Genetic Testing

Pre-implantation Genetic Testing for Aneuploidy

Pre-Implantation Genetic Testing for Aneuploidy (PGT-A) is a technique that counts the number of chromosomes present in embryos before they are transferred to the womb. The embryos are created during In Vitro Fertilisation (IVF) treatment. The aim of PGT-A is to increase the likelihood of having a baby by transferring embryos that have the correct number of chromosomes and are therefore deemed genetically balanced. By performing PGT-A on IVF embryos, we aim to do one or more of the below:

• Reduce the risk of miscarriage
• Reduce the risk of having an abnormal pregnancy
• Reduce the risk of having a child with a chromosome abnormality, such as Downs Syndrome.
• Reduce the number of multiple pregnancies by transferring a SINGLE “genetically competent” embryo
• Provide useful diagnostic information regarding the likelihood of IVF success
• A quicker time to a successful outcome of IVF
• Reduced overall financial and emotional costs of achieving a viable pregnancy
• Reduce the number of stored embryos that are genetically imbalanced and therefore unlikely to result in viable pregnancies.

The following page will provide information:

• How chromosome errors occur in embryos
• How PGT-A testing is performed at the Zita West Clinic
• The Benefits, Risks and Limitations of PGT-A
• Practical points relating to PGT-A

Introduction

Every cell in an embryo should contain 23 pairs of chromosomes – 46 chromosomes in total. One chromosome from each pair comes from the sperm and one from the egg that creates the embryo. As the cells of the embryo divide the chromosomes are copied and each new cell contains an identical copy of the same 46 chromosomes.

Sometimes, the sperm or egg that form an embryo has fewer or more than 23 chromosomes and because of this, the resulting embryo also has too few or too many chromosomes. These embryos may fail to develop or develop in the laboratory but fail to implant or implant then miscarry. Sometimes, an embryo with more or fewer than 46 chromosomes can develop to term but the baby is affected by a serious condition like Down’s syndrome (where there are three copies of chromosome 21) or Turner’s syndrome (which occurs when girls inherit only one X chromosome and so have only 45 rather than 46 chromosomes). Embryos with the usual 46 chromosomes are known as euploid and those with fewer or more than 46 chromosomes are known as aneuploid.

What causes aneuploidy?

Women are born with all the eggs they will ever have in their lifetime; they do not make any more.  As they age their eggs age with them.  Every month from the age of puberty, as an egg matures in the ovary, it undergoes a series of changes (called meiosis) that reduce the number of chromosomes in the egg from 46 to 23.  Sperm cells undergo a similar process as they develop in the testes. A mistake in this complex biological process can result in eggs or sperm with too many or too few chromosomes.

 

It is well documented that as an egg provider gets older there is an increased risk they will miscarry or have a child with Down’s Syndrome. Approximately half of the embryos created using the eggs of a person aged 35-36 are aneuploid. This rises to three quarters when the eggs of a person aged 40-42 are used to create embryos.

 

The incidence of aneuploidy does not affect sperm to the same extent.  This is mainly because sperm continue to be made throughout a person’s lifetime.  However, where semen analysis shows poor motility, a reduced sperm count, or where sperm have an anormal shape this may indicate a chromosomal abnormality in the sperm.

 

How can we check if an embryo is aneuploid?

 

Unfortunately, we can’t tell whether an embryo has 46 chromosomes or not by looking at it through a microscope. Chromosomally abnormal embryos can develop well in the laboratory and look very similar to chromosomally normal embryos even to an expert embryologist. Because IVF treatment aims to create more than one embryo in a cycle, selection of the embryo that has the best chance of developing into a baby is a challenge, particularly where the risk of abnormality is high or where there are a large number of embryos to choose from. For this reason, we may want to look inside some of an embryo’s cells to check the chromosomes. We can do this using PGT-A.

 

What is PGT-A and how is it performed at the Zita West Clinic?

 

Following fertilisation, an embryo divides into 2 cells, then four, eight, sixteen and so on, until 5 or 6 days after fertilisation there are over 100 cells.  At this stage the embryo is known as a blastocyst and it has an outer layer of cells called the trophoblast which surround the outside of the embryo. These are the cells that develop into the placenta. There is also a ball of cells inside the trophoblast called the inner cell mass and it is these cells that develop into the foetus and then baby.   In PGT-A, approximately 5 outer cells are removed from the blastocyst. This procedure, called a biopsy, is performed by a highly skilled senior embryologist.  Biopsied embryos are then cryopreserved (frozen) and the biopsied cells are sent to a specialist laboratory for PGT-A analysis. The Zita West Clinic is partnered with the HFEA-licensed embryology laboratory at CARE Fertility London, where all of our embryology, including PGT-A biopsies, take place.

 

The results of the PGT-A test are available within a few weeks. If the biopsied cells have 46 chromosomes, the embryo they came from is considered euploid and the transfer of these embryos can take place in a frozen embryo replacement cycle. Where the biopsied cells had fewer or more that 46 chromosomes, the embryo they came from is considered aneuploid and the embryos are not used in treatment. Occasionally, the results are more complex to interpret and, in these cases, the Zita West Clinic has access to expert genetic counselling services to help patients decide whether to transfer an embryo or not.

 

Studies have shown that removal of cells from the blastocyst doesn’t harm the embryo’s development and thousands of babies have been born after transfer of embryos that were biopsied.

 

Benefits of PGT-A

• PGT-A testing can help identify the embryo with the best chance of developing into a baby. PGT-A testing can’t change the number of viable embryos available for transfer but, by transferring only those that have the usual number of chromosomes, the time taken to establish a pregnancy can be shorter and the misery of failed cycles and risks of miscarriage can be reduced.

• Where patients have undergone multiple rounds of IVF and have no explanation for the treatment failure, PGT-A testing can sometimes provide answers and help with decisions about future treatment options.

• CARE’s own data shows that by performing PGT-A and transferring euploid embryos clinical pregnancy rates (CPR) are increased. In the year to 30 September 2019 CPR per embryo transfer across patients of all ages following PGT-A was 49%¹ compared with 38% in non PGT-A cycles².

PGT-A and blastocyst biopsy – things to consider 

• Although PGT-A testing methods are generally very accurate, the test may miss an abnormality or detect one that isn’t there. It is estimated that PGT-A testing will result in a false positive or false negative result in 5% of cases. In the case of a false positive, an embryo that may have implanted and developed may be discarded. In the case of a false negative, an embryo with more or fewer than 46 chromosomes may be transferred. For this reason, PGT-A testing can’t guarantee that an embryo that is transferred has a normal number of chromosomes or won’t miscarry. Where your obstetrician thinks it’s indicated, the Zita West Clinic and CARE recommends you consider additional prenatal testing even after PGT-A. 

• The Zita West Clinic and CARE will not usually transfer aneuploid embryos and can never transfer aneuploid embryos where a euploid is available.

• Using PGT-A may mean you have fewer embryos available to use in treatment or for freezing to use in future treatment.

• There is a possible but unquantified risk that removing cells from an embryo may damage it and prevent it from developing. However, the first births following embryo biopsy for genetic screening were reported in 1990 and since then, thousands of children have been born, and health risks following embryo biopsy have not been identified as different from IVF/ICSI pregnancies in general.

• Chromosome abnormalities can also arise spontaneously as embryos divide. Where this ahppens early in development (shown in red in the diagram below), some cells of the embryo may be chromosomally normal and other abnormal. 

   

  Depending on where these cells are clustered in the embryo, the biopsy may take cells that are all abnormal, all normal or a mixture of the two. Embryos with both chromosomally normal and abnormal cells are known as mosaic.

  The presence of mosaicism can lead to false positive or false negative PGT-A results but is identified in fewer than 9% of cases. The impact of mosaicism is hard to quantify, but we can provide you with expert genetic counselling and support to help you decide whether to transfer a mosaic embryo.

• As with any treatment there can be financial and emotional costs where treatment including PGT-A is not successful.

Is it possible to know the sex of the embryo?

Although the test does identify the presence of sex chromosomes of the embryo, it is unlawful to select which embryo to transfer on the basis of the sex. For this reason, you won’t know or be able to select the sex of any embryo that is transferred. The selection is made by the embryologist solely on the basis of the PGT-A test result and the embryo quality.

 

Limitations of the PGT-A test

• The PGT-A testing method cannot reliably detect abnormalities involving the loss or gain of an entire extra set of chromosomes (the presence of 69 chromosomes or 92 chromosomes).

• Sometimes, PGT-A can detect large deletions and duplications of sections of chromosomes (known as segmental aneuploidies), but the clinical significance of these is hard to predict. We can provide access to expert advice in cases where the test results require interpretation.

• The test cannot detect small changes in chromosomes and the risks of a child inheriting a condition caused by mutation in a single gene (like cystic fibrosis or sickle cell disease, for example) remain the same after PGT-A.
• Because testing can take some time then embryos have to be frozen then thawed and transferred in a frozen embryo cycle. Freezing by vitrification is very effective and 95% of all embryos (biopsied and non-biopsied) survive this process. However, there is a 5% risk that a frozen embryo will not survive.
• Sometimes, biopsied cells do not contain enough chromosomal material (DNA) for the test to be carried out. This can lead to a test report that is inconclusive or a ‘no result’. In these cases, the embryo can sometimes be thawed and re-biopsied (with the risks to survival as above) or transfer can proceed without the test result as it would in a non  PGT-A IVF cycle.
• Only blastocyst embryos are suitable for biopsy. If no embryos develop to blastocyst stage, the test cannot be carried out. If embryo development is poor, the embryology team may advise an early transfer of a developing embryo without PGT-A testing.
• Biopsied cells are couriered to the diagnostic laboratory for PGT-A analysis. Although it’s considered unlikely, it is possible that events or circumstances beyond our control could delay or prevent the delivery of the sample. In this case embryos could be re-biopsied or transferred as in a non PGT-A treatment cycle.

 What does PGT-A cost?

There is an additional charge for PGT-A and for the transfer of any frozen euploid embryos, and ICSI. You can find information on the costs of PGT-A here or by speaking with a member of our team.