam D.J.
      • Hummel P.
      Cervical incompetence prevention randomized cerclage trial (CIPRACT): study design and preliminary results.
      • 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.
      • 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.
      • Final report of the Medical Research Council/Royal College of Obstetricians and Gynaecologists multicentre randomised trial of cervical cerclage
      MRC/RCOG Working Party on Cervical Cerclage.
      and some systematic reviews.
      • Belej-Rak T.
      • Okun N.
      • Windrim R.
      • Ross S.
      • Hannah M.E.
      Effectiveness of cervical cerclage for a sonographically shortened cervix: a systematic review and meta-analysis.
      • Drakeley A.J.
      • Roberts D.
      • Alfirevic Z.
      Cervical cerclage for prevention of preterm delivery: meta-analysis of randomized trials.
      • Drakeley A.J.
      • Roberts D.
      • Alfirevic Z.
      Cervical stitch (cerclage) for preventing pregnancy loss in women.
      • Odibo A.O.
      • Elkousy M.
      • Ural S.H.
      • Macones G.A.
      Prevention of preterm birth by cervical cerclage compared with expectant management: a systematic review.
      Moreover, the paper published in this issue of the Journal by Sakai et al raises the issue of whether cerclage can worsen pregnancy outcome in patients with endocervical inflammation.
      • Sakai M.
      • Shiozaki A.
      • Tabata M.
      • Sasaki Y.
      • Yoneda S.
      • Arai T.
      • et al.
      Evaluation of effectiveness of prophylactic cerclage of a short cervix according to interleukin-8 in cervical mucus.
      The lack of an objective diagnosis,
      • American College of Obstetricians and Gynecologists
      ACOG Practice Bulletin. Cervical insufficiency.
      Abortions.
      • Althuisius S.M.
      • Dekker G.A.
      A five century evolution of cervical incompetence as a clinical entity.
      and the lack of unequivocal efficacy of cerclage, has created confusion about the standard of care in obstetrics and increased the number of medicolegal disputes. Moreover, the introduction of cervical sonography has further compounded the complexity of diagnosis and treatment of “cervical insufficiency” during pregnancy.
      Although the term “cervical incompetence” has been used for many years,
      • Grant A.
      Cervical cerclage to prolong pregnancy.
      we and others refer to this condition as “cervical insufficiency” to avoid the negative connotation that the term “incompetence” implies to patients.

      Problems with the definition of “cervical insufficiency”

      Harger defined “cervical insufficiency” as “the inability of the uterine cervix to retain a pregnancy in the absence of contractions or labor.”
      • American College of Obstetricians and Gynecologists
      ACOG Practice Bulletin. Cervical insufficiency.
      Yet, it is unclear how a clinician can objectively use this definition. For example, 1) How can an obstetrician identify “the inability of the cervix to retain the pregnancy?”; 2) What is the scientific evidence that the typical description of a patient with “cervical insufficiency” truly identifies a primary cervical disorder?; 3) What is the proportion of patients who meet the clinical definition of “cervical insufficiency” that will have an adverse pregnancy outcome (spontaneous mid-trimester abortion or preterm delivery) in future pregnancies without intervention?; and 4) What is the evidence that “prophylactic” cervical cerclage will change the natural history of “cervical insufficiency” and improve pregnancy outcome? The latter question is important because some authors have stated that “unless effectively treated, the condition tends to repeat in each pregnancy.”
      Abortions.

      Description of the typical patient with “cervical insufficiency”

      The clinical diagnosis of “cervical insufficiency” is traditionally applied to patients with a history of recurrent mid-trimester spontaneous abortions and/or early preterm deliveries in which “the basic process is thought to be the failure of the cervix to remain closed during pregnancy.”
      • Grant A.
      Cervical cerclage to prolong pregnancy.
      The assumption is that cervical dilatation and effacement have occurred in the absence of increased uterine contractility.
      • Grant A.
      Cervical cerclage to prolong pregnancy.
      The presenting symptom is reported to be a feeling of vaginal pressure caused by the protruding membranes and eventual membrane rupture in the mid-trimester of pregnancy. Typically, there is no vaginal bleeding, the fetuses are born alive, and labor is short.
      • McDonald I.A.
      Suture of the cervix for inevitable miscarriage.
      • Grant A.
      Cervical cerclage to prolong pregnancy.
      • Bengtsson L.P.
      Cervical insufficiency.
      However, we find difficulty in establishing a causal relationship between the clinical presentation outlined above and primary cervical disease (ie, “insufficiency”).

      The lack of an objective test

      Although the existence of “cervical insufficiency” is widely accepted among obstetricians, there is no objective diagnostic test for this condition. Several methods have been proposed for the diagnosis of “cervical insufficiency” in the nonpregnant state, including the progressive passage of Hegar number 6 to 8 mm or Pratt dilators through the internal cervical os,
      • Kiwi R.
      • Neuman M.R.
      • Merkatz I.R.
      • Selim M.A.
      • Lysikiewicz A.
      Determination of the elastic properties of the cervix.
      • Page E.W.
      Incompetent internal os of the cervix causing late abortion and premature labor; technic for surgical repair.
      • Toaff R.
      • Toaff M.E.
      • Ballas S.
      • Ophir A.
      Cervical incompetence: diagnostic and therapeutic aspects.
      the use of balloon elastance test,
      • Kiwi R.
      • Neuman M.R.
      • Merkatz I.R.
      • Selim M.A.
      • Lysikiewicz A.
      Determination of the elastic properties of the cervix.
      or the ability of the cervix to hold an inflated Foley catheter during hysterosalpingography.
      • Zlatnik F.J.
      • Burmeister L.F.
      • Feddersen D.A.
      • Brown R.C.
      Radiologic appearance of the upper cervical canal in women with a history of premature delivery. II. Relationship to clinical presentation and to tests of cervical compliance.
      • Bergman P.
      • Svennerud S.
      Traction test for demonstrating incompetence of the internal os of the cervix.
      However, there is a paucity of scientific evidence to support the value of these tests in predicting subsequent pregnancy outcome.
      • American College of Obstetricians and Gynecologists
      ACOG Practice Bulletin. Cervical insufficiency.
      This area of clinical investigation has been overlooked.

      Sonographic cervical length

      Digital examination of the cervix is the method used to determine cervical status (effacement, dilatation, position, and consistency). Cervical sonography has become an objective and reliable method to assess cervical length, which approximates cervical effacement. The shorter the sonographic cervical length in the mid-trimester, the higher the risk of spontaneous preterm labor/delivery.
      • 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.
      • Mercer B.M.
      • Moawad A.
      • Das A.
      • et al.
      The length of the cervix and the risk of spontaneous premature delivery. National Institute of Child Health and Human Development Maternal Fetal Medicine Unit Network.
      • 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.
      • Hassan S.S.
      • Romero R.
      • Berry S.M.
      • Dang K.
      • Blackwell S.C.
      • Treadwell M.C.
      • et al.
      Patients with an ultrasonographic cervical length ≤15 mm have nearly a 50% risk of early spontaneous preterm delivery.
      However, there is no agreement on what is a sonographic short cervix. For example, Iams et al
      • Iams J.D.
      • Goldenberg R.L.
      • Meis P.J.
      • Mercer B.M.
      • Moawad A.
      • Das A.
      • et al.
      The length of the cervix and the risk of spontaneous premature delivery. National Institute of Child Health and Human Development Maternal Fetal Medicine Unit Network.
      proposed that a cervix of 26 mm or shorter at 24 weeks of gestation increases the risk for spontaneous preterm delivery (relative risk [RR] 6.19, 95% CI 3.84-9.97). The prevalence of spontaneous preterm delivery (defined as less than 35 weeks) in this study was 4.3% and the positive predictive value was 17.8% for a cervical length ≤25 mm at 24 weeks of gestation.
      • Iams J.D.
      • Goldenberg R.L.
      • Meis P.J.
      • Mercer B.M.
      • Moawad A.
      • Das A.
      • et al.
      The length of the cervix and the risk of spontaneous premature delivery. National Institute of Child Health and Human Development Maternal Fetal Medicine Unit Network.
      Thus, most women with a short cervix (defined as 25 mm or less) and no previous history of preterm delivery will not deliver a preterm neonate. Other investigators have proposed a cut-off of 15 mm because a cervical length of 15 mm or less is associated with nearly a 50% risk of spontaneous preterm delivery at 32 weeks of gestation or less when neonatal morbidity is substantial.
      • 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.
      • Hassan S.S.
      • Romero R.
      • Berry S.M.
      • Dang K.
      • Blackwell S.C.
      • Treadwell M.C.
      • et al.
      Patients with an ultrasonographic cervical length ≤15 mm have nearly a 50% risk of early spontaneous preterm delivery.
      It is important to stress that sonographic cervical length is not a screening test for spontaneous preterm delivery because only a small fraction of all patients who will have a spontaneous preterm birth have a short cervix in the mid-trimester. Previous studies conducted at our institution indicate that only 8% of all patients who will have a preterm delivery at less than 32 weeks of gestation have a cervical length of 15 mm or less in the mid-trimester.
      • Hassan S.S.
      • Romero R.
      • Berry S.M.
      • Dang K.
      • Blackwell S.C.
      • Treadwell M.C.
      • et al.
      Patients with an ultrasonographic cervical length ≤15 mm have nearly a 50% risk of early spontaneous preterm delivery.
      Therefore, sonographic cervical length is a method for risk assessment for spontaneous preterm delivery and not a screening test. Cervical length can modify the a priori risk for preterm delivery.
      • Owen J.
      • Yost N.
      • Berghella V.
      • Thom E.
      • Swain M.
      • Dildy G.A.
      • et al.
      Midtrimester endovaginal sonography in women at high risk for spontaneous preterm birth.
      For example, a woman with a history of preterm delivery or one with a twin or triplet gestation will have a higher risk for preterm delivery than a patient without such history and the same cervical length.
      • Goldenberg R.L.
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      • Thurnau G.
      • Bottoms S.
      • et al.
      The preterm prediction study: risk factors in twin gestations. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network.
      • Souka A.P.
      • Heath V.
      • Flint S.
      • Sevastopoulou I.
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      Cervical length at 23 weeks in twins in predicting spontaneous preterm delivery.
      • Guzman E.R.
      • Walters C.
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      • Meirowitz N.B.
      • Gipson K.
      • Nigam J.
      • et al.
      Use of cervical ultrasonography in prediction of spontaneous preterm birth in triplet gestations.
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      • Kinzler W.L.
      • Waldron R.
      • Nigam J.
      • et al.
      Use of cervical ultrasonography in prediction of spontaneous preterm birth in twin gestations.
      • To M.S.
      • Skentou C.
      • Cicero S.
      • Liao A.W.
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      Cervical length at 23 weeks in triplets: prediction of spontaneous preterm delivery.
      • Yang J.H.
      • Kuhlman K.
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      • Berghella V.
      Prediction of preterm birth by second trimester cervical sonography in twin pregnancies.
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      • Herman A.
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      Transvaginal sonographic assessment of cervical length changes during triplet gestation.
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      • Liao A.W.
      • Nicolaides K.H.
      Prediction of preterm delivery in twins by cervical assessment at 23 weeks.
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      • et al.
      Cervical length and funneling at 22 and 27 weeks to predict spontaneous birth before 32 weeks in twin pregnancies: a French prospective multicenter study.

      Cervical sufficiency/insufficiency as a continuum

      The hypothesis that cervical competence or sufficiency represents a spectrum was proposed by Parikh and Mehta, who used digital examination of the cervix to assess sufficiency. The authors, however, concluded that degrees of cervical competence did not exist.
      • Parikh M.N.
      • Mehta A.C.
      Internal cervical os during the second half of pregnancy.
      Iams et al, using sonographic examination of the cervix, suggested that cervical sufficiency/insufficiency is a continuum.
      • Iams J.D.
      • Johnson F.F.
      • Sonek J.
      • Sachs L.
      • Gebauer C.
      • Samuels P.
      Cervical competence as a continuum: a study of ultrasonographic cervical length and obstetric performance.
      The authors reported a strong relationship between cervical length in pregnancy and previous obstetric history. This relationship was nearly linear, and patients with a typical history of an incompetent cervix did not constitute a separate group from those who delivered preterm.
      • Iams J.D.
      • Johnson F.F.
      • Sonek J.
      • Sachs L.
      • Gebauer C.
      • Samuels P.
      Cervical competence as a continuum: a study of ultrasonographic cervical length and obstetric performance.
      Similar results have been reported by Guzman et al.
      • Guzman E.R.
      • Mellon R.
      • Vintzileos A.M.
      • Ananth C.V.
      • Walters C.
      • Gipson K.
      Relationship between endocervical canal length between 15-24 weeks gestation and obstetric history.
      Collectively, these studies suggest that there is a relationship between a history of preterm delivery and the cervical length in a subsequent pregnancy. Inasmuch as patients with a short cervix are at increased risk for a mid-trimester pregnancy loss (clinically referred to as “cervical insufficiency”) or spontaneous preterm delivery with intact or rupture of membranes,
      • Berghella V.
      • Daly S.F.
      • Tolosa J.E.
      • DiVito M.M.
      • Chalmers R.
      • Garg N.
      • et al.
      Prediction of preterm delivery with transvaginal ultrasonography of the cervix in patients with high-risk pregnancies: does cerclage prevent prematurity?.
      • Hassan S.S.
      • Romero R.
      • Maymon E.
      • Berry S.M.
      • Blackwell S.C.
      • Treadwell M.C.
      • et al.
      Does cervical cerclage prevent preterm delivery in patients with a short cervix?.
      • 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.
      • Berghella V.
      • Haas S.
      • Chervoneva I.
      • Hyslop T.
      Patients with prior second-trimester loss: prophylactic cerclage or serial transvaginal sonograms?.
      • Williams M.
      • Iams J.D.
      Cervical length measurement and cervical cerclage to prevent preterm birth.
      • Althuisius S.M.
      The short and funneling cervix: when to use cerclage?.
      • 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.
      • Mercer B.M.
      • Moawad A.
      • Das A.
      • et al.
      The length of the cervix and the risk of spontaneous premature delivery. National Institute of Child Health and Human Development Maternal Fetal Medicine Unit Network.
      • 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.
      • Iams J.D.
      • Johnson F.F.
      • Sonek J.
      • Sachs L.
      • Gebauer C.
      • Samuels P.
      Cervical competence as a continuum: a study of ultrasonographic cervical length and obstetric performance.
      • Guzman E.R.
      • Mellon R.
      • Vintzileos A.M.
      • Ananth C.V.
      • Walters C.
      • Gipson K.
      Relationship between endocervical canal length between 15-24 weeks gestation and obstetric history.
      • Kushnir O.
      • Vigil D.A.
      • Izquierdo L.
      • Schiff M.
      • Curet L.B.
      Vaginal ultrasonographic assessment of cervical length changes during normal pregnancy.
      • Andersen H.F.
      Transvaginal and transabdominal ultrasonography of the uterine cervix during pregnancy.
      • Okitsu O.
      • Mimura T.
      • Nakayama T.
      • Aono T.
      Early prediction of preterm delivery by transvaginal ultrasonography.
      • Guzman E.R.
      • Rosenberg J.C.
      • Houlihan C.
      • Ivan J.
      • Waldron R.
      • Knuppel R.
      A new method using vaginal ultrasound and transfundal pressure to evaluate the asymptomatic incompetent cervix.
      • Guzman E.R.
      • Vintzileos A.M.
      • McLean D.A.
      • Martins M.E.
      • Benito C.W.
      • Hanley M.L.
      The natural history of a positive response to transfundal pressure in women at risk for cervical incompetence.
      • Guzman E.R.
      • Pisatowski D.M.
      • Vintzileos A.M.
      • Benito C.W.
      • Hanley M.L.
      • Ananth C.V.
      A comparison of ultrasonographically detected cervical changes in response to transfundal pressure, coughing, and standing in predicting cervical incompetence.
      • Guzman E.R.
      • Mellon C.
      • Vintzileos A.M.
      • Ananth C.V.
      • Walters C.
      • Gipson K.
      Longitudinal assessment of endocervical canal length between 15 and 24 weeks' gestation in women at risk for pregnancy loss or preterm birth.
      • Macdonald R.
      • Smith P.
      • Vyas S.
      Cervical incompetence: the use of transvaginal sonography to provide an objective diagnosis.
      • 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.
      a short cervix could be considered as the expression of a spectrum of cervical disease or function. However, it is noteworthy that some women with a short cervix have an adverse pregnancy outcome while others have an uncomplicated term delivery.
      • Berghella V.
      • Daly S.F.
      • Tolosa J.E.
      • DiVito M.M.
      • Chalmers R.
      • Garg N.
      • et al.
      Prediction of preterm delivery with transvaginal ultrasonography of the cervix in patients with high-risk pregnancies: does cerclage prevent prematurity?.
      • Hassan S.S.
      • Romero R.
      • Maymon E.
      • Berry S.M.
      • Blackwell S.C.
      • Treadwell M.C.
      • et al.
      Does cervical cerclage prevent preterm delivery in patients with a short cervix?.
      • 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.
      • Berghella V.
      • Haas S.
      • Chervoneva I.
      • Hyslop T.
      Patients with prior second-trimester loss: prophylactic cerclage or serial transvaginal sonograms?.
      • Williams M.
      • Iams J.D.
      Cervical length measurement and cervical cerclage to prevent preterm birth.
      • Althuisius S.M.
      The short and funneling cervix: when to use cerclage?.
      • 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.
      • Mercer B.M.
      • Moawad A.
      • Das A.
      • et al.
      The length of the cervix and the risk of spontaneous premature delivery. National Institute of Child Health and Human Development Maternal Fetal Medicine Unit Network.
      • 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.
      • Iams J.D.
      • Johnson F.F.
      • Sonek J.
      • Sachs L.
      • Gebauer C.
      • Samuels P.
      Cervical competence as a continuum: a study of ultrasonographic cervical length and obstetric performance.
      • Guzman E.R.
      • Mellon R.
      • Vintzileos A.M.
      • Ananth C.V.
      • Walters C.
      • Gipson K.
      Relationship between endocervical canal length between 15-24 weeks gestation and obstetric history.
      • Kushnir O.
      • Vigil D.A.
      • Izquierdo L.
      • Schiff M.
      • Curet L.B.
      Vaginal ultrasonographic assessment of cervical length changes during normal pregnancy.
      • Andersen H.F.
      Transvaginal and transabdominal ultrasonography of the uterine cervix during pregnancy.
      • Okitsu O.
      • Mimura T.
      • Nakayama T.
      • Aono T.
      Early prediction of preterm delivery by transvaginal ultrasonography.
      • Guzman E.R.
      • Rosenberg J.C.
      • Houlihan C.
      • Ivan J.
      • Waldron R.
      • Knuppel R.
      A new method using vaginal ultrasound and transfundal pressure to evaluate the asymptomatic incompetent cervix.
      • Guzman E.R.
      • Vintzileos A.M.
      • McLean D.A.
      • Martins M.E.
      • Benito C.W.
      • Hanley M.L.
      The natural history of a positive response to transfundal pressure in women at risk for cervical incompetence.
      • Guzman E.R.
      • Pisatowski D.M.
      • Vintzileos A.M.
      • Benito C.W.
      • Hanley M.L.
      • Ananth C.V.
      A comparison of ultrasonographically detected cervical changes in response to transfundal pressure, coughing, and standing in predicting cervical incompetence.
      • Guzman E.R.
      • Mellon C.
      • Vintzileos A.M.
      • Ananth C.V.
      • Walters C.
      • Gipson K.
      Longitudinal assessment of endocervical canal length between 15 and 24 weeks' gestation in women at risk for pregnancy loss or preterm birth.
      • Macdonald R.
      • Smith P.
      • Vyas S.
      Cervical incompetence: the use of transvaginal sonography to provide an objective diagnosis.
      • 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.
      Indeed, approximately 50% of women with a cervix of 15 mm or less deliver after 32 weeks.
      • Hassan S.S.
      • Romero R.
      • Berry S.M.
      • Dang K.
      • Blackwell S.C.
      • Treadwell M.C.
      • et al.
      Patients with an ultrasonographic cervical length ≤15 mm have nearly a 50% risk of early spontaneous preterm delivery.
      This indicates that cervical length may be only one of the factors determining the degree of cervical competence and that a short cervix should not be equated with “cervical insufficiency.”

      Cerclage to prevent mid-trimester abortion/preterm birth: A summary of the evidence

      The clinical value of cervical cerclage has been subject of many observational and randomized clinical trials,
      • Guzman E.R.
      • Forster J.K.
      • Vintzileos A.M.
      • Ananth C.V.
      • Walters C.
      • Gipson K.
      Pregnancy outcomes in women treated with elective versus ultrasound-indicated cervical cerclage.
      • Berghella V.
      • Daly S.F.
      • Tolosa J.E.
      • DiVito M.M.
      • Chalmers R.
      • Garg N.
      • et al.
      Prediction of preterm delivery with transvaginal ultrasonography of the cervix in patients with high-risk pregnancies: does cerclage prevent prematurity?.
      • Althuisius S.M.
      • Dekker G.A.
      • van Geijn H.P.
      • Bekedam D.J.
      • Hummel P.
      Cervical incompetence prevention randomized cerclage trial (CIPRACT): study design and preliminary results.
      • Hassan S.S.
      • Romero R.
      • Maymon E.
      • Berry S.M.
      • Blackwell S.C.
      • Treadwell M.C.
      • et al.
      Does cervical cerclage prevent preterm delivery in patients with a short cervix?.
      • Althuisius S.
      • Dekker G.
      • Hummel P.
      • Bekedam D.
      • Kuik D.
      • van Geijn H.
      Cervical Incompetence Prevention Randomized Cerclage Trial (CIPRACT): effect of therapeutic cerclage with bed rest vs. bed rest only on cervical length.
      • Berghella V.
      • Haas S.
      • Chervoneva I.
      • Hyslop T.
      Patients with prior second-trimester loss: prophylactic cerclage or serial transvaginal sonograms?.
      • To M.S.
      • Palaniappan V.
      • Skentou C.
      • Gibb D.
      • Nicolaides K.H.
      Elective cerclage vs. ultrasound-indicated cerclage in high-risk pregnancies.
      • 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.
      • To M.S.
      • Alfirevic Z.
      • Heath V.C.
      • Cicero S.
      • Cacho A.M.
      • Williamson P.R.
      • et al.
      Cervical cerclage for prevention of preterm delivery in women with short cervix: randomised controlled trial.
      • 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.
      • 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.
      • Final report of the Medical Research Council/Royal College of Obstetricians and Gynaecologists multicentre randomised trial of cervical cerclage
      MRC/RCOG Working Party on Cervical Cerclage.
      • Briggs R.M.
      • Thompson Jr., W.B.
      Treatment of the incompetent cervix.
      • Seppala M.
      • Vara P.
      Cervical cerclage in the treatment of incompetent cervix. A retrospective analysis of the indications and results of 164 operations.
      • Robboy M.S.
      The management of cervical incompetence. UCLA experience with cerclage procedures.
      • Crombleholme W.R.
      • Minkoff H.L.
      • Delke I.
      • Schwarz R.H.
      Cervical cerclage: an aggressive approach to threatened or recurrent pregnancy wastage.
      • Ayhan A.
      • Mercan R.
      • Tuncer Z.S.
      • Tuncer R.
      • Kisnisci H.A.
      Postconceptional cervical cerclage.
      • Golan A.
      • Wolman I.
      • Arieli S.
      • Barnan R.
      • Sagi J.
      • David M.P.
      Cervical cerclage for the incompetent cervical os. Improving the fetal salvage rate.
      • Olatunbosun O.A.
      • al Nuaim L.
      • Turnell R.W.
      Emergency cerclage compared with bed rest for advanced cervical dilatation in pregnancy.
      • Guzman E.R.
      • Houlihan C.
      • Vintzileos A.
      • Ivan J.
      • Benito C.
      • Kappy K.
      The significance of transvaginal ultrasonographic evaluation of the cervix in women treated with emergency cerclage.
      • Kurup M.
      • Goldkrand J.W.
      Cervical incompetence: elective, emergent, or urgent cerclage.
      • 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 versus bed rest alone.
      • 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.
      • Guzman E.R.
      • Ananth C.V.
      Cervical length and spontaneous prematurity: laying the foundation for future interventional randomized trials for the short cervix.
      • Althuisius S.M.
      • Dekker G.A.
      • Hummel P.
      • van Geijn H.P.
      Cervical incompetence prevention randomized cerclage trial: emergency cerclage with bed rest versus bed rest alone.
      • Odibo A.O.
      • Farrell C.
      • Macones G.A.
      • Berghella V.
      Development of a scoring system for predicting the risk of preterm birth in women receiving cervical cerclage.
      and the studies have been subject to several systematic reviews.
      • Belej-Rak T.
      • Okun N.
      • Windrim R.
      • Ross S.
      • Hannah M.E.
      Effectiveness of cervical cerclage for a sonographically shortened cervix: a systematic review and meta-analysis.
      • Drakeley A.J.
      • Roberts D.
      • Alfirevic Z.
      Cervical cerclage for prevention of preterm delivery: meta-analysis of randomized trials.
      • Drakeley A.J.
      • Roberts D.
      • Alfirevic Z.
      Cervical stitch (cerclage) for preventing pregnancy loss in women.
      The evidence suggests the following conclusions:
      • 1)
        Cervical cerclage in women with a sonographic short cervix (15 mm or less) and at low risk for preterm delivery (by history) does not reduce the rate of spontaneous preterm birth.
        • To M.S.
        • Alfirevic Z.
        • Heath V.C.
        • Cicero S.
        • Cacho A.M.
        • Williamson P.R.
        • et al.
        Cervical cerclage for prevention of preterm delivery in women with short cervix: randomised controlled trial.
      • 2)
        The effectiveness of cervical cerclage in women with a sonographic short cervix and at high risk (by history) for preterm delivery remains controversial.
        • Althuisius S.M.
        • Dekker G.A.
        • van Geijn H.P.
        • Bekedam D.J.
        • Hummel P.
        Cervical incompetence prevention randomized cerclage trial (CIPRACT): study design and preliminary results.
        • Rust O.A.
        • Atlas R.O.
        • Jones K.J.
        • Benham B.N.
        • Balducci J.
        A randomized trial of cerclage versus no cerclage among patients with ultrasonographically detected second-trimester preterm dilatation of the internal os.
        • 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.
        • 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 versus bed rest alone.
      • 3)
        The role of prophylactic cerclage in high-risk patients without a sonographic short cervix for the prevention of preterm delivery/mid-trimester abortion (by history) is unclear.
        • Odibo A.O.
        • Elkousy M.
        • Ural S.H.
        • Macones G.A.
        Prevention of preterm birth by cervical cerclage compared with expectant management: a systematic review.
        • 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.
        • 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.
        • Final report of the Medical Research Council/Royal College of Obstetricians and Gynaecologists multicentre randomised trial of cervical cerclage
        MRC/RCOG Working Party on Cervical Cerclage.
        • 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 versus bed rest alone.
        While the largest trial conducted before the introduction of ultrasound evaluation of the cervix suggested a modest beneficial effect,
        • Final report of the Medical Research Council/Royal College of Obstetricians and Gynaecologists multicentre randomised trial of cervical cerclage
        MRC/RCOG Working Party on Cervical Cerclage.
        other trials
        • 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.
        • 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.
        and systematic reviews
        • Grant A.
        Cervical cerclage to prolong pregnancy.
        before the use of ultrasound have indicated that the evidence of effectiveness is either weak or nonexistent.
      • 4)
        In patients at risk for preterm delivery, serial sonographic examination of the cervix followed by cerclage in those who shortened the cervix is a reasonable alternative to prophylactic placement of a cerclage based upon uncontrolled studies.
        • Guzman E.R.
        • Forster J.K.
        • Vintzileos A.M.
        • Ananth C.V.
        • Walters C.
        • Gipson K.
        Pregnancy outcomes in women treated with elective versus ultrasound-indicated cervical cerclage.
        • To M.S.
        • Palaniappan V.
        • Skentou C.
        • Gibb D.
        • Nicolaides K.H.
        Elective cerclage vs. ultrasound-indicated cerclage in high-risk pregnancies.
        • Higgins S.P.
        • Kornman L.H.
        • Bell R.J.
        • Brennecke S.P.
        Cervical surveillance as an alternative to elective cervical cerclage for pregnancy management of suspected cervical incompetence.
      • 5)
        In one trial, emergency cerclage combined with indomethacin administration appeared to reduce the rate of preterm delivery in patients with the clinical presentation of “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 versus bed rest alone.
      This evidence indicates that patients with the clinical presentation of “acute cervical insufficiency” and those with a previous history consistent with “cervical insufficiency” and progressive shortening of the cervix demonstrated with ultrasound may benefit from cerclage placement. However, these conclusions are based on the results of one randomized clinical trial each.
      • 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 versus bed rest alone.
      • Althuisius S.M.
      • Dekker G.A.
      • Hummel P.
      • van Geijn H.P.
      Cervical incompetence prevention randomized cerclage trial: emergency cerclage with bed rest versus bed rest alone.
      In this issue of the Journal, Sakai et al support that the inflammatory status in the endocervix may be an additional criteria to identify those patients who could benefit from cerclage placement and those in which this intervention may be harmful.
      • Sakai M.
      • Shiozaki A.
      • Tabata M.
      • Sasaki Y.
      • Yoneda S.
      • Arai T.
      • et al.
      Evaluation of effectiveness of prophylactic cerclage of a short cervix according to interleukin-8 in cervical mucus.

      Is “cervical insufficiency” a discrete condition or a syndrome?

      In a similar manner to preterm labor, preeclampsia, small-for-gestational age, fetal death, preterm prelabor rupture of membranes, the clinical conditions that describe “cervical insufficiency” can be considered “an obstetrical syndrome.”
      • Romero R.
      Prenatal medicine: the child is the father of the man.
      Cervical ripening in the mid-trimester may be the result of: 1) the loss of connective tissue after a cervical operation such as conization
      • Moinian M.
      • Andersch B.
      Does cervix conization increase the risk of complications in subsequent pregnancies?.
      • Kristensen J.
      • Langhoff-Roos J.
      • Wittrup M.
      • Bock J.E.
      Cervical conization and preterm delivery/low birth weight. A systematic review of literature.
      • 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.
      ; 2) a congenital disorder such as cervical hypoplasia after diethylstilbestrol (DES) exposure
      • Craig C.J.
      Congenital abnormalities of the uterus and foetal wastage.
      • 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.
      • Ludmir J.
      • Landon M.B.
      • Gabbe S.G.
      • Samuels P.
      • Mennuti M.T.
      Management of the diethylstilbestrol-exposed pregnant patient: a prospective study.
      • Levine R.U.
      • Berkowitz K.M.
      Conservative management and pregnancy outcome in diethylstilbestrol-exposed women with and without gross genital tract abnormalities.
      ; 3) intrauterine infection
      • Romero R.
      • Gonzalez R.
      • Sepulveda W.
      • Brandt F.
      • Ramirez M.
      • Sorokin Y.
      • 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.
      ; and 4) a suspension of progesterone action
      • Bengtsson L.P.
      Cervical insufficiency.
      (There is experimental evidence that progesterone can reverse cervical compliance induced by the administration of dexamethasone to pregnant sheep.
      • Stys S.J.
      • Clewell W.H.
      • Meschia G.
      Changes in cervical compliance at parturition independent of uterine activity.
      Sherman et al have also generated evidence that the administration of 17 alpha hydroxyprogesterone may be beneficial in patients with clinically diagnosed “cervical insufficiency”
      • Sherman A.I.
      Hormonal therapy for control of the incompetent os of pregnancy.
      ); and 5) a cervical disorder that manifests itself with the clinical presentation of “cervical insufficiency.” Each of these different causes of the syndrome could be affected by genetic or environmental factors (Figure). Moreover, more than one mechanism of disease may be operative in a specific patient. The possibility that novel and yet undiscovered mechanisms of disease may play a role must also be considered.
      Figure thumbnail gr1
      FigureThe syndromic nature of a short cervix.

      “Cervical insufficiency” as a clinical manifestation of intrauterine infection

      A proportion of patients presenting with asymptomatic cervical dilatation in the mid-trimester have microbial invasion of amniotic cavity (MIAC)
      • Romero R.
      • Gonzalez R.
      • Sepulveda W.
      • Brandt F.
      • Ramirez M.
      • Sorokin Y.
      • et al.
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      that can be as high as 51.5%.
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      • et al.
      Infection and labor. VIII. Microbial invasion of the amniotic cavity in patients with suspected cervical incompetence: prevalence and clinical significance.
      MIAC may be caused by premature cervical dilatation with the exposure of the chorioamniotic membranes to the microbial flora of the lower genital tract. Microorganisms may gain access to the amniotic cavity by crossing intact membranes.
      • Romero R.
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      • Sorokin Y.
      • et al.
      Infection and labor. VIII. Microbial invasion of the amniotic cavity in patients with suspected cervical incompetence: prevalence and clinical significance.
      Under these circumstances, infection would be a secondary phenomenon to primary cervical disease. An alternative is that intrauterine infection (ascending, hematogeneous
      • Boggess K.A.
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      ), or one caused by activation of microorganisms present within the uterine cavity
      • Romero R.
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      Can endometrial infection/inflammation explain implantation failure, spontaneous abortion, and preterm birth after in vitro fertilization?.
      in the second trimester of pregnancy produces myometrial contractility and cervical ripening. Because uterine contractions are usually clinically silent in the mid-trimester of pregnancy, the clinical picture of an infection-induced spontaneous abortion may be indistinguishable from that of an incompetent cervix.
      • Romero R.
      • Mazor M.
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      Cervix, incompetence and premature labor.
      • Romero R.
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      • et al.
      Infection and labor. VIII. Microbial invasion of the amniotic cavity in patients with suspected cervical incompetence: prevalence and clinical significance.
      Recently, we have established that 9% (5/57) of asymptomatic women with a short endocervix (less than 25 mm) have microbiologically proven intra-amniotic infection,
      • Hassan S.
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      • Hendler I.
      • Gomez R.
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      • Espinoza J.
      • et al.
      A sonographic short cervix as the only clinical manifestation of intra-amniotic infection.
      suggesting that these infections are subclinical and may precede the development of the clinical picture of acute “cervical insufficiency” (dilated and effaced cervix with bulging membranes).

      Cervical mucus concentrations of interleukin-8 in the mid-trimester of pregnancy: A risk factor for preterm delivery

      Interleukin (IL)-8, a chemokine capable of inducing neutrophil chemotaxis,
      • Huber A.R.
      • Kunkel S.L.
      • Todd III, R.F.
      • Weiss S.J.
      Regulation of transendothelial neutrophil migration by endogenous interleukin-8.
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      • Geiser T.
      • Baggiolini M.
      • et al.
      Neutrophil activation by monomeric interleukin-8.
      • Gura T.
      Chemokines take center stage in inflammatory ills.
      is produced by cervical tissue
      • Sennstrom M.K.
      • Brauner A.
      • Lu Y.
      • Granstrom L.M.
      • Malmstrom A.L.
      • Ekman G.E.
      Interleukin-8 is a mediator of the final cervical ripening in humans.
      • Barclay C.G.
      • Brennand J.E.
      • Kelly R.W.
      • Calder A.A.
      Interleukin-8 production by the human cervix.
      and is capable of inducing cervical ripening when applied topically.
      • 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 tumour necrosis factor alpha in guinea-pigs.
      The cervical mucus of normal pregnant women contains IL-8, and its concentration increases during the third trimester of pregnancy and labor, as do the number of granulocytes.
      • Luo L.
      • Ibaragi T.
      • Maeda M.
      • Nozawa M.
      • Kasahara T.
      • Sakai M.
      • et al.
      Interleukin-8 levels and granulocyte counts in cervical mucus during pregnancy.
      IL-8 concentrations in cervical mucus can reflect physiologic changes such as cervical ripening but also pathology: endocervical inflammation (ie, cervicitis).
      • Wennerholm U.B.
      • Holm B.
      • Mattsby-Baltzer I.
      • Nielsen T.
      • Platz-Christensen J.J.
      • Sundell G.
      • et al.
      Interleukin-1alpha, interleukin-6 and interleukin-8 in cervico/vaginal secretion for screening of preterm birth in twin gestation.
      • von Minckwitz G.
      • Grischke E.M.
      • Schwab S.
      • Hettinger S.
      • Loibl S.
      • Aulmann M.
      • et al.
      Predictive value of serum interleukin-6 and -8 levels in preterm labor or rupture of the membranes.
      • Sakai M.
      • Sasaki Y.
      • Yoneda S.
      • Kasahara T.
      • Arai T.
      • Okada M.
      • et al.
      Elevated interleukin-8 in cervical mucus as an indicator for treatment to prevent premature birth and preterm, pre-labor rupture of membranes: a prospective study.
      • Sakai M.
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      • et al.
      Relationship between cervical mucus interleukin-8 concentrations and vaginal bacteria in pregnancy.
      • Sawada M.
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      • Okai T.
      Cervical inflammatory cytokines and other markers in the cervical mucus of pregnant women with lower genital tract infection.
      • Holst R.M.
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      • Wennerholm U.B.
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      Interleukin-6 and interleukin-8 in cervical fluid in a population of Swedish women in preterm labor: relationship to microbial invasion of the amniotic fluid, intra-amniotic inflammation, and preterm delivery.
      An elevated concentration of IL-8 in cervical mucus (≥360 ng/mL) between 20-28 weeks is a risk factor for spontaneous preterm delivery (at <32, <34, and <37 weeks).
      • Sakai M.
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      • et al.
      Relationship between cervical mucus interleukin-8 concentrations and vaginal bacteria in pregnancy.
      It is unknown whether the elevation of IL-8 in cervical mucus reflects premature cervical ripening or endocervicitis. However, elevated IL-8 in cervical mucus has been reported in women with bacterial vaginosis, MIAC, and intra-amniotic inflammation.
      • Sawada M.
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      Cervical inflammatory cytokines and other markers in the cervical mucus of pregnant women with lower genital tract infection.
      Moreover, a high concentration of IL-8 and IL-18 in the cervical mucus or cervical secretions has been associated with preterm labor and MIAC.
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      • Jacobsson B.
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      Interleukin-18 in cervical mucus and amniotic fluid: relationship to microbial invasion of the amniotic fluid, intra-amniotic inflammation and preterm delivery.
      A role for infection in the elevation of cervical mucus IL-8 concentration is suggested by the observation that treatment with vaginal washing with povidone iodine and vaginal tablets of chloramphenicol can “normalize” IL-8 concentration in the cervical mucus in 23.2% (195/840) of patients. In addition, this treatment has been associated with a lower rate of preterm delivery at less than 34 and 37 weeks in an uncontrolled study.
      • Sakai M.
      • Sasaki Y.
      • Yoneda S.
      • Kasahara T.
      • Arai T.
      • Okada M.
      • et al.
      Elevated interleukin-8 in cervical mucus as an indicator for treatment to prevent premature birth and preterm, pre-labor rupture of membranes: a prospective study.

      Can the combination of cervical ultrasound and markers of endocervical inflammation identify the patient who may benefit from a cerclage?

      The study by Sakai et al published in this issue of the Journal included 16,508 women with singleton pregnancies in whom sonographic cervical length was determined. A short cervix (defined as 25 mm or less) was detected in 252 women and 246 were eligible for the study. A cervical cerclage was placed in women with a short cervix at the discretion of the attending physicians (cerclages were placed in 165 and not placed in 81). Cervical mucus was collected at the time of ultrasound examination, but the results of IL-8 concentrations were not used for patient management. Cervical cerclage did not reduce the rate of preterm delivery or lengthen the procedure to delivery interval, an observation that is consistent with that of other investigators. However, two observations are novel and noteworthy. Among women with an IL-8 concentration <360 ng/mL, those who underwent a cerclage had a lower rate of preterm delivery (defined as 34 weeks or 37 weeks) than those who did not have a cerclage. In contrast, among patients with an elevated IL-8, those who had a cerclage had a higher rate of preterm delivery (<37 weeks) and a shorter procedure to delivery interval than those who did not have a cerclage. There are two messages to be taken from the series of studies reported by the group at the Toyama Medical and Pharmaceutical University in Japan.
      • Sakai M.
      • Shiozaki A.
      • Tabata M.
      • Sasaki Y.
      • Yoneda S.
      • Arai T.
      • et al.
      Evaluation of effectiveness of prophylactic cerclage of a short cervix according to interleukin-8 in cervical mucus.
      • Sakai M.
      • Sasaki Y.
      • Yoneda S.
      • Kasahara T.
      • Arai T.
      • Okada M.
      • et al.
      Elevated interleukin-8 in cervical mucus as an indicator for treatment to prevent premature birth and preterm, pre-labor rupture of membranes: a prospective study.
      First, patients with an elevated concentration of IL-8 and a short cervix (<25 mm) may not benefit from a cerclage. These patients may have an inflammatory or infection-related process in the endocervix and placement of a cerclage either does not improve the natural history of this process or worsen the outcome. Second, a subset of patients who may benefit from cerclage may include those with cervical mucus IL-8 concentrations <360 ng/mL.
      These observations are important because it is becoming increasingly clear that the identification of the patient who can benefit from a cerclage cannot be made on the basis of either history or cervical ultrasound alone. We propose that the patient with severe endocervical inflammation may have subclinical intra-amniotic inflammation/infection or extra-amniotic inflammation/infection and may be in the advanced stages of the process that culminates in the expulsion of the conceptus to enhance maternal survival. On the other hand, the combination of a sonographic short cervix, a history of a previous preterm delivery, and the absence of endocervical inflammation (and vaginal inflammation), is more likely to identify the patient who has primary cervical disease. This patient may benefit from a cerclage or a similar intervention aimed at preventing or correcting a cervical disorder, which may lead to cervical ripening and pregnancy loss. Although cerclage is the focus of this article, it is worth mentioning that it is not the only therapy available for a cervical factor responsible for preterm birth. Others may include medical interventions (progesterone,
      • Sherman A.I.
      Hormonal therapy for control of the incompetent os of pregnancy.
      COX-2-selective non-steroidal anti-inflammatory agents
      • Sawdy R.
      • Slater D.
      • Fisk N.
      • Edmonds D.K.
      • Bennett P.
      Use of a cyclo-oxygenase type-2-selective non-steroidal anti-inflammatory agent to prevent preterm delivery.
      or anti-chemokine agents), the use of devices such as pessaries, the injection of collagen into the cervix to strengthen the cervical scaffold or total cervical occlusion, which was first reported by Professor Erich Saling.

      Saling E. Early total operative occlusion of the cervix for prevention of recurrent late abortions. Society of Perinatal Obstetricians, 9th Annual Meeting, New Orleans, LA.

      Randomized clinical trials of cerclage may benefit from collecting information about the state of inflammation of the cervix and consider this as a factor for stratification. This subject is being addressed by a randomized clinical trial sponsored by the National Institute of Child Health and Human Development, National Institutes of Health. This trial is led by Dr John Owen and his collaborators at the University of Alabama. The new information published in this issue of the Journal is that assessment of the inflammatory state of the endocervix may add important information to the evaluation of risk for preterm birth and the identification of the patient who may benefit or be harmed by a cerclage. The new knowledge provided by Sakai et al improves the understanding of a very complex problem in obstetrics: the identification of the patient who may benefit from cerclage.

      Acknowledgment

      The authors wish to acknowledge the contribution of Dr Jay lams for the insightful discussion on the subject of cervical insufficiency and cervical cerclage.

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      Additional Recommended Reading:

      1. Althuisius S. Cervical incompetence, you better believe it. [dissertation] Amsterdam.

      2. Hjelm Cluff A. The uterine proteoglycan expression in pregnancy and labor. [dissertation] Stockholm, 2004.

      3. Abelin Törnblom S. Mediators of cervical ripening in preterm birth: Experimental and clinical investigations. [dissertation] Stockholm, 2005.