Semin Reprod Med 2017; 35(02): 190-200
DOI: 10.1055/s-0037-1599091
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Distinct Roles of Cervical Epithelia and Stroma in Pregnancy and Parturition

Shanmugasundaram Nallasamy
1   Department of Obstetrics and Gynecology and Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, Texas
,
Mala Mahendroo
1   Department of Obstetrics and Gynecology and Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, Texas
› Author Affiliations
Further Information

Publication History

Publication Date:
09 March 2017 (online)

Abstract

Through pregnancy the cervix must simultaneously remain competent for pregnancy maintenance and yet become progressively compliant to ensure on time parturition. Cervical changes precede not only term but also preterm birth. Thus, an understanding of the molecular mechanisms by which the cervix maintains the delicate balance between competence and compliance is required to prevent the potential for lifelong health complications that can result from a premature birth. Recent advances and accumulating evidence support distinct roles for the cervical epithelia and stroma in sustaining competence. Concurrently, structural reorganization of the stromal extracellular matrix allows for the gradual decline in tissue compliance. In recent years, advances in our understanding of the cervical remodeling process has resulted from the collective insights derived from biological, genomics, engineering, and mathematical modeling studies on clinical samples and animal models. This review will highlight recent literature that advances understanding of (1) the importance of barrier function in the lower female reproductive tract in protection against ascending infection, (2) cellular and extracellular matrix changes in the cervical stroma that influence the mechanical function of the cervix, (3) the potential translation of biological insights into clinical tools that impact preterm birth, and (4) the distinction between term and specific pathways of preterm birth. Finally, we present a discussion of future areas of investigation that are likely to advance understanding and lead to the development of clinical tools for accurate detection and prevention of premature birth.

 
  • References

  • 1 Vinturache AE, Gyamfi-Bannerman C, Hwang J, Mysorekar IU, Jacobsson B ; Preterm Birth International Collaborative (PREBIC). Maternal microbiome - a pathway to preterm birth. Semin Fetal Neonatal Med 2016; 21 (2) 94-99
  • 2 Racicot K, Cardenas I, Wünsche V , et al. Viral infection of the pregnant cervix predisposes to ascending bacterial infection. J Immunol 2013; 191 (2) 934-941
  • 3 Costello EK, Lauber CL, Hamady M, Fierer N, Gordon JI, Knight R. Bacterial community variation in human body habitats across space and time. Science 2009; 326 (5960) 1694-1697
  • 4 Ravel J, Gajer P, Abdo Z , et al. Vaginal microbiome of reproductive-age women. Proc Natl Acad Sci U S A 2011; 108 (Suppl. 01) 4680-4687
  • 5 Akgul Y, Word RA, Ensign LM , et al. Hyaluronan in cervical epithelia protects against infection-mediated preterm birth. J Clin Invest 2014; 124 (12) 5481-5489
  • 6 Hein M, Valore EV, Helmig RB, Uldbjerg N, Ganz T. Antimicrobial factors in the cervical mucus plug. Am J Obstet Gynecol 2002; 187 (1) 137-144
  • 7 Curlin M, Bursac D. Cervical mucus: from biochemical structure to clinical implications. Front Biosci (Schol Ed) 2013; 5: 507-515
  • 8 Wira CR, Rodriguez-Garcia M, Patel MV. The role of sex hormones in immune protection of the female reproductive tract. Nat Rev Immunol 2015; 15 (4) 217-230
  • 9 Hillier SL, Nugent RP, Eschenbach DA , et al; The Vaginal Infections and Prematurity Study Group. Association between bacterial vaginosis and preterm delivery of a low-birth-weight infant. N Engl J Med 1995; 333 (26) 1737-1742
  • 10 Nadeau HC, Subramaniam A, Andrews WW. Infection and preterm birth. Semin Fetal Neonatal Med 2016; 21 (2) 100-105
  • 11 MacIntyre DA, Chandiramani M, Lee YS , et al. The vaginal microbiome during pregnancy and the postpartum period in a European population. Sci Rep 2015; 5: 8988
  • 12 DiGiulio DB, Callahan BJ, McMurdie PJ , et al. Temporal and spatial variation of the human microbiota during pregnancy. Proc Natl Acad Sci U S A 2015; 112 (35) 11060-11065
  • 13 Aagaard K, Riehle K, Ma J , et al. A metagenomic approach to characterization of the vaginal microbiome signature in pregnancy. PLoS One 2012; 7 (6) e36466
  • 14 Gajer P, Brotman RM, Bai G , et al. Temporal dynamics of the human vaginal microbiota. Sci Transl Med 2012; 4 (132) 132ra52
  • 15 Romero R, Hassan SS, Gajer P , et al. The composition and stability of the vaginal microbiota of normal pregnant women is different from that of non-pregnant women. Microbiome 2014; 2 (1) 4
  • 16 Walther-António MR, Jeraldo P, Berg Miller ME , et al. Pregnancy's stronghold on the vaginal microbiome. PLoS One 2014; 9 (6) e98514
  • 17 Fettweis JM, Serrano MG, Girerd PH, Jefferson KK, Buck GA. A new era of the vaginal microbiome: advances using next-generation sequencing. Chem Biodivers 2012; 9 (5) 965-976
  • 18 Kindinger LM, MacIntyre DA, Lee YS , et al. Relationship between vaginal microbial dysbiosis, inflammation, and pregnancy outcomes in cervical cerclage. Sci Transl Med 2016; 8 (350) 350ra102
  • 19 Read CP, Word RA, Ruscheinsky MA, Timmons BC, Mahendroo MS. Cervical remodeling during pregnancy and parturition: molecular characterization of the softening phase in mice. Reproduction 2007; 134 (2) 327-340
  • 20 Tribe RM. Small peptides with a big role: antimicrobial peptides in the pregnant female reproductive tract. Am J Reprod Immunol 2015; 74 (2) 123-125
  • 21 Itaoka N, Nagamatsu T, Schust DJ , et al. Cervical expression of elafin and SLPI in pregnancy and their association with preterm labor. Am J Reprod Immunol 2015; 73 (6) 536-544
  • 22 Becher N, Adams Waldorf K, Hein M, Uldbjerg N. The cervical mucus plug: structured review of the literature. Acta Obstet Gynecol Scand 2009; 88 (5) 502-513
  • 23 Bastholm SK, Samson MH, Becher N , et al. Trefoil factor peptide 3 is positively correlated with the viscoelastic properties of the cervical mucus plug. Acta Obstet Gynecol Scand 2017; 96 (1) 47-52
  • 24 Moncla BJ, Chappell CA, Debo BM, Meyn LA. The effects of hormones and vaginal microflora on the glycome of the female genital tract: cervical-vaginal fluid. PLoS One 2016; 11 (7) e0158687
  • 25 Critchfield AS, Yao G, Jaishankar A , et al. Cervical mucus properties stratify risk for preterm birth. PLoS One 2013; 8 (8) e69528
  • 26 Ghartey J, Bastek JA, Brown AG, Anglim L, Elovitz MA. Women with preterm birth have a distinct cervicovaginal metabolome. Am J Obstet Gynecol 2015; 212 (6) 776.e1-776.e12
  • 27 Lashkari BS, Shahana S, Anumba DO. Toll-like receptor 2 and 4 expression in the pregnant and non-pregnant human uterine cervix. J Reprod Immunol 2015; 107: 43-51
  • 28 Timmons BC, Mitchell SM, Gilpin C, Mahendroo MS. Dynamic changes in the cervical epithelial tight junction complex and differentiation occur during cervical ripening and parturition. Endocrinology 2007; 148 (3) 1278-1287
  • 29 Timmons B, Akins M, Mahendroo M. Cervical remodeling during pregnancy and parturition. Trends Endocrinol Metab 2010; 21 (6) 353-361
  • 30 Anderson JM, Van Itallie CM. Physiology and function of the tight junction. Cold Spring Harb Perspect Biol 2009; 1 (2) a002584
  • 31 Blaskewicz CD, Pudney J, Anderson DJ. Structure and function of intercellular junctions in human cervical and vaginal mucosal epithelia. Biol Reprod 2011; 85 (1) 97-104
  • 32 Hassan SS, Romero R, Pineles B , et al. MicroRNA expression profiling of the human uterine cervix after term labor and delivery. Am J Obstet Gynecol 2010; 202 (1) 80.e1-80.e8
  • 33 Elovitz MA, Brown AG, Anton L, Gilstrop M, Heiser L, Bastek J. Distinct cervical microRNA profiles are present in women destined to have a preterm birth. Am J Obstet Gynecol 2014; 210 (3) 221.e1-221.e11
  • 34 Sanders AP, Burris HH, Just AC , et al. microRNA expression in the cervix during pregnancy is associated with length of gestation. Epigenetics 2015; 10 (3) 221-228
  • 35 Straach KJ, Shelton JM, Richardson JA, Hascall VC, Mahendroo MS. Regulation of hyaluronan expression during cervical ripening. Glycobiology 2005; 15 (1) 55-65
  • 36 Toole BP. Hyaluronan: from extracellular glue to pericellular cue. Nat Rev Cancer 2004; 4 (7) 528-539
  • 37 Ruscheinsky M, De la Motte C, Mahendroo M. Hyaluronan and its binding proteins during cervical ripening and parturition: dynamic changes in size, distribution and temporal sequence. Matrix Biol 2008; 27 (5) 487-497
  • 38 Vink JY, Qin S, Brock CO , et al. A new paradigm for the role of smooth muscle cells in the human cervix. Am J Obstet Gynecol 2016; 215 (4) 478.e1-478.e11
  • 39 Ferland DJ, Darios ES, Watts SW. The persistence of active smooth muscle in the female rat cervix through pregnancy. Am J Obstet Gynecol 2015; 212 (2) 244.e1-244.e8
  • 40 Mahendroo M. Cervical remodeling in term and preterm birth: insights from an animal model. Reproduction 2012; 143 (4) 429-438
  • 41 Myers KM, Feltovich H, Mazza E , et al. The mechanical role of the cervix in pregnancy. J Biomech 2015; 48 (9) 1511-1523
  • 42 Zork NM, Myers KM, Yoshida K , et al. A systematic evaluation of collagen cross-links in the human cervix. Am J Obstet Gynecol 2015; 212 (3) 321.e1-321.e8
  • 43 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
  • 44 Akins ML, Luby-Phelps K, Bank RA, Mahendroo M. Cervical softening during pregnancy: regulated changes in collagen cross-linking and composition of matricellular proteins in the mouse. Biol Reprod 2011; 84 (5) 1053-1062
  • 45 Ozasa H, Tominaga T, Nishimura T, Takeda T. Lysyl oxidase activity in the mouse uterine cervix is physiologically regulated by estrogen. Endocrinology 1981; 109 (2) 618-621
  • 46 Calabro NE, Kristofik NJ, Kyriakides TR. Thrombospondin-2 and extracellular matrix assembly. Biochim Biophys Acta 2014; 1840 (8) 2396-2402
  • 47 Akins ML, Luby-Phelps K, Mahendroo M. Second harmonic generation imaging as a potential tool for staging pregnancy and predicting preterm birth. J Biomed Opt 2010; 15 (2) 026020
  • 48 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
  • 49 Hassan SS, Romero R, Vidyadhari D , et al; PREGNANT Trial. Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol 2011; 38 (1) 18-31
  • 50 Mahendroo MS, Porter A, Russell DW, Word RA. The parturition defect in steroid 5alpha-reductase type 1 knockout mice is due to impaired cervical ripening. Mol Endocrinol 1999; 13 (6) 981-992
  • 51 Andersson S, Minjarez D, Yost NP, Word RA. Estrogen and progesterone metabolism in the cervix during pregnancy and parturition. J Clin Endocrinol Metab 2008; 93 (6) 2366-2374
  • 52 House M, Tadesse-Telila S, Norwitz ER, Socrate S, Kaplan DL. Inhibitory effect of progesterone on cervical tissue formation in a three-dimensional culture system with human cervical fibroblasts. Biol Reprod 2014; 90 (1) 18
  • 53 Arslan SY, Yu Y, Burdette JE , et al. Novel three dimensional human endocervix cultures respond to 28-day hormone treatment. Endocrinology 2015; 156 (4) 1602-1609
  • 54 Yoshida K, Mahendroo M, Vink J, Wapner R, Myers K. Material properties of mouse cervical tissue in normal gestation. Acta Biomater 2016; 36: 195-209
  • 55 Feltovich H, Hall TJ, Berghella V. Beyond cervical length: emerging technologies for assessing the pregnant cervix. Am J Obstet Gynecol 2012; 207 (5) 345-354
  • 56 O'Brien CM, Vargis E, Paria BC, Bennett KA, Mahadevan-Jansen A, Reese J. Raman spectroscopy provides a noninvasive approach for determining biochemical composition of the pregnant cervix in vivo. Acta Paediatr 2014; 103 (7) 715-721
  • 57 Vargis E, Brown N, Williams K , et al. Detecting biochemical changes in the rodent cervix during pregnancy using Raman spectroscopy. Ann Biomed Eng 2012; 40 (8) 1814-1824
  • 58 Gan Y, Yao W, Myers KM, Vink JY, Wapner RJ, Hendon CP. Analyzing three-dimensional ultrastructure of human cervical tissue using optical coherence tomography. Biomed Opt Express 2015; 6 (4) 1090-1108
  • 59 Holt R, Timmons BC, Akgul Y, Akins ML, Mahendroo M. The molecular mechanisms of cervical ripening differ between term and preterm birth. Endocrinology 2011; 152 (3) 1036-1046
  • 60 Timmons BC, Reese J, Socrate S , et al. Prostaglandins are essential for cervical ripening in LPS-mediated preterm birth but not term or antiprogestin-driven preterm ripening. Endocrinology 2014; 155 (1) 287-298
  • 61 Timmons BC, Mahendroo MS. Timing of neutrophil activation and expression of proinflammatory markers do not support a role for neutrophils in cervical ripening in the mouse. Biol Reprod 2006; 74 (2) 236-245
  • 62 Hari Kishore A, Li XH, Word RA. Hypoxia and PGE(2) regulate MiTF-CX during cervical ripening. Mol Endocrinol 2012; 26 (12) 2031-2045
  • 63 Kishore AH, Owens D, Word RA. Prostaglandin E2 regulates its own inactivating enzyme, 15-PGDH, by EP2 receptor-mediated cervical cell-specific mechanisms. J Clin Endocrinol Metab 2014; 99 (3) 1006-1018
  • 64 Cunningham FG, Leveno KJ, Bloom SL , et al. Induction and augmentation of labor. In: Williams Obstetrics. 24e. New York, NY: McGraw-Hill Education; 2013
  • 65 Choksuchat C. Clinical use of misoprostol in nonpregnant women: review article. J Minim Invasive Gynecol 2010; 17 (4) 449-455
  • 66 Platz-Christensen JJ, Pernevi P, Bokström H, Wiqvist N. Prostaglandin E and F2 alpha concentration in the cervical mucus and mechanism of cervical ripening. Prostaglandins 1997; 53 (4) 253-261
  • 67 Toth M, Rehnström J, Fuchs AR. Prostaglandins E and F in cervical mucus of pregnant women. Am J Perinatol 1989; 6 (2) 142-144
  • 68 Cox SM, King MR, Casey ML, MacDonald PC. Interleukin-1 beta, -1 alpha, and -6 and prostaglandins in vaginal/cervical fluids of pregnant women before and during labor. J Clin Endocrinol Metab 1993; 77 (3) 805-815
  • 69 Rådestad A, Bygdeman M. Cervical softening with mifepristone (RU 486) after pretreatment with naproxen. A double-blind randomized study. Contraception 1992; 45 (3) 221-227
  • 70 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
  • 71 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
  • 72 Kirby MA, Heuerman AC, Custer M , et al. Progesterone receptor-mediated actions regulate remodeling of the cervix in preparation for preterm parturition. Reprod Sci 2016; 23 (11) 1473-1483
  • 73 Shynlova O, Nedd-Roderique T, Li Y, Dorogin A, Lye SJ. Myometrial immune cells contribute to term parturition, preterm labour and post-partum involution in mice. J Cell Mol Med 2013; 17 (1) 90-102
  • 74 Dobyns AE, Goyal R, Carpenter LG, Freeman TC, Longo LD, Yellon SM. Macrophage gene expression associated with remodeling of the prepartum rat cervix: microarray and pathway analyses. PLoS One 2015; 10 (3) e0119782
  • 75 Dubicke A, Ekman-Ordeberg G, Mazurek P, Miller L, Yellon SM. Density of stromal cells and macrophages associated with collagen remodeling in the human cervix in preterm and term birth. Reprod Sci 2016; 23 (5) 595-603
  • 76 Gordon S, Hamann J, Lin H-H, Stacey M. F4/80 and the related adhesion-GPCRs. Eur J Immunol 2011; 41 (9) 2472-2476
  • 77 Hassan SS, Romero R, Tarca AL , et al. The transcriptome of cervical ripening in human pregnancy before the onset of labor at term: identification of novel molecular functions involved in this process. J Matern Fetal Neonatal Med 2009; 22 (12) 1183-1193
  • 78 Filipovich Y, Agrawal V, Crawford SE , et al. Depletion of polymorphonuclear leukocytes has no effect on preterm delivery in a mouse model of Escherichia coli-induced labor. Am J Obstet Gynecol 2015; 213 (5) 697.e1-697.e10
  • 79 Rinaldi SF, Catalano RD, Wade J, Rossi AG, Norman JE. Decidual neutrophil infiltration is not required for preterm birth in a mouse model of infection-induced preterm labor. J Immunol 2014; 192 (5) 2315-2325
  • 80 Blencowe H, Cousens S, Chou D , et al; Born Too Soon Preterm Birth Action Group. Born too soon: the global epidemiology of 15 million preterm births. Reprod Health 2013; 10 (Suppl. 01) S2