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Published in final edited form as: Ultrasound Med Biol. 2017 Dec 12;44(3):515–521. doi: 10.1016/j.ultrasmedbio.2017.10.017

Detection of changes in cervical softness using shear wave speed in early vs. late pregnancy: an in vivo cross-sectional study

Lindsey C Carlson a, Timothy J Hall a, Ivan M Rosado-Mendez a, Mark L Palmeri b, Helen Feltovich a,c
PMCID: PMC5801067  NIHMSID: NIHMS918764  PMID: 29246767

Abstract

The aim of this study was to assess the ability of Shear Wave Elasticity Imaging (SWEI) to detect changes in cervical softness between early and late pregnancy. Using a cross-sectional study design, shear wave speed (SWS) measurements were obtained from women in the 1st trimester (5-14 weeks gestation) and compared to estimates from a previous study of women at term (37-41 weeks). Two sets of 5 SWS measurements were made using commercial SWEI applications on an ultrasound system equipped with a prototype catheter transducer (128 elements, 3mm diameter, 14mm aperture). Average SWS estimates were 4.42±0.32 m/s (n=12) for 1st trimester and 2.13±0.66 m/s (n = 18) for 3rd trimester (p<0.0001). The AUC was 0.95 (95% CI: 0.82-0.99) with a sensitivity and specificity of 83%. SWS estimates indicated that the 3rd trimester cervix is significantly softer than the 1st trimester cervix. SWEI methods may be promising for assessing changes in cervical softness.

Keywords: cervix, shear wave speed, shear wave elasticity imaging, cervical softness, cervical remodeling

Introduction

Soon after conception, the cervix begins to soften (‘remodel’), and just before delivery, this softening accelerates as the cervix also shortens and dilates.(Aspden 1988; Danforth 1983; Maul et al. 2006; Read et al. 2007; Word et al. 2007) Recent studies suggest that this process is precipitated by complex signaling from the fetus, membranes, placenta, and decidua.(Menon 2016a) Premature activation/signaling in any of these tissues feasibly results in premature cervical remodeling and could lead to spontaneous preterm birth (sPTB, birth at less than 37 weeks gestation), the leading global cause of death in children under 5.(Menon et al. 2016b; Vink and Feltovich 2016) Cervical softening initiates early (weeks after conception) and accelerates just prior to delivery. Because of that, one way clinicians try to detect a woman's readiness for labor is to assess the softness of her cervix via vaginal examination. This assessment is entirely subjective, which may explain part of why cervical exam is a poor predictor of both delivery timing and success of labor induction.(Feltovich 2017)

Our goal is to refine and develop objective, quantitative methods to evaluate the cervix. Ultimately, we hope that combining imaging biomarkers with other factors that inform delivery events (bodily fluid biomarkers, demographics, race/ethnicity, etc) will improve prediction of delivery timing and induction success. Shear Wave Elasticity Imaging (SWEI) is a non-invasive method to quantify tissue softness. The basic principle is that measuring shear wave speeds in tissue provides objective information about stiffness/softness because shear waves travel faster in stiffer tissue.(Sarvazyan et al. 1998) SWEI methods have been successfully used in women (Carlson et al. 2014a; Carlson et al. 2014b; Carlson et al. 2015; Hernandez-Andrade et al. 2014; Muller et al. 2015) as well as in animal models (Peralta et al. 2015, Huang et al. 2016, Rosado-Mendez et al. 2017). We have previously shown that we can quantify cervical softness induced by ‘ripening’ (pharmacologic softening of the cervix with prostaglandins in preparation for labor induction) in both the nonpregnant and late pregnant (term, 37-41 weeks of gestation) cervix. (Carlson et al. 2014a; Carlson et al. 2014b; Carlson et al. 2015). To further our investigation in preparation for larger trials, we undertook this simple study to determine if SWEI methods can quantify a difference in cervical softness in early vs. late pregnancy, and investigate the range and variability of SWS estimates at both timepoints. To this end, we recruited a group of women in early pregnancy (1st trimester, 5-14 weeks) and compared their average cervical SWS to those in a group of women in late (term) pregnancy from a previous study.

Materials and Methods

Study Design

This was a cross-sectional study of SWS measurements in the cervix in a group of women in early pregnancy (1st trimester, 5-14 weeks) compared to a group of women at term (37-41 weeks) from a previous study.(Carlson et al. 2015)

Patient Population

Pregnant women scheduled for 1st trimester termination of pregnancy were recruited (n = 15) from Planned Parenthood – Metro Health Center in Salt Lake City, UT from August 2015 to August 2016. This study was approved by the institutional review boards at the University of Utah and the University of Wisconsin, and each subject provided written informed consent. Data were compared to deidentified data from our previous study of cervical softening in pregnant women (n=18) presenting for induction of labor at term. (Carlson et al. 2015) In that study, pregnant women scheduled for cervical ripening prior to induction were recruited from the Labor and Delivery Unit at Intermountain Medical Center in Salt Lake City, UT from March to August 2013. A summary flow diagram of recruitment is shown in Figure 1. Exclusion criteria for both groups included history of preterm birth, cervical surgery, or collagen vascular disease. The age, pregnancy history, and gestational age were recorded for each patient.

Figure 1. A summary flow diagram of recruitment for the 1st and 3rd trimester studies.

Figure 1

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Data Acquisition and Processing

All examinations were done by the same clinician (H.F.) and acquisitions were supervised by the same engineer (L.C.D.) to reduce interobserver variability. The same transducer, scanning technique, and data processing methods applied in our previous study of women at term (37 – 41 weeks)(Carlson et al. 2015) were utilized to facilitate direct comparison between findings in early versus late pregnancy. Specifically, scanning was performed using a Siemens ACUSON S3000™ ultrasound system (Siemens Medical Solutions USA, Inc., Malvern, PA, USA). A prototype catheter transducer (128 elements, 14mm aperture, 3mm diameter), operated in linear array mode, was used to acquire shear wave data. (We use a linear transducer to align ultrasound echo signals with underlying cervical structure and because we have found that a typical curvilinear array creates wave behavior that is too complex for meaningful evaluation.) The transducer was secured to the clinician's finger and inserted into a glove filled with gel for acoustic coupling (as shown by Carlson et al. (2015) Figure 1). The clinician's finger was placed on the posterior surface of the cervix as shown in the illustration in Figure 2(a), roughly parallel to the endocervical canal, in the mid-position along the length of the canal. Location was verified by comparing B-mode images from sector imaging mode as shown by Figure 2(b), which has a larger field of view, to the rectilinear mode image shown in Figure 2(c). The dotted lines in Figure 2(a) show the location of the sector image in (b) and similarly, the dotted lines in (b) show the location of the rectilinear image in (c). This location was chosen based on our ex vivo studies of the human cervix. (Carlson et al. 2014b) Because undue pressure may cause a tissue to stiffen and bias SWS estimates, contact force was minimized by tactile feedback and observed tissue displacement in B-mode imaging prior to SWS measurement.

Figure 2.

Figure 2

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(a) An illustration showing the position of the clinician's finger on the posterior side of the cervix. The dotted lines show the location of the B-mode sector field and the position of the SWS region of interest mid-way through the thickness of the posterior half of the cervix. (b) A B-mode sector image of the cervix with the dotted line showing the field of view for the rectilinear B-mode image in (c) with the ROI just above the canal.

Shear wave data were acquired with the Siemens Virtual Touch™ Quantification software package (Siemens Medical Solutions USA, Inc., Malvern, PA, USA). A 5×5 mm2 region of interest (ROI) was placed mid-thickness through the posterior half of the cervix (as shown by the ROI in Figure 2(b),(c)), 5-10 mm from the outer surface of the cervix to avoid boundaries that complicate shear wave propagation. Two sets of 5 replicate SWS measurements were made at the location halfway between internal and external os.

Data processing was performed offline using MATLAB (v. 2016b, MathWorks, Natick, MA, USA). Tissue displacement was estimated using the Loupas' Method on raw in-phase and quadrature (IQ) ultrasound signals.(Loupas et al. 1995, Pinton et al. 2006) Low correlation (< 0.98) displacement estimates were discarded. A quadratic motion filter was used to remove bulk motion (Nightingale et al. 2015) and each set of 5 measurements were averaged to reduce noise. The SWS was estimated using the RANdom SAmple Consensus (RANSAC) method, a time-of-flight approach that determines SWS from the time-to-peak versus lateral location. (Wang et al. 2010)

Based on a similar analysis by Rosado-Mendez et al. (2017), SWS estimate reliability was assessed by comparing SWS estimates using the RANSAC method to a Radon-sum method, another time-of-flight approach.(Rouze et al. 2010) Criteria for rejection of unreliable data were a percentage of inliers (a measure of data quality quantifying the fraction of data points within the 5×5mm ROI used to make RANSAC SWS estimate) less than 50% and/or a disagreement in SWS greater than 2.5 m/s between the two SWS estimation methods. Any SWS estimate that met these criteria was discarded. In addition, data sets from 3 patients were discarded because of significant motion (clinician's finger slipping off the cervix), as verified by B-mode images.

Sample Size

Sample sizes were based on our previous study on the ex vivo cervix (Carlson 2014b) which suggested that 10 subjects were sufficient to establish a difference in softness. To maximize statistical power, we included all pre-ripened measurements from the late pregnancy study (n=18 women). For the early pregnancy group, our goal was to recruit 10 subjects with reliable shear wave data and we exceeded this goal by recruiting 15 subjects, 12 of which had reliable data (as explained below). The final subject numbers are summarized in the flow diagram in Figure 1.

Statistical Analysis

First, we determined whether data from women of different parity and gestational ages within the 1st trimester could be grouped to increase statistical power. Neither parity nor gestational age significantly influenced SWS estimates; therefore, all 12 data sets were combined.

To compare cervical SWS from this group of women in early pregnancy with a group from late pregnancy, data from all (n = 18) women presenting for induction of labor at term (37 – 41 weeks) before administration of a prostaglandin ripening agent were combined from our previous 3rd trimester study.(Carlson et al. 2015) A statistical analysis on the effects of parity and gestational age on SWS estimates was not necessary in this group because all subjects were nulliparous and at term.

Trends in SWS versus gestational age in the 1st trimester were analyzed using simple linear regression in MATLAB. All statistical comparisons of SWS estimates were made using the Wilcoxon rank-sum test in MATLAB with the probability of equal medians (p) less than 0.05 (two-sided) as a criterion for statistical significance. This test was chosen because it is non-parametric and does not rely on data being normally distributed. SWS estimates are summarized as mean±standard deviation(median, interquartile range (IQR)) and represented graphically with box and whisker plots. To test the performance of SWS estimates to discriminate between cervical softness in early vs. late pregnancy, receiver operating characteristic (ROC) curves and the area under the receiver operating characteristic (ROC) curve (AUC) was calculated.

Results

Three (of 15) data sets were excluded from analysis because of significant motion (clinician's hand slipping off the cervix) evident in B-mode images. Technical issues are an expected part of introductory studies to assess the feasibility and approach of new technology. Based on early experience of SWS technology in other tissues, such as liver, we expected that about 50% of data would not meet quality criteria, and that is why we recruited more women than our statistician indicated would be needed to detect statistically meaningful differences in SWS. Of the women included in the final analysis, 6 were nulliparous and 6 multiparous. Data collected from patients and analysis results are summarized in Table 1.

Table 1. Data collected from first and third trimester patients.

Trimester Gestational Age (Weeks) Parity Number of Patients Cervical SWS (m/s) p-value (Wilcoxon rank-sum test)
mean±SD median (IQR)
Nulliparous 6 4.67±1.23 4.96 (3.90-5.52) 0.70
T1 5-14 Multiparous 6 4.16±1.47 3.85 (2.90-5.72)
All 12 4.42±1.32 4.54 (3.18-5.62) <0.001
T3 37-41 Nulliparous 18 2.13±0.66 2.02 (1.65-2.50)
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SWS estimates did not vary with parity or gestational age within the 1st trimester. Figure 3 is a boxplot of the median SWS estimate from each subject grouped by parity. The center line indicates the median, the boxes are the 25th and 75th percentiles, and the whiskers represent the maxima and minima. The means were 4.67±1.23 m/s (median, 4.96 m/s (IQR, 3.90-5.52 m/s)) for nulliparous subjects and 4.16±1.47 m/s (median, 3.85 m/s (IQR, 2.90-5.72 m/s)) for multiparous subjects. SWS did not significantly differ between nulliparous and multiparous subjects using the Wilcoxon rank sum test (p = 0.70). Further, SWS estimates were not correlated with gestational age within the 1st trimester (r2=0.0056). These results justified combining all 1st trimester data.

Figure 3.

Figure 3

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Box-and-whisker plots of median shear wave speed for nulliparous and multiparous 1st trimester subject groups. The boxes represent interquartile range (IQR), the interior line is the median, and whiskers are maxima and minima within 1.5*IQR.

SWS estimates were significantly different between early and late pregnancy (Figure 4). The boxplot shows SWS estimates from subjects in the 1st trimester (all gestational ages and parity) and the 3rd trimester (prior to prostaglandin ripening). The corresponding mean SWS values for 1st trimester were 4.42±1.32 (median, 4.54 (IQR, 3.18-5.62)) m/s and 2.13±0.66 m/s (median, 2.02 (IQR, 1.65- 2.50)) m/s for 3rd trimester (p<0.0001).

Figure 4.

Figure 4

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Box-and-whisker plots of median shear wave speed for 1st trimester (n=12) and 3rd trimester (n = 18). The SWS decreased for 3rd trimester and there was also a significant reduction in variance (although the fractional standard deviation is constant) .

Estimates of SWS effectively differentiated cervical softness between early and late pregnancy. The ROC curve is shown in Figure 5 in gray. A positive condition was categorizing a SWS measurement as a 1st trimester cervix. The dotted black line shows a 50% chance of correctly identifying a 1st trimester cervix. The AUC value was 0.95 (95% CI: 0.82-0.99), the sensitivity and specificity were 83% at the operating point of maximum combined sensitivity and specificity. The SWS value at this chosen operating point was 2.65 m/s, meaning that any SWS estimate less than 2.65 m/s would be classified as cervical softness typical in 3rd trimester and more than this threshold would be classified as softness typical in 1st trimester.

Figure 5. Empirical receiver operating characteristic curve (ROC) for median SWS estimates at the mid location identifying a SWS estimate as a 1st trimester cervix.

Figure 5

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Discussion

Our results suggest that SWS estimates can quantify cervical softening from early to late pregnancy, and provide reference values for expected SWS in the 1st and the 3rd trimester cervix. Specifically, we found that average SWS estimates in a group of women in late pregnancy were significantly lower, suggesting softer tissue, than those in a group of women in early pregnancy. This statistical difference is demonstrated by the lack of overlap in the notched regions (95% confidence that medians are not equivalent) in Figure 4, as well as an AUC of 0.95 with the lowest 95% CI of 0.82. In addition, the variability of SWS values within each group was smaller than the range of SWS values at each endpoint (early or late pregnancy). This suggests that we should be able to track changes in between these two endpoints.

SWS variance was lower by a factor of 2 (1.23 to 0.66 m/s) in late, compared to early, pregnancy. This is partly because our estimation method is associated with smaller estimate variance in slow shear wave speeds (such as the 3rd trimester cervix) and higher variance are expected in faster shear wave speeds (such as the 1st trimester cervix).(Wang et al. 2013) However, it is also biologically plausible that this decreased variance could be due to increasing disorganization (and thus homogeneity) of cervical microstructure that is known to occur from early to late pregnancy.(Clark et al. 2006; Feltovich et al. 2006; Myers et al. 2009; Zhang et al. 2012)

Our results also agree with trends observed by Muller et al. (2015), who reported that SWS significantly differed between the 1st and 3rd, as well as the 2nd and 3rd, trimesters. However, they found the reduction of mean SWS from the 1st to 3rd trimester was small (0.2 m/s, ∼1 standard deviation). In contrast, our SWS estimates and variances were higher; we observed a 2.29 m/s decrease in mean SWS from the 1st to 3rd trimester (∼2 standard deviations). A notable difference between our study and that of Muller et al. (2015) is sampling location. They measured SWS in the distal cervix near the external os, and we evaluated the mid cervix, nearer the internal os. This is because our investigation of SWS in multiple locations in the nonpregnant ex vivo cervix revealed little SWS variation with cervical softening distally (near the external os) but significant differences at the mid- and proximal cervix.(Carlson et al. 2014a; Carlson et al. 2014b) This seems biologically plausible because the internal os is characterized by greater heterogeneity (more cellular content and cross-link heterogeneity) and is where cervical change initiates .(Vink and Feltovich 2016; Zork et al. 2015) Therefore, it is possible that our estimates and variances were higher because we were sampling the region in the cervix at which that would be expected.

Like Muller et al., we intended to study patients in both the 1st and 2nd trimesters for comparison to those in our previous 3rd trimester study. However, low availability of women scheduled for 2nd trimester termination precluded enrollment of women. Nevertheless, extrapolation of our results allows us to expect that SWS estimates and variance in the 2nd trimester cervix would be between 1st and 3rd trimester values. Muller et al. (2015) did not observe a significant difference in SWS between the 1st and 2nd trimesters. However, as discussed above, they sampled near the external os while we sampled more proximally, and this could have contributed to their nonsignificant findings.

One limitation of our feasibility study is its small numbers. For instance, Figure 3 shows that SWS is not significantly influenced by parity. While our results are consistent with the findings of Zork et al.(2015) who observed that collagen crosslink types do not significantly differ in multiparous versus nulliparous cervical tissue, and with a study in the ex vivo Rhesus macaque cervix (Huang et al. 2016), our small sample numbers make it difficult to draw conclusions. Our results do show slightly higher mean and median SWS values for nulliparous samples. Because differences based on parity could be relevant to study of preterm birth, this is currently under investigation in our Rhesus macaque model. Second, contrary to expectations, we found no correlation between SWS and gestational age within the 1st trimester (5 – 14 weeks). This also could be related to low sample numbers; specifically, any progressive change may have been too small to detect due to intersubject variability in this limited number of subjects.

Another issue is that 1st trimester data were acquired on the posterior cervix, and 3rd trimester data on the anterior cervix. This was simply because it was technically difficult to acquire from the anterior cervix in the 1st trimester. (While it would have been easy to sample the posterior cervix in late pregnancy, we randomly chose anterior without considering potential logistical issues with the 1st trimester cervix.) This issue is relevant because in our previous ex vivo study of the nonpregnant cervix, SWS gradients along the length of the canal differed in the anterior versus posterior cervix. (Carlson et al. 2014a; Carlson et al. 2014b) In the ripened ex vivo cervix, average SWS in the mid-position of the anterior compared to the posterior cervix was 0.6 m/s slower. (We focus on the ripened cervix because it more closely resembles the pregnant cervix.) Consistent with this, Hernandez et al. (2014) found SWS in the anterior cervix to be 0.3 m/s slower than the posterior in a group of 154 pregnant women. To account for this potential difference, we subtracted 0.6 m/s from the 1st trimester SWS median and repeated the analysis. There remained a significant decrease in SWS (p<0.001) between the 1st and 3rd trimesters.

Moreover, although SWS gradients were higher in the ex vivo posterior versus anterior cervix (0.83 m/s/cm vs. 0.31 m/s/cm), those gradients are small compared to standard deviations across subjects in each trimester in vivo. This means that changes in position (±1cm) should only cause small changes in SWS. (Carlson et al. 2014a; Carlson et al. 2014b).

Another challenge is presented by our prototype linear transducer because that limits the ability of other groups to reproduce our results. We chose this transducer because it allows alignment of the ultrasound beams along the canal for more understandable data interpretation, reduces potential confounding from tissue stiffening due to unnecessary operator force, and because we have found that the typical curvilinear array of transvaginal probes creates wave behavior that is too complex for meaningful evaluation. Fortunately, a commercially available linear array transducer for transvaginal SWS estimation, while not trivial, is certainly possible, and would allow for reproducibility studies.

This is critical because of course, before any diagnostic decisions can be based on shear wave elasticity imaging on the cervix during pregnancy, repeatability and reproducibility must be established. In other words, while our results suggest that SWS can be used as a biomarker for cervical softening during pregnancy, the value of a biomarker as an objective surrogate to a clinical endpoint strongly depends on its repeatability (the ability to obtain the same number when repeating the measurement on the same subject by the same observer with the same equipment) and reproducibility (the ability to obtain agreement in measurements among various observers with different equipment).(Barnhart and Barboriak 2009) We are currently evaluating the repeatability of SWS measurements in a clinical longitudinal study. Reproducibility will be a topic of future research, which we will model upon studies of SWEI in the liver. (Hall et al. 2013; Palmeri et al. 2015)

Conclusion

This cross-sectional study establishes that SWS estimates reflect the clinically-expected increased cervical softness in the cervix in late, as compared to early, pregnancy. Average SWS were 4.42±0.32 m/s in the posterior cervix in late pregnancy and 2.13±0.66 m/s in the anterior cervix in early pregnancy, a statistically significant difference. Although preliminary, this study establishes the feasibility of this technique for assessing cervical softness, supporting the launch of larger clinical studies to evaluate sources of bias, technical limitations, as well as repeatability and reproducibility of the technique.

Acknowledgments

This work was supported by NIH Grants F31HD082911 and R01HD072077 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, T32CA009206 from the National Cancer Institute, the Intermountain Research and Medical Foundation and the University of Utah. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors would also like to recognize Marci Fjelstad and Veronica Galindo for their invaluable assistance, and the obstetrician-gynecologist, RNs, and staff at PPMHC for providing access to their patients for this study. We are also grateful to Siemens Healthcare Ultrasound division for an equipment loan and technical support.

Footnotes

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