Preterm birth (PTB) is defined as delivery before completing 37 weeks of gestation, with a prevalence of 5%–18% of live births.1 It is the main cause of neonatal morbidity and mortality in the most countries. PTB can be spontaneous or iatrogenic. Spontaneous preterm birth (sPTB) is associated with premature rupture of membranes or preterm labor, accounting for about 70% of all PTB. PTB is a complex condition resulting from multiple etiologic pathways, which makes the prediction and prevention of PTB a challenging process in antenatal care.2,3
Cervix is the structure located at caudal end of the uterus whose function is to keep the fetus in utero until term. In the nongravid state the uterine cervix measures approximately 25 mm in length and 20–25 mm in total width, equating to an approximately 10 mm width of collagenous and smooth muscle tissue around the central canal.4 At the end of pregnancy, the cervix goes from a firm, strong structure that can withstand the increasing load of a growing pregnancy to one that is soft and compliant to allow for delivery. Although the mechanisms underlying premature cervical change in pregnancy are poorly understood, transvaginal cervical length assessment has been proved to be effective in predicting PTB in asymptomatic women.5–7 Cervical strength is another factor determines whether or not a pregnant woman is at risk for PTB. During pregnancy, the objective evaluation of cervical strength is how it changes in response to the pressure generated by the intrauterine contents. Recently, ultrasound elastography has been used as a noninvasive technique to assess cervical stiffness in pregnant women.8,9 In this paper, we will discuss the measurement methods of cervical length and cervical stiffness, and compare the value of cervical assessment by transvaginal ultrasound for predicting PTB in asymptomatic women.
Cervical length measurement
Standardization of the cervical length measurement is critical to be useful in for predicting PTB. This includes standardized methods of image acquisition, identification of the cervical canal, and localization of the cervical external os and internal os. Fetal Medicine Foundation has proposed guidelines on the measurement of cervical length by transvaginal ultrasound.10 The pregnant woman is asked to empty her bladder. With the pregnant woman in the dorsal lithotomy position, a vaginal probe is inserted into the anterior vaginal fornix. A sagittal view of the cervix was obtained. The cervical canal is identified as a thin line running along the longitudinal axis in the center of the cervix. The image is enlarged to fill at least half of the screen. Pressure from the probe on the cervix should be as little as possible. Duration of the examination should be 3–5 min. The single-line between the internal os and external os is measured as cervical length.
The single-line method may underestimate the true cervical length for curl cervical cannel. Retzke et al. described that almost all cervices in the first trimester are curved to some extent. They measured the cervical length by tracing on cannel or two-line method (adding the distance from the external os to the point of the maximum excursion of the cervical curvature and the distance from this point of the curvature to the internal os). They also measured the distance from the point of the maximum excursion to the straight line connecting the two cervical os. If the greatest excursion distance is less than 5 mm, the single-line measurement is acceptable. When the distance is more than 5 mm, two-line method or tracing method is recommended to gain accurate measurement at the first trimester.11
Different from the first trimester, the presence of cervical canal curvature is dependent on cervical length at the second trimester. To et al. demonstrated that the curvature was observed in 51% cases with cervical length of 26–55 mm, 25% with cervical length of 16–25 mm, and none with length of 1–15 mm at 23 weeks.12 The disparity of measurements between the single-line measurement and tracing measurement was seen at the second trimester, while this is of little clinical significance because of the cervix always being straight in women with short cervical length. Therefore, it seems that the single-line measurement is still acceptable at the second trimester.
The undeveloped lower uterine segment, called as isthmus, is very common in the first trimester.11,13 It is critical to identified the point where the cervical mucosa is replaced by the endometrium of the lower uterine segment. Some studies described the first-trimester cervical length was 40–44 mm, while Retzke and Greco proposed that the mean or median cervical length was 32–33 mm at the first trimester.11,14–16 They suspected that the studies with mean cervical length ≥40 mm included the undeveloped lower uterine segment in their measurements. The longer cervical length may affect the value of cervical length in predicting PTB.17
Cervical length assessment for predicting PTB
Increased risk of PTB is associated with reproductive history, antepartum bleeding, rupture of membranes, cervical/uterine factors, fetal/intrauterine factors, infection, demographic factors, lifestyle issues, inadequate prenatal care, low pre-pregnancy weight, and poor weight gain in pregnancy. A history of a prior sPTB is one of the strongest known risk factors for sPTB.3,5 In a study by Iams et al. risk of recurrent PTB (<35 weeks) was 14%–15% while women with a previous history of uncomplicated term delivery had 3% risk for spontaneous term delivery.18 In 2008, a systematic review showed that cervical length revealed a positive likelihood ratio of 11.30 (95% confidence interval: 3.59–35.57) at <20 weeks and 2.86% (95% confidence interval: 2.12–3.87) at 20–24 weeks in women with a history of sPTB if cervical length <25 mm was used as a cut-off.19 At present, routine transvaginal cervical length screening was recommended for women with singleton pregnancy and history of prior sPTB by the American College of Obstetricians and Gynecologists, the Society of Obstetricians and Gynecologists of Canada, and Society for Maternal-Fetal Medicine.6,20,21
The issue of universal transvaginal ultrasound cervical length screening of singleton gestations without prior PTB remains an object of debate. Son et al. conducted cervical length screening in 17 590 women, of which 157 (0.89%) cases with a measurement of ≤25 mm. The introduction of universal cervical length screening shows a significant decrease in the frequency of PTB at <37 weeks of gestation (6.7% vs. 6.0%), <34 weeks of gestation (1.9% vs. 1.7%), and <32 weeks of gestation (1.1% vs. 1.0%).22 In 2005, in a prospective observational study including 2 880 Chinese women with singleton pregnancies, the positive likelihood ratio of cervical length ≤27 mm in predicting sPTB <34 weeks was 9.8, but the positive predictive value was only 6.1%.23 The costs and effects of universal cervical length screening are highly dependent on the prevalence of short cervical length in the population. It has been reported the prevalence of the short cervix between 10 mm and 20 mm was about 1.7%–2.3% before 24 weeks in the general population.24 Given the low prevalence of short cervix and the poor positive predictive values, routine cervical length assessment was not recommended currently in women at low risk by Society of Obstetricians and Gynecologists of Canada or Society for Maternal-Fetal Medicine.6,21
Women with multiple gestations are more likely to have short cervical length and increased risk of sPTB compared to those with singleton gestations. Goldenberg et al. addressed that approximately 18% of twin gestations had a cervical length <25 mm at 22–24 weeks of gestation. The risk of PTB with a cervical length <25 mm was increased eight-fold in twins, compared to six-fold in singletons.25 However, in a multicenter randomized controlled study including 125 twin pregnancies without PTB history, there was no difference on the percentage of deliveries <35 weeks between women with and without short cervical length.26 Despite it is the known increased risk of sPTB in women with multiple gestations, available data does not indicate adequate clinical benefit to justify routine screening of all women with multiple gestations.5,6,20
Previous studies have reported the utility of cervical length measurement in the first trimester for predicting PTB, but the results are discordant. In 2012, Greco et al. addressed the detection rate of PTB was 54.8% in screening by a combination of maternal characteristics and cervical length at the first trimester, with a 10% false positive rate.14 Wulff et al. described there is an association between first-trimester cervical length and risk of short cervix in the second trimester. The performance of first-trimester cervical length for prediction of short second-trimester cervical length was 50% at a 10% false positive rate.27 However, there are also some studies in which cervical length was not shown to be a useful predictor of PTB at the first trimester.15,28 The means difference in cervical length between patients destined to have PTB and those deliver at term is relatively small.14,29 Therefore, more accurate cervical length measurement method is needed for PTB prediction at the first trimester.
Cervical elastography measurement
Two approaches on cervical elastography for quantitative determination of the stiffness of the cervix have been developed: strain sonoelastography and shear-wave sonoelastography (SWS). Strain sonoelastography, defined as static elastography, is a method that can quantitate tissue deform ability. A contact force is induced, and the displacement field between two points tracked to determine strain. The relationship between the contact force and strain value depends upon tissue deform-ability, with greater strain seen in softer tissues. Strain sonoelastography depends on the compression generated manually and is inability to standardize the force applied for inducing the tissue deformation. The SWS overcomes the limitations of strain sonoelastography by automatically generating an acoustic force, has been widely used in the assessment of breast or prostate mass and liver cirrhosis. The advantage of SWS is that the generation of the mechanical impulse is operator independent.8,9
To gain the elastography score of the cervix, the region of interest (ROI) was placed on the circumferential layer of collagen and smooth muscles. It was known that the concentration of smooth muscle cells in the circumferential layer reduces gradually from the inner part to the external part, with 50%–60% at inner os, 40% at mid-cervix and 10% at external os.30 The stiffer inner part has been reported in cervical elastography studies by stain sonoelastography or SWS, which probably is associated with the denser concentration of smooth muscle cells.4,31,32 Until now, there is no standard method of cervical elastography measurement was proposed. Hernandez-Andrade et al. measured the elastography at the cross section of cervix, while some studies used longitudinal section.33–36 It is difficult to compare the elastography scores reported in previous studies because the different ROIs have been used. The anatomic plane or ROIs provide the most reliable estimates of cervical stiffness is still a matter under discussion.
Some factors may affect the elastography scores of the cervix. Strain values depends on the compression generated by operators, while the SWS scores are affected by spatial variations of cervical tissue composition and structure. O’Hara et al. demonstrated that the internal os of the posterior is most likely to produce inaccurate or a loss of shear wave propagation for the depth of interrogation appearing to be problematic in nonpregnant women. Meyberg-Solomayer et al. examined 131 patients between 17 and 41 gestational weeks by transvaginal cervical strain elastography. They found the anterior lip and the cervical canal were significantly softer with increasing gestational weeks, and the posterior lip was significantly harder with increasing maternal age, weight and parity.37 In 2015, Muller et al. proposed there was a weak correlation (r = 0.46) between cervical SWS scores and cervical length measured by vaginal ultrasound. Cervical stiffness declined progressively with gestational age, but no correlation between SWS scores and parity, gravidity or maternal age could be observed.34 Further large samples studies with more accurate and standard measurement are needed to evaluate the relationship between cervical elastography and cervical length or maternal characteristic.
Cervical elastography for predicting PTB
In 2015, Hernandez-Andrade et al. used strain elastography to estimate cervical stiffness in 545 pregnant women with singleton pregnancies at 11–28 weeks of gestation. They demonstrated that increased strain in the internal cervical os was associated with higher risk of sPTB both at ≤34 and <37 weeks of gestation.38 Three years later, they got the similar conclusions in 628 women with a singleton pregnancy using transvaginal SWS. A soft cervix increased the risk of sPTB <37 weeks by 4.5-fold and of sPTB <34 weeks by 21-fold compared to a non-soft cervix.33 In a systematic review including 1 488 pregnant women at 11–37 gestational weeks, cervical elastography showed a good prediction value, with a sensitivity of 0.84, a specificity of 0.82, and an area under the curve of 0.90.39 However, in 2019, Suthasmalee et al. reported the cervical SWS scores in preterm and term groups were not significantly different at 18–24 weeks of gestation. They proposed that the SWS may not be sensitive enough to use solely as a predictor for sPTB <37 weeks.40 These discordant results on cervical elastography for predicting PTB are probably associated with the difference on study design, such as screening gestational weeks and the placement of ROIs.
Combined cervical assessment
Previous research has focused on combined screening strategies involving cervical length, cervical elastography, biochemical markers and maternal characteristic. Park et al. addressed that no difference on cervical length or cervical elastography was detected between pregnancies with and without sPTB in women with a short cervix (≤25 mm) at the second trimester. However, when only patients with cervical length ≥1.5 cm were included in the analysis, combination of cervical length, cervical elastography, gestational weeks, and pre-pregnancy body mass index significantly increased the predicting ability up to an area under the curve of 0.83.41 Hernandez-Andrade et al. demonstrated that the combination of a soft and a short cervix increased the risk of sPTB <37 weeks by 18-fold and the risk of sPTB ≤34 weeks by 120-fold compared to women with normal cervical length.33 Some studies reported that the combination of cervical length and fetal fibronectin may be more effective than using one alone, but again conflicting results have been found.21 The value of the combination screening strategies has not been fully validated in large scale studies, and further research is needed in the prediction of PTB.
At present, cervical length measurement can be used to identify increased risk of PTB in women with risk factors for PTB at the second trimester. However, routine transvaginal cervical length assessment is not recommended in women at low risk because of poor positive predictive values. There was a conflicting evidence on the value of cervical length screening at the first trimester. Because there is no compelling evidence for an effective intervention for women with multiple gestations, routine cervical length screening is currently not recommended in this population. Cervical elastography is a potentially useful marker for PTB prediction, while more accurate and standard measurement are needed in future. None of the combined screening strategies reported previously can fulfill the criteria for ideal screening test for PTB currently. Therefore, further well-designed studies investigating the predictive value of cervical assessment and other screening biomarkers with high sensitivity and specificity are needed for predicting PTB.
Conflicts of Interest
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