J. Perinat. Med. 2015; aop
Dinah von Schöning, Thomas Fischer, Elisabeth von Tucher, Torsten Slowinski, Alexander Weichert, Wolfgang Henrich and Anke Thomas*
Cervical sonoelastography for improving prediction of preterm birth compared with cervical length measurement and fetal fibronectin test Abstract Aim: Accurate prediction of the risk of spontaneous preterm birth is crucial for the clinical management of patients with preterm labor. The aim of the study was to investigate whether cervical sonoelastography improves prediction of spontaneous preterm birth compared with cervical length measurement and a fetal fibronectin (fFN) test. Methods: A prospective cohort study was conducted including 64 patients with preterm labor at 23–34 weeks of gestation. Patients had an fFN test and transvaginal cervical length measurement, followed by real-time cervical sonoelastography. The ratio of nondeformable tissue to the total area of a designed region of interest was analyzed and related to the gestational week of delivery. Results: Cervical sonoelastography and fFN test show a significant correlation with spontaneous preterm delivery (P = 0.007, P = 0.001), resulting in 72.7%/36% sensitivity and 73%/95% specificity. The positive predictive value (PPV) was 61.5%/81.8% and the negative predictive value was 81.8%/70%. The cervical length was not different in cases with and without term delivery (P = 0.165). Conclusions: Cervical sonoelastography is a promising technique that can complement routine diagnostic
*Corresponding author: PD Dr med. Anke Thomas, Ultrasound Research Lab, Department of Obstetrics, Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; and Ultrasound Research Lab, Department of Radiology, Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany, Tel.: +49-30-450664564; Fax: +49-30-450527975, E-mail: [email protected] Dinah von Schöning, Elisabeth von Tucher, Alexander Weichert and Wolfgang Henrich: Ultrasound Research Lab, Department of Obstetrics, Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany Thomas Fischer: Ultrasound Research Lab, Department of Radiology, Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany Torsten Slowinski: Department of Nephrology, Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
procedures to improve prediction of preterm birth. The PPV is improved by an fFN test. Keywords: Cervical length measurement; elastography; fetal fibronectin; premature birth; transvaginal ultrasound. DOI 10.1515/jpm-2014-0356 Received November 17, 2014. Accepted December 3, 2014.
Introduction Preterm delivery is a leading cause of perinatal mortality and morbidity [1]. It occurs in 5–18% of pregnancies worldwide [2]. To focus clinical management on patients at high risk and to avoid unnecessary treatment and hospitalization, accurate prediction of preterm delivery is required. The best predictors of spontaneous preterm birth available today are a shortened cervical length in the second trimester of pregnancy and an elevated concentration of fetal fibronectin (fFN) in the cervicovaginal fluid [3]. A correlation between spontaneous preterm delivery and a short cervix has been demonstrated by many investigators, including Tsoi [4], To [5], and Iams [6]. The sensitivity and specificity of cervical length measurement depend on the cut-off value and on the risk factors of the study population. The concentration of fFN, a glycoprotein present in the cervicovaginal fluid between 22 and 35 gestational weeks, was shown to correlate with the risk of spontaneous premature delivery. As demonstrated in several studies reviewed by Daskalakis et al. [7], the fFN test has a high negative predictive value (NPV), 93–99.7% for symptomatic patients and 86–99% for asymptomatic patients. However, the positive predictive value (PPV) is low and very variable (13–85%), depending on the characteristics of the study population. The combination of fFN with cervical length measurement can improve the PPV in symptomatic patients while maintaining a high NPV [8]. Sonoelastography is an emerging ultrasound technique that has been successfully used for detecting focal
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2 Schöning et al., Cervical sonoelastography to predict preterm birth
pathologies in various organs such as breast, liver, and thyroid gland based on divergent mechanical properties [9–12]. Combined with transvaginal ultrasound, cervical sonoelastography permits quantitative evaluation of cervical tissue elasticity [13]. Several investigators have demonstrated the technical feasibility and reproducibility of the method in assessing the cervical tissue stiffness in asymptomatic women at different stages of pregnancy [14–16]. In the clinical context, cervical sonoelastography has been used to detect focal pathologies of the cervix [17] and to predict the success of labor induction at term [18, 19]. The potential to improve risk management of preterm delivery is being discussed [20]. However, women with risk factors or women with preterm labor have not been examined by cervical sonoelastography so far. In the present study, cervical sonoelastography was combined with cervical length measurement and the fFN test in patients with preterm labor during the second trimester. A detailed and precise risk assessment would help to focus therapeutic interventions on patients at high risk.
The patients received a routine pelvic examination. First, premature rupture of membranes was excluded using a commercially available test (AmniSure®, QIAGEN, Hilden, Germany). As a second step, a commercial qualitative fFN enzyme immunoessay (Rapid fFN TLiIQ® System, Hologic, Marlborough, MA, USA) was performed following the manufacturer’s instructions. An fFN concentration ≥ 50 ng/mL was considered positive. Transvaginal ultrasound was performed (9 MHz, Hi Vision Preirus, Hitachi Medical Systems, Wiesbaden, Germany) for cervical length measurement and assessment of cervical funneling. Patients were examined with the emptied urinary bladder. The cervical length was measured in a sagittal plane of the cervix. For the subsequent real-time sonoelastography, the color-encoded mode was superimposed on the B-mode image. No additional pressure was applied on the cervix. Each examination was repeated three times by two different investigators. The information on cervical tissue displacement was represented by a color scale, with blue indicating stiff tissue, green representing average stiffness, and red indicating soft deformable tissue. More technical details of the method are reported by Thomas et al. [17]. A rectangular region of interest (ROI) was placed manually, covering the anterior cervical lip and the endocervical canal. The mean proportion of the blue area (stiff tissue) from three measurements was calculated for further statistical analysis. Patients were followed up for gestational age at the time of delivery.
Methods Statistical analysis
Study design A prospective cohort study was conducted that was double-blinded for the fFN test. The study design and protocol were approved by the local ethics board (EA2/007/08).
Study population The study was conducted in the Department of Obstetrics at Charité University Hospital, Campus Mitte, Berlin, Germany, from January to December 2013. The patients included in the study were aged above 18 and between 23/0 and 33/6 weeks of gestation. They had clinical criteria of preterm labor, including uterine contractions, intermittent lower abdominal pain, and pelvic pressure. Singleton and multiple pregnancies were included in the study. Written informed consent was obtained from all patients at the time of enrollment. Patients with vaginal bleeding, cervical dilatation, rupture of membranes, polyhydramnios, placenta previa, or prior cerclage were excluded. Due to possible false positive results of the fFN test, patients with pelvic examination, transvaginal ultrasound, or intercourse in the previous 24 h were also excluded from the study.
Study protocol and data collection The patients’ data and history were assessed regarding the following aspects: age, gravidity, parity, gestational age at time of enrollment, prior preterm delivery, and nicotine abuse.
Data were analyzed using univariate analysis of variance and logistic regression analysis by Pearson. P-value ≤ 0.05 was considered statistically significant. Receiver operating characteristic (ROC) curves were used to determine the best cut-off values for cervical length and the mean percentage of the blue area in relation to preterm birth. The area under the curve (AUC) was derived. Statistical analysis was performed using two software packages, PASW Statistics, version 18.0 (SPSS Inc., Chicago, IL, USA) and GraphPad Prism, version 5.0 (GraphPad Software, San Diego, CA, USA).
Results Initially, 67 patients were included in the study. However, two patients were excluded retrospectively because follow-up was not possible. One patient was excluded four days after enrollment due to pathologic fetal Doppler findings that led to iatrogenic preterm delivery. This resulted in 64 patients for further analysis. The characteristics of the study population are summarized in Table 1. Patients were aged between 18 and 43 years. Six patients were smokers (9.4%). Gestational age at the time of enrollment was between 23/0 and 33/6 weeks (mean 28/1 weeks). Nine women with twin pregnancies were included. Forty patients (62.5%) were nulliparous, and eight patients (12.5%) had a history of
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Schöning et al., Cervical sonoelastography to predict preterm birth 3
Table 1 Characteristics of the study population. Data are shown as range [mean value, standard deviation (SD)] or n (%). Study population, n = 64 Age Nulliparous Prior preterm birth Nicotine abuse Twin pregnancies Gestational age at enrollment Cervical length Cervical funneling fFN test positive Gestational age at delivery Preterm delivery
18–43 years (30.6, SD ± 6.0) 40 (62.5) 8 (12.5) 6 (9.4) 9 (14.0) 23/0–33/6 weeks (28/1, SD ± 26 days) 6–41 mm (19.4, SD ± 9.3) 36 (56.3) 11 (17.2) 24/1–41/5 weeks (36/5, SD ± 27 days) 25 (39.1)
fFN = fetal fibronectin.
preterm birth. The cervical length was 6–41 mm at the time of enrollment (mean 19.4 mm). Cervical funneling was found in 36 cases (56.3%). In 11 cases, the fFN test was positive (17.2%). Gestational age at the time of delivery was between 24/1 and 41/5 weeks. In total, 25 patients (39.1%) had a preterm delivery. Three patients were delivered within 10 days of enrollment, one of them within 48 h. Data from the patients’ history such as parity, prior preterm birth, and nicotine abuse did not correlate significantly with gestational age at delivery (Table 2). For analysis of the elastographic data, the mean proportion of the blue area (stiff tissue) in the ROI of each case was related to the gestational week at delivery (Figure 1). The mean proportion of the blue area ranged from 0% to 70.4% [mean 17.5%, standard deviation (SD) 17.4%] and correlated significantly with preterm birth (P = 0.007). The data were represented as the ROC curve, which resulted in an AUC of 0.711 (Figure 2). A cut-off value of 9.1% for the proportion of the blue area in the ROI was derived. When applied for the prediction of preterm birth, this resulted
Table 2 Correlation between patients’ history and gestational age at delivery. Delivery
Parity Prior preterm birth Nicotine abuse
0 ≥ 1 Yes No Yes No
Preterm
Term
13 12 5 20 2 23
27 12 3 36 4 35
P-value
0.165 0.146 0.763
in a sensitivity of 72.7%, a specificity of 73.0%, a PPV of 61.5%, and an NPV of 81.8%, as shown in Table 3. In contrast, the cervical length was not significantly different between cases with term delivery and cases with preterm delivery (P = 0.165). The mean cervical length of patients with preterm birth was 18.4 mm (SD 11.2 mm). Patients with term delivery had a mean cervical length of 19.9 mm (SD 8.0 mm). ROC curve analysis resulted in an AUC of 0.604 (Figure 2). However, the presence of cervical funneling was shown to be a sensitive and significant predictor of preterm birth in the study population (P = 0.011). Cervical funneling occurred in 19 of 25 patients with preterm delivery, and thus had 76.0% sensitivity. Specificity was 56.4%. Data are summarized in Table 3. The fFN test was positive in 9 of 25 cases with preterm birth. Only two patients who were delivered at term had a positive fFN test, resulting in 36.0% sensitivity and 95.0% specificity (Table 3).
Discussion Ultrasound elastography has been successfully integrated into diagnostic imaging procedures. It can contribute to better detection and characterization of a variety of pathologies, such as diffuse liver disease, breast lesions, thyroid nodules, and prostate abnormalities [9], by providing additional information on the elasticity of a lesion relative to that of surrounding tissue. Sonoelastography of the uterine cervix is an emerging technique for quantifying cervical tissue stiffness. The technical feasibility and reproducibility of results in all three trimesters of pregnancy has been demonstrated by several investigators [14, 15, 21]. However, different technical approaches and the need for standardization are important issues under discussion [22]. In the present study, for the first time, a selected study population with premature labor is examined by cervical sonoelastography to evaluate its potential for prediction of preterm delivery. Experience during the study has revealed cervical sonoelastography to be a fast and feasible method that could be used in symptomatic patients without any complication or risk. In combination with cervical length measurement, it can easily be integrated into clinical routine. Different approaches have been suggested to standardize the pressure applied during elastography, e.g., advancement of the probe into the cervical tissue for 1 cm [16] or compression of the anterior portion of the cervical tissue until dislocation of
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4 Schöning et al., Cervical sonoelastography to predict preterm birth
A
B
C
D
Figure 1 Transvaginal ultrasound for cervical length measurement and cervical sonoelastography in two patients with premature contractions. (A) Transvaginal ultrasound in a 36-year-old woman in the 30th week of gestation, who presented to the hospital with premature contractions. B-mode ultrasound shows a shortened cervix of 16.6 mm with funneling. Elastography (B) shows the cervical area in the ROI to be soft (left). The color portion in the histogram lies in the red and green area. Only 2.2% of the area is blue. With the positive fFN test, the patient had preterm birth in the 32nd week of gestation. (C) A 26-year-old patient with premature contractions in the 29th week of gestation has a cervical length of 31 mm without funneling. Elastography (D) suggests greater stiffness of cervical tissue with a blue portion of 27.4%, which is also seen in the histogram. fFN was negative, and the woman gave birth in the 40th week of gestation.
0.8
0.8
0.6
0.6
Sensitivity
B 1.0
Sensitivity
A 1.0
0.4
0.2
0
0.4
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0
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0.4
0.6
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0
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Figure 2 Receiver operating characteristic (ROC) curves representing correlation between gestational age at delivery and cervical length (A) and gestational age at delivery and elastography findings (B). (A) Correlation between cervical length and gestational age at delivery was not significant (P = 0.165). ROC curve analysis resulted in an area under the curve (AUC) of 0.604. (B) Analysis of elastography findings yielded a significant correlation between the mean proportion of the blue area in the ROI and gestational age at delivery (P = 0.007). An AUC of 0.711 was shown, resulting in a cut-off value of 9.1% for the proportion of the blue area in the ROI. Brought to you by | University of California Authenticated Download Date | 6/5/15 2:28 PM
Schöning et al., Cervical sonoelastography to predict preterm birth 5
Table 3 Test parameters for prediction of preterm birth.
Sensitivity Specificity Positive predictive value Negative predictive value
fFN test
Cervical funneling
Elastography, blue area in ROI, 9.1% cut-off
P = 0.001
P = 0.011
P = 0.007
36.0% 95.0% 81.8% 70.0%
76.0% 56.4% 52.8% 78.6%
72.7% 73.0% 61.5% 81.8%
ROI = region of interest.
the posterior cervical lip occurs [14]. In the present study, no additional pressure was applied to avoid manipulation of the cervix in symptomatic patients. The elastographic image was created by the patient’s breathing or arterial pulsation, according to the technique published by Swiatkowska-Freund and Preis [19] and Thomas et al. [17]. More than half of the patients showed cervical funneling with different length and shape. Previous studies or guidelines for the analysis of cervical elastography with funneling are lacking. In our experience, the most reliable data could be obtained when the rectangular ROI was placed manually on the anterior cervical lip, including the endocervical canal, but avoiding most of the posterior lip. It appeared difficult to reach the posterior cervical lip by elastography when cervical funneling was present. We found a significant correlation between cervical sonoelastographic findings and preterm birth in our study population. Cervical length was not a predictor of preterm delivery, which might be attributable to the small number of patients. This might also explain why no significant correlation was found for the known risk factor of prior preterm birth. The primary outcome of the study was delivery ≥ 37/0 gestational weeks. Although usually used to predict delivery within the next 7–10 days [23], the fFN test was compared to the other diagnostic tests for the primary outcome of the study. This is the reason for the relatively low sensitivity and NPV of the test. When the fFN test results are correlated to delivery within the next 7–10 days, sensitivity increases to 100% and specificity to 86.9%. The PPV is 27.3% and the NPV is 100%. These data correspond to the test characteristics published so far. The use of a quantitative fFN test could improve risk management in the future [24, 25]. The benefit of combined cervical screening and the fFN test in symptomatic patients is still under discussion. It was shown by Schmitz et al. [26] and Hincz et al. [27] that the sequential use of the fFN test after cervical
length measurement can improve diagnostic accuracy. Sensitivity and specificity for predicting spontaneous preterm delivery in < 35 weeks were increased to 67% and 81%, respectively [26]. In contrast, Deplagne and colleagues [28] found the combined use of cervical length measurement and fFN determination to be as effective as either test alone. In a systematic review, DeFranco and co-workers [8] concluded that combined screening, including cervical length and fFN, provides useful information for predicting the short-term risk of spontaneous preterm birth. In the present study, the elastographic information alone had 72.7% sensitivity and 73% specificity for prediction of spontaneous preterm birth. However, comparison of data is difficult due to heterogeneous study populations and different outcomes. It needs to be investigated if the use of a triple test combining cervical length measurement, cervical sonoelastography, and the fFN test can further improve diagnostic accuracy. The present study results are clearly limited by the lack of standardized procedures for the analysis of elastographic information especially in symptomatic patients with a short cervix or funneling. The study population was small, included singleton and multiple pregnancies, and was selected from a specialized obstetrical department in a university hospital. Further studies with a larger patient collective are needed to develop guidelines for cervical elastography in symptomatic patients. The calculation of elastographic strain values, indicating numerically the displacement of tissue within an ROI [29], might help in standardizing the technique.
Conclusion Cervical sonoelastography is a promising technique for predicting spontaneous preterm delivery in patients with preterm labor. Further studies are required to improve standardization and to assess the clinical impact of the technique. It might potentially supplement routine diagnostic procedures. Accurate identification of patients at high risk could help to focus therapeutic management on them [30]. Unnecessary treatment, cost-intensive hospitalization, and potential side effects of tocolytic agents and corticosteroids could thus be minimized for low-risk patients. Acknowledgments: We thank the medical team of the obstetric department, Charité University Medicine, Berlin, for assistance in patient enrollment.
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6 Schöning et al., Cervical sonoelastography to predict preterm birth
References [1] Beck S, Wojdyla D, Say L, Betran AP, Merialdi M, Requejo JH, et al. The worldwide incidence of preterm birth: a systematic review of maternal mortality and morbidity. Bull World Health Organ. 2010;88:31–8. [2] Blencowe H, Cousens S, Oestergaard MZ, Chou D, Moller AB, Narwal R, et al. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet. 2012;379:2162–72. [3] Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet. 2008;371:75–84. [4] Tsoi E, Fuchs IB, Rane S, Geerts L, Nicolaides KH. Sonographic measurement of cervical length in threatened preterm labor in singleton pregnancies with intact membranes. Ultrasound Obstet Gynecol. 2005;25:353–6. [5] To MS, Skentou CA, Royston P, Yu CK, Nicolaides KH. 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;27:362–7. [6] Iams JD, Goldenberg RL, Meis PJ, Mercer BM, Moawad A, Das A, et al. The length of the cervix and the risk of spontaneous premature delivery. N Engl J Med. 1996;334:567–72. [7] Daskalakis GJ, Papantoniou NE, Koutsodimas NB, Papapanagiotou A, Antsaklis AJ. Fetal fibronectin as predictor for preterm birth. J Obstet Gynecol. 2000;20:347–53. [8] DeFranco EA, Lewis DF, Odibo AO. Improving the screening accuracy for preterm labor: is the combination of fetal fibronectin and cervical length in symptomatic patients a useful predictor for preterm birth? A systematic review. Am J Obstet Gynecol. 2013;208:233.e1–6. [9] Cosgrove D, Piscaglia F, Bamber J, Bojunga J, Correas JM, Gilja OH, et al. EFSUMB guidelines and recommendations on the clinical use of ultrasound elastography. Part 2: Clinical applications. Ultraschall Med. 2013;34:238–53. [10] Frulio N, Trillaud H. Ultrasound elastography in liver. Diagn Interv Imaging. 2013;94:515–34. [11] Thomas A, Degenhardt F, Farrokh A, Wojcinski S, Slowinski T, Fischer T. Significant differentiation of focal breast lesions: calculation of strain ratio in breast sonoelastography. Acad Radiol. 2010;17:558–63. [12] Thomas A, Warm M, Hoopmann M, Diekmann F, Fischer T. Tissue Doppler and strain imaging for evaluating tissue elasticity of breast lesions. Acad Radiol. 2007;14:522–9. [13] Feltovich H, Hall TJ, Berghella V. Beyond cervical length: emerging technologies for assessing the pregnant cervix. Am J Obstet Gynecol. 2012;207:345–54. [14] Fruscalzo A, Steinhard J, Londero AP, Fröhlich C, Bijnens B, Klockenbusch W, et al. Reliability of quantitative elastography of the uterine cervix in at-term pregnancies. J Perinat Med. 2013;41:421–7. [15] Hernandez-Andrade E, Hassan SS, Ahn H, Korzeniewski SJ, Yeo L, Chaiworapongsa T, et al. Evaluation of cervical stiffness during pregnancy using semiquantitative ultrasound elastography. Ultrasound Obstet Gynecol. 2013;41:152–61.
[16] Molina FS, Gómez LF, Florido J, Padilla MC, Nicolaides KH. Quantification of cervical elastography: a reproducibility study. Ultrasound Obstet Gynecol. 2012;39:685–9. [17] Thomas A, Kümmel S, Gemeinhardt O, Fischer T. Real-time sonoelastography of the cervix: tissue elasticity of the normal and abnormal cervix. Acad Radiol. 2007;14:193–200. [18] Hwang HS, Sohn IS, Kwon HS. Imaging analysis of cervical elastography of prediction of successful induction of labor at term. J Ultrasound Med. 2013;32:937–46. [19] Swiatkowska-Freund M, Preis K. Elastography of the uterine cervix: implications for success of induction of labor. Ultrasound Obstet Gynecol. 2011;38:52–6. [20] Khalil MR, Thorsen P, Uldbjerg N. Cervical ultrasound elastography may hold the potential to predict risk of preterm birth. Dan Med J. 2013;60:A4570. [21] Fruscalzo A, Schmitz R, Klockenbusch W, Steinhard J. Reliability of cervix elastography in the late first and second trimester of pregnancy. Ultraschall Med. 2012;33:E101–7. [22] Fruscalzo A, Schmitz R. Quantitative cervical elastography in pregnancy. Ultrasound Obstet Gynecol. 2012;40:612–3. [23] Honest H, Bachmann LM, Gupta JK, Kleijnen J, Khan KS. Accuracy of cervicovaginal fetal fibronectin test in predicting risk of spontaneous preterm birth: systematic review. Br Med J. 2002;325:301. [24] Abbott DS, Radford SK, Seed PT, Tribe RM, Shennan AH. Evaluation of a quantitative fetal fibronectin test for spontaneous preterm birth in symptomatic women. Am J Obstet Gynecol. 2013;208:122.e1–6. [25] Kurtzman J, Chandiramani M, Briley A, Poston L, Das A, Shennan A. Quantitative fetal fibronectin screening in asymptomatic high-risk patients and the spectrum of risk for recurrent preterm delivery. Am J Obstet Gynecol. 2009;200:263.e1–6. [26] Schmitz T, Maillard F, Bessard-Bacquaert S, Kayem G, Fulla Y, Cabrol D, et al. Selective use of fetal fibronectin detection after cervical length measurement to predict spontaneous preterm delivery in women with preterm labor. Am J Obstet Gynecol. 2006;194:138–43. [27] Hincz P, Wilczynski J, Kozarzewski M, Szaflik K. Two-step test: the combined use of fetal fibronectin and sonographic examination of the uterine cervix for prediction of preterm delivery in symptomatic patients. Acta Obstet Gynecol Scand. 2002;81:58–63. [28] Deplagne C, Maurice-Tison S, Coatleven F, Vandenbossche F, Horovitz J. Sequential use of cervical length measurement before fetal fibronectin detection to predict spontaneous preterm delivery in women with preterm labor. J Gynecol Obstet Biol Reprod. 2010;39:575–83. [29] Greenleaf JF, Fatemi M, Insana M. Selected methods for imaging elastic properties of biological tissues. Annu Rev Biomed Eng. 2003;5:57–78. [30] Dutta D, Norman JE. The efficacy of fetal fibronectin testing in minimising hospital admissions, length of hospital stay, and cost savings in women presenting with symptoms of pre-term labor. J Obstet Gynecol. 2010;30:768–73.
The authors stated that there are no conflicts of interest regarding the publication of this article.
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Dinah von Schöning, Thomas Fischer, Elisabeth von Tucher, Torsten Slowinski, Alexander Weichert, Wolfgang Henrich and Anke Thomas*
Cervical sonoelastography for improving prediction of preterm birth compared with cervical length measurement and fetal fibronectin test Abstract Aim: Accurate prediction of the risk of spontaneous preterm birth is crucial for the clinical management of patients with preterm labor. The aim of the study was to investigate whether cervical sonoelastography improves prediction of spontaneous preterm birth compared with cervical length measurement and a fetal fibronectin (fFN) test. Methods: A prospective cohort study was conducted including 64 patients with preterm labor at 23–34 weeks of gestation. Patients had an fFN test and transvaginal cervical length measurement, followed by real-time cervical sonoelastography. The ratio of nondeformable tissue to the total area of a designed region of interest was analyzed and related to the gestational week of delivery. Results: Cervical sonoelastography and fFN test show a significant correlation with spontaneous preterm delivery (P = 0.007, P = 0.001), resulting in 72.7%/36% sensitivity and 73%/95% specificity. The positive predictive value (PPV) was 61.5%/81.8% and the negative predictive value was 81.8%/70%. The cervical length was not different in cases with and without term delivery (P = 0.165). Conclusions: Cervical sonoelastography is a promising technique that can complement routine diagnostic
*Corresponding author: PD Dr med. Anke Thomas, Ultrasound Research Lab, Department of Obstetrics, Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; and Ultrasound Research Lab, Department of Radiology, Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany, Tel.: +49-30-450664564; Fax: +49-30-450527975, E-mail: [email protected] Dinah von Schöning, Elisabeth von Tucher, Alexander Weichert and Wolfgang Henrich: Ultrasound Research Lab, Department of Obstetrics, Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany Thomas Fischer: Ultrasound Research Lab, Department of Radiology, Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany Torsten Slowinski: Department of Nephrology, Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
procedures to improve prediction of preterm birth. The PPV is improved by an fFN test. Keywords: Cervical length measurement; elastography; fetal fibronectin; premature birth; transvaginal ultrasound. DOI 10.1515/jpm-2014-0356 Received November 17, 2014. Accepted December 3, 2014.
Introduction Preterm delivery is a leading cause of perinatal mortality and morbidity [1]. It occurs in 5–18% of pregnancies worldwide [2]. To focus clinical management on patients at high risk and to avoid unnecessary treatment and hospitalization, accurate prediction of preterm delivery is required. The best predictors of spontaneous preterm birth available today are a shortened cervical length in the second trimester of pregnancy and an elevated concentration of fetal fibronectin (fFN) in the cervicovaginal fluid [3]. A correlation between spontaneous preterm delivery and a short cervix has been demonstrated by many investigators, including Tsoi [4], To [5], and Iams [6]. The sensitivity and specificity of cervical length measurement depend on the cut-off value and on the risk factors of the study population. The concentration of fFN, a glycoprotein present in the cervicovaginal fluid between 22 and 35 gestational weeks, was shown to correlate with the risk of spontaneous premature delivery. As demonstrated in several studies reviewed by Daskalakis et al. [7], the fFN test has a high negative predictive value (NPV), 93–99.7% for symptomatic patients and 86–99% for asymptomatic patients. However, the positive predictive value (PPV) is low and very variable (13–85%), depending on the characteristics of the study population. The combination of fFN with cervical length measurement can improve the PPV in symptomatic patients while maintaining a high NPV [8]. Sonoelastography is an emerging ultrasound technique that has been successfully used for detecting focal
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2 Schöning et al., Cervical sonoelastography to predict preterm birth
pathologies in various organs such as breast, liver, and thyroid gland based on divergent mechanical properties [9–12]. Combined with transvaginal ultrasound, cervical sonoelastography permits quantitative evaluation of cervical tissue elasticity [13]. Several investigators have demonstrated the technical feasibility and reproducibility of the method in assessing the cervical tissue stiffness in asymptomatic women at different stages of pregnancy [14–16]. In the clinical context, cervical sonoelastography has been used to detect focal pathologies of the cervix [17] and to predict the success of labor induction at term [18, 19]. The potential to improve risk management of preterm delivery is being discussed [20]. However, women with risk factors or women with preterm labor have not been examined by cervical sonoelastography so far. In the present study, cervical sonoelastography was combined with cervical length measurement and the fFN test in patients with preterm labor during the second trimester. A detailed and precise risk assessment would help to focus therapeutic interventions on patients at high risk.
The patients received a routine pelvic examination. First, premature rupture of membranes was excluded using a commercially available test (AmniSure®, QIAGEN, Hilden, Germany). As a second step, a commercial qualitative fFN enzyme immunoessay (Rapid fFN TLiIQ® System, Hologic, Marlborough, MA, USA) was performed following the manufacturer’s instructions. An fFN concentration ≥ 50 ng/mL was considered positive. Transvaginal ultrasound was performed (9 MHz, Hi Vision Preirus, Hitachi Medical Systems, Wiesbaden, Germany) for cervical length measurement and assessment of cervical funneling. Patients were examined with the emptied urinary bladder. The cervical length was measured in a sagittal plane of the cervix. For the subsequent real-time sonoelastography, the color-encoded mode was superimposed on the B-mode image. No additional pressure was applied on the cervix. Each examination was repeated three times by two different investigators. The information on cervical tissue displacement was represented by a color scale, with blue indicating stiff tissue, green representing average stiffness, and red indicating soft deformable tissue. More technical details of the method are reported by Thomas et al. [17]. A rectangular region of interest (ROI) was placed manually, covering the anterior cervical lip and the endocervical canal. The mean proportion of the blue area (stiff tissue) from three measurements was calculated for further statistical analysis. Patients were followed up for gestational age at the time of delivery.
Methods Statistical analysis
Study design A prospective cohort study was conducted that was double-blinded for the fFN test. The study design and protocol were approved by the local ethics board (EA2/007/08).
Study population The study was conducted in the Department of Obstetrics at Charité University Hospital, Campus Mitte, Berlin, Germany, from January to December 2013. The patients included in the study were aged above 18 and between 23/0 and 33/6 weeks of gestation. They had clinical criteria of preterm labor, including uterine contractions, intermittent lower abdominal pain, and pelvic pressure. Singleton and multiple pregnancies were included in the study. Written informed consent was obtained from all patients at the time of enrollment. Patients with vaginal bleeding, cervical dilatation, rupture of membranes, polyhydramnios, placenta previa, or prior cerclage were excluded. Due to possible false positive results of the fFN test, patients with pelvic examination, transvaginal ultrasound, or intercourse in the previous 24 h were also excluded from the study.
Study protocol and data collection The patients’ data and history were assessed regarding the following aspects: age, gravidity, parity, gestational age at time of enrollment, prior preterm delivery, and nicotine abuse.
Data were analyzed using univariate analysis of variance and logistic regression analysis by Pearson. P-value ≤ 0.05 was considered statistically significant. Receiver operating characteristic (ROC) curves were used to determine the best cut-off values for cervical length and the mean percentage of the blue area in relation to preterm birth. The area under the curve (AUC) was derived. Statistical analysis was performed using two software packages, PASW Statistics, version 18.0 (SPSS Inc., Chicago, IL, USA) and GraphPad Prism, version 5.0 (GraphPad Software, San Diego, CA, USA).
Results Initially, 67 patients were included in the study. However, two patients were excluded retrospectively because follow-up was not possible. One patient was excluded four days after enrollment due to pathologic fetal Doppler findings that led to iatrogenic preterm delivery. This resulted in 64 patients for further analysis. The characteristics of the study population are summarized in Table 1. Patients were aged between 18 and 43 years. Six patients were smokers (9.4%). Gestational age at the time of enrollment was between 23/0 and 33/6 weeks (mean 28/1 weeks). Nine women with twin pregnancies were included. Forty patients (62.5%) were nulliparous, and eight patients (12.5%) had a history of
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Schöning et al., Cervical sonoelastography to predict preterm birth 3
Table 1 Characteristics of the study population. Data are shown as range [mean value, standard deviation (SD)] or n (%). Study population, n = 64 Age Nulliparous Prior preterm birth Nicotine abuse Twin pregnancies Gestational age at enrollment Cervical length Cervical funneling fFN test positive Gestational age at delivery Preterm delivery
18–43 years (30.6, SD ± 6.0) 40 (62.5) 8 (12.5) 6 (9.4) 9 (14.0) 23/0–33/6 weeks (28/1, SD ± 26 days) 6–41 mm (19.4, SD ± 9.3) 36 (56.3) 11 (17.2) 24/1–41/5 weeks (36/5, SD ± 27 days) 25 (39.1)
fFN = fetal fibronectin.
preterm birth. The cervical length was 6–41 mm at the time of enrollment (mean 19.4 mm). Cervical funneling was found in 36 cases (56.3%). In 11 cases, the fFN test was positive (17.2%). Gestational age at the time of delivery was between 24/1 and 41/5 weeks. In total, 25 patients (39.1%) had a preterm delivery. Three patients were delivered within 10 days of enrollment, one of them within 48 h. Data from the patients’ history such as parity, prior preterm birth, and nicotine abuse did not correlate significantly with gestational age at delivery (Table 2). For analysis of the elastographic data, the mean proportion of the blue area (stiff tissue) in the ROI of each case was related to the gestational week at delivery (Figure 1). The mean proportion of the blue area ranged from 0% to 70.4% [mean 17.5%, standard deviation (SD) 17.4%] and correlated significantly with preterm birth (P = 0.007). The data were represented as the ROC curve, which resulted in an AUC of 0.711 (Figure 2). A cut-off value of 9.1% for the proportion of the blue area in the ROI was derived. When applied for the prediction of preterm birth, this resulted
Table 2 Correlation between patients’ history and gestational age at delivery. Delivery
Parity Prior preterm birth Nicotine abuse
0 ≥ 1 Yes No Yes No
Preterm
Term
13 12 5 20 2 23
27 12 3 36 4 35
P-value
0.165 0.146 0.763
in a sensitivity of 72.7%, a specificity of 73.0%, a PPV of 61.5%, and an NPV of 81.8%, as shown in Table 3. In contrast, the cervical length was not significantly different between cases with term delivery and cases with preterm delivery (P = 0.165). The mean cervical length of patients with preterm birth was 18.4 mm (SD 11.2 mm). Patients with term delivery had a mean cervical length of 19.9 mm (SD 8.0 mm). ROC curve analysis resulted in an AUC of 0.604 (Figure 2). However, the presence of cervical funneling was shown to be a sensitive and significant predictor of preterm birth in the study population (P = 0.011). Cervical funneling occurred in 19 of 25 patients with preterm delivery, and thus had 76.0% sensitivity. Specificity was 56.4%. Data are summarized in Table 3. The fFN test was positive in 9 of 25 cases with preterm birth. Only two patients who were delivered at term had a positive fFN test, resulting in 36.0% sensitivity and 95.0% specificity (Table 3).
Discussion Ultrasound elastography has been successfully integrated into diagnostic imaging procedures. It can contribute to better detection and characterization of a variety of pathologies, such as diffuse liver disease, breast lesions, thyroid nodules, and prostate abnormalities [9], by providing additional information on the elasticity of a lesion relative to that of surrounding tissue. Sonoelastography of the uterine cervix is an emerging technique for quantifying cervical tissue stiffness. The technical feasibility and reproducibility of results in all three trimesters of pregnancy has been demonstrated by several investigators [14, 15, 21]. However, different technical approaches and the need for standardization are important issues under discussion [22]. In the present study, for the first time, a selected study population with premature labor is examined by cervical sonoelastography to evaluate its potential for prediction of preterm delivery. Experience during the study has revealed cervical sonoelastography to be a fast and feasible method that could be used in symptomatic patients without any complication or risk. In combination with cervical length measurement, it can easily be integrated into clinical routine. Different approaches have been suggested to standardize the pressure applied during elastography, e.g., advancement of the probe into the cervical tissue for 1 cm [16] or compression of the anterior portion of the cervical tissue until dislocation of
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4 Schöning et al., Cervical sonoelastography to predict preterm birth
A
B
C
D
Figure 1 Transvaginal ultrasound for cervical length measurement and cervical sonoelastography in two patients with premature contractions. (A) Transvaginal ultrasound in a 36-year-old woman in the 30th week of gestation, who presented to the hospital with premature contractions. B-mode ultrasound shows a shortened cervix of 16.6 mm with funneling. Elastography (B) shows the cervical area in the ROI to be soft (left). The color portion in the histogram lies in the red and green area. Only 2.2% of the area is blue. With the positive fFN test, the patient had preterm birth in the 32nd week of gestation. (C) A 26-year-old patient with premature contractions in the 29th week of gestation has a cervical length of 31 mm without funneling. Elastography (D) suggests greater stiffness of cervical tissue with a blue portion of 27.4%, which is also seen in the histogram. fFN was negative, and the woman gave birth in the 40th week of gestation.
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B 1.0
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Figure 2 Receiver operating characteristic (ROC) curves representing correlation between gestational age at delivery and cervical length (A) and gestational age at delivery and elastography findings (B). (A) Correlation between cervical length and gestational age at delivery was not significant (P = 0.165). ROC curve analysis resulted in an area under the curve (AUC) of 0.604. (B) Analysis of elastography findings yielded a significant correlation between the mean proportion of the blue area in the ROI and gestational age at delivery (P = 0.007). An AUC of 0.711 was shown, resulting in a cut-off value of 9.1% for the proportion of the blue area in the ROI. Brought to you by | University of California Authenticated Download Date | 6/5/15 2:28 PM
Schöning et al., Cervical sonoelastography to predict preterm birth 5
Table 3 Test parameters for prediction of preterm birth.
Sensitivity Specificity Positive predictive value Negative predictive value
fFN test
Cervical funneling
Elastography, blue area in ROI, 9.1% cut-off
P = 0.001
P = 0.011
P = 0.007
36.0% 95.0% 81.8% 70.0%
76.0% 56.4% 52.8% 78.6%
72.7% 73.0% 61.5% 81.8%
ROI = region of interest.
the posterior cervical lip occurs [14]. In the present study, no additional pressure was applied to avoid manipulation of the cervix in symptomatic patients. The elastographic image was created by the patient’s breathing or arterial pulsation, according to the technique published by Swiatkowska-Freund and Preis [19] and Thomas et al. [17]. More than half of the patients showed cervical funneling with different length and shape. Previous studies or guidelines for the analysis of cervical elastography with funneling are lacking. In our experience, the most reliable data could be obtained when the rectangular ROI was placed manually on the anterior cervical lip, including the endocervical canal, but avoiding most of the posterior lip. It appeared difficult to reach the posterior cervical lip by elastography when cervical funneling was present. We found a significant correlation between cervical sonoelastographic findings and preterm birth in our study population. Cervical length was not a predictor of preterm delivery, which might be attributable to the small number of patients. This might also explain why no significant correlation was found for the known risk factor of prior preterm birth. The primary outcome of the study was delivery ≥ 37/0 gestational weeks. Although usually used to predict delivery within the next 7–10 days [23], the fFN test was compared to the other diagnostic tests for the primary outcome of the study. This is the reason for the relatively low sensitivity and NPV of the test. When the fFN test results are correlated to delivery within the next 7–10 days, sensitivity increases to 100% and specificity to 86.9%. The PPV is 27.3% and the NPV is 100%. These data correspond to the test characteristics published so far. The use of a quantitative fFN test could improve risk management in the future [24, 25]. The benefit of combined cervical screening and the fFN test in symptomatic patients is still under discussion. It was shown by Schmitz et al. [26] and Hincz et al. [27] that the sequential use of the fFN test after cervical
length measurement can improve diagnostic accuracy. Sensitivity and specificity for predicting spontaneous preterm delivery in < 35 weeks were increased to 67% and 81%, respectively [26]. In contrast, Deplagne and colleagues [28] found the combined use of cervical length measurement and fFN determination to be as effective as either test alone. In a systematic review, DeFranco and co-workers [8] concluded that combined screening, including cervical length and fFN, provides useful information for predicting the short-term risk of spontaneous preterm birth. In the present study, the elastographic information alone had 72.7% sensitivity and 73% specificity for prediction of spontaneous preterm birth. However, comparison of data is difficult due to heterogeneous study populations and different outcomes. It needs to be investigated if the use of a triple test combining cervical length measurement, cervical sonoelastography, and the fFN test can further improve diagnostic accuracy. The present study results are clearly limited by the lack of standardized procedures for the analysis of elastographic information especially in symptomatic patients with a short cervix or funneling. The study population was small, included singleton and multiple pregnancies, and was selected from a specialized obstetrical department in a university hospital. Further studies with a larger patient collective are needed to develop guidelines for cervical elastography in symptomatic patients. The calculation of elastographic strain values, indicating numerically the displacement of tissue within an ROI [29], might help in standardizing the technique.
Conclusion Cervical sonoelastography is a promising technique for predicting spontaneous preterm delivery in patients with preterm labor. Further studies are required to improve standardization and to assess the clinical impact of the technique. It might potentially supplement routine diagnostic procedures. Accurate identification of patients at high risk could help to focus therapeutic management on them [30]. Unnecessary treatment, cost-intensive hospitalization, and potential side effects of tocolytic agents and corticosteroids could thus be minimized for low-risk patients. Acknowledgments: We thank the medical team of the obstetric department, Charité University Medicine, Berlin, for assistance in patient enrollment.
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6 Schöning et al., Cervical sonoelastography to predict preterm birth
References [1] Beck S, Wojdyla D, Say L, Betran AP, Merialdi M, Requejo JH, et al. The worldwide incidence of preterm birth: a systematic review of maternal mortality and morbidity. Bull World Health Organ. 2010;88:31–8. [2] Blencowe H, Cousens S, Oestergaard MZ, Chou D, Moller AB, Narwal R, et al. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet. 2012;379:2162–72. [3] Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet. 2008;371:75–84. [4] Tsoi E, Fuchs IB, Rane S, Geerts L, Nicolaides KH. Sonographic measurement of cervical length in threatened preterm labor in singleton pregnancies with intact membranes. Ultrasound Obstet Gynecol. 2005;25:353–6. [5] To MS, Skentou CA, Royston P, Yu CK, Nicolaides KH. 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;27:362–7. [6] Iams JD, Goldenberg RL, Meis PJ, Mercer BM, Moawad A, Das A, et al. The length of the cervix and the risk of spontaneous premature delivery. N Engl J Med. 1996;334:567–72. [7] Daskalakis GJ, Papantoniou NE, Koutsodimas NB, Papapanagiotou A, Antsaklis AJ. Fetal fibronectin as predictor for preterm birth. J Obstet Gynecol. 2000;20:347–53. [8] DeFranco EA, Lewis DF, Odibo AO. Improving the screening accuracy for preterm labor: is the combination of fetal fibronectin and cervical length in symptomatic patients a useful predictor for preterm birth? A systematic review. Am J Obstet Gynecol. 2013;208:233.e1–6. [9] Cosgrove D, Piscaglia F, Bamber J, Bojunga J, Correas JM, Gilja OH, et al. EFSUMB guidelines and recommendations on the clinical use of ultrasound elastography. Part 2: Clinical applications. Ultraschall Med. 2013;34:238–53. [10] Frulio N, Trillaud H. Ultrasound elastography in liver. Diagn Interv Imaging. 2013;94:515–34. [11] Thomas A, Degenhardt F, Farrokh A, Wojcinski S, Slowinski T, Fischer T. Significant differentiation of focal breast lesions: calculation of strain ratio in breast sonoelastography. Acad Radiol. 2010;17:558–63. [12] Thomas A, Warm M, Hoopmann M, Diekmann F, Fischer T. Tissue Doppler and strain imaging for evaluating tissue elasticity of breast lesions. Acad Radiol. 2007;14:522–9. [13] Feltovich H, Hall TJ, Berghella V. Beyond cervical length: emerging technologies for assessing the pregnant cervix. Am J Obstet Gynecol. 2012;207:345–54. [14] Fruscalzo A, Steinhard J, Londero AP, Fröhlich C, Bijnens B, Klockenbusch W, et al. Reliability of quantitative elastography of the uterine cervix in at-term pregnancies. J Perinat Med. 2013;41:421–7. [15] Hernandez-Andrade E, Hassan SS, Ahn H, Korzeniewski SJ, Yeo L, Chaiworapongsa T, et al. Evaluation of cervical stiffness during pregnancy using semiquantitative ultrasound elastography. Ultrasound Obstet Gynecol. 2013;41:152–61.
[16] Molina FS, Gómez LF, Florido J, Padilla MC, Nicolaides KH. Quantification of cervical elastography: a reproducibility study. Ultrasound Obstet Gynecol. 2012;39:685–9. [17] Thomas A, Kümmel S, Gemeinhardt O, Fischer T. Real-time sonoelastography of the cervix: tissue elasticity of the normal and abnormal cervix. Acad Radiol. 2007;14:193–200. [18] Hwang HS, Sohn IS, Kwon HS. Imaging analysis of cervical elastography of prediction of successful induction of labor at term. J Ultrasound Med. 2013;32:937–46. [19] Swiatkowska-Freund M, Preis K. Elastography of the uterine cervix: implications for success of induction of labor. Ultrasound Obstet Gynecol. 2011;38:52–6. [20] Khalil MR, Thorsen P, Uldbjerg N. Cervical ultrasound elastography may hold the potential to predict risk of preterm birth. Dan Med J. 2013;60:A4570. [21] Fruscalzo A, Schmitz R, Klockenbusch W, Steinhard J. Reliability of cervix elastography in the late first and second trimester of pregnancy. Ultraschall Med. 2012;33:E101–7. [22] Fruscalzo A, Schmitz R. Quantitative cervical elastography in pregnancy. Ultrasound Obstet Gynecol. 2012;40:612–3. [23] Honest H, Bachmann LM, Gupta JK, Kleijnen J, Khan KS. Accuracy of cervicovaginal fetal fibronectin test in predicting risk of spontaneous preterm birth: systematic review. Br Med J. 2002;325:301. [24] Abbott DS, Radford SK, Seed PT, Tribe RM, Shennan AH. Evaluation of a quantitative fetal fibronectin test for spontaneous preterm birth in symptomatic women. Am J Obstet Gynecol. 2013;208:122.e1–6. [25] Kurtzman J, Chandiramani M, Briley A, Poston L, Das A, Shennan A. Quantitative fetal fibronectin screening in asymptomatic high-risk patients and the spectrum of risk for recurrent preterm delivery. Am J Obstet Gynecol. 2009;200:263.e1–6. [26] Schmitz T, Maillard F, Bessard-Bacquaert S, Kayem G, Fulla Y, Cabrol D, et al. Selective use of fetal fibronectin detection after cervical length measurement to predict spontaneous preterm delivery in women with preterm labor. Am J Obstet Gynecol. 2006;194:138–43. [27] Hincz P, Wilczynski J, Kozarzewski M, Szaflik K. Two-step test: the combined use of fetal fibronectin and sonographic examination of the uterine cervix for prediction of preterm delivery in symptomatic patients. Acta Obstet Gynecol Scand. 2002;81:58–63. [28] Deplagne C, Maurice-Tison S, Coatleven F, Vandenbossche F, Horovitz J. Sequential use of cervical length measurement before fetal fibronectin detection to predict spontaneous preterm delivery in women with preterm labor. J Gynecol Obstet Biol Reprod. 2010;39:575–83. [29] Greenleaf JF, Fatemi M, Insana M. Selected methods for imaging elastic properties of biological tissues. Annu Rev Biomed Eng. 2003;5:57–78. [30] Dutta D, Norman JE. The efficacy of fetal fibronectin testing in minimising hospital admissions, length of hospital stay, and cost savings in women presenting with symptoms of pre-term labor. J Obstet Gynecol. 2010;30:768–73.
The authors stated that there are no conflicts of interest regarding the publication of this article.
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