Skip to main content
SpringerLink
Log in

Preimplantation Genetic Testing for Aneuploidies (PGT-A) in Recurrent Miscarriage

  • Chapter
  • First Online:
Textbook of Assisted Reproduction

  • 1308 Accesses

Abstract

Recurrent miscarriage (RM) is an important issue in the field of reproductive medicine. It has been estimated that it affects 2–5% of the women trying to conceive. From a clinical perspective, few cases of RM are caused by a single cause; most of them may in fact have a multifactorial background which involves the interaction of multiple genetic and environmental parameters. Indeed, if the fertility rate decreases as the woman ages, the miscarriage rate follows an opposite trend. RM is one of the suggested indications to preimplantation genetic testing for aneuploidies (PGT-A). PGT-A is a comprehensive chromosome testing approach aimed at identifying chromosomally normal embryos within a cohort of blastocysts produced by a couple during an IVF treatment. This embryo selection strategy prevents aneuploid blastocysts from being transferred, thus reducing both the risk for implantation failure per transfer and miscarriage due to chromosomal impairments. However, some limitations to PGT exist, data about its clinical efficacy per intention to treat and cost-effectiveness are yet missing, and a clear international consensus has not been reached yet.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 139.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. El Hachem H, Crepaux V, May-Panloup P, Descamps P, Legendre G, Bouet PE. Recurrent pregnancy loss: current perspectives. Int J Women's Health. 2017;9:331–45.

    Article  Google Scholar 

  2. Zegers-Hochschild F, Adamson GD, de Mouzon J, Ishihara O, Mansour R, Nygren K, et al. International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) revised glossary of ART terminology, 2009. Fertil Steril. 2009;92:1520–4.

    Article  CAS  PubMed  Google Scholar 

  3. Kolte AM, Bernardi LA, Christiansen OB, Quenby S, Farquharson RG, Goddijn M, et al. Terminology for pregnancy loss prior to viability: a consensus statement from the ESHRE early pregnancy special interest group. Hum Reprod. 2015;30:495–8.

    Article  CAS  PubMed  Google Scholar 

  4. Jauniaux E, Farquharson RG, Christiansen OB, Exalto N. Evidence-based guidelines for the investigation and medical treatment of recurrent miscarriage. Hum Reprod. 2006;21:2216–22.

    Article  PubMed  Google Scholar 

  5. Practice Committee of the American Society for Reproductive M. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril. 2012;98:1103–11.

    Article  Google Scholar 

  6. Lenton EA, Hooper M, King H, Kumar A, Monks N, Verma S, et al. Normal and abnormal implantation in spontaneous in-vivo and in-vitro human pregnancies. J Reprod Fertil. 1991;92:555–65.

    Article  CAS  PubMed  Google Scholar 

  7. Heffner LJ. Advanced maternal age - how old is too old? N Engl J Med. 2004;351:1927–9.

    Article  CAS  PubMed  Google Scholar 

  8. Nybo Andersen AM, Wohlfahrt J, Christens P, Olsen J, Melbye M. Maternal age and fetal loss: population based register linkage study. BMJ. 2000;320:1708–12.

    Article  CAS  PubMed  Google Scholar 

  9. Hassold T, Hunt P. To err (meiotically) is human: the genesis of human aneuploidy. Nat Rev Genet. 2001;2:280–91.

    Article  CAS  PubMed  Google Scholar 

  10. Nagaoka SI, Hassold TJ, Hunt PA. Human aneuploidy: mechanisms and new insights into an age-old problem. Nat Rev Genet. 2012;13:493–504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kutteh WH. Novel strategies for the management of recurrent pregnancy loss. Semin Reprod Med. 2015;33:161–8.

    Article  PubMed  Google Scholar 

  12. Chen H, Fu J, Huang W. Dopamine agonists for preventing future miscarriage in women with idiopathic hyperprolactinemia and recurrent miscarriage history. Cochrane Database Syst Rev. 2016;7:CD008883.

    PubMed  Google Scholar 

  13. De Carolis C, Greco E, Guarino MD, Perricone C, Dal Lago A, Giacomelli R, et al. Anti-thyroid antibodies and antiphospholipid syndrome: evidence of reduced fecundity and of poor pregnancy outcome in recurrent spontaneous aborters. Am J Reprod Immunol. 2004;52:263–6.

    Article  PubMed  Google Scholar 

  14. Opatrny L, David M, Kahn SR, Shrier I, Rey E. Association between antiphospholipid antibodies and recurrent fetal loss in women without autoimmune disease: a metaanalysis. J Rheumatol. 2006;33:2214–21.

    CAS  PubMed  Google Scholar 

  15. Rey E, Kahn SR, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet. 2003;361:901–8.

    Article  PubMed  Google Scholar 

  16. de Jong PG, Kaandorp S, Di Nisio M, Goddijn M, Middeldorp S. Aspirin and/or heparin for women with unexplained recurrent miscarriage with or without inherited thrombophilia. Cochrane Database Syst Rev. 2014:CD004734.

    Google Scholar 

  17. Sugiura-Ogasawara M, Ozaki Y, Katano K, Suzumori N, Mizutani E. Uterine anomaly and recurrent pregnancy loss. Semin Reprod Med. 2011;29:514–21.

    Article  PubMed  Google Scholar 

  18. Hassold T, Hall H, Hunt P. The origin of human aneuploidy: where we have been, where we are going. Hum Mol Genet. 2007;16(2):R203–8.

    Article  CAS  PubMed  Google Scholar 

  19. Franasiak JM, Forman EJ, Hong KH, Werner MD, Upham KM, Treff NR, et al. The nature of aneuploidy with increasing age of the female partner: a review of 15,169 consecutive trophectoderm biopsies evaluated with comprehensive chromosomal screening. Fertil Steril. 2014;101:656–63.

    Article  PubMed  Google Scholar 

  20. Capalbo A, Rienzi L, Cimadomo D, Maggiulli R, Elliott T, Wright G, et al. Correlation between standard blastocyst morphology, euploidy and implantation: an observational study in two centers involving 956 screened blastocysts. Hum Reprod. 2014;29:1173–81.

    Article  PubMed  Google Scholar 

  21. Rienzi L, Capalbo A, Stoppa M, Romano S, Maggiulli R, Albricci L, et al. No evidence of association between blastocyst aneuploidy and morphokinetic assessment in a selected population of poor-prognosis patients: a longitudinal cohort study. Reprod Biomed Online. 2015;30:57–66.

    Article  CAS  PubMed  Google Scholar 

  22. Sugiura-Ogasawara M, Ozaki Y, Katano K, Suzumori N, Kitaori T, Mizutani E. Abnormal embryonic karyotype is the most frequent cause of recurrent miscarriage. Hum Reprod. 2012;27:2297–303.

    Article  PubMed  Google Scholar 

  23. Werner M, Reh A, Grifo J, Perle MA. Characteristics of chromosomal abnormalities diagnosed after spontaneous abortions in an infertile population. J Assist Reprod Genet. 2012;29:817–20.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Ottolini CS, Newnham LJ, Capalbo A, Natesan SA, Joshi HA, Cimadomo D, et al. Genome-wide maps of recombination and chromosome segregation in human oocytes and embryos show selection for maternal recombination rates. Nat Genet. 2015;47:727–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Capalbo A, Bono S, Spizzichino L, Biricik A, Baldi M, Colamaria S, et al. Sequential comprehensive chromosome analysis on polar bodies, blastomeres and trophoblast: insights into female meiotic errors and chromosomal segregation in the preimplantation window of embryo development. Hum Reprod. 2013;28:509–18.

    Article  CAS  PubMed  Google Scholar 

  26. Handyside AH, Montag M, Magli MC, Repping S, Harper J, Schmutzler A, et al. Multiple meiotic errors caused by predivision of chromatids in women of advanced maternal age undergoing in vitro fertilisation. Eur J Hum Genet. 2012;20:742–7.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Turner JM. Meiotic silencing in mammals. Annu Rev Genet. 2015;49:395–412.

    Article  CAS  PubMed  Google Scholar 

  28. Forabosco A, Percesepe A, Santucci S. Incidence of non-age-dependent chromosomal abnormalities: a population-based study on 88965 amniocenteses. Eur J Hum Genet. 2009;17:897–903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Franssen MT, Korevaar JC, Leschot NJ, Bossuyt PM, Knegt AC, Gerssen-Schoorl KB, et al. Selective chromosome analysis in couples with two or more miscarriages: case-control study. BMJ. 2005;331:137–41.

    Article  PubMed  PubMed Central  Google Scholar 

  30. De Braekeleer M, Dao TN. Cytogenetic studies in couples experiencing repeated pregnancy losses. Hum Reprod. 1990;5:519–28.

    Article  PubMed  Google Scholar 

  31. Kurahashi H, Tsutsumi M, Nishiyama S, Kogo H, Inagaki H, Ohye T. Molecular basis of maternal age-related increase in oocyte aneuploidy. Congenit Anom (Kyoto). 2012;52:8–15.

    Article  CAS  Google Scholar 

  32. Ottolini CS, Capalbo A, Newnham L, Cimadomo D, Natesan SA, Hoffmann ER, et al. Generation of meiomaps of genome-wide recombination and chromosome segregation in human oocytes. Nat Protoc. 2016;11:1229–43.

    Article  CAS  PubMed  Google Scholar 

  33. Wang Y, Cheng Q, Meng L, Luo C, Hu H, Zhang J, et al. Clinical application of SNP array analysis in first-trimester pregnancy loss: a prospective study. Clin Genet. 2016;91(6):849–58.

    Article  PubMed  CAS  Google Scholar 

  34. Levy B, Sigurjonsson S, Pettersen B, Maisenbacher MK, Hall MP, Demko Z, et al. Genomic imbalance in products of conception: single-nucleotide polymorphism chromosomal microarray analysis. Obstet Gynecol. 2014;124:202–9.

    Article  CAS  PubMed  Google Scholar 

  35. Kort DH, Chia G, Treff NR, Tanaka AJ, Xing T, Vensand LB, et al. Human embryos commonly form abnormal nuclei during development: a mechanism of DNA damage, embryonic aneuploidy, and developmental arrest. Hum Reprod. 2016;31:312–23.

    CAS  PubMed  Google Scholar 

  36. Vega M, Breborowicz A, Moshier EL, McGovern PG, Keltz MD. Blastulation rates decline in a linear fashion from euploid to aneuploid embryos with single versus multiple chromosomal errors. Fertil Steril. 2014;102:394–8.

    Article  PubMed  Google Scholar 

  37. Wapner RJ, Martin CL, Levy B, Ballif BC, Eng CM, Zachary JM, et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med. 2012;367:2175–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Huang A, Adusumalli J, Patel S, Liem J, Williams J 3rd, Pisarska MD. Prevalence of chromosomal mosaicism in pregnancies from couples with infertility. Fertil Steril. 2009;91:2355–60.

    Article  PubMed  Google Scholar 

  39. Gueye NA, Devkota B, Taylor D, Pfundt R, Scott RT Jr, Treff NR. Uniparental disomy in the human blastocyst is exceedingly rare. Fertil Steril. 2014;101:232–6.

    Article  PubMed  Google Scholar 

  40. Vermeesch JR, Voet T, Devriendt K. Prenatal and pre-implantation genetic diagnosis. Nat Rev Genet. 2016;17:643–56.

    Article  CAS  PubMed  Google Scholar 

  41. Dahdouh EM, Balayla J, Garcia-Velasco JA. Comprehensive chromosome screening improves embryo selection: a meta-analysis. Fertil Steril. 2015;104:1503–12.

    Article  PubMed  Google Scholar 

  42. Chen M, Wei S, Hu J, Quan S. Can comprehensive chromosome screening technology improve IVF/ICSI outcomes? A meta-analysis. PLoS One. 2015;10:e0140779.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Vaiarelli A, Cimadomo D, Capalbo A, Orlando G, Sapienza F, Colamaria S, et al. Pre-implantation genetic testing in ART: who will benefit and what is the evidence? J Assist Reprod Genet. 2016;33:1273–8.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Mastenbroek S, Twisk M, van der Veen F, Repping S. Preimplantation genetic screening: a systematic review and meta-analysis of RCTs. Hum Reprod Update. 2011;17:454–66.

    Article  CAS  PubMed  Google Scholar 

  45. Scott RT Jr, Upham KM, Forman EJ, Zhao T, Treff NR. Cleavage-stage biopsy significantly impairs human embryonic implantation potential while blastocyst biopsy does not: a randomized and paired clinical trial. Fertil Steril. 2013;100:624–30.

    Article  PubMed  Google Scholar 

  46. Cimadomo D, Capalbo A, Ubaldi FM, Scarica C, Palagiano A, Canipari R, et al. The impact of biopsy on human embryo developmental potential during preimplantation genetic diagnosis. Biomed Res Int. 2016;2016:7193075.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Scott RT Jr, Ferry K, Su J, Tao X, Scott K, Treff NR. Comprehensive chromosome screening is highly predictive of the reproductive potential of human embryos: a prospective, blinded, nonselection study. Fertil Steril. 2012;97:870–5.

    Article  PubMed  Google Scholar 

  48. Ubaldi FM, Capalbo A, Colamaria S, Ferrero S, Maggiulli R, Vajta G, et al. Reduction of multiple pregnancies in the advanced maternal age population after implementation of an elective single embryo transfer policy coupled with enhanced embryo selection: pre- and post-intervention study. Hum Reprod. 2015;30:2097–106.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Forman EJ, Hong KH, Ferry KM, Tao X, Taylor D, Levy B, et al. In vitro fertilization with single euploid blastocyst transfer: a randomized controlled trial. Fertil Steril. 2013;100:100–7.

    Article  PubMed  Google Scholar 

  50. Forman EJ, Hong KH, Franasiak JM, Scott RT Jr. Obstetrical and neonatal outcomes from the BEST Trial: single embryo transfer with aneuploidy screening improves outcomes after in vitro fertilization without compromising delivery rates. Am J Obstet Gynecol. 2014;210:157.e1–6.

    Article  Google Scholar 

  51. Murugappan G, Shahine LK, Perfetto CO, Hickok LR, Lathi RB. Intent to treat analysis of in vitro fertilization and preimplantation genetic screening versus expectant management in patients with recurrent pregnancy loss. Hum Reprod. 2016;31:1668–74.

    Article  PubMed  Google Scholar 

  52. Rienzi L, Capalbo A, Vajta G, Ubaldi FM. PGS for recurrent pregnancy loss: still an open question. Hum Reprod. 2017;32:476–7.

    Article  PubMed  Google Scholar 

  53. Werner MD, Leondires MP, Schoolcraft WB, Miller BT, Copperman AB, Robins ED, et al. Clinically recognizable error rate after the transfer of comprehensive chromosomal screened euploid embryos is low. Fertil Steril. 2014;102:1613–8.

    Article  PubMed  Google Scholar 

  54. Tiegs AW, Hodes-Wertz B, McCulloh DH, Munne S, Grifo JA. Discrepant diagnosis rate of array comparative genomic hybridization in thawed euploid blastocysts. J Assist Reprod Genet. 2016;33:893–7.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Capalbo A, Rienzi L. Mosaicism between trophectoderm and inner cell mass. Fertil Steril. 2017;107:1098–106.

    Article  PubMed  Google Scholar 

  56. Capalbo A, Ubaldi FM, Rienzi L, Scott R, Treff N. Detecting mosaicism in trophectoderm biopsies: current challenges and future possibilities. Hum Reprod. 2016;32(3):492–8.

    PubMed Central  Google Scholar 

  57. Greco E, Minasi MG, Fiorentino F. Healthy babies after intrauterine transfer of mosaic aneuploid blastocysts. N Engl J Med. 2015;373:2089–90.

    Article  PubMed  Google Scholar 

  58. Capalbo A, Treff NR, Cimadomo D, Tao X, Upham K, Ubaldi FM, et al. Comparison of array comparative genomic hybridization and quantitative real-time PCR-based aneuploidy screening of blastocyst biopsies. Eur J Hum Genet. 2015;23:901–6.

    Article  CAS  PubMed  Google Scholar 

  59. Gawad C, Koh W, Quake SR. Single-cell genome sequencing: current state of the science. Nat Rev Genet. 2016;17:175–88.

    Article  CAS  PubMed  Google Scholar 

  60. Hunter JE, Allen EG, Shin M, Bean LJ, Correa A, Druschel C, et al. The association of low socioeconomic status and the risk of having a child with Down syndrome: a report from the national Down syndrome project. Genet Med. 2013;15:698–705.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Wu LL, Russell DL, Wong SL, Chen M, Tsai TS, St John JC, et al. Mitochondrial dysfunction in oocytes of obese mothers: transmission to offspring and reversal by pharmacological endoplasmic reticulum stress inhibitors. Development. 2015;142:681–91.

    Article  CAS  PubMed  Google Scholar 

  62. Caburet S, Arboleda VA, Llano E, Overbeek PA, Barbero JL, Oka K, et al. Mutant cohesin in premature ovarian failure. N Engl J Med. 2014;370:943–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Hopkins J, Hwang G, Jacob J, Sapp N, Bedigian R, Oka K, et al. Meiosis-specific cohesin component, Stag3 is essential for maintaining centromere chromatid cohesion, and required for DNA repair and synapsis between homologous chromosomes. PLoS Genet. 2014;10:e1004413.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Jiang J, Jing Y, Cost GJ, Chiang JC, Kolpa HJ, Cotton AM, et al. Translating dosage compensation to trisomy 21. Nature. 2013;500:296–300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Amano T, Jeffries E, Amano M, Ko AC, Yu H, Ko MS. Correction of Down syndrome and Edwards syndrome aneuploidies in human cell cultures. DNA Res. 2015;22:331–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Larsen EC, Christiansen OB, Kolte AM, Macklon N. New insights into mechanisms behind miscarriage. BMC Med. 2013;11:154.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Weimar CH, Macklon NS, Post Uiterweer ED, Brosens JJ, Gellersen B. The motile and invasive capacity of human endometrial stromal cells: implications for normal and impaired reproductive function. Hum Reprod Update. 2013;19:542–57.

    Article  CAS  PubMed  Google Scholar 

  68. Weimar CH, Post Uiterweer ED, Teklenburg G, Heijnen CJ, Macklon NS. In-vitro model systems for the study of human embryo-endometrium interactions. Reprod Biomed Online. 2013;27:461–76.

    Article  CAS  PubMed  Google Scholar 

  69. Diaz-Gimeno P, Ruiz-Alonso M, Blesa D, Bosch N, Martinez-Conejero JA, Alama P, et al. The accuracy and reproducibility of the endometrial receptivity array is superior to histology as a diagnostic method for endometrial receptivity. Fertil Steril. 2013;99:508–17.

    Article  PubMed  Google Scholar 

  70. Ruiz-Alonso M, Blesa D, Diaz-Gimeno P, Gomez E, Fernandez-Sanchez M, Carranza F, et al. The endometrial receptivity array for diagnosis and personalized embryo transfer as a treatment for patients with repeated implantation failure. Fertil Steril. 2013;100:818–24.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. GENERA, Center for Reproductive Medicine, Valle Giulia Clinic, Rome, Italy

    A. Vaiarelli, D. Cimadomo, L. Rienzi & F. M. Ubaldi

Authors
  1. A. Vaiarelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. Cimadomo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L. Rienzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. F. M. Ubaldi
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Consultant Reproductive Endocrinology & IVF Millennium Medical Center MMC IVF, Dubai Health Care City, Dubai, United Arab Emirates

    Gautam Nand Allahbadia

  2. Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Koç University School of Medicine, Istanbul, Turkey

    Baris Ata

  3. Department of Obstetrics and Gynecology, Wright State University, Boonshoft School of Medicine, Dayton, OH, USA

    Steven R. Lindheim

  4. X&Y Fertility, Leicester, UK

    Bryan J. Woodward

  5. School of Medicine and Dentistry, University of Rochester Medical Center, Newyork, USA

    Bala Bhagavath

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Vaiarelli, A., Cimadomo, D., Rienzi, L., Ubaldi, F.M. (2020). Preimplantation Genetic Testing for Aneuploidies (PGT-A) in Recurrent Miscarriage. In: Allahbadia, G.N., Ata, B., Lindheim, S.R., Woodward, B.J., Bhagavath, B. (eds) Textbook of Assisted Reproduction. Springer, Singapore. https://doi.org/10.1007/978-981-15-2377-9_73

Download citation

  • DOI: https://doi.org/10.1007/978-981-15-2377-9_73

  • Published:

  • Publisher Name: Springer, Singapore

  • Print ISBN: 978-981-15-2376-2

  • Online ISBN: 978-981-15-2377-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation