New Prenatal Genetic Tests Offer Safe Early Screening for Birth Defects

"The cell-free fetal DNA test gives expectant mothers an earlier (and safer) look than ever at [their unborn babies]."

In the following viewpoint, Erin Biba argues that a new blood test available to pregnant women in earlypregnancy allows the safe detection of birth defects earlier than ever. She claims that the test will now detect chromosomal abnormalities but in the future will give much more information, allowing pregnant women the ability to terminate a pregnancy earlier or have more information in preparation for the birth of a child. Biba is a science and technology reporter and writer.

Candace Weiss didn't know she had a family history of birth defects until she got pregnant with her daughter. That's when she learned that her grandmother, at the age of 42, had given birth to a baby with Down syndrome. "That child died young," she says. "But back in that time, they sent them away. She wasn't even raised in the family."

Weiss' own child was born perfectly healthy. Not long after, she and her husband started trying for a second baby. But she had a miscarriage. And then another. The second miscarriage was the result of triploid syndrome—the fetus had three of every chromosome instead of the normal two. So when Weiss, a 32-year-old lawyer turned stay-at-home mom in Westchester, New York (her name has been changed for this story), got pregnant again, her doctors watched her closely. "We did a lot of ultrasounds," she says. "Everything looked like it was going well."

 

A New Blood Test

 

Many women with high-risk pregnancies (which also includes women over 35) elect to undergo amniocentesis or chorionic villus samplings—invasive procedures that check for chromosomal abnormalities but carry with them a risk of miscarriage. Weiss says there was "no way in hell" she was going to do that. She didn't want to risk losing another baby. Well, said her doctor at her 10-week office visit, we've got this new test that checks for the most common chromosomal disorders (like Down syndrome). All it requires is a blood draw. And you can do it right now. The test was so new, in fact, that Weiss was one of the first patients in her doctor's practice to have it.

A week or so later the doctor called. The baby had Down syndrome. "We were obviously shocked," Weiss says. "Even the doctor was shocked." Weiss then had a chorionic villus sampling performed, on the remote chance of a false positive. It confirmed the blood test result, but she and her husband were already resigned to what was to follow. She says she needed to talk through the decision to end the pregnancy, but her husband never had any doubt. "His coping mechanism was just to be done with it," Weiss says. But for her, it was a bit different. "You hear this news and you make your decision. But meanwhile you're still pregnant. I mean, I was still nauseous."

Weiss terminated the pregnancy last fall at 12 and a half weeks. She and her husband hadn't told very many people that she was pregnant, and the procedure at that stage is mercifully swift and relatively simple. Some women do not find out their babies have serious medical problems until much later in their pregnancies. At that point, many doctors don't even perform abortions, obliging patients to travel to distant cities to get one. "It's huge to know early on," Weiss says. "Not that what we went through wasn't heartbreaking, but we were able to put it behind us faster. We get to start over sooner."

 

The Risks of Prenatal Testing

 

Before she knew about the blood test, Weiss—like hundreds of thousands of pregnant women each year—had been facing a complicated decision: Risk a perfectly healthy pregnancy to find out for sure if there's something wrong with your child, or live with a degree of uncertainty. It's a trade-off inherent in prenatal tests. Some are accurate—they can say for sure whether a child has a serious disorder—but may cause side effects; others are safer but give a more ambiguous level of information—all you get is the odds of whether or not the child has problems.

Yet plenty of patients today still go ahead with risky prenatal tests anyway. About 200,000 amniocenteses are performed in the US every year; the miscarriage rate for those is between 1 in 400 and 1 in 200. The miscarriage rate for chorionic villus sampling (CVS) is between 1 in 200 and 1 in 100, and it carries other risks, including infection and, in very rare cases, birth defects.

But with the advent of the kind of test Weiss took, which first hit the market in October 2011, there's an option that's about as accurate as amnio and CVS but as low-risk as a blood draw. Known as cell-free fetal DNA testing, it's now offered by Sequenom, Verinata, and Ariosa Diagnostics. The new test is expected to upend how prenatal screening and diagnosis are done—as well as create a financial windfall for the labs that perform it. (Market research firm Frost & Sullivan estimates that revenue in the prenatal testing industry will grow to $1.6 billion by 2017, up from $1.3 billion in 2010.) For the most part, the tests offered by these companies check for only three of the most common chromosomal disorders, but that's just the beginning. They presage a future when we can easily scan for a range of genetic defects, from the truly devastating to the not-so-serious, allowing parents and doctors to look past a baby's organs, beyond its cells, and down into its very DNA. Based on a small sample of a woman's blood, the cell-free fetal DNA test gives expectant mothers an earlier (and safer) look than ever at just who it is that's growing inside them.

 

The History of Prenatal Tests

 

The first time anyone got a peek into the womb was in 1896. X-rays had recently been discovered, and Edward Parker Davis, professor of obstetrics at Jefferson Medical College in Philadelphia, decided to use the new technology to observe a fetus inside a pregnant woman. Easily able to see the skull of the baby on the photographic plate, Davis later wrote in his Manual of Obstetrics: "When pregnancy is advanced so far that the fetal skeleton is well formed, the x-ray will give an outline of the fetus which may be available for diagnosis ... The position of the child in the pelvis, the presence of pelvic deformity, multiple pregnancy, and sometimes fetal deformity maybe outlined in this way."

It was, quite literally, a revelation. Before long, doctors started to use x-rays on pregnant women regularly. And, despite the fact that early radiological technology was so primitive that the patient had to sit still for up to an hour with her feet on a stool, arching over the back of a chair and thrusting her belly toward the machine, the practice began to catch on.

At first, doctors used the procedure to determine, say, if a woman was carrying twins. Then, in 1916, surgeon James Thomas Case was working with a patient who at seven months pregnant could no longer feel her baby moving. Case turned to the x-ray. He discovered that the baby was missing its cranial bones—the fetus had not developed a large part of its brain and skull. Ultimately Case induced labor, and the baby was stillborn. But with this first-ever diagnosis of a fetal abnormality, he proved that the x-ray could be a powerful tool for prenatal medicine; even though evidence emerged in the 1950s suggesting that radiation was a danger to fetuses, it would continue to be used into the 1980s.

By then, other prenatal tests had come along. But you always had to choose. Safe? Or accurate? Amniocentesis, for example, involves doctors inserting a long needle through the mother's abdomen and into the uterus to sample the fluid bath that envelops the growing fetus. The procedure provides clear data about some potentialbirth defects—technicians essentially examine chromosomes under a microscope—but the risk of miscarriage has persisted since the technique was developed in the 1960s. The accurate CVS test, which gained popularity in the 1980s, can be done earlier, but because it too involves a long needle or tube (either through the abdomen or cervix) it exposes the fetus to risks. Blood tests called multiple marker screens, meanwhile, measure specific hormones and proteins in the mother's bloodstream. Abnormal levels raise red flags and indicate that a more invasive and definitive test—amniocentesis or CVS—should be performed. Unfortunately, these blood tests produce numerous false negatives and false positives. So some serious problems are missed altogether and some tests result in unnecessary procedures, which, in turn, cause an estimated 1,000 miscarriages of healthy fetuses every year.

 

The Cell-Free Fetal DNA Test

 

The cell-free fetal DNA test totally upends this equation. And it relies on the slightly creepy fact that the bloodstream of a pregnant woman is full of genetic material from her baby. Some of this DNA is inside the nucleus of intact fetal cells, and some is just floating around loose. We've known about the intact cells since the 1970s. As a fetus develops, the placenta sheds some of its cells. And each of them contains a set of the baby's chromosomes—the 23 pairs of curled-up packets that house a human's genetic material. Some of those intact cells (plus a few other types, like red and white blood cells) migrate into the mother's bloodstream with the baby's DNA on board. The problem, from a prenatal testing point of view, is that these cells are extremely rare and difficult to isolate from a sea of maternal blood. Plus, they can remain present for years. This means that you would only get useful test readings during a woman's first pregnancy.

But fetal DNA gets into the mother's bloodstream another way too: As cells from the placenta die and come apart, the loose "cell-free" genetic material they carry seeps into the mother's system. In fact, around 10 percent of all the free-floating DNA in a pregnant woman's blood plasma belongs to her baby. About a day after the mother gives birth, this genetic evidence disappear—it's filtered out by the kidneys—leaving a clean slate for testing subsequent pregnancies.

Cell-free fetal DNA was discovered about 15 years ago by a scientist named Dennis Lo. He had come across two papers in Nature Medicine describing free-floating tumor DNA in the blood plasma of cancer patients. "I thought that if a tumor could release sufficient DNA into the circulation for us to detect it, then surely we should be able to find fetal DNA in the plasma of pregnant women," he says. The notion would ultimately make Lo famous in the world of obstetrics and prenatal testing. He's now director of the Li Ka Shing Institute of Health Sciences in Hong Kong and a member of Sequenom's clinical advisory board.

Starting in 1996, Lo's research team began searching for the Y chromosome of male fetuses in the blood plasma of pregnant women (since only boys have Y chromosomes, if they were found in a woman's bloodstream, they'd have to belong to the baby). They guessed that a baby's DNA would be relatively easy to find in the later stages of pregnancy—after all, the larger the baby grew the more DNA it would release, right? What they discovered, however, was that they could detect fetal DNA as early as six weeks (although testing at about 10 weeks yields more accurate results because DNA levels are higher). The implications were enormous. Getting a sample was easy, and it could be done much earlier than amniocentesis (usually performed between the 16th and 18th weeks of pregnancy) and even a bit earlier than CVS (often done in the 12-week range). If the results meant that the parents chose an abortion, the timing at least would be a little easier on the family. If the test was normal, as it usually would be, the parents could breathe a sigh of relief that much earlier. "The scientific community has been looking for a noninvasive way to perform prenatal diagnostics for the past 20 years," says Dirk van den Boom, Sequenom's senior vice president of research and development. "You take away a lot of anxiety when you get accurate results early in the pregnancy."

 

The Detection of Chromosomal Abnormalities

 

Sequenom, the first company to offer this test, is located just down the road from the beautiful oceanfront scenery of the Scripps Institution of Oceanography in La Jolla, California. Its dull office-park headquarters is about what you'd expect for a blood-test operation: Every day, boxes filled with samples arrive from doctors' offices around the country. The tubes of blood are unpacked and stored in a freezer at -80 degrees Fahrenheit. When it's time to test, they're placed into centrifuges and the plasma is separated out. But appearances can be deceiving. In the next room over sit millions of dollars' worth of next-generation genetic sequencers. It may look dull, but this was the first testing lab in the US to use sequencers in a large-scale, high-throughput prenatal test.

Green lights on the boxy sequencers hum back and forth, making them look a little like Cylons [cyborgs in the old TV series Battlestar Gallactica]. The machines are searching for chromosomal abnormalities called trisomies. That's a genetic defect where, instead of having the usual two copies of a particular chromosome in each cell, the fetus has three. Most newborns affected by this have problems with chromosomes 13, 18, and 21, and the sex chromosomes (X and Y). Trisomy 21, better known as Down syndrome (after John Langdon Down, who first described it in 1866), is characterized by physical features like upward slanting eyes and a flattened nose. People with the disorder can live into adulthood, but they experience a range of mild to severe mental disabilities, heart defects, hearing problems, and difficulty seeing. The prospects for self-sufficient living in adulthood vary depending on the severity. Many are able to care for themselves, but those with severe disabilities require assistance throughout their lives.

The effects of a triple-set of the 18th chromosome (known as Edwards syndrome) and of the 13th (known as Patau syndrome) are far more serious. Many children born with these disorders live only a few days, and 90 percent die before their first birthday (though there are outliers—2012 Republican presidential hopeful Rick Santorum has a daughter with Edwards syndrome who is almost 5 years old). In fact, many affected fetuses naturally miscarry—though this can happen painfully late in a pregnancy. As a woman gets older, her likelihood of having a child with one of these conditions increases: At 25, her chances of giving birth to a child with Down are 1 in 1,250. By age 35—not an uncommon age for women to have a child these days—they jump to 1 in 378. In 2007 the increasing accuracy of screening meant that the American Congress of Obstetricians and Gynecologists decided to throw out old guidelines that recommended screening only for pregnant women over 35 and instead advised offering it to all women, regardless of age. Because of the chance of side effects, however, patients usually opt for invasive testing only if they are high-risk or if there is an indication that something may be wrong with the pregnancy. Up to 85 percent of parents in the US who discover their child has Down syndrome opt for abortion.

To detect chromosomal abnormalities, Sequenom uses a technique called massively parallel shotgun sequencing. (Companies could also take a more targeted approach that analyzes only the relevant chromosomes.) First they use PCR technology to make copies of millions of snippets of DNA in the blood sample, then they sift through the mix for specific sections that scientists know show up only on, say, chromosome 21. Think of it as a bowl of M&Ms, where the brown ones represent segments of chromosome 21. You expect to find a factory-set proportion of them, and you know that some come from the mom and some from the baby. If the fetus has three copies of chromosome 21 instead of the normal two, you're going to find too many brown M&Ms in your bowl. This means there's a problem.

 

New Prenatal Testing Recommendations

 

At the end of November [2012], the American Congress of Obstetricians and Gynecologists released a long-awaited opinion on the cell-free fetal DNA test. The group recommended it for patients at an increased risk for chromosomal defects, including those over age 35 and those with a history of trisomy pregancies. It did not advise using the test as a routine part of prenatal care for low-risk patients or women who are carrying multiples. The recommendation is likely to make doctors more aware of the test; many ob-gyns [obstetrics-gynecologyphysicians] have never even heard of it, and though some insurance companies have worked out coverage for the test, many patients are paying around $500 out of pocket.

Until news of the test reaches more physicians, demand will largely be driven by the women themselves, many of whom find out about it online. Jennifer Schaefer, a 38-year-old Google employee and mother of two, first heard about the test on parenting message boards. Her ob-gyn didn't know about it, so Schaefer requested the test from her genetic counselor. She isn't so unusual. Very often, women who hear about the new blood test immediately seek it out. (One doctor points out that her more educated, higher-socioeconomic-status patients are the ones who ask for it the most.) Indeed, Sequenom alone has run 37,000 tests since its version debuted in October 2011. That said, most women still end up having an ultrasound, a noninvasive peek at the developing baby that can tell doctors about other issues like neural tube defects or, later in pregnancy, kidney or heart problems.

Interestingly, it's not at all clear that the cell-free fetal DNA test will increase abortion rates. Some 90 percent of all genetically disabled babies are already identified in utero—further detection would add only that last 10 percent. "I wouldn't think there's going to be a dramatic increase" in abortion if the new test proliferates, says Joanne Taylor, a genetic-counseling supervisor at Lucile Packard Children's Hospital in Palo Alto, California. "You're only adding babies that wouldn't have been seen before—say, in a 22-year-old woman who wouldn't have been screened in the past. They'll be added to the pool to make a decision. You're looking at a small group to begin with."

And some families, of course, choose to continue with the pregnancy. They, too, could take advantage of this test: Studies have shown that when it comes to Down syndrome, the psychological benefits of early knowledge are significant. "Most families report that they are happy to have learned the information during the pregnancy," Taylor says. "They can prepare and not have a shock at delivery that they have to quickly adjust to."

 

The Future of Prenatal Testing

 

The cell-free fetal DNA test will eventually be able to look for more than just the big three chromosomal disorders. In fact, Verinata just announced that it will offer a screen for Turner and Klinefelter syndromes along with other sex chromosome disorders. Turner syndrome affects about one in 2,000 births, and it results when one of a girl's two X chromosomes is missing or incomplete. Cases can be quite mild, but women with Turner can exhibit a webbed neck, infertility, and heart problems. Klinefelter affects about 1 in 1,000 boys—they have two X chromosomes and a Y instead of the normal XY pair. Boys with Klinefelter might have the suggestion of breasts, less body hair, impaired fertility, and a higher propensity for other diseases, but they can and do lead pretty normal lives. A cheap, easy, safe test for conditions like these raises uncomfortable questions: Your slightly soft-bodied high school math teacher could well have had Klinefelter syndrome, maybe without even knowing it. This makes the decision to abort a baby with Klinefelter a lot more difficult than the decision to abort a trisomy 18 pregnancy.

Other, further-out applications of this test might include looking for issues like Tay-Sachs (usually fatal), sickle cell anemia and cystic fibrosis (both survivable with treatment), or even the presence of the BRCA1 or BRCA2 gene, which are associated with a high likelihood of some breast cancers. But as Glenn Palomaki, associate director of the Institute for Preventive Medicine and Medical Screening and head of the independent research team that validated Sequenom's test, puts it, "If you can test for 20 disorders, should you do 40? 60? 400?"

John Stuelpnagel, executive chair at Ariosa Diagnostics, which offers a cell-free fetal DNA test, says the way to think about future options is like this: You want to test for things that are either really severe and have a clear-cut diagnosis, or you want to test for milder conditions that can be treated in some way. "The genetic disorder must be well understood," he says. "It does not benefit anyone if there is ambiguity in diagnosis created by a test."

For now, then, and into the foreseeable future, we'll have to be content with accepting that humans exist on a kind of bell curve of normalcy: No matter how deep we poke and prod and look and worry, our ability—and our desire—to know who our children are before they are born will always have limits. Until they come squalling into the world, there's not much more to do but watch and wait. Which makes us little different than those mothers in the late 1800s, backs bent over chairs, bellies thrust into the air, hoping for the best.