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Licensed Unlicensed Requires Authentication Published by De Gruyter August 31, 2020

Pregnancy-specific transcriptional changes upon endotoxin exposure in mice

Kenichiro Motomura, Roberto Romero, Adi L. Tarca, Jose Galaz, Gaurav Bhatti, Bogdan Done, Marcia Arenas-Hernandez, Dustyn Levenson, Rebecca Slutsky, Chaur-Dong Hsu and Nardhy Gomez-Lopez



Pregnant women are more susceptible to certain infections; however, this increased susceptibility is not fully understood. Herein, systems biology approaches were utilized to elucidate how pregnancy modulates tissue-specific host responses to a bacterial product, endotoxin.


Pregnant and non-pregnant mice were injected with endotoxin or saline on 16.5 days post coitum (n=8–11 per group). The uterus, cervix, liver, adrenal gland, kidney, lung, and brain were collected 12 h after injection and transcriptomes were measured using microarrays. Heatmaps and principal component analysis were used for visualization. Differentially expressed genes between groups were assessed using linear models that included interaction terms to determine whether the effect of infection differed with pregnancy status. Pathway analysis was conducted to interpret gene expression changes.


We report herein a multi-organ atlas of the transcript perturbations in pregnant and non-pregnant mice in response to endotoxin. Pregnancy strongly modified the host responses to endotoxin in the uterus, cervix, and liver. In contrast, pregnancy had a milder effect on the host response to endotoxin in the adrenal gland, lung, and kidney. However, pregnancy did not drastically affect the host response to endotoxin in the brain.


Pregnancy imprints organ-specific host immune responses upon endotoxin exposure. These findings provide insight into the host-response against microbes during pregnancy.

Corresponding author: Nardhy Gomez-Lopez, MSc, PhD, Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, and Detroit, MI, USA; Wayne State University School of Medicine, 275 E. Hancock, Detroit, MI 48201, USA, Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA; Department of Biochemistry, Microbiology and Immunology, Wayne State University School of Medicine, Detroit, MI, USA, Phone: +1 (313) 577-8904, E-mail: ; and Roberto Romero, MD, D. Med. Sci., Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, and Detroit, MI, USA; Hutzel Women’s Hospital, 3990 John R, Box 4, Detroit, MI 48201, USA; Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA; Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI, USA; Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA; Detroit Medical Center, Detroit, MI, USA; Department of Obstetrics and Gynecology, Florida International University, Miami, FL, USA, Phone: (313) 993-2700, Fax: (313) 993-2694, E-mail: .

Funding source: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services (NICHD/NIH/DHHS)

Funding source: NICHD/NIH/DHHS, HHSN275201300006C

Funding source: Wayne State University Perinatal Initiative in Maternal, Perinatal and Child Health


The authors are grateful to Daniel Lott for conducting the RNA extraction and the microarray experiments at the Applied Genomics Technology Center of Wayne State University in Detroit, Michigan.

  1. Research funding: This research was supported, in part, by the Perinatology Research Branch (PRB), Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services (NICHD/NIH/DHHS), and, in part, with federal funds from the NICHD/NIH/DHHS under Contract No. HHSN275201300006C. Dr. Romero has contributed to this work as part of his official duties as an employee of the United States Federal Government. This research was also supported by the Wayne State University Perinatal Initiative in Maternal, Perinatal and Child Health.

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: Authors state no conflict of interest.

  4. Ethical approval: All procedures were approved by the Institutional Animal Care and Use Committee (IACUC) at Wayne State University, Detroit, MI, USA (Protocol Number A 09-08-12).


1. Medawar, PB. Some immunological and endocrinological problems raised by the evolution of viviparity in vertebrates. Symp Soc Exp Biol 1953;7:320–8.Search in Google Scholar

2. Clemens, LE, Siiteri, PK, Stites, DP. Mechanism of immunosuppression of progesterone on maternal lymphocyte activation during pregnancy. J Immunol 1979;122:1978–85.Search in Google Scholar

3. Weinberg, ED. Pregnancy-associated immune suppression: risks and mechanisms. Microb Pathog 1987;3:393–7. in Google Scholar

4. Wegmann, TG, Lin, H, Guilbert, L, Mosmann, TR. Bidirectional cytokine interactions in the maternal–fetal relationship: is successful pregnancy a TH2 phenomenon?. Immunol Today 1993;14:353–6. in Google Scholar

5. Efrati, P, Presentey, B, Margalith, M, Rozenszajn, L. Leukocytes of normal pregnant women. Obstet Gynecol 1964;23:429–32.Search in Google Scholar

6. Koumandakis, E, Koumandaki, I, Kaklamani, E, Sparos, L, Aravantinos, D, Trichopoulos, D. Enhanced phagocytosis of mononuclear phagocytes in pregnancy. Br J Obstet Gynaecol 1986;93:1150–4. in Google Scholar

7. Shibuya, T, Izuchi, K, Kuroiwa, A, Okabe, N, Shirakawa, K. Study on nonspecific immunity in pregnant women: increased chemiluminescence response of peripheral blood phagocytes. Am J Reprod Immunol Microbiol 1987;15:19–23. in Google Scholar

8. Sacks, GP, Studena, K, Sargent, K, Redman, CW. Normal pregnancy and preeclampsia both produce inflammatory changes in peripheral blood leukocytes akin to those of sepsis. Am J Obstet Gynecol 1998;179:80–6. in Google Scholar

9. Sacks, G, Sargent, I, Redman, C. An innate view of human pregnancy. Immunol Today 1999;20:114–8. in Google Scholar

10. Sacks, G, Sargent, I, Redman, C. Innate immunity in pregnancy. Immunol Today 2000;21:200–1. in Google Scholar

11. Naccasha, N, Gervasi, MT, Chaiworapongsa, T, Berman, S, Yoon, BH, Maymon, E, et al. Phenotypic and metabolic characteristics of monocytes and granulocytes in normal pregnancy and maternal infection. Am J Obstet Gynecol 2001;185:1118–23. in Google Scholar PubMed

12. Germain, SJ, Sacks, GP, Sooranna, SR, Sargent, IL, Redman, CW. Systemic inflammatory priming in normal pregnancy and preeclampsia: the role of circulating syncytiotrophoblast microparticles. J Immunol 2007;178:5949–56. in Google Scholar PubMed

13. Zhang, J, Shynlova, O, Sabra, S, Bang, A, Briollais, L, Lye, SJ. Immunophenotyping and activation status of maternal peripheral blood leukocytes during pregnancy and labour, both term and preterm. J Cell Mol Med 2017;21:2386–402. in Google Scholar PubMed PubMed Central

14. Jamieson, DJ, Theiler, RN, Rasmussen, SA. Emerging infections and pregnancy. Emerg Infect Dis 2006;12:1638–43. in Google Scholar

15. Sappenfield, E, Jamieson, DJ, Kourtis, AP. Pregnancy and susceptibility to infectious diseases. Infect Dis Obstet Gynecol 2013;2013:752852. in Google Scholar

16. Kourtis, AP, Read, JS, Jamieson, DJ. Pregnancy and infection. N Engl J Med 2014;370:2211–8. in Google Scholar

17. Rasmussen, SA, Smulian, JC, Lednicky, JA, Wen, TS, Jamieson, DJ. Coronavirus Disease 2019 (COVID-19) and pregnancy: what obstetricians need to know. Am J Obstet Gynecol 2020;222:415–26. in Google Scholar

18. Qiao, J. What are the risks of COVID-19 infection in pregnant women?. Lancet 2020;395:760–2. in Google Scholar

19. Mullins, E, Evans, D, Viner, RM, O’Brien, P, Morris, E. Coronavirus in pregnancy and delivery: rapid review. Ultrasound Obstet Gynecol 2020;55:586–92. in Google Scholar PubMed

20. Schwartz, DA. An analysis of 38 pregnant women with COVID-19, their newborn infants, and maternal-fetal transmission of SARS-CoV-2: maternal coronavirus infections and pregnancy outcomes. Arch Pathol Lab Med 2020. in Google Scholar PubMed

21. Dashraath, P, Jing Lin Jeslyn, W, Mei Xian Karen, L, Li Min, L, Sarah, L, Biswas, A, et al. Coronavirus disease 2019 (COVID-19) pandemic and pregnancy. Am J Obstet Gynecol 2020;222:521–31. in Google Scholar PubMed PubMed Central

22. Neuzil, KM, Reed, GW, Mitchel, EF, Simonsen, L, Griffin, MR. Impact of influenza on acute cardiopulmonary hospitalizations in pregnant women. Am J Epidemiol 1998;148:1094–102. in Google Scholar PubMed

23. Lindsay, L, Jackson, LA, Savitz, DA, Weber, DJ, Koch, GG, Kong, L, et al. Community influenza activity and risk of acute influenza-like illness episodes among healthy unvaccinated pregnant and postpartum women. Am J Epidemiol 2006;163:838–48. in Google Scholar PubMed

24. Siston, AM, Rasmussen, SA, Honein, MA, Fry, AM, Seib, K, Callaghan, WM, et al. Pandemic 2009 influenza A(H1N1) virus illness among pregnant women in the United States. JAMA 2010;303:1517–25. in Google Scholar PubMed PubMed Central

25. Cervantes-Gonzalez, M, Launay, O. Pandemic influenza A (H1N1) in pregnant women: impact of early diagnosis and antiviral treatment. Expert Rev Anti Infect Ther 2010;8:981–4. in Google Scholar PubMed

26. Mosby, LG, Rasmussen, SA, Jamieson, DJ. Pandemic influenza A (H1N1) in pregnancy: a systematic review of the literature. Am J Obstet Gynecol 2009;205:10–8. in Google Scholar PubMed

27. Pazos, M, Sperling, RS, Moran, TM, Kraus, TA. The influence of pregnancy on systemic immunity. Immunol Res 2012;54:254–61. in Google Scholar PubMed PubMed Central

28. Triebwasser, JH, Harris, RE, Bryant, RE, Rhoades, ER. Varicella pneumonia in adults. Report of seven cases and a review of literature. Medicine (Baltimore) 1967;46:409–23. in Google Scholar

29. Paryani, SG, Arvin, AM. Intrauterine infection with varicella-zoster virus after maternal varicella. N Engl J Med 1986;314:1542–6. in Google Scholar PubMed

30. Esmonde, TF, Herdman, G, Anderson, G. Chickenpox pneumonia: an association with pregnancy. Thorax 1989;44:812–5. in Google Scholar PubMed PubMed Central

31. Haake, DA, Zakowski, PC, Haake, DL, Bryson, YJ. Early treatment with acyclovir for varicella pneumonia in otherwise healthy adults: retrospective controlled study and review. Rev Infect Dis 1990;12:788–98. in Google Scholar PubMed

32. Swamy, GK, Dotters-Katz, SK. Safety and varicella outcomes after varicella zoster immune globulin administration in pregnancy. Am J Obstet Gynecol 2019;221:655–6. in Google Scholar PubMed

33. Christensen, PE, Schmidt, H, Bang, HO, Andersen, V, Jordal, B, Jensen, O. Measles in virgin soil, Greenland 1951. Dan Med Bull 1954;1:2–6.Search in Google Scholar

34. Atmar, RL, Englund, JA, Hammill, H. Complications of measles during pregnancy. Clin Infect Dis 1992;14:217–26. in Google Scholar PubMed

35. Menendez, C, D’Alessandro, U, ter Kuile, FO. Reducing the burden of malaria in pregnancy by preventive strategies. Lancet Infect Dis 2007;7:126–35. in Google Scholar

36. Eisele, TP, Larsen, DA, Anglewicz, PA, Keating, J, Yukich, J, Bennett, A, et al. Malaria prevention in pregnancy, birthweight, and neonatal mortality: a meta-analysis of 32 national cross-sectional datasets in Africa. Lancet Infect Dis 2012;12:942–9. in Google Scholar

37. Kochar, DK, Thanvi, I, Joshi, A, Shubhakaran, Agarwal, N, Jain, N. Mortality trends in falciparum malaria—effect of gender difference and pregnancy. J Assoc Phys India 1999;47:774–8.Search in Google Scholar

38. Takem, EN, D’Alessandro, U. Malaria in pregnancy. Mediterr J Hematol Infect Dis 2013;5:e2013010. in Google Scholar

39. Goodnight, WH, Soper, DE. Pneumonia in pregnancy. Crit Care Med 2005;33:S390–7. in Google Scholar

40. Patterson, TF, Andriole, VT. Bacteriuria in pregnancy. Infect Dis Clin North Am 1987;1:807–22.10.1016/S0891-5520(20)30151-3Search in Google Scholar

41. Glaser, AP, Schaeffer, AJ. Urinary tract infection and bacteriuria in pregnancy. Urol Clin North Am 2015;42:547–60. in Google Scholar PubMed

42. Wingert, A, Pillay, J, Sebastianski, M, Gates, M, Featherstone, R, Shave, K, et al. Asymptomatic bacteriuria in pregnancy: systematic reviews of screening and treatment effectiveness and patient preferences. BMJ Open 2019;9:e021347. in Google Scholar PubMed PubMed Central

43. Madan, I, Than, NG, Romero, R, Chaemsaithong, P, Miranda, J, Tarca, AL, et al. The peripheral whole-blood transcriptome of acute pyelonephritis in human pregnancya. J Perinat Med 2014;42:31–53. in Google Scholar PubMed PubMed Central

44. Naamany, E, Ayalon-Dangur, I, Hadar, E, Sagy, I, Yahav, D, Shiber, S. Pregnancy outcome following bacteriuria in pregnancy and the significance of nitrites in urinalysis – a retrospective cohort study. J Perinat Med 2019;47:611–8. in Google Scholar PubMed

45. Kaul, AK, Khan, S, Martens, MG, Crosson, JT, Lupo, VR, Kaul, R. Experimental gestational pyelonephritis induces preterm births and low birth weights in C3H/HeJ mice. Infect Immun 1999;67:5958–66. in Google Scholar

46. Millar, LK, DeBuque, L, Wing, DA. Uterine contraction frequency during treatment of pyelonephritis in pregnancy and subsequent risk of preterm birth. J Perinat Med 2003;31:41–6. in Google Scholar

47. Dawkins, JC, Fletcher, HM, Rattray, CA, Reid, M, Gordon-Strachan, G. Acute pyelonephritis in pregnancy: a retrospective descriptive hospital based-study. ISRN Obstet Gynecol 2012;2012:519321. in Google Scholar

48. Wing, DA, Fassett, MJ, Getahun, D. Acute pyelonephritis in pregnancy: an 18-year retrospective analysis. Am J Obstet Gynecol 2014;210:219 e1–6. in Google Scholar

49. Kalinderi, K, Delkos, D, Kalinderis, M, Athanasiadis, A, Kalogiannidis, I. Urinary tract infection during pregnancy: current concepts on a common multifaceted problem. J Obstet Gynaecol 2018;38:448–53. in Google Scholar

50. Blencowe, H, Cousens, S, Chou, D, Oestergaard, M, Say, L, Moller, AB, et al. Born too soon: the global epidemiology of 15 million preterm births. Reprod Health 2013;10:S2. in Google Scholar

51. Monier, I, Ancel, PY, Ego, A, Jarreau, PH, Lebeaux, C, Kaminski, M, et al. Fetal and neonatal outcomes of preterm infants born before 32 weeks of gestation according to antenatal vs postnatal assessments of restricted growth. Am J Obstet Gynecol 2017;216:516 e1–10. in Google Scholar

52. Chawanpaiboon, S, Vogel, JP, Moller, AB, Lumbiganon, P, Petzold, M, Hogan, D, et al. Global, regional, and national estimates of levels of preterm birth in 2014: a systematic review and modelling analysis. Lancet Glob Health 2019;7:e37–46. in Google Scholar

53. Tal, R, Taylor, HS, Burney, RO, Mooney, SB, Giudice, LC. Endocrinology of pregnancy. In: Feingold, KR, Anawalt, B, Boyce, A, Chrousos, G, Dungan, K, Grossman, A, et al., editors. Endotext. South Dartmouth (MA); 2000.Search in Google Scholar

54. Meo, SA, Hassain, A. Metabolic physiology in pregnancy. J Pak Med Assoc 2016;66:S8–10.Search in Google Scholar

55. Norwitz, ER, Robinson, JN, Challis, JR. The control of labor. N Engl J Med 1999;341:660–6. in Google Scholar

56. Smith, R. Parturition. N Engl J Med 2007;356:271–83. in Google Scholar PubMed

57. Norwitz, ER, Bonney, EA, Snegovskikh, VV, Williams, MA, Phillippe, M, Park, JS, et al. Molecular regulation of parturition: the role of the Decidual clock. Cold Spring Harb Perspect Med 2015;5:a023143. in Google Scholar PubMed PubMed Central

58. Longo, LD. Maternal blood volume and cardiac output during pregnancy: a hypothesis of endocrinologic control. Am J Physiol 1983;245:R720–9. in Google Scholar

59. Clark, SL, Cotton, DB, Lee, W, Bishop, C, Hill, T, Southwick, J, et al. Central hemodynamic assessment of normal term pregnancy. Am J Obstet Gynecol 1989;161:1439–42. in Google Scholar

60. Mahendru, AA, Everett, TR, Wilkinson, IB, Lees, CC, McEniery, CM. Maternal cardiovascular changes from pre-pregnancy to very early pregnancy. J Hypertens 2012;30:2168–72. in Google Scholar

61. Liu, LX, Arany, Z. Maternal cardiac metabolism in pregnancy. Cardiovasc Res 2014;101:545–53. in Google Scholar

62. Ling, HZ, Guy, GP, Bisquera, A, Poon, LC, Nicolaides, KH, Kametas, NA. The effect of parity on longitudinal maternal hemodynamics. Am J Obstet Gynecol 2019;221:249 e1–14. in Google Scholar

63. Zeldis, SM. Dyspnea during pregnancy. Distinguishing cardiac from pulmonary causes. Clin Chest Med 1992;13:567–85.10.1016/S0272-5231(21)01126-6Search in Google Scholar

64. Elkus, R, Popovich, JJr. Respiratory physiology in pregnancy. Clin Chest Med 1992;13:555–65.10.1016/S0272-5231(21)01125-4Search in Google Scholar

65. Heenan, AP, Wolfe, LA. Plasma osmolality and the strong ion difference predict respiratory adaptations in pregnant and nonpregnant women. Can J Physiol Pharmacol 2003;81:839–47. in Google Scholar PubMed

66. Kolarzyk, E, Szot, WM, Lyszczarz, J. Lung function and breathing regulation parameters during pregnancy. Arch Gynecol Obstet 2005;272:53–8. in Google Scholar PubMed

67. Bobrowski, RA. Pulmonary physiology in pregnancy. Clin Obstet Gynecol 2010;53:285–300. in Google Scholar

68. Hegewald, MJ, Crapo, RO. Respiratory physiology in pregnancy. Clin Chest Med 2011;32:1–13. in Google Scholar

69. Grindheim, G, Toska, K, Estensen, ME, Rosseland, LA. Changes in pulmonary function during pregnancy: a longitudinal cohort study. BJOG 2012;119:94–101. in Google Scholar

70. Mendenhall, HW. Serum protein concentrations in pregnancy. I. Concentrations in maternal serum. Am J Obstet Gynecol 1970;106:388–99. in Google Scholar

71. Clapp, JF, Stepanchak, W, Tomaselli, J, Kortan, M, Faneslow, S. Portal vein blood flow-effects of pregnancy, gravity, and exercise. Am J Obstet Gynecol 2000;183:167–72. in Google Scholar

72. Ruiz-Extremera, A, Lopez-Garrido, MA, Barranco, E, Quintero, MD, Ocete-Hita, E, Munoz de Rueda, P, et al. Activity of hepatic enzymes from week sixteen of pregnancy. Am J Obstet Gynecol 2005;193:2010–6. in Google Scholar

73. Mufti, AR, Reau, N. Liver disease in pregnancy. Clin Liver Dis 2012;16:247–69. in Google Scholar

74. Cattozzo, G, Calonaci, A, Albeni, C, Guerra, E, Franzini, M, Ghezzi, F, et al. Reference values for alanine aminotransferase, alpha-amylase, aspartate aminotransferase, gamma-glutamyltransferase and lactate dehydrogenase measured according to the IFCC standardization during uncomplicated pregnancy. Clin Chem Lab Med 2013;51:e239–41. in Google Scholar

75. Schulman, A, Herlinger, H. Urinary tract dilatation in pregnancy. Br J Radiol 1975;48:638–45. in Google Scholar

76. Cietak, KA, Newton, JR. Serial quantitative maternal nephrosonography in pregnancy. Br J Radiol 1985;58:405–13. in Google Scholar

77. Lindheimer, MD, Richardson, DA, Ehrlich, EN, Katz, AI. Potassium homeostasis in pregnancy. J Reprod Med 1987;32:517–22.Search in Google Scholar

78. Higby, K, Suiter, CR, Phelps, JY, Siler-Khodr, T, Langer, O. Normal values of urinary albumin and total protein excretion during pregnancy. Am J Obstet Gynecol 1994;171:984–9. in Google Scholar

79. Lindheimer, MD, Kanter, D. Interpreting abnormal proteinuria in pregnancy: the need for a more pathophysiological approach. Obstet Gynecol 2010;115:365–75. in Google Scholar

80. Odutayo, A, Hladunewich, M. Obstetric nephrology: renal hemodynamic and metabolic physiology in normal pregnancy. Clin J Am Soc Nephrol 2012;7:2073–80. in Google Scholar

81. Conrad, KP, Davison, JM. The renal circulation in normal pregnancy and preeclampsia: is there a place for relaxin?. Am J Physiol Renal Physiol 2014;306:F1121–35. in Google Scholar

82. Watanabe, M, Meeker, CI, Gray, MJ, Sims, EA, Solomon, S. Secretion rate of aldosterone in normal pregnancy. J Clin Invest 1963;42:1619–31. in Google Scholar

83. Parker, CRJr, Everett, RB, Whalley, PJ, Quirk, JGJr, Gant, NF, MacDonald, PC. Hormone production during pregnancy in the primigravid patient. II. Plasma levels of deoxycorticosterone throughout pregnancy of normal women and women who developed pregnancy-induced hypertension. Am J Obstet Gynecol 1980;138:626–31. in Google Scholar

84. Carr, BR, Parker, CRJr, Madden, JD, MacDonald, PC, Porter, JC. Maternal plasma adrenocorticotropin and cortisol relationships throughout human pregnancy. Am J Obstet Gynecol 1981;139:416–22. in Google Scholar

85. Nolten, WE, Rueckert, PA. Elevated free cortisol index in pregnancy: possible regulatory mechanisms. Am J Obstet Gynecol 1981;139:492–8. in Google Scholar

86. Keller-Wood, M, Wood, CE. Pregnancy alters cortisol feedback inhibition of stimulated ACTH: studies in adrenalectomized ewes. Am J Physiol Regul Integr Comp Physiol 2001;280:R1790–8. in Google Scholar

87. Aghaeepour, N, Ganio, EA, McIlwain, D, Tsai, AS, Tingle, M, Van Gassen, S, et al. An immune clock of human pregnancy. Sci Immunol 2017;2:eaan2946. in Google Scholar PubMed PubMed Central

88. Tarca, AL, Romero, R, Xu, Z, Gomez-Lopez, N, Erez, O, Hsu, CD, et al. Targeted expression profiling by RNA-Seq improves detection of cellular dynamics during pregnancy and identifies a role for T cells in term parturition. Sci Rep 2019;9:848. in Google Scholar PubMed PubMed Central

89. Gomez-Lopez, N, Romero, R, Hassan, SS, Bhatti, G, Berry, SM, Kusanovic, JP, et al. The cellular transcriptome in the maternal circulation during normal pregnancy: a longitudinal study. Front Immunol 2019;10:2863. in Google Scholar

90. Harris, LK, Benagiano, M, D’Elios, MM, Brosens, I, Benagiano, G. Placental bed research: II. Functional and immunological investigations of the placental bed. Am J Obstet Gynecol 2019;221:457–69. in Google Scholar

91. Goldman-Wohl, D, Gamliel, M, Mandelboim, O, Yagel, S. Learning from experience: cellular and molecular bases for improved outcome in subsequent pregnancies. Am J Obstet Gynecol 2019;221:183–93. in Google Scholar

92. Wong, TC. A study on the generalized Shwartzman reaction in pregnant rats induced by bacterial endotoxin. Am J Obstet Gynecol 1962;84:786–97. in Google Scholar

93. Muller-Berghaus, G, Schmidt-Ehry, B. The role of pregnancy in the induction of the generalized Shwartzman reaction. Am J Obstet Gynecol 1972;114:847–9. in Google Scholar

94. Mori, W. The Shwartzman reaction: a review including clinical manifestations and proposal for a univisceral or single organ third type. Histopathology 1981;5:113–26. in Google Scholar PubMed

95. Arenas-Hernandez, M, Romero, R, St Louis, D, Hassan, SS, Kaye, EB, Gomez-Lopez, N. An imbalance between innate and adaptive immune cells at the maternal–fetal interface occurs prior to endotoxin-induced preterm birth. Cell Mol Immunol 2016;13:462–73. in Google Scholar PubMed PubMed Central

96. Gomez-Lopez, N, Romero, R, Arenas-Hernandez, M, Panaitescu, B, Garcia-Flores, V, Mial, TN, et al. Intra-amniotic administration of lipopolysaccharide induces spontaneous preterm labor and birth in the absence of a body temperature change. J Matern Fetal Neonatal Med 2018;31:439–46. in Google Scholar PubMed PubMed Central

97. Bolstad, B. Probe level quantile normalization of high density oligonucleotide array data. 2001. in Google Scholar

98. Bolstad, B. PreprocessCore: a collection of pre-processing functions. R package 1360 ed. 2016.Search in Google Scholar

99. Gentleman, RC, Carey, VJ, Bates, DM, Bolstad, B, Dettling, M, Dudoit, S, et al. Bioconductor: open software development for computational biology and bioinformatics. Genome Biol 2004;5:R80. in Google Scholar PubMed PubMed Central

100. Dunning, M, Lynch, A, Eldridge, M. illuminaMousev2.db: illumina MouseWG6v2 annotation data (chip illuminaMousev2). R package 1260 ed. 2015.Search in Google Scholar

101. Ritchie, ME, Phipson, B, Wu, D, Hu, Y, Law, CW, Shi, W, et al. Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 2015;43:e47. in Google Scholar PubMed PubMed Central

102. Benjamini, Y, Hochberg, Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B 1995;57:289–300. in Google Scholar

103. Benjamini, Y, Yekutieli, D. The control of the false discovery rate in multiple testing under dependency. Ann Stat 2001;29:1165–88. in Google Scholar

104. Dusa, A. Venn: draw Venn diagrams. R package 17 ed. 2018.Search in Google Scholar

105. Conway, JR, Lex, A, Gehlenborg, N. UpSetR: an R package for the visualization of intersecting sets and their properties. Bioinformatics 2017;33:2938–40. in Google Scholar

106. Draghici, S, Khatri, P, Tarca, AL, Amin, K, Done, A, Voichita, C, et al. A systems biology approach for pathway level analysis. Genome Res 2007;17:1537–45. in Google Scholar

107. Khatri, P, Draghici, S, Tarca, AD, Hassan, SS, Romero, R. A system biology approach for the steady-state analysis of gene signaling networks. Lect Notes Comput Sci 2007;4756:32–41.10.1007/978-3-540-76725-1_4Search in Google Scholar

108. Tarca, AL, Draghici, S, Khatri, P, Hassan, SS, Mittal, P, Kim, JS, et al. A novel signaling pathway impact analysis. Bioinformatics 2009;25:75–82. in Google Scholar

109. Kanehisa, M, Goto, S. KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res 2000;28:27–30. in Google Scholar

110. Kanehisa, M, Goto, S, Sato, Y, Furumichi, M, Tanabe, M. KEGG for integration and interpretation of large-scale molecular data sets. Nucleic Acids Res 2012;40:D109–14. in Google Scholar

111. Fidel, PLJr, Romero, R, Wolf, N, Cutright, J, Ramirez, M, Araneda, H, et al. Systemic and local cytokine profiles in endotoxin-induced preterm parturition in mice. Am J Obstet Gynecol 1994;170:1467–75. in Google Scholar

112. Toyama, RP, Xikota, JC, Schwarzbold, ML, Frode, TS, Buss Zda, S, Nunes, JC, et al. Dose-dependent sickness behavior, abortion and inflammation induced by systemic LPS injection in pregnant mice. J Matern Fetal Neonatal Med 2015;28:426–30. in Google Scholar PubMed

113. Kadam, L, Gomez-Lopez, N, Mial, TN, Kohan-Ghadr, HR, Drewlo, S. Rosiglitazone regulates TLR4 and rescues HO-1 and NRF2 expression in myometrial and decidual macrophages in inflammation-induced preterm birth. Reprod Sci 2017;24:1590–9. in Google Scholar PubMed PubMed Central

114. Garcia-Flores, V, Romero, R, Miller, D, Xu, Y, Done, B, Veerapaneni, C, et al. Inflammation-induced adverse pregnancy and neonatal outcomes can be improved by the immunomodulatory peptide exendin-4. Front Immunol 2018;9:1291. in Google Scholar PubMed PubMed Central

115. Arenas-Hernandez, M, Romero, R, Xu, Y, Panaitescu, B, Garcia-Flores, V, Miller, D, et al. Effector and activated T cells induce preterm labor and birth that is prevented by treatment with progesterone. J Immunol 2019;202:2585–608. in Google Scholar PubMed PubMed Central

116. Huszar, G, Naftolin, F. The myometrium and uterine cervix in normal and preterm labor. N Engl J Med 1984;311:571–81. in Google Scholar

117. Iams, JD, Paraskos, J, Landon, MB, Teteris, JN, Johnson, FF. Cervical sonography in preterm labor. Obstet Gynecol 1994;84:40–6.Search in Google Scholar

118. Heath, VC, Southall, TR, Souka, AP, Elisseou, A, Nicolaides, KH. Cervical length at 23 weeks of gestation: prediction of spontaneous preterm delivery. Ultrasound Obstet Gynecol 1998;12:312–7. in Google Scholar PubMed

119. Hassan, SS, Romero, R, Berry, SM, Dang, K, Blackwell, SC, Treadwell, MC, et al. Patients with an ultrasonographic cervical length < or =15 mm have nearly a 50% risk of early spontaneous preterm delivery. Am J Obstet Gynecol 2000;182:1458–67. in Google Scholar PubMed

120. Suhag, A, Berghella, V. Cervical cerclage. Clin Obstet Gynecol 2014;57:557–67. in Google Scholar PubMed

121. Sen, C. Preterm labor and preterm birth. J Perinat Med 2017;45:911–3. in Google Scholar PubMed

122. Sharvit, M, Weiss, R, Ganor Paz, Y, Tzadikevitch Geffen, K, Danielli Miller, N, Biron-Shental, T. Vaginal examination vs. cervical length - which is superior in predicting preterm birth?. J Perinat Med 2017;45:977–83. in Google Scholar PubMed

123. Hernandez-Andrade, E, Maymon, E, Luewan, S, Bhatti, G, Mehrmohammadi, M, Erez, O, et al. A soft cervix, categorized by shear-wave elastography, in women with short or with normal cervical length at 18–24 weeks is associated with a higher prevalence of spontaneous preterm delivery. J Perinat Med 2018;46:489–501. in Google Scholar PubMed PubMed Central

124. Knell, AJ. Liver function and failure: the evolution of liver physiology. J R Coll Physicians Lond 1980;14:205–8.Search in Google Scholar

125. Corless, JK, Middleton, HM3rd. Normal liver function. A basis for understanding hepatic disease. Arch Intern Med 1983;143:2291–4. in Google Scholar

126. Pineiro-Carrero, VM, Pineiro, EO. Liver. Pediatrics. 2004;113:1097–106.10.1542/peds.113.S3.1097Search in Google Scholar

127. Protzer, U, Maini, MK, Knolle, PA. Living in the liver: hepatic infections. Nat Rev Immunol 2012;12:201–13. in Google Scholar

128. Schnabl, B, Brenner, DA. Interactions between the intestinal microbiome and liver diseases. Gastroenterology 2014;146:1513–24. in Google Scholar

129. Strnad, P, Tacke, F, Koch, A, Trautwein, C. Liver – guardian, modifier and target of sepsis. Nat Rev Gastroenterol Hepatol 2017;14:55–66. in Google Scholar

130. Boonen, E, Bornstein, SR, Van den Berghe, G. New insights into the controversy of adrenal function during critical illness. Lancet Diabetes Endocrinol 2015;3:805–15. in Google Scholar

131. Peart, WS. The kidney as an endocrine organ. Lancet 1977;2:543–8. in Google Scholar

132. Wallace, MA. Anatomy and physiology of the kidney. AORN J 1998;68:800–20.10.1016/S0001-2092(06)62377-6Search in Google Scholar

133. Knepper, MA, Kwon, TH, Nielsen, S. Molecular physiology of water balance. N Engl J Med 2015;372:1349–58. in Google Scholar PubMed PubMed Central

134. Farhi, LE. Respiration. Annu Rev Physiol 1965;27:233–56. in Google Scholar PubMed

135. Petersson, J, Glenny, RW. Gas exchange and ventilation-perfusion relationships in the lung. Eur Respir J 2014;44:1023–41. in Google Scholar

136. Weibel, ER. Lung morphometry: the link between structure and function. Cell Tissue Res 2017;367:413–26. in Google Scholar

137. Perry, KGJr. Martin, RW, Blake, PG, Roberts, WE, Martin, JNJr. Maternal mortality associated with adult respiratory distress syndrome. Southern medical journal. 1998;91:441–4. in Google Scholar

138. Vasquez, DN, Estenssoro, E, Canales, HS, Reina, R, Saenz, MG, Das Neves, AV, et al. Clinical characteristics and outcomes of obstetric patients requiring ICU admission. Chest 2007;131:718–24. in Google Scholar

139. Cunningham, FG, Leveno, KJ, Bloom, SL, Dashe, JS, Hoffman, BL, Casey, BM, et al. editors. Maternal physiology. In: Williams obstetrics. 25 ed. New York: McGraw-Hill; 2018: 49–78.Search in Google Scholar

140. Csapo, AI, Jaffin, H, Kerenyi, T, Lipman, JI, Wood, C. Volume and activity of the pregnant human uterus. Am J Obstet Gynecol 1963;85:819–35. in Google Scholar

141. Geirsson, RT. Intrauterine volume in pregnancy. Acta Obstet Gynecol Scand Suppl 1986;136:1–74. in Google Scholar

142. Degani, S, Leibovitz, Z, Shapiro, I, Gonen, R, Ohel, G. Myometrial thickness in pregnancy: longitudinal sonographic study. J Ultrasound Med 1998;17:661–5. in Google Scholar PubMed

143. Riemer, RK, Heymann, MA. Regulation of uterine smooth muscle function during gestation. Pediatr Res 1998;44:615–27. in Google Scholar PubMed

144. Osol, G, Moore, LG. Maternal uterine vascular remodeling during pregnancy. Microcirculation 2014;21:38–47. in Google Scholar PubMed

145. Shynlova, O, Mitchell, JA, Tsampalieros, A, Langille, BL, Lye, SJ. Progesterone and gravidity differentially regulate expression of extracellular matrix components in the pregnant rat myometrium. Biol Reprod 2004;70:986–92. in Google Scholar PubMed

146. Shynlova, O, Kwong, R, Lye, SJ. Mechanical stretch regulates hypertrophic phenotype of the myometrium during pregnancy. Reproduction 2010;139:247–53. in Google Scholar PubMed

147. Gomez-Lopez, N, Guilbert, LJ, Olson, DM. Invasion of the leukocytes into the fetal-maternal interface during pregnancy. J Leukoc Biol 2010;88:625–33. in Google Scholar PubMed

148. Arck, PC, Hecher, K. Fetomaternal immune cross-talk and its consequences for maternal and offspring’s health. Nat Med 2013;19:548–56. in Google Scholar PubMed

149. Rehman, KS, Yin, S, Mayhew, BA, Word, RA, Rainey, WE. Human myometrial adaptation to pregnancy: cDNA microarray gene expression profiling of myometrium from non-pregnant and pregnant women. Mol Hum Reprod 2003;9:681–700. in Google Scholar PubMed

150. Aguan, K, Carvajal, JA, Thompson, LP, Weiner, CP. Application of a functional genomics approach to identify differentially expressed genes in human myometrium during pregnancy and labour. Mol Hum Reprod 2000;6:1141–5. in Google Scholar PubMed

151. Chan, EC, Fraser, S, Yin, S, Yeo, G, Kwek, K, Fairclough, RJ, et al. Human myometrial genes are differentially expressed in labor: a suppression subtractive hybridization study. J Clin Endocrinol Metab 2002;87:2435–41. in Google Scholar PubMed

152. Charpigny, G, Leroy, MJ, Breuiller-Fouche, M, Tanfin, Z, Mhaouty-Kodja, S, Robin, P, et al. A functional genomic study to identify differential gene expression in the preterm and term human myometrium. Biol Reprod 2003;68:2289–96. in Google Scholar PubMed

153. Esplin, MS, Fausett, MB, Peltier, MR, Hamblin, S, Silver, RM, Branch, DW, et al. The use of cDNA microarray to identify differentially expressed labor-associated genes within the human myometrium during labor. Am J Obstet Gynecol 2005;193:404–13. in Google Scholar PubMed

154. Havelock, JC, Keller, P, Muleba, N, Mayhew, BA, Casey, BM, Rainey, WE, et al. Human myometrial gene expression before and during parturition. Biol Reprod 2005;72:707–19. in Google Scholar PubMed

155. Breuiller-Fouche, M, Charpigny, G, Germain, G. Functional genomics of the pregnant uterus: from expectations to reality, a compilation of studies in the myometrium. BMC Pregnancy Childbirth 2007;7:S4. in Google Scholar

156. Bollapragada, S, Youssef, R, Jordan, F, Greer, I, Norman, J, Nelson, S. Term labor is associated with a core inflammatory response in human fetal membranes, myometrium, and cervix. Am J Obstet Gynecol 2009;200:104 e1–11. in Google Scholar

157. Mittal, P, Romero, R, Tarca, AL, Gonzalez, J, Draghici, S, Xu, Y, et al. Characterization of the myometrial transcriptome and biological pathways of spontaneous human labor at term. J Perinat Med 2010;38:617–43. in Google Scholar

158. Weiner, CP, Mason, CW, Dong, Y, Buhimschi, IA, Swaan, PW, Buhimschi, CS. Human effector/initiator gene sets that regulate myometrial contractility during term and preterm labor. Am J Obstet Gynecol 2010;202:474 e1–20. in Google Scholar

159. Chaemsaithong, P, Madan, I, Romero, R, Than, NG, Tarca, AL, Draghici, S, et al. Characterization of the myometrial transcriptome in women with an arrest of dilatation during labor. J Perinat Med 2013;41:665–81. in Google Scholar

160. Chan, YW, van den Berg, HA, Moore, JD, Quenby, S, Blanks, AM. Assessment of myometrial transcriptome changes associated with spontaneous human labour by high-throughput RNA-seq. Exp Physiol 2014;99:510–24. in Google Scholar

161. Sharp, GC, Hutchinson, JL, Hibbert, N, Freeman, TC, Saunders, PT, Norman, JE. Transcription analysis of the myometrium of labouring and non-labouring women. PLoS One 2016;11:e0155413. in Google Scholar

162. Migale, R, MacIntyre, DA, Cacciatore, S, Lee, YS, Hagberg, H, Herbert, BR, et al. Modeling hormonal and inflammatory contributions to preterm and term labor using uterine temporal transcriptomics. BMC Med 2016;14:86. in Google Scholar

163. Stanfield, Z, Lai, PF, Lei, K, Johnson, MR, Blanks, AM, Romero, R, et al. Myometrial transcriptional signatures of human parturition. Front Genet 2019;10:185. in Google Scholar

164. Wray, S, Prendergast, C. The myometrium: from excitation to contractions and labour. Adv Exp Med Biol 2019;1124:233–63. in Google Scholar

165. Osmers, RG, Blaser, J, Kuhn, W, Tschesche, H. Interleukin-8 synthesis and the onset of labor. Obstet Gynecol 1995;86:223–9. in Google Scholar

166. Thomson, AJ, Telfer, JF, Young, A, Campbell, S, Stewart, CJ, Cameron, IT, et al. Leukocytes infiltrate the myometrium during human parturition: further evidence that labour is an inflammatory process. Hum Reprod 1999;14:229–36. in Google Scholar

167. Keelan, JA, Blumenstein, M, Helliwell, RJ, Sato, TA, Marvin, KW, Mitchell, MD. Cytokines, prostaglandins and parturition--a review. Placenta 2003;24:S33–46. in Google Scholar PubMed

168. Osman, I, Young, A, Ledingham, MA, Thomson, AJ, Jordan, F, Greer, IA, 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;9:41–5. in Google Scholar PubMed

169. Romero, R, Gotsch, F, Pineles, B, Kusanovic, JP. Inflammation in pregnancy: its roles in reproductive physiology, obstetrical complications, and fetal injury. Nutr Rev 2007;65:S194–202. in Google Scholar

170. Shynlova, O, Tsui, P, Dorogin, A, Lye, SJ. Monocyte chemoattractant protein-1 (CCL-2) integrates mechanical and endocrine signals that mediate term and preterm labor. J Immunol 2008;181:1470–9. in Google Scholar PubMed

171. Shynlova, O, Lee, YH, Srikhajon, K, Lye, SJ. Physiologic uterine inflammation and labor onset: integration of endocrine and mechanical signals. Reprod Sci 2013;20:154–67. in Google Scholar PubMed

172. Gomez-Lopez, N, Tanaka, S, Zaeem, Z, Metz, GA, Olson, DM. Maternal circulating leukocytes display early chemotactic responsiveness during late gestation. BMC Pregnancy Childbirth 2013;13:S8. in Google Scholar PubMed PubMed Central

173. Gomez-Lopez, N, Tong, WC, Arenas-Hernandez, M, Tanaka, S, Hajar, O, Olson, DM, et al. Chemotactic activity of gestational tissues through late pregnancy, term labor, and RU486-induced preterm labor in Guinea pigs. Am J Reprod Immunol 2015;73:341–52. in Google Scholar PubMed

174. Bethin, KE, Nagai, Y, Sladek, R, Asada, M, Sadovsky, Y, Hudson, TJ, et al. Microarray analysis of uterine gene expression in mouse and human pregnancy. Mol Endocrinol 2003;17:1454–69. in Google Scholar PubMed

175. Brubaker, D, Liu, Y, Wang, J, Tan, H, Zhang, G, Jacobsson, B, et al. Finding lost genes in GWAS via integrative-omics analysis reveals novel sub-networks associated with preterm birth. Hum Mol Genet 2016;25:5254–64. in Google Scholar PubMed PubMed Central

176. Bukowski, R, Sadovsky, Y, Goodarzi, H, Zhang, H, Biggio, JR, Varner, M, et al. Onset of human preterm and term birth is related to unique inflammatory transcriptome profiles at the maternal fetal interface. PeerJ 2017;5:e3685. in Google Scholar PubMed PubMed Central

177. Martyn, F, McAuliffe, FM, Wingfield, M. The role of the cervix in fertility: is it time for a reappraisal?. Hum Reprod 2014;29:2092–8. in Google Scholar PubMed

178. Lee, SK, Kim, CJ, Kim, DJ, Kang, JH. Immune cells in the female reproductive tract. Immune Netw 2015;15:16–26. in Google Scholar PubMed PubMed Central

179. Nallasamy, S, Mahendroo, M. Distinct roles of cervical epithelia and stroma in pregnancy and parturition. Semin Reprod Med 2017;35:190–200. in Google Scholar PubMed

180. Barrios De Tomasi, J, Opata, MM, Mowa, CN. Immunity in the cervix: interphase between immune and cervical epithelial cells. J Immunol Res 2019;2019:7693183. in Google Scholar PubMed PubMed Central

181. Yellon, SM. Immunobiology of cervix ripening. Front Immunol 2019;10:3156. in Google Scholar PubMed PubMed Central

182. Word, RA, Li, XH, Hnat, M, Carrick, K. Dynamics of cervical remodeling during pregnancy and parturition: mechanisms and current concepts. Semin Reprod Med 2007;25:69–79. in Google Scholar PubMed

183. Timmons, B, Akins, M, Mahendroo, M. Cervical remodeling during pregnancy and parturition. Trends Endocrinol Metab 2010;21:353–61. in Google Scholar PubMed PubMed Central

184. Leppert, PC. Anatomy and physiology of cervical ripening. Clin Obstet Gynecol 1995;38:267–79. in Google Scholar PubMed

185. Sung, SJ, Lee, SM, Oh, S, Choi, JH, Park, JY, Kim, BJ, et al. Mid-pregnancy cervical length as a risk factor for cesarean section in women with twin pregnancies. J Perinat Med 2018;46:780–5. in Google Scholar PubMed

186. O’Brien, CM, Vargis, E, Rudin, A, Slaughter, JC, Thomas, G, Newton, JM, et al. In vivo Raman spectroscopy for biochemical monitoring of the human cervix throughout pregnancy. Am J Obstet Gynecol 2018;218:528 e1–e18. in Google Scholar PubMed PubMed Central

187. Juhasova, J, Kreft, M, Zimmermann, R, Kimmich, N. Impact factors on cervical dilation rates in the first stage of labor. J Perinat Med 2018;46:59–66. in Google Scholar PubMed

188. Horinouchi, T, Yoshizato, T, Muto, M, Fujii, M, Kozuma, Y, Shinagawa, T, et al. Gestational age-related changes in shear wave speed of the uterine cervix in normal pregnancy at 12–35 weeks’ gestation. J Perinat Med 2019;47:393–401. in Google Scholar PubMed

189. Norman, JE. Preterm labour. Cervical function and prematurity. Best Pract Res Clin Obstet Gynaecol 2007;21:791–806. in Google Scholar PubMed

190. Holt, R, Timmons, BC, Akgul, Y, Akins, ML, Mahendroo, M. The molecular mechanisms of cervical ripening differ between term and preterm birth. Endocrinology 2011;152:1036–46. in Google Scholar PubMed PubMed Central

191. 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:e26877. in Google Scholar PubMed PubMed Central

192. Gonzalez, JM, Romero, R, Girardi, G. Comparison of the mechanisms responsible for cervical remodeling in preterm and term labor. J Reprod Immunol 2013;97:112–9. in Google Scholar PubMed PubMed Central

193. Vink, J, Feltovich, H. Cervical etiology of spontaneous preterm birth. Semin Fetal Neonatal Med 2016;21:106–12. in Google Scholar PubMed PubMed Central

194. Park, JY, Cho, SH, Jeon, SJ, Kook, SY, Park, H, Oh, KJ, et al. Outcomes of physical examination-indicated cerclage in twin pregnancies with acute cervical insufficiency compared to singleton pregnancies. J Perinat Med 2018;46:845–52. in Google Scholar PubMed

195. Monckeberg, M, Valdes, R, Kusanovic, JP, Schepeler, M, Nien, JK, Pertossi, E, et al. Patients with acute cervical insufficiency without intra-amniotic infection/inflammation treated with cerclage have a good prognosis. J Perinat Med 2019;47:500–9. in Google Scholar PubMed PubMed Central

196. Bokstrom, H, Brannstrom, M, Alexandersson, M, Norstrom, A. Leukocyte subpopulations in the human uterine cervical stroma at early and term pregnancy. Hum Reprod 1997;12:586–90. in Google Scholar PubMed

197. 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;61:879–83. in Google Scholar PubMed

198. Timmons, BC, Fairhurst, AM, Mahendroo, MS. Temporal changes in myeloid cells in the cervix during pregnancy and parturition. J Immunol 2009;182:2700–7. in Google Scholar PubMed PubMed Central

199. Payne Kimberly, J, Clyde Lindsey, A, Weldon Abby, J, Milford, Terry-Ann, Yellon Steven, M. Residency and activation of myeloid cells during remodeling of the prepartum murine cervix. Biol Reprod 2012;87:106. in Google Scholar PubMed PubMed Central

200. Myers, DA. The recruitment and activation of leukocytes into the immune cervix: further support that cervical remodeling involves an immune and inflammatory mechanism. Biol Reprod 2012;87:107. in Google Scholar PubMed

201. Young, A, Thomson, AJ, Ledingham, M, Jordan, F, Greer, IA, Norman, JE. Immunolocalization of proinflammatory cytokines in myometrium, cervix, and fetal membranes during human parturition at term. Biol Reprod 2002;66:445–9. in Google Scholar PubMed

202. Ledingham, MA, Denison, FC, Riley, SC, Norman, JE. Matrix metalloproteinases-2 and -9 and their inhibitors are produced by the human uterine cervix but their secretion is not regulated by nitric oxide donors. Hum Reprod 1999;14:2089–96. in Google Scholar PubMed

203. Stygar, D, Wang, H, Vladic, YS, Ekman, G, Eriksson, H, Sahlin, L. Increased level of matrix metalloproteinases 2 and 9 in the ripening process of the human cervix. Biol Reprod 2002;67:889–94. in Google Scholar PubMed

204. 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 Pathol 2011;179:838–49. in Google Scholar PubMed PubMed Central

205. 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;84:1053–62. in Google Scholar PubMed PubMed Central

206. 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;74:236–45. in Google Scholar PubMed

207. Mahendroo, M. Cervical remodeling in term and preterm birth: insights from an animal model. Reproduction 2012;143:429–38. in Google Scholar

208. 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:e0119782. in Google Scholar PubMed PubMed Central

209. Hassan, SS, Romero, R, Tarca, AL, Nhan-Chang, CL, Vaisbuch, E, Erez, O, 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;22:1183–93. in Google Scholar PubMed PubMed Central

210. Hassan, SS, Romero, R, Tarca, AL, Draghici, S, Pineles, B, Bugrim, A, et al. Signature pathways identified from gene expression profiles in the human uterine cervix before and after spontaneous term parturition. Am J Obstet Gynecol 2007;197:250 e1–7. in Google Scholar PubMed PubMed Central

211. Hassan, SS, Romero, R, Tarca, AL, Nhan-Chang, CL, Mittal, P, Vaisbuch, E, et al. The molecular basis for sonographic cervical shortening at term: identification of differentially expressed genes and the epithelial-mesenchymal transition as a function of cervical length. Am J Obstet Gynecol 2010;203:472 e1–e14. in Google Scholar PubMed

212. Makieva, S, Dubicke, A, Rinaldi, SF, Fransson, E, Ekman-Ordeberg, G, Norman, JE. The preterm cervix reveals a transcriptomic signature in the presence of premature prelabor rupture of membranes. Am J Obstet Gynecol 2017;216:602 e1–e21. in Google Scholar PubMed

213. Gonzalez, JM, Xu, H, Chai, J, Ofori, E, Elovitz, MA. Preterm and term cervical ripening in CD1 Mice (Mus musculus): similar or divergent molecular mechanisms?. Biol Reprod 2009;81:1226–32. in Google Scholar PubMed

214. Willcockson, AR, Nandu, T, Liu, CL, Nallasamy, S, Kraus, WL, Mahendroo, M. Transcriptome signature identifies distinct cervical pathways induced in lipopolysaccharide-mediated preterm birth. Biol Reprod 2018;98:408–21. in Google Scholar PubMed PubMed Central

215. Gomez-Lopez, N, Romero, R, Xu, Y, Plazyo, O, Unkel, R, Leng, Y, et al. A role for the inflammasome in spontaneous preterm labor with acute histologic chorioamnionitis. Reprod Sci 2017;24:1382–401. in Google Scholar PubMed PubMed Central

216. Gomez-Lopez, N, Romero, R, Panaitescu, B, Leng, Y, Xu, Y, Tarca, AL, et al. Inflammasome activation during spontaneous preterm labor with intra-amniotic infection or sterile intra-amniotic inflammation. Am J Reprod Immunol 2018;80:e13049. in Google Scholar PubMed PubMed Central

217. Strauss, JF, Romero, R, Gomez-Lopez, N, Haymond-Thornburg, H, Modi, BP, Teves, ME, et al. Spontaneous preterm birth: advances toward the discovery of genetic predisposition. Am J Obstet Gynecol 2018;218:294–314 e2. in Google Scholar PubMed PubMed Central

218. Faro, J, Romero, R, Schwenkel, G, Garcia-Flores, V, Arenas-Hernandez, M, Leng, Y, et al. Intra-amniotic inflammation induces preterm birth by activating the NLRP3 inflammasome. Biol Reprod 2019;100:1290–305. in Google Scholar PubMed PubMed Central

219. Gomez-Lopez, N, Romero, R, Garcia-Flores, V, Leng, Y, Miller, D, Hassan, SS, et al. Inhibition of the NLRP3 inflammasome can prevent sterile intra-amniotic inflammation, preterm labor/birth, and adverse neonatal outcomes. Biol Reprod 2019;100:1306–18. in Google Scholar PubMed PubMed Central

220. Gomez-Lopez, N, Romero, R, Tarca, AL, Miller, D, Panaitescu, B, Schwenkel, G, et al. Gasdermin D: Evidence of pyroptosis in spontaneous preterm labor with sterile intra-amniotic inflammation or intra-amniotic infection. Am J Reprod Immunol 2019;82:e13184. in Google Scholar PubMed PubMed Central

221. Gomez-Lopez, N, Motomura, K, Miller, D, Garcia-Flores, V, Galaz, J, Romero, R. Inflammasomes: their role in normal and complicated pregnancies. J Immunol 2019;203:2757–69. in Google Scholar PubMed PubMed Central

222. Theis, KR, Romero, R, Motomura, K, Galaz, J, Winters, AD, Pacora, P, et al. Microbial burden and inflammasome activation in amniotic fluid of patients with preterm prelabor rupture of membranes. J Perinat Med 2020;48:115–31. in Google Scholar PubMed PubMed Central

223. Van Thiel, DH, Gavaler, JS. Pregnancy-associated sex steroids and their effects on the liver. Semin Liver Dis 1987;7:1–7. in Google Scholar PubMed

224. Price, LR, Lillycrop, KA, Irvine, NA, Hanson, MA, Burdge, GC. Transcriptome-wide analysis suggests that temporal changes in the relative contributions of hyperplasia, hypertrophy and apoptosis underlie liver growth in pregnant mice. Biol Reprod 2017;97:762–71. in Google Scholar PubMed

225. Paquette, A, Baloni, P, Holloman, AB, Nigam, S, Bammler, T, Mao, Q, et al. Temporal transcriptomic analysis of metabolic genes in maternal organs and placenta during murine pregnancy. Biol Reprod 2018;99:1255–65. in Google Scholar PubMed PubMed Central

226. Jenne, CN, Kubes, P. Immune surveillance by the liver. Nat Immunol 2013;14:996–1006. in Google Scholar PubMed

227. Mathison, JC, Ulevitch, RJ. The clearance, tissue distribution, and cellular localization of intravenously injected lipopolysaccharide in rabbits. J Immunol 1979;123:2133–43.Search in Google Scholar

228. Gao, B, Jeong, WI, Tian, Z. Liver: an organ with predominant innate immunity. Hepatology 2008;47:729–36. in Google Scholar PubMed

229. Soto, E, Richani, K, Romero, R, Espinoza, J, Chaiworapongsa, T, Nien, JK, et al. Increased concentration of the complement split product C5a in acute pyelonephritis during pregnancy. J Matern Fetal Neonatal Med 2005;17:247–52. in Google Scholar PubMed PubMed Central

230. Vaisbuch, E, Romero, R, Erez, O, Mazaki-Tovi, S, Kusanovic, JP, Soto, E, et al. Fragment Bb in amniotic fluid: evidence for complement activation by the alternative pathway in women with intra-amniotic infection/inflammation. J Matern Fetal Neonatal Med 2009;22:905–16. in Google Scholar PubMed PubMed Central

231. Soto, E, Romero, R, Richani, K, Yoon, BH, Chaiworapongsa, T, Vaisbuch, E, et al. Evidence for complement activation in the amniotic fluid of women with spontaneous preterm labor and intra-amniotic infection. J Matern Fetal Neonatal Med 2009;22:983–92. in Google Scholar PubMed PubMed Central

232. Soto, E, Romero, R, Vaisbuch, E, Erez, O, Mazaki-Tovi, S, Kusanovic, JP, et al. Fragment Bb: evidence for activation of the alternative pathway of the complement system in pregnant women with acute pyelonephritis. J Matern Fetal Neonatal Med 2010;23:1085–90. in Google Scholar PubMed PubMed Central

233. Vaisbuch, E, Romero, R, Erez, O, Mazaki-Tovi, S, Kusanovic, JP, Soto, E, et al. Activation of the alternative pathway of complement is a feature of pre-term parturition but not of spontaneous labor at term. Am J Reprod Immunol 2010;63:318–30. in Google Scholar PubMed PubMed Central

234. Galindo-Sevilla, N, Reyes-Arroyo, F, Mancilla-Ramirez, J. The role of complement in preterm birth and prematurity. J Perinat Med 2019;47:793–803. in Google Scholar PubMed

Supplementary Material

The online version of this article offers supplementary material (

Received: 2020-04-12
Accepted: 2020-05-27
Published Online: 2020-08-31
Published in Print: 2020-09-25

© 2020 Walter de Gruyter GmbH, Berlin/Boston

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