Advertisement

Journal of Assisted Reproduction and Genetics

, Volume 35, Issue 3, pp 355–366 | Cite as

Genetic and epigenetic variations associated with idiopathic recurrent pregnancy loss

  • Luis Alejandro Arias-Sosa
  • Iván Darío Acosta
  • Elkin Lucena-Quevedo
  • Harold Moreno-Ortiz
  • Clara Esteban-Pérez
  • Maribel Forero-Castro
Review
  • 471 Downloads

Abstract

Recurrent pregnancy loss (RPL) is a reproductive disorder defined as two or more successive and spontaneous pregnancy losses (before 20 weeks of gestation), which affects approximately 1–2% of couples. At present, the causes of RPL remain unknown in a considerable number of cases, leading to complications in treatment and high levels of stress in couples. Idiopathic recurrent pregnancy loss (iRPL) has become one of the more complicated reproductive problems worldwide due to the lack of information about its etiology, which limits the counseling and treatment of patients. For that reason, iRPL requires further study of novel factors to provide scientific information for determining clinical prevention and targeted strategies. The aim of this study is to describe the most recent and promising progress in the identification of potential genetic and epigenetic risk factors for iRPL, expanding the genetic etiology of the disease.

Keywords

Epigenetic Genetic Idiopathic recurrent pregnancy loss Immune tolerance Thrombophilia Tissue remodeling 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

References

  1. 1.
    Ford HB, Schust DJ. Recurrent pregnancy loss: etiology, diagnosis, and therapy. Rev Obstet Gynecol. 2009;2:76–83.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Jeve YB, Davies W. Evidence-based management of recurrent miscarriages. J Hum Reprod Sci. 2014;7:159–69.  https://doi.org/10.4103/0974-1208.142475.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Saravelos SH, Li T-C. Unexplained recurrent miscarriage: how can we explain it? Hum Reprod. 2012;27:1882–6.  https://doi.org/10.1093/humrep/des102.CrossRefPubMedGoogle Scholar
  4. 4.
    Sheth FJ, Liehr T, Kumari P, Akinde R, Sheth HJ, Sheth JJ. Chromosomal abnormalities in couples with repeated fetal loss: an Indian retrospective study. Indian J Hum Genet. 2013;19:415–22.  https://doi.org/10.4103/0971-6866.124369.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Ocak Z, Özlü T, Ozyurt O. Association of recurrent pregnancy loss with chromosomal abnormalities and hereditary thrombophilias. Afr Health Sci. 2013;13:447–52.  https://doi.org/10.4314/ahs.v13i2.35.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Asgari A, Ghahremani S, Saeedi S, Kamrani E. The study of chromosomal abnormalities and heteromorphism in couples with 2 or 3 recurrent abortions in Shahid Beheshti Hospital of Hamedan. Iran J Reprod Med. 2013;11:201–8.PubMedPubMedCentralGoogle Scholar
  7. 7.
    El-Dahtory FAM. Chromosomal abnormalities as a cause of recurrent abortions in Egypt. Indian J Hum Genet. 2011;17:82–4.  https://doi.org/10.4103/0971-6866.86186.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Marquard K, Westphal LM, Milki AA, Lathi RB. Etiology of recurrent pregnancy loss in women over the age of 35 years. Fertil Steril. 2010;94:1473–7.  https://doi.org/10.1016/j.fertnstert.2009.06.041.CrossRefPubMedGoogle Scholar
  9. 9.
    Hodes-Wertz B, Grifo J, Ghadir S, Kaplan B, Laskin CA, Glassner M, et al. Idiopathic recurrent miscarriage is caused mostly by aneuploid embryos. Fertil Steril. 2012;98:675–80.  https://doi.org/10.1016/j.fertnstert.2012.05.025.CrossRefPubMedGoogle Scholar
  10. 10.
    McCoy RC, Demko ZP, Ryan A, Banjevic M, Hill M, Sigurjonsson S, et al. Evidence of selection against complex mitotic-origin aneuploidy during preimplantation development. PLoS Genet. 2015;11:e1005601.  https://doi.org/10.1371/journal.pgen.1005601.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Bolor H, Mori T, Nishiyama S, Ito Y, Hosoba E, Inagaki H, et al. Mutations of the SYCP3 gene in women with recurrent pregnancy loss. Am J Hum Genet. 2009;84:14–20.  https://doi.org/10.1016/j.ajhg.2008.12.002.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Sazegari A, Kalantar SM, Pashaiefar H, Mohtaram S, Honarvar N, Feizollahi Z, et al. The T657C polymorphism on the SYCP3 gene is associated with recurrent pregnancy loss. J Assist Reprod Genet. 2014;31:1377–81.  https://doi.org/10.1007/s10815-014-0272-6.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Miyamoto T, Minase G, Shin T, Ueda H, Okada H, Sengoku K. Human male infertility and its genetic causes. Reprod Med Biol. 2017;16:81–8.  https://doi.org/10.1002/rmb2.12017.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Stouffs K, Vandermaelen D, Tournaye H, Liebaers I, Lissens W. Mutation analysis of three genes in patients with maturation arrest of spermatogenesis and couples with recurrent miscarriages. Reprod BioMed Online. 2011;22:65–71.  https://doi.org/10.1016/j.rbmo.2010.08.004.CrossRefPubMedGoogle Scholar
  15. 15.
    Blasco MA. Telomeres and human disease: ageing, cancer and beyond. Nat Rev Genet. 2005;6:611–22.  https://doi.org/10.1038/nrg1656.CrossRefPubMedGoogle Scholar
  16. 16.
    Thilagavathi J, Mishra SS, Kumar M, Vemprala K, Deka D, Dhadwal V, et al. Analysis of telomere length in couples experiencing idiopathic recurrent pregnancy loss. J Assist Reprod Genet. 2013;30:793–8.  https://doi.org/10.1007/s10815-013-9993-1.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Hanna CW, Bretherick KL, Gair JL, Fluker MR, Stephenson MD, Robinson WP. Telomere length and reproductive aging. Hum Reprod. 2009;24:1206–11.  https://doi.org/10.1093/humrep/dep007.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Zidi-Jrah I, Hajlaoui A, Mougou-Zerelli S, Kammoun M, Meniaoui I, Sallem A, et al. Relationship between sperm aneuploidy, sperm DNA integrity, chromatin packaging, traditional semen parameters, and recurrent pregnancy loss. Fertil Steril. 2015;105:58–64.  https://doi.org/10.1016/j.fertnstert.2015.09.041. CrossRefPubMedGoogle Scholar
  19. 19.
    Bareh GM, Jacoby E, Binkley P, Chang T-CA, Schenken RS, Robinson RD. Sperm deoxyribonucleic acid fragmentation assessment in normozoospermic male partners of couples with unexplained recurrent pregnancy loss: a prospective study. Fertil Steril. 2016;105:329–36.e1.  https://doi.org/10.1016/j.fertnstert.2015.10.033.CrossRefPubMedGoogle Scholar
  20. 20.
    Kumar K, Deka D, Singh A, Mitra DK, Vanitha BR, Dada R. Predictive value of DNA integrity analysis in idiopathic recurrent pregnancy loss following spontaneous conception. J Assist Reprod Genet. 2012;29:861–7.  https://doi.org/10.1007/s10815-012-9801-3.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Imam SN, Shamsi MB, Kumar K, Deka D, Dada R. Idiopathic recurrent pregnancy loss: role of paternal factors; a pilot study. J Reprod Infertil. 2011;12:267–76.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Ramasamy R, Scovell JM, Kovac JR, Cook PJ, Lamb DJ, Lipshultz LI. Fluorescence in situ hybridization detects increased sperm aneuploidy in men with recurrent pregnancy loss. Fertil Steril. 2015;103:906–9.e1.  https://doi.org/10.1016/j.fertnstert.2015.01.029.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Morales R, Lledó B, Ortiz JA, Ten J, Llácer J, Bernabeu R. Chromosomal polymorphic variants increase aneuploidies in male gametes and embryos. Syst Biol Reprod Med. 2016;62:317–24.  https://doi.org/10.1080/19396368.2016.1212949.CrossRefPubMedGoogle Scholar
  24. 24.
    Agarwal S, Agarwal A, Khanna A, Singh K. Microdeletion of Y chromosome as a cause of recurrent pregnancy loss. J Hum Reprod Sci. 2015;8:159–64.  https://doi.org/10.4103/0974-1208.165145.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Soleimanian S, Kalantar SM, Sheikhha MH, Zaimy MA, Rasti A, Fazli H. Association between Y-chromosome AZFc region micro-deletions with recurrent miscarriage. Iran J Reprod Med. 2013;11:431–4.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Ghorbian S, Saliminejad K, Sadeghi MR, Javadi GR, Kamali K, Amirjannati N, et al. The association between Y chromosome microdeletion and recurrent pregnancy loss. Iran Red Crescent Med J. 2012;14:358–62.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Wettasinghe TK, Jayasekara RW, Dissanayake VHW. Y chromosome microdeletions are not associated with spontaneous recurrent pregnancy loss in a Sinhalese population in Sri Lanka. Hum Reprod. 2010;25:3152–6.  https://doi.org/10.1093/humrep/deq271.CrossRefPubMedGoogle Scholar
  28. 28.
    Krieg SA, Fan X, Hong Y, Sang Q-X, Giaccia A, Westphal LM, et al. Global alteration in gene expression profiles of deciduas from women with idiopathic recurrent pregnancy loss. Mol Hum Reprod. 2012;18:442–50.  https://doi.org/10.1093/molehr/gas017.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Othman R, Omar MH, Shan LP, Shafiee MN, Jamal R, Mokhtar NM. Microarray profiling of secretory-phase endometrium from patients with recurrent miscarriage. Reprod Biol. 2012;12:183–99.  https://doi.org/10.1016/S1642-431X(12)60085-0.CrossRefPubMedGoogle Scholar
  30. 30.
    Pereza N, Ostojić S, Smirčić A, Hodžić A, Kapović M, Peterlin B. The -2549 insertion/deletion polymorphism in the promoter region of the VEGFA gene in couples with idiopathic recurrent spontaneous abortion. J Assist Reprod Genet. 2015;32  https://doi.org/10.1007/s10815-015-0593-0.
  31. 31.
    Su M-T, Lin S-H, Chen Y-C. Genetic association studies of angiogenesis- and vasoconstriction-related genes in women with recurrent pregnancy loss: a systematic review and meta-analysis. Hum Reprod Update. 2011;17:803–12.  https://doi.org/10.1093/humupd/dmr027.CrossRefPubMedGoogle Scholar
  32. 32.
    Su M-T, Lin S-H, Chen Y-C, Kuo P-L. Gene-gene interactions and gene polymorphisms of VEGFA and EG-VEGF gene systems in recurrent pregnancy loss. J Assist Reprod Genet. 2014;31:699–705.  https://doi.org/10.1007/s10815-014-0223-2.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Cao Y, Zhang Z, Wang J, Miao M, Xu J, Shen Y, et al. Association between polymorphisms of prokineticin receptor (PKR1 rs4627609 and PKR2 rs6053283) and recurrent pregnancy loss. J Zhejiang Univ Sci B. 2016;17:218–24.  https://doi.org/10.1631/jzus.B1500180.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Chen H, Yang X, Wang Z. Association between p53 Arg72Pro polymorphism and recurrent pregnancy loss: an updated systematic review and meta-analysis. Reprod BioMed Online. 2015;31:149–53.  https://doi.org/10.1016/j.rbmo.2015.05.003.CrossRefPubMedGoogle Scholar
  35. 35.
    Cao Y, Zhang Z, Xu J, Wang J, Yuan W, Shen Y, et al. Genetic association studies of endothelial nitric oxide synthase gene polymorphisms in women with unexplained recurrent pregnancy loss: a systematic and meta-analysis. Mol Biol Rep. 2014;41:3981–9.  https://doi.org/10.1007/s11033-014-3266-7.CrossRefPubMedGoogle Scholar
  36. 36.
    Pereza N, Ostojić S, Volk M, Kapović M, Peterlin B. Matrix metalloproteinases 1, 2, 3 and 9 functional single-nucleotide polymorphisms in idiopathic recurrent spontaneous abortion. Reprod BioMed Online. 2012;24:567–75.  https://doi.org/10.1016/j.rbmo.2012.01.008.CrossRefPubMedGoogle Scholar
  37. 37.
    Su M-T, Lin S-H, Chen Y-C. Association of sex hormone receptor gene polymorphisms with recurrent pregnancy loss: a systematic review and meta-analysis. Fertil Steril. 2011;96:1435–44.e1.  https://doi.org/10.1016/j.fertnstert.2011.09.030.CrossRefPubMedGoogle Scholar
  38. 38.
    Cao Y, Zhang Z, Zheng Y, Yuan W, Wang J, Liang H, et al. The association of idiopathic recurrent early pregnancy loss with polymorphisms in folic acid metabolism-related genes. Genes Nutr. 2014;9:402.  https://doi.org/10.1007/s12263-014-0402-x.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Nair RR, Khanna A, Singh K. MTHFR C677T polymorphism and recurrent early pregnancy loss risk in north Indian population. Reprod Sci. 2012;19:210–5.  https://doi.org/10.1177/1933719111417888.CrossRefPubMedGoogle Scholar
  40. 40.
    Yang Y, Luo Y, Yuan J, Tang Y, Xiong L, Xu M, et al. Association between maternal, fetal and paternal MTHFR gene C677T and A1298C polymorphisms and risk of recurrent pregnancy loss: a comprehensive evaluation. Arch Gynecol Obstet. 2015;  https://doi.org/10.1007/s00404-015-3944-2.
  41. 41.
    Wu X, Zhao L, Zhu H, He D, Tang W, Luo Y. Association between the MTHFR C677T polymorphism and recurrent pregnancy loss: a meta-analysis. Genet Test Mol Biomarkers. 2012;16:806–11.  https://doi.org/10.1089/gtmb.2011.0318.CrossRefPubMedGoogle Scholar
  42. 42.
    Chen H, Yang X, Lu M. Methylenetetrahydrofolate reductase gene polymorphisms and recurrent pregnancy loss in China: a systematic review and meta-analysis. Arch Gynecol Obstet. 2015;293:283–90.  https://doi.org/10.1007/s00404-015-3894-8.CrossRefPubMedGoogle Scholar
  43. 43.
    Cao Y, Xu J, Zhang Z, Huang X, Zhang A, Wang J, et al. Association study between methylenetetrahydrofolate reductase polymorphisms and unexplained recurrent pregnancy loss: a meta-analysis. Gene. 2013;514:105–11.  https://doi.org/10.1016/j.gene.2012.10.091.CrossRefPubMedGoogle Scholar
  44. 44.
    Udry S, Aranda FM, Latino JO, de Larrañaga GF. Paternal factor V Leiden and recurrent pregnancy loss: a new concept behind fetal genetics? J Thromb Haemost. 2014;12:666–9.CrossRefPubMedGoogle Scholar
  45. 45.
    Ozdemir O, Yenicesu GI, Silan F, Köksal B, Atik S, Ozen F, et al. Recurrent pregnancy loss and its relation to combined parental thrombophilic gene mutations. Genet Test Mol Biomarkers. 2012;16:279–86.  https://doi.org/10.1089/gtmb.2011.0191.CrossRefPubMedGoogle Scholar
  46. 46.
    Gao H, Tao F. Prothrombin G20210A mutation is associated with recurrent pregnancy loss: a systematic review and meta-analysis update. Thromb Res. 2015;135:339–46.  https://doi.org/10.1016/j.thromres.2014.12.001.CrossRefPubMedGoogle Scholar
  47. 47.
    Cao Y, Zhang Z, Xu J, Yuan W, Wang J, Huang X, et al. The association of idiopathic recurrent pregnancy loss with polymorphisms in hemostasis-related genes. Gene. 2013;530:248–52.  https://doi.org/10.1016/j.gene.2013.07.080.CrossRefPubMedGoogle Scholar
  48. 48.
    Dendana M, Messaoudi S, Hizem S, Jazia KB, Almawi WY, Gris J-C, et al. Endothelial protein C receptor 1651C/G polymorphism and soluble endothelial protein C receptor levels in women with idiopathic recurrent miscarriage. Blood Coagul Fibrinolysis. 2012;23:30–4.  https://doi.org/10.1097/MBC.0b013e328349cae5.CrossRefPubMedGoogle Scholar
  49. 49.
    Guerra-Shinohara EM, Bertinato JF, Tosin Bueno C, Cordeiro da Silva K, Burlacchini de Carvalho MH, Pulcineli Vieira Francisco R, et al. Polymorphisms in antithrombin and in tissue factor pathway inhibitor genes are associated with recurrent pregnancy loss. Thromb Haemost. 2012;108:693–700.  https://doi.org/10.1160/TH12-03-0177.CrossRefPubMedGoogle Scholar
  50. 50.
    Elmahgoub IR, Afify RA, Abdel Aal AA, El-Sherbiny WS. Prevalence of coagulation factor XIII and plasminogen activator inhibitor-1 gene polymorphisms among Egyptian women suffering from unexplained primary recurrent miscarriage. J Reprod Immunol. 2014;103:18–22.  https://doi.org/10.1016/j.jri.2014.02.007.CrossRefPubMedGoogle Scholar
  51. 51.
    Jeddi-Tehrani M, Torabi R, Mohammadzadeh A, Arefi S, Keramatipour M, Zeraati H, et al. Investigating association of three polymorphisms of coagulation factor XIII and recurrent pregnancy loss. Am J Reprod Immunol. 2010;64:212–7.  https://doi.org/10.1111/j.1600-0897.2010.00838.x.CrossRefPubMedGoogle Scholar
  52. 52.
    Patil R, Ghosh K, Vora S, Shetty S. Inherited and acquired thrombophilia in Indian women experiencing unexplained recurrent pregnancy loss. Blood Cells Mol Dis. 2015;55:200–5.  https://doi.org/10.1016/j.bcmd.2015.06.008.CrossRefPubMedGoogle Scholar
  53. 53.
    Jeon YJ, Kim YR, Lee BE, Choi YS, Kim JH, Shin JE, et al. Genetic association of five plasminogen activator inhibitor-1 (PAI-1) polymorphisms and idiopathic recurrent pregnancy loss in Korean women. Thromb Haemost. 2013;110:742–50.  https://doi.org/10.1160/TH13-03-0242.CrossRefPubMedGoogle Scholar
  54. 54.
    Salazar Garcia MD, Sung N, Mullenix TM, Dambaeva S, Beaman K, Gilman-Sachs A, et al. Plasminogen activator inhibitor-1 4G/5G polymorphism is associated with reproductive failure: metabolic, hormonal, and immune profiles. Am J Reprod Immunol. 2016;76:70–81.  https://doi.org/10.1111/aji.12516.CrossRefPubMedGoogle Scholar
  55. 55.
    Shakarami F, Akbari MT, Zare Karizi S. Association of plasminogen activator inhibitor-1 and angiotensin converting enzyme polymorphisms with recurrent pregnancy loss in Iranian women. Iran J Reprod Med. 2015;13:627–32.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Fazelnia S, Farazmandfar T, Hashemi-Soteh SMB. Significant correlation of angiotensin converting enzyme and glycoprotein IIIa genes polymorphisms with unexplained recurrent pregnancy loss in north of Iran. Int J Reprod Biomed (Yazd, Iran). 2016;14:323–8.CrossRefGoogle Scholar
  57. 57.
    Su M-T, Lin S-H, Chen Y-C, Kuo P-L. Genetic association studies of ACE and PAI-1 genes in women with recurrent pregnancy loss. Thromb Haemost. 2012;109:8–15.  https://doi.org/10.1160/TH12-08-0584.CrossRefPubMedGoogle Scholar
  58. 58.
    Kim JO, Lee WS, Lee BE, Jeon YJ, Kim YR, Jung SH, et al. Interleukin-1beta -511T>C genetic variant contributes to recurrent pregnancy loss risk and peripheral natural killer cell proportion. Fertil Steril. 2014;102:206–12.e5.  https://doi.org/10.1016/j.fertnstert.2014.03.037.CrossRefPubMedGoogle Scholar
  59. 59.
    Zidan HE, Rezk NA, Alnemr AAA, Moniem MIA. Interleukin-17 and leptin genes polymorphisms and their levels in relation to recurrent pregnancy loss in Egyptian females. Immunogenetics. 2015;67:665–73.  https://doi.org/10.1007/s00251-015-0876-8.CrossRefPubMedGoogle Scholar
  60. 60.
    Chen H, Yang X, Du J, Lu M. Interleukin-18 gene polymorphisms and risk of recurrent pregnancy loss: a systematic review and meta-analysis. J Obstet Gynaecol Res. 2015;41:1506–13.  https://doi.org/10.1111/jog.12800.CrossRefPubMedGoogle Scholar
  61. 61.
    Qaddourah RH, Magdoud K, Saldanha FL, Mahmood N, Mustafa FE, Mahjoub T, et al. IL-10 gene promoter and intron polymorphisms and changes in IL-10 secretion in women with idiopathic recurrent miscarriage. Hum Reprod. 2014;29:1025–34.  https://doi.org/10.1093/humrep/deu043.CrossRefPubMedGoogle Scholar
  62. 62.
    Bohiltea LC, Radoi EV. Interleukin-6 and interleukin-10 gene polymorphisms and recurrent pregnancy loss in Romanian population. Iran J Reprod Med. 2014;12:617–22.Google Scholar
  63. 63.
    Rasti Z, Nasiri M, Kohan L. The IL-6-634C/G polymorphism: a candidate genetic marker for the prediction of idiopathic recurrent pregnancy loss. Int J Reprod Biomed (Yazd, Iran). 2016;14:103–8.CrossRefGoogle Scholar
  64. 64.
    Magdoud K, Granados Herbepin V, Messaoudi S, Hizem S, Bouafia N, Almawi WY, et al. Genetic variation in TGFB1 gene and risk of idiopathic recurrent pregnancy loss. Mol Hum Reprod. 2013;19:438–43.  https://doi.org/10.1093/molehr/gat012.CrossRefPubMedGoogle Scholar
  65. 65.
    Jang HG, Choi Y, Kim JO, Jeon YJ, Rah H, Cho SH, et al. Polymorphisms in tumor necrosis factor-alpha (-863C>A, -857C>T and +488G>A) are associated with idiopathic recurrent pregnancy loss in Korean women. Hum Immunol. 2016;77:506–11.  https://doi.org/10.1016/j.humimm.2016.04.012.CrossRefPubMedGoogle Scholar
  66. 66.
    Nasiri M, Rasti Z. CTLA-4 and IL-6 gene polymorphisms: risk factors for recurrent pregnancy loss. Hum Immunol. 2016;  https://doi.org/10.1016/j.humimm.2016.07.236.
  67. 67.
    Saxena D, Misra MK, Parveen F, Phadke SR, Agrawal S. The transcription factor Forkhead Box P3 gene variants affect idiopathic recurrent pregnancy loss. Placenta. 2015;36:226–31.  https://doi.org/10.1016/j.placenta.2014.11.014.CrossRefPubMedGoogle Scholar
  68. 68.
    Dendana M, Hizem S, Magddoud K, Messaoudi S, Zammiti W, Nouira M, et al. Common polymorphisms in the P-selectin gene in women with recurrent spontaneous abortions. Gene. 2012;495:72–5.  https://doi.org/10.1016/j.gene.2011.11.034.CrossRefPubMedGoogle Scholar
  69. 69.
    Jung YW, Jeon YJ, Rah H, Kim JH, Shin JE, Choi DH, et al. Genetic variants in microRNA machinery genes are associated [corrected] with idiopathic recurrent pregnancy loss risk. PLoS One. 2014;9:e95803.  https://doi.org/10.1371/journal.pone.0095803.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Hu Y, Liu C-M, Qi L, He T-Z, Shi-Guo L, Hao C-J, et al. Two common SNPs in pri-miR-125a alter the mature miRNA expression and associate with recurrent pregnancy loss in a Han-Chinese population. RNA Biol. 2011;8:861–72.  https://doi.org/10.4161/rna.8.5.16034.CrossRefPubMedGoogle Scholar
  71. 71.
    Hu Y, Huo Z-H, Liu C-M, Liu S-G, Zhang N, Yin K-L, et al. Functional study of one nucleotide mutation in pri-miR-125a coding region which related to recurrent pregnancy loss. PLoS One. 2014;9:e114781.  https://doi.org/10.1371/journal.pone.0114781.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Su X, Hu Y, Li Y, Cao J-L, Wang X-Q, Ma X, et al. The polymorphism of rs6505162 in the MIR423 coding region and recurrent pregnancy loss. Reproduction. 2015;150:65–76.  https://doi.org/10.1530/REP-15-0007.CrossRefPubMedGoogle Scholar
  73. 73.
    Rah H, Chung KW, Ko KH, Kim ES, Kim JO, Sakong JH, et al. miR-27a and miR-449b polymorphisms associated with a risk of idiopathic recurrent pregnancy loss. PLoS One. 2017;12:e0177160.  https://doi.org/10.1371/journal.pone.0177160.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Banerjee P, Ghosh S, Dutta M, Subramani E, Khalpada J, Roychoudhury S, et al. Identification of key contributory factors responsible for vascular dysfunction in idiopathic recurrent spontaneous miscarriage. PLoS One. 2013;8:e80940.  https://doi.org/10.1371/journal.pone.0080940.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Gonçalves RO, Fraga LR, Santos WVB, Carvalho AFL, Veloso Cerqueira BAV, Sarno M, et al. Association between the thrombophilic polymorphisms MTHFR C677T, Factor V Leiden, and prothrombin G20210A and recurrent miscarriage in Brazilian women. Genet Mol Res. 2016;15  https://doi.org/10.4238/gmr.15038156.
  76. 76.
    Comba C, Bastu E, Dural O, Yasa C, Keskin G, Ozsurmeli M, et al. Role of inflammatory mediators in patients with recurrent pregnancy loss. Fertil Steril. 2015;104:1467–74.e1.  https://doi.org/10.1016/j.fertnstert.2015.08.011.CrossRefPubMedGoogle Scholar
  77. 77.
    Lee SK, Kim JY, Hur SE, Kim CJ, Na BJ, Lee M, et al. An imbalance in interleukin-17-producing T and Foxp3+ regulatory T cells in women with idiopathic recurrent pregnancy loss. Hum Reprod. 2011;26:2964–71.  https://doi.org/10.1093/humrep/der301.CrossRefPubMedGoogle Scholar
  78. 78.
    Rull K, Nagirnaja L, Laan M. Genetics of recurrent miscarriage: challenges, current knowledge, future directions. Front Genet. 2012;3:34.  https://doi.org/10.3389/fgene.2012.00034.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Lyon MF. Sex chromatin and gene action in the mammalian X-chromosome. Am J Hum Genet. 1962;14:135–48.PubMedPubMedCentralGoogle Scholar
  80. 80.
    Busque L, Paquette Y, Provost S, Roy D-C, Levine RL, Mollica L, et al. Skewing of X-inactivation ratios in blood cells of aging women is confirmed by independent methodologies. Blood. 2009;113:3472–4.  https://doi.org/10.1182/blood-2008-12-195677.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Minks J, Robinson WP, Brown CJ. A skewed view of X chromosome inactivation. J Clin Invest. 2008;118:20–3.  https://doi.org/10.1172/JCI34470.CrossRefPubMedGoogle Scholar
  82. 82.
    Kurzawińska G, Barlik M, Drews K, Różycka A, Seremak-Mrozikiewicz A, Ożarowski M, et al. Coexistence of ACE (I/D) and PAI-1 (4G/5G) gene variants in recurrent miscarriage in Polish population. Ginekol Pol. 2016;87:271–6.  https://doi.org/10.17772/gp/62203.CrossRefPubMedGoogle Scholar
  83. 83.
    Mosaad YM, Abdel-Dayem Y, El-Deek BS, El-Sherbini SM. Association between HLA-E *0101 homozygosity and recurrent miscarriage in Egyptian women. Scand J Immunol. 2011;74:205–9.  https://doi.org/10.1111/j.1365-3083.2011.02559.x.CrossRefPubMedGoogle Scholar
  84. 84.
    Sui Y, Chen Q, Sun X. Association of skewed X chromosome inactivation and idiopathic recurrent spontaneous abortion: a systematic review and meta-analysis. Reprod BioMed Online. 2015;31:140–8.  https://doi.org/10.1016/j.rbmo.2015.05.007.CrossRefPubMedGoogle Scholar
  85. 85.
    Bock C, Beerman I, Lien W-H, Smith ZD, Gu H, Boyle P, et al. DNA methylation dynamics during in vivo differentiation of blood and skin stem cells. Mol Cell. 2012;47:633–47.  https://doi.org/10.1016/j.molcel.2012.06.019.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Hanna CW, McFadden DE, Robinson WP. DNA methylation profiling of placental villi from karyotypically normal miscarriage and recurrent miscarriage. Am J Pathol. 2013;182:2276–84.  https://doi.org/10.1016/j.ajpath.2013.02.021.CrossRefPubMedGoogle Scholar
  87. 87.
    Zhu Y, Lu H, Huo Z, Ma Z, Dang J, Dang W, et al. MicroRNA-16 inhibits feto-maternal angiogenesis and causes recurrent spontaneous abortion by targeting vascular endothelial growth factor. Sci Rep. 2016;6:35536.  https://doi.org/10.1038/srep35536.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Wang L, Tang H, Xiong Y, Tang L. Differential expression profile of long noncoding RNAs in human chorionic villi of early recurrent miscarriage. Clin Chim Acta. 2017;464:17–23.  https://doi.org/10.1016/j.cca.2016.11.001.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Luis Alejandro Arias-Sosa
    • 1
  • Iván Darío Acosta
    • 1
  • Elkin Lucena-Quevedo
    • 2
  • Harold Moreno-Ortiz
    • 2
  • Clara Esteban-Pérez
    • 2
  • Maribel Forero-Castro
    • 1
  1. 1.School of Biological ScienceUniversidad Pedagógica y Tecnológica de ColombiaTunjaColombia
  2. 2.Department of Reproductive Genetic, Fertility and Sterility Colombian Center (CECOLFES)BogotáColombia

Personalised recommendations