Preimplantation Genetic Screening (PGS) Test

Preimplantation genetic screening (PGS), refers to removing one or more cells from an IVF generated embryo to test for chromosomal abnormality. PGS screens the embryo for normal chromosome number. Humans have 23 pairs of chromosomes. Down syndrome has an extra chromosome 21, referred to as trisomy 21. This can be detected by PGS. PGS does not test for a specific disease – such as cystic fibrosis, thalassemia. Detection of disease such as cystic fibrosis, thalassemia through embryo biopsy is known as Preimplantation Genetic Diagnosis (PGD)

Many studies have shown that about 60% of human preimplantation embryos from IVF are chromosomally abnormal. The rate of abnormalities to a large extent is affected by the female age. Chromosomes in eggs from older women have a significantly increased rate of abnormalities.

chromosomal abnormalities are mostly responsible for the failure of the implantation of IVF embryos. Chromosomal abnormalities are also responsible for about 70% of miscarriages in early pregnancy.

Problems in the past with Aneuploidy Screening of IVF embryos

PGS in IVF embryo for aneuploidy (an abnormal number of chromosomes) has been used since the mid-1990s. However, studies showed that performing embryo biopsy on day 3 and performing the genetic analysis using FISH technology (fluorescent in situ hybridization) did not result in an increased pregnancy rate.

There were two main problems with Day-3 PGS

  1. FISH technology was usually looking at only 5 chromosomes out of 23. Therefore, the FISH test would miss many chromosomal abnormalities. This resulted in abnormal embryos being transferred even after the screening test result comes as “normal”.
  2. The biopsies on day 3 were removing a cell (or 2cells) from a 6 to 10 cell embryo. This required a relatively large hole being made in the zona of the embryo and then removal of a significant percentage of “biomass”.

Recent advances in technology give better IVF success rates after aneuploidy screening

Improvements in genetic technologies

Advances in the field have led to the utilization of improved genetics technologies that allow assessment of all 23 pairs of chromosomes.

There are currently 4 technologies that can be utilized for assessment of normality of all 23 chromosomes :

  1. Next-Generation Sequencing (NGS)
  2. Array Comparative Genomic Hybridization (aCGH)
  3. Single nucleotide polymorphism microarrays (SNP)
  4. Quantitative real-time polymerase chain reaction(qPCR)

Comparative Genomic Hybridization (often referred to as CGH, or a CGH) is microarray technology that is often used now instead of the older and far less comprehensive FISH. With microarray CGH, the actual DNA in the embryo is compared to a known normal DNA specimen utilizing thousands of specific genetic markers. This gives a more accurate result, with far fewer false normal or false abnormal results.

Some studies have determined that the error rate using array CGH technology is about 2%. FISH has an error rate of about 5-10%. Additionally, many other abnormal embryos would be reported by FISH as normal because the abnormality was in a chromosome that was not part of the FISH panel being used.

Next-Generation Sequencing (NGS) is a newer technology that has been increasingly utilized for testing IVF embryos since about 2015. NGS appears to be better at detecting smaller segmental changes compared to aCGH. It is also thought to be better at detecting partial aneuploidy and small unbalanced translocations. Mosaicism is probably more likely to be discovered using Next-Generation Sequencing.

Improvement in embryo biopsy techniques

Trophectoderm biopsy is done at the blastocyst stage on day 5 and 6. At this stage, there are many more cells present in the embryo. This allows multiple cells to be removed from the trophectoderm which is precursors to the placenta and the inner mass cells which are precursors to the fetus can be left undisturbed during the biopsy. With trophectoderm biopsy, about 4-5 cells are snipped off for testing. This does not significantly weaken the embryo because it has about 100 cells at this stage.

The combination of these two modifications (advanced genetics and trophectoderm biopsy) has led to significantly improved pregnancy success rates for patients that want to utilize PGS for their IVF treatment.

We are seeing substantially improved ongoing pregnancy rates in patients that are having trophectoderm biopsy performed at the blastocyst stage with subsequent freezing of their embryos.

A frozen-thawed transfer cycle is done after the chromosomal analysis results come back.

Uterine receptivity issues

There is some interesting speculation that the uterine lining could be less receptive during a stimulated cycle as compared to the controlled or “artificial” embryo replacement cycle.
Transferring embryos in a controlled cycle (using frozen embryos) gives a higher pregnancy rate than in a “fresh cycle”.

The improved success rate seen following blastocyst biopsy and comprehensive chromosomal analysis is also due to the benefit of transferring chromosomally normal embryos.

Who should go for PGS (Aneuploidy Screening)

This is currently an evolving issue in the field of reproductive medicine
Some potential candidates could be :

  1. Women over (about) 35 years old that want IVF and make enough embryos so that they will have multiple blastocysts available for biopsy.
  2. Patients at any age that have failed multiple IVF cycles. They want answers about why they are failing. They also want to know what to do in order to improve their chances to have a baby.
  3. PGS can sometimes provide answers in these cases.
  4. PGS can also provide a ‘’weeding out’’ of the abnormal embryos. For example, if one embryo out of 6 is chromosomally normal and 5 out 0f 6 are abnormal - we transfer the one normal embryo and should have a very good chance for a baby.
  5. Couples with recurrent miscarriages.