Helen Feltovich

Beyond cervical length: emerging technologies for assessing the pregnant cervix

Spontaneous preterm birth is a heterogeneous phenotype. A multitude of pathophysiologic pathways culminate in the final common denominator of cervical softening, shortening, and dilation that leads to preterm birth. A precise description of specific microstructural changes to the cervix is imperative if we are to identify the causative upstream molecular processes and resultant biomechanical events that are associated with each unique pathway. Currently, however, we have no reliable clinical tools for quantitative and objective evaluation, which likely contributes to the reason the singleton spontaneous preterm birth rate has not changed appreciably in >100 years. Fortunately, promising techniques to evaluate tissue hydration, collagen structure, and/or tissue elasticity are emerging. These will add to the body of knowledge about the cervix and facilitate the coordination of molecular studies and ultimately lead to novel approaches to preterm birth prediction and, finally, prevention.

The mechanical role of the cervix in pregnancy

Appropriate mechanical function of the uterine cervix is critical for maintaining a pregnancy to term so that the fetus can develop fully. At the end of pregnancy, however, the cervix must allow delivery, which requires it to markedly soften, shorten and dilate. There are multiple pathways to spontaneous preterm birth, the leading global cause of death in children less than 5 years old, but all culminate in premature cervical change, because that is the last step in the final common pathway to delivery. The mechanisms underlying premature cervical change in pregnancy are poorly understood, and therefore current clinical protocols to assess preterm birth risk are limited to surrogate markers of mechanical function, such as sonographically measured cervical length. This is what motivates us to study the cervix, for which we propose investigating clinical cervical function in parallel with a quantitative engineering evaluation of its structural function. We aspire to develop a common translational language, as well as generate a rigorous integrated clinical-engineering framework for assessing cervical mechanical function at the cellular to organ level. In this review, we embark on that challenge by describing the current landscape of clinical, biochemical, and engineering concepts associated with the mechanical function of the cervix during pregnancy. Our goal is to use this common platform to inspire novel approaches to delineate normal and abnormal cervical function in pregnancy.

Quantitative Ultrasound Assessment of Cervical Microstructure

The objective of this preliminary study was to determine whether quantitative ultrasound (QUS) can provide insight into, and characterization of, uterine cervical microstructure. Throughout pregnancy, cervical collagen reorganizes (from aligned and anisotropic to disorganized and isotropic) as the cervix changes in preparation for delivery. Premature changes in collagen are associated with premature birth in mammals. Because QUS is able to detect structural anisotropy/isotropy, we hypothesized that it may provide a means of noninvasively assessing cervical microstructure. Thorough study of cervical microstructure has been limited by lack of technology to detect small changes in collagen organization, which has in turn limited our ability to detect abnormal and/or premature changes in collagen that may lead to preterm birth. In order to determine whether QUS may be useful for detection of cervical microstructure, radiofrequency (rf) echo data were acquired from the cervices of human hysterectomy specimens (n = 10). The angle between the acoustic beam and tissue was used to assess anisotropic acoustic propagation by control of transmit/receive angles from −20° to +20°. The power spectrum of the echo signals from within a region of interest was computed in order to investigate the microstructure of the tissue. An identical analysis was performed on a homogeneous phantom with spherical scatterers for system calibration. Power spectra of backscattered rf from the cervix were 6 dB higher for normal (0°) than steered (±20°) beams. The spectral power for steered beams decreased monotonically (0.4 dB at +5° to 3.6 dB at +20°). The excess difference (compared to similar analysis for the phantom) in normally-incident (0°) versus steered beams is consistent with scattering from an aligned component of the cervical microstructure. Therefore, QUS appears to reliably identify an aligned component of cervical microstructure; because collagen is ubiquitously and abundantly present in the cervix, this is the most likely candidate. Detection of changes in cervical collagen and microstructure may provide information about normal versus abnormal cervical change and thus guide development of earlier, more specific interventions for preterm birth.

Quantitative imaging of the cervix: setting the bar

Information assessment is fundamentally either qualitative or quantitative. The former is subjective, based on apparent qualities, and the latter is objective, involving measurable quantities and numerical descriptors. Medicine is primarily quantitative; routinely, we use biomarkers to make diagnoses, distinguish normal from abnormal physiological conditions and monitor treatments. According to Wikipedia, a biomarker is: ‘anything that can be used as an indicator of a particular disease state or some other physiological state of an organism’. In order for a biomarker to be clinically useful, it must be validated, and its assessment standardized and reproducible between different laboratories and equipment, and the information provided by the biomarker should be relevant to the physiological condition1. A simple example is body temperature: fever is a biomarker of infection or inflammation. Medical imaging, in contrast, is primarily qualitative. The details of the physical interactions that occur between an object and an imaging modality hold a wealth of information but, historically, we have ignored these details in favor of qualitative interpretation. In other words, we rely on pattern recognition of the spatially varying image brightness to identify a structure and distinguish normal from abnormal. This is changing, however, as the value of image quantification is being recognized increasingly. Quantitative imaging is: ‘the extraction of quantifiable features from medical images for the assessment of normal or the severity, degree of change, or status of a disease, injury or chronic condition’1. The process for evaluating a biomarker can be simple – most people keep thermometers at home to test for fever – or it can be fairly sophisticated, involving tracking of radiolabeled substances introduced into the body to identify sites of interest. For instance, positron emission tomography (PET) using radiolabeled 18 F-fluorodeoxyglucose provides information about sites of metabolic activity (glucose uptake). Similarly, gadolinium-based magnetic resonance imaging (MRI) contrast agents can be tagged to improve target specificity and provide analogous information about tumor volume or pharmacokinetics. These complex imaging techniques are presently receiving a great deal of attention as the field of quantitative imaging is exploding. However, one of the earliest successful examples of quantitative imaging is simple and is quietly being used daily in clinical practice: fetal biometry. The metrics (biparietal diameter, head circumference, abdominal circumference and femur length) have been validated and standardized, they are applicable across different imaging systems and the information is relevant to the fetal condition and clearly clinically useful. We in obstetrics and gynecology continue to push the boundaries of quantitative imaging. Evaluation of the fetal heart is an excellent example2–5. Recently, the Journal published a summary of the state of quantitative fetal heart imaging5, in which Hornberger described how relating individual fetal cardiovascular measurements to normative data improves neonatal prognosis, because it allows interventions to be based on a more sophisticated understanding of individual cardiac pathophysiology. In other words, validation and standardization of specific measures which are relevant to the fetal condition has resulted in clinically useful interventions. This is precisely the role of an effective biomarker. There are many other examples of quantitative imaging in the fetus, including of bones6, craniofacial structures7, lungs8 and brain9. Quantitative ultrasound techniques are also being explored actively for assessment of the placenta10 and especially the cervix11–17. The first reference to cervical quantitative imaging17 was in this Journal in 2006, and the current issue holds a compelling paper by Hernandez-Andrade et al.18, which is likely the most recent word.

Nonlinear optical microscopy and ultrasound imaging of human cervical structure.

Abstract. The cervix softens and shortens as its collagen microstructure rearranges in preparation for birth, but premature change may lead to premature birth. The global preterm birth rate has not decreased despite decades of research, likely because cervical microstructure is poorly understood. Our group has developed a multilevel approach to evaluating the human cervix. We are developing quantitative ultrasound (QUS) techniques for noninvasive interrogation of cervical microstructure and corroborating those results with high-resolution images of microstructure from second harmonic generation imaging (SHG) microscopy. We obtain ultrasound measurements from hysterectomy specimens, prepare the tissue for SHG, and stitch together several hundred images to create a comprehensive view of large areas of cervix. The images are analyzed for collagen orientation and alignment with curvelet transform, and registered with QUS data, facilitating multiscale analysis in which the micron-scale SHG images and millimeter-scale ultrasound data interpretation inform each other. This novel combination of modalities allows comprehensive characterization of cervical microstructure in high resolution. Through a detailed comparative study, we demonstrate that SHG imaging both corroborates the quantitative ultrasound measurements and provides further insight. Ultimately, a comprehensive understanding of specific microstructural cervical change in pregnancy should lead to novel approaches to the prevention of preterm birth.

Estimation of shear wave speed in the human uterine cervix.

To explore spatial variability within the cervix and the sensitivity of shear wave speed (SWS) to assess softness/stiffness differences in ripened (softened) vs unripened tissue.

The role of routine cervical length screening in selected high- and low-risk women for preterm birth prevention.

Preterm birth remains a major cause of neonatal death and short and long-term disability in the US and across the world. The majority of preterm births are spontaneous and cervical length screening is one tool that can be utilized to identify women at increased risk who may be candidates for preventive interventions. The purpose of this document is to review the indications and rationale for CL screening to prevent preterm birth in various clinical scenarios. The Society for Maternal-Fetal Medicine recommends (1) routine transvaginal cervical length screening for women with singleton pregnancy and history of prior spontaneous preterm birth (grade 1A); (2) routine transvaginal cervical length screening not be performed for women with cervical cerclage, multiple gestation, preterm premature rupture of membranes, or placenta previa (grade 2B); (3) practitioners who decide to implement universal cervical length screening follow strict guidelines (grade 2B); (4) sonographers and/or practitioners receive specific training in the acquisition and interpretation of cervical imaging during pregnancy (grade 2B).

Changes in shear wave speed pre- and post-induction of labor: a feasibility study.

To explore the feasibility of using shear wave speed (SWS) estimates to detect differences in cervical softening pre‐ and post‐ripening in women undergoing induction of labor.

Three-dimensional, extended field-of-view ultrasound method for estimating large strain mechanical properties of the cervix during pregnancy.

Cervical shortening and cervical insufficiency contribute to a significant number of preterm births. However, the deformation mechanisms that control how the cervix changes its shape from long and closed to short and dilated are not clear. Investigation of the biomechanical problem is limited by (1) lack of thorough characterization of the three-dimensional anatomical changes associated with cervical deformation and (2) difficulty measuring cervical tissue properties in vivo. The objective of the present study was to explore the feasibility of using three-dimensional ultrasound and fundal pressure to obtain anatomically-accurate numerical models of large-strain cervical deformation during pregnancy and enable noninvasive assessment of cervical-tissue compliance. Healthy subjects (n = 6) and one subject with acute cervical insufficiency in the midtrimester were studied. Extended field-of-view ultrasound images were obtained of the entire uterus and cervix. These images aided construction of anatomically accurate numerical models. Cervical loading was achieved with fundal pressure, which was quantified with a vaginal pressure catheter. In one subject, the anatomical response to fundal pressure was matched by a model-based simulation of the deformation response, thereby deriving the corresponding cervical mechanical properties and showing the feasibility of noninvasive assessment of compliance. The results of this pilot study demonstrate the feasibility of a biomechanical modeling framework for estimating cervical mechanical properties in vivo. An improved understanding of cervical biomechanical function will clarify the pathophysiology of cervical shortening.

Statistical analysis of shear wave speed in the uterine cervix.

Although cervical softening is critical in pregnancy, there currently is no objective method for assessing the softness of the cervix. Shear wave speed (SWS) estimation is a noninvasive tool used to measure tissue mechanical properties such as stiffness. The goal of this study was to determine the spatial variability and assess the ability of SWS to classify ripened versus unripened tissue samples. Ex vivo human hysterectomy samples (n = 22) were collected; a subset (n = 13) were ripened. SWS estimates were made at 4 to 5 locations along the length of the canal on both anterior and posterior halves. A linear mixed model was used for a robust multivariate analysis. Receiver operating characteristic (ROC) analysis and the area under the ROC curve (AUC) were calculated to describe the utility of SWS to classify ripened versus unripened tissue samples. Results showed that all variables used in the linear mixed model were significant ( p <; 0.05). Estimates at the mid location for the unripened group were 3.45 ± 0.95 m/s (anterior) and 3.56 ± 0.92 m/s (posterior), and 2.11 ± 0.45 m/s (anterior) and 2.68 ± 0.57 m/s (posterior) for the ripened ( p <; 0.001). The AUCs were 0.91 and 0.84 for anterior and posterior, respectively, suggesting that SWS estimates may be useful for quantifying cervical softening.