The rush to pick a perfect embryo

06/09/04

FOR couples desperate for children, hope, it seems, comes packaged in acronyms. The latest is PGD, for pre-implantation genetic diagnosis. In countries such as the US and Australia, more and more clinics are offering PGD to couples struggling to conceive as a way of improving the chances of becoming pregnant after IVF.

The question is, does it work? So far there is no solid evidence that PGD improves pregnancy rates- and the latest research, revealed last week, suggests that it cannot help all women.

"In Europe we have been much more sceptical," says Alan Handyside of the University of Leeds, and director of The Bridge Fertility Centre in London, one of a group of clinics in Europe testing this use of PGD. "I can tell you that the European group feels that some groups in the US oversell these diagnostic services."

As the name implies, PGD is a way of screening embryos during IVF. The technique involves removing one or two cells from each embryo, usually at the eight-cell stage (pictured left).

Various genetic tests can be done on these cells, and any abnormal embryos discarded. Embryos seem to develop normally despite the removal of cells: Handyside, who led the team that pioneered PGD, says a mainly European consortium of clinics is monitoring about 200 children born after PGD, aged up to 15.

So far the rate of congenital abnormalities is the same as in standard IVF. PGD was first used in the early 1990s to screen out embryos carrying the mutations that cause inherited diseases such as Duchenne's muscular dystrophy.

The clinics offering it as a way of improving pregnancy rates look instead at whether the right number of chromosomes is present.

Having extra chromosomes or fewer than normal is known as aneuploidy, and most aneuploid embryos die early in pregnancy (the notable exception being Down's syndrome).

The older a women, the more likely aneuploidy is: while about 1 per cent of embryos from women in their 20s and early 30s are aneuploid, in women over 40 the figure is over 50 per cent.

Many of these embryos look normal on visual inspection, which is why in the mid-1990s researchers suggested using PGD to spot aneuploid embryos (see Graphic).

In theory, this should increase a woman's chances of getting pregnant and having a healthy baby, because only normal embryos will be implanted. This is the basis on which a growing number of clinics are offering this form of PGD, and ever more patients are demanding it, despite a price tag of up to $10,000 per IVF cycle.

But several experts told New Scientist that proof that PGD screening for aneuploidy (PGD-AS) improves the outcome of IVF is still lacking.

What evidence exists is encouraging, but it all comes from trials that have not been done with proper controls. Part of the problem, says fertility doctor Stan Williams of the University of Florida, is the lack of a system for monitoring the outcome of PGD treatments in the US. "It is not a reportable event," he says.

Clinics must submit data about their IVF success rates to the Centers for Disease Control, he says, but PGD is left out of the calculation.

The European-led consortium of about 30 clinics is keeping track of PGD results, but this is voluntary. At least two randomised controlled trials of PGD-AS are now under way, however. One is being led by researchers in Belgium, who have yet to publish any results. The other is being carried out in the US by a team including Lawrence Werlin of the Coastal Fertility Medical Center in Irvine, California, which last week revealed its latest results.

The trial initially included three categories: women who are older, women who have had several miscarriages, and women who had not become pregnant after several IVF cycles.

In the first two groups, involving 55 women altogether, the results appear to be positive, but the numbers are too small for the results to be statistically significant. However, there did not seem to be any benefit for women who had undergone several failed attempts at IVF.

In fact, this category was dropped altogether as the trial moved to its second phase, says Werlin, even though these results were not statistically significant either.

Handyside says it would not be surprising if PGD-AS turns out not to improve pregnancy rates in this group of women. His own research suggests most have a very high proportion of abnormal embryos.

Despite dropping this category from the trial, Werlin's clinic still offers PGD-AS to this group of women. He says the technique can be useful for a quite different reason: to reveal when further IVF attempts will be futile.

If a high percentage of a patient's embryos are found to be aneuploid after one cycle, there is growing evidence that the same percentage of embryos will be defective in subsequent cycles.

Many of these women have no normal embryos to implant. Using PGD-AS in this way might help couples accept that IVF will not work, and spare them the emotional agonies of further failures, not to mention the financial costs. "It's different when you can say we have looked at the embryos and they are not normal," says Jeffrey Steinberg, director of The Fertility Institutes clinic in Las Vegas.

Part of the problem with working out how effective PGD-AS is, experts point out, is that the technique is not foolproof. It is not uncommon for embryos at an early stage to have a few aneuploid cells even if the rest are normal.

If one of those rare aneuploid cells is taken for analysis, the embryo would be discarded as defective even though it could develop into a healthy baby. Such false positives may happen 10 per cent of the time, according to Handyside.

The opposite mistake can be made as well- a cell chosen for analysis may be normal while the rest of the embryo has a high number of aneuploid cells. At least one case of a baby born with Down's syndrome has been reported after a negative PGD screen for aneuploidy.

What's more, right now the tests for aneuploidy look at only 10 of the 24 different human chromosomes. Many groups are trying to extend the test to cover all 24 chromosomes. "We are all chasing that," says Handyside.

When all chromosomes can be tested at once, the results might be better. More women may have to be given the bad news that all their embryos are aneuploid.

But if many others are having aneuploid embryos implanted that are missed by the existing tests, eliminating these false negatives might dramatically improve the pregnancy rate.

And no matter how effective- or not PGD-AS eventually turns out be for improving pregnancy rates, there may be another reason for doing it.

If a very high percentage of older women's embryos are aneuploid, it might be unethical not to screen them out, whatever the consequences, suggests Handyside. "If we now know that, then it is our duty as clinicians to screen them."

Source: Eurekalert & others

Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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