Responding to requests from the CGD community for clear information on PGD, we explain the science of the technique, and highlight some of the issues facing couples who might consider it.
Preimplantation genetic diagnosis (PGD) can tell whether a human embryo, in its earliest stage, has or carries a particular genetic illness. It can detect a specific disease-causing mutation within embryos in the laboratory, enabling doctors to select which if any embryo/s to transfer to the womb to start a pregnancy. To achieve this, couples have in vitro fertilisation (IVF) treatment followed by an additional genetic testing stage.
PGD is a very specialised technique and unlike prenatal diagnosis (PND), does not test an established embryo/foetus in the womb but tests embryos when they are clusters of a few cells in the laboratory. It can help couples at risk of having a child with a genetic condition who wish to avoid doing so, long before the stage where termination of a pregnancy might otherwise be considered.
The choices facing families affected by CGD
Individuals and families affected by CGD, and other genetic conditions, face difficult decisions when considering having children. PGD may be one of many options being considered. Other options include proceeding with a pregnancy and having a prenatal diagnosis for CGD (see below), egg donation, sperm donation, a decision not to have a child and adoption. All of these options need to be discussed fully with the help of trained genetic counsellors. The aim of this article is solely to provide factual information on PGD, in particular for CGD.
What is involved in PGD?
Preimplantation genetic diagnosis uses routine IVF and a special form of fertilisation of the woman’s egg by a man’s sperm. Hormones are used to stimulate her ovaries and enable the collection of a number of eggs, or oocytes. After the eggs are removed, they are fertilised in the laboratory with sperm using a technique called ICSI. With ICSI the embryologist will inject a single sperm into the main part of an egg, allowing the two to join, which is fertilisation. ICSI maximises the chances of sperm fertilising the egg and ensures that the genetic test on the fertilised embryos is clean and not contaminated by extraneous bound sperm, i.e. ones that become attached but have not penetrated the egg. Any eggs that are successfully fertilised are allowed to divide and multiply until they are 3 days old (post egg collection), when they contain about 8 cells.
At this time one or two cells are removed in order to test for the specific genetic condition in question. The cells are then tested to see if the embryo from which they were removed contains the faulty gene. The results are usually available to allow transfer on day 5 or 6 of selected suitable embryos (those without a copy of the faulty gene) back to the womb, in the hope they will develop. Any remaining unaffected embryos can be stored for possible later use. Those embryos that had a copy of the faulty gene can be allowed to perish or be kept for donation to research.
Can PGD be used for CGD?
Yes. This testing process is available at present for the most prevalent, X-linked form of CGD. Often the motivation to explore PGD arises from the diagnosis or birth in the family of a child with a genetic condition. Most IVF centres require a referral by a medical professional such as a GP or hospital doctor.
PGD for CGD is available in several UK-based fertility centres. Costs will depend on the individual as it is often impossible to predict how much ovarian stimulation will be required and therefore how much the drugs will cost for a given cycle of IVF. It is important for parents making a decision to realise the cumulative cost. As a guide, £7,200 would cover a consultation package, semen analysis, the screening procedure, one cycle of IVF and the PGD.
It is also important to recognise that more than one cycle of IVF may be needed to find an embryo unaffected by the condition. Primary Care Trusts (PCTs) are not currently obliged to pay for PGD for CGD and would definitely not do so where the estimated chance of success was less than 5% (as it may well be for a mother over 38).
PGD and HLA Tissue Typing
PGD can also be used to try and select a tissue-matched (HLA identical) embryo if a couple already have a child affected by a genetic disorder such as CGD who might be cured with a transplant of stem cells from their new sibling. Such scenarios have been referred to as ‘saviour sibling’ cases (with some opposition, especially to the notion that a child might be conceived primarily to be used as a donor).
In the context of CGD, PGD could be used to select an embryo fulfilling two criteria: first, that it did not have CGD and second, that it also had an identical tissue type to the affected older sibling. This would mean that stem cells could be retrieved from the umbilical cord of the new baby at birth or taken at a later stage from their bone marrow, to treat the affected brother or sister. The procedure used here is called Pre-implantation genetic haplotyping (PGH).
If the woman is a carrier - what are the chances of finding an embryo that does not have CGD?
Typically a clinic has a ‘cohort’ of 12-15 embryos to select from. If the mother is a CGD carrier then of those, 9-12 are likely to be CGD-free but taking other factors into account, considerably fewer will actually be considered viable for selection. The PGD procedure allows for the identification of healthy male embryos and the identification of female carriers.
If all the embryos were of equivalent quality the clinic would preferentially transfer a completely unaffected embryo (whether male or female) over one that was a carrier (only females can be carriers). Parents would be informed of the genetic status (affected, unaffected or carrier) of all the embryos in the cohort, whether implanted, discarded or donated for research.
If the woman is a carrier - what are the chances of finding an embryo that does not have CGD and is also an HLA match?
The chances of finding an HLA match are 1 in 4 (25%) so the chances of an embryo being healthy with respect to CGD and a tissue match are 3 in 16, or less than 1 in 5 ( less than 20%). So in a normal cohort you’d be pleased to find two or more such embryos, which could easily dwindle to one or none if some were discarded because they appeared of doubtful or unclear viability.
Hence, addition of HLA tissue matching does reduce considerably the chance of finding a suitable embryo. The embryo then faces all the usual risks of a pregnancy and might of course have an unrelated genetic condition that was not tested for. If all goes well, the family and its medical team still faces the usual decisions about whether and when to attempt a transplant, whether using the sibling’s cord blood or bone marrow.
So it is clear that as a strategy, trying for a sibling saviour involves multiple hurdles along the way and a relatively small chance of ultimate success. But some CGD parents will think it is worth trying for, especially if their child has a rare tissue type for which they are unlikely to find a suitable donor any other way. There are some clinics that do not charge extra for HLA matching but some clinics may.
Pregnancy rates for PGD and IVF/ISCI
Success rates for having a child from an IVF cycle followed by PGD varies from centre to centre but is usually slightly lower than ‘standard’ IVF success rates because doctors have fewer healthy embryos to choose from. As explained above, a pregnancy and an unaffected child can in no way be guaranteed using this technique. It is important for an IVF unit to have a high pregnancy rate to be able to offer reliable PGD with a real chance of achieving pregnancy.
It is very important that couples have a realistic chance of success and the woman’s age is an important factor in this. Success rates for IVF decrease from 35 years, dramatically so around 40. There is some debate about the effect of PGD on pregnancy rates of women over the age of 35 (read more in the Nature article cited below) but fertility assessment rates using PGD for inheritable disorders are not available at present.
A guideline to success rates using IVF and ICSI is given below but each clinic offering this service will have its own published rates of success. Detailed statistics are also available on the Human Fertilisation and Embryology Authority website www.hfea.gov.uk. Success rates are quoted per embryo transfer but it is important to recognise that some couples may not get to the transfer of embryo stage due to the problems already noted and listed below.
| Live birth rates for IVF and ISCI using own eggs GUIDELINE FIGURES ONLY | |||||
| Maternal age | Under 35 | 35-37 | 38-39 | 40-42 | Over 44 |
| Per embryo transfer | 37% | 32% | 29% | 14% | Less than 5% |
Like any IVF procedure, it is accompanied by severe stress and often, disappointment. Couples will need to balance the financial and emotional burden of the IVF procedure against that of the alternatives, including for some people, potential termination of an affected child conceived naturally. Emotional problems can also result from feelings associated with discarding embryos of whatever status.
What problems can be encountered?
Low egg numbers
If you have fewer eggs there is a lower chance of finding, from a genetic and developmental perspective, suitable embryos. A decision must then be taken whether to proceed or not with PGD. Embryos can be frozen and used in combination with another fresh cycle.
Poor embryo quality
If some or all of the embryos are of poor quality, or are not developing correctly, it may not be possible to test them by PGD. Embryos of unclear quality are generally not used.
The risk posed by removal of cells from the embryo
The procedure has been used for many years and clinics are extremely well trained and experienced. Each person responsible for this procedure must be licensed by the HFEA. Accidental damage to the embryo is usually less than 0.8% (less than one in a hundred)
No results are obtained from the genetic testing of the embryo
In very rare cases the clinic may not be able to tell if some or all of the embryos are affected or not. This is usually related to poor quality embryos.
Poor embryo development
When embryos are replaced in the womb, on day 5 or 6, they should have reached a stage in development known as a blastocyst. Not all embryos reach this stage.
All embryos are affected
There is a chance that all of your otherwise viable embryos may be affected by the genetic condition. Affected embryos cannot be transferred.
Misdiagnosis
The misdiagnosis rate worldwide is less than 1%. While this is rare it is still strongly advised that couples undergo prenatal testing too.
New advances for embryo screening for genetic disorders – Pre-implantation genetic haplotyping (PGH)
Pre-implantation genetic haplotyping (PGH) works for thousands of heritable conditions, most of which are too rare or complicated to be pinpointed by other known means. In PGH, instead of detecting the genetic mutation itself, scientists look at a set of nearby DNA ‘markers’ that can distinguish the chromosome with the faulty version of the gene from one carrying the healthy version.
It allows for PGD where no mutation analysis is available as the inheritance of linked markers is followed through the family rather than by looking at the specific gene mutation. This means that PGD is available to families that have a diagnosis of a genetic condition but do not have information on the exact mutation involved.
The test also has the potential to eliminate inherited diseases from susceptible families. It can detect not only embryos that will become ill, but also carriers who will remain healthy but capable of passing rogue genes down to their own offspring.
The Law
Clinics offering PGD are licensed through the Human Fertilisation and Embryology Authority (HFEA). A clinic needs to apply for a licence the first time they screen for a specific disorder. This can take 12 weeks. Some clinics may already have used PGD screening for CGD and in this case there is no need to reapply for subsequent patients.
Couple specific HFEA licence applications are required for PGD and HLA matching in their first IVF/ICSI cycle. In the context of CGD, an application would have to be submitted to the HFEA for parents wishing to have an HLA matched and non CGD-affected sibling. After that application has been accepted the couple will be on the clinic’s licence as named patients and will not need to reapply on subsequent cycles.
Combining PGD and HLA matching would mean that an embryo would be selected that did not have CGD and also had an identical tissue type to an affected sibling. This would mean that the unaffected child could be a donor of stem cells for the affected sibling.
Some relevant articles on this topic
PATIENT PATHWAY INVOLVED IN STARTING PGD
Related articles
Currently we have no personal stories involving experiences of parents choosing PGD to have a non CGD-affected child. However, below are articles on the web that have discussed PGD for other genetic conditions.
A selection of further information available on PGD and related issues
PGD
‘FAQs - Preimplantation Genetic Diagnosis (PGD)’
Human Fertilisation & Embryology Authority
http://www.hfea.gov.uk/en/910.html
Nature
July 2007
http://www.nature.com/news/2007/070702/full/070702-9.html
Doubt cast on fertility technique
PGH
The Times
June 19, 2006
Embryo screening set to take giant step in battling hereditary disease. Sensitive technique enters new ethical ground, reports our correspondent from the Reproduction and Embryology conference, held in Prague.
http://www.timesonline.co.uk/tol/news/uk/health/article676259.ece
Saviour siblings
April 2005
Lords back 'designer baby' choice
http://news.bbc.co.uk/1/hi/health/4492345.stm
‘Law Lords back saviour siblings ruling’
The Public Health Genetics Unit
http://genome.wellcome.ac.uk/doc_WTD020969.html
‘Lords to rule on 'saviour siblings'’
March 2005
The Guardian
http://www.guardian.co.uk/uk_news/story/0,3604,1431787,00.html
'Saviour sibling' babies get green light
July 2004
New Scientist
http://www.newscientist.com/article.ns?id=dn6195
Ethics
Bio Centre - The Centre for Bioethics and Public Policy
Preimplantation Genetic Diagnosis
http://www.bioethics.ac.uk/index.php?do=topic&sid=14
Progress Trust www.progress.org.uk
Legal and ethical discussion on the implications of infertility and human genetics. Holds regular public debates, conferences and free web & email news and information service.
GLOSSARY OF TERMS
Blastocyst – a ball of around 250 cells formed about five days after fertilisation.
Embryo - is used to describe the early stages of development from conception to the eighth week of pregnancy.
Genetic Testing – testing to detect the presence or absence of, or change in, a particular gene or chromosome.
Genetic counselling - A process by which information is imparted to those affected by, or at risk of a genetic disorder. It includes information on the nature of the disorder, the size and extent of genetic risks, the options, including genetic testing that may clarify the risks, and the available preventative, supportive and therapeutic measures. In the context of genetic testing it may include responding to the concerns of individuals referred and their families, discussing the consequences of a test, and help to choose the optimal decision for themselves, but not determining a particular course of action.
HLA tissue matching - a test that looks at the genetic messages in an embryo that will code for markers expressed on the white blood cells of the baby. These markers help the immune system to tell the difference between body tissue and foreign substances. If these genetic messages are the same as the affected sibling then the likelihood of rejection following stem cell transplantation treatment of the affected sibling is minimal.
ICSI – this stands for intracytoplasmic sperm injection. It maximises the chances of sperm fertilising the woman's egg. Having both ICSI and IVF (in vitro fertilisation) means that more of the woman's eggs get fertilised than if she has IVF without ICSI.
In-Vitro Fertilisation –sperm and eggs are collected and put together to achieve fertilisation outside the body.
Mutation – the change in a gene or chromosome that causes a disorder or the inherited susceptibility to a disorder.
Preimplantation Genetic Diagnosis – use of genetic testing on a live embryo to determine the presence, absence or change in a particular gene or chromosome prior to implantation of the embryo in the uterus of a woman.
Prenatal Diagnosis (PND)
(a)Amniocentesis – This method involves examining foetal cells taken between 15 and 16 weeks of pregnancy from the amniotic fluid, which surround the foetus. The foetal cells are cultured and the genetic make-up of the foetus determined. This allows testing for chromosomal abnormalities.
(b)Chorionic Villus Sampling (CVS) - This method involves the removal of a sample of placental tissue between 9 and 11 weeks of pregnancy, which is tested for genetic abnormalities.
Sibling – a brother or sister
X-Linked Disorders – disorders due to a mutation on the X chromosome. X-linked disorders usually only affect males, but the disorders can be transmitted through healthy female carriers.IMPORTANT NOTE :
The information contained on this website is intended only as a guideline, not as a substitute for medical advice. Always consult your doctor if you or your child has any CGD symptoms or concerns.
© 2001-2007 The Chronic Granulomatous Disorder (CGD) Research Trust
Registered Charity No. 1003425 email:cgd@cgdrt.co.uk
The CGD Research Trust is a member of the Association of Medical Research Charities (AMRC), the Genetic Interest Group (GiG) and an associate member of the International Patient Organisation of Primary Immunodeficiencies (IPOPI)
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