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Playing the Odds

Detailed genetic diagnostic tests may soon become routine for women undergoing in vitro fertilization. But for most women who become pregnant, the tools for detecting genetic defects still offer risks and uncertainties.

It is a warm London morning in June, and Kypros Nicolaides is bouncing from room to room in the Fetal Medicine Centre, a clinic just down the block from the city’s majestic Royal Academy of Music. An obstetrician and gynecologist who runs the Harris Birthright Centre for Fetal Medicine at King’s College Hospital and, one day a week, this private clinic, Nicolaides has his own intimate relationship with sound: he has developed an international reputation for pushing the bounds of prenatal ultrasound.

In an examination room, Nicolaides greets a 31-year-old woman, 13 weeks pregnant, who has been anxiously awaiting him. As a technician moves an ultrasound transducer over the woman’s belly, Nicolaides points to a monitor that shows the grainy image of a fetus. He then has the technician focus in on the folds of skin behind the fetus’s neck.

Over the past 10 years, Nicolaides has convinced many of his colleagues that looking for fluid in this region, in a procedure called a nuchal translucency screen, can in the first trimester reveal cases of Down’s syndrome as well as other even more severe syndromes that result from extra copies of chromosomes 13 and 18. The ultrasound shows that this woman’s fetus has a slightly larger than normal nuchal translucency measurement, but Nicolaides assures her that it’s nothing to worry about.

On a separate computer screen, software developed by Nicolaides’ foundation graphically shows the risk this fetus has of a chromosomal abnormality. By the woman’s age alone, the risk factor is one in 650. The nuchal translucency slightly increased the risk to one in 600. But earlier that morning, Nicolaides’ team drew blood from the woman and analyzed it for a protein associated with these chromosome problems and for levels of a pregnancy hormone that serves as a marker for abnormalities. With the blood tests factored in, her risk plummets to 1 in 1,000, making her look like a woman in her early 20s. But then the woman tells Nicolaides that she had previously conceived a baby with Down’s syndrome, a pregnancy that she had terminated. Plugging that into the software, Nicolaides calculates her risk to be one in 180.

The woman and her husband decide then and there that they want to have a chorionic villus sampling performed. Nicolaides explains that this procedure, in his hands, carries a risk of one in 200 or so, maybe higher, of causing a miscarriage. They weigh the options but are resolute. Nicolaides, under guidance of the ultrasound, inserts a catheter into her abdomen and removes fetal cells from the villus-the area that links the part of the placenta known as the chorion to the mother’s uterus. The cells are then sent to the lab for chromosome analysis.

Both chorionic villus sampling and its diagnostic cousin amniocentesis can detect Down’s syndrome, spina bifida and many other disorders with 99 percent accuracy. Adding to their value, they have a low “false positive” rate: when they report that a problem exists, they are hardly ever mistaken. But because, on average, both of these invasive tests cause miscarriages up to 1.5 percent of the time, they are also extremely dangerous.

Indeed, in the opinion of Nicolaides and others, many more women than ought to undergo amniocentesis and chorionic villus sampling, given the risks of the procedures and the odds of detecting a fetal abnormality. This concern has driven the development of Nicolaides nuchal translucency test and several noninvasive blood screens. Vivienne Souter, an obstetrician and gynecologist at the University of Washington, sees great value in these new technologies. “If we can get better screening with higher sensitivity and lower false positivity,” says Souter, “we can potentially save babies’ lives.”

In the United States, a multicenter trial is now recruiting 40,000 pregnant women as subjects and will perform the most rigorous analysis yet of nuchal screens and various blood markers used in both the first and second trimester. Fergal Malone, a perinatologist at Columbia University and the coprincipal investigator of the study, says he expects to have results by the winter of 2003. “If we choose the right combination of screening tests, we could have detection rates as high as 90 to 95 percent with a one percent false-positive rate,” says Malone. “That would be a huge advantage.”

Many clinicians contend that, as ever increasing computing power improves the resolution of ultrasound, screening of the nuchal region and other anatomical features will have an increasing ability to reveal problems. “Fifteen years ago, it was a very blurry image,” says Beryl Benacerraf, a radiologist at Diagnostic Ultrasound Associates in Boston. She published a report in 1985 about the promise of nuchal screening. “As it’s gotten better and better, the images look more like Kodak pictures.”

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Tagged: Biomedicine

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