Abstract
Introduction
Embryo selection can be carried out via morphological criteria or by using genetic studies based on Preimplantation Genetic Screening. In the present study, we evaluate the clinical validity of Preimplantation Genetic Screening with fluorescence in situ hybridization (PGS-FISH) compared with morphological embryo criteria.
Material and methods
A systematic review was made of the bibliography, with the following goals: firstly, to determine the prevalence of embryo chromosome alteration in clinical situations in which the PGS-FISH technique has been used; secondly, to calculate the statistics of diagnostic efficiency (negative Likelihood Ratio), using 2 × 2 tables, derived from PGS-FISH. The results obtained were compared with those obtained from embryo morphology. We calculated the probability of transferring at least one chromosome-normal embryo when it was selected using either morphological criteria or PGS-FISH, and considered what diagnostic performance should be expected of an embryo selection test with respect to achieving greater clinical validity than that obtained from embryo morphology.
Results
After an embryo morphology selection that produced a negative result (normal morphology), the likelihood of embryo aneuploidies was found to range from a pre-test value of 65% (prevalence of embryo chromosome alteration registered in all the study groups) to a post-test value of 55% (Confidence interval: 50–61), while after PGS-FISH with a negative result (euploid), the post-test probability was 42% (Confidence interval: 35–49) (p < 0.05). The probability of transferring at least one euploid embryo was the same whether 3 embryos were selected according to morphological criteria or whether 2, selected by PGS-FISH, were transferred. Any embryo selection test, if it is to provide greater clinical validity than embryo morphology, must present a LR-value of 0.40 (Confidence interval: 0.32–0.51) in single embryo transfer, and 0.06 (CI: 0.05–0.07) in double embryo transfer.
Discussion
With currently available technology, and taking into account the number of embryos to be transferred, the clinical validity of PGS-FISH, although superior to that of morphological criteria, does not appear to be clinically relevant.
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References
Van Royen E, Mangelschots K, De Neubourg D, Laureys I, Ryckaert G, Gerris J. Calculating the implantation potential of day 3 embryos in women younger than 38 years of age: a new model. Hum Reprod. 2001;16(2):326–32.
Holte J, Berglund L, Milton K, et al. Construction of an evidence-based integrated morphology cleavage embryo score for implantation potential of embryos scored and transferred on day 2 after oocyte retrieval. Hum Reprod. 2007;22(2):548–57.
De Placido G, Wilding M, Strina I, et al. High outcome predictability alter IVF using a combined score for zygote and embryo morphology and growth rate. Hum Reprod. 2002;17(9):2402–9.
Caglar GS, Asimakopoulos B, Nikolettos N, Diedrich K, Al-Hasani S. Preimplantation genetic diagnosis for aneuploidy screening in repeated implantation failure. Reprod Biomed Online. 2005;10:381–8.
Gianaroli L, Magli MC, Ferraretti AP, et al. The beneficial effects of preimplantation genetic diagnosis for aneuploidy support extensive clinical application. Reprod Biomed Online. 2005;10(5):633–40.
Donoso P, Devroey P. PGD for aneuploidy screening: an expensive hoax? Best Pract Res Clin Obstet Gynaecol. 2007;21(1):157–68.
Harper J, Sermon K, Geraedts J, et al. What next for preimplantation genetic screening? Hum Reprod. 2008;23(3):478–80.
Kuliev A, Verlinsky Y. Impact of preimplantation genetic diagnosis for chromosomal disorders on reproductive outcome. Reprod Biomed Online. 2008;16(1):9–10.
Blockeel C, Schutyser V, De Vos A, et al. Prospectively randomized controlled trial of PGS in IVF/ICSI patients with poor implantation. Reprod Biomed Online. 2008;17(6):848–54.
Debrock S, Melotte C, Spiessens C, et al. Preimplantation genetic screening for aneuploidy of embryos after in vitro fertilization in women aged at least 35 years: a prospective randomized trial. Fertil Steril. 2010;93(2):364–73.
Hardarson T, Hanson C, Lundin K, et al. Preimplantation genetic screening in women of advanced maternal age caused a decrease in clinical pregnancy rate: a randomized controlled trial. Hum Reprod. 2008;23:2806–12.
Jansen RP, Bowman MC, de Boer KA, Leigh DA, Lieberman DB, McArthur SJ. What next for preimplantation genetic screening (PGS)? Experience with blastocyst biopsy and testing for aneuploidy. Hum Reprod. 2008;23(7):1476–8.
Mastenbroek S, Twisk MV, Sikkema-Raddatz B, et al. In vitro fertilization with preimplantation genetic screening. N Engl J Med. 2007;357(1):9–17.
Mersereau JE, Pergament E, Zhang X, Milad MP. Preimplantation genetic screening to improve in vitro fertilization pregnancy rates: a prospective randomized controlled trial. Fertil Steril. 2008;90(4):1287–9.
Meyer LR, Klipstein S, Hazlett WD, Nasta T, Mangan P, Karande VC. A prospective randomized controlled trial of preimplantation genetic screening in the “good prognosis” patient. Fertil Steril. 2009;91(5):1731–8.
Schoolcraft WB, Katz-Jaffe MG, Stevens J, Rawlins M, Munne S. Preimplantation aneuploidy testing for infertile patients of advanced maternal age: a randomized prospective trial. Fertil Steril. 2009;92(1):157–62.
Staessen C, Platteau P, Van Assche E, et al. Comparison of blastocyst transfer with or without preimplantation genetic diagnosis for aneuploidy screening in couples with advanced maternal age: a prospective randomized controlled trial. Hum Reprod. 2004;19(12):2849–58.
Staessen C, Verpoest W, Donoso P, et al. Preimplantation genetic screening does not improve delivery rate in women under the age of 36 following single-embryo transfer. Hum Reprod. 2008;23(12):2818–25.
Stevens J, Wale P, Surrey ES, Schoolcraft WB. Is aneuploidy screening for patients aged 35 or over beneficial? A prospective randomized trial. Fertil Steril. 2004;82(2):249.
Cohen J, Grifo JA. Multicentre trial of preimplantation genetic screening reported in the New England Journal of Medicine: an in-depth look at the findings. Reprod Biomed Online. 2007;15(4):365–6.
Munné S, Gianaroli L, Tur-Kaspa I, et al. Substandard application of preimplantation genetic screening may interfere with its clinical success. Fertil Steril. 2007;88(4):781–4.
Colls P, Escudero T, Cekleniak N, Sadowy S, Cohen J, Munné S. Increased efficiency of preimplantation genetic diagnosis for infertility using “no result rescue”. Fertil Steril. 2007;88(1):53–61.
Munné S, Magli C, Bahçe M, et al. Preimplantation diagnosis of the aneuploidies most commonly found in spontaneous abortions and live births: XY, 13, 14, 15, 16, 18, 21, 22. Prenat Diagn. 1998;18(13):1459–66.
Silber S, Escudero T, Lenahan K, Abdelhadi I, Kilani Z, Munné S. Chromosomal abnormalities in embryos derived from testicular sperm extraction. Fertil Steril. 2003;79(1):30–8.
Baart EB, Van Opstal D, Los FJ, Fauser BC, Martini E. Fluorescence in situ hybridization analysis of two blastomeres from day 3 frozen-thawed embryos followed by analysis of the remaining embryo on day 5. Hum Reprod. 2004;19(3):685–93.
Baart EB, Martini E, Van den Berg I, et al. Preimplantation genetic screening reveals a high incidence of aneuploidy and mosaicism in embryos from young women undergoing IVF. Hum Reprod. 2006;21(1):223–33.
Michiels A, Van Assche E, Liebaers I, Van Steirteghem A, Staessen C. The analysis of one or two blastomeres for PGD using fluorescence in-situ hybridization. Hum Reprod. 2006;21(9):2396–402.
DeUgarte CM, Li M, Surrey M, Danzer H, Hill D, DeCherney AH. Accuracy of FISH analysis in predicting chromosomal status in patients undergoing preimplantation genetic diagnosis. Fertil Steril. 2008;90(4):1049–54.
Greenhalgh T. How to read a paper. Papers that report diagnostic or screening tests. BMJ. 1997;315(7107):540–3.
Sackett DL, Haynes RB, Guyatt GH, Tugwell P. Clinical epidemiology: A basic science for clinical medicine. Boston: Williams and Wilkins; 1991.
Donoso P, Platteau P, Papanikolaou EG, Staessen C, Van Steirteghem A, Devroey P. Does PGD for aneuploidy screening change the selection of embryos derived from testicular sperm extraction in obstructive and non-obstructive azoospermic men? Hum Reprod. 2006;21(9):2390–5.
Moayeri SE, Allen RB, Brewster WR, Kim MH, Porto M, Werlin LB. Day-3 embryo morphology predicts euploidy among older subjects. Fertil Steril. 2008;89(1):118–23.
Donoso P, Staessen C, Fauser BC, Devroey P. Current value of preimplantation genetic aneuploidy screening in IVF. Hum Reprod Update. 2007;13(1):15–25.
Bossuyt PM, Reitsma JB, Bruns DE, et al. Standards for reporting of diagnostic accuracy. The STARD statement for reporting studies of diagnostic accuracy: explanation and elaboration. Clin Chem. 2003;49(1):7–17.
Jialiang L, Fine JP, Safdar N. Prevalence-dependent diagnostic accuracy measures. Stat Med. 2007;26(17):3258–73.
Zhou XH, Obuchowski NA, McClish DK. Statistical methods in diagnostic medicine. New York: Wiley; 2002.
Fagan TJ. Nomogram for Bayes theorem. N Engl J Med. 1975;293(5):257.
Greenland S. Quantitative methods in the review of epidemiologic literature. Epidemiol Rev. 1987;9:1–30.
Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Statistics in Medicine. 2001;21(11):1539–58.
Dersimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–88.
Gart JJ, Zweiful JR. On the bias of various estimators of the logit and its variance with applications to quantal bioassay. Biometrika. 1967;54(1):181–7.
Platteau P, Staessen C, Michiels A, Van Steirteghem A, Liebaers I, Devroey P. Preimplantation genetic diagnosis for aneuploidy screening in women older than 37 years. Fertil Steril. 2005;84(2):319–24.
Kahraman S, Bahçe M, Samli H, et al. Healthy births and ongoing pregnancies obtained by preimplantation genetic diagnosis in patients with advanced maternal age and recurrent implantation failure. Hum Reprod. 2000;15(9):2003–7.
Munné S, Sandalinas M, Escudero T, Márquez C, Cohen J. Chromosome mosaicism in cleavage-stage human embryos: evidence of a maternal age effect. Reprod Biomed Online. 2002;4(3):223–32.
Preimplantation genetic testing: a Practice Committee Opinion. Fertil Steril. 2007;88:1497–504.
Wilton L, Voullaire L, Sargeant P, Williamson R, McBain J. Preimplantation aneuploidy screening using comparative genomic hybridization or fluorescence in situ hybridization of embryos from patients with recurrent implantation failure. Fertil Steril. 2003;80(4):860–8.
Gleicher N, Weghofer A, Barad D. Preimplantation genetic screening: “established” and ready for prime time? Fertil Steril. 2008;89(4):780–8.
Ruangvutilert P, Delhanty JD, Serhal P, Simopoulou M, Rodeck CH, Harper JC. FISH analysis on day 5 post-insemination of human arrested and blastocyst stage embryos. Prenat Diagn. 2000;20(7):552–60.
Gonzalez-Merino E, Emiliani S, Vassart G, Van den Bergh M, Vannin AS, Abramowicz M, et al. Incidence of chromosomal mosaicism in human embryos at different developmental stages analyzed by fluorescence in situ hybridization. Genet Test. 2003;7(2):85–95.
Coonen E, Derhaag JG, Dumoulin JC, et al. Anaphase lagging mainly explains chromosomal mosaicism in human preimplantation embryos. Human Reprod. 2004;19(2):316–24.
Bielanska M, Jin S, Bernier M, Tan SL, Ao A. Diploid-aneuploid mosaicism in human embryos cultured to the blastocyst stage. Fertil Steril. 2005;84(2):336–42.
Daphnis DD, Fragouli E, Economou K, et al. Analysis of the evolution of chromosome abnormalities in human embryos from Day 3 to 5 using CGH and FISH. Mol Hum Reprod. 2008;14(2):117–25.
Los FJ, Van Opstal D, Van den Berg C. The development of cytogenetically normal, abnormal and mosaic embryos: a theoretical model. Hum Reprod Update. 2004;10(1):79–94.
Wilton L, Thornhill A, Traeger-Synodinos J, Sermon KD, Harper JC. The causes of misdiagnosis and adverse outcomes in PGD. Hum Reprod. 2009;24(5):1221–8.
Cohen J, Wells D, Munné S. Removal of 2 cells from cleavage stage embryos is likely to reduce the efficacy of chromosomal tests that are used to enhance implantation rates. Fertil Steril. 2007;87(3):496–503.
Goossens V, De Rycke M, De Vos A, et al. Diagnostic efficiency, embryonic development and clinical outcome after the biopsy of one or two blastomeres for preimplantation genetic diagnosis. Hum Reprod. 2008;23(3):481–92.
Vanneste E, Voet T, Le Caignec C, et al. Chromosome instability is common in human cleavage-stage embryos. Nat Med. 2009;15(5):577–83.
Derhaag JG, Coonen E, Bras M, et al. Chromosomally abnormal cells are not selected for the extra-embryonic compartment of the human preimplantation embryo at the blastocyst stage. Hum Reprod. 2003;18(12):2565–74.
Trussler JL, Pickering SJ, Ogilvie CM. Investigation of chromosomal imbalance in human embryos using comparative genomic hybridization. Reprod Biomed Online. 2004;8(6):701–11.
Goossens V, Harton G, Moutou C, Traeger-Synodinos J, Van Rij M, Harper JC. ESHRE PGD Consortium data collection IX: cycles from January to December 2006 with pregnancy follow-up to October 2007. Hum Reprod. 2009;24(8):1786–810.
Knotternus JA, Van Weel C. General introduction: Evaluation of diagnostic procedures. In: Knottnerus JA, editor. The evidence base of clinical diagnosis. London: BMA Books; 2002.
Dreesen J, Drüsedau M, Smeets H, et al. Validation of preimplantation genetic diagnosis by PCR analysis: genotype comparison of the blastomere and corresponding embryo, implications for clinical practice. Mol Hum Reprod. 2008;14(10):573–9.
Twisk M, Mastenbroek S, Hoek A, et al. No beneficial effect of preimplantation genetic screening in women of advanced maternal age with a high risk for embryonic aneuploidy. Hum Reprod. 2008;23(12):2813–7.
Summers MC, Foland AD. Quantitative decision-making in preimplantation genetic (aneuploidy) screening (PGS). J Assist Reprod Genet. 2009;26(9–10):487–502.
Wells D, Delhanty JD. Comprehensive chromosomal analysis of human preimplantation embryos using whole genome amplification and single cell comparative genomic hybridization. Mol Hum Reprod. 2000;6(11):1055–62.
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.
Wells D, Alfarawati S, Fragouli E. Use of comprehensive chromosomal screening for embryo assessment: microarrays and CGH. Mol Hum Reprod. 2008;14(12):703–10.
Brison DR, Hollywood K, Arnesen R, Goodacre R. Predicting human embryo viability: the road to non-invasive analysis of the secretome using metabolic footprinting. Reprod Biomed Online. 2007;15(3):296–302.
Katz-Jaffe MG, McReynolds S, Gardner DK, Schoolcraft WB. The role of proteomics in defining the human embryonic secretome. Mol Hum Reprod. 2009;15(5):271–7.
Lopes AS, Greve T, Callesen H. Quantification of embryo quality by respirometry. Theriogenology. 2007;67(1):21–31.
Montag M, Schimming T, Köster M, et al. Oocyte zona birefringence intensity is associated with embryonic implantation potential in ICSI cycles. Reprod Biomed Online. 2008;16(2):239–44.
Scott L, Berntsen J, Davies D, Gundersen J, Hill J, Ramsing N. Symposium: innovative techniques in human embryo viability assessment. Human oocyte respiration-rate measurement–potential to improve oocyte and embryo selection? Reprod Biomed Online. 2008;17(4):461–9.
Seli E, Sakkas D, Scott R, Kwok SC, Rosendahl SM, Burns DH. Noninvasive metabolomic profiling of embryo culture media using Raman and near-infrared spectroscopy correlates with reproductive potential of embryos in women undergoing in vitro fertilization. Fertil Steril. 2007;88(5):1350–7.
Kearns WG, Pen R, Graham J, et al. Preimplantation genetic diagnosis and screening. Semin Reprod Med. 2005;23(4):336–47.
Reis Soares S, Rubio C, Rodrigo L, et al. High frequency of chromosomal abnormalities in embryos obtained from oocyte donation cycles. Fertil Steril. 2003;80(3):656–7.
Nelson JR, Potter DA, Wilcox JG, Frederick JL, Kolb BA, Behr BR. Preimplantation genetic diagnosis in embryos created from oocytes donation. Fertil Steril. 2005;84(1):328–9.
Nagy ZP, Chang CC. Current advances in artificial gametes. Reprod Biomed Online. 2005;11(3):332–9.
Munné S, Ary J, Zouves C, et al. Wide range of chromosome abnormalities in the embryos of young egg donors. Reprod Biomed Online. 2006;12(3):340–6.
Werlin L, Rodi I, DeCherney A, Marello E, Hill D, Munné S. Preimplantation genetic diagnosis as both a therapeutic and diagnostic tool in assisted reproductive technology. Fertil Steril. 2003;80(2):467–8.
Gianaroli L, Magli MC, Munné S, Fiorentino A, Montanaro N, Ferraretti AP. Will preimplantation genetic diagnosis assist patients with a poor prognosis to achieve pregnancy? Hum Reprod. 1997;12(8):1762–7.
Rubio C, Rodrigo L, Pérez-Cano I, et al. FISH screening of aneuploidies in preimplantation embryos to improve IVF outcome. Reprod Biomed Online. 2005;11(4):497–506.
Vidal F, Giménez C, Rubio C, et al. FISH preimplantation diagnosis of chromosome aneuploidy in recurrent pregnancy wastage. J Assist Reprod Genet. 1998;15(5):310–3.
Platteau P, Staessen C, Michiels A, Van Steirteghem A, Liebaers I, Devroey P. Preimplantation genetic diagnosis for aneuploidy screening in patients with unexplained recurrent miscarriages. Fertil Steril. 2005;83(2):393–7.
Munné S, Chen S, Fischer J, et al. Preimplantation genetic diagnosis reduces pregnancy loss in women aged 35 years and older with a history of recurrent miscarriages. Fertil Steril. 2005;84(2):331–5.
Pellicer A, Rubio C, Vidal F, et al. In vitro fertilization plus preimplantation genetic diagnosis in patients with recurrent miscarriage: an analysis of chromosome abnormalities in human preimplantation embryos. Fertil Steril. 1999;71(6):1033–9.
Simón C, Rubio C, Vidal F, et al. Increased chromosome abnormalities in human preimplantation embryos after in-vitro fertilization in patients with recurrent miscarriage. Reprod Fertil Dev. 1998;10(1):87–92.
Garrisi JG, Colls P, Ferry KM, Zheng X, Garrisi MG, Munné S. Effect of infertility, maternal age, and number of previous miscarriages on the outcome of preimplantation genetic diagnosis for idiopathic recurrent pregnancy loss. Fertil Steril. 2009;92(1):288–95.
Rubio C, Simón C, Vidal F, et al. Chromosomal abnormalities and embryo development in recurrent miscarriage couples. Hum Reprod. 2003;18(1):182–8.
Pehlivan T, Rubio C, Rodrigo L, et al. Impact of preimplantation genetic diagnosis on IVF outcome in implantation failure patients. Reprod Biomed Online. 2003;6(2):232–7.
Platteau P, Staessen C, Michiels A, et al. Comparison of the aneuploidy frequency in embryos derived from testicular sperm extraction in obstructive and nonobstructive azoospermic men. Hum Reprod. 2004;19(7):1570–4.
Kahraman S, Sertyel S, Findikli N, et al. Effect of PGD on implantation and ongoing pregnancy rates in cases with predominantly macrocephalic spermatozoa. Reprod Biomed Online. 2004;9(1):79–85.
Baltaci V, Satiroglu H, Kabukçu C, et al. Relationship between embryo quality and aneuploidies. Reprod Biomed Online. 2006;12(1):77–82.
Magli MC, Gianaroli L, Ferraretti AP, Lappi M, Ruberti A, Farfalli V. Embryo morphology and development are dependent on the chromosomal complement. Fertil Steril. 2007;87(3):534–41.
Munné S, Chen S, Colls P, et al. Maternal age, morphology, development and chromosome abnormalities in over 6000 cleavage-stage embryos. Reprod Biomed Online. 2007;14(5):628–34.
Rubio C, Rodrigo L, Mercader A, et al. Impact of chromosomal abnormalities on preimplantation embryo development. Prenat Diagn. 2007;27(8):748–56.
Ziebe S, Lundin K, Loft A, et al. FISH analysis for chromosomes 13, 16, 18, 21, 22, X and Y in all blastomeres of IVF pre-embryos from 144 randomly selected donated human oocytes and impact on pre-embryo morphology. Hum Reprod. 2003;18(12):2575–81.
Keskintepe L, Sher G, Keskintepe M. Reproductive oocyte/embryo genetic analysis: comparison between fluorescence in-situ hybridization and comparative genomic hybridization. Reprod Biomed Online. 2007;15(2):303–9.
Veeck LL. An Atlas of Human Gametes and Conceptuses. London: Parthenon; 1998.
Alikani M, Cohen J, Tomkin G, et al. Human embryo fragmentation in vitro and its implications for pregnancy and implantation. Fertil Steril. 1999;71:836–42.
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Capsule Taking into account PGS-FISH technology and the number of embryos to be transferred, the clinical validity of PGS-FISH does not appear to be clinically relevant.
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Zamora, S., Clavero, A., Gonzalvo, M.C. et al. PGS-FISH in reproductive medicine and perspective directions for improvement: a systematic review. J Assist Reprod Genet 28, 747–757 (2011). https://doi.org/10.1007/s10815-011-9578-9
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DOI: https://doi.org/10.1007/s10815-011-9578-9