Accuracy of preimplantation genetic screening (PGS) is compromised by degree of mosaicism of human embryos.
BACKGROUND
To preclude transfer of aneuploid embryos, current preimplantation genetic screening (PGS) usually involves one trophectoderm biopsy at blastocyst stage, assumed to represent embryo ploidy. Whether one such biopsy can correctly assess embryo ploidy has recently, however, been questioned.


METHODS
This descriptive study investigated accuracy of PGS in two ways. Part I: Two infertile couples donated 11 embryos, previously diagnosed as aneuploid and, therefore, destined to be discarded. They were dissected into 37 anonymized specimens, and sent to another national laboratory for repeat analyses to assess (i) inter-laboratory congruity and (ii) intra-embryo congruity of multiple embryo biopsies in a single laboratory. Part II: Reports on human IVF cycle outcomes after transfer of allegedly aneuploid embryos into 8 infertile patients.


RESULTS
Only 2/11 (18.2 %) embryos were identically assessed at two PGS laboratories; 4/11 (36.4 %), on repeat analysis were chromosomally normal, 2 mosaic normal/abnormal, and 5/11 (45.5 %) completely differed in reported aneuploidies. In intra-embryo analyses, 5/10 (50 %) differed between biopsy sites. Eight transfers of previously reported aneuploid embryos resulted in 5 chromosomally normal pregnancies, 4 delivered and 1 ongoing. Three patients did not conceive, though 1 among them experienced a chemical pregnancy.


CONCLUSIONS
Though populations of both study parts are too small to draw statistically adequately powered conclusions on specific degrees of inaccuracy of PGS, here presented results do raise concerns especially about false-positive diagnoses. While inter-laboratory variations may at least partially be explained by different diagnostic platforms utilized, they cannot explain observed intra-embryo variations, suggesting more frequent trophectoderm mosiaicsm than previously reported. Together with recentl published mouse studies of lineages-specific degrees of survival of aneuploid cells in early stage embryos, these results call into question the biological basis of PGS, based on the assumption that a single trophectoderm biopsy can reliably determine embryo ploidy.
The Center for Human Reproduction, 21 East 69th Street, New York, NY, 10021, USA. ngleicher@thechr.com.|The Foundation for Reproductive Medicine, New York, NY, USA. ngleicher@thechr.com.|The Brivanlou Laboratory for Stem Cell Biology and Molecular Embryology, Rockefeller University, New York, NY, USA. ngleicher@thechr.com.
Norbert
N
Gleicher
The Center for Human Reproduction, 21 East 69th Street, New York, NY, 10021, USA.|Fertility Specialist in New York, New York, NY, USA.
Andrea
A
Vidali
Braverman IVF & Reproductive Immunology, New York, NY, USA.
Jeffrey
J
Braverman
The Center for Human Reproduction, 21 East 69th Street, New York, NY, 10021, USA.|Department of Obstetrics and Gynecology, Wake Forest University, Winston Salem, NC, USA.
Vitaly A
VA
Kushnir
The Center for Human Reproduction, 21 East 69th Street, New York, NY, 10021, USA.|The Foundation for Reproductive Medicine, New York, NY, USA.|Department of Obstetrics and Gynecology, Albert Einstein College of Medicine, Bronx, NY, USA.
David H
DH
Barad
The Center for Human Reproduction, 21 East 69th Street, New York, NY, 10021, USA.
Cynthia
C
Hudson
The Center for Human Reproduction, 21 East 69th Street, New York, NY, 10021, USA.
Yang-Guan
YG
Wu
The Center for Human Reproduction, 21 East 69th Street, New York, NY, 10021, USA.
Qi
Q
Wang
The Center for Human Reproduction, 21 East 69th Street, New York, NY, 10021, USA.
Lin
L
Zhang
The Center for Human Reproduction, 21 East 69th Street, New York, NY, 10021, USA.|Department of Molecular and Integrative Physiology, University of Kansas School of Medicine, Wichita, KS, USA.
David F
DF
Albertini
D004624:Embryo Transfer / Q000592:standards; D005260:Female; D005820:Genetic Testing / Q000592:standards*; D006801:Humans; D009030:Mosaicism / Q000196:embryology*; D011247:Pregnancy; D018873:Pregnancy Rate / Q000639:trends; D019836:Preimplantation Diagnosis / Q000592:standards*; D011897:Random Allocation
Blastocyst; Embryo mosaicism; Embryos; In vitro fertilization (IVF); Preimplantation genetic screening (PGS); Trophectoderm biopsy