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Sharing care must also mean sharing information

In the last of our series,

Dr Tarek El-Toukhy looks at

the fast-developing field of preimplantation genetic diagnosis


in general practice

Preimplantation genetic diagnosis (PGD) was established in the early 1990s as an early form of prenatal diagnosis in which embryos created by in-vitro fertilisation (IVF) are tested for genetic disorders and only unaffected embryos are replaced into the uterus. It is suitable for patients at substantial risk of conceiving a pregnancy likely to be affected by a known genetic defect, but wishing to avoid termination of pregnancy.

The first clinical application of PGD was in 1990 for an X-linked genetic condition (adrenoleukodystrophy) where a polymerase chain reaction (PCR) test was used to sex embryos through detection of the Y chromosome. Only female embryos were replaced. Subsequently, the development of a simpler genetic test called in situ fluorescent hybridisation (FISH) in early 1993 facilitated diagnosis of chromosome disorders in single nuclei. PGD is now becoming an established clinical option in reproductive medicine.

A major advance

Before the introduction of PGD into clinical practice, couples who had a genetic risk were faced with a limited number of reproductive options. One was to accept the consequences of the genetic risk and continue with the pregnancy hoping that the favourable odds would be with them (for example, a risk of 1:4 for mendalian recessive disorders such as cystic fibrosis or 1:2 for dominant conditions).

Alternatively, couples could opt for some form of prenatal diagnosis (such as chorionic villus sampling or amniocentesis) and be prepared for a termination of pregnancy if the fetus was shown to be affected. However, this decision cannot be taken lightly, as terminations can have substantial psychological and physical morbidity, particularly in the case of late second trimester procedures. Other options included the use of donated gametes,with all its ethical and financial difficulties, not to procreate at all or to adopt.

Patients who choose PGD do so for a variety of reasons. They may have already had affected children and wish to avoid future risk; they may have a religious or moral objection to pregnancy termination; or they may have had to experience recurrent miscarriage (as is often the case in translocation carriers) or multiple terminations of pregnancy and now seek ways of eliminating or minimising that risk. Those who carry a dominant disorder either are, or will be, affected by it and choose not to have a child like themselves, and in so doing try to eliminate the condition from their bloodline.

Nowadays, PGD is performed for three main groups of genetic disorders (see table, right):

·recessive or dominant mendalian single gene disorders (using PCR)

·gender selection for sex chromosome linked disorders (using FISH)

·chromosomal structural aberrations (using FISH).

The list of diseases amenable to genetic detection by PGD is increasing rapidly. Other indications for PGD are embryo-sexing for gender selection (the so-called family balancing) and selection of embryos according to their HLA type so that a child born after PGD can be a stem-cell donor for his sick sibling (sometimes known as designer babies). But these raise ethical and legal questions.

How it's done

In order to perform PGD, a sample of the genetic material of the presumptive embryo is required and a test of sufficient reliability needed to make a diagnosis. Procedures used to obtain embryos are standard and include ovarian hyperstimulation, oocyte collection, IVF or intracytoplasmic sperm injection (ICSI) and embryo culture. Most commonly, a single cell is removed from an early human pre-implantation embryo on day three of in-vitro culture when the embryo is usually between six and 10 cells.

Less commonly, a genetic sample can be obtained at the blastocyst stage (days five and six of culture), or by removal of the polar bodies from the unfertilised egg and the early zygote, although this latter option can only provide information about the maternal genotype and therefore cannot be used in cases of paternally carried genetic or chromosomal disorders.

Blastocyst stage biopsy overcomes some of the difficulties of the paucity of material available at the earlier cleavage stages but has the added problem that the diagnosis may not be ready in time for optimal transfer requiring the biopsied blastocyst to be frozen ­ a technique that is still in development.

The outcome and safety of PGD

Although PGD techniques (PCR and FISH) are highly reliable, there is still a

1-5 per cent risk of misdiagnosis mainly due to technical errors in analysing the biopsy result. This rate should be explained to prospective patients who may need to be advised of the added benefit of undergoing a prenatal test in special situations.

Funding ­ and success rates:

Approximately 50 per cent of patients referred for PGD will obtain NHS funding for at least one cycle through their primary care trusts. Self-funded PGD cycles are expected to cost about £5,000 per attempt. The time interval between referral and starting treatment is usually six to nine months. The overall live birth rate (take-home baby rate) after PGD in good centres is about 20 per cent per cycle started. Nearly 1,000 children have been born after using PGD techniques worldwide. The evidence accumulated so far is that children born after PGD are as healthy as those born after IVF and ICSI. Only 5 per cent of the babies born had some kind of abnormality, a figure comparable to that found in IVF/ICSI babies. However, larger and longer term studies are needed to fully establish the safety of PGD.

The future

PGD technology is expanding into new areas, challenging reproductive boundaries and raising ethical concerns. For example, the use of PGD to improve IVF outcome for infertile patients is an exciting area that is rapidly expanding, although randomised controlled studies are still required to establish its efficacy. New methods for diagnosis of genetic diseases are currently being developed (such as real-time PCR) to improve both the efficiency and reliability of the test. Other genetic techniques such as mini-sequencing or the use of micro-arrays are also being rapidly developed to help bring even more genetic disorders under the umbrella of PGD and to improve the robustness and accuracy of PGD results and eliminate the misdiagnosis risk.

Tarek A El-Toukhy, fellow in reproductive medicine, Guy's and St Thomas' Hospital, London

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