Preimplantation genetic screening: a systematic review and meta-analysis of RCTs.

BACKGROUND Preimplantation genetic screening (PGS) has increasingly been used in the past decade. Here we present a systematic review and meta-analysis of RCTs on the effect of PGS on the probability of live birth after IVF. METHODS PubMed and trial registers were searched for RCTs on PGS. Trials were assessed following predetermined quality criteria. The primary outcome was live birth rate per woman, secondary outcomes were ongoing pregnancy rate, miscarriage rate, multiple pregnancy rate and pregnancy outcome. RESULTS Nine RCTs comparing IVF with and without PGS were included in our meta-analysis. Fluorescence in situ hybridization was used in all trials and cleavage stage biopsy was used in all but one trial. PGS significantly lowered live birth rate after IVF for women of advanced maternal age (risk difference: -0.08; 95% confidence interval: -0. 13 to -0.03). For a live birth rate of 26% after IVF without PGS, the rate would be between 13 and 23% using PGS. Trials where PGS was offered to women with a good prognosis and to women with repeated implantation failure suggested similar outcomes. CONCLUSIONS There is no evidence of a beneficial effect of PGS as currently applied on the live birth rate after IVF. On the contrary, for women of advanced maternal age PGS significantly lowers the live birth rate. Technical drawbacks and chromosomal mosaicism underlie this inefficacy of PGS. New approaches in the application of PGS should be evaluated carefully before their introduction into clinical practice.

[1]  A. Hellani,et al.  Successful pregnancies after application of array-comparative genomic hybridization in PGS-aneuploidy screening. , 2008, Reproductive biomedicine online.

[2]  C. Márquez,et al.  Chromosome abnormalities in 1255 cleavage-stage human embryos. , 2000, Reproductive biomedicine online.

[3]  James A Grifo,et al.  Multicentre trial of preimplantation genetic screening reported in the New England Journal of Medicine: an in-depth look at the findings. , 2007, Reproductive biomedicine online.

[4]  C. Rodeck,et al.  Relative efficiency of FISH on metaphase and interphase nuclei from non‐mosaic trisomic or triploid fibroblast cultures , 2000, Prenatal diagnosis.

[5]  P. Bossuyt,et al.  Diagnostic accuracy: theoretical models for preimplantation genetic testing of a single nucleus using the fluorescence in situ hybridization technique. , 2010, Human reproduction.

[6]  M. Summers,et al.  Quantitative decision-making in preimplantation genetic (aneuploidy) screening (PGS) , 2009, Journal of Assisted Reproduction and Genetics.

[7]  O. Kato,et al.  Minimal ovarian stimulation with clomiphene citrate: a large-scale retrospective study. , 2007, Reproductive biomedicine online.

[8]  J. Habbema,et al.  Predicting ongoing pregnancy chances after IVF and ICSI: a national prospective study. , 2007, Human reproduction.

[9]  L. Shulman Preimplantation genetic screening for aneuploidy of embryos after in vitro fertilization in women aged at least 35 years: a prospective randomized trial , 2010 .

[10]  M. Heineman,et al.  Comment 1 on Staessen et al. (2004). Design and analysis of a randomized controlled trial studying preimplantation genetic screening. , 2005, Human reproduction.

[11]  P. Hunt,et al.  To err (meiotically) is human: the genesis of human aneuploidy , 2001, Nature Reviews Genetics.

[12]  L. Gianaroli,et al.  Paternal contribution to aneuploidy in preimplantation embryos. , 2009, Reproductive biomedicine online.

[13]  S. Munné,et al.  Preimplantation aneuploidy testing for infertile patients of advanced maternal age: a randomized prospective trial. , 2009, Fertility and sterility.

[14]  J. Simpson What next for preimplantation genetic screening? Randomized clinical trial in assessing PGS: necessary but not sufficient. , 2008, Human reproduction.

[15]  P. Braude,et al.  Reduction of the multiple pregnancy rate in a preimplantation genetic diagnosis programme after introduction of single blastocyst transfer and cryopreservation of blastocysts biopsied on day 3. , 2009, Human reproduction.

[16]  A. Kuliev,et al.  Meiotic and mitotic nondisjunction: lessons from preimplantation genetic diagnosis. , 2004, Human reproduction update.

[17]  J. Grifo,et al.  Embryo morphology, developmental rates, and maternal age are correlated with chromosome abnormalities. , 1995, Fertility and sterility.

[18]  J. Jarow,et al.  Chromosomal abnormalities in embryos derived from testicular sperm extraction. , 2003, The Journal of urology.

[19]  P. Haentjens,et al.  Preimplantation genetic screening does not improve delivery rate in women under the age of 36 following single-embryo transfer. , 2008, Human reproduction.

[20]  P. Colls,et al.  Increased efficiency of preimplantation genetic diagnosis for aneuploidy by testing 12 chromosomes. , 2009, Reproductive biomedicine online.

[21]  C. Moutou,et al.  ESHRE PGD Consortium data collection IX: cycles from January to December 2006 with pregnancy follow-up to October 2007. , 2009, Human reproduction.

[22]  L. Wilton Preimplantation genetic diagnosis for aneuploidy screening in early human embryos: a review , 2002, Prenatal diagnosis.

[23]  A. Handyside,et al.  Human preimplantation development in vitro is not adversely affected by biopsy at the 8-cell stage. , 1990, Human reproduction.

[24]  Y. Verlinsky,et al.  Pregnancies following pre-conception diagnosis of common aneuploidies by fluorescent in-situ hybridization. , 1995, Human reproduction.

[25]  P. Haentjens,et al.  Impact of cleavage-stage embryo biopsy in view of PGD on human blastocyst implantation: a prospective cohort of single embryo transfers. , 2009, Human reproduction.

[26]  K Lundin,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. , 2003, Human reproduction.

[27]  D. Edgar,et al.  The developmental potential of cryopreserved human embryos , 2000, Molecular and Cellular Endocrinology.

[28]  J. Korevaar,et al.  Chromosomal mosaicism in human preimplantation embryos: a systematic review. , 2011, Human reproduction update.

[29]  I. Sargent,et al.  Trophectoderm biopsy in human blastocysts. , 1990, Human reproduction.

[30]  M. Montag,et al.  Polar body biopsy: a viable alternative to preimplantation genetic diagnosis and screening. , 2009, Reproductive biomedicine online.

[31]  M. Kuwayama,et al.  Highly efficient vitrification for cryopreservation of human oocytes and embryos: the Cryotop method. , 2007, Theriogenology.

[32]  B. Levy,et al.  SNP microarray-based 24 chromosome aneuploidy screening demonstrates that cleavage-stage FISH poorly predicts aneuploidy in embryos that develop to morphologically normal blastocysts , 2010, Molecular human reproduction.

[33]  E. Pergament,et al.  Preimplantation genetic screening to improve in vitro fertilization pregnancy rates: a prospective randomized controlled trial. , 2008, Fertility and sterility.

[34]  Jacques Cohen,et al.  Increased efficiency of preimplantation genetic diagnosis for infertility using "no result rescue". , 2007, Fertility and sterility.

[35]  D. Gardner,et al.  IS ANEUPLOIDY SCREENING FOR PATIENTS AGED 35 OR OVER BENEFICIAL? A PROSPECTIVE RANDOMIZED TRIAL , 2004 .

[36]  P. Bossuyt,et al.  No beneficial effect of preimplantation genetic screening in women of advanced maternal age with a high risk for embryonic aneuploidy. , 2008, Human reproduction.

[37]  Richard T. Scott,et al.  SNP microarray-based 24 chromosome aneuploidy screening is significantly more consistent than FISH , 2010, Molecular human reproduction.

[38]  P. Devroey,et al.  Diagnostic efficiency, embryonic development and clinical outcome after the biopsy of one or two blastomeres for preimplantation genetic diagnosis. , 2008, Human reproduction.

[39]  Simmy Bank Comment 1 , 1990 .

[40]  Y. Agca,et al.  Vitrification of human embryos subjected to blastomere biopsy for pre-implantation genetic screening produces higher survival and pregnancy rates than slow freezing , 2009, Journal of Assisted Reproduction and Genetics.

[41]  R. Williamson,et al.  Birth of a healthy infant after preimplantation confirmation of euploidy by comparative genomic hybridization. , 2001, The New England journal of medicine.

[42]  D. Warburton,et al.  Increased rate of aneuploid embryos in young women with previous aneuploid conceptions , 2004, Prenatal diagnosis.

[43]  B. Dale,et al.  Preimplantation genetic diagnosis for the treatment of failed in vitro fertilization-embryo transfer and habitual abortion. , 2004, Fertility and sterility.

[44]  L. Gianaroli,et al.  Cryopreservation of biopsied embryos at the blastocyst stage. , 2006, Human reproduction.

[45]  A. H. Handyside,et al.  Pregnancies from biopsied human preimplantation embryos sexed by Y-specific DNA amplification , 1990, Nature.

[46]  L. Gianaroli,et al.  Substandard application of preimplantation genetic screening may interfere with its clinical success. , 2007, Fertility and sterility.

[47]  D. Wells,et al.  Use of comprehensive chromosomal screening for embryo assessment: microarrays and CGH , 2008, Molecular human reproduction.

[48]  B. Fauser,et al.  Preimplantation genetic screening reveals a high incidence of aneuploidy and mosaicism in embryos from young women undergoing IVF. , 2006, Human reproduction.

[49]  Birgit Sikkema-Raddatz,et al.  In vitro fertilization with preimplantation genetic screening. , 2007, New England Journal of Medicine.

[50]  Luca Gianaroli,et al.  Embryo morphology and development are dependent on the chromosomal complement. , 2007, Fertility and sterility.

[51]  P. C. Steptoe,et al.  BIRTH AFTER THE REIMPLANTATION OF A HUMAN EMBRYO , 1978, The Lancet.

[52]  M. Petersen,et al.  Origin and mechanisms of non-disjunction in human autosomal trisomies. , 1998, Human reproduction.

[53]  Jacques Cohen,et al.  Removal of 2 cells from cleavage stage embryos is likely to reduce the efficacy of chromosomal tests that are used to enhance implantation rates. , 2007, Fertility and sterility.

[54]  C. Simón,et al.  Embryo Aneuploidy Screening for Unexplained Recurrent Miscarriage: A Minireview , 2005, American journal of reproductive immunology.

[55]  Jacques Cohen,et al.  Technology requirements for preimplantation genetic diagnosis to improve assisted reproduction outcomes. , 2010, Fertility and sterility.

[56]  Jacques Cohen,et al.  Improved implantation after preimplantation genetic diagnosis of aneuploidy. , 2003, Reproductive biomedicine online.

[57]  Jacques Cohen,et al.  Cryopreservation of biopsied cleavage stage human embryos. , 2005, Reproductive biomedicine online.

[58]  H. Danzer,et al.  Accuracy of FISH analysis in predicting chromosomal status in patients undergoing preimplantation genetic diagnosis. , 2008, Fertility and sterility.

[59]  R. Jansen,et al.  What next for preimplantation genetic screening (PGS)? Experience with blastocyst biopsy and testing for aneuploidy. , 2008, Human reproduction.

[60]  Michel Camus,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. , 2004, Human reproduction.

[61]  D. Edgar,et al.  A quantitative analysis of the impact of cryopreservation on the implantation potential of human early cleavage stage embryos. , 2000, Human reproduction.

[62]  Chromosome Instability Is Common in Human Cleavage-Stage Embryos , 2012 .

[63]  C. Moutou,et al.  ESHRE PGD Consortium data collection VIII: cycles from January to December 2005 with pregnancy follow-up to October 2006. , 2008, Human reproduction.

[64]  L. Horton,et al.  CHRONIC NON-SPECIFIC ENDOMETRITIS , 1976, The Lancet.

[65]  L. Gianaroli,et al.  Will preimplantation genetic diagnosis assist patients with a poor prognosis to achieve pregnancy? , 1997, Human reproduction.

[66]  K. Hudson,et al.  Genetic testing of embryos: practices and perspectives of US in vitro fertilization clinics. , 2008, Fertility and sterility.

[67]  L. Gianaroli,et al.  Preimplantation diagnosis for aneuploidies in patients undergoing in vitro fertilization with a poor prognosis: identification of the categories for which it should be proposed. , 1999, Fertility and sterility.

[68]  J. Vermeesch,et al.  What next for preimplantation genetic screening? High mitotic chromosome instability rate provides the biological basis for the low success rate , 2009, Human reproduction.

[69]  K. Vesela,et al.  ESHRE PGD Consortium data collection VI: cycles from January to December 2003 with pregnancy follow-up to October 2004. , 2007, Human reproduction.

[70]  A. V. Van Steirteghem,et al.  The analysis of one or two blastomeres for PGD using fluorescence in-situ hybridization. , 2006, Human reproduction.

[71]  Z. Rosenwaks,et al.  Diagnosis of major chromosome aneuploidies in human preimplantation embryos. , 1993 .

[72]  Seang Lin Tan,et al.  Chromosomal mosaicism throughout human preimplantation development in vitro: incidence, type, and relevance to embryo outcome. , 2002, Human reproduction.

[73]  A. Handyside,et al.  Human embryo biopsy on the 2nd day after insemination for preimplantation diagnosis: removal of a quarter of embryo retards cleavage. , 1992, Fertility and sterility.

[74]  S. Klipstein,et al.  A prospective randomized controlled trial of preimplantation genetic screening in the "good prognosis" patient. , 2009, Fertility and sterility.

[75]  D. Griffin,et al.  Detection of aneuploidy and chromosomal mosaicism in human embryos during preimplantation sex determination by fluorescent in situ hybridisation, (FISH). , 1993, Human molecular genetics.

[76]  D. Griffin,et al.  Dual fluorescent in situ hybridisation for simultaneous detection of X and Y chromosome-specific probes for the sexing of human preimplantation embryonic nuclei , 1992, Human Genetics.

[77]  Santiago Munné,et al.  Chromosomal abnormalities in embryos derived from testicular sperm extraction. , 2003, Fertility and sterility.

[78]  Elpida Fragouli,et al.  Clinical application of comprehensive chromosomal screening at the blastocyst stage. , 2010, Fertility and sterility.

[79]  L. Gianaroli,et al.  Over a decade of experience with preimplantation genetic diagnosis: a multicenter report. , 2004, Fertility and sterility.

[80]  P. Haentjens,et al.  Prospectively randomized controlled trial of PGS in IVF/ICSI patients with poor implantation. , 2008, Reproductive biomedicine online.

[81]  L. Nilsson,et al.  Preimplantation genetic screening in women of advanced maternal age caused a decrease in clinical pregnancy rate: a randomized controlled trial. , 2008, Human reproduction.

[82]  L. Gianaroli,et al.  What next for preimplantation genetic screening? A polar body approach! , 2009, Human reproduction.

[83]  D. Van Opstal,et al.  The development of cytogenetically normal, abnormal and mosaic embryos: a theoretical model. , 2004, Human reproduction update.

[84]  Jacques Cohen,et al.  Comment 2 on Staessen et al. (2004). Two-cell biopsy and PGD pregnancy outcome. , 2005, Human reproduction.

[85]  A. Handyside,et al.  Cell allocation in twin half mouse embryos bisected at the 8‐cell stage: Implications for preimplantation diagnosis , 1993, Molecular reproduction and development.

[86]  A. Decherney,et al.  Preimplantation genetic diagnosis as both a therapeutic and diagnostic tool in assisted reproductive technology. , 2003, Fertility and sterility.

[87]  L. Wilton In vitro fertilization with preimplantation genetic screening. , 2007, The New England journal of medicine.

[88]  A. Steirteghem,et al.  Aspects of biopsy procedures prior to preimplantation genetic diagnosis. , 2001 .

[89]  K. Sermon,et al.  Preimplantation genetic diagnosis , 2003, The Lancet.