An essential part of normal pregnancy is cervical remodeling, the process by which the collagen microstructure disorganizes and the cervix softens throughout pregnancy to allow eventual delivery of a fetus. Timing is everything;errors result in preterm or post-dates birth, both of which are costly and morbid. Remark- ably, there are currently no tools to objectively quantify these changes, leaving clinicians without a means to precisely determine risk or even a language to accurately communicate the status of a patient's cervix. The primary objective of this proposed effort is to further develop and test technology to objectively describe and quantify cervical microstructural collagen arrangement and softening. A secondary objective is to establish a nonhuman primate (NHP) model for the study of cervical remodeling in pregnancy. Our preliminary studies suggest that two quantitative ultrasound techniques can accurately assess changes in microstructural organization and softness: quantitative ultrasound with beamsteering (QUS) and acoustic radiation force impulse (ARFI). Within this proposed effort we will use these techniques to study the microstructural changes that the cervix undergoes during normal pregnancy in NHPs. There are two branches: the first involves hysterectomy specimens and the second live NHPs. For the former, we will study normal specimens from animals being euthanized for unrelated research projects. Half of the group will undergo cervical ripening with a drug used clinically to ripen the cervix prior to induction of labor, and half will receive no treatment. Quantitative ultrasound measurements of acoustic scattering properties (to describe collagen structure) and tissue softness will be compared in these two groups, and nonlinear optical microscopy (for imaging collagen) will be used to corroborate the ultrasound findings. (This comparison parallels that underway in similar studies of human subject hysterectomy specimens.) The other branch will be a serial study of quantitative ultrasound parameters at several time points throughout normal menstruation (to establish underlying biological variability), and then normal pregnancy (to describe collagen reorganization and cervical softening in pregnancy). A successful NHP model of cervical ripening in pregnancy would add significantly to the body of knowledge about the cervix and accelerate transition to in vivo human studies. Ultimately, a comprehensive understanding of cervical change in pregnancy could allow (a) selection of appropriate candidates for post-dates induction of labor, (b) prediction of patients at greatest risk for preterm delivery, (c) monitorin of treatments for preterm birth or failed post-dates ripening, and most importantly, (d) development of innovative therapeutic strategies for both preterm and post-dates birth via targeted investigation of associated molecular events based on thorough understanding of specific microstructural changes that lead to abnormal cervical remodeling.

Public Health Relevance

This is a proposal to develop and refine quantitative ultrasound technology for objective quantification of the microstructural changes (collagen organization and cervical softness) in the in vivo pregnant cervix in a nonhuman primate model. While microstructural change (evidenced by cervical softening and shortening) is an essential component of normal pregnancy, morbidity is likely when the cervix is too soft or short too early (preterm birth), or too firm too late (post-dates birth), and yet there are no tools to objectively quantify microstructural change. This alone makes quantification clinically useful;more critically objective description of cervical change in pregnancy is imperative to comprehensive study of abnormal birth timing, a significant public health problem.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD072077-02
Application #
8605088
Study Section
Special Emphasis Panel (ZRG1-BMIT-J (01))
Program Officer
Ilekis, John V
Project Start
2013-01-15
Project End
2017-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
2
Fiscal Year
2014
Total Cost
$492,901
Indirect Cost
$152,860
Name
University of Wisconsin Madison
Department
Physics
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Guerrero, Quinton W; Feltovich, Helen; Rosado-Mendez, Ivan M et al. (2018) Anisotropy and Spatial Heterogeneity in Quantitative Ultrasound Parameters: Relevance to the Study of the Human Cervix. Ultrasound Med Biol 44:1493-1503
Guerrero, Quinton W; Feltovich, Helen; Rosado-Mendez, Ivan M et al. (2018) Quantitative Ultrasound Biomarkers Based on Backscattered Acoustic Power: Potential for Quantifying Remodeling of the Human Cervix during Pregnancy. Ultrasound Med Biol :
Rosado-Mendez, Ivan M; Carlson, Lindsey C; Woo, Kaitlin M et al. (2018) Quantitative assessment of cervical softening during pregnancy in the Rhesus macaque with shear wave elasticity imaging. Phys Med Biol 63:085016
Vajihi, Zara; Rosado-Mendez, Ivan M; Hall, Timothy J et al. (2018) Low Variance Estimation of Backscatter Quantitative Ultrasound Parameters Using Dynamic Programming. IEEE Trans Ultrason Ferroelectr Freq Control 65:2042-2053
Guerrero, Quinton W; Fan, Liexiang; Brunke, Shelby et al. (2018) Power Spectrum Consistency among Systems and Transducers. Ultrasound Med Biol 44:2358-2370
Carlson, Lindsey C; Hall, Timothy J; Rosado-Mendez, Ivan M et al. (2018) Detection of Changes in Cervical Softness Using Shear Wave Speed in Early versus Late Pregnancy: An in Vivo Cross-Sectional Study. Ultrasound Med Biol 44:515-521
Tyagi, Mohit; Wang, Yuqi; Hall, Timothy J et al. (2017) Improving three-dimensional mechanical imaging of breast lesions with principal component analysis. Med Phys 44:4194-4203
Feltovich, Helen (2017) Cervical Evaluation: From Ancient Medicine to Precision Medicine. Obstet Gynecol 130:51-63
Guerrero, Quinton W; Rosado-Mendez, Ivan M; Drehfal, Lindsey C et al. (2017) Quantifying Backscatter Anisotropy Using the Reference Phantom Method. IEEE Trans Ultrason Ferroelectr Freq Control 64:1063-1077
Rosado-Mendez, Ivan M; Palmeri, Mark L; Drehfal, Lindsey C et al. (2017) Assessment of Structural Heterogeneity and Viscosity in the Cervix Using Shear Wave Elasticity Imaging: Initial Results from a Rhesus Macaque Model. Ultrasound Med Biol 43:790-803

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