Abstract
Remodeling of the cervix occurs in advance of labor both at term and at preterm birth. Morphological characteristics associated with remodeling in rodents were assessed in cervix biopsies from women at term (39 weeks’ gestation) and preterm (<33 weeks’ gestation). Collagen I and III messenger RNA and hydroxyproline concentrations declined in cervix biopsies from women in labor at term and preterm compared to that in the cervix from nonlaboring women. Extracellular collagen was more degraded in sections of cervix from women at term, based on optical density of picrosirius red stain, versus that in biopsies from nonpregnant women. However, collagen structure was unchanged in the cervix from women at preterm labor versus the nonpregnant group. As an indication of inflammation, cell nuclei density was decreased in cervix biopsies from pregnant women irrespective of labor compared to the nonpregnant group. Moreover, CD68-stained macrophages increased to an equivalent extent in cervix subepithelium and stroma from groups in labor, both at term and preterm, as well as in women not in labor at term. Evidence for a similar inflammatory process in the remodeled cervix of women at term and preterm birth parallels results in rodent models. Thus, a conserved final common mechanism involving macrophages and inflammation may characterize the transition to a ripe cervix before birth at term and in advance of premature birth.
Similar content being viewed by others
References
Beck S, Wojdyla D, Say L, et al. The worldwide incidence of preterm birth: a systematic review of maternal mortality and morbidity. Bull World Health Organ. 2010;88(1):31–38.
Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet. 2008;371(9606):75–84.
Mitchell BF, Taggart MJ. Are animal models relevant to key aspects of human parturition? Am J Physiol Regul Integr Comp Physiol. 2009;297(3):r525–r545.
Word RA, Li XH, Hnat M, Carrick K. Dynamics of cervical remodeling during pregnancy and parturition: mechanisms and current concepts. Semin Reprod Med. 2007;25(1):69–79.
Iwahashi M, Muragaki Y, Ooshima A, Umesaki N. Decreased type I collagen expression in human uterine cervix during pregnancy. J Clin Endocrinol Metab. 2003;88(5):2231–2235.
Danforth DN. The fibrous nature of the human cervix, and its relation to the isthmic segment in gravid and nongravid uteri. Am J Obstet Gynecol. 1947;53(4):541–560.
Schwalm H, Dubrauszky V. The structure of the musculature of the human uterus—muscles and connective tissue. Am J Obstet Gynecol. 1966;94(3):391–404.
Rorie DK, Newton M. Histologic and chemical studies of the smooth muscle in the human cervix and uterus. Am J Obstet Gynecol. 1967;99(4):466–469.
Badir S, Mazza E, Zimmermann R, Bajka M. Cervical softening occurs early in pregnancy: characterization of cervical stiffness in 100 healthy women using the aspiration technique. Prenat Diagn. 2013;33(8):737–741.
Onizawa S. Studies on changes in the uterine cervix during pregnancy [in Japanese]. Nihon Sanka Fujinka Gakkai Zasshi. 1987; 39(4):633–640.
Uldbjerg N, Ekman G, Malmstrom A, Olsson K, Ulmsten U. Ripening of the human uterine cervix related to changes in collagen, glycosaminoglycans, and collagenolytic activity. Am J Obstet Gynecol. 1983;147(6):662–666.
Granstrom L, Ekman G, Ulmsten U, Malmstrom A. Changes in the connective tissue of corpus and cervix uteri during ripening and labour in term pregnancy. Br J Obstet Gynaecol. 1989; 96(10):1198–1202.
Ekman G, Malmstrom A, Uldbjerg N, Ulmsten U. Cervical collagen: an important regulator of cervical function in term labor. Obstet Gynecol. 1986;67(5):633–636.
Mackler AM, Iezza G, Akin MR, McMillan P, Yellon SM. Macrophage trafficking in the uterus and cervix precedes parturition in the mouse. Biol Reprod. 1999;61(4):879–883.
Gonzalez JM, Romero R, Girardi G. Comparison of the mechanisms responsible for cervical remodeling in preterm and term labor. J Reprod Immunol. 2013;97(1):112–119.
Yoshida K, Jiang H, Kim M, et al. Quantitative evaluation of collagen crosslinks and corresponding tensile mechanical properties in mouse cervical tissue during normal pregnancy. PLoS One. 2014;9(11):e112391.
Garfield RE, Saade G, Buhimschi C, et al. Control and assessment of the uterus and cervix during pregnancy and labour. Hum Reprod Update. 1998;4(5):673–695.
Kemp B, Rath W, Winkler M, Reineke T, Beier HM, von Rango U. Is cervical dilatation during parturition at term associated with apoptosis?. J Perinat Med. 2005;33(2):137–143.
Allaire AD, D’Andrea N, Truong P, McMahon MJ, Lessey BA. Cervical stroma apoptosis in pregnancy. Obstet Gynecol. 2001; 97(3):399–403.
Leppert PC. Proliferation and apoptosis of fibroblasts and smooth muscle cells in rat uterine cervix throughout gestation and the effect of the antiprogesterone onapristone. Am J Obstet Gynecol. 1998;178(4):713–725.
Yellon SM, Mackler AM, Kirby MA. The role of leukocyte traffic and activation in parturition. J Soc Gynecol Investig. 2003; 10(6): 323–338.
Payne KJ, Clyde LA, Weldon AJ, Milford TA, Yellon SM. Residency and activation of myeloid cells during remodeling of the prepartum murine cervix. Biol Reprod. 2012;87(5):106.
Yellon SM, Ebner CA, Elovitz MA. Medroxyprogesterone acetate modulates remodeling, immune cell census, and nerve fibers in the cervix of a mouse model for inflammation-induced preterm birth. Reprod Sci. 2009;16(3):257–264.
Yellon SM, Dobyns AE, Beck HL, Kurtzman JT, Garfield RE, Kirby MA. Loss of progesterone receptor-mediated actions induce preterm cellular and structural remodeling of the cervix and premature birth. PLoS One. 2013;8(12): e81340.
Osman I, Young A, Ledingham MA, et al. Leukocyte density and pro-inflammatory cytokine expression in human fetal membranes, decidua, cervix and myometrium before and during labour at term. Mol Hum Reprod. 2003;9(1):41–45.
Challis JR, Lockwood CJ, Myatt L, Norman JE, Strauss JF III, Petraglia F. Inflammation and pregnancy. Reprod Sci. 2009; 16(2):206–215.
Dubicke A, Fransson E, Centini G, et al. Pro-inflammatory and anti-inflammatory cytokines in human preterm and term cervical ripening. J Reprod Immunol. 2010;84(2):176–185.
Tornblom SA, Klimaviciute A, Bystrom B, Chromek M, Brauner A, Ekman-Ordeberg G. Non-infected preterm parturition is related to increased concentrations of IL-6, IL-8 and MCP-1 in human cervix. Reprod Biol Endocrinol. 2005;3:39–48.
Sennstrom MB, Ekman G, Westergren-Thorsson G, et al. Human cervical ripening, an inflammatory process mediated by cytokines. Mol Hum Reprod. 2000;6(4):375–381.
Sakamoto Y, Moran P, Bulmer JN, Searle RF, Robson SC. Macrophages and not granulocytes are involved in cervical ripening. J Reprod Immunol. 2005;66(2):161–173.
Whitworth MK, Pafilis I, Vince G, Quenby S. Cervical leukocyte sub-populations in idiopathic preterm labour. J Reprod Immunol. 2007;75(1):48–55.
Dubicke A, Andersson P, Fransson E, et al. High-mobility group box protein 1 and its signalling receptors in human preterm and term cervix. J Reprod Immunol. 2010;84(1):86–94.
Dubicke A, Akerud A, Sennstrom M, et al. Different secretion patterns of matrix metalloproteinases and IL-8 and effect of corticotropin-releasing hormone in preterm and term cervical fibroblasts. Mol Hum Reprod. 2008;14(11):641–647.
Stegemann H, Stalder K. Determination of hydroxyproline. Clin Chim Acta. 1967;18(2):267–273.
Yellon SM, Oshiro BT, Chhaya TY, et al. Remodeling of the cervix and parturition in mice lacking the progesterone receptor B isoform. Biol Reprod. 2011;85(3):498–502.
Nold C, Maubert M, Anton L, Yellon S, Elovitz MA. Prevention of preterm birth by progestational agents: what are the molecular mechanisms? Am J Obstet Gynecol. 2013;208(3): 223.e221–e227.
Norman M, Ekman G, Malmstrom A. Changed proteoglycan metabolism in human cervix immediately after spontaneous vaginal delivery. Obstet Gynecol. 1993;81(2):217–223.
Feltovich H, Ji H, Janowski JW, Delance NC, Moran CC, Chien EK. Effects of selective and nonselective PGE2 receptor agonists on cervical tensile strength and collagen organization and microstructure in the pregnant rat at term. Am J Obstet Gynecol. 2005; 192(3):753–760.
Meath AJ, Ramsey PS, Mulholland TA, Rosenquist RG, Lesnick T, Ramin KD. Comparative longitudinal study of cervical length and induced shortening changes among singleton, twin, and triplet pregnancies. Am J Obstet Gynecol. 2005;192(5):1410–1415.
Leppert PC, Cerreta JM, Mandl I. Orientation of elastic fibers in the human cervix. Am J Obstet Gynecol. 1986;155(1):219–224.
Shi L, Shi SQ, Saade GR, Chwalisz K, Garfield RE. Changes in cervical resistance and collagen fluorescence during gestation in rats. J Perinatal Med. 1999;27(3): 188–194.
Danforth DN. The morphology of the human cervix. Clin Obstet Gynecol. 1983;26(1):7–13.
Carlson LC, Feltovich H, Palmeri ML, Dahl JJ, Munoz del Rio A, Hall TJ. Estimation of shear wave speed in the human uterine cervix. Ultrasound Obstet Gynecol. 2014;43(4):452–458.
Gonzalez JM, Dong Z, Romero R, Girardi G. Cervical remodeling/ripening at term and preterm delivery: the same mechanism initiated by different mediators and different effector cells. PLoS One. 2011;6(11):e26877.
Gonzalez JM, Franzke CW, Yang F, Romero R, Girardi G. Complement activation triggers metalloproteinases release inducing cervical remodeling and preterm birth in mice. Am J Pathology. 2011;179(2):838–849.
Timmons BC, Fairhurst AM, Mahendroo MS. Temporal changes in myeloid cells in the cervix during pregnancy and parturition. J Immunol. 2009;182(5):2700–2707.
Hamilton S, Oomomian Y, Stephen G, et al. Macrophages infiltrate the human and rat decidua during term and preterm labor: evidence that decidual inflammation precedes labor. Biol Reprod. 2012;86(2):39.
Menon R, Torloni MR, Voltolini C, et al. Biomarkers of spontaneous preterm birth: an overview of the literature in the last four decades. Reprod Sci. 2011;18(11):1046–1070.
Iams JD, Grobman WA, Lozitska A, et al. Adherence to criteria for transvaginal ultrasound imaging and measurement of cervical length. Am J Obstet Gynecol. 2013;209(4):365.e361–e365.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Dubicke, A., Ekman-Ordeberg, G., Mazurek, P. et al. Density of Stromal Cells and Macrophages Associated With Collagen Remodeling in the Human Cervix in Preterm and Term Birth. Reprod. Sci. 23, 595–603 (2016). https://doi.org/10.1177/1933719115616497
Published:
Issue Date:
DOI: https://doi.org/10.1177/1933719115616497