Clinically recognizable error rate after the transfer of comprehensive chromosomal screened euploid embryos is low

Capsule:
We discuss how the clinically recognizable error rate among embryos designated as euploid was low in ongoing gestations. Among clinical losses, where products of conception were evaluable, all errors were attributable to mosaicism.

Authors:
Marie D. Werner, M.D., Mark P. Leondires, M.D., William B. Schoolcraft, M.D., H.C.L.D., Brad T. Miller, M.D., Alan B. Copperman, M.D., Edwin D. Robins, M.D., Francisco Arredondo, M.D., M.P.H., Timothy N. Hickman, M.D., Jacqueline Gutmann, M.D., Wendy J. Schillings, M.D., Brynn Levy, Ph.D., Deanne Taylor, Ph.D., Nathan R. Treff, Ph.D., Richard T. Scott Jr., M.D., H.C.L.D.

Volume 102, Issue 6, Pages 1613-1618

Abstract:

Objective:
To determine the clinically recognizable error rate with the use of quantitative polymerase chain reaction (qPCR)–based comprehensive chromosomal screening (CCS).

Design:
Retrospective study.

Setting:
Multiple fertility centers.

Patient(s):
All patients receiving euploid designated embryos.

Intervention(s):
Trophectoderm biopsy for CCS.

Main Outcome Measure(s):
Evaluation of the pregnancy outcomes following the transfer of qPCR-designated euploid embryos. Calculation of the clinically recognizable error rate.

Result(s):
A total of 3,168 transfers led to 2,354 pregnancies (74.3%). Of 4,794 CCS euploid embryos transferred, 2,976 gestational sacs developed, reflecting a clinical implantation rate of 62.1%. In the cases where a miscarriage occurred and products of conception were available for analysis, ten were ultimately found to be aneuploid. Seven were identified in the products of conception following clinical losses and three in ongoing pregnancies. The clinically recognizable error rate per embryo designated as euploid was 0.21% (95% confidence interval [CI] 0.10–0.37). The clinically recognizable error rate per transfer was 0.32% (95% CI 0.16–0.56). The clinically recognizable error rate per ongoing pregnancy was 0.13% (95% CI 0.03–0.37). Three products of conception from aneuploid losses were available to the molecular laboratory for detailed examination, and all of them demonstrated fetal mosaicism.

Conclusion(s):
The clinically recognizable error rate with qPCR-based CCS is real but quite low. Although evaluated in only a limited number of specimens, mosaicism appears to play a prominent role in misdiagnoses. Mosaic errors present a genuine limit to the effectiveness of aneuploidy screening, because they are not attributable to technical issues in the embryology or analytic laboratories.

  • Shvetha Zarek

    This is a retrospective observational study of 4,794 CCS euploid embryos (3,168 transfers) that encompassed ten RMA centers that all utilized q-PCR CCS technology through Reproductive Medicine Associates Genetics. The objective was to determine the “clinically recognizable error rate” after the transfer of CCS determined euploid embryos. This technology is unable to currently distinguish haploidy, triploidy, and tetraploidy. The authors collected karyotype data from the pregnancies in the following manner: products of conception from 50% of the subjects who had a clinical loss, amniocentesis, chorionic villus sampling or cytogenetic analysis of a liveborn infant. They calculated the error rate as the total number of implantations found to be aneuploid divided by the total number of embryos transferred and expressed as a percentage.

    They report that the clinical implantation rate was 62.1% (n=2,976) of which 92% progressed to delivery and 238 (8%) miscarried or spontaneously reduced. They report that the clinically recognizable error rate per euploid designated embryo was 10/4974 or 0.21%. The clinically recognizable error rate as an expression of total gestational sacs was 3 out of 2,976 or 0.1%.

    Given the increasing interest in utilizing CCS as standard practice before embryo transfer, this is an important topic in quantifying the clinically recognizable error rate. However, the low number of aneuploid pregnancies should be viewed with caution, as the authors also highlight, given that they were limited in the number of tissue specimens that they were able to obtain from the clinical losses in order to confirm euploid status.

    • Marie Werner

      Thank you for your comments on our research.

      In this retrospective review, the routine clinical utilization of qPCR based
      CCS was evaluated and the clinically recognizable error rate following the transfer of embryos designated as euploid was evaluated. This study found that
      the clinically recognizable error rate per ongoing pregnancy to be 0.13%, lending increased confidence to recommending routine use of this technology. The findings mentioned in this study may prove useful for patient counseling when deciding to use this technology. While the risk of a clinical recognizable error is exceedingly low, these errors are primarily attributed to mosaicism. The ability to better diagnose mosaicism within the embryo is of great interest to the future development of improved CCS and embryo selection technologies.

      • Shvetha Zarek

        Thank you for the reply and for underscoring that the clinically recognizable error is quite low such that increasing the number of tissue specimens available for analysis will not raise the error rate dramatically, We very
        much enjoyed reviewing this study in our group and send our best regards.

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