pgs testing

PGS Testing of Age-Related Aneuploidy

Up to the present decade, PGS testing was based primarily on biopsy of polar bodies or cleavage stage embryos with diagnosis based on FISH/PCR. This has now been replaced with blastocyst TE biopsy in combination with advanced CCS techniques blastocyst vitrification, a strategy known as “PGS 2.0.” However, considerable controversy continues about the safety, efficacy and economic effectiveness of PGS 2.0.

Industry pressure, competition between professionals, and sometimes inflexible scientific logic have created tough pros and cons that do not help patients make informed choices. Whereas the benefits of using PGD for selecting healthy embryos in couples with known genetic or chromosomal problems outweighs the use of invasive techniques, the same cannot be said for PGS testing. Although PGS testing after blastocyst biopsy (counting chromosomes in an embryo) has been likened to amniocentesis (counting chromosomes in an early fetus), this is an unfortunate comparison.

Blastocyst biopsy removes TE cells, part of an essential structure of the embryo: not only does this not necessarily represent the chromosomal constitution of the embryo, but the embryo is still differentiating before it implants. Amniocentesis samples cells are external to a largely differentiated fetus. This comparison is even more irrational when we consider the tragedy of losing a fetus after amniocentesis, which occurs in about 1 in 200 cases, and the “nonchalance” of losing a potential baby at the blastocyst stage, which occurs in up to 50% of cases in experienced hands due to damage at biopsy or technical/amplification failure.

Current Indications for PGS Testing

  1. Patients of advanced maternal age, who tend to produce a higher number of aneuploid embryos than younger patients.
  2. Patients with repeated implantation failure, recurrent miscarriage and with severe male factor infertility.
  3. “Reduced Time to Pregnancy (TTP)”: patients may be told that PGS testing can reduce the time to achieve a normal pregnancy and may reduce the incidence of miscarriage.

There is currently no clear consensus regarding which patient groups, if any, can benefit from PGS 2.0. However, several considerations are important when a patient is counseled to undertake PGS testing:

  1. Offering a patient PGS testing at the time of initial consultation, i.e., there is intention to treat, does not increase the patient’s chance of pregnancy.
  2. PGS testing does not improve an embryo but is merely a selection procedure.
  3. Many embryos (up to 50% in less experienced laboratories) are lost in the diagnosis due to biopsy or amplification failure.
  4. The biopsy is always invasive and leads to damage to the TE.
  5. Next generation sequencing (NGS) can diagnose inherited genetic disease, but it does not define embryo viability or health: it does not guarantee that genes are free from DNA breaks/errors, or that they will be expressed/transcribed correctly at the appropriate time in preimplantation development.
  6. PGS testing cannot detect embryos whose health has been jeopardized by metabolic malfunctions due to epigenetic effects resulting from inherent gamete physiology or suboptimal in vitro culture and handling.
  7. The phenomenon of mosaicism is of crucial importance. The cells in the TE may differ from one region to another and therefore a biopsy may not be representative of the whole embryo.
  8. Mosaic embryos in any case can give rise to healthy babies.
  9. The correct number of chromosomes does not guarantee either live births or even successful implantation. It has become increasingly clear that non-genomic factors, including mitochondrial activity, methylation patterns, cytoplasmic glutathione levels, or a myriad of biochemical and physiological parameters are necessary for a viable embryo and a healthy birth.
  10. Blastocyst formation is a fundamental step in embryogenesis. An amazingly complex structure with clear developmental purpose, it is subject to regulation at the morphological, cellular, transcriptional and epigenetic levels. TE biopsy is a radical intervention involving an essential layer of cells that leads to collapse of the blastocyst cavity at a delicate moment in preimplantation development, with probable modification of epithelial elements important in cellular communication and differentiation, such as gap junctions and ion and water pumps. The TE plays a fundamental part in crosstalk with the endometrium and the production of enzymes for hatching: bovine implantation may be improved by adding trophectoderm tissue to the blastocyst. Introducing widespread blastocyst stage PGS testing would mean that a sizable part of the TE is eliminated in all biopsied healthy embryos that give birth and children born with an essential part of their preimplantation development compromised by dissection. Although the preimplantation mammalian embryo is highly regulated and may recover from such surgery, we do not know the long-term consequences of TE biopsy.
  11. A three-fold increase in the risk of maternal preeclampsia has been found after trophectoderm biopsy for preimplantation genetic testing.
  12. PGS testing may double the cost of a standard IVF treatment.
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