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The risk of impending preterm delivery in asymptomatic patients with a nonmeasurable cervical length in the second trimester

  • Edi Vaisbuch
    Affiliations
    Perinatology Research Branch, Intramural Division, NICHD/NIH/DHHS, Hutzel Women's Hospital, Bethesda, MD, and Detroit, MI

    Department of Obstetrics and Gynecology, Wayne State University/Hutzel Women's Hospital, Detroit, MI
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  • Roberto Romero
    Correspondence
    Reprints: Roberto Romero, MD, Perinatology Research Branch, NICHD, NIH, DHHS, Wayne State University/Hutzel Women's Hospital, 3990 John R, Box 4, Detroit, MI 48201
    Affiliations
    Perinatology Research Branch, Intramural Division, NICHD/NIH/DHHS, Hutzel Women's Hospital, Bethesda, MD, and Detroit, MI

    Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI
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  • Shali Mazaki-Tovi
    Affiliations
    Perinatology Research Branch, Intramural Division, NICHD/NIH/DHHS, Hutzel Women's Hospital, Bethesda, MD, and Detroit, MI

    Department of Obstetrics and Gynecology, Wayne State University/Hutzel Women's Hospital, Detroit, MI
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  • Offer Erez
    Affiliations
    Perinatology Research Branch, Intramural Division, NICHD/NIH/DHHS, Hutzel Women's Hospital, Bethesda, MD, and Detroit, MI

    Department of Obstetrics and Gynecology, Wayne State University/Hutzel Women's Hospital, Detroit, MI
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  • Juan Pedro Kusanovic
    Affiliations
    Perinatology Research Branch, Intramural Division, NICHD/NIH/DHHS, Hutzel Women's Hospital, Bethesda, MD, and Detroit, MI

    Department of Obstetrics and Gynecology, Wayne State University/Hutzel Women's Hospital, Detroit, MI
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  • Pooja Mittal
    Affiliations
    Perinatology Research Branch, Intramural Division, NICHD/NIH/DHHS, Hutzel Women's Hospital, Bethesda, MD, and Detroit, MI

    Department of Obstetrics and Gynecology, Wayne State University/Hutzel Women's Hospital, Detroit, MI
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  • Francesca Gotsch
    Affiliations
    Perinatology Research Branch, Intramural Division, NICHD/NIH/DHHS, Hutzel Women's Hospital, Bethesda, MD, and Detroit, MI
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  • Clara Ward
    Affiliations
    Department of Obstetrics and Gynecology, Wayne State University/Hutzel Women's Hospital, Detroit, MI
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  • Vivian Romero
    Affiliations
    Department of Obstetrics and Gynecology, Wayne State University/Hutzel Women's Hospital, Detroit, MI
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  • Tinnakorn Chaiworapongsa
    Affiliations
    Perinatology Research Branch, Intramural Division, NICHD/NIH/DHHS, Hutzel Women's Hospital, Bethesda, MD, and Detroit, MI

    Department of Obstetrics and Gynecology, Wayne State University/Hutzel Women's Hospital, Detroit, MI
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  • Percy Pacora
    Affiliations
    Perinatology Research Branch, Intramural Division, NICHD/NIH/DHHS, Hutzel Women's Hospital, Bethesda, MD, and Detroit, MI
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  • Lami Yeo
    Affiliations
    Perinatology Research Branch, Intramural Division, NICHD/NIH/DHHS, Hutzel Women's Hospital, Bethesda, MD, and Detroit, MI

    Department of Obstetrics and Gynecology, Wayne State University/Hutzel Women's Hospital, Detroit, MI
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  • Sonia S. Hassan
    Affiliations
    Perinatology Research Branch, Intramural Division, NICHD/NIH/DHHS, Hutzel Women's Hospital, Bethesda, MD, and Detroit, MI

    Department of Obstetrics and Gynecology, Wayne State University/Hutzel Women's Hospital, Detroit, MI
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      Objective

      The purpose of this study was to determine the pregnancy outcome of asymptomatic patients in the second trimester with a nonmeasurable cervical length (0 mm).

      Study Design

      This retrospective cohort study included 78 patients with singleton pregnancies and a sonographic nonmeasurable cervix that was detected at 14-28 weeks of gestation. Patients with cervical cerclage were excluded.

      Results

      We found that (1) 75.3% of the patients delivered before 32 weeks of gestation; (2) the median diagnosis-to-delivery interval was 20.5 days, and the delivery rate within 7 and 14 days was 28.2% and 35.6%, respectively; and (3) patients with a nonmeasurable cervix that was diagnosed at <24 weeks of gestation had a shorter median diagnosis-to-delivery interval than patients who were diagnosed at 24-28 weeks of gestation (17.5 vs 41 days; P = .009).

      Conclusion

      Asymptomatic women with a nonmeasurable cervix in the second trimester have a median diagnosis-to-delivery interval of approximately 3 weeks. Almost 65% of these patients will not deliver within 2 weeks, yet 75% of them will deliver before 32 weeks of gestation. The earlier a nonmeasurable cervix is identified, the shorter the diagnosis-to-delivery interval.

      Key words

      Preterm birth is the leading cause of perinatal morbidity and death worldwide.
      • McCormick M.C.
      The contribution of low birth weight to infant mortality and childhood morbidity.
      • Steer P.
      The epidemiology of preterm labour.
      • Hamilton B.E.
      • Martin J.A.
      • Ventura S.J.
      Births: preliminary data for 2005.
      A short cervical length is recognized as a powerful predictor of spontaneous preterm birth;
      • 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.
      • Iams J.D.
      • Paraskos J.
      • Landon M.B.
      • Teteris J.N.
      • Johnson F.F.
      Cervical sonography in preterm labor.
      • 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.
      • Iams J.D.
      • Goldenberg R.L.
      • Meis P.J.
      • et al.
      The length of the cervix and the risk of spontaneous premature delivery.
      • Hasegawa I.
      • Tanaka K.
      • Takahashi K.
      • et al.
      Transvaginal ultrasonographic cervical assessment for the prediction of preterm delivery.
      • Berghella V.
      • Kuhlman K.
      • Weiner S.
      • Texeira L.
      • Wapner R.J.
      Cervical funneling: sonographic criteria predictive of preterm delivery.
      • Goldenberg R.L.
      • Iams J.D.
      • Mercer B.M.
      • et al.
      The preterm prediction study: the value of new vs standard risk factors in predicting early and all spontaneous preterm births: NICHD MFMU Network.
      • 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.
      • 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.
      • Watson W.J.
      • Stevens D.
      • Welter S.
      • Day D.
      Observations on the sonographic measurement of cervical length and the risk of premature birth.
      • Hibbard J.U.
      • Tart M.
      • Moawad A.H.
      Cervical length at 16-22 weeks' gestation and risk for preterm delivery.
      • Andrews W.W.
      • Copper R.
      • Hauth J.C.
      • Goldenberg R.L.
      • Neely C.
      • Dubard M.
      Second-trimester cervical ultrasound: associations with increased risk for recurrent early spontaneous delivery.
      • Hassan S.S.
      • Romero R.
      • Berry S.M.
      • et al.
      Patients with an ultrasonographic cervical length ≤15 mm have nearly a 50% risk of early spontaneous preterm delivery.
      • Owen J.
      • Yost N.
      • Berghella V.
      • et al.
      Mid-trimester endovaginal sonography in women at high risk for spontaneous preterm birth.
      • 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.
      • Durnwald C.P.
      • Walker H.
      • Lundy J.C.
      • Iams J.D.
      Rates of recurrent preterm birth by obstetrical history and cervical length.
      • Matijevic R.
      • Grgic O.
      • Vasilj O.
      Is sonographic assessment of cervical length better than digital examination in screening for preterm delivery in a low-risk population?.
      and transvaginal cervical sonography is the most objective and reliable method to assess cervical length.
      • Iams J.D.
      • Goldenberg R.L.
      • Meis P.J.
      • et al.
      The length of the cervix and the risk of spontaneous premature delivery.
      • 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.
      • et al.
      Patients with an ultrasonographic cervical length ≤15 mm have nearly a 50% risk of early spontaneous preterm 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.
      • Tekesin I.
      • Eberhart L.H.
      • Schaefer V.
      • Wallwiener D.
      • Schmidt S.
      Evaluation and validation of a new risk score (CLEOPATRA score) to predict the probability of premature delivery for patients with threatened preterm labor.
      • To M.S.
      • Skentou C.A.
      • Royston P.
      • Yu C.K.
      • Nicolaides K.H.
      Prediction of patient-specific risk of early preterm delivery using maternal history and sonographic measurement of cervical length: a population-based prospective study.
      • Visintine J.
      • Berghella V.
      • Henning D.
      • Baxter J.
      Cervical length for prediction of preterm birth in women with multiple prior induced abortions.
      However, there is no agreement as to the definition of a sonographic short cervix.
      • Iams J.D.
      • Goldenberg R.L.
      • Meis P.J.
      • et al.
      The length of the cervix and the risk of spontaneous premature delivery.
      • Heath V.C.
      • Southall T.R.
      • Souka A.P.
      • Elisseou A.
      • Nicolaides K.H.
      Cervical length at 23 weeks of gestation: prediction of spontaneous preterm delivery.
      • Hassan S.S.
      • Romero R.
      • Berry S.M.
      • et al.
      Patients with an ultrasonographic cervical length ≤15 mm have nearly a 50% risk of early spontaneous preterm delivery.
      Iams et al
      • Iams J.D.
      • Goldenberg R.L.
      • Meis P.J.
      • et al.
      The length of the cervix and the risk of spontaneous premature delivery.
      reported that a sonographic cervical length of ≤25 mm at 24 weeks of gestation is associated with a prevalence of 4.3% of spontaneous preterm delivery at <35 weeks of gestation and a positive predictive value of only 17.8%. Subsequently, a cutoff of 15 mm has been proposed.
      • 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.
      • et al.
      Patients with an ultrasonographic cervical length ≤15 mm have nearly a 50% risk of early spontaneous preterm delivery.
      The prevalence of a sonographic cervical length of ≤15 mm ranges from 0.6%
      • Hassan S.S.
      • Romero R.
      • Berry S.M.
      • et al.
      Patients with an ultrasonographic cervical length ≤15 mm have nearly a 50% risk of early spontaneous preterm delivery.
      at 14-24 weeks of gestation to 1-1.7%
      • 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.
      • Heath V.C.
      • Southall T.R.
      • Souka A.P.
      • Novakov A.
      • Nicolaides K.H.
      Cervical length at 23 weeks of gestation: relation to demographic characteristics and previous obstetric history.
      • 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.
      • Palma-Dias R.S.
      • Fonseca M.M.
      • Stein N.R.
      • Schmidt A.P.
      • Magalhaes J.A.
      Relation of cervical length at 22-24 weeks of gestation to demographic characteristics and obstetric history.
      • Celik E.
      • To M.
      • Gajewska K.
      • Smith G.C.
      • Nicolaides K.H.
      Cervical length and obstetric history predict spontaneous preterm birth: development and validation of a model to provide individualized risk assessment.
      at 20-24 weeks of gestation. The rate of preterm delivery in these patients varies according to the gestational age at diagnosis. In asymptomatic women with a sonographic cervical length of ≤15 mm between 14 and 24 weeks of gestation, the rate of spontaneous preterm delivery at ≤32 weeks of gestation is 48%.
      • Hassan S.S.
      • Romero R.
      • Berry S.M.
      • et al.
      Patients with an ultrasonographic cervical length ≤15 mm have nearly a 50% risk of early spontaneous preterm delivery.
      For Editors' Commentary, see Table of Contents
      Despite the broad range of criteria for the definition of a sonographic short cervix,
      • Iams J.D.
      • Goldenberg R.L.
      • Meis P.J.
      • et al.
      The length of the cervix and the risk of spontaneous premature delivery.
      • Taipale P.
      • Hiilesmaa V.
      Sonographic measurement of uterine cervix at 18-22 weeks' gestation and the risk of preterm delivery.
      • Andrews W.W.
      • Copper R.
      • Hauth J.C.
      • Goldenberg R.L.
      • Neely C.
      • Dubard M.
      Second-trimester cervical ultrasound: associations with increased risk for recurrent early spontaneous delivery.
      • Hassan S.S.
      • Romero R.
      • Berry S.M.
      • et al.
      Patients with an ultrasonographic cervical length ≤15 mm have nearly a 50% risk of early spontaneous preterm delivery.
      • Owen J.
      • Yost N.
      • Berghella V.
      • et al.
      Mid-trimester endovaginal sonography in women at high risk for spontaneous preterm birth.
      • Andersen H.F.
      • Nugent C.E.
      • Wanty S.D.
      • Hayashi R.H.
      Prediction of risk for preterm delivery by ultrasonographic measurement of cervical length.
      • Tongsong T.
      • Kamprapanth P.
      • Srisomboon J.
      • Wanapirak C.
      • Piyamongkol W.
      • Sirichotiyakul S.
      Single transvaginal sonographic measurement of cervical length early in the third trimester as a predictor of preterm delivery.
      • Berghella V.
      • Tolosa J.E.
      • Kuhlman K.
      • Weiner S.
      • Bolognese R.J.
      • Wapner R.J.
      Cervical ultrasonography compared with manual examination as a predictor of preterm delivery.
      • To M.S.
      • Skentou C.
      • Cicero S.
      • Liao A.W.
      • Nicolaides K.H.
      Cervical length at 23 weeks in triplets: prediction of spontaneous preterm delivery.
      it is generally accepted that the shorter the sonographic cervical length in the midtrimester, the higher the risk of spontaneous preterm labor/delivery.
      • Iams J.D.
      • Goldenberg R.L.
      • Meis P.J.
      • et al.
      The length of the cervix and the risk of spontaneous premature delivery.
      • Heath V.C.
      • Southall T.R.
      • Souka A.P.
      • Elisseou A.
      • Nicolaides K.H.
      Cervical length at 23 weeks of gestation: prediction of spontaneous preterm delivery.
      • 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.
      • et al.
      Patients with an ultrasonographic cervical length ≤15 mm have nearly a 50% risk of early spontaneous preterm 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.
      However, data regarding pregnancy outcome of asymptomatic patients with a nonmeasurable cervical length (usually described as a “0 mm” cervix) are limited and based on a small number of patients.
      • 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.
      • Berghella V.
      • Roman A.
      • Daskalakis C.
      • Ness A.
      • Baxter J.K.
      Gestational age at cervical length measurement and incidence of preterm birth.
      These patients are considered to be at a very high risk of preterm delivery. Furthermore, therapeutic interventions such as 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.
      • 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.
      • Dodd J.M.
      • Flenady V.J.
      • Cincotta R.
      • Crowther C.A.
      Progesterone for the prevention of preterm birth: a systematic review.
      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.
      • Althuisius S.M.
      The short and funneling cervix: when to use 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.
      • Owen J.
      Multicenter randomized trial of cerclage for preterm birth prevention in high-risk women with shortened mid-trimester cervical length.
      antibiotics,
      • Hassan S.
      • Romero R.
      • Hendler I.
      • et al.
      A sonographic short cervix as the only clinical manifestation of intra-amniotic infection.
      or indomethacin
      • Berghella V.
      • Rust O.A.
      • Althuisius S.M.
      Short cervix on ultrasound: does indomethacin prevent preterm birth?.
      are of limited success in women with an extremely short cervix.
      • 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.
      • Rust O.A.
      • Althuisius S.M.
      Short cervix on ultrasound: does indomethacin prevent preterm birth?.
      • Hassan S.S.
      • Romero R.
      • Maymon E.
      • 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.
      • 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.
      • Fox N.S.
      • Chervenak F.A.
      Cervical cerclage: a review of the evidence.
      The aim of this study was to determine the pregnancy outcome of asymptomatic patients with a nonmeasurable cervical length (0 mm) that was diagnosed in the second trimester of pregnancy (14-28 weeks of gestation) by transvaginal sonography.

      Materials and Methods

      Study population

      This retrospective cohort study included pregnant women with a singleton pregnancy whose cases were followed at our cervix clinic between January 2002 and December 2008. With a computer-based search of our clinical and sonographic databases, consecutive asymptomatic patients between 14 and 28 weeks of gestation with a nonmeasurable cervical length (0 mm), as determined by a documented transvaginal ultrasound (TVUS) examination, were identified. Patients with ≥1 of the following conditions were excluded: (1) multifetal pregnancy; (2) premature contractions, preterm labor, or preterm prelabor rupture of membranes at the time of diagnosis; (3) cervical cerclage (placed before or after the diagnosis of a short cervix); (4) placenta previa, and (5) fetuses with chromosomal and/or congenital anomalies.
      Patients were diagnosed with a nonmeasurable cervical length during TVUS evaluation of the cervix. Digital assessment of the cervix was performed in all patients. The ultrasound findings were recorded and stored in a dedicated database. After the diagnosis of a short cervix, the patients were referred to the labor and delivery ward for further evaluation and treatment. Both the sonographic cervical length and the result of the digital vaginal examination were available to the managing physicians. The standard obstetrics practice in our institution is to offer amniocentesis to determine the microbial status of the amniotic cavity to patients with an asymptomatic short cervix, based on previous observations that suggest an association between a sonographic short cervix and histologic chorioamnionitis
      • Guzman E.R.
      • Shen-Schwarz S.
      • Benito C.
      • Vintzileos A.M.
      • Lake M.
      • Lai Y.L.
      The relationship between placental histology and cervical ultrasonography in women at risk for pregnancy loss and spontaneous preterm birth.
      and intraamniotic infection.
      • Hassan S.
      • Romero R.
      • Hendler I.
      • et al.
      A sonographic short cervix as the only clinical manifestation of intra-amniotic infection.
      • 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.
      • Mays J.K.
      • Figueroa R.
      • Shah J.
      • Khakoo H.
      • Kaminsky S.
      • Tejani N.
      Amniocentesis for selection before rescue cerclage.
      All participating women provided written informed consent before inclusion in this study. The use of clinical and ultrasound data for research purposes was approved by the Institutional Review Boards of Wayne State University and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services.

      Definitions and study procedures

      Gestational age was determined by the last menstrual period or by ultrasound if the sonographic determination of gestational age was not consistent with the menstrual dating by >1 week in the first trimester and by >2 weeks in the second trimester of pregnancy. Gestational age at diagnosis was defined as the earliest gestation at which a cervical length of 0 mm was documented by TVUS examination. Data regarding pregnancy outcomes were obtained from the clinical and research records. Patients who were lost to follow-up and for whom delivery data were not available were censored from the last available follow-up visit.
      Patients with an a priori increased risk for spontaneous preterm delivery included those patients with a history of at least 1 of the following conditions: (1) ≥1 previous spontaneous preterm deliveries (≤35 weeks of gestation), (2) ≥1 late midtrimester spontaneous miscarriages (≥16 weeks of gestation), (3) ≥2 curettage procedures, and (4) previous cervical surgery (loop electrosurgical excision procedure or cone biopsy).
      To maintain an interpretable temporal relationship between the results of amniocentesis and pregnancy outcome, only the results from amniocentesis that had been performed within 7 days of diagnosis of a nonmeasurable cervical length were included in the statistical analyses. Intraamniotic infection was defined as a positive amniotic fluid culture for microorganisms (aerobic/anaerobic bacteria or genital mycoplasmas). Intraamniotic inflammation was defined as an amniotic fluid interleukin-6 (IL-6) concentration ≥2.6 ng/mL.
      • Yoon B.H.
      • Romero R.
      • Moon J.B.
      • et al.
      Clinical significance of intra-amniotic inflammation in patients with preterm labor and intact membranes.
      Amniotic fluid IL-6 concentrations were determined using a specific and sensitive immunoassay (R&D Systems, Minneapolis, MN) after all patients were delivered and were not used in clinical management.
      From a clinical perspective, the gestational age at delivery is more important than the diagnosis-to-delivery interval per se. For example, an interval to delivery of 6 weeks for a patient whose condition was diagnosed at 16 weeks of gestation is not associated with a better outcome than an interval of only 2 weeks in a patient whose condition was diagnosed at 26 weeks of gestation. To overcome this limitation and to take into account the relative wide range (14-28 weeks) of gestational age at diagnosis that was included in this study, an “interval ratio” was calculated for each patient according to the following formula: diagnosis-to-delivery interval (days)/diagnosis-to-37-week interval (days). Ratios of ≥1 represent patients who delivered at term (≥37 weeks of gestation). The lower the ratio, the shorter the time the patient remained pregnant after diagnosis relative to expected remaining time to term.

      Sonographic assessment of the cervix

      Transvaginal ultrasound examination was conducted with commercially available 2-dimensional and 3-dimensional ultrasound systems (Acuson Sequoia: Siemens Medical Systems, Mountain View, CA; and Voluson 730 Expert or Voluson E8: GE Healthcare, Milwaukee, WI) that were equipped with endovaginal transducers with frequency ranges of 5-7.5 MHz and 5-9 MHz, respectively. All sonographic examinations of the cervical length were performed by registered diagnostic medical sonographers who used a technique previously described
      • Iams J.D.
      • Goldenberg R.L.
      • Meis P.J.
      • et al.
      The length of the cervix and the risk of spontaneous premature 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.
      and were reviewed by an experienced physician. Amniotic fluid sludge was identified by the presence of dense aggregates of particulate matter in proximity to the internal cervical os, as previously described.
      • Espinoza J.
      • Goncalves L.F.
      • Romero R.
      • et al.
      The prevalence and clinical significance of amniotic fluid “sludge” in patients with preterm labor and intact membranes.
      Two experienced sonographers who were blinded to clinical outcome reviewed the 2-dimensional images and 3-dimensional volume datasets of the cervix for the presence of amniotic fluid sludge, which was considered to be present only when identified by both examiners.

      Statistical analysis

      The main outcome variables were the diagnosis-to-delivery interval, the rate of delivery within 7 and 14 days from diagnosis, and the rate of early preterm delivery (<32 weeks of gestation). Patients were further stratified by gestational age at diagnosis (<24 weeks vs 24-28 weeks of gestation). Subjects who had an indicated preterm delivery because of a diagnosis that could not be attributed directly to the initial diagnosis of a short cervix (eg, preeclampsia, fetal growth restriction, fetal death, etc) were censored from the statistical analyses at the corresponding gestational age at induction of labor.
      Comparisons among groups were performed with the Fisher's exact test for categoric variables and the Mann-Whitney U test for comparisons of continuous variables. Correlation between continuous variables was assessed by Spearman's rho correlation test. Multivariable logistic regression (backward-stepwise) analyses were performed to determine the relationship between maternal age, gestational age at the time of ultrasound diagnosis, cervical dilation (as continuous variables), nulliparity, an a priori risk for preterm delivery, 17-hydroxyprogesterone caproate prophylactic treatment and the presence of amniotic fluid sludge (as categoric variables), and pregnancy outcomes (delivery within 7-14 days and at <32 weeks of gestation). A Kaplan-Meier survival analysis was performed to assess the diagnosis-to-delivery interval according to the cervical length and presence or absence of amniotic fluid sludge. A probability value of < .05 was considered statistically significant. SPSS statistical package (version 14.0; SPSS Inc, Chicago, IL) was used for analysis.

      Results

      During the study period, 78 asymptomatic patients with a sonographic cervical length of 0 mm during the second trimester of pregnancy met the inclusion criteria of this study. The earliest gestational age at which an asymptomatic nonmeasurable cervical length was recorded by TVUS examination was 17 weeks and 4 days. There was a high correlation between the gestational age at diagnosis and the gestational age at delivery (Spearman's rho, 0.73; P < .0001).
      Demographic and clinical characteristics of the study population are listed in Table 1. Women who received a diagnosis of a nonmeasurable cervical length at 24-28 weeks of gestation had a higher median prepregnancy body mass index than did the women who received the diagnoses at <24 weeks of gestation (P = .027). Both the median gestational age at delivery and the median neonatal birthweight were lower in patients whose condition was diagnosed at <24 weeks of gestation than in patients whose case was diagnosed between 24 and 28 weeks of gestation (P < .001 for both; Table 1). The median cervical dilation was slightly greater in patients whose condition was diagnosed at 24-28 weeks of gestation than in the women whose condition was diagnosed earlier in the midtrimester (P = .041). Yet, the median diagnosis-to-delivery interval was shorter among the group of patients whose condition was diagnosed earlier in pregnancy (P = .009; Table 2). Similarly, the interval ratio (diagnosis-to-delivery interval/diagnosis-to-37 weeks of gestation interval) was significantly lower in patients whose condition was diagnosed at <24 weeks of gestation than in those women who received the diagnosis at 24-28 weeks of gestation (P = .001; Table 2)
      TABLE 1Demographic and clinical characteristics of the study population
      VariableGestational age at diagnosis, wkP value
      Between gestational age at diagnosis at <24 weeks and 24-28 weeks;
      14-28 (n = 78)<24 (n = 42)24-28 (n = 36)
      Age, y
      Data are presented median (interquartile range);
      24 (21.4–29.5)25 (22–31.2)22.7 (21–27.2).1
      African American origin, n (%)68 (87.2)37 (88.1)31 (86.1).99
      Smoking status, n (%)14 (17.9)10 (23.8)4 (11.1).2
      Prepregnancy body mass index, kg/m2
      Data are presented median (interquartile range);
      29.2 (23.9–34.9)27.2 (22.3–32)32.3 (26.4–40.1).027
      Nulliparity, n (%)39 (50.0)20 (47.6)19 (52.8).8
      History of curettage, n/N (%)42/74 (56.8)22/39 (56.4)20/35 (57.1).7
      History of spontaneous preterm delivery, n (%)26 (33.3)15 (35.7)11 (30.6).8
      History of cervical surgery, n/N (%)3/75 (4.0)3/40 (7.5)0/35 (0).2
      An a priori risk for preterm delivery, n (%)
      Defined by the presence of history of at least 1 of the following events: (1) ≥2 curettage procedures, (2) spontaneous preterm delivery, and (3) cervical surgery.
      34 (43.6)19 (45.2)15 (41.7).8
      17-hydroxyprogesterone caproate treatment, n (%)11 (14.1)3 (8.3)8 (19).2
      Gestational age at diagnosis, wk
      Data are presented median (interquartile range);
      23.6 (21.0–25.5)21.6 (20–23)25.9 (24.7–26.9)< .001
      Cervical dilation at diagnosis, cm
      Data are presented median (interquartile range);
      1 (0–2.5)1 (0–2)1.5 (0.5–2.5).041
      Gestational age at delivery, wk
      Data are presented median (interquartile range);
      27 (23.9–31.9)24.3 (21.2–27.1)31.5 (27–36.4)< .001
      Birthweight, g
      Data are presented median (interquartile range);
      853 (546–1670)670 (375–853)1670 (910–2685)< .001
      Vaisbuch. The risk of impending delivery in nonmeasurable cervix. Am J Obstet Gynecol 2010.
      a Between gestational age at diagnosis at <24 weeks and 24-28 weeks;
      b Data are presented median (interquartile range);
      c Defined by the presence of history of at least 1 of the following events: (1) ≥2 curettage procedures, (2) spontaneous preterm delivery, and (3) cervical surgery.
      TABLE 2Diagnosis-to-delivery interval and the rate of spontaneous preterm delivery
      VariableGestational age at diagnosis, wkP value
      Between gestational age at diagnosis at <24 and 24-28 weeks;
      14-28 (n = 78)<24 (n = 42)24-28 (n = 36)
      Diagnosis-to-delivery interval, d
      Data are presented as median (interquartile range);
      20.5 (5.7–57)17.5 (4–38.5)41 (13–75.5).009
      Interval ratio
      Diagnosis-to-delivery interval/diagnosis-to-37 week interval.
      0.23 (0.06–0.57)0.16 (0.04–0.37)0.49 (0.16–0.9).001
      Delivery within 7 d, n (%)22 (28.2)16 (38.1)6 (16.7).04
      Delivery within 14 d, n (%)28 (35.6)19 (45.2)9 (25.0).1
      Gestational age at delivery, wk
       <24, n (%)NA19 (45.2)NANA
       <28, n (%)42 (53.8)32 (76.2)10 (27.8)< .001
       <32, n/N (%)58/77 (75.3)39 (92.9)19/35 (54.3)< .001
       <34, n/N (%)61/75 (81.3)39/41 (95.1)22/34 (64.7).001
       <37, n/N (%)67/75 (89.3)40/41 (97.6)27/34 (79.4).02
      NA, not available.
      Vaisbuch. The risk of impending delivery in nonmeasurable cervix. Am J Obstet Gynecol 2010.
      a Between gestational age at diagnosis at <24 and 24-28 weeks;
      b Data are presented as median (interquartile range);
      c Diagnosis-to-delivery interval/diagnosis-to-37 week interval.

      Rate of delivery within 7 days and at <32 weeks of gestation: the association with gestational age at diagnosis

      Table 2 shows the rate of preterm delivery within 7 and 14 days from diagnosis and the rate of delivery at <24, <28, <32, <34, and <37 weeks of gestation. Patients who had a nonmeasurable cervical length at <24 weeks of gestation had a higher rate of preterm delivery within 7 days from diagnosis (38.1% vs 16.7%; P = .04) and at <32 weeks of gestation (92.9% vs 54.3%; P < .001) than those who were diagnosed at 24-28 weeks of gestation.
      Kaplan-Meier survival curves of asymptomatic patients who received the diagnosis of a nonmeasurable cervical length at <24 weeks of gestation and those who received the diagnosis between 24 and 28 weeks of gestation are shown in Figure 1. One patient was lost to follow-up evaluation and was censored at 32 weeks of gestation (the last available follow-up visit). All undelivered patients were censored at term (37 completed weeks of gestation). The survival curves of patients who received the diagnosis at <24 weeks of gestation and of those who were diagnosed at 24-28 weeks differed significantly (P = .002, log rank test).
      Figure thumbnail gr1
      FIGURE 1Survival curves according to gestational age at diagnosis
      A Kaplan-Meier survival analysis of the diagnosis-to-delivery interval (days) according to the gestational age at diagnosis (<24 weeks and 24-28 weeks of gestation) in asymptomatic women with a nonmeasurable cervical length in the second trimester of pregnancy. All patients were censored at 37 completed weeks of gestation. The survival curves differed significantly between the 2 groups (P = .002, log rank test).
      Vaisbuch. The risk of impending delivery in nonmeasurable cervix. Am J Obstet Gynecol 2010.

      Association among an a priori risk for preterm delivery, a nonmeasurable cervical length, and preterm birth

      Nineteen patients (45.2%) in the group that received the diagnosis at <24 weeks of gestation and 15 patients (41.7%) in the group that received the diagnosis between 24 and 28 weeks of gestation had an a priori increased risk for a spontaneous preterm delivery (P = .8). There was no significant difference between the Kaplan-Meier survival curves of patients with or without an a priori increased risk for a preterm delivery (P = .32, log rank test; Figure 2).
      Figure thumbnail gr2
      FIGURE 2Survival curves according to an a priori risk for preterm delivery
      A Kaplan-Meier survival analysis of the diagnosis-to-delivery interval (days) according to the presence of an a priori increased risk for spontaneous preterm delivery among asymptomatic women with a nonmeasurable cervical length in the second trimester of pregnancy. An a priori risk for preterm delivery was defined by a history of at least 1 of the following events: (1) ≥2 curettage procedures, (2) spontaneous preterm delivery, and (3) cervical surgery. All patients were censored at 37 completed weeks of gestation. The survival curves of patients with and without such a history did not differ significantly (P = .32, log rank test).
      Vaisbuch. The risk of impending delivery in nonmeasurable cervix. Am J Obstet Gynecol 2010.

      Amniotic fluid sludge

      Amniotic fluid sludge was observed by TVUS examination in 59% of the patients (46/78). The rate of amniotic fluid sludge was higher among patients whose condition was diagnosed at <24 weeks of gestation than among those women who received the diagnosis later in the midtrimester (76.2% vs 38.9%; P = .001). Among patients who received the diagnosis at <24 weeks of gestation, those with amniotic fluid sludge had a shorter median diagnosis-to-delivery interval (11 days; interquartile range [IQR], 3.2–25.7 vs 39.5 days; IQR, 14.5–67.2, respectively; P = .026) and a lower interval ratio (0.09; IQR, 0.03–0.23 vs 0.37; IQR, 0.15–0.63; P = .016) than those without sludge. In addition, among patients whose condition was diagnosed at <24 weeks of gestation, the rate of preterm delivery at <32 weeks gestation was higher in patients with sludge than in patients without this sonographic finding (100% [32/32] vs 70% [7/10]; P = .01), but not among those with the diagnosis at 24-28 weeks of gestation (53.8% [7/13] vs 54.5% [12/22]; P = .99). In contrast, among patients who received the diagnosis at 24-28 weeks of gestation, the median diagnosis-to-delivery interval (34 days; IQR, 12–72.2 vs 45 days; IQR, 13–77.7, respectively; P = .7) and the interval ratio (0.48; IQR, 0.14–0.9 vs 0.55; IQR, 0.18–0.93, respectively; P = .8) were not significantly different between patients with or without amniotic fluid sludge.

      Intraamniotic infection and/or inflammation

      Forty-six patients (60.5% of the study population) had undergone an amniocentesis within 7 days of diagnosis. Amniotic fluid samples for retrospective analysis of IL-6 concentration were available for 41 patients (89%). Table 3 shows the rate of intraamniotic infection and/or inflammation among these patients. Overall, the rate of intraamniotic infection among asymptomatic patients with a nonmeasurable cervical length in the second trimester of pregnancy was 10.9% (5/46). While the rate of intraamniotic inflammation (IL-6, ≥2.6 ng/mL) in these patients was 63.4% (26/41). Among patients who had a negative amniotic fluid culture, the rate was 58.3% (21/36). There were no significant differences in the rate of intraamniotic infection and/or inflammation between women who received the diagnosis at <24 weeks of gestation and those who received the diagnosis at 24-28 weeks of gestation (Table 3). Of note, there was no correlation between amniotic fluid IL-6 concentrations and gestational age at amniocentesis (Spearman's rho, –0.11; P = .47). However, there was a negative correlation between IL-6 concentration and diagnosis-to-delivery interval (Spearman's rho, –0.54; P < .001). Furthermore, the rate of intraamniotic inflammation among patients who delivered within 7 days was higher than that of those who had a diagnosis-to-delivery interval of >7 days (83.3% [15/18] vs 47.8% [11/23]; P = .02).
      TABLE 3Rate of intraamniotic infection and/or intraamniotic inflammation
      VariableGestational age at diagnosis, wkP value
      Between gestational age at diagnosis at <24 and 24-28 weeks;
      14-28 (n = 78)<24 (n = 42)24-28 (n = 36)
      Amniocentesis within 7 d, n (%)46 (60.5)31 (73.8)15 (41.7).006
      Intraamniotic infection, n/N (%)5/46 (10.9)3/31 (9.7)2/15 (13.3)NS
      Amniotic fluid white blood cell count ≥50 cells/mm3, n/N (%)8/46 (17.4)6/31 (19.4)2/15 (13.3)NS
      Intraamniotic inflammation, n/N (%)
      Defined as interleukin-6 concentration ≥2.6 ng/mL.
      26/41 (63.4)17/27 (63.0)9/14 (64.3)NS
      Intraamniotic infection and/or inflammation, n/N (%)27/41 (65.9)18/27 (66.7)9/14 (64.3)NS
      NS, not significant.
      Vaisbuch. The risk of impending delivery in nonmeasurable cervix. Am J Obstet Gynecol 2010.
      a Between gestational age at diagnosis at <24 and 24-28 weeks;
      b Defined as interleukin-6 concentration ≥2.6 ng/mL.
      Among patients who received the diagnosis at <24 weeks of gestation, the rate of intraamniotic infection/inflammation was higher in women with amniotic fluid sludge than in those without the sludge (77.3% [17/22] vs 20% [1/5]; P = .03). In contrast, among patients who received the diagnosis at 24-28 weeks of gestation, there was no difference in the rate of intraamniotic infection/inflammation between those with and without amniotic fluid sludge (50% [3/6] vs 75% [6/8]; P = .58).

      Logistic regression analyses

      Multivariable logistic regression (backward-stepwise) analyses of maternal age, gestational age at diagnosis, cervical dilation (as continuous variables), an a priori risk for preterm delivery, nulliparity, the presence of amniotic fluid sludge, and progesterone treatment (as categoric variables) as explanatory variables for the pregnancy outcome revealed that only gestational age at diagnosis (odds ratio [OR], 0.71; 95% confidence interval [CI], 0.56–0.9; P = .004) and cervical dilation (OR, 1.78; 95% CI, 1.18–2.69; P = .006) were associated independently with a preterm delivery within 7 days. In other words, the risk to deliver within 7 days of diagnosis of a nonmeasurable cervical length decreased by 29% for every 1 week of increase in gestational age at diagnosis and increased by 78% for every 1 cm of cervical dilation. In addition, only gestational age at diagnosis (OR, 0.57; 95% CI, 0.4–0.83; P = .003) and the presence of amniotic fluid sludge (OR, 4.25; 95% CI, 1.02–17.75; P = .047) were associated independently with a preterm delivery at <32 weeks of gestation.

      Comment

      Asymptomatic women in the second trimester of pregnancy with a sonographic cervical length of 0 mm had a median diagnosis-to-delivery interval of almost 3 weeks: one-third of the patients delivered within 2 weeks, and 75% of the women delivered at <32 weeks of gestation. Patients with a nonmeasurable cervical length that was diagnosed at <24 weeks of gestation had a shorter diagnosis-to-delivery interval than those whose condition was diagnosed at 24-28 weeks of gestation, regardless of the presence or absence of an a priori risk for preterm delivery. Approximately two-thirds of patients with a nonmeasurable cervical length have intraamniotic infection/inflammation.
      The present study was designed explicitly to address the question of the clinical significance and natural history of the non-measurable cervical length (0 mm) in asymptomatic patients in the second trimester of pregnancy. Although these patients are considered to be at a very high risk for impending preterm delivery, the current data concerning the natural history of such patients are scarce. Indeed, the expected rate of preterm delivery of these patients is extrapolated from data that were obtained from patients with a short cervix (defined as <15 or <25 mm) or from observations that included a small number of patients with a 0 mm cervical length.
      • 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.
      • Berghella V.
      • Roman A.
      • Daskalakis C.
      • Ness A.
      • Baxter J.K.
      Gestational age at cervical length measurement and incidence of preterm birth.
      Our findings are in agreement with the study by Berghella et al
      • Berghella V.
      • Roman A.
      • Daskalakis C.
      • Ness A.
      • Baxter J.K.
      Gestational age at cervical length measurement and incidence of preterm birth.
      in which the authors reported that the gestational age at which cervical length is measured significantly affects the calculation of risk of spontaneous preterm birth. Using a logistic regression model to calculate the risk of preterm delivery at <32 weeks of gestation, the authors reported a risk of 60-70% for patients whose condition was diagnosed as a 0-mm cervix at <24 weeks of gestation. A slightly lower risk (54-59%) was calculated for women with a 0 mm cervix whose condition was diagnosed at 24-28 weeks of gestation. The present study demonstrates a higher rate of preterm delivery at <32 weeks of gestation, with a more striking difference in this rate between patients who received the diagnosis at <24 weeks of gestation (93%) and between 24 and 28 weeks of gestation (51.5%). Moreover, our study includes the largest sample size of asymptomatic patients with a nonmeasurable cervical length. This allowed us to report that the rate of preterm delivery within 14 days was relatively low and that almost two-thirds of the patients were still pregnant 2 weeks after ultrasound diagnosis. Moreover, women with a nonmeasurable cervical length at <24 weeks of gestation had a significantly higher rate (38.1%) of preterm delivery within 7 days of ultrasound diagnosis than patients whose condition was diagnosed at 24-28 weeks of gestation (16.7%), despite a similar rate of intraamniotic infection/inflammation in these 2 groups of patients. These data are beneficial in counseling patients with a nonmeasurable cervical length regarding possible treatment interventions (ie, cervical cerclage, although we cannot argue about its beneficial effect from this study) or treatments (ie, betamethasone).
      Amniotic fluid sludge, defined as particulate matter seen in proximity of the internal cervical os during a transvaginal sonographic examination of the cervix, occurs in 1% of uncomplicated term pregnancies.
      • Espinoza J.
      • Goncalves L.F.
      • Romero R.
      • et al.
      The prevalence and clinical significance of amniotic fluid “sludge” in patients with preterm labor and intact membranes.
      Our group demonstrated that, among patients with preterm labor, amniotic fluid sludge is a risk factor for microbial invasion of the amniotic cavity (MIAC), histologic chorioamnionitis, and impending spontaneous preterm delivery.
      • Espinoza J.
      • Goncalves L.F.
      • Romero R.
      • et al.
      The prevalence and clinical significance of amniotic fluid “sludge” in patients with preterm labor and intact membranes.
      Moreover, among asymptomatic patients who are at high risk for preterm birth (based on a history of spontaneous preterm delivery, previous midtrimester loss, a cervical length <25 mm, Müllerian duct anomalies, or a history of cone biopsy), amniotic fluid sludge was reported to be an independent risk factor for spontaneous preterm delivery, preterm premature rupture of membranes, MIAC, and histologic chorioamnionitis.
      • Kusanovic J.P.
      • Espinoza J.
      • Romero R.
      • et al.
      Clinical significance of the presence of amniotic fluid “sludge” in asymptomatic patients at high risk for spontaneous preterm delivery.
      In the present study, the rate of amniotic fluid sludge among asymptomatic women with a nonmeasurable cervical length in the midtrimester was 59%. Importantly, the rate of amniotic fluid sludge was significantly higher in women whose condition was diagnosed at <24 weeks of gestation than that in those women whose condition was diagnosed at 24-28 weeks of gestation. Consistent with the aforementioned studies, among asymptomatic patients with a nonmeasurable cervical length, amniotic fluid sludge was associated independently with a preterm delivery at <32 weeks of gestation. Of note, amniotic fluid sludge was associated significantly with a shorter diagnosis-to-delivery interval and a higher rate of preterm delivery at <32 weeks of gestation only among patients whose condition was diagnosed at <24 weeks of gestation. Consistent with this finding, amniotic fluid sludge was associated with a higher rate of intraamniotic infection/inflammation only in patients whose condition was diagnosed at <24 weeks of gestation.
      The present study does not allow us to determine whether a nonmeasurable cervix is the result of MIAC or a predisposing factor. Nevertheless, in our study, a nonmeasurable cervical length was associated with an 11% rate of intraamniotic infection. This finding is in accordance with a previous report by our group in which 9% of asymptomatic women in the midtrimester with a cervical length of <25 mm and without cervical dilation have a microbiologically proven intraamniotic infection.
      • Hassan S.
      • Romero R.
      • Hendler I.
      • et al.
      A sonographic short cervix as the only clinical manifestation of intra-amniotic infection.
      Intraamniotic inflammation was present in almost two-thirds of patients with an asymptomatic nonmeasurable cervical length who had amniocentesis within 1 week of ultrasound diagnosis. The rate of intraamniotic inflammation in these patients is remarkably higher than that reported in patients with a cervical length of ≤15 mm (23%),
      • Vaisbuch E.
      • Hassan S.S.
      • Mazaki-Tovi S.
      • et al.
      Patients with an asymptomatic short cervix (≤15mm) have a high rate of subclinical intra-amniotic inflammation: implications for patient counseling.
      preterm labor (23%),
      • Yoon B.H.
      • Romero R.
      • Moon J.B.
      • et al.
      Clinical significance of intra-amniotic inflammation in patients with preterm labor and intact membranes.
      or with preterm premature rupture of membranes (30%)
      • Shim S.S.
      • Romero R.
      • Hong J.S.
      • et al.
      Clinical significance of intra-amniotic inflammation in patients with preterm premature rupture of membranes.
      and only slightly lower than that of patients with acute cervical insufficiency (79%).
      • 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.
      Consistent with previous reports of patients with a short cervix,
      • Vaisbuch E.
      • Hassan S.S.
      • Mazaki-Tovi S.
      • et al.
      Patients with an asymptomatic short cervix (≤15mm) have a high rate of subclinical intra-amniotic inflammation: implications for patient counseling.
      • Keeler S.M.
      • Kiefer D.G.
      • Rust O.A.
      • et al.
      Comprehensive amniotic fluid cytokine profile evaluation in women with a short cervix: which cytokine(s) correlates best with outcome?.
      • 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?.
      intraamniotic inflammation, even in the absence of proven MIAC (data not shown), was a risk factor for preterm delivery within 7 days of the diagnosis of a nonmeasurable cervical length. Furthermore, amniotic fluid concentrations of IL-6 significantly correlated with diagnosis-to-delivery interval.
      A history of a spontaneous preterm birth,
      • Mercer B.M.
      • Goldenberg R.L.
      • Moawad A.H.
      • et al.
      The preterm prediction study: effect of gestational age and cause of preterm birth on subsequent obstetric outcome: National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network.
      • Ananth C.V.
      • Getahun D.
      • Peltier M.R.
      • Salihu H.M.
      • Vintzileos A.M.
      Recurrence of spontaneous versus medically indicated preterm birth.
      • Goldenberg R.L.
      • Andrews W.W.
      • Faye-Petersen O.
      • Cliver S.
      • Goepfert A.R.
      • Hauth J.C.
      The Alabama Preterm Birth Project: placental histology in recurrent spontaneous and indicated preterm birth.
      a cervical surgery,
      • Berghella V.
      • Pereira L.
      • Gariepy A.
      • Simonazzi G.
      Prior cone biopsy: prediction of preterm birth by cervical ultrasound.
      or a termination of pregnancy
      • Visintine J.
      • Berghella V.
      • Henning D.
      • Baxter J.
      Cervical length for prediction of preterm birth in women with multiple prior induced abortions.
      • Shah P.S.
      • Zao J.
      Induced termination of pregnancy and low birthweight and preterm birth: a systematic review and meta-analyses.
      have all been demonstrated previously to be associated with an increased risk of preterm delivery. In our study, however, an a priori risk for a recurrent spontaneous preterm birth was not contributory to the risk assessment of asymptomatic patients with a nonmeasurable cervical length. Indeed, the survival curves of low-risk and high-risk patients for preterm delivery were similar. It is possible that, among patients with an extremely short cervix, the presence of an a priori risk factor for preterm delivery does not confer an additional risk.
      Individualized risk assessment has been advocated in the prediction of preterm parturition. As a single variable, sonographic cervical length is currently the most powerful predictor of preterm birth. The results of the present study indicate that, even in the presence of a nonmeasurable cervical length, the diagnosis-to-delivery interval varies considerably. Paradoxically, in this subset of patients with an extremely high rate of preterm delivery at <32 weeks of gestation (75%), we cannot use the most reliable tool available to further refine risk assessment. Potential variables that may be beneficial in this context include the patient's history, gestational age at diagnosis, the rate of cervical shortening over time, cervical dilation, the presence of intraamniotic infection and/or inflammation, the presence of amniotic fluid sludge, and the fetal fibronectin test. In the present study, we were able to demonstrate that gestational age at diagnosis, cervical dilation, and amniotic fluid sludge were associated independently with 1 or more of the pregnancy outcomes. Further studies are needed to determine the relevance and relative importance of each of the aforementioned putative variables.
      In conclusion, our findings demonstrate that asymptomatic women in the second trimester of pregnancy with a nonmeasurable sonographic cervical length have a median diagnosis-to-delivery interval that is dependent largely on the gestational age at diagnosis. Patients whose condition was diagnosed at <24 weeks of gestation have a significantly shorter diagnosis-to-delivery interval than those who received the diagnosis ≥24 weeks of gestation. However, because most patients with a 0-mm cervix in the midtrimester will not deliver within 2 weeks, further studies are warranted to develop a customized integrated risk assessment to predict pregnancy outcome. Until that time, the findings of the present study can be helpful to physicians in the counseling and clinical management of patients with a nonmeasurable cervical length diagnosed in the second trimester of pregnancy.

      Acknowledgment

      We acknowledge the contributions of the Registered Diagnostic Medical Sonographers staff and the Research Nurses of the Perinatology Research Branch.

      References

        • McCormick M.C.
        The contribution of low birth weight to infant mortality and childhood morbidity.
        N Engl J Med. 1985; 312: 82-90
        • Steer P.
        The epidemiology of preterm labour.
        BJOG. 2005; 112: 1-3
        • Hamilton B.E.
        • Martin J.A.
        • Ventura S.J.
        Births: preliminary data for 2005.
        Natl Vital Stat Rep. 2006; 55: 1-18
        • Kushnir O.
        • Vigil D.A.
        • Izquierdo L.
        • Schiff M.
        • Curet L.B.
        Vaginal ultrasonographic assessment of cervical length changes during normal pregnancy.
        Am J Obstet Gynecol. 1990; 162: 991-993
        • Andersen H.F.
        Transvaginal and transabdominal ultrasonography of the uterine cervix during pregnancy.
        J Clin Ultrasound. 1991; 19: 77-83
        • Okitsu O.
        • Mimura T.
        • Nakayama T.
        • Aono T.
        Early prediction of preterm delivery by transvaginal ultrasonography.
        Ultrasound Obstet Gynecol. 1992; 2: 402-409
        • Iams J.D.
        • Paraskos J.
        • Landon M.B.
        • Teteris J.N.
        • Johnson F.F.
        Cervical sonography in preterm labor.
        Obstet Gynecol. 1994; 84: 40-46
        • 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.
        Am J Obstet Gynecol. 1995; 172: 1097-1103
        • Iams J.D.
        • Goldenberg R.L.
        • Meis P.J.
        • et al.
        The length of the cervix and the risk of spontaneous premature delivery.
        N Engl J Med. 1996; 334: 567-572
        • Hasegawa I.
        • Tanaka K.
        • Takahashi K.
        • et al.
        Transvaginal ultrasonographic cervical assessment for the prediction of preterm delivery.
        J Matern Fetal Med. 1996; 5: 305-309
        • Berghella V.
        • Kuhlman K.
        • Weiner S.
        • Texeira L.
        • Wapner R.J.
        Cervical funneling: sonographic criteria predictive of preterm delivery.
        Ultrasound Obstet Gynecol. 1997; 10: 161-166
        • Goldenberg R.L.
        • Iams J.D.
        • Mercer B.M.
        • et al.
        The preterm prediction study: the value of new vs standard risk factors in predicting early and all spontaneous preterm births: NICHD MFMU Network.
        Am J Public Health. 1998; 88: 233-238
        • 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.
        Obstet Gynecol. 1998; 92: 31-37
        • 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.
        Ultrasound Obstet Gynecol. 1998; 12: 312-317
        • Taipale P.
        • Hiilesmaa V.
        Sonographic measurement of uterine cervix at 18-22 weeks' gestation and the risk of preterm delivery.
        Obstet Gynecol. 1998; 92: 902-907
        • Watson W.J.
        • Stevens D.
        • Welter S.
        • Day D.
        Observations on the sonographic measurement of cervical length and the risk of premature birth.
        J Matern Fetal Med. 1999; 8: 17-19
        • Hibbard J.U.
        • Tart M.
        • Moawad A.H.
        Cervical length at 16-22 weeks' gestation and risk for preterm delivery.
        Obstet Gynecol. 2000; 96: 972-978
        • Andrews W.W.
        • Copper R.
        • Hauth J.C.
        • Goldenberg R.L.
        • Neely C.
        • Dubard M.
        Second-trimester cervical ultrasound: associations with increased risk for recurrent early spontaneous delivery.
        Obstet Gynecol. 2000; 95: 222-226
        • Hassan S.S.
        • Romero R.
        • Berry S.M.
        • et al.
        Patients with an ultrasonographic cervical length ≤15 mm have nearly a 50% risk of early spontaneous preterm delivery.
        Am J Obstet Gynecol. 2000; 182: 1458-1467
        • Owen J.
        • Yost N.
        • Berghella V.
        • et al.
        Mid-trimester endovaginal sonography in women at high risk for spontaneous preterm birth.
        JAMA. 2001; 286: 1340-1348
        • 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.
        Ultrasound Obstet Gynecol. 2001; 18: 200-203
        • Durnwald C.P.
        • Walker H.
        • Lundy J.C.
        • Iams J.D.
        Rates of recurrent preterm birth by obstetrical history and cervical length.
        Am J Obstet Gynecol. 2005; 193: 1170-1174
        • Matijevic R.
        • Grgic O.
        • Vasilj O.
        Is sonographic assessment of cervical length better than digital examination in screening for preterm delivery in a low-risk population?.
        Acta Obstet Gynecol Scand. 2006; 85: 1342-1347
        • Andersen H.F.
        • Nugent C.E.
        • Wanty S.D.
        • Hayashi R.H.
        Prediction of risk for preterm delivery by ultrasonographic measurement of cervical length.
        Am J Obstet Gynecol. 1990; 163: 859-867
        • Tekesin I.
        • Eberhart L.H.
        • Schaefer V.
        • Wallwiener D.
        • Schmidt S.
        Evaluation and validation of a new risk score (CLEOPATRA score) to predict the probability of premature delivery for patients with threatened preterm labor.
        Ultrasound Obstet Gynecol. 2005; 26: 699-706
        • To M.S.
        • Skentou C.A.
        • Royston P.
        • Yu C.K.
        • Nicolaides K.H.
        Prediction of patient-specific risk of early preterm delivery using maternal history and sonographic measurement of cervical length: a population-based prospective study.
        Ultrasound Obstet Gynecol. 2006; 27: 362-367
        • Visintine J.
        • Berghella V.
        • Henning D.
        • Baxter J.
        Cervical length for prediction of preterm birth in women with multiple prior induced abortions.
        Ultrasound Obstet Gynecol. 2008; 31: 198-200
        • Heath V.C.
        • Southall T.R.
        • Souka A.P.
        • Novakov A.
        • Nicolaides K.H.
        Cervical length at 23 weeks of gestation: relation to demographic characteristics and previous obstetric history.
        Ultrasound Obstet Gynecol. 1998; 12: 304-311
        • 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.
        Lancet. 2004; 363: 1849-1853
        • Palma-Dias R.S.
        • Fonseca M.M.
        • Stein N.R.
        • Schmidt A.P.
        • Magalhaes J.A.
        Relation of cervical length at 22-24 weeks of gestation to demographic characteristics and obstetric history.
        Braz J Med Biol Res. 2004; 37: 737-744
        • Celik E.
        • To M.
        • Gajewska K.
        • Smith G.C.
        • Nicolaides K.H.
        Cervical length and obstetric history predict spontaneous preterm birth: development and validation of a model to provide individualized risk assessment.
        Ultrasound Obstet Gynecol. 2008; 31: 549-554
        • Tongsong T.
        • Kamprapanth P.
        • Srisomboon J.
        • Wanapirak C.
        • Piyamongkol W.
        • Sirichotiyakul S.
        Single transvaginal sonographic measurement of cervical length early in the third trimester as a predictor of preterm delivery.
        Obstet Gynecol. 1995; 86: 184-187
        • Berghella V.
        • Tolosa J.E.
        • Kuhlman K.
        • Weiner S.
        • Bolognese R.J.
        • Wapner R.J.
        Cervical ultrasonography compared with manual examination as a predictor of preterm delivery.
        Am J Obstet Gynecol. 1997; 177: 723-730
        • To M.S.
        • Skentou C.
        • Cicero S.
        • Liao A.W.
        • Nicolaides K.H.
        Cervical length at 23 weeks in triplets: prediction of spontaneous preterm delivery.
        Ultrasound Obstet Gynecol. 2000; 16: 515-518
        • Berghella V.
        • Roman A.
        • Daskalakis C.
        • Ness A.
        • Baxter J.K.
        Gestational age at cervical length measurement and incidence of preterm birth.
        Obstet Gynecol. 2007; 110: 311-317
        • 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.
        N Engl J Med. 2007; 357: 462-469
        • 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.
        Ultrasound Obstet Gynecol. 2007; 30: 697-705
        • Dodd J.M.
        • Flenady V.J.
        • Cincotta R.
        • Crowther C.A.
        Progesterone for the prevention of preterm birth: a systematic review.
        Obstet Gynecol. 2008; 112: 127-134
        • 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.
        Ultrasound Obstet Gynecol. 1998; 12: 318-322
        • Althuisius S.M.
        The short and funneling cervix: when to use cerclage?.
        Curr Opin Obstet Gynecol. 2005; 17: 574-578
        • 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.
        Obstet Gynecol. 2005; 106: 181-189
        • Owen J.
        Multicenter randomized trial of cerclage for preterm birth prevention in high-risk women with shortened mid-trimester cervical length.
        Am J Obstet Gynecol. 2009; 201: 375.e1-375.e8
        • Hassan S.
        • Romero R.
        • Hendler I.
        • et al.
        A sonographic short cervix as the only clinical manifestation of intra-amniotic infection.
        J Perinat Med. 2006; 34: 13-19
        • Berghella V.
        • Rust O.A.
        • Althuisius S.M.
        Short cervix on ultrasound: does indomethacin prevent preterm birth?.
        Am J Obstet Gynecol. 2006; 195: 809-813
        • Hassan S.S.
        • Romero R.
        • Maymon E.
        • et al.
        Does cervical cerclage prevent preterm delivery in patients with a short cervix?.
        Am J Obstet Gynecol. 2001; 184: 1325-1329
        • 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.
        Am J Obstet Gynecol. 2001; 185: 1098-1105
        • 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.
        Am J Obstet Gynecol. 2004; 191: 1311-1317
        • Fox N.S.
        • Chervenak F.A.
        Cervical cerclage: a review of the evidence.
        Obstet Gynecol Surv. 2008; 63: 58-65
        • Guzman E.R.
        • Shen-Schwarz S.
        • Benito C.
        • Vintzileos A.M.
        • Lake M.
        • Lai Y.L.
        The relationship between placental histology and cervical ultrasonography in women at risk for pregnancy loss and spontaneous preterm birth.
        Am J Obstet Gynecol. 1999; 181: 793-797
        • Mays J.K.
        • Figueroa R.
        • Shah J.
        • Khakoo H.
        • Kaminsky S.
        • Tejani N.
        Amniocentesis for selection before rescue cerclage.
        Obstet Gynecol. 2000; 95: 652-655
        • Yoon B.H.
        • Romero R.
        • Moon J.B.
        • et al.
        Clinical significance of intra-amniotic inflammation in patients with preterm labor and intact membranes.
        Am J Obstet Gynecol. 2001; 185: 1130-1136
        • Espinoza J.
        • Goncalves L.F.
        • Romero R.
        • et al.
        The prevalence and clinical significance of amniotic fluid “sludge” in patients with preterm labor and intact membranes.
        Ultrasound Obstet Gynecol. 2005; 25: 346-352
        • Kusanovic J.P.
        • Espinoza J.
        • Romero R.
        • et al.
        Clinical significance of the presence of amniotic fluid “sludge” in asymptomatic patients at high risk for spontaneous preterm delivery.
        Ultrasound Obstet Gynecol. 2007; 30: 706-714
        • Vaisbuch E.
        • Hassan S.S.
        • Mazaki-Tovi S.
        • et al.
        Patients with an asymptomatic short cervix (≤15mm) have a high rate of subclinical intra-amniotic inflammation: implications for patient counseling.
        Am J Obstet Gynecol. 2010; 202 (e1-8): 433
        • Shim S.S.
        • Romero R.
        • Hong J.S.
        • et al.
        Clinical significance of intra-amniotic inflammation in patients with preterm premature rupture of membranes.
        Am J Obstet Gynecol. 2004; 191: 1339-1345
        • 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.
        Am J Obstet Gynecol. 2008; 198: 633-638
        • Keeler S.M.
        • Kiefer D.G.
        • Rust O.A.
        • et al.
        Comprehensive amniotic fluid cytokine profile evaluation in women with a short cervix: which cytokine(s) correlates best with outcome?.
        Am J Obstet Gynecol. 2009; 201 (e1-6): 276
        • 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?.
        Am J Obstet Gynecol. 2009; 200: 374-375
        • Mercer B.M.
        • Goldenberg R.L.
        • Moawad A.H.
        • et al.
        The preterm prediction study: effect of gestational age and cause of preterm birth on subsequent obstetric outcome: National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network.
        Am J Obstet Gynecol. 1999; 181: 1216-1221
        • Ananth C.V.
        • Getahun D.
        • Peltier M.R.
        • Salihu H.M.
        • Vintzileos A.M.
        Recurrence of spontaneous versus medically indicated preterm birth.
        Am J Obstet Gynecol. 2006; 195: 643-650
        • Goldenberg R.L.
        • Andrews W.W.
        • Faye-Petersen O.
        • Cliver S.
        • Goepfert A.R.
        • Hauth J.C.
        The Alabama Preterm Birth Project: placental histology in recurrent spontaneous and indicated preterm birth.
        Am J Obstet Gynecol. 2006; 195: 792-796
        • Berghella V.
        • Pereira L.
        • Gariepy A.
        • Simonazzi G.
        Prior cone biopsy: prediction of preterm birth by cervical ultrasound.
        Am J Obstet Gynecol. 2004; 191: 1393-1397
        • Shah P.S.
        • Zao J.
        Induced termination of pregnancy and low birthweight and preterm birth: a systematic review and meta-analyses.
        BJOG. 2009; 116: 1425-1442

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