A review of the Evidence for Placental Ageing in Prolonged Pregnancy.

Main Article Content

Amber Carroll Stacey Lee Michelle Desforges Alexander E P Heazell

Abstract

Prolonged pregnancy describes a pregnancy that progresses beyond 42 weeks (294 days). The aetiology of prolonged pregnancy is incompletely understood, although factors such as advanced maternal age and obesity increase the risk of prolonged pregnancy. Prolonged pregnancy is associated with an increased incidence of perinatal mortality; in particular, the incidence of stillbirth increases from 39 weeks onwards, with a significant increase beyond 41 weeks’ gestation. The biological explanation for this has yet to be confirmed. Placental ageing has been proposed as a possible mechanism. As the placenta is responsible for the nutrient and energy demands of the fetus, which are considerable in late pregnancy, a decrease in its ability to function may provide an explanation for the increasing perinatal mortality rate seen in prolonged pregnancy.


Here we review evidence for ageing processes occurring in the placenta. A number of biomarkers of ageing are seen within the placenta as gestation progresses. These include evidence of increased apoptosis, senescence, autophagy, and oxidative stress in trophoblast, the primary functional cell in the placenta, in prolonged pregnancy. As these processes play a key role in the ageing process of other tissues, the accumulation of these markers here is consistent with placental ageing. In addition, there are morphological changes in trophoblast in prolonged pregnancy which suggest impaired mitochondrial and placental function. The findings summarised in this review illustrate the growing evidence of both structural and biochemical features of ageing shown in placentas of prolonged pregnancy, providing insight into underlying mechanisms which may initially be adaptation to in utero stress, but later develop to become pathological. Future work is needed to determine whether these changes impact upon placental function and whether placental biomarkers could be used as a surveillance tool in prolonged pregnancy.

Keywords: prolonged pregnancy, ageing, placenta, oxidative stress, autophagy, senescence, apoptosis

Article Details

How to Cite
CARROLL, Amber et al. A review of the Evidence for Placental Ageing in Prolonged Pregnancy.. Medical Research Archives, [S.l.], v. 8, n. 8, aug. 2020. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/2188>. Date accessed: 29 mar. 2024. doi: https://doi.org/10.18103/mra.v8i8.2188.
Section
Review Articles

References

1. ACOG Practice Patterns. Management of Postterm Pregnancy. Number 6, October 1997. American College of Obstetricians and Gynecologists - PubMed. https://pubmed.ncbi.nlm.nih.gov/9506424/. Accessed June 17, 2020.
2. Overview | Inducing labour | Guidance | NICE. https://www.nice.org.uk/guidance/cg70. Accessed June 17, 2020.
3. WHO: Recommended Definitions, Terminology and Format for Statistical Tables Related to the Perinatal Period and Use of a New Certificate for Cause of Perinatal Deaths. Modifications Recommended by FIGO as Amended October 14, 1976 - PubMed. https://pubmed.ncbi.nlm.nih.gov/560099/. Accessed June 17, 2020.
4. (No Title). https://www.npeu.ox.ac.uk/downloads/files/mbrrace-uk/reports/MBRRACE-UK Perinatal Mortality Surveillance Report for Births in 2017 - FINAL Revised.pdf. Accessed June 17, 2020.
5. Zeitlin J, Blondel B, Alexander S, Bréart G. Variation in rates of postterm birth in Europe: reality or artefact? BJOG An Int J Obstet Gynaecol. 2007;114(9):1097-1103. doi:10.1111/j.1471-0528.2007.01328.x
6. Galal M, Symonds I, Murray H, Petraglia F, Smith R. Postterm pregnancy. Int J Gynecol Obstet. 1996;53(1):89-90. doi:10.1016/S0020-7292(96)80020-8
7. Muglu J, Rather H, Arroyo-Manzano D, et al. Risks of stillbirth and neonatal death with advancing gestation at term: A systematic review and meta-analysis of cohort studies of 15 million pregnancies. PLoS Med. 2019;16(7). doi:10.1371/journal.pmed.1002838
8. Usha Kiran TS, Hemmadi S, Bethel J, Evans J. Outcome of pregnancy in a woman with an increased body mass index. BJOG An Int J Obstet Gynaecol. 2005;112(6):768-772. doi:10.1111/j.1471-0528.2004.00546.x
9. Reece EA. Perspectives on obesity, pregnancy and birth outcomes in the United States: The scope of the problem. Am J Obstet Gynecol. 2008;198(1):23-27. doi:10.1016/j.ajog.2007.06.076
10. Halloran DR, Cheng YW, Wall TC, MacOnes GA, Caughey AB. Effect of maternal weight on postterm delivery. In: Journal of Perinatology. Vol 32. Nature Publishing Group; 2012:85-90. doi:10.1038/jp.2011.63
11. Stotland NE, Washington AE, Caughey AB. Prepregnancy body mass index and the length of gestation at term. Am J Obstet Gynecol. 2007;197(4):378.e1-378.e5. doi:10.1016/j.ajog.2007.05.048
12. 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 An Int J Obstet Gynaecol. 2008;115(6):720-725. doi:10.1111/j.1471-0528.2008.01694.x
13. Jansson N, Nilsfelt A, Gellerstedt M, et al. Maternal Hormones Linking Maternal Body Mass Index and Dietary Intake to Birth Weight 1-3.; 2008. https://academic.oup.com/ajcn/article-abstract/87/6/1743/4633314. Accessed June 17, 2020.
14. Al-Qahtani S, Heath A, Quenby S, et al. Diabetes is associated with impairment of uterine contractility and high Caesarean section rate. Diabetologia. 2012;55(2):489-498. doi:10.1007/s00125-011-2371-6
15. Arrowsmith S, Quenby S, Weeks A, Burdyga T, Wray S. Poor spontaneous and oxytocin-stimulated contractility in human myometrium from postdates pregnancies. PLoS One. 2012;7(5). doi:10.1371/journal.pone.0036787
16. Heslehurst N, Vieira R, Hayes L, et al. Maternal body mass index and post-term birth: a systematic review and meta-analysis. Obes Rev. 2017;18(3):293-308. doi:10.1111/obr.12489
17. National Statistics O for. Births by parents’ characteristics in England and Wales - Office for National Statistics. https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/livebirths/bulletins/birthsbyparentscharacteristicsinenglandandwales/2016. Accessed July 20, 2018.
18. Lean SC, Derricott H, Jones RL, Heazell AEP. Advanced maternal age and adverse pregnancy outcomes: A systematic review and meta-analysis. 2017. doi:10.1371/journal.pone.0186287
19. Reddy UM, Ko CW, Willinger M. Maternal age and the risk of stillbirth throughout pregnancy in the United States. Am J Obstet Gynecol. 2006;195(3):764-770. doi:10.1016/j.ajog.2006.06.019
20. Rand L, Robinson JN, Economy KE, Norwitz ER. Post-term induction of labor revisited. Obstet Gynecol. 2000;96(5):779-783. doi:10.1016/s0029-7844(00)01002-4
21. Campbell MK, ØStbye T, Irgens LM. Post-term birth: Risk factors and outcomes in a 10-year cohort of Norwegian births. Obstet Gynecol. 1997;89(4):543-548. doi:10.1016/S0029-7844(97)00049-5
22. Alexander JM, McIntire DD, Leveno KJ. Forty weeks and beyond: Pregnancy outcomes by week of gestation. Obstet Gynecol. 2000;96(2):291-294. doi:10.1016/S0029-7844(00)00862-0
23. Treger M, Hallak M, Silberstein T, Friger M, Katz M, Mazor M. Post-term pregnancy: Should induction of labor be considered before 42 weeks? J Matern Fetal Med. 2002;11(1):50-53. doi:10.1080/jmf.11.1.50.53
24. Middleton P, Shepherd E, Crowther CA. Induction of labour for improving birth outcomes for women at or beyond term. Cochrane Database Syst Rev. 2018;2018(5). doi:10.1002/14651858.CD004945.pub4
25. Kashanian M, Akbarian A, Baradaran H, Samiee MM. Effect of Membrane Sweeping at Term Pregnancy on Duration of Pregnancy and Labor Induction: A Randomized Trial. Gynecol Obstet Invest. 2006;62(1):41-44. doi:10.1159/000091842
26. de Miranda E, van der Bom J, Bonsel G, Bleker O, Rosendaal F. Membrane sweeping and prevention of post-term pregnancy in low-risk pregnancies: a randomised controlled trial. BJOG An Int J Obstet Gynaecol. 2006;113(4):402-408. doi:10.1111/j.1471-0528.2006.00870.x
27. CROWLEY P, O’HERLIHY C, BOYLAN P. The value of ultrasound measurement of amniotic fluid ume in the management of prolonged pregnancies. BJOG An Int J Obstet Gynaecol. 1984;91(5):444-448. doi:10.1111/j.1471-0528.1984.tb04781.x
28. Tongsong T, Srisomboon J. Amniotic fluid volume as a predictor of fetal distress in postterm pregnancy. Int J Gynecol Obstet. 1993;40(3):213-217. doi:10.1016/0020-7292(93)90833-I
29. Oz AU, Holub B, Mendilcioglu I, Mari G, Bahado-Singh RO. Renal artery Doppler investigation of the etiology of oligohydramnios in postterm pregnancy. Obstet Gynecol. 2002;100(4):715-718. doi:10.1016/S0029-7844(02)02203-2
30. Clement D, Schifrin BS, Kates RB. Acute Oligohydramnios in postdate pregnancy. Am J Obstet Gynecol. 1987;157(4):884-886. doi:10.1016/S0002-9378(87)80078-9
31. Chamberlain PF, Manning FA, Morrison I, Harman CR, Lange IR. Ultrasound evaluation of amniotic fluid volume: I. The relationship of marginal and decreased amniotic fluid volumes to perinatal outcome. Am J Obstet Gynecol. 1984;150(3):245-249. doi:10.1016/S0002-9378(84)90359-4
32. Maiti K, Sultana Z, Aitken RJ, et al. Evidence that fetal death is associated with placental aging. Am J Obstet Gynecol. 2017;217(4):441.e1-441.e14. doi:10.1016/j.ajog.2017.06.015
33. Gude NM, Roberts CT, Kalionis B, King RG. Growth and function of the normal human placenta. Thromb Res. 2004;114(5-6 SPEC. ISS.):397-407. doi:10.1016/j.thromres.2004.06.038
34. Benirschke K, Driscoll SG, Benirschke, Driscoll. The Pathology of the Human Placenta. In: The Pathology of the Human Placenta. Springer New York; 1967:100-105. doi:10.1007/978-1-4612-9809-0_2
35. Green-Armytage FBRCOG, Hamilton WJ, Boyd JD. Proccedings Ot the Royal Society of Medicine Section of Obstetrics and Gynecology Observations on the Human Placenta.
36. Rodesch F, Simon P, Donner C, Jauniaux E. Oxygen measurements in endometrial and trophoblastic tissues during early pregnancy. Obstet Gynecol. 1992;80(2):283-285.
37. Jaffe R, Jauniaux E, Hustin J. Maternal circulation in the first-trimester human placenta - Myth or reality? Am J Obstet Gynecol. 1997;176(3):695-705. doi:10.1016/S0002-9378(97)70572-6
38. Maternal, Fetal, & Neonatal Physiology - E-Book: A Clinical Perspective - Susan Blackburn - Google Books. https://books.google.co.uk/books?hl=en&lr=&id=2d49DwAAQBAJ&oi=fnd&pg=PP1&dq=41.%09Blackburn,+S.,+2017.+Maternal,+Fetal,+%26+neonatal+physiology-E-book:+a+clinical+perspective.+Elsevier+Health+Sciences.&ots=yiZ5xMUsyt&sig=9HT8tRYYfyV0Om7S8aJPj26cIC8&redir_esc=y#v=onepage&q=41.%09Blackburn%2C S.%2C 2017. Maternal%2C Fetal%2C %26 neonatal physiology-E-book%3A a clinical perspective. Elsevier Health Sciences.&f=false. Accessed June 17, 2020.
39. Brett K, Ferraro Z, Yockell-Lelievre J, Gruslin A, Adamo K. Maternal–Fetal Nutrient Transport in Pregnancy Pathologies: The Role of the Placenta. Int J Mol Sci. 2014;15(9):16153-16185. doi:10.3390/ijms150916153
40. Baumann MU, Deborde S, Illsley NP. Placental glucose transfer and fetal growth. Endocrine. 2002;19(1):13-22. doi:10.1385/ENDO:19:1:13
41. Illsley NP, Illsley NP. Glucose transporters in the human placenta The epithelial-mesenchymal transition in the differentiation of human cyto-to extravillous trophoblast View project Trophoblast invasion in Abnormally Invasive Placenta (AIP) View project CURRENT TOPIC Glucose Transporters in the Human Placenta. Placenta. 2000;21:14-22. doi:10.1053/plac.1999.0448
42. Ericsson A, Hamark B, Powell TL, Jansson T. Glucose transporter isoform 4 is expressed in the syncytiotrophoblast of first trimester human placenta. doi:10.1093/humrep/deh596
43. Cetin I, Marconi AM, Corbetta C, et al. Fetal amino acids in normal pregnancies and in pregnancies complicated by intrauterine growth retardation. Early Hum Dev. 1992;29(1-3):183-186. doi:10.1016/0378-3782(92)90136-5
44. Jansson T. Amino acid transporters in the human placenta. Pediatr Res. 2001;49(2):141-147. doi:10.1203/00006450-200102000-00003
45. Desforges M, Mynett KJ, Jones RL, et al. The SNAT4 isoform of the system A amino acid transporter is functional in human placental microvillous plasma membrane. J Physiol. 2009;587(1):61-72. doi:10.1113/jphysiol.2008.161331
46. Evain-Brion D, Malassine A. Human placenta as an endocrine organ. Growth Horm IGF Res. 2003;13(SUPPL. A):S34-S37. doi:10.1016/S1096-6374(03)00053-4
47. Zygmunt M, Herr F, Keller-Schoenwetter S, et al. Characterization of Human Chorionic Gonadotropin as a Novel Angiogenic Factor. J Clin Endocrinol Metab. 2002;87(11):5290-5296. doi:10.1210/jc.2002-020642
48. Bansal AS, Bora SA, Saso S, Smith JR, Johnson MR, Thum MY. Mechanism of human chorionic gonadotrophin-mediated immunomodulation in pregnancy. Expert Rev Clin Immunol. 2012;8(8):747-753. doi:10.1586/eci.12.77
49. Albrecht ED, Pepe GJ. Estrogen regulation of placental angiogenesis and fetal ovarian development during primate pregnancy. Int J Dev Biol. 2010;54(2-3):397-407. doi:10.1387/ijdb.082758ea
50. KLIMAN HJ, NESTLER JE, SERMASI E, SANGER JM, STRAUSS JF. Purification, Characterization, and in vitro Differentiation of Cytotrophoblasts from Human Term Placentae*. Endocrinology. 1986;118(4):1567-1582. doi:10.1210/endo-118-4-1567
51. Tarrade A, Lai Kuen R, Malassiné A, et al. Characterization of human villous and extravillous trophoblasts isolated from first trimester placenta. Lab Investig. 2001;81(9):1199-1211. doi:10.1038/labinvest.3780334
52. Sciarra JJ, Sherwood LM, Varma AA, Lundberg WB. Human placental lactogen (HPL) and placental weight. Am J Obstet Gynecol. 1968;101(3):413-416. doi:10.1016/0002-9378(68)90075-6
53. Faulk WP, Johnson PM. Immunological studies of human placentae: identification and distribution of proteins in mature chorionic villi. Clin Exp Immunol. 1977;27(2):365-375. http://www.ncbi.nlm.nih.gov/pubmed/321168. Accessed June 17, 2020.
54. Lin CT. Immunoelectron microscopy localization of immunoglobulin G in human placenta. J Histochem Cytochem. 1980;28(4):339-346. doi:10.1177/28.4.6768794
55. Ben-Hur H, Gurevich P, Berman V, Tchanyshev R, Gurevich E, Zusman I. The secretory immune system as part of the placental barrier in the second trimester of pregnancy in humans. In Vivo (Brooklyn). 2001;15(5):429-435.
56. Ben-Hur H, Gurevich P, Elhayany A, Avinoach I, Schneider DF, Zusman I. Transport of maternal immunoglobulins through the human placental barrier in normal pregnancy and during inflammation. Int J Mol Med. 2005;16(3):401-407. doi:10.3892/ijmm.16.3.401
57. Simister NE, Story CM. Human placental Fc receptors and the transmission of antibodies from mother to fetus. J Reprod Immunol. 1997;37(1):1-23. doi:10.1016/S0165-0378(97)00068-5
58. Jones CJP, Fox H. Ultrastructure of the placenta in prolonged pregnancy. J Pathol. 1978;126(3):173-179. doi:10.1002/path.1711260306
59. Calvert SJ, Longtine MS, Cotter S, et al. Studies of the dynamics of nuclear clustering in human syncytiotrophoblast. Reproduction. 2016;151(6):657-671. doi:10.1530/REP-15-0544
60. Cantle SJ, Kaufmann P, Luckhardt M, Schweikhart G. Interpretation of syncytial sprouts and bridges in the human placenta. Placenta. 1987;8(3):221-234. doi:10.1016/0143-4004(87)90046-4
61. Burton GJ, Jones CJP. Syncytial knots, sprouts, apoptosis, and trophoblast deportation from the human placenta. Taiwan J Obstet Gynecol. 2009;48(1):28-37. doi:10.1016/S1028-4559(09)60032-2
62. Fogarty NME, Ferguson-Smith AC, Burton GJ. Syncytial knots (Tenney-parker changes) in the human placenta: Evidence of loss of transcriptional activity and oxidative damage. Am J Pathol. 2013;183(1):144-152. doi:10.1016/j.ajpath.2013.03.016
63. Fox H. THE SIGNIFICANCE OF VILLOUS SYNCYTIAL KNOTS IN THE HUMAN PLACENTA. BJOG An Int J Obstet Gynaecol. 1965;72(3):347-355. doi:10.1111/j.1471-0528.1965.tb01469.x
64. Jones CJ, Fox H. Syncytial knots and intervillous bridges in the human placenta: an ultrastructural study. J Anat. 1977;124(Pt 2):275-286. http://www.ncbi.nlm.nih.gov/pubmed/591426. Accessed June 17, 2020.
65. Anat GB-J, 1986 undefined. Intervillous bridges in the mature human placenta; syncytial fusion or section artifacts.
66. Martin BJ, Spicer SS. Ultrastructural features of cellular maturation and aging in human trophoblast. J Ultrastruct Res. 1973;43(1-2):133-149. doi:10.1016/S0022-5320(73)90074-9
67. Burton GJ, Jauniaux E. Oxidative stress. Best Pract Res Clin Obstet Gynaecol. 2011;25(3):287-299. doi:10.1016/j.bpobgyn.2010.10.016
68. Lagouge M, Larsson NG. The role of mitochondrial DNA mutations and free radicals in disease and ageing. J Intern Med. 2013;273(6):529-543. doi:10.1111/joim.12055
69. Myatt L, Cui X. Oxidative stress in the placenta. Histochem Cell Biol. 2004;122(4):369-382. doi:10.1007/s00418-004-0677-x
70. Smith R, Maiti K, Aitken RJ. Unexplained antepartum stillbirth: A consequence of placental aging? Placenta. 2013;34(4):310-313. doi:10.1016/j.placenta.2013.01.015
71. Effects of Maternal Smoking on Placental Morphology - PubMed. https://pubmed.ncbi.nlm.nih.gov/14727331/. Accessed June 17, 2020.
72. Ahmed A, Perkins J. Angiogenesis and intrauterine growth restriction. Best Pract Res Clin Obstet Gynaecol. 2000;14(6):981-998. doi:10.1053/beog.2000.0139
73. Londero AP, Orsaria M, Marzinotto S, et al. Placental aging and oxidation damage in a tissue micro-array model: an immunohistochemistry study. Histochem Cell Biol. 2016;146(2):191-204. doi:10.1007/s00418-016-1435-6
74. Mizushima N. Autophagy: Process and function. Genes Dev. 2007;21(22):2861-2873. doi:10.1101/gad.1599207
75. Gong JS, Kim GJ. The role of autophagy in the placenta as a regulator of cell death. Clin Exp Reprod Med. 2014;41(3):97-107. doi:10.5653/cerm.2014.41.3.97
76. Kroemer G, Mariño G, Levine B. Autophagy and the Integrated Stress Response. Mol Cell. 2010;40(2):280-293. doi:10.1016/j.molcel.2010.09.023
77. Oh S-Y, Choi S-J, Kim KH, Cho EY, Kim J-H, Roh C-R. Autophagy-related proteins, LC3 and Beclin-1, in placentas from pregnancies complicated by preeclampsia. Reprod Sci. 2008;15(9):912-920. doi:10.1177/1933719108319159
78. Fortunato F, Bürgers H, Bergmann F, et al. Impaired Autolysosome Formation Correlates With Lamp-2 Depletion: Role of Apoptosis, Autophagy, and Necrosis in Pancreatitis. Gastroenterology. 2009;137(1):350-360.e5. doi:10.1053/j.gastro.2009.04.003
79. Curtis S, Jones CJP, Garrod A, Hulme CH, Heazell AEP. Identification of autophagic vacuoles and regulators of autophagy in villous trophoblast from normal term pregnancies and in fetal growth restriction. J Matern Neonatal Med. 2013;26(4):339-346. doi:10.3109/14767058.2012.733764
80. Korolchuk VI, Saiki S, Lichtenberg M, et al. Lysosomal positioning coordinates cellular nutrient responses. Nat Cell Biol. 2011;13(4):453-462. doi:10.1038/ncb2204
81. Hung TH, Hsieh TT an., Chen SF, Li MJ, Yeh YL. Autophagy in the human placenta throughout gestation. PLoS One. 2013;8(12). doi:10.1371/journal.pone.0083475
82. Boland B, Kumar A, Lee S, et al. Autophagy induction and autophagosome clearance in neurons: Relationship to autophagic pathology in Alzheimer’s disease. J Neurosci. 2008;28(27):6926-6937. doi:10.1523/JNEUROSCI.0800-08.2008
83. Tanaka Y, Guhde G, Suter A, et al. Accumulation of autophagic vacuoles and cardiomyopathy LAMP-2-deficient mice. Nature. 2000;406(6798):902-906. doi:10.1038/35022595
84. Fedarko NS. The Biology of Aging and Frailty. Clin Geriatr Med. 2011;27(1):27-37. doi:10.1016/j.cger.2010.08.006
85. Burton DGA. Cellular senescence, ageing and disease. Age (Omaha). 2009;31(1):1-9. doi:10.1007/s11357-008-9075-y
86. Van Deursen JM. The role of senescent cells in ageing. Nature. 2014;509(7501):439-446. doi:10.1038/nature13193
87. Raffetto JD, Leverkus M, Park HY, Menzoian JO. Synopsis on cellular senescence and apoptosis. J Vasc Surg Off Publ Soc Vasc Surg [and] Int Soc Cardiovasc Surgery, North Am Chapter. 2001;34(1):173-177. doi:10.1067/mva.2001.115964
88. Sultana Z, Maiti K, Dedman L, Smith R. Is there a role for placental senescence in the genesis of obstetric complications and fetal growth restriction? Am J Obstet Gynecol. 2018;218(2):S762-S773. doi:10.1016/j.ajog.2017.11.567
89. Chuprin A, Gal H, Biron-Shental T, et al. Cell fusion induced by ERVWE1 or measles virus causes cellular senescence. Genes Dev. 2013;27(21):2356-2366. doi:10.1101/gad.227512.113
90. Cindrova-Davies T, Fogarty NME, Jones CJP, Kingdom J, Burton GJ. Evidence of oxidative stress-induced senescence in mature, post-mature and pathological human placentas. Placenta. 2018;68:15-22. doi:10.1016/j.placenta.2018.06.307
91. Torricelli M, Novembri R, Conti N, De Falco G, De Bonis M, Petraglia F. Correlation with placental kisspeptin in postterm pregnancy and apoptosis. Reprod Sci. 2012;19(10):1133-1137. doi:10.1177/1933719112443878
92. Moyzis RK, Buckingham JM, Cram LS, et al. A highly conserved repetitive DNA sequence, (TTAGGG)(n), present at the telomeres of human chromosomes. Proc Natl Acad Sci U S A. 1988;85(18):6622-6626. doi:10.1073/pnas.85.18.6622
93. Fagagna F d’Adda di, Reaper PM, Clay-Farrace L, et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature. 2003;426(6963):194-198. doi:10.1038/nature02118
94. De Lange T. How telomeres solve the end-protection problem. Science (80- ). 2009;326(5955):948-952. doi:10.1126/science.1170633
95. Zhu Y, Liu X, Ding X, Wang F, Geng X. Telomere and its role in the aging pathways: telomere shortening, cell senescence and mitochondria dysfunction. Biogerontology. 2019;20(1). doi:10.1007/s10522-018-9769-1
96. Chen R-J, Chu C-T, Huang S-C, Chow S-N, Hsieh C-Y. Telomerase Activity in Gestational Trophoblastic Disease and Placental Tissue from Early and Late Human Pregnancies. Vol 17.; 2002.
97. Maiti K, Sultana Z, Aitken J, Smith R. The human placenta at 41 weeks of gestation shows evidence of aging with shortened telomeres, DNA oxidation and changes in IGFR2, autophagy and mTOR. Placenta. 2015;36(9):A49. doi:10.1016/j.placenta.2015.07.334
98. Kerr JFR, Wyllie AH, Currie AR. Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972;26(4):239-257. doi:10.1038/bjc.1972.33
99. Koncurat M, Merkis C, Cristofolini A, Sanchis E, Koncurat M. Expresión de los Receptores de Muerte Celular FAS/CD95 y DR4 Durante la Placentación Porcina Expression of Death Cellular Receptors FAS/CD95 and DR4 During Porcine Placentation Expresión de los Receptores de Muerte Celular FAS/CD95 y DR4 Durante la Placentación Porcina. Artic Int J Morphol. 2010;28(3):829-834. doi:10.4067/S0717-95022010000300026
100. Guenther S, Vrekoussis T, Heublein S, et al. Decidual Macrophages Are Significantly Increased in Spontaneous Miscarriages and Over-Express FasL: A Potential Role for Macrophages in Trophoblast Apoptosis. Int J Mol Sci. 2012;13(7):9069-9080. doi:10.3390/ijms13079069
101. Shang W, Shu MM, Liu M, et al. Elevated expressions of p53, CDKNA1, and Bax in placental villi from patients with recurrent spontaneous abortion. European Review for Medical and Pharmacological Sciences. 2013 Dec;17(24):3376-3380.
102. Smith SC, Baker PN. Placental apoptosis is increased in post-term pregnancies. BJOG An Int J Obstet Gynaecol. 1999;106(8):861-862. doi:10.1111/j.1471-0528.1999.tb08410.x
103. Axt R, Meyberg R, Mink D, Wasemann C, Reitnauer K, Schmidt W. Immunohistochemical detection of apoptosis in the human term and post-term placenta. Clin Exp Obstet Gynecol. 1999;26(2):56-59.
104. Adams JM, Cory S. The Bcl-2 protein family: Arbiters of cell survival. Science (80- ). 1998;281(5381):1322-1326. doi:10.1126/science.281.5381.1322
105. Kanduc D, Mittelman A, Serpico R, et al. Cell death: apoptosis versus necrosis (review). Int J Oncol. 2002;21(1):165-170. doi:10.3892/ijo.21.1.165
106. Straszewski-Chavez SL, Abrahams VM, Mor G. The role of apoptosis in the regulation of trophoblast survival and differentiation during pregnancy. Endocr Rev. 2005;26(7):877-897. doi:10.1210/er.2005-0003
107. Smith S, Krajewski S. Expression of BCL-2, BAX and BAK in the Trophoblast Layer of the Term Human Placenta: a Unique Model of Apoptosis within a Syncytium. 2000. doi:10.1053/plac.1999.0486
108. Daher S, Guimarães AJ, Mattar R, Ishigai MM, Barreiro EG, Bevilacqua E. ORIGINAL ARTICLE: Bcl-2 and Bax Expressions in Pre-Term, Term and Post-Term Placentas. Am J Reprod Immunol. 2008;60(2):172-178. doi:10.1111/j.1600-0897.2008.00609.x
109. De Falco M, De Luca L, Acanfora F, et al. Alteration of the Bcl-2: Bax ratio in the placenta as pregnancy proceeds. Histochem J. 2001;33(7):421-425. doi:10.1023/A:1013728012048