Previously reported and here added cases demonstrate euploid pregnancies followed by PGT-A as "mosaic" as well as "aneuploid" designated embryos.

BACKGROUND: After the longest time opposing all transfers of embryos by preimplantation genetic testing for aneuploidy (PGT-A) diagnosed as "chromosomal-abnormal," the field has over recent years slowly been moving toward selective transfers of by PGT-A as "mosaic" diagnosed embryos, but is still rejecting transfers of embryos by PGT-A defined as "aneuploid." METHODS: Upon review of the literature, we report published cases of euploid pregnancies following transfers of PGT-A as "aneuploid" diagnosed embryos and add several additional, ongoing cases at our center. RESULTS: Among the published cases from our center, we identified seven euploid pregnancies from "aneuploid" embryos, four of which preceded the PGT-A industry's 2016 switch from binary "euploid" - "aneuploid" reporting to "euploid," "mosaic," and "aneuploid" reporting. That those four cases post 2016 PGT-A definition involving "mosaic" embryos, therefore, cannot be ruled out. Since then, we recently established three additional ongoing pregnancies from transfers of "aneuploid" embryos which still await confirmation of euploidy after delivery. A recent fourth pregnancy from the transfer of a trisomy 9 embryo miscarried before a fetal heart. Outside our own center's experience, the literature revealed only one additional such transfer, involving PGT-A as a "chaotic-aneuploid" diagnosed embryo with six abnormalities, leading to normal euploid delivery. In reviewing the literature, we furthermore demonstrate why current PGT-A reporting that differentiates between "mosaic" and "aneuploid" embryos based on relative percentages of euploid and aneuploid DNA in a single trophectoderm biopsy of on average 5-6 cells, is biologically non-sensical. CONCLUSION: Basic biological evidence and a clinically still very limited experience with transfers of PGT-A as "aneuploid" labeled embryos demonstrate beyond reasonable doubt that at least some "aneuploid" embryos can lead to healthy euploid births. Therefore, this observation establishes beyond reasonable doubt that the rejection of all "aneuploid" embryos from transfer reduces pregnancy and live birth chances for IVF patients. Whether (and to what possible degree) pregnancy and live birth chances differ between "mosaic" and "aneuploid" embryos, remains to be determined. The answer will likely depend on the aneuploidy(ies) of an embryo and to what degree percentages of "mosaicism" in a single, on average 5/6-cell trophectoderm biopsy can reflect the ploidy-status of a complete embryo.

A review of the 2021/2022 PGDIS Position Statement on the transfer of mosaic embryos.

The practice of preimplantation genetic testing for aneuploidy (PGT-A) in association with in vitro fertilization (IVF) since 2016 has been mostly directed by three highly controversial guidance documents issued by the Preimplantation Genetic Diagnosis International Society (PGDIS). Because these documents are so influential on worldwide IVF practice, the most recent one is here the subject of a detailed review, again revealing important misrepresentations and internal contradictions. Most importantly, however, this most recent guidance document still does not prevent the non-use and/or disposal of large numbers of embryos with substantial pregnancy and live-birth potential and, therefore, continues to propagate an IVF practice harmful to many infertile women.

Revisiting selected ethical aspects of current clinical in vitro fertilization (IVF) practice.

Ethical considerations are central to all medicine though, likely, nowhere more essential than in the practice of reproductive endocrinology and infertility. Through in vitro fertilization (IVF), this is the only field in medicine involved in creating human life. IVF has, indeed, so far led to close to 10 million births worldwide. Yet, relating to substantial changes in clinical practice of IVF, the medical literature has remained surprisingly quiet over the last two decades. Major changes especially since 2010, however, call for an updated commentary. Three key changes deserve special notice: Starting out as a strictly medical service, IVF in recent years, in efforts to expand female reproductive lifespans in a process given the term "planned" oocyte cryopreservation, increasingly became more socially motivated. The IVF field also increasingly underwent industrialization and commoditization by outside financial interests. Finally, at least partially driven by industrialization and commoditization, so-called add-ons, the term describing mostly unvalidated tests and procedures added to IVF since 2010, have been held responsible for worldwide declines in fresh, non-donor live birthrates after IVF, to levels not seen since the mid-1990s. We here, therefore, do not offer a review of bioethical considerations regarding IVF as a fertility treatment, but attempt to point out ethical issues that arose because of major recent changes in clinical IVF practice.

Time associations between U.S. birth rates and add-Ons to IVF practice between 2005-2016.

Until 2010, the National Assisted Reproductive Technology Surveillance System (NASS) report, published annually by the Center for Disease Control and Prevention (CDC), demonstrated almost constantly improving live birth rates following fresh non-donor (fnd) in vitro fertilization (IVF) cycles. Almost unnoticed by profession and public, by 2016 they, however, reached lows not seen since 1996-1997. We here attempted to understand underlying causes for this decline. This study used publicly available IVF outcome data, reported by the CDC annually under Congressional mandate, involving over 90% of U.S. IVF centers and over 95% of U.S. IVF cycles. Years 2005, 2010, 2015 and 2016 served as index years, representing respectively, 27,047, 30,425, 21,771 and 19,137 live births in fnd IVF cycles. Concomitantly, the study associated timelines for introduction of new add-ons to IVF practice with changes in outcomes of fnd IVF cycles. Median female age remained at 36.0 years during the study period and center participation was surprisingly stable, thereby confirming reasonable phenotype stability. Main outcome measures were associations of specific IVF practice changes with declines in live IVF birth rates. Time associations were observed with increased utilization of "all-freeze" cycles (embryo banking), mild ovarian stimulation protocols, preimplantation genetic testing for aneuploidy (PGT-A) and increasing utilization of elective single embryo transfer (eSET). Among all add-ons, PGT-A, likely, affected fndIVF most profoundly. Though associations cannot denote causation, they can be hypothesis-generating. Here presented time-associations are compelling, though some of observed pregnancy and live birth loss may have been compensated by increases in frozen-thawed cycles and consequential pregnancies and live births not shown here. Pregnancies in frozen-thawed cycles, however, represent additional treatment cycles, time delays and additional costs. IVF live birth rates not seen since 1996-1997, and a likely continuous downward trend in U.S. IVF outcomes, therefore, mandate a reversal of current outcome trends, whatever ultimately the causes.

Commentary on two recently published formal guidelines on management of "mosaic" embryos after preimplantation genetic testing for aneuploidy (PGT-A).

Two professional societies recently published opinions on the clinical management of "mosaic" results from preimplantation genetic testing for aneuploidy (PGT-A) in human blastocyst-stage embryos in associations with in vitro fertilization (IVF). We here point out three principal shortcomings: (i) Though a most recent societal opinion states that it should not be understood as an endorsement of the use of PGT-A, any discussion of how PGT-A should be clinically interpreted for all practical purposes does offer such an endorsement. (ii) The same guideline derived much of its opinion from a preceding guidance in favor of utilization of PGT-A that did not follow even minimal professional requirements for establishment of practice guidelines. (iii) Published guidelines on so-called "mosaic" embryos from both societies contradict basic biological characteristics of human preimplantation-stage embryos. They, furthermore, are clinically unvalidated and interpret results of a test, increasingly seen as harmful to IVF outcomes for many infertile women. Qualified professional organizations, therefore, should finally offer transparent guidelines about the utilization of PGT-A in association with IVF in general.

The PGS/PGT-A controversy in IVF addressed as a formal conflict resolution analysis.

PURPOSE: To use conflict resolution analysis on the conflict between proponents and opponents of preimplantation genetic testing for aneuploidy (PGT-A), previously called preimplantation genetic screening (PGS). METHODS: Considered in conflict analysis a case study, we reviewed the English literature based on key-word searches at www.pubmed.com and www.google.com, and interviewed professional opinion leaders and other actor-representatives. This analysis was the product of a mandated externship by L.M. at the Foundation for Reproductive Medicine (FRM), as part of the Master of Science Program in Negotiations and Conflict Resolution at Columbia University, New York, NY. RESULTS: Initially a typical difference of opinion, conflict evolved after proponents rejected studies that failed to confirm expected benefits, and authors felt demeaned by their criticism. Becoming "destructive," the conflict evolved according to Glasl's escalation model stages. Proponents became continuous attractors. Unable to produce validations for PGT-A, proponents moved goal posts through 3 stages (PGS 1.0-PGS 3.0). Ultimately concurring that pregnancy and live birth rates are unaffected, they started claiming new benefits. CONCLUSIONS: The FRM underwrote this study as a starting tool for a conflict resolution process. A consensus building conference of stakeholders appears as of this point to represent the most promising potential intervention. The goal of such a conference should be sustainable consensus about clinical utilization of PGS/PGT-A in IVF, based on transparent and validated criteria. A potential date for such a conference is set for 2020.