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ref:Letters
doi.org/10.103...
1.Laboratory of Stem Cell Biology and Molecular Embryology, The Rockefeller University, New York, NY, USA.
2.The Center for Human Reproduction, New
York, NY, USA.
3.The Foundation for Reproductive Medicine, New York, NY, USA. 4.Department of Obstetrics and Gynecology, Medical University of Vienna,
Vienna, Austria.
5.These authors contributed equally: Min Yang, Tiago Rito. e-mail: brvnlou@rockefeller.edu; ngleicher@thechr.com
Chromosomal instability leading to aneuploidy is pervasive in early human embryos1-3
and is considered as a major
cause of infertility and pregnancy wastage.
. Here we provide several lines of evidence that blastocysts containing
aneuploid cells are worthy of in vitro fertilization transfer.
First, we show clinically that aneuploid embryos can lead to
healthy births, suggesting the presence of an in vivo mechanism to eliminate aneuploidy. Second, early development and
cell specification modelled in micropatterned human ‘gastruloids’ grown in confined geometry show that aneuploid
cells are depleted from embryonic germ layers, but not from
extraembryonic tissue, by apoptosis in a bone morphogenetic
protein 4 (BMP4)-dependent manner. Third, a small percentage of euploid cells rescues embryonic tissue in mosaic gastruloids when mixed with aneuploid cells. Finally, single-cell
RNA-sequencing analysis of early human embryos revealed a
decline of aneuploidy beginning on day 3.
"Our findings challenge two current dogmas: that a single trophectoderm biopsy
at blastocyst stage to perform prenatal genetic testing can
accurately determine the chromosomal make-up of a human
embryo, and that aneuploid embryos should be withheld from
embryo transfer in association with in vitro fertilization."
Although chromosomal mosaicism is common in human
embryos derived from in vitro fertilization (IVF),most IVF centres
consider the mosaic or aneuploid embryos to be abnormal, and thus
withhold them from transfer into uteri.
Indeed, more than 80% of
these embryos contain aneuploid blastomeres, while only 12.5% of
fertilized oocytes are aneuploid7
; approximately 60% of embryos
are euploid-aneuploid mosaic and only 22% are euploid8
. The use
of preimplantation genetic testing for aneuploidy (PGT-A) before
embryo transfer to screen out aneuploidy has been proposed to
improve delivery rates and reduce miscarriages in association with
IVF.
and has become an increasingly common clinical practice.
Whether PGT-A improves IVF outcomes has, however, remained
controversial. The high false-positive and false-negative rates
in PGT-A means that a substantial number of diagnosed aneuploid
or euploid embryos are actually mosaic. As spontaneous and IVF
pregnancies demonstrate similar levels of mosaicism (12% versus
6.3%), excluding all embryos containing aneuploid cells from
transfer would therefore deprive patients of options.
To test whether mosaic human embryos develop normally,
we report on 32 women who underwent frozen-thawed embryo
transfers with 77 blastocysts that were diagnosed as mosaic and
aneuploid by PGT-A. Nine clinical pregnancies were established
(28.2%) from these transfers, 4 of which miscarried (44.4% of
pregnancies, 12.5% of cycles), and the remaining ones were delivered (15.6%; Supplementary Table 1). Characteristics of participants
and IVF cycles are presented in Supplementary Table 2. Median age
was 40.6±4.1 years. Our observed pregnancy and live birth rate
matched or even exceed the national average of expected outcomes
for age-matched individuals who did not use PGT-A diagnostics
(18% pregnancy and 12% live birth rate at age 40). Interestingly,
while all transferred embryos were aneuploid, prenatal chromosomal analyses performed with chronic villus biopsies (CVS) or
amniocenteses in delivered pregnancies uniformly revealed normal
karyotypes. Comprehensive chromosomal analysis on the products
of conception from three participants who miscarried in the first
trimester showed that two demonstrated the same chromosomal
abnormalities as previously detected in the original PGT-A analysis of the transferred embryos (Supplementary Table 1, patients 8
and 9), while the third (patient 7) had a normal karyotype, indicating the elimination of aneuploidy and suggesting a different
cause for her miscarriage. Furthermore, successful cases of transferring diagnosed mosaic embryos have been reported. Together,
these clinical results unveil the developmental capacity of mosaic
embryos, thereby supporting the possibility of a developmental rescue mechanism.
Indeed, an innate ability of the embryo to select against aneu ploid cells has been demonstrated using a mouse model.
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