Molecular, Functional, and Microstructural Imaging of Cervical Remodeling Biomarkers

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Summary. Preterm birth (PTB) is the leading cause of neonatal mortality and morbidity worldwide [1, 2], with an estimated incidence of 15 million neonates born preterm annually. Healthcare costs associated with prematurity are estimated to be >$26 billion annually in the United States [18]. The most common clinical indicator of risk for PTB is a short cervix, as determined by ultrasound (US) imaging identifies only 37.3% (low sensitivity) of women who will deliver <35 weeks of gestation, with a very limited positive predictive value of 17.8%. Cervical ripening during labor induction (more than 23% of pregnancies in United States) is accomplished by administration of drugs such as prostaglandin. Current standard of care relies on measuring cervical length and consistency by subjective/qualitative manual examination (a Bishop score), which has limited ability to determine the success of labor induction. Currently, there are no reliable, clinically translatable, and non-invasive imaging instruments capable of acquiring quantitative diagnostic information about the underlying mechanisms of cervical insufficiency and PTB. Similarly, there are no clinically applicable instruments for the objective and quantitative assessment of cervical ripening during labor induction. Therefore, there is an urgent need for an imaging instrument that enables quantitative visualization of pathophysiological changes of cervix at the molecular, microstructural, and functional levels. To address this unmet clinical need, we have been developing a combined multi-modal imaging instrument that merges Photoacoustic (PA), Viscoelasticity (VE), and conventional ultrasound (US) in a single transvaginal probe. In this instrument, PA imaging will provide quantitative measurements of molecular and microstructural mechanistic biomarkers of cervical remodeling (i.e. collagen network organization, water content, microvascular and oxygenation status); VE will assess the changes in tissue biomechanical biomarkers of cervical remodeling (i.e. degree of stiffness/softness and viscosity); and US for imaging cervical morphology (i.e. cervical length). Because TVUS is the standard of care imaging modality for monitoring cervical status during pregnancy and labor, the proposed multi-modal imaging instrument will add only 3-5 minutes to conventional TVUS examination and, therefore, will be readily acceptable in the routine clinical practice. The proposed instrument will have two immediate clinical applications: (a) improving the detection of patients at risk of PTB, particularly in a subset of women without an apparent short cervix; (b) objective and quantitative determination of cervical ripening status prior to induction of contractions, as a part of labor induction procedures. At the conclusion of this study, the diagnostic efficacy of the proposed technique to assess cervical ripening biomarkers will be quantitatively evaluated.