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Comprehensive Chromosomal Screening

It is no secret that in many IVF cycles , the transfer of apparently nice looking embryos will fail to result in a pregnancy or a live birth. There is a substantial amount of evidence that points to the likelihood that most of these failures are due to chromosome abnormalities in the embryos. Even in apparently normal healthy couples, a high percentage of embryos will not have the correct number of chromosomes. It has been thought that if abnormal embryos could be identified and then not used to attempt pregnancy, that the chance for a healthy live birth would be increased.

What is the correct number of chromosomes in an embryo?

 

A normal healthy embryo has 23 pairs of chromosomes

Normal embryos should have 46 chromosomes arranged in 23 pairs. There should be two copies of chromosome #1 and two copies of chromosome #2 and so on. The 23rd pair of chromosomes are known as the sex chromosomes. These are the two chromosomes responsible for determining the gender of the individual. If there are two “X” chromosomes, the embryo will develop into a female. If there is one “X” and one “Y” chromosome, the embryo will develop into a male.

How many chromosomes can be tested?

In the early 1990s, we developed a technique known as preimplantation genetic diagnosis to “count” the number of chromosomes in an embryo. PGD in those days relied on a technology known as fluorescent in-situ hybridization or FISH to count chromosomes. PGD with FISH allowed us to looked at 8 to 9 chromosome pairs.

Today, newer technologies such as Next Generation Sequencing (NGS) and microarray comparative genomic hybridization or aCGH allow us to test all 23 pairs of chromosomes in an embryo. This is known as comprehensive chromosomal screening (CCS) or preimplantation genetic screening (PGS).

How does comprehensive chromosome screening work?

To look at the chromosomes in an embryo, it is necessary to remove one or more cells from the embryo. This is called an embryo biopsy. At IVF1, we are skilled at biopsying embryos at several stages.

CCS with polar body biopsy

One option for couples, is to remove two tiny cells that are normally disposed of by the embryo just after fertilization. These cells are called polar bodies. It is possible to do comprehensive chromosome screening on polar bodies. The main advantage of CCS with polar body biopsy is that results can be obtained in time to transfer the embryos at the normal time. No embryo freezing is required. The main disadvantage is that the polar bodies only give us information about embryo abnormalities that originated in the egg prior to fertilization. Recent data (2011) indicates that between 10-30% of chromosome abnormalities in an embryo may be missed by polar body testing. This means that is the CCS result is normal, that there is a 10-30% chance of abnormality being missed. Another disadvantage of CCS with polar body biopsy is that it is impossible to determine the gender of the embryos since gender is determined by the sperm chromosomes. Many babies have been born using polar body biopsy and CCS and this is the most common method used in Europe. However, it is no longer our recommended method at IVF1.

CCS with blastomere biopsy

On the 3rd day of embryo development, most normal embryos should have divided into 8 cells or blastomeres. Biopsying one blastomere and performing comprehensive chromosome screening can also be performed. Again, the main advantage is that results can be obtained in time to do a blastocyst transfer on day 5 of development. It is also possible to determine gender at this stage.

There are two main disadvantages to blastomere biopsy. First, there is very good evidence that the chance for embryo implantation will be reduced by biopsying at this stage. Second, in many cases, all eight of the blastomeres may not be identical. This is called mosaicism and it can lead to misdiagnosis.

CCS with trophoblast biopsy

By the 5th or 6th day of embryo development, a small percentage of the embryos should have reached the blastocyst stage. A blastocyst is an embryo which has divided into about 100 cells and has separated into two cell types. The inner cell mass is a small group of cells that will go on to form the fetus and should not be disturbed. This makes up about 5% of the blastocyst. The remaining 95% forms a fluid filled sphere and are called trophoblast cells. Trophoblast cells go on to make the placenta and all the other tissues except for the fetus. Trophoblast cells can be biopsied without affecting the development of the embryo. A recent study (2011) found NO ADVERSE EFFECTS of biopsy at the trophoblast stage.

Since many trophoblast cells can be removed, the results are going to be more accurate than either polar body or blastomere cells. Since only a portion of the embryos have the ability to reach the blastocyst stage, we don’t have to waste time or resources testing embryos that would not have developed anyway. Like blastomere biopsy, gender can be determined at the trophoblast stage.

The disadvantages of trophoblast biopsy occur because of the time it takes to get results (12-24 hours). Depending on the embryo development, this may require that we either freeze embryos and replace them at a later time after the results are in. If a patient has well developed blastocysts by the 5th day after egg retrieval, trophoblast biopsy can be performed and results obtained in time to do a transfer on the morning of Day 6. Recent studies (2013) have suggested that the combination of trophoblast biopsy, embryos freezing and 23 chromosome screening is a powerful method of embryo selection and the chance for embryo implantation and delivery of a child is very high. This is now the current recommended method for CCS at IVF1.

A cell with multiple chromosome abnormalities

Summary

New techniques for evaluating embryos in IVF cycles are emerging. Comprehensive chromosome screening (CCS) with microarray comparative genomic hybridization (CGH) has been adopted worldwide as a successful method for testing embryos. Next Generation Sequencing (NGS) is allowing us to assess embryos for abnormal numbers of chromosomes more quickly and for lower cost then we have been able to do in the past. Embryos that have reached the expanded blastocyst stage and have normal chromosomes by CCS have a very high potential to produce a baby.