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Preimplantation Genetic Testing for Aneuploidies

Chromosomal Screening of Embryos – PGT-A

PGT-A, or preimplantation genetic testing for aneuploidies, is a comprehensive screening performed on embryos before transfer. This test reveals the number and structure of chromosomes (bearing genetic material) in each tested embryo.

Normally, embryos have 23 pairs of chromosomes (euploid embryos). But nearly half of the embryos will have abnormal chromosome numbers (aneuploid embryos). When an extra, or missing chromosome, is found in the embryo it is less likely to implant. Often, they will miscarry, or in some cases can still develop to full-term, but a baby with a genetic condition is born (e.g. Down syndrome – an extra chromosome 21).

PGT-A tests the number of chromosomes in DNA taken from embryos. Embryos with an abnormal number of chromosomes will not lead to a healthy live birth, hence they are excluded from use. Embryos with a normal number of chromosomes would be used for embryo transfer.

What are the goals of PGT-A?

  • To increase pregnancy rates
  • To reduce miscarriage rates
  • To increase live birth rates per embryo transfer
  • To shorten the time to pregnancy (reduce the amount of embryo transfers required to create a pregnancy)

What are the indications for PGT-A?

To get the DNA from the embryo we need to biopsy it. Embryo biopsy, despite its safety, is an invasive procedure. It is another additional step in IVF, so needs solid indication of the benefits before being carried out.

But there are, in several patient groups, unquestionable benefits for using PGT-A.

Advanced Maternal Age

It is well-documented that the chromosomally abnormal status of an embryo is contributed mainly by the egg (more than 90%). Maternal age is crucial for the genetic constitution of the egg and hence of the embryo, as the embryo derives from the egg. For example, only 13% (one in eight) of the embryos from women, between the ages of 43-44, are chromosomally normal.

How is PGT-A done?

The only way to perform PGT-A is during IVF cycle.

Egg Fertilization
After fertilization the embryos grow in the lab for 5-6 days and become blastocysts. During that time, natural selection is in action, so on average only half of the fertilized eggs reach blastocyst stage. Those that stopped their development are believed to be genetically incompetent.

Embryo Biopsy + Freezing
Blastocysts with good morphology are biopsied on Days 5-6. During the biopsy an embryologist takes 3-7 cells from the outer part of the blastocyst (trophectoderm, TE). The inner cell mass (ICM) of the blastocyst remains intact, so there is no harm to the future baby. Biopsies from each blastocyst are marked and sent to the genetics lab for analysis. Then the blastocysts are frozen and stored individually.
Genetic Testing Results
There are several methods for PGT-A, the most modern and reliable is next generation sequencing (NGS). It takes around two weeks to gain the results from the genetic lab for each embryo.
Frozen Embryo Transfer
When the genetic results are ready, and at least one euploid embryo is available based on PGT-A result, the preparation of endometrium for embryo transfer begins. On the day of transfer an embryologist thaws the chosen embryo and prepares it for transfer.

How to interpret the results of PGT-A?

The sensitivity (no false negatives) and specificity (no false positives) of NGS method of PGT-A are around 95-98%, as confirmed by various authors. It means that you can trust the results, but also that no diagnostic method can give 100% accuracy. Embryos are highly dynamic structures, embryonic cells divide very actively, so genetic errors in these divisions can occur. This leads to a mosaicism of the embryo — different cells in the embryo may have a different set of chromosomes. But the biopsy only takes out 3-7 cells of the blastocyst, so the question is – ‘are these cells representative of the rest of the embryo’? For now, the answer is ‘YES’ in most cases, these cells are concordant (representative) of the others.

Results for each embryo will be given by a simple definition — ‘recommended for transfer’, ‘not recommended for transfer’, or ‘recommended upon signing the consent form’. But, what does this later definition usually mean? In most cases those embryos are considered mosaic or bearing some light form of abnormalities. Mosaicism in the fetus and newborn baby is a much rarer event than in the embryo, so there must be some mechanism for the elimination of abnormal cells throughout pregnancy. If you receive a PGT-A result of some embryos being considered as mosaic, it is better to plan an appointment with your doctor to assess the possible risks and benefits of transferring a mosaic embryo. If euploid embryos are also available for transfer, then preferably these should be transferred instead.