Clinical error rates of next generation sequencing and array comparative genomic hybridization with single thawed euploid embryo transfer

Friedenthal, Jenna; Maxwell, Susan; Tiegs, Ashley W.; Besser, Andria G.; McCaffrey, C.; Munné, Santiago; Noyes, N.; Grifo, James A.

doi:10.1016/j.ejmg.2020.103852

Cited by 26 publications

(13 citation statements)

References 26 publications

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“…This was confirmed by a metaanalysis that concluded using PGT-A that implantation, clinical pregnancy, live birth, and ongoing pregnancy rates were similar for euploid day-5 and day-6 blastocyst transfers (21). These results align with those of previous reports that used PGT-A, with similar outcomes for day-5 or day-6 euploid transfers (22)(23)(24)(25). A recent study evaluating the effect of the day of cryopreservation showed that in frozen transfers of euploid embryos assessed by PGT-A, the day of cryopreservation did not significantly affect live birth rates (26).…”

Section: What Additional Evidence Is Needed To Support the Pro?supporting

confidence: 84%

Noninvasive preimplantation genetic testing for aneuploidy in spent culture medium as a substitute for trophectoderm biopsy

Rubio

Racowsky

Barad

et al. 2021

Fertility and Sterility

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Section: What Additional Evidence Is Needed To Support the Pro?supporting

confidence: 84%

Noninvasive preimplantation genetic testing for aneuploidy in spent culture medium as a substitute for trophectoderm biopsy

Rubio

Racowsky

Barad

et al. 2021

Fertility and Sterility

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show abstract

“…Mosaic embryos were also excluded from this study, since they may show lower implantation and higher miscarriage rates [ 12 – 14 ]. We considered mosaicism as the presence in an embryo of several cell lines with a different chromosome constitution.…”

Section: Methodsmentioning

confidence: 99%

Association between clinical and IVF laboratory parameters and miscarriage after single euploid embryo transfers

Nogales

Cruz

Frutos

et al. 2021

Reprod Biol Endocrinol

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Background The goal of this study was to investigate which factors, excluding embryo aneuploidies, are associated with miscarriage in patients who have undergone a single euploid blastocyst transfer. Methods Retrospective, observational and multicenter study with 2832 patients undergoing preimplantational genetic testing for aneuploidies (PGT-A) due to repeated implantation failure, recurrent pregnancy loss, advanced maternal age or severe male factor were transferred one single euploid embryo. Results One of the main findings was a significant relationship between body mass index (BMI) and miscarriage rates (13.4% in underweight women, 12.1% in normal weight, 14.5% in overweight, and 19.2% in obese women, odds ratio [OD] 1.04; 95% confidence interval [CI], 1.01–1.07 p = 0.006). Endometrial thickness (OD 0.65; 95%, 0.52–0.77 p = 0.04) and type of endometrial preparation (natural cycle or hormone replacement cycle) (OD 0.77; 95%, 0.52–0.77, p = 0.04) were also associated with miscarriage rates. Conclusions BMI was strongly associated to miscarriage rates. We also observed a weaker association with endometrial thickness and with the type of endometrial preparation (natural cycle or hormone replacement cycle). None of the other studied variables (biopsy day, maternal and male age, duration of infertility, cycle length, previous miscarriages, previous live births, previous In Vitro Fertilization (IVF) cycles, endometrial pattern and/or diagnosis) were associated with miscarriage rates.

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“…With regards to negative predictive value, that is the likelihood of reducing the prevalence of true mosaic pregnancies by avoiding the clinical utilization of putative mosaic embryos, data are lacking, and a large sample size would be needed considering the low general prevalence of the condition (around 0.3% of pregnancies). However, few observations so far have highlighted high rates of true mosaicism findings in cytogenetic analysis of POCs from uniformly euploid embryos diagnosed with high resolution aCGH and NGS 22 . Furthermore, in our trial, the only instance of mosaicism detected in the cytogenetic follow-up of pregnancies and newborns was identified following the transfer a uniformly euploid embryo, further suggesting the inherent limitation in detecting or excluding mosaicism in PGT-A cycle with sufficient accuracy.…”

Section: Discussionmentioning

confidence: 99%

A prospective double-blinded non-selection trial of reproductive outcomes and chromosomal normalcy of newborns derived from putative low/moderate-degree mosaic IVF embryos

Capalbo

Poli

Rienzi

et al. 2021

Preprint

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Background Next generation sequencing (NGS) has increased detection sensitivity of intermediate chromosome copy number variations (CNV) consistent with chromosomal mosaicism. Recently, this methodology has found application in preimplantation genetic testing (PGT) of trophectoderm (TE) biopsies collected from IVF-generated human embryos. As a consequence, the detection rate of intermediate CNV states in IVF embryos has drastically increased, posing questions about the accuracy in identifying genuine mosaicism in highly heterogeneous biological specimens. The association between analytical values consistent with mosaicism and the reproductive potential of the embryo, as well as newborn's chromosomal normalcy, have not yet been thoroughly determined. Methods We conducted a multicentre, double-blinded, non-selection trial including 1,190 patients undergoing in a total of 1,337 IVF with preimplantation genetic testing for aneuploidies (PGT-A) treatment cycles. NGS was performed on clinical TE biopsies collected from blastocyst-stage embryos. All embryos were reported as euploid if all autosomes had a chromosomal copy number value below the threshold of 50% abnormal cells per sample. After embryo transfer, three comparative classes were analysed: uniformly euploid profiles (<20% aneuploid cells), putative low-degree mosaicism (20%-30% aneuploid cells) or putative moderate-degree mosaicism (30%-50% aneuploid cells). Primary outcome measure was live birth rate (LBR) per transfer and newborn's karyotype. Results LBR after transfer of uniformly euploid embryos, low-degree, and moderate-degree mosaic embryos were 43.4% (95% C.I. 38.9 - 47.9), 42.9% (95% C.I. 37.1 - 48.9) and 42% (95% C.I. 33.4 - 50.9), respectively. No difference was detected for this primary outcome between euploid and mosaic low/moderate categories (OR= 0.96; 95% CI 0.743 to 1.263; P=0.816). The non-inferiority endpoint was met as the confidence interval for the difference fell below the planned 7.5% margin (95% C.I. -5.7 - 7.3). Likewise, no statistically significant difference was observed comparing moderate versus low degree mosaic embryos (P=0.92). Neonatal karyotypes were also similar and no instances of mosaicism or uniparental disomies (UPDs) were detected in babies born following putative low or moderate-degree mosaic embryo transfer. Should the embryos with low or moderate-degree mosaic TE biopsies had been classified as chromosomally abnormal and thus discarded for clinical use, LBR per cycle would have decreased by 36% without any clinical benefit. Conclusions This prospective non-selection trial provides substantial evidence that reporting and/or not transferring embryos with low/moderate-degree mosaicism for whole chromosomes have no clinical utility. Moreover, dismissing these embryos from clinical use has the counterproductive effect of reducing overall embryo availability, thus reducing the chance of successful outcome derived from an IVF treatment without any clinical benefit. (Funded by Igenomix; ClinicalTrials.gov number, NCT03673592)

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Clinical error rates of next generation sequencing and array comparative genomic hybridization with single thawed euploid embryo transfer

Cited by 26 publications

References 26 publications

Noninvasive preimplantation genetic testing for aneuploidy in spent culture medium as a substitute for trophectoderm biopsy

Noninvasive preimplantation genetic testing for aneuploidy in spent culture medium as a substitute for trophectoderm biopsy

Association between clinical and IVF laboratory parameters and miscarriage after single euploid embryo transfers

A prospective double-blinded non-selection trial of reproductive outcomes and chromosomal normalcy of newborns derived from putative low/moderate-degree mosaic IVF embryos

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