<p>FISHING FOR A HEALTHY BABY:</p>

Courtesy of the Reproductive Science Center of the San Francisco Bay Area, http://www.rscbayarea.com

Multicolor Fluorescence in Situ Hybridization (FISH) can detect chromosomal abnormalities, such as aneuploidy, in cells removed from a developing embryo.

Fast improving techniques for detecting genetic and chromosomal abnormalities via preimplantation genetic diagnosis (PGD) may boost the success rate of in vitro fertilization (IVF). Some clinics report a twofold to threefold higher take-home baby rate when PGD is used and have begun prescribing the costly procedure regularly. PGD provides an alternative to traditional prenatal diagnostic techniques such as amniocentesis, and it also may avert some difficult abortion decisions and ensure that a healthy embryo is selected prior to implantation.

Yet questions remain over the risks posed by IVF, and PGD introduces an additional risk factor because it involves extraction of a single cell, or blastomere, from the early embryo. Regardless, some clinics...

ASSESSING THE RISKS

PGD is mainly being applied for five categories of disorders, according to Randy Morris, medical director of a fertility clinic in Chicago. These include chromosomal aneuplodies (wrong number of chromosomes), with single-gene disorders the next biggest group, followed by chromosomal translocations, gender selection, and human leukocyte antigen (HLA) typing. Chromosomal disorder screening and sex selection require the same techniques. Detection of single-gene disorders and HLA immunological matching are the most difficult and are performed by relatively few clinics.

At present IVF clinics vary in their relative assessments of PGD's risks, benefits, and the considerable costs. According to Ian Craft, director of the London Fertility Centre, a number of clinics in the United States now perform PGD as a matter of course, even though it may add as much as $3,000 (US) to the cost per patient. Craft calls such automatic application of PGD an unnecessary waste of resources. "For some people it may not be relevant to their chance of success." In some cases IVF on its own, without additional genetic tests, would be Craft's prescribed treatment.

And no one is yet sure of PGD's additional risks beyond those already associated with IVF. To test the blastomere, an opening is made in the covering of the embryo during its third day of development, when there are eight to 10 cells in total. At this stage the cells are still totipotent, so removal of one does not immediately affect the subsequent cell, but as yet there is no definitive study to prove that the interference has no adverse developmental effects. According to Morris, PGD may well introduce new, as yet unknown risks at the same time as eliminating known genetic or chromosomal disorders, but more work needs to be done. "Where the balance lies at present we just don't know."

Lawrence Werlin, leading fertility researcher and cofounder of the GENESYS (Gender in Economic and Social Systems Project) Network for Reproductive Health, argues that risks associated with the embryo biopsy process of PGD can be reduced significantly through good laboratory technique. "In controlled situations, where people are used to doing embryo biopsies and blastomere fixation, your risk of having a false negative would be very low, and your chance of damaging the embryo is probably in the region of 5%, while the risk of embryos arresting due to the PGD is probably 5% to 10%."

FINDING THE BENEFITS

A wide variety of tests are available for specific disorders, with some clinics specializing in particular applications of PGD. King's College London has a research and clinical program relating to PGD for epidermolysis bullosa (EB), a genetic disorder that causes painful blistering and affects 1 in 50,000 births. The program is supported by DebRA UK, part of an international charity supporting EB research.

Some perceive broader benefits. PGD is now performed routinely at one of the world's leading IVF clinics, the Reproductive Genetics Institute in Chicago. "It should be done for every IVF cycle, in my view," says Yury Verlinsky, the institute's director. "It doubles or triples the implantation rate, while decreasing dramatically the miscarriage rate." The overall effect, says Verlinsky, is to more than double the average success rate per IVF cycle, so that couples have a greater chance of conceiving a child and to do so sooner.

Apart from miscarriage, the greatest historical risk of IVF is multiple births, and PGD proponents argue that this event also can be reduced. Generally, several embryos (currently, about three) are created during IVF sessions to increase the chances that at least one will attach to the uterus; this increases the chance of twins or triplets and enhances delivery risks. Some argue that with preimplantation screening, the same chances for success can be achieved with just two embryos or even one.

GETTING THE DATA

A recent study indicated a US-wide reduction for multiple births among women undergoing IVF.1 But the study did not take PGD into account. Now, a follow-up study being conducted by GENESYS specifically addresses the question of whether, and to what extent, PGD can reduce multiple births, while at least maintaining existing pregnancy success rates.

<p>ASPIRATIONS FOR A BETTER LIFE:</p>

Courtesy of Georgia Reproductive Specialists, http://www.ivf.com

Technicians remove a single nucleated cell from a human eight cell embryo to conduct preimplantation genetic diagnosis.

The GENESYS study, slated to start this month, will investigate PGD screening across nine chromosomes, according to Werlin. He says that US fertility clinics, under greater pressure than those elsewhere to achieve quick results, introduce more embryos. But he adds that while this increases the multiple birth rate, it may have little impact on overall success. "Our goal is to assess whether PGD can be beneficial in helping us put back fewer embryos, but ones which are normal for the nine chromosomes that we test," says Werlin.

But just when PGD may promise to bring real benefits to assisted reproduction, IVF now has come under increased scrutiny as a result of studies suggesting elevated risks at birth. The British Medical Journal recently conducted a review of various controlled studies and reported that twins, and more particularly single babies, faced much higher risk of death and other problems such as low birth weight during delivery than babies conceived naturally.2

Other epidemiological studies indicate that IVF babies face higher risk of various problems later in life.3 But many fertility experts dismiss studies of IVF children as misleading. IVF codeveloper Robert Edwards says, "It's complicated because IVF is given to sick people. If you go to those patients, you're going to stumble on other disorders." Craft agrees, pointing out that the incidence of disorders is very low in any case, whatever the cause.

There had been particular concerns with intracytoplasmic sperm injection (ICSI), in which extracted oocytes from the woman are impregnated with single sperm, rather than exposed to a culture as in standard IVF. ICSI is often prescribed for couples where the male partner has a low sperm count. "With ICSI, there appears to be a three times greater risk of chromosome abnormality," says Craft. "But you expect that when you're dealing with people whose sperm counts are low, and it's only an increase from 0.3% to 0.9%."

For Edwards, the greatest concern with IVF is imprinting syndrome. Imprinting regulates the integration of maternal and paternal genes at conception, and directs how their relative expression ensures normal embryonic development. Edwards admits that some evidence suggests that the IVF process disrupts imprinting, but he reiterates that the absolute numbers involved are small.

The difficulty in calculating the differences lies in finding a sufficiently large control group of non-IVF mothers of comparable age and risk to those who have sought IVF. Yet two such groups would probably not have the same risk factors, according to Morris. "For example, there is evidence to suggest that patients with infertility, who tend to be older, may be at greater risk for certain chromosome problems like Down's syndrome."

Though controversial for some applications and of uncertain benefit for others, there is no question that PGD can detect a growing variety of genetic and chromosomal disorders. Technology remains a limiting factor. A primary challenge involves amplifying the DNA sufficiently from a single cell to detect a wide spectrum of known gene disorders and at the same time identify abnormalities such as duplication or transposition on all 23 chromosomes, according to Aniruddha Malpani, founder of the Malpani Infertility Clinic in Bombay, India.

Until the technology improves, tests performed during early pregnancy will continue to be used as a final screen, says Malpani. "Once we can amplify the genetic material in a single cell, PGD will become the method of choice."

Philip Hunter phunter@philiphunter.com is a freelance writer in London.

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