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Cell-Free Fetal DNA, Telomeres, and the Spontaneous Onset of Parturition

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Abstract

Multiple previous reports have provided compelling support for the premise that spontaneous parturition is mediated by activation of inflammation-related signaling pathways leading to increased secretion of cytokines and chemokines, the influx of neutrophils and macrophages into the pregnant uterus, increased production of uterine activation proteins (eg, connexin-43, cyclo-oxygenase-2, oxytocin receptors, etc), activation of matrix metalloproteinases, and the release of uterotonins leading to cervical ripening, membrane rupture, and myometrial contractions. The missing link has been the fetal/placental signal that triggers these proinflammatory events in the absence of microbial invasion and intrauterine infection. This article reviews the biomedical literature regarding the increase in cell-free fetal DNA (cffDNA), which is released during apoptosis in the placenta and fetal membranes at term, the ability of apoptosis modified vertebrate DNA to stimulate toll-like receptor-9 (TLR9) leading to increased release of cytokines and chemokines, and the potential “fail-safe” role for the anti-inflammatory cytokine IL-10. This article also reviews the literature supporting the key role that telomere loss plays in regard to increasing the ability of vertebrate (including placental) DNA to stimulate TLR9, and in regard to signaling the onset of apoptosis in the placenta and fetal membranes, thereby providing a biologic clock that determines the length of gestation and the timing for the onset of parturition. In summary, this literature review provides a strong rationale for future research to test the hypothesis that telomere loss and increased cffDNA levels trigger the proinflammatory events leading to the spontaneous onset of parturition in mammals: the “cffDNA/telomere hypothesis.”

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References

  1. Phillippe M. Cell-free fetal DNA–a trigger for parturition. N Engl J Med. 2014;370(26):2534–2536.

    PubMed  Google Scholar 

  2. Kelly RW. Inflammatory Mediators and Parturition. Rev Reprod. 1996;1(2):89–96.

    CAS  PubMed  Google Scholar 

  3. Norman JE, Bollapragada S, Yuan M, Nelson SM. Inflammatory pathways in the mechanism of parturition. BMC Pregnancy Childbirth. 2007;7(suppl 1):S7.

    PubMed  PubMed Central  Google Scholar 

  4. Lindstrom TM, Bennett PR. The role of nuclear factor kappa B in human labour. Reproduction. 2005;130(5):569–581.

    CAS  PubMed  Google Scholar 

  5. Patni S, Flynn P, Wynen LP, et al. An introduction to Toll-like receptors and their possible role in the initiation of labour. BJOG. 2007;114(11):1326–1134.

    CAS  PubMed  Google Scholar 

  6. Romero R, Espinoza J, Gonçalves LF, Kusanovic JP, Friel LA, Nien JK. Inflammation in preterm and term labour and delivery. Semin Fetal Neonatal Med. 2006;11(5):317–326.

    PubMed  PubMed Central  Google Scholar 

  7. Condon JC, Jeyasuria P, Faust JM, Mendelson CR. Surfactant protein secreted by the maturing mouse fetal lung acts as a hormone that signals the initiation of parturition. Proc Natl Acad Sci U S A. 2004;101(14):4978–4983.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Christiaens I, Zaragoza DB, Guilbert L, Robertson SA, Mitchell BF, Olson DM. Inflammatory processes in preterm and term parturition. J Reprod Immunol. 2008;79(1):50–57.

    CAS  PubMed  Google Scholar 

  9. Golightly E, Jabbour HN, Norman JE. Endocrine immune interactions in human parturition. Mol Cell Endocrinol. 2011;335(1):52–59.

    CAS  PubMed  Google Scholar 

  10. Doyle SL, O’Neill LA. Toll-like receptors: from the discovery of NFkappaB to new insights into transcriptional regulations in innate immunity. Biochem Pharmacol. 2006;72(9):1102–1113.

    CAS  PubMed  Google Scholar 

  11. Wickelgren I. Immunology. Targeting the tolls. Science. 2006;312(5771):184–187.

    CAS  PubMed  Google Scholar 

  12. Amjadi F, Salehi E, Mehdizadeh M, Aflatoonian R. Role of the innate immunity in female reproductive tract. Adv Biomed Res. 2014;3:1.

    PubMed  PubMed Central  Google Scholar 

  13. Koblansky AA, Jankovic D, Oh H, et al. Recognition of profilin by Toll-like receptor 12 is critical for host resistance to Toxoplasma gondii. Immunity. 2013;38(1):119–130.

    CAS  PubMed  Google Scholar 

  14. Hidmark A, von Saint Paul A, Dalpke AH. Cutting Edge: TLR13 is A Receptor for Bacterial RNA. J Immunol. 2012;189(6):2717–2721.

    CAS  PubMed  Google Scholar 

  15. Lee SM, Kok KH, Jaume M, et al. Toll-like receptor 10 is involved in induction of innate immune responses to influenza virus infection. Proc Natl Acad Sci USA. 2014;111(10):3793–3798.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Miyake Y, Yamasaki S. Sensing necrotic cells. Adv Exp Med Biol. 2012;738:144–152.

    CAS  PubMed  Google Scholar 

  17. Romero R, Chaiworapongsa T, Alpay Savasan Z, et al., Damage-associated molecular patterns (DAMPs) in preterm labor with intact membranes and preterm PROM: a study of the alarmin HMGB1. J Matern Fetal Neonatal Med. 2011;24(12):1444–1455.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Tolle LB, Standiford TJ. Danger-associated molecular patterns (DAMPs) in acute lung injury. J Pathol. 2013;229(2):145–156.

    CAS  PubMed  Google Scholar 

  19. Mogami H, Kishore AH, Shi H, Keller PW, Akgul Y, Word RA. Fetal fibronectin signaling induces matrix metalloproteases and cyclooxygenase-2 (COX-2) in amnion cells and preterm birth in mice. J Biol Chem. 2013;288(3):1953–1966.

    CAS  PubMed  Google Scholar 

  20. Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol. 2004;4(7):499–511.

    CAS  PubMed  Google Scholar 

  21. Lo YM, Corbetta N, Chamberlain PF, et al. Presence of fetal DNA in maternal plasma and serum. Lancet. 1997;350(9076):485–487.

    CAS  PubMed  Google Scholar 

  22. Lo YM, Tein MS, Lau TK, et al. Quantitative analysis of fetal DNA in maternal plasma and serum: implications for noninvasive prenatal diagnosis. Am J Hum Genet. 1998;62(4):768–775.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Chan KC, Zhang J, Hui AB, et al. Size distributions of maternal and fetal DNA in maternal plasma. Clin Chem. 2004;50(1):88–92.

    CAS  PubMed  Google Scholar 

  24. Lo YM, Zhang J, Leung TN, Lau TK, Chang AM, Hjelm NM. Rapid clearance of fetal DNA from maternal plasma. Am J Hum Genet. 1999;64(1):218–224.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Taglauer ES, Wilkins-Haug L, Bianchi DW. Review: Cell-free fetal DNA in the maternal circulation as an indication of placental health and disease. Placenta. 2014;35 suppl:S64–S68.

    CAS  PubMed  Google Scholar 

  26. Bischoff FZ, Lewis DE, Simpson JL. Cell-free fetal DNA in maternal blood: kinetics, source and structure. Hum Reprod Update. 2005;11(1):59–67.

    CAS  PubMed  Google Scholar 

  27. Ariga H, Ohto H, Busch MP, et al. Kinetics of fetal cellular and cell-free DNA in the maternal circulation during and after pregnancy: implications for noninvasive prenatal diagnosis. Transfusion. 2001;41(12):1524–1530.

    CAS  PubMed  Google Scholar 

  28. Birch L, English CA, O’Donoghue K, Barigye O, Fisk NM, Keer JT. Accurate and robust quantification of circulating fetal and total DNA in maternal plasma from 5 to 41 weeks of gestation. Clin Chem. 2005;51(2):312–320.

    CAS  PubMed  Google Scholar 

  29. Majer S, Bauer M, Magnet E, et al. Maternal urine for prenatal diagnosis–an analysis of cell-free fetal DNA in maternal urine and plasma in the third trimester. Prenat Diagn. 2007;27(13):1219–1223.

    CAS  PubMed  Google Scholar 

  30. Wang E, Batey A, Struble C, Musci T, Song K, Oliphant A. Gestational age and maternal weight effects on fetal cell-free DNA in maternal plasma. Prenat Diagn. 2013. 33(7):662–666.

    CAS  PubMed  Google Scholar 

  31. Leung TN, Zhang J, Lau TK, Hjelm NM, Lo YM. Maternal plasma fetal DNA as a marker for preterm labour. Lancet. 1998;352(9144):1904–1905.

    CAS  PubMed  Google Scholar 

  32. Farina A, LeShane ES, Romero R, et al. High levels of fetal cell-free DNA in maternal serum: a risk factor for spontaneous preterm delivery. Am J Obstet Gynecol. 2005;193(2):421–425.

    CAS  PubMed  Google Scholar 

  33. Jakobsen TR, Clausen FB, Rode L, Dziegiel MH, Tabor A. High levels of fetal DNA are associated with increased risk of spontaneous preterm delivery. Prenat Diagn. 2012;32(9):840–845.

    CAS  PubMed  Google Scholar 

  34. Stein W, Müller S, Gutensohn K, Emons G, Legler T. Cell-free fetal DNA and adverse outcome in low risk pregnancies. Eur J Obstet Gynecol Reprod Biol. 2013;166(1):10–13.

    CAS  PubMed  Google Scholar 

  35. Khosrotehrani K, Wataganara T, Bianchi DW, Johnson KL. Fetal cell-free DNA circulates in the plasma of pregnant mice: relevance for animal models of fetomaternal trafficking. Hum Reprod. 2004;19(11):2460–2464.

    CAS  PubMed  Google Scholar 

  36. Wang G, Cui Q, Cheng K, Zhang X, Xing G, Wu S. Prediction of fetal sex by amplification of fetal DNA present in cow plasma. J Reprod Dev. 2010;56(6):639–642.

    CAS  PubMed  Google Scholar 

  37. de Leon PM, Campos VF, Dellagostin OA, Deschamps JC, Seixas FK, Collares T. Equine fetal sex determination using circulating cell-free fetal DNA (ccffDNA). Theriogenology. 2012;77(3):694–698.

    PubMed  Google Scholar 

  38. Kadivar A, Hassanpour H, Mirshokraei P, Azari M, Gholamhosseini K, Karami A. Detection and quantification of cell-free fetal DNA in ovine maternal plasma; use it to predict fetal sex. Theriogenology. 2013;79(6):995–1000.

    CAS  PubMed  Google Scholar 

  39. Jimenez DF, Tarantal AF. Quantitative analysis of male fetal DNA in maternal serum of gravid rhesus monkeys (Macaca mulatta). Pediatr Res. 2003;53(1):18–23.

    CAS  PubMed  Google Scholar 

  40. Mitsunaga F, Ueiwa M, Kamanaka Y, Morimoto M, Nakamura S. Fetal sex determination of macaque monkeys by a nested PCR using maternal plasma. Exp Anim. 2010;59(2):255–260.

    CAS  PubMed  Google Scholar 

  41. Hemmi H, Takeuchi O, Kawai T, et al. A Toll-like receptor recognizes bacterial DNA. Nature. 2000;408(6813):740–745.

    CAS  PubMed  Google Scholar 

  42. Krieg AM, Yi AK, Matson S, et al. CpG motifs in bacterial DNA trigger direct B-cell activation. Nature. 1995;374(6522):546–549.

    CAS  PubMed  Google Scholar 

  43. Kumagai Y, Takeuchi O, Akira S. TLR9 as a key receptor for the recognition of DNA. Adv Drug Deliv Rev. 2008;60(7):795–804.

    CAS  PubMed  Google Scholar 

  44. Scharfe-Nugent A, Corr SC, Carpenter SB, et al. TLR9 provokes inflammation in response to fetal DNA: mechanism for fetal loss in preterm birth and preeclampsia. J Immunol. 2012;188(11):5706–5712.

    CAS  PubMed  Google Scholar 

  45. Thaxton JE, Romero R, Sharma S. TLR9 activation coupled to IL-10 deficiency induces adverse pregnancy outcomes. J Immunol. 2009;183(2):1144–1154.

    CAS  PubMed  Google Scholar 

  46. Sun Y, Qin X, Shan B, et al. Differential effects of the CpG-Toll-like receptor 9 axis on pregnancy outcome in nonobese diabetic mice and wild-type controls. Fertil Steril. 2013;99(6):1759–1767.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Murphy SP, Hanna NN, Fast LD, et al., Evidence for participation of uterine natural killer cells in the mechanisms responsible for spontaneous preterm labor and delivery. Am J Obstet Gynecol. 2009;200(3):308.e1–e9.

    PubMed  Google Scholar 

  48. Hanna N, Hanna I, Hleb M, et al., Gestational age-dependent expression of IL-10 and its receptor in human placental tissues and isolated cytotrophoblasts. J Immunol. 2000; 164(11):5721–5728.

    CAS  PubMed  Google Scholar 

  49. Simpson KL, Keelan JA, Mitchell MD. Labor-associated changes in interleukin-10 production and its regulation by immunomodulators in human choriodecidua. J Clin Endocrinol Metab. 1998;83(12):4332–4337.

    CAS  PubMed  Google Scholar 

  50. Pisetsky DS, Reich CF. Inhibition of murine macrophage IL-12 production by natural and synthetic DNA. Clin Immunol. 2000;96(3): 198–204.

    CAS  PubMed  Google Scholar 

  51. Dong L, Ito S, Ishii KJ, Klinman DM. Suppressive oligonucleotides protect against collagen-induced arthritis in mice. Arthritis Rheum. 2004;50(5):1686–1689.

    CAS  PubMed  Google Scholar 

  52. Gursel I, Gursel M, Yamada H, Ishii KJ, Takeshita F, Klinman DM. Repetitive elements in mammalian telomeres suppress bacterial DNA-induced immune activation. J Immunol. 2003;171(3):1393–1400.

    CAS  PubMed  Google Scholar 

  53. Shirota H, Gursel M, Klinman DM. Suppressive oligodeoxynucleotides inhibit Th1 differentiation by blocking IFN-gamma- and IL-12-mediated signaling. J Immunol. 2004;173(8):5002–5007.

    CAS  PubMed  Google Scholar 

  54. Panter G, Kuznik A, Jerala R. Therapeutic applications of nucleic acids as ligands for Toll-like receptors. Curr Opin Mol Ther. 2009;11(2):133–145.

    CAS  PubMed  Google Scholar 

  55. Takagi T, Hashiguchi M, Mahato RI, Tokuda H, Takakura Y, Hashida M. Involvement of specific mechanism in plasmid DNA uptake by mouse peritoneal macrophages. Biochem Biophys Res Commun. 1998;245(3):729–733.

    CAS  PubMed  Google Scholar 

  56. Imaeda AB, Watanabe A, Sohail MA, et al. Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome. J Clin Invest. 2009;119(2):305–314.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Watanabe A, Hashmi A, Gomes DA, et al. Apoptotic hepatocyte DNA inhibits hepatic stellate cell chemotaxis via toll-like receptor 9. Hepatology. 2007;46(5):1509–1518.

    CAS  PubMed  Google Scholar 

  58. Yasuda K, Kawano H, Yamane I, et al. Restricted cytokine production from mouse peritoneal macrophages in culture in spite of extensive uptake of plasmid DNA. Immunology. 2004;111(3):282–290.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Viglianti GA, Lau CM, Hanley TM, Miko BA, Shlomchik MJ, Marshak-Rothstein A. Activation of autoreactive B cells by CpG dsDNA. Immunity. 2003;19(6):837–847.

    CAS  PubMed  Google Scholar 

  60. Yasuda K, Yu P, Kirschning CJ, et al. Endosomal translocation of vertebrate DNA activates dendritic cells via TLR9-dependent and -independent pathways. J Immunol. 2005;174(10):6129–6136.

    CAS  PubMed  Google Scholar 

  61. Yasuda K, Ogawa Y, Yamane I, Nishikawa M, Takakura Y. Macrophage activation by a DNA/cationic liposome complex requires endosomal acidification and TLR9-dependent and -independent pathways. J Leukoc Biol. 2005;77(1):71–79.

    CAS  PubMed  Google Scholar 

  62. Zeuner RA, Ishii KJ, Lizak MJ, et al. Reduction of CpG-induced arthritis by suppressive oligodeoxynucleotides. Arthritis Rheum. 2002;46(8):2219–2224.

    CAS  PubMed  Google Scholar 

  63. Sackesen C, van de Veen W, Akdis M, et al. Suppression of B-cell activation and IgE, IgA, IgG1 and IgG4 production by mammalian telomeric oligonucleotides. Allergy. 2013;68(5):593–603.

    CAS  PubMed  Google Scholar 

  64. Krieg AM, Wu T, Weeratna R, et al. Sequence motifs in adenoviral DNA block immune activation by stimulatory CpG motifs. Proc Natl Acad Sci U S A. 1998;95(21):12631–12636.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Lenert PS. Classification, mechanisms of action, and therapeutic applications of inhibitory oligonucleotides for Toll-like receptors (TLR) 7 and 9. Mediators Inflamm. 2010;2010:986596.

    PubMed  PubMed Central  Google Scholar 

  66. Murchie AI, Lilley DM. Tetraplex folding of telomere sequences and the inclusion of adenine bases. EMBO J. 1994;13(4):993–1001.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Zhong XY, Holzgreve W, Hahn S. Cell-free fetal DNA in the maternal circulation does not stem from the transplacental passage of fetal erythroblasts. Mol Hum Reprod. 2002;8(9):864–870.

    CAS  PubMed  Google Scholar 

  68. Goswami D, Tannetta DS, Magee LA, et al. Excess syncytiotrophoblast microparticle shedding is a feature of early-onset preeclampsia, but not normotensive intrauterine growth restriction. Placenta. 2006;27(1):56–61.

    CAS  PubMed  Google Scholar 

  69. Reddy A, Zhong XY, Rusterholz C, et al. The effect of labour and placental separation on the shedding of syncytiotrophoblast microparticles, cell-free DNA and mRNA in normal pregnancy and pre-eclampsia. Placenta. 2008;29(11):942–949.

    CAS  PubMed  Google Scholar 

  70. Smith SC, Baker PN, Symonds EM. Placental apoptosis in normal human pregnancy. Am J Obstet Gynecol. 1997;177(1):57–65.

    CAS  PubMed  Google Scholar 

  71. Smith SC, Baker PN. Placental apoptosis is increased in post-term pregnancies. Br J Obstet Gynaecol. 1999;106(8):861–862.

    CAS  PubMed  Google Scholar 

  72. Ishihara N, Matsuo H, Murakoshi H, et al. Changes in proliferative potential, apoptosis and Bcl-2 protein expression in cytotrophoblasts and syncytiotrophoblast in human placenta over the course of pregnancy. Endocr J. 2000;47(3):317–327.

    CAS  PubMed  Google Scholar 

  73. Longtine MS, Chen B, Odibo AO, Zhong Y, Nelson DM. Caspase-mediated apoptosis of trophoblasts in term human placental villi is restricted to cytotrophoblasts and absent from the multinucleated syncytiotrophoblast. Reproduction. 2012;143(1):107–121.

    CAS  PubMed  Google Scholar 

  74. Hirayama H, Ushizawa K, Takahashi T, et al. Differences in apoptotic status in the bovine placentome between spontaneous and induced parturition. J Reprod Dev. 2012;58(5):585–591.

    CAS  PubMed  Google Scholar 

  75. Mu J, Kanzaki T, Tomimatsu T, et al. Expression of apoptosis in placentae from mice lacking the prostaglandin F receptor. Placenta. 2002;23(2–3):215–223.

    CAS  PubMed  Google Scholar 

  76. Kakinuma C, Kuwayama C, Kaga N, Futamura Y, Katsuki Y, Shibutani Y. Trophoblastic apoptosis in mice with preterm delivery and its suppression by urinary trypsin inhibitor. Obstet Gynecol. 1997;90(1):117–124.

    CAS  PubMed  Google Scholar 

  77. Jaiswal MK, Agrawal V, Mallers T, Gilman-Sachs A, Hirsch E, Beaman KD. Regulation of apoptosis and innate immune stimuli in inflammation-induced preterm labor. J Immunol. 2013;191(11):5702–5713.

    CAS  PubMed  Google Scholar 

  78. McLaren J, Taylor DJ, Bell SC. Increased incidence of apoptosis in non-labour-affected cytotrophoblast cells in term fetal membranes overlying the cervix. Hum Reprod. 1999;14(11):2895–2900.

    CAS  PubMed  Google Scholar 

  79. Runić R, Lockwood CJ, LaChapelle L, et al. Apoptosis and Fas expression in human fetal membranes. J Clin Endocrinol Metab. 1998;83(2):660–666.

    PubMed  Google Scholar 

  80. Kumagai K, Otsuki Y, Ito Y, Shibata MA, Abe H, Ueki M. Apoptosis in the normal human amnion at term, independent of Bcl-2 regulation and onset of labour. Mol Hum Reprod. 2001;7(7):681–689.

    CAS  PubMed  Google Scholar 

  81. Paavola LG, Furth EE, Delgado V, et al. Striking changes in the structure and organization of rat fetal membranes precede parturition. Biol Reprod. 1995;53(2):321–338.

    CAS  PubMed  Google Scholar 

  82. Lei H, Furth EE, Kalluri R, et al. A program of cell death and extracellular matrix degradation is activated in the amnion before the onset of labor. J Clin Invest. 1996;98(9):1971–1978.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Luo G, Abrahams VM, Tadesse S, et al. Progesterone inhibits basal and TNF-alpha-induced apoptosis in fetal membranes: a novel mechanism to explain progesterone-mediated prevention of preterm birth. Reprod Sci. 2010;17(6):532–539.

    CAS  PubMed  Google Scholar 

  84. Lu W, Zhang Y, Liu D, Songyang Z, Wan M. Telomeres-structure, function, and regulation. Exp Cell Res. 2013;319(2):133–141.

    CAS  PubMed  Google Scholar 

  85. Harley CB, Futcher AB, Greider CW. Telomeres shorten during ageing of human fibroblasts. Nature. 1990;345(6274):458–460.

    CAS  PubMed  Google Scholar 

  86. Graakjaer J, Bischoff C, Korsholm L, et al. The pattern of chromosome-specific variations in telomere length in humans is determined by inherited, telomere-near factors and is maintained throughout life. Mech Ageing Dev. 2003;124(5):629–640.

    CAS  PubMed  Google Scholar 

  87. Zou Y, Sfeir A, Gryaznov SM, Shay JW, Wright WE. Does a sentinel or a subset of short telomeres determine replicative senescence? Mol Biol Cell. 2004;15(8):3709–3718.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Menon R, Yu J, Basanta-Henry P, et al. Short fetal leukocyte telomere length and preterm prelabor rupture of the membranes. PLoS One. 2012;7(2):e31136.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Gielen M, Hageman G, Pachen D, Derom C, Vlietinck R, Zeegers MP. Placental telomere length decreases with gestational age and is influenced by parity: a study of third trimester liveborn twins. Placenta. 2014;35(10):791–796.

    CAS  PubMed  Google Scholar 

  90. Prowse KR, Greider CW. Developmental and tissue-specific regulation of mouse telomerase and telomere length. Proc Natl Acad Sci U S A. 1995;92(11):4818–4822.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Bekaert S, Derradji H, Baatout S. Telomere biology in mammalian germ cells and during development. Dev Biol. 2004;274(1):15–30.

    CAS  PubMed  Google Scholar 

  92. Lee HW, Blasco MA, Gottlieb GJ, Horner JW 2nd, Greider CW, DePinho RA. Essential role of mouse telomerase in highly proliferative organs. Nature. 1998;392(6676):569–574.

    CAS  PubMed  Google Scholar 

  93. Herrera E, Samper E, Martín-Caballero J, Flores JM, Lee HW, Blasco MA. Disease states associated with telomerase deficiency appear earlier in mice with short telomeres. EMBO J. 1999;18(11):2950–2960.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Passos JF, Saretzki G, von Zglinicki T. DNA damage in telomeres and mitochondria during cellular senescence: is there a connection? Nucleic Acids Res. 2007;35(22):7505–7513.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Kipling D, Cooke HJ. Hypervariable ultra-long telomeres in mice. Nature. 1990;347(6291):400–402.

    CAS  PubMed  Google Scholar 

  96. Starling JA, Maule J, Hastie ND, Allshire RC. Extensive telomere repeat arrays in mouse are hypervariable. Nucleic Acids Res. 1990;18(23):6881–6888.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Gomes NM, Ryder OA, Houck ML, et al. Comparative biology of mammalian telomeres: hypotheses on ancestral states and the roles of telomeres in longevity determination. Aging Cell. 2011;10(5):761–768.

    CAS  PubMed  Google Scholar 

  98. Liu L, Bailey SM, Okuka M, et al. Telomere lengthening early in development. Nat Cell Biol. 2007;9(12):1436–1441.

    CAS  PubMed  Google Scholar 

  99. Schaetzlein S, Lucas-Hahn A, Lemme E, et al. Telomere length is reset during early mammalian embryogenesis. Proc Natl Acad Sci U S A. 2004;101(21):8034–8038.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Keefe DL, Marquard K, Liu L. The telomere theory of reproductive senescence in women. Curr Opin Obstet Gynecol. 2006;18(3):280–285.

    PubMed  Google Scholar 

  101. Xu J, Yang X. Telomerase activity in bovine embryos during early development. Biol Reprod. 2000;63(4):1124–1128.

    CAS  PubMed  Google Scholar 

  102. Wright WE, Piatyszek MA, Rainey WE, Byrd W, Shay JW. Telomerase activity in human germline and embryonic tissues and cells. Dev Genet. 1996;18(2):173–179.

    CAS  PubMed  Google Scholar 

  103. Iqbal K, Kues WA, Baulain U, Garrels W, Herrmann D, Niemann H. Species-specific telomere length differences between blastocyst cell compartments and ectopic telomere extension in early bovine embryos by human telomerase reverse transcriptase. Biol Reprod. 2011;84(4):723–733.

    CAS  PubMed  Google Scholar 

  104. Cheng G, Kong F, Luan Y, et al., Differential shortening rate of telomere length in the development of human fetus. Biochem Biophys Res Commun. 2013;442(1–2):112–115.

    CAS  PubMed  Google Scholar 

  105. Chen RJ, Chu CT, Huang SC, Chow SN, Hsieh CY. Telomerase activity in gestational trophoblastic disease and placental tissue from early and late human pregnancies. Hum Reprod. 2002;17(2):463–468.

    CAS  PubMed  Google Scholar 

  106. Kyo S, Takakura M, Tanaka M, et al. Expression of telomerase activity in human chorion. Biochem Biophys Res Commun. 1997;241(2):498–503.

    PubMed  Google Scholar 

  107. Mosquera A, Fernández JL, Campos A, Goyanes VJ, Ramiro-Díaz J, Gosálvez J. Simultaneous decrease of telomere length and telomerase activity with ageing of human amniotic fluid cells. J Med Genet. 1999;36(6):494–496.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Hemann MT, Strong MA, Hao LY, Greider CW. The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell. 2001;107(1):67–77.

    CAS  PubMed  Google Scholar 

  109. Petersen S, Saretzki G, von Zglinicki T. Preferential accumulation of single-stranded regions in telomeres of human fibroblasts. Exp Cell Res. 1998;239(1):152–160.

    CAS  PubMed  Google Scholar 

  110. Chin L, Artandi SE, Shen Q, et al. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell. 1999;97(4):527–538.

    CAS  PubMed  Google Scholar 

  111. Espejel S, Franco S, Rodríguez-Perales S, Bouffler SD, Cigudosa JC, Blasco MA. Mammalian Ku86 mediates chromosomal fusions and apoptosis caused by critically short telomeres. EMBO J. 2002;21(9):2207–2219.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Multani AS, Ozen M, Narayan S, et al. Caspase-dependent apoptosis induced by telomere cleavage and TRF2 loss. Neoplasia. 2000;2(4):339–345.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Canick JA, Kloza EM, Lambert-Messerlian GM, et al. DNA sequencing of maternal plasma to identify Down syndrome and other trisomies in multiple gestations. Prenat Diagn. 2012;32(8):730–734.

    CAS  PubMed  Google Scholar 

  114. Ehrenberg HM, Iams JD, Goldenberg RL, et al. Maternal obesity, uterine activity, and the risk of spontaneous preterm birth. Obstet Gynecol. 2009;113(1):48–52.

    PubMed  PubMed Central  Google Scholar 

  115. Smith GC, Shah I, Pell JP, Crossley JA, Dobbie R. Maternal obesity in early pregnancy and risk of spontaneous and elective preterm deliveries: a retrospective cohort study. Am J Public Health. 2007;97(1):157–162.

    PubMed  PubMed Central  Google Scholar 

  116. Denison FC, Price J, Graham C, Wild S, Liston WA. Maternal obesity, length of gestation, risk of postdates pregnancy and spontaneous onset of labour at term. BJOG. 2008;115(6):720–725.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Schoen CN, Tabbah S, Iams JD, Caughey AB, Berghella V. Why the United States preterm birth rate is declining [published online December 12, 2014]. Am J Obstet Gynecol. 2014.

  118. Gotsch F, Romero R, Kusanovic JP, et al. The anti-inflammatory limb of the immune response in preterm labor, intra-amniotic infection/inflammation, and spontaneous parturition at term: a role for interleukin-10. J Matern Fetal Neonatal Med. 2008;21(8):529–547.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Cobo T, Kacerovsky M, Holst RM, et al. Intra-amniotic inflammation predicts microbial invasion of the amniotic cavity but not spontaneous preterm delivery in preterm prelabor membrane rupture. Acta Obstet Gynecol Scand. 2012;91(8):930–935.

    PubMed  Google Scholar 

  120. Apuzzio J, Chan Y, Al-Khan A, Illsley N, Kim PL, Vonhaggen S. Second-trimester amniotic fluid interleukin-10 concentration predicts preterm delivery. J Matern Fetal Neonatal Med. 2004;15(5):313–317.

    CAS  PubMed  Google Scholar 

  121. Menon R, Camargo MC, Thorsen P, Lombardi SJ, Fortunato SJ. Amniotic fluid interleukin-6 increase is an indicator of spontaneous preterm birth in white but not black Americans. Am J Obstet Gynecol. 2008;198(1):77.e1–e7.

    PubMed  Google Scholar 

  122. Mittendorf R, Williams MA, Berkey CS, Lieberman E, Monson RR. Predictors of human gestational length. Am J Obstet Gynecol. 1993;168(2):480–484.

    CAS  PubMed  Google Scholar 

  123. Culhane JF, Goldenberg RL. Racial disparities in preterm birth. Semin Perinatol. 2011;35(4):234–239.

    PubMed  Google Scholar 

  124. Collins JW Jr, David RJ, Simon DM, Prachand NG. Preterm birth among African American and white women with a lifelong residence in high-income Chicago neighborhoods: an exploratory study. Ethn Dis. 2007;17(1):113–117.

    PubMed  Google Scholar 

  125. Papiernik E, Alexander GR, Paneth N. Racial differences in pregnancy duration and its implications for perinatal care. Med Hypotheses. 1990;33(3):181–186.

    CAS  PubMed  Google Scholar 

  126. Balchin I, Steer PJ. Race, prematurity and immaturity. Early Hum Dev. 2007;83(12):749–754.

    PubMed  Google Scholar 

  127. Loftin R, Chen A, Evans A, DeFranco E. Racial differences in gestational age-specific neonatal morbidity: further evidence for different gestational lengths. Am J Obstet Gynecol. 2012;206(3):259.e1–e6.

    PubMed  Google Scholar 

  128. Harper M, Li L, Zhao Y, et al. Change in mononuclear leukocyte responsiveness in midpregnancy and subsequent preterm birth. Obstet Gynecol. 2013;121(4):805–811.

    PubMed  Google Scholar 

  129. Hanna CW, Bretherick KL, Gair JL, Fluker MR, Stephenson MD, Robinson WP. Telomere length and reproductive aging. Hum Reprod. 2009;24(5):1206–1211.

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Wong JY, De Vivo I, Lin X, Fang SC, Christiani DC. The relationship between inflammatory biomarkers and telomere length in an occupational prospective cohort study. PLoS One. 2014;9(1):e87348.

    PubMed  PubMed Central  Google Scholar 

  131. Cherkas LF, Aviv A, Valdes AM, et al. The effects of social status on biological aging as measured by white-blood-cell telomere length. Aging Cell. 2006;5(5):361–365.

    CAS  PubMed  Google Scholar 

  132. Adler N, Pantell MS, O’Donovan A, et al. Educational attainment and late life telomere length in the Health, Aging and Body Composition Study. Brain Behav Immun. 2013;27(1):15–21.

    PubMed  Google Scholar 

  133. Needham BL, Carroll JE, Diez Roux AV, Fitzpatrick AL, Moore K, Seeman TE. Neighborhood characteristics and leukocyte telomere length: the Multi-Ethnic Study of Atherosclerosis. Health Place. 2014;28:167–172.

    PubMed  PubMed Central  Google Scholar 

  134. Hunt SC, Chen W, Gardner JP, et al. Leukocyte telomeres are longer in African Americans than in whites: the National Heart, Lung, and Blood Institute Family Heart Study and the Bogalusa Heart Study. Aging Cell. 2008;7(4):451–458.

    CAS  PubMed  Google Scholar 

  135. Rewak M, Buka S, Prescott J, et al., Race-related health disparities and biological aging: does rate of telomere shortening differ across blacks and whites? Biol Psychol. 2014;99:92–99.

    PubMed  PubMed Central  Google Scholar 

  136. Kempe A, Wise PH, Barkan SE, et al. Clinical determinants of the racial disparity in very low birth weight. N Engl J Med. 1992;327(14):969–973.

    CAS  PubMed  Google Scholar 

  137. Tsai HJ, Hong X, Chen J, et al. Role of African ancestry and gene-environment interactions in predicting preterm birth. Obstet Gynecol. 2011;118(5):1081–1089.

    PubMed  PubMed Central  Google Scholar 

  138. Osypuk TL, Acevedo-Garcia D. Are racial disparities in preterm birth larger in hypersegregated areas? Am J Epidemiol. 2008;167(11):1295–1304.

    PubMed  Google Scholar 

  139. Collins JW Jr, Rankin KM, Janowiak CM. Suburban migration and the birth outcome of Chicago-born white and African-American women: the merit of the healthy migrant theory? Matern Child Health J. 2013;17(9):1559–1566.

    PubMed  Google Scholar 

  140. Howard DL, Marshall SS, Kaufman JS, Savitz DA. Variations in low birth weight and preterm delivery among blacks in relation to ancestry and nativity: New York City, 1998–2002. Pediatrics. 2006;118(5):e1399–e1405.

    PubMed  Google Scholar 

  141. Allsopp RC, Vaziri H, Patterson C, et al. Telomere length predicts replicative capacity of human fibroblasts. Proc Natl Acad Sci USA. 1992;89:10114–10118.

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Allsopp RC, Chang E, Kashefi-Aazam M, et al. Telomere shortening is associated with cell division in vitro and in vivo. Exp Cell Res. 1995;220:194–200.

    CAS  PubMed  Google Scholar 

  143. Yang L, Suwa T, Wright WE, et al. Telomere shortening and decline in replicative potential as a function of donor age in human adrenocortical cells. Mech Ageing Dev. 2001;122(5):1685–94.

    CAS  PubMed  Google Scholar 

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  1. Department of Obstetrics, Gynecology & Reproductive Biology, Harvard Medical School, Boston, MA, USA

    Mark Phillippe MD, MHCM

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Phillippe, M. Cell-Free Fetal DNA, Telomeres, and the Spontaneous Onset of Parturition. Reprod. Sci. 22, 1186–1201 (2015). https://doi.org/10.1177/1933719115592714

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