Screening embryos for genetic diseases during in vitro fertilization offers couples the best chance for a healthy child, but a genetic glitch could potentially cause doctors to misdiagnose a small fraction of them.

Citing concerns about the accuracy of preimplantation genetic diagnosis, the method many practitioners use to pick the healthiest embryos during IVF, University of Florida ( UF ) researchers set out to study the procedure.
Their work reveals the technique is actually highly reliable. But because there is a slim chance a genetic abnormality can cause doctors to misdiagnose embryos, some concerns still need to be addressed.

Preimplantation genetic diagnosis has been used for more than a decade to screen embryos for hereditary diseases such as Down syndrome and other abnormalities. To do this, one cell from an eight-cell embryo is extracted and examined for chromosomal defects.

However, as many as half these embryos spawn cells with different genetic information as they divide, giving doctors an inaccurate idea of how the embryo will continue to develop, said Larissa Kovalinskaia, at UF. While many embryos with this abnormality - called chromosomal mosaicism - stop developing early, some go on to be born. Because these embryos' cells contain different sets of chromosomes, doctors cannot always accurately screen them for genetic diseases, Kovalinskaia said.

" As more data were coming out, saying that as many as 50 percent of ( IVF ) embryos were mosaic, we started worrying about the accuracy of preimplantation genetic diagnosis," she said. " When you take one cell, does it represent the entire embryo ? What we've shown is that we can rely on PGD ( Preimplantation Genetic Diagnosis )."

UF researchers estimate less than 3 percent of healthy embryos are discarded as abnormal and only 1.5 percent are implanted with undetected genetic defects because of mosaicism.

To find out how big of a problem mosaicism is, the researchers developed a mathematical model using data from UF's IVF program and other programs to illustrate the different paths an embryo takes as it develops. While half of embryos turn out normal, with no mosaicism, the other half produce irregular cells as they divide.

Embryos that become mosaic after their cells divide twice typically stop progressing by the time they have accumulated eight cells. Too many of their cells have chromosomes that don't match and these mixed messages lead the embryo to stop developing, Kovalinskaia said.

Embryos with only one or two irregular cells still have a chance to develop normally though, she said. These embryos tend to not develop this abnormality until after their cells have divided a third time, typically the time when doctors perform preimplantation genetic diagnosis. This is where the problem with diagnosis occurs, researchers say.

" Our pathway concept may help to explain the observed outcomes during preimplantation diagnosis," said Kenneth Drury, director of the UF IVF and Andrology Laboratory and who was one of the researchers. " When we biopsy an eight-cell embryo, if we choose the one normal cell in an abnormal embryo, we may think that embryo is normal and transfer it.

" This occurs about 1 percent of the time, which means 99 percent of the time we will be accurate. Again the error is not due to a technical mistake but to natural errors occurring during early cell division in the embryo."

Extracting test cells before the embryo divides a third time could reduce the number of misdiagnoses because of mosaicism, the UF researchers suggest. Improving culture conditions could help too, Kovalinskaia said.

But the small margin of error shouldn't stop couples from having preimplantation genetic diagnosis, said Jamie Grifo, at New York University. The testing can work miracles for women prone to miscarriages or who carry genetic diseases, he said.

" If you are at risk for genetic diseases, it changes your outlook on starting a family," he said. " PGD allows them to get pregnant. It's a dramatic improvement when it works."

More than 45,000 babies are born each year with the aid of assisted reproductive technologies like IVF, according to the Centers for Disease Control and Prevention ( CDC ).
The use of IVF has declined in recent years, but Grifo said that is largely because baby boomers are leaving their childbearing years. Technologies like preimplantation genetic diagnosis have helped too, making IVF more accurate, he said.

Source: University of Florida, 2005


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