The value of IGFBP1 combined with cervical length testing to predict preterm birth
Author:Huang Xiaoping,Xu Qian (E-mail:[email protected])
Author Affiliation:Wuxi Maternal and Child Health Hospital, Nanjing Medical University, China Zip Code:214002
Tel:13915292556
Chinese Abstract
OBJECTIVE: To investigate the value of detecting hyperphosphorylated insulin-like growth factor binding protein-1 (phIGFBP-1) in cervical secretions and cervical length by abdominal ultrasound to predict preterm labor in pregnant women at high risk of preterm labor. Huang Xiaoping, Department of Obstetrics and Gynecology, Wuxi Maternal and Child Health Hospital
Methods: The ph IGFBP-1 (Amnioquick test) was detected in cervical secretion by immunochromatographic method at 20-35 weeks of gestation, and the cervical length (CL) was detected by abdominal ultrasound, and the delivery outcome was recorded.
Results: The positive rate of phIGFBP-1 was 63.64% (14/22) in the preterm group and 7.69% (6/78) in the term group, and the difference between the two groups was statistically significant (P < 0.01). According to the subject operating characteristic curve (ROC curve), CL< 35 mm was the best reference value. The sensitivity of CL < 35 mm was 68.18% (15/22), specificity 74.35% (58/78), positive predictive value 88.23% (15/17) and negative predictive value 93.54% (58/62), using CL < 35 mm as the cut-off point in combination with cervical secretion ph IGFBP- 1.
Conclusion: A positive cervical secretion phIGFBP-1 and a CL <3.5 cm is a sensitive and reliable predictor of preterm labor.
Key words】：preterm labor; insulin growth factor binding protein 1; cervical length; preterm labor prediction
The role of phosphorylated insulin-like growth factor binding protein-1 and cervical length in the prediction of preterm delivery.
ABSTRACT
Objective: To explore the significance of cervical length and phosphorylated insulin- like growth factor- binding protein- 1 in predicting preterm delivery in high risk gravidity.
Methods: Cervical length was measured by transabdominalsonography and a rapid strip test (Amnioquick test) was performed to detect phIGFBP- 1 in cervical secretions from 20 to 35 weeks.
Results: The positive rate of phIGFBP- 1 in preterm labor group and term birth group was respectively 63.64% ( 14/22) and 7.69% ( 6 /78). There were statistically significant differences between the two groups ( P < 0.01) .According to ROC curve , 35mm or less of the cervical length seemed to be the most suitable com promise. the sensitivity , the specificity , the positive predictive value and negative predictive value was 68.18%, 74.35%,88.23%, 93. 54%, respectively by combined application of cervical length and phIGFBP- 1.
Conclusion: Cervical length<3.5 cm and phIGFBP-1 positive can be used as the sensitive and objective indicators for prediction of preterm delivery.
Key word】: Preface In recent years, the rate of preterm delivery has been increasing worldwide, and preterm delivery is one of the major causes of neonatal death and disability. The prediction and prevention of preterm delivery is a popular topic in perinatal medicine, and is the key to reducing perinatal morbidity and mortality. The aim of this study was to analyze the relationship between hyperphosphorylated insulin-like growth factor binding protein-1 in cervical secretions and cervical length and preterm delivery in women with high-risk pregnancies for preterm delivery by combined measurement of hyperphosphorylated insulin-like growth factor binding protein-1 in cervical secretions and ultrasound measurement of cervical length and follow-up of pregnancy outcomes, and to evaluate their predictive value for the timely prediction and diagnosis of preterm delivery. The aim of this study was to provide a new scientific basis for the detection and management of preterm birth in women with high risk of preterm birth, thereby reducing the incidence of preterm birth and improving adverse pregnancy outcomes. Data and Methods 1.1 General information 1.1.1 From March 2012 to November 2012, 103 high-risk pregnant women with preterm labor, mean age ( 27.58 ± 4.3) years, mean number of deliveries ( 1.4 ± 0.5), 20~35 weeks of gestation, unruptured membranes, and no vaginitis were selected from the Department of Obstetrics and Gynecology, Wuxi Maternal and Child Health Hospital, Nanjing Medical University. 1.1.2 Inclusion criteria:1,Those with high risk factors for preterm delivery [13] included: 1) history of preterm delivery; 2) history of late miscarriage; 3) age < 18 years or > 40 years; 4) suffering from somatic diseases and pregnancy complications; 5) underweight or overweight, body mass index < 18 kg/m2 or > 30 kg/m2.; 6) no prenatal care, poor economic status; 7) drug or alcohol abusers; 8) prolonged standing during pregnancy, especially more than 40 h per week; 9) having reproductive tract infection 2) a history of preterm birth or a history of sexually transmitted infections, or a history of combined sexually transmitted diseases such as syphilis, etc.10) pregnancy after assisted conception techniques; 11) anomalies in the development of the reproductive system; 12) multiple pregnancies. 2) Preterm birth with preeclampsia diagnosed according to the 2010 Clinical Guidelines for Obstetrics and Gynecology. 1.1.3 Exclusion criteria: The following complications were excluded: placental abruption, premature rupture of membranes, severe pre-eclampsia, vaginitis. 1.1.4 Informed consent: The subject content and requirements were introduced to the selected subjects, and those who agreed and were willing to cooperate with the follow-up were formally enrolled in the study and signed the relevant consent forms. 1.2 Study methods 1.2.1 The subjects were firstly examined by abdominal ultrasound for cervical length, and then the level of hyperphosphorylated insulin-like growth factor binding protein-1 in the cervical secretion was measured, and the gestational week and cervical canal length at the time of measurement were accurately recorded. The subjects were divided into preterm delivery group and term delivery group according to the final delivery status. 1. 2.2 Cervical length measurement (1) Measuring instrument: abdominal ultrasound was performed with an American GE E830 color Doppler ultrasound machine, with ultrasound frequencies of 5.0-5.2 MHz and probe frequencies of 4.0-5.5 MHz. (2) The cervical length was measured by transabdominal ultrasound with a little bladder filling before the examination, as long as the cervical canal could be visualized, or without bladder filling if the lining of the anterior amniotic sac could clearly visualize the cervical canal, and the length of the cervix was measured and recorded. 1.2.3 Measurement of phIGFBP-1 in cervical secretions using an immunoassay kit from Biosynex, France, supplied by Shanghai Preci Medical Devices Co. Qualitative detection of phIGFBP-1: Amniotic fluid is rich in IGFBP-1, while other body fluids are rich in IGFBP-1. The amount of IGFBP was low. It is synthesized in the meconium and in the liver and has a different phosphorylated structure. The meconium and liver have been found to secrete a large amount of phosphorylated IGFBP-1, while amniotic fluid, fetal serum and maternal plasma are rich in non-phosphorylated IGFBP-1. The mechanical pressure, protein hydrolysis and local inflammatory response caused by uterine contractions start to separate the meconium and chorionic villus, and the meconium cells are disrupted and phosphorylated IGFBP-1 leaks into the cervix and vagina. The product adopts the principle of immunochromatography, using anti-human IGFBP1 monoclonal antibody as the detection antibody and anti-human IGFBP1 polyclonal antibody as the capture antibody. IGFBP1 in the specimen first binds to monoclonal antibodies and then, after chromatographic swimming action of the carrier membrane, binds to capture antibodies immobilized on the carrier membrane detection line. Method: Pregnant women are placed in the cystotomy position, the vulva is routinely disinfected, the vagina is opened with a speculum in most cases, the cervix is exposed, and the intimate swab from the kit is placed in the cervical canal for 15 s. (Very few pregnant women who refuse the speculum use a disposable sterile cotton swab to carefully insert the swab into the vagina to a depth of about 5-7 cm in the posterior fornix for about 30 s.) and then removed. Immediately place in a tube containing 0.5 m l of extraction solution for at least 30 s and rotate the end as far as possible to extract the liquid from the swab, remove the swab, retain the extraction solution, dip the yellow dipping zone of the test strip provided in the kit into the specimen extraction solution and hold for about 20 s, or directly until the liquid penetrates into the reaction zone, remove the strip, place horizontally, and observe the results within 5 m in. Result determination: If two blue lines appear on the test strip, it is positive; if one blue line appears, it is negative. 1.3 Statistical methods SPSS 13.0 statistical software was used to process the data, and P<0.05 indicates statistical significance. The measurement data were first tested for normality and expressed as X±S if normally distributed, and non-normal data were transformed (natural logarithm, square root). The data were analyzed and processed by X2 test, exact probability method and correlation analysis. The sensitivity, specificity, positive predictive value and negative predictive value of IGFBP-1 method and cervical canal length were calculated by using a four-cell table. Results 2. 1 General profile of pregnant women Mean age ( 27.38 ± 4.3 ) years, mean number of pregnancies (2.1 ± 1.1), mean number of deliveries ( 1.4 ± 0.5 ), and mean sampling gestational weeks (30.2 ± 4.5). The differences between the two groups were not statistically significant (P>0.05) compared to age, number of pregnancies, number of miscarriages, and gestational weeks sampled. The results are shown in Table 1. Table 1 General profile of pregnant women in both groups General preterm birth (n=22) Full term (n=78) P Age (years) 27.26 ± 4.38 27.45 ± 4.26 >0.05 number of pregnancies (times) 2.32 ± 1.12 2.13±1.11 (>0.05 The results are shown in Table 1. 0.96±0.99 Table 1 >Table 1 Sampling time (weeks) 30.26±4.24 30.70±4.31 >0.05 2.2 Pregnancy outcome Among the 103 subjects, 3 cases of spontaneous abortion before 28 weeks (2 twins and 1 singleton) were observed and followed up, except for the above 3 cases, 100 cases were analyzed. 22 cases were delivered at 28-37 weeks (preterm birth group), accounting for 22. 0%, and 78 cases were delivered at full term (term birth group), accounting for 78. 0%. The analysis of preterm birth factors is shown in Table 2. Exhibit 2 Analysis of causes of preterm delivery preterm birth factors Number of cases n Percentage Number of vaginal deliveries n cesarean delivery n premature rupture of membranes 5 22.73 4 1 multiple pregnancies 3 13.64 3 1 Anemia 2 9.09 1 1 Uterine factors 3 13.64 1 2 Fetal distress 4 months 18.18 3 1 Heart disease 1 4.55 0 1 anterior placenta Table 1 4.55 0 1 Other 3 13.64
1 2 Total 22 100 13 9 2. 3 Relationship between cervical length and preterm delivery
2.3.1 The mean cervical length was ( 3.31 ± 0.59) cm in the preterm group and ( 3.81 ± 0.65) cm in the term group, with a statistically significant difference between the two groups (t = – 3.249, P < 0. 05).
See Exhibit 3. Table 3:Comparison of cervical canal length between preterm and term group (cm) Preterm delivery group (n=22) 3.31±0.59 cm Full-term group (n=78) 3.61 ± 0.65 cm t = – 3.249, P < 0.05 2.3.2 Relationship between cervical length at the threshold value of 3.5 cm on abdominal ultrasound and preterm delivery Its sensitivity was 86.36% (19/22), specificity 79.48% (62/78), positive predictive value 54.29% (19/35), negative predictive value 95.38% (62/65), positive likelihood ratio 4.20, negative likelihood ratio 0.17, see Table 4 Table 4 Relationship between abdominal ultrasound cervical length and preterm delivery Cervical length cm preterm delivery full term total Abdominal ultrasound CL ≤ 3.5 19 16 35 Abdominal ultrasound CL3.5 3 62 65 Total 22 78 100 χ 2 = 32. 70,P < 0.01 2.3.3 The sensitivity and specificity of abdominal ultrasound for predicting preterm labor were compared using abdominal ultrasound cervical length ≤2.5 cm, ≤3.0 cm, ≤3.5 cm, ≤4.0 cm, and ≤4.5 cm as predictive values, respectively, and are shown in the accompanying Figure (1). Appendix Figure (1) Comparison of the sensitivity of different cervical lengths in predicting preterm labor 2. 4 phIGFBP- 1 test results 2.4.1 Among the 100 cases, 20 cases (20.0%) were positive for phIGFBP-1, 14 cases were positive for phIGFBP-1 in the preterm labor group and 6 cases were positive for phIGFBP-1 in the term labor group, and the difference between the two groups was statistically significant (χ 2 = 33. 57, P < 0.01). phIGFBP-1 positive group had a preterm labor incidence of 70.0%. Sensitivity 63.64% ( 14/22), specificity 92.30% ( 72 /78), positive predictive value 70.00% ( 14 /20), negative predictive value 90.00% ( 72/80) for predicting preterm labor. See Table 5. Exhibit 5:Predicted outcome of delivery by IGFBP1 test (cases) IGFBP1 positive IGFBP1 negative Total Preterm birth n 14 8 22 Full term n 6 72 78 Total n 20 80 100 χ 2 = 33. 57,P < 0.01 2.4.2 Comparison of the accuracy of IGFBP1 in predicting the occurrence of preterm labor at various stages: for those who tested positive for IGFBP1, the sensitivity was 20.00% and the specificity was 72.5% in 4 cases who delivered within one week; for those who delivered within two weeks, the sensitivity was 60.00% and the specificity was 84.50% in 12 cases; for those who delivered within 35 weeks, the sensitivity was 50.00% and the specificity was 85% in 10 cases; and for those who delivered within 37 weeks, the sensitivity was 20.00% and the specificity was 85%. parturition in 14 cases, sensitivity was 70%, specificity was 90.00 See Table 6. Table 6: Comparison of the accuracy of IGFBP1 in predicting the occurrence of preterm labor at various stages Subgroup Number of cases n Sensitivity % Specificity Preterm birth within one week 4 20 72.5 Premature birth within 2 weeks 12 60 84.5 Preterm delivery before 35 weeks 10 50 85 Preterm birth before 37 weeks 14 70 90 2. 5 phIGFBP- 1 combined with cervical length to predict preterm delivery The best reference value was CL <3.5 cm according to the ROC curve. The results of the prediction of preterm labor in combination with cervical secretion phIGFBP-1, using CL < 3.5 cm as the cut-off point, are shown in Table (7). There was a positive correlation between cervical length on ultrasound and phIGFBP-1 in cervical secretions, and phIGFBP-1 testing was more positive in short cervical lengths. Table 7 Relationship between cervical length and phIGFBP-1 in cervical secretions at abdominal ultrasound Cervical length cm IGFBP1 positive Negative IGFBP1 Total Abdominal ultrasound CL≤3.5 17 18 35 Abdominal ultrasound CL3.5 3 62 65 combined 20 80 100 χ 2 = 27. 47,P < 0.05 The combination of the two assays had a sensitivity of 68.18% (15/22), a specificity of 74.35% (58/78), a positive predictive value of 88.23% (15/17) and a negative predictive value of 93.54% (58/62) for predicting the occurrence of preterm labor. Exhibit 8. Exhibit 8 Predicted outcome of phIGFBP- 1 combined with cervical length delivery (cases) Cervical length (cm) ph IGFBP- 1 positive ph IGFBP- 1 negative Preterm birth full-term birth preterm birth full-term birth abdominal ultrasound CL≤3.5 15 2 6 12 Abdominal ultrasound CL3.5 2 1 4 58 2.6 Logistic regression analysis of factors such as age of pregnant women, number of pregnancies, number of abortions, cervical length and phIGFBP-1 showed that both cervical length and phIGFBP-1 positivity were independent risk factors for preterm delivery; the positive predictive value and negative predictive value of combined abdominal ultrasound CL ≤ 3.5 cm and cervical secretion phIGFBP-1 to predict the occurrence of preterm delivery were higher than Both were predicted separately. See Table 9 Table 9 Comparison of the accuracy of each indicator in predicting preterm birth Subgroups Sensitivity % specificity positive predictive value negative predictive value abdominal ultrasound CL≤3.5cm 86.36 79.48 54.29 90.38 IGFBP1 positive 63.64 92.31 70 90 IGFBP1 positive combined with CL ≤3.5 68.18 74.35 88.23 93.54 Discussion
3. 1 Ultrasound detection of cervical length for predicting preterm labor It is currently believed that although the factors predisposing to preterm labor are different, all have premature cervical shortening. The use of ultrasound for clinical monitoring of cervical changes during pregnancy to screen for the risk of preterm delivery and to estimate the treatment and prognosis of patients with preterm delivery started in the 1980’s. Michiel et al. in 2001 studied the preterm labor group, observing 70 cases of preterm labor at 30.7 ± 3.7 weeks of gestation. The sensitivity, specificity, positive and negative predictive values for preterm birth were 98%, 46%, 57% and 99%, respectively, for CL < 30 mm before 36 weeks of gestation. A study by Irene et al. in 2001 showed that the likelihood of preterm delivery was < 7% for CL > 35 mm and 25% for CL < 25 mm, so a cut-off CL of < 25 mm was usually established [14]. The risk of preterm delivery is significantly higher if CL < 25 mm (OR = 4. 04). In China, Huang Lei et al [15] found that the positive predictive value of preterm delivery was 48.1% for CL<30 mm. A similar study by Irene et al. showed that abdominal ultrasound cervical length values were greater than vaginal ultrasound cervical length at all times of gestation, with a difference of about 5 mm and a significant difference (Ρ< 0. 01). However, in this study, considering the ease of acceptance of abdominal ultrasound in pregnant women, abdominal ultrasound was used to detect the cervical length and the mean cervical length was found to be (3.31 ± 0.59) cm in the preterm group and (3.81 ± 0.65) cm in the term group. However, in the present study, we considered pregnancy and the ROC curve, CL<3.5 cm as the best reference value. The sensitivity was 86.36% (19/22), the specificity 79.48% (62/78), the positive predictive value 54.29% (19/35), the negative predictive value 95.38% (62/65), the positive likelihood ratio 4.20 and the negative likelihood ratio 0.17. It is suggested that cervical length is one of the objective indicators for predicting preterm labor, but it has a significant difference (Ρ< 0. 01). The positive predictive value was low, suggesting that its value as a predictor of preterm labor alone is limited and needs to be combined with other indices to improve its accuracy in predicting preterm labor. The variation in the results of cervical length monitoring during pregnancy may be related to the different methods of monitoring and the different groups and weeks of gestation. 3. 2 IGFBP-1 and preterm labor Insulin-like growth factor binding protein-1 (IGFBP-1) in cervical secretions is a 28 kU-sized protein synthesized and secreted by the fetus, adult liver and maternal meconium, and is an insulin- and progesterone-dependent protein with seven isomers depending on its phosphorylation, which varies with the progression of pregnancy [16]. In early pregnancy, maternal serum, amniotic fluid and meconium are dominated by unphosphorylated IGFBP-1; in mid- and late pregnancy, maternal serum and meconium are dominated by hyperphosphorylated IGFBP-1; amniotic fluid does not contain this component, but is dominated by hypophosphorylated and dephosphorylated IGFBP-1. 16]. The level of IGFBP-1 gradually increases after pregnancy, reaching a peak at 28-30 weeks and decreasing after 33 weeks, mainly produced by meconium cells and liver. During mid- and late-trimester, maternal serum, amniotic fluid, and meconium are dominated by non-phosphorylated IGFBP-1; during mid- and late-trimester, maternal serum, amniotic fluid, and meconium are dominated by phosphorylated IGFBP-1. According to this principle, the likelihood of preterm delivery is significantly higher if phosphorylated IGFBP- 1 is found in cervical mucus. Bittar [18] et al. found that ph IGFBP-1 was particularly sensitive in predicting preterm labor at 30 weeks of gestation. balic D [19] et al. found that if ph IGFBP-1 concentration was < 10 g/l (negative Actim Partus test), then the risk of preterm labor was low in asymptomatic pregnant women. pa [18] et al. Tanir [20] showed that the Actim Partus test positive and negative groups did not have high predictive values for maternal demographic characteristics and neonatal outcome in 68 pregnant women with 24-37 weeks of gestation, CL < 3 cm, and signs and symptoms of preterm labor. The sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio of the Actim Partus test for predicting labor before 34 weeks were 70%, 74%, 48%, 88%, 2. 80, and 0.39, respectively. In 108 pregnant women, hyperphosphorylated IGFBP-1 was detected in cervicovaginal secretions, and the positive rate of IGFBP-1 was 48.2% (27/56) and 7.7% (4/52) in the preterm and normal pregnancy groups, respectively, and the difference between the two groups was statistically significant. Liu Weihong [22] et al. reported that phosphorylated IGFBP-1 was detected in the cervical secretion of 90 pregnant women with preterm labor and the delivery was recorded. The results: 36 positive cases with a delivery rate of 50% within 1 week; 54 negative cases with a delivery rate of 7.4% within 1 week, the difference was statistically significant. In this study, the sensitivity of IGFBP1 in predicting preterm delivery was 63.64% ( 14/22), specificity 92.30% ( 72 /78), positive predictive value 70.00% ( 14 /20) and negative predictive value 90.00% ( 72/80). The sensitivity of the results was similar to that of foreign studies, but the specificity was significantly higher, which may be related to the fact that there are more high-risk factors involving pregnant women, and the sensitivity of the test for predicting delivery in the short term differs significantly from the literature, suggesting the need to combine it with other indicators to predict delivery in order to improve its accuracy. 3.3 Detection of cervical length, phIGFBP- 1 combined to predict preterm delivery In 2011, Danti L [14] et al. found that in a study of 42 pregnant women with symptoms of preterm delivery, those with a cervical canal length of less than 30 mm and a combined IGFBP1 positive using a cervicometer were four times more likely to deliver before 34 weeks than those with a positive IGFBP1 alone, while those with a canal length greater than 30 mm who were negative for IGFBP1 rarely had preterm labor, but it was also mentioned that multiple applications of cervicometry would likely increase the risk of preterm labor. Therefore, in this study, the combined application of abdominal ultrasound for cervical length and cervical secretion IGFBP1 test to predict preterm labor showed that the cervical length in the preterm labor group was significantly less than that in the term labor group, and the difference between the two was statistically significant. The sensitivity of predicting the occurrence of preterm labor was 68.18% (15/22), specificity 74.35% (58/78), positive predictive value 88.23% (15/17), and negative predictive value 93.54% (58/62). The results showed that the sensitivity and specificity of cervical secretion phIGFBP-1 combined with cervical length measurement for predicting preterm delivery decreased compared with the two methods alone, but the positive and negative predictive values increased, i.e., when phIGFBP-1 was positive and CL < 3.5 cm, 88.23% of patients had preterm delivery, whereas when ph IGFBP-1 was negative and CL > 3.5 cm, 93.54% of patients delivered at term, which was a decrease for treatment. The combination of cervical discharge phIGFBP-1 and cervical length measurement is more sensitive and specific than the two methods alone, and the timing and duration of application of drugs to suppress contractions and promote fetal lung maturation in preterm labor are useful for timely and early treatment of high-risk pregnancies, while avoiding unnecessary obstetric interventions in low-risk pregnancies. We focused on the methodological search for a convenient, simple, non-invasive or less invasive test. We tried to select pregnant women at high risk of preterm delivery for testing, considering the cost of testing cervical secretions phIGFBP-1 and the discomfort caused by propping up the vagina to improve the clinical value. The prediction method used in this study combines various predictive tools in an analytical and comprehensive way to predict preterm labor more objectively, avoiding excessive intervention in negative cases and providing timely diagnosis and prevention in positive cases. The low cost of the test is worthy of wide clinical application. We believe that with the joint efforts of obstetrics and gynecology medical staff, there will be more and better methods to predict preterm labor. The humanistic care for pregnant women and their families is the starting point, and the ethical and scientific principles are fully observed and applied so that the rights and interests of pregnant women and fetuses can be maximized and the quality and quality of life of our birth population can be improved so that the interests of individuals, families and society can be harmonized. Conclusion 1, cervical length and hyperphosphorylated IGFBP-1 are both independent risk factors for preterm birth, both are closely related to the occurrence of preterm birth, and can be used as objective indicators for preterm birth prediction. Ultrasound detection of cervical length is useful in predicting the occurrence of preterm labor in pregnant women at high risk of preterm labor, and transabdominal measurement of cervical length is also useful in predicting preterm labor when transvaginal detection is not possible. However, attention needs to be paid to the joint use of monitoring with gestational week and cervical morphology to improve its predictive accuracy. 2. Combining cervical secretion hyperphosphorylated IGFBP-1 and cervical length can improve the positive predictive value and negative predictive value of preterm labor, i.e., when phIGFBP-1 test is positive and abdominal ultrasound CL ≤ 3.5 cm, 88.23% of the patients have preterm labor, which requires intensive monitoring and active treatment to reduce the incidence of preterm labor; while phIGFBP-1 test is negative and abdominal ultrasound CL > 3.5 cm can improve the positive predictive value of preterm labor. At 3.5 cm, 93.54% of patients delivered at term, which can reduce unnecessary obstetric interventions. 3. In conclusion, combined detection of positive cervical secretion phIGFBP-1 and abdominal ultrasound CL ≤3.5 cm is a sensitive and reliable predictor of preterm labor. Reference [1] Hoyert D,Mathews T J,Menacker F, et al. 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