Preimplantation genetic testing for aneuploidy: It's déjà vu all over again!

Reflections

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Volume 112, Issue 6, Pages 1046–1047

Author:

Glenn L. Schattman, M.D.

Abstract:

Reflections on "Preimplantation genetic testing for aneuploidy versus morphology as selection criteria for single frozen embryo transfer in good prognosis patients: a multicenter randomized clinical trial" by Munné et al.


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Fertility and Sterility

Editorial Office, American Society for Reproductive Medicine

Fertility and Sterility® is an international journal for obstetricians, gynecologists, reproductive endocrinologists, urologists, basic scientists and others who treat and investigate problems of infertility and human reproductive disorders. The journal publishes juried original scientific articles in clinical and laboratory research relevant to reproductive endocrinology, urology, andrology, physiology, immunology, genetics, contraception, and menopause. Fertility and Sterility® encourages and supports meaningful basic and clinical research, and facilitates and promotes excellence in professional education, in the field of reproductive medicine.

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Go to the profile of Prof Alan Handyside
Prof Alan Handyside 11 months ago

Preimplantation genetic testing for aneuploidy: improved clinical outcomes per single embryo transfer in women aged 35-40 years


In this issue of the journal, we report the outcome of a large randomised clinical trial (RCT) of preimplantation genetic testing for aneuploidy (PGT-A) using next generation sequencing (NGS) based copy number analysis of all 24 chromosomes.  The RCT was focussed on patients between the ages of 25 and 40 years with at least two blastocysts of sufficient quality for trophectoderm biopsy and randomisation was therefore on day 6 post insemination. Given this scenario, the question addressed was simply ‘does the use of PGT-A to select euploid embryos versus embryo morphology alone improve clinical outcomes at 20 weeks gestation following single vitrified-warmed blastocyst transfer?’  The overall results in women of this age range (average age 34 years) demonstrated no significant improvement in clinical outcomes, but were equally not harmed, in these relatively good prognosis patients. In women aged 35-40 years, however, there was a significant improvement from 37 to 51% per embryo transfer (p=0.035), a relative increase of 38%. On the basis of this evidence, therefore, we argue that patients fitting these criteria (35-40 of age with 2 or more blastocysts) and considering single embryo transfer should be offered PGT-A to improve their chances of a clinical pregnancy and healthy singleton live birth.


On the principle of ‘primum non nocere’, recent evidence from genetic analysis of products of conception following IVF confirms that many of the transferred embryos were aneuploid and often grossly aneuploid and incapable of development to term (Segawa et al. 2017). There can be no clinical or ethical justification for transferring aneuploid embryos giving patients false-hope of pregnancy and healthy livebirth, especially with NGS-based testing where all studies so far demonstrate excellent positive predictive value when the result is euploid and where fully aneuploid embryos invariably result in failure after replacement (Munne et al. 2019). This study was started before the current criteria of mosaicism were established. Embryos classified as mosaic in this study were not replaced (not necessarily discarded) and some may have resulted in pregnancy, but we doubt this would have changed the overall outcome of the study.


We agree that testing for aneuploidy even with NGS-based methods remains challenging but the alternative of transferring embryos blindly without testing can result in poor clinical management with multiple futile cycles and transfers of grossly aneuploid embryos, an increased risk of miscarriage and encourages multiple embryo transfers with all of the known adverse clinical outcomes. The lack of improvement in young good prognosis patients, in which 40% of embryos were identified as aneuploid, suggests that either poor embryo biopsy protocols and/or ill-defined NGS results may have counteracted the beneficial effects of testing and further research and standardisation is required. Given that several single-center RCTs have demonstrated a significant benefit of PGT-A in these patients, this study involving multiple genetic testing labs and clinics highlights the challenges of the widespread application of new technologies.


Instead of déjà vu and an inclination to go back to the pre-testing era and day 3 transfers when the answer to a failed cycle was often simply to increase ovarian stimulation and try again, our vision for the future is one in which improved PGT-A accurately discriminates between aneuploid and chromosomally mosaic embryos, can be performed non-invasively and at low cost.  Then good and poor prognosis patients of all ages will be able to benefit from the advantages of PGT-A and any residual adverse effects minimised.


 


Santiago Munné 1,2, Alan Handyside3 and Susan Willman4,5


1Overture Life, Barcelona, Spain


2Dept. Ob/Gyn, Yale University, New Heaven, CT


3School of Biosciences, University of Kent, Canterbury, UK


4Reproductive Science Center of the San Francisco Bay Area, San Ramon, CA


5Contra Costa Regional Medical Center, Martinez, CA


 


 


 


Segawa, Tomoya, Tomoko Kuroda, Keiichi Kato, Masako Kuroda, Kenji Omi, Osamu Miyauchi, Yoshiaki Watanabe, Tsuyoshi Okubo, Hisao Osada, and Shokichi Teramoto. 2017. “Cytogenetic Analysis of the Retained Products of Conception after Missed Abortion Following Blastocyst Transfer: A Retrospective, Large-Scale, Single-Centre Study.” Reproductive Biomedicine Online 34 (2): 203–10. https://doi.org/10.1016/j.rbmo.2016.11.005.


Munné S, Spinella F, Grifo J, Zhang J, Parriego Beltran M, Fragouli E, Fiorentino F. 2019. Clinical outcomes after the transfer of blastocysts characterized as mosaic by high resolution Next Generation Sequencing- further insights. European J Med Genet, in press