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Recurrent Implantation Failure pp 77–91Cite as

The Genetics of Pregnancy Failure

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Abstract

Genetic competence is an essential component of an embryo’s ability to implant and progress to a normal delivery. This chapter will assess the known genetic factors that contribute to early embryo failure to implant or to miscarry after implantation. Much of our knowledge has been accumulated through analysis of products of conception which reveals that aneuploidy, particularly trisomy, is the leading cause of early pregnancy failure. The role of translocations and single gene disorders will also be examined. With the advent and rapid application of assisted reproductive technologies, knowledge regarding the preimplantation embryo has rapidly increased. A vast amount of historical data points toward genetic abnormalities related to advancing oocyte age as the leading contributor to early pregnancy failure. The in vitro fertilization experience with preimplantation genetic screening using a variety of technologies will be critically examined. Finally, the limitations of these technologies as well as future areas of research to improve genetic selection of embryos for IVF will be reviewed.

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References

  1. Boue J, Bou A, Lazar P. Retrospective and prospective epidemiological studies of 1500 karyotyped spontaneous human abortions. Teratology. 1975;12(1):11–26.

    Article  CAS  PubMed  Google Scholar 

  2. Nussbaum RL, McInnes RR, Willard HF, Thompson MW, Hamosh A. Thompson & Thompson genetics in medicine. 7th ed. Philadelphia: Saunders/Elsevier; 2007. p. xi, 585pp.

    Google Scholar 

  3. Shen J, Wu W, Gao C, Ochin H, Qu D, Xie J, et al. Chromosomal copy number analysis on chorionic villus samples from early spontaneous miscarriages by high throughput genetic technology. Mol Cytogenet. 2016;9:7.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Maslow BS, Budinetz T, Sueldo C, Anspach E, Engmann L, Benadiva C, et al. Single-nucleotide polymorphism-microarray ploidy analysis of paraffin-embedded products of conception in recurrent pregnancy loss evaluations. Obstet Gynecol. 2015;126(1):175–81.

    Article  CAS  PubMed  Google Scholar 

  5. Sahoo T, Dzidic N, Strecker MN, Commander S, Travis MK, Doherty C, et al. Comprehensive genetic analysis of pregnancy loss by chromosomal microarrays: outcomes, benefits, and challenges. Genet Med. 2017;19:83.

    Article  CAS  PubMed  Google Scholar 

  6. 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(2 Pt 1):202–9.

    Article  CAS  PubMed  Google Scholar 

  7. Neri G, Serra A, Campana M, Tedeschi B. Reproductive risks for translocation carriers: cytogenetic study and analysis of pregnancy outcome in 58 families. Am J Med Genet. 1983;16(4):535–61.

    Article  CAS  PubMed  Google Scholar 

  8. Campana M, Serra A, Neri G. Role of chromosome aberrations in recurrent abortion: a study of 269 balanced translocations. Am J Med Genet. 1986;24(2):341–56.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  10. Jacobs PA, Browne C, Gregson N, Joyce C, White H. Estimates of the frequency of chromosome abnormalities detectable in unselected newborns using moderate levels of banding. J Med Genet. 1992;29(2):103–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Maeda T, Ohno M, Matsunobu A, Yoshihara K, Yabe N. A cytogenetic survey of 14,835 consecutive liveborns. Jinrui Idengaku Zasshi. 1991;36(1):117–29.

    Article  CAS  PubMed  Google Scholar 

  12. Treff NR, Northrop LE, Kasabwala K, Su J, Levy B, Scott RT Jr. Single nucleotide polymorphism microarray-based concurrent screening of 24 chromosome aneuploidy and unbalanced translocations in preimplantation human embryos. Fertil Steril. 2010;95(5):1606–12.e1-2.

    Article  PubMed  Google Scholar 

  13. Therman E, Susman B, Denniston C. The nonrandom participation of human acrocentric chromosomes in Robertsonian translocations. Ann Hum Genet. 1989;53(Pt 1):49–65.

    Article  CAS  PubMed  Google Scholar 

  14. Fryns JP, Van Buggenhout G. Structural chromosome rearrangements in couples with recurrent fetal wastage. Eur J Obstet Gynecol Reprod Biol. 1998;81(2):171–6.

    Article  CAS  PubMed  Google Scholar 

  15. Lazarin GA, Haque I, Evans EA, Goldberg JD. Smith-Lemli-Opitz syndrome carrier frequency and estimates of in utero mortality rates. Prenat Diagn. 2017;37:350.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Loffler J, Trojovsky A, Casati B, Kroisel PM, Utermann G. Homozygosity for the W151X stop mutation in the delta7-sterol reductase gene (DHCR7) causing a lethal form of Smith-Lemli-Opitz syndrome: retrospective molecular diagnosis. Am J Med Genet. 2000;95(2):174–7.

    Article  CAS  PubMed  Google Scholar 

  17. Schollen E, Kjaergaard S, Legius E, Schwartz M, Matthijs G. Lack of Hardy-Weinberg equilibrium for the most prevalent PMM2 mutation in CDG-Ia (congenital disorders of glycosylation type Ia). Eur J Hum Genet. 2000;8(5):367–71.

    Article  CAS  PubMed  Google Scholar 

  18. Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536(7616):285–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 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(10):1377–81.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Eagles N, Sebire NJ, Short D, Savage PM, Seckl MJ, Fisher RA. Risk of recurrent molar pregnancies following complete and partial hydatidiform moles. Hum Reprod. 2015;30(9):2055–63.

    Article  CAS  PubMed  Google Scholar 

  21. Shi X, Xie X, Jia Y, Li S. Maternal genetic polymorphisms and unexplained recurrent miscarriage: a systematic review and meta-analysis. Clin Genet. 2017;91:265.

    Article  CAS  PubMed  Google Scholar 

  22. Woods DC, Tilly JL. Isolation, characterization and propagation of mitotically active germ cells from adult mouse and human ovaries. Nat Protoc. 2013;8(5):966–88.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Block E. Quantitative morphological investigations of the follicular system in women; variations at different ages. Acta Anat. 1952;14(1-2):108–23.

    Article  CAS  PubMed  Google Scholar 

  24. Menken J, Trussell J, Larsen U. Age and infertility. Science. 1986;233(4771):1389–94.

    Article  CAS  PubMed  Google Scholar 

  25. Schwartz D, Mayaux MJ. Female fecundity as a function of age: results of artificial insemination in 2193 nulliparous women with azoospermic husbands. Federation CECOS. N Engl J Med. 1982;306(7):404–6.

    Article  CAS  PubMed  Google Scholar 

  26. Ripley M, Lanes A, Leveille MC, Shmorgun D. Does ovarian reserve predict egg quality in unstimulated therapeutic donor insemination cycles? Fertil Steril. 2015;103(5):1170–5.e2.

    Article  PubMed  Google Scholar 

  27. Streuli I, de Mouzon J, Paccolat C, Chapron C, Petignat P, Irion OP, et al. AMH concentration is not related to effective time to pregnancy in women who conceive naturally. Reprod Biomed Online. 2014;28(2):216–24.

    Article  CAS  PubMed  Google Scholar 

  28. Schieve LA, Tatham L, Peterson HB, Toner J, Jeng G. Spontaneous abortion among pregnancies conceived using assisted reproductive technology in the United States. Obstet Gynecol. 2003;101(5 Pt 1):959–67.

    PubMed  Google Scholar 

  29. Causio F, Fischetto R, Sarcina E, Geusa S, Tartagni M. Chromosome analysis of spontaneous abortions after in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). Eur J Obstet Gynecol Reprod Biol. 2002;105(1):44–8.

    Article  PubMed  Google Scholar 

  30. Kim JW, Lee WS, Yoon TK, Seok HH, Cho JH, Kim YS, et al. Chromosomal abnormalities in spontaneous abortion after assisted reproductive treatment. BMC Med Genet. 2010;11:153.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bingol B, Abike F, Gedikbasi A, Tapisiz OL, Gunenc Z. Comparison of chromosomal abnormality rates in ICSI for non-male factor and spontaneous conception. J Assist Reprod Genet. 2012;29(1):25–30.

    Article  PubMed  Google Scholar 

  32. Nayak S, Pavone ME, Milad M, Kazer R. Aneuploidy rates in failed pregnancies following assisted reproductive technology. J Women's Health. 2011;20(8):1239–43.

    Article  Google Scholar 

  33. 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(8):817–20.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Lathi RB, Milki AA. Rate of aneuploidy in miscarriages following in vitro fertilization and intracytoplasmic sperm injection. Fertil Steril. 2004;81(5):1270–2.

    Article  PubMed  Google Scholar 

  35. Nasseri A, Mukherjee T, Grifo JA, Noyes N, Krey L, Copperman AB. Elevated day 3 serum follicle stimulating hormone and/or estradiol may predict fetal aneuploidy. Fertil Steril. 1999;71(4):715–8.

    Article  CAS  PubMed  Google Scholar 

  36. Navot D, Drews MR, Bergh PA, Guzman I, Karstaedt A, Scott RT Jr, et al. Age-related decline in female fertility is not due to diminished capacity of the uterus to sustain embryo implantation. Fertil Steril. 1994;61(1):97–101.

    Article  CAS  PubMed  Google Scholar 

  37. Sagi-Dain L, Sagi S, Dirnfeld M. The effect of paternal age on oocyte donation outcomes. Obstet Gynecol Surv. 2016;71(5):301–6.

    Article  PubMed  Google Scholar 

  38. Dubov T, Toledano-Alhadef H, Bokstein F, Constantini S, Ben-Shachar S. The effect of parental age on the presence of de novo mutations - lessons from neurofibromatosis type I. Mol Genet Genomic Med. 2016;4(4):480–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Munne S, Lee A, Rosenwaks Z, Grifo J, Cohen J. Diagnosis of major chromosome aneuploidies in human preimplantation embryos. Hum Reprod. 1993;8(12):2185–91.

    Article  CAS  PubMed  Google Scholar 

  40. Northrop LE, Treff NR, Levy B, Scott RT Jr. SNP microarray-based 24 chromosome aneuploidy screening demonstrates that cleavage-stage FISH poorly predicts aneuploidy in embryos that develop to morphologically normal blastocysts. Mol Hum Reprod. 2010;16(8):590–600.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 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(4):454–66.

    Article  CAS  PubMed  Google Scholar 

  42. Mastenbroek S, Twisk M, van Echten-Arends J, Sikkema-Raddatz B, Korevaar JC, Verhoeve HR, et al. In vitro fertilization with preimplantation genetic screening. N Engl J Med. 2007;357(1):9–17.

    Article  CAS  PubMed  Google Scholar 

  43. Rubio C, Bellver J, Rodrigo L, Bosch E, Mercader A, Vidal C, et al. Preimplantation genetic screening using fluorescence in situ hybridization in patients with repetitive implantation failure and advanced maternal age: two randomized trials. Fertil Steril. 2013;99(5):1400–7.

    Article  PubMed  Google Scholar 

  44. 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(4):870–5.

    Article  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(3):624–30.

    Article  PubMed  Google Scholar 

  46. Kokkali G, Traeger-Synodinos J, Vrettou C, Stavrou D, Jones GM, Cram DS, et al. Blastocyst biopsy versus cleavage stage biopsy and blastocyst transfer for preimplantation genetic diagnosis of beta-thalassaemia: a pilot study. Hum Reprod. 2007;22(5):1443–9.

    Article  CAS  PubMed  Google Scholar 

  47. 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(7):742–7.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Salvaggio CN, Forman EJ, Garnsey HM, Treff NR, Scott RT Jr. Polar body based aneuploidy screening is poorly predictive of embryo ploidy and reproductive potential. J Assist Reprod Genet. 2014;31:1221.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Forman EJ, Treff NR, Stevens JM, Garnsey HM, Katz-Jaffe MG, Scott RT Jr, et al. Embryos whose polar bodies contain isolated reciprocal chromosome aneuploidy are almost always euploid. Hum Reprod. 2013;28(2):502–8.

    Article  CAS  PubMed  Google Scholar 

  50. Scott RT Jr, Treff NR, Stevens J, Forman EJ, Hong KH, Katz-Jaffe MG, et al. Delivery of a chromosomally normal child from an oocyte with reciprocal aneuploid polar bodies. J Assist Reprod Genet. 2012;29(6):533–7.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Scott KL, Hong KH, Scott RT Jr. Selecting the optimal time to perform biopsy for preimplantation genetic testing. Fertil Steril. 2013;100(3):608–14.

    Article  PubMed  Google Scholar 

  52. Yang Z, Liu J, Collins GS, Salem SA, Liu X, Lyle SS, et al. Selection of single blastocysts for fresh transfer via standard morphology assessment alone and with array CGH for good prognosis IVF patients: results from a randomized pilot study. Mol Cytogenet. 2012;5(1):24.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Treff NR, Tao X, Ferry KM, Su J, Taylor D, Scott RT Jr. Development and validation of an accurate quantitative real-time polymerase chain reaction-based assay for human blastocyst comprehensive chromosomal aneuploidy screening. Fertil Steril. 2012;97(4):819–24.e2.

    Article  CAS  PubMed  Google Scholar 

  54. Scott RT Jr, Upham KM, Forman EJ, Hong KH, Scott KL, Taylor D, et al. Blastocyst biopsy with comprehensive chromosome screening and fresh embryo transfer significantly increases in vitro fertilization implantation and delivery rates: a randomized controlled trial. Fertil Steril. 2013;100(3):697–703.

    Article  PubMed  Google Scholar 

  55. 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(1):100–7.e1.

    Article  PubMed  Google Scholar 

  56. 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.

    Article  Google Scholar 

  57. Dahdouh EM, Balayla J, Garcia-Velasco JA. Comprehensive chromosome screening improves embryo selection: a meta-analysis. Fertil Steril. 2015;104(6):1503–12.

    Article  PubMed  Google Scholar 

  58. Dahdouh EM, Balayla J, Garcia-Velasco JA. Impact of blastocyst biopsy and comprehensive chromosome screening technology on preimplantation genetic screening: a systematic review of randomized controlled trials. Reprod Biomed Online. 2015;30(3):281–9.

    Article  PubMed  Google Scholar 

  59. Harton GL, Munne S, Surrey M, Grifo J, Kaplan B, McCulloh DH, et al. Diminished effect of maternal age on implantation after preimplantation genetic diagnosis with array comparative genomic hybridization. Fertil Steril. 2013;100(6):1695–703.

    Article  CAS  PubMed  Google Scholar 

  60. Rabinowitz M, Ryan A, Gemelos G, Hill M, Baner J, Cinnioglu C, et al. Origins and rates of aneuploidy in human blastomeres. Fertil Steril. 2012;97(2):395–401.

    Article  PubMed  Google Scholar 

  61. Ledger WL. Measurement of antimullerian hormone: not as straightforward as it seems. Fertil Steril. 2014;101(2):339.

    Article  PubMed  Google Scholar 

  62. Franasiak JM, Forman EJ, Hong KH, Werner MD, Upham KM, Treff NR, et al. Aneuploidy across individual chromosomes at the embryonic level in trophectoderm biopsies: changes with patient age and chromosome structure. J Assist Reprod Genet. 2014;31(11):1501–9.

    Article  PubMed  PubMed Central  Google Scholar 

  63. 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(6):1613–8.

    Article  PubMed  Google Scholar 

  64. 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(7):893–7.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Kung A, Munne S, Bankowski B, Coates A, Wells D. Validation of next-generation sequencing for comprehensive chromosome screening of embryos. Reprod Biomed Online. 2015;31(6):760–9.

    Article  CAS  PubMed  Google Scholar 

  66. Maxwell SM, Colls P, Hodes-Wertz B, McCulloh DH, McCaffrey C, Wells D, et al. Why do euploid embryos miscarry? A case-control study comparing the rate of aneuploidy within presumed euploid embryos that resulted in miscarriage or live birth using next-generation sequencing. Fertil Steril. 2016;106:1414.

    Article  CAS  PubMed  Google Scholar 

  67. Sher G, Keskintepe L, Keskintepe M, Maassarani G, Tortoriello D, Brody S. Genetic analysis of human embryos by metaphase comparative genomic hybridization (mCGH) improves efficiency of IVF by increasing embryo implantation rate and reducing multiple pregnancies and spontaneous miscarriages. Fertil Steril. 2009;92(6):1886–94.

    Article  CAS  PubMed  Google Scholar 

  68. Keltz MD, Vega M, Sirota I, Lederman M, Moshier EL, Gonzales E, et al. Preimplantation genetic screening (PGS) with comparative genomic hybridization (CGH) following day 3 single cell blastomere biopsy markedly improves IVF outcomes while lowering multiple pregnancies and miscarriages. J Assist Reprod Genet. 2013;30(10):1333–9.

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Reproductive Endocrinology and Infertility, Columbia University, New York, NY, USA

    Eric J. Forman MD, HCLD

  2. Rutgers University School of Medicine, Newark, NJ, USA

    Nathan Treff PhD

  3. Genomic Prediction, Newark, NJ, USA

    Nathan Treff PhD

  4. Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Rebekah S. Zimmerman PhD, FACMG

Authors
  1. Eric J. Forman MD, HCLD
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  2. Nathan Treff PhD
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  3. Rebekah S. Zimmerman PhD, FACMG
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Corresponding author

Correspondence to Eric J. Forman MD, HCLD .

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Editors and Affiliations

  1. Reproductive Medicine Associates of NJ, Thomas Jefferson University, Basking Ridge, New Jersey, USA

    Jason M. Franasiak

  2. Reproductive Medicine Associates of NJ, Thomas Jefferson University, Basking Ridge, New Jersey, USA

    Richard T. Scott Jr.

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Forman, E.J., Treff, N., Zimmerman, R.S. (2018). The Genetics of Pregnancy Failure. In: Franasiak, J., Scott Jr., R. (eds) Recurrent Implantation Failure. Springer, Cham. https://doi.org/10.1007/978-3-319-71967-2_5

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  • DOI: https://doi.org/10.1007/978-3-319-71967-2_5

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