A single trophectoderm biopsy at blastocyst stage is mathematically unable to determine embryo ploidy accurately enough for clinical use

Norbert Gleicher,David F Albertini,Jacob Metzger,Gist Croft,Vitaly A Kushnir,David H Barad

doi:10.1186/s12958-017-0251-8

Abstract

BackgroundIt has become increasingly apparent that the trophectoderm (TE) at blastocyst stage is much more mosaic than has been appreciated. Whether preimplantation genetic screening (PGS), utilizing a single TE biopsy (TEB), can reliably determine embryo ploidy has, therefore, increasingly been questioned in parallel.MethodsWe for that reason here established 2 mathematical models to assess probabilities of false-negative and false-positive results of an on average 6-cell biopsy from an approximately 300-cell TE. This study was a collaborative effort between investigators at The Center for Human Reproduction in New York City and the Center for Studies in Physics and Biology and the Brivanlou Laboratory of Stem Cell Biology and Molecular Embryology, the latter two both at Rockefeller University in New York City.ResultsBoth models revealed that even under best case scenario, assuming even distribution of mosaicism in TE (since mosaicism is usually clonal, a highly unlikely scenario), a biopsy of at least 27 TE cells would be required to reach minimal diagnostic predictability from a single TEB.ConclusionsAs currently performed, a single TEB is, therefore, mathematically incapable of reliably determining whether an embryo can be transferred or should be discarded. Since a single TEB, as currently performed, apparently is not representative of the complete TE, this study, thus, raises additional concern about the clinical utilization of PGS.

Highlights

It has become increasingly apparent that the trophectoderm (TE) at blastocyst stage is much more mosaic than has been appreciated
preimplantation genetic screening (PGS), questions arose whether a single trophectoderm (TE) biopsy (TEB), can reliably reflect ploidy of the total TE, how accurately a TE biopsy represents the inner cell mass (ICM), from which the embryo arises, and how extensively an embryo self-corrects downstream from blastocyst stage [10, 11]
Since a very high r means almost no mosaicism, decreasing numbers of aneuploid cells in the TEB lead to the hypothesis that an increasingly non-mosaic euploid embryo has to be considered a reasonable explanation for the observed biopsy results

Summary

Introduction

It has become increasingly apparent that the trophectoderm (TE) at blastocyst stage is much more mosaic than has been appreciated. Whether preimplantation genetic screening (PGS), utilizing a single TE biopsy (TEB), can reliably determine embryo ploidy has, increasingly been questioned in parallel. Challenging the biological concept of PGS, questions arose whether a single trophectoderm (TE) biopsy (TEB), can reliably reflect ploidy of the total TE, how accurately a TE biopsy represents the inner cell mass (ICM), from which the embryo arises, and how extensively an embryo self-corrects downstream from blastocyst stage [10, 11]. Self-correction was more efficient within the ICM than within TE, from which the placenta develops (Fig. 1) [12] Faced with such genetic heterogeneity between early embryonic compartments, more aneuploid cells

Methods

Discussion

Conclusion