Embryo selection in IVF: Comparative Genomic Hybridisation

The selection of IVF embryos by pre-implantation genetic screening has so far proved disappointing, but hopes are that a new technique of 'comparative genomic hybridisation - or CGH - will overcome many previous problems in embryo screening.

IVF success rates

It's a sad fact of life in IVF that for every treatment cycle resulting in a healthy birth three will be unsuccessful. It's not the fault of the treatments, nor the techniques - it's simply that human beings, unlike rabbits, are not efficient at breeding. An overall live birth rate of around 25% per cycle in IVF is actually the same as in healthy couples trying to conceive naturally.

Genetic abnormalities and poor conception rates

No-one has a simple biological explanation for this poor performance, but one contributing factor is that many eggs produced by the ovary - and the embryos formed from them - have genetic abnormalities which hinder their progress and ability to implant in the womb as a pregnancy. Many studies have shown that at least 50% of IVF embryos have chromosomal problems, and the likelihood of these problems increases with age.

The risk of Down's syndrome, for example, which is a post-conception disorder of chromosome 21, is reported to be less than one in 1,000 for women under the age of 30, but around one in 25 for those pregnant at the age of 45. So it's long been believed - as the holy grail of IVF - that if the chromosomal status of an embryo can be determined post-conception, abnormalities can be detected at the outset and only healthy embryos transferred.

Using pre-implementation genetic (PGD) diagnosis to screen IVG embryos

Each cell normally contains 23 pairs of thread-like structures called chromosomes, a total of 46. Twenty-two of these pairs look the same in both males and females. The 23rd pair, however, known as the sex chromosomes because they determine gender, differ between males and females, with females having two copies of the X chromosome, and males having one X and one Y chromosome. All chromosomal abnormalities detected in early embryos are disorders of these pairings.

In 1989, reproductive scientists at the Hammersmith Hospital in London reported the case of a couple at serious risk of transmitting an inherited degenerative disease known to affect only male offspring (and therefore linked to the single x chromosome). In what was a landmark report, the Hammersmith group created embryos by IVF from the carrier couple, and after a day or two analysed those embryos for their chromosomal status. Embryos carrying the XY (male) chromosome were discarded as potentially affected, and only female embryos transferred. The resulting baby was unaffected by the genetic disorder.

Today, more than 20 years later, that same principle of pre-implantation genetic diagnosis (PGD) has now been applied to screening IVF embryos for any type of chromosomal disorder in a bid to spot the defects and transfer only healthy embryos with a likely chance of implanting as a pregnancy.

Success rates for PGD

However, what seems logical in principle has not yet proved successful in practice. The IVF patients who seem most affected by chromosome problems are those in an older age group and those with a history of spontaneous abortion. But studies in both these patient groups have shown no benefit in those whose embryos were screened by PGD. Indeed, one study even found that pregnancy rates in those having PGS were lower than in those having conventional IVF and ICSI (without PGS).

As a result of this and other studies, the British Fertility Society recently issued less than enthusiastic guidelines about PGS, stating that 'at present patients should be informed that there is no robust evidence that PGS for advanced maternal age improves live birth rate per cycle started'.

Comparative genomic hybridisation (CGH)

All the studies proving so disappointing in PGS used a chromosome investigation method which could analyse no more than nine chromosomes - when the full complement in an embryo is made up of 23 pairs. As a result, concerns arose that the problem with PGS was not so much the logic but more the technology for the analysis. That problem, however, may now have been solved by the introduction of a new technique which can screen all 23 pairs of chromosomes. And it's a technique - known as comparative genomic hybridisation, or CGH - used by the London Women’s Clinic.

When pilot studies of the CGH technique were performed in poor prognosis IVF patients in the USA, results were described as 'absolutely phenomenal'. One study in 45 infertile couples, with an average maternal age of 38 years and at least one previous unsuccessful IVF cycle, reported a pregnancy rate of more than 80% - and a 70% probability that each screened and transferred embryo would progress to a viable pregnancy.

This technique, like all the earlier versions, requires the biopsy of a single cell from an embryo (in this case after five days of culture growth) and its complex chromosomal analysis. But because this analysis takes several days to complete, the embryo must be frozen until a 'diagnosis' is available and a 'healthy' embryo is ready for transfer. Another CGH technique is able to perform the analysis in 'real time' (though from a very early fertilised egg) and so does not require embryo freezing before transfer.

The future of CGH

There are many questions still to be answered about embryo selection with PGS, one of which is the central question of whether CGH will prove more effective than the earlier technologies. But many other questions still remain - when best to perform the biopsy, whether the analysis of a single cell accurately reflects the full chromosomal, and what effect will freezing have on the screened embryo.

The need to transfer fewer embryos to reduce multiple pregnancy rates has put added pressure on embryo selection and the quest to find the one embryo most likely to implant in the womb and become a pregnancy. If, as studies suggest, the likelihood of implantation is most affected by genetic factors inherited from the egg, then an analysis of the full chromosomal complement of the embryo - as CGH allows - may well prove one step nearer to that holy grail.

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