01 August 2014

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Pre-implantation Genetic Screening

What is a chromosome?

Chromosome

A chromosome is a highly complex structure containing genes that make us who we are, and they are found in every cell of our body (except red blood cells). One chromosome may carry over 1000 genes. Chromosomes are in pairs, and in humans there are 23 pairs. 

Why are chromosomes important in fertility?

Success in assisted conception is dependent on the quality of the sperm and eggs.  Egg quality falls with age, hence one of the strongest predictors of whether an IVF cycle will be successful is the age of the woman.  A major cause of this age-related decline is the development of chromosomal abnormalities in the egg as it matures, which can in turn be passed on to the embryo.  If the embryo contains chromosomal abnormalities, it is unlikely to be able to develop properly, although at the very early stages before it is replaced in the womb, it may appear normal.  

Approximately 70% of embryos produced either through natural conception or IVF are lost before birth. The vast majority of embryos are lost within the first three months of pregnancy, most of these even before implantation. A major cause of embryo loss, including miscarriage, is a chromosome anomaly (known as ‘aneuploidy’) where there is either a loss of a chromosome or a gain. Some of these anomalies are compatible with full term delivery, such as three copies of chromosome 21 (known as Down syndrome) or three copies of chromosome 18 (Edward Syndrome). Some are not compatible with full term delivery; and others cause the embryo to arrest its development before implantation.  

The rate of aneuploidy in eggs also increases with a woman’s age, with Down syndrome being the most commonly known. As age increases, so does the risk of aneuploidy and chromosome-related miscarriage, causing a major reduction in live birth rates.  

The incidence of Down syndrome rises from 1 in 900 at age 30, through 1 in 230 at age 37 to 1 in 20 at 46. 

Pre-Implantation Genetic Screening (PGS)

The most common reason why IVF fails is chromosomal abnormality. Using the technique of Polar Body Array CGH, it is possible to screen all the chromosomes of a human egg prior to the creation of the embryo. During the procedure, a microscopic structure called the polar body (which lies between the egg itself and its outer 'shell'), is removed before the egg is fertilised. The polar body of an egg has the same chromosomal content as the egg itself. It is tested using the Array CGH method which provides us with the complete chromosome make up of the egg. In this way we can screen for the chromosomally normal eggs. As the polar body is a 'surplus' structure within the egg and normally disappears a few days after fertilisation, this is an ideal way of testing the chromosome material without disrupting the actual chromosomes within the egg itself. 

What is CGH?

CGH or Comparative Genomic Hybridization is a technique developed to look at the total number of chromosomes in a single cell. Array CGH is the latest approach of this technology that examines the entire number of chromosomes in a single cell to check for extra or missing chromosomes. Approximately 70% of embryos produced either through natural conception or IVF are lost before birth and most before implantation. As mentioned earlier, major cause of embryo loss, including miscarriage, is a chromosome anomaly (known as 'aneuploidy'), where there is either a loss or a gain of one or multiple chromosomes. Array CGH Array CGH is a significant advance on conventional CGH as it is a more refined technique to detect changes in multiple copies of the chromosomes. It is also much quicker and results are typically available within 24 - 48 hours allowing a fresh embryo transfer, whereas conventional CGH can take up to 5 days, making it necessary to freeze the embryos and transfer at a later date.  

How can the egg be tested? 

Egg

Before a gamete (sperm or egg) matures and is capable of fusing with its counterpart, it must contain only half the number of chromosomes so that the newly formed entity (fertilized egg) has the full complement of 23 pairs. As gametes come from cells that during their development phase contain the full 46 (23 pairs) of chromosomes, they need to halve their chromosome complement before fusing together. The egg's ingenious way of doing this whilst, critically, still keeping most of its cell mass, is to shunt out in only a tiny amount of cytoplasm half of all the chromosomes; the tiny cytoplasm is called the ‘polar body’. The process of extruding the polar body gives us the opportunity to study the chromosomes of the egg without damaging the egg – by a process known as ‘polar body biopsy’.  

Once the polar body is removed it can be tested for its chromosome content using the Array CGH technology. The polar body plays no role in fertilisation or embryo development and is therefore redundant. The polar body is gently removed from the egg by a process known as ‘polar body biopsy’ as seen in the picture below.

Polar Body 

The process of extruding the polar body gives us the very opportunity to study the chromosomes of the egg without damaging the egg itself.  

The technology of Array CGH has the potential to: 

Embryologists in routine IVF practice cannot differentiate between chromosomally viable and aneuploid eggs/embryos, and hence aneuploid embryos will unwittingly and inevitably be transferred to the womb, thereby compromising IVF outcome. Conversely, it follows that by identifying the aneuploid status of the egg, embryologists have up to 85% chance of eliminating the chromosomally abnormal embryos before transfer.
It is hoped that this technology should greatly improve IVF birth rate per embryo transferred. Minimize the incidence of miscarriages and birth defects caused by irregularity in the chromosome number of eggs. Reduce the incidence of multiple pregnancies whilst maintaining a high live birth rate.
Risks – related to biopsy and analysis procedures. The procedure for this technique has been used for many years. Each biopsy practitioner is licensed by the HFEA (Human Fertilisation and Embryology Authority). Accidental risk to the egg is less than 0.2%.

Misdiagnosis

It is estimated that the risk of a misdiagnosis [either positive or negative] is less than 5%. However we advise that a prenatal diagnosis (CVS or amniocentesis in early pregnancy) is still performed in the routine way for pregnant women, for further reassurance.  

No normal eggs/embryos

There is approximately a 25% chance that all polar bodies tested show abnormal results, with none of the embryos therefore being available for transfer. If this occurs you will be offered a detailed review with your consultant to discuss the relevance and options. We cannot under any circumstances transfer any embryo(s) shown to carry abnormal chromosomes.  

Indeterminate results

Occasionally it could arise that there are no results from any of the chromosomes from a polar body. In this case we do not know if the egg is chromosomally normal or abnormal. If this occurs for the only available embryo(s) for transfer, the relevance of this will be discussed between you and your consultant.   Pregnancies following CGH  There is no guarantee against miscarriage occurring even after screening all the chromosomes. Some miscarriages occur due to other factors such as immune conditions or undiagnosed genetic problems.  

If you do become pregnant following screening the pregnancy will still be subject to all risks and problems that can be associated with natural pregnancies including ectopic pregnancies and congenital abnormalities. The procedure itself should not affect any resulting pregnancy. Thousands of children have now been born following biopsy for other reasons.  

FREQUENTLY ASKED QUESTIONS 

Why test eggs and not embryos? 

When we test embryos, we usually take one cell away from the embryo on Day 3, leaving around 6-8 cells so the embryo can grow on. The problem with this approach is that it is possible for an embryo to have one abnormal cell but the rest of the embryo’s cells remain normal. Conversely, it is possible that the cell examined is normal but several of the remaining cells could be abnormal, giving the impression the embryo has no chromosome anomalies whilst in fact it is unable to develop normally. This difference in cells is known as ‘mosaicism’ and is unfortunately relatively common in embryo development. Either of the above scenarios will give us a false result, hence the reason why we do not use Day 3 embryos for aneuploidy screening.  

How will array CGH work for me?

IVF will be planned in the normal way:   Phase 1: A protocol of drugs will be prescribed for ensuring the most appropriate ovarian stimulation regimen. You will come to the Hewitt Centre for monitoring and at the appropriate time undergo egg collection. At this point you can return home whilst the work continues in the laboratory. The collected eggs will be examined for their maturity. Only mature eggs that have their polar body extruded will be used. Each of these mature eggs will undergo ICSI and then have its polar body removed, prepared and stored. Fertilised eggs will be developed in the embryology laboratory.   Phase 2: Because array CGH is a very expensive technology, and not every egg will fertilise we have designed a strategy that should minimise the cost of having to examine every single polar body from every single egg.   Once fertilisation has occurred, we will send the prepared polar bodies of only those eggs that have fertilised for testing. Only those embryos that have come from an egg whose chromosomes were normal will be transferred or frozen for future use.   Please note that only a maximum of two embryos will be transferred, and in many cases we would counsel couples to have only a single embryo transferred.   Risks There are no health risks associated with the programme that are not apparent in conventional IVF. Array CGH is a new experimental technology and as such must still be considered to be in a test environment.   There is insufficient data to provide any reliable guide to how effective this technique is in embryo selection. We acknowledge that there is therefore a risk of technical, equipment or analysis failure or malfunction which may affect the accuracy of assay results, or prevent the delivery of any results.   Is Chromosome Screening regulated?  Yes, and it is mandatory for a UK clinic to hold an HFEA (Human Fertilisation and Embryology Authority) licence.  

Does preimplantation genetic screening work? 

Before introducing new tests and treatments such as PGS into widespread use, it is important to confirm that they really do work.  Often, promising results from early studies with small numbers of patients are not substantiated when larger, better designed trials are carried out.  There have now been two large randomised controlled trials looking at whether PGS does in reality help increase the pregnancy rate in older women.  The first trial involved women who were 37 years or older. In the trial, fewer women in the PGS group had embryos replaced into their wombs than in the control group. This may perhaps be because of damage to the embryos from removing the cells for PGS analysis, as well as because PGS had identified embryos with abnormalities, leading to a reduction in the number of useable embryos; however the final pregnancy rates were similar with or without PGS.  In the second trial, which included women aged 35 and older, pregnancy was in fact less likely in women having PGS (25%, compared to 37% in those not having PGS).   How do I consider if this is right for me? We can offer you a detailed clinical consultation where the medical and scientific issues will be discussed, and you will also be offered counselling by a trained independent counsellor. We recognise that the issues are complicated and we urge all patients to feel free to discuss with our specialised team any aspect of the procedure or any concerns.   

Are there any additional tests we will need before we proceed? 

All the normal screening tests required before a normal IVF/ICSI cycle are also needed before an array CGH cycle and these are documented in our separate “IVF/ICSI Cycle” Information pack. In addition though, we will need to have information on karyotypes for both partners and we advise that the man considers having his sperm tested for both sperm aneuploidy and Sperm DNA Fragmentation.   We advise these additional tests before treatments as abnormalities in these tests can be significant confounding variables for outcome of a treatment cycle and may affect the decision whether to proceed with array CGH.    Costs  The cost of array CGH is additional to the cost of IVF with ICSI. Please see the relevant fee schedule.   PLEASE NOTE: SHOULD POLAR BODY BIOPSY BE UNDERTAKEN BUT ARRAY CGH IS NOT PERFORMED ON THE POLAR BODIES FOR ANY REASON, THE CHARGE FOR THE BIOPSY WILL STILL APPLY. (PLEASE SEE OURCURRENT FEE SCHEDULE).   We recognise that there is a lot of information contained in this document. However, as this technology is very new it is important that we provide you with comprehensive information to help you make an informed decision. Please read the information carefully and do ask any questions of our consultants or senior clinical staff during your consultation or at any time. 

Flowchart

Glossary  

Aneuploid (aneuploidy) - An abnormal chromosome profile in a cell 
Biopsy - The removal of a portion of cellular material for testing 
Blastocyst -The stage 5 – 6 days after fertilisation when the zygote has reached about 30 or more cells 
CGH “Comparative Genomic Hybridization” – a technique used to analyse all the chromosomes of a single cell Chromosome Paired structures within each cell containing the genes of the individual Embryo The name given to the fertilised egg once it divides into two cells, and continues cell Division 
Euploid - A normal chromosome profile 
Gamete - The sperm or egg 
ICSI “Intra Cytoplasmic Sperm Injection” – a method to directly inject a single sperm into an egg 
Nucleus - The central part of almost all cells, which contains the chromosomes and genetic material
Oocyte - The female gamete; egg 
Polar Body - The tiny part of an egg that contains half the egg’s chromosomes but does not take part in the fertilization process

 

References

http://www.britishfertilitysociety.org.uk/public/factsheets/PGS.html

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