The cervix, which is the opening into the uterus, is a remarkable organ. It is the only structure in the entire body that has diametrically opposed functions. The normal cervix stays stiff and closed throughout most of pregnancy while the baby develops and then completely softens and opens at just the right time so the full-grown baby can be born normally, through the vagina. This process of softening and opening involves remodeling, or breaking down, of the cervix’s collagen structure together with an increase in water, or hydration, of the cervix. When the process happens too soon, babies can be born prematurely, which can cause serious lifelong disability and even death. When it happens too late, mothers may need a cesarean delivery. [1,2]

Amazingly, even after 100 years of research, nobody understands how this happens. Specifically, it is unclear how the cervix knows when to soften, or what molecular signals initiate and control this process. As a result, obstetrical providers today evaluate cervical softness in exactly the same way as they did in the 1800s: they feel the cervix with their fingers and classify it as ‘soft’, ‘medium’ or ‘firm’. And, unsurprisingly, despite significant research effort, the preterm birth rate remains unacceptably high and more than 95% of preterm births are intractable to any available therapies.

The cervix is like a cylinder with a canal in the middle that goes up into the uterus. This is where the sperm travels to fertilize the egg, which then nests in the uterus. Cervical collagen is roughly arranged in 3 layers. There is a thin layer on the inner part that where collagen is mostly aligned along the cervical canal, and similarly a thin layer that runs along the outside of the cervix. Between these layers, in the middle of the cervix is a thicker layer of collagen that is circumferential, aligned like a belt around the canal. Researchers theorize that the inner and outer layers stabilize the cervix from tearing off as it shortens and dilates for childbirth, while the middle circumferential layer is most important for the strength and stiffness of the cervix to prevent it from opening prematurely, but nobody is certain. This information is critical to understanding the process of normal, and abnormal, cervical remodeling, and that is why recently there is growing interest in developing technology that can non-invasively and thoroughly assess the collagen in the cervix and measure its softness and hydration status. The most promising approaches use regular clinical ultrasound systems that have special processing strategies to evaluate these tissue properties.

One approach to assessing tissue softness uses ultrasound pressure to induce a shear wave, which moves outward like rings in water after a stone is dropped. The speed of the shear wave provides a measurement of tissue stiffness because these waves travel slower in softer tissue. This method is used clinically in simple tissues without layers of collagen, such as the liver for staging fibrosis. Cervical tissue is very complex because of the collagen layers, but, after many years of research, we finally have adapted this method for the cervix. The first thing we did was compare shear wave speeds in hysterectomy specimens (surgically removed uterus and cervix) between two groups of women. The first group was given a medicine that softens the cervix in preparation for induction of labor, a process called “ripening”. The second group was not treated. We found that the shear wave speeds were slower in the women who had the medicine, indicating that our method could detect the cervices that had been softened with the medicine.[3] We also found that the cervix was even more complex than we’d thought, that shear wave speeds are different in different parts of the cervix. Fortunately, we learned we could easily control for that by measuring the same place on every woman’s cervix. We confirmed that our measurements were accurate by performing second harmonic generation microscopy on the cervix samples in which we measured shear wave speeds. This is a sophisticated way of looking at the tiny collagen structure of a tissue. It told us that indeed, when the collagen structure was more organized, the shear wave speeds were faster, indicating stiffer tissue, and when the collagen started breaking down, the shear wave speeds were slower, indicating softer tissue.
The next step was to see if our methods worked outside of the laboratory. So we studied pregnant women who were undergoing cervical ripening in preparation for induction of labor. We took measurements from each woman before they got the ripening medicine, and then afterwards. We found that the shear wave speeds were slower after the cervix had been ripened, indicating the tissue had softened.[4] This told us that we could obtain useful information about the cervix in pregnant women.
We also evaluated attenuation, which is loss of ultrasound signal as the wave propagates, because attenuation should increase as tissue hydration increases. This is a very complicated measurement, but we found that if we carefully control the angle of the ultrasound beams relative to the underlying cervical structure, attenuation estimates are sensitive to the difference between ripened and unripened tissue in hysterectomy specimens. This suggests the potential for an additional parameter to quantify and monitor the status of the cervix during pregnancy, and we are currently analyzing attenuation in the pregnant women before and after they received the ripening medicine.

This technology is exciting because it could change clinical practice. On a very basic level, obstetrical providers would be able to talk in objective terms about a woman’s cervix instead of the subject “soft, medium, or firm” designation they currently use, which would improve provider communication and thus patient care. More importantly, it could provide a means to thoroughly study normal and abnormal cervical remodeling, and associate structural changes in the cervix with molecular changes, which is the only way to discover new interventions for preterm birth.

References
1. Feltovich H, Hall TJ, and Berghella V. Beyond cervical length: Emerging technologies for assessing the pregnant cervix. Am J Obst & Gyn, 207(5): 345-354, 2012.
2. Feltovich, H and Hall TJ. Quantitative Imaging of the Cervix: Setting the Bar. Ultrasound Obstet Gynecol. 42(2): 121-128, 2013.
3. Carlson LC, Feltovich H, Palmeri ML, Dahl JJ, Del Rio AM, Hall TJ, Estimation of shear wave speed in the human uterine cervix. Ultrasound Obstet Gynecol. 43( 4): 452–458, 2014.
4. Carlson LC, Romero ST, Palmeri ML, Munoz del Rio A, Esplin SM, Rotemberg VM, Hall TJ, Feltovich H. Changes in shear wave speed pre and post induction of labor: A feasibility study. Ultrasound Obstet Gynecol.published online ahead of print Sep.2014.

 

Unlocking the Mystery of the Cervix
Timothy J Hall, Helen Feltovich, Lindsey C. Carlson, Quinton W. Guerrero, Ivan M. Rosado-Mendez
University of Wisconsin, Madison, WI (tjhall@wisc.edu)

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