By Krista Conger
Illustration by Christopher Silas Neal
Few moments are as life-changing as the appearance of that blue line in a positive pregnancy test. But for many, after that first heart-stopping catch of breath comes a litany of questions and decisions: “Is my baby OK? How can I be sure? What should I eat, drink, do?”
I well remember that anticipation — and the stress during my three pregnancies. During my last, about 10 years ago, I had the ignominy of, at the age of 35, falling into the “advanced maternal age” category. Babies of women of my age, I was reminded, are more likely to have genetic abnormalities than those born to younger women.
Thankfully, even at that time a variety of tests were available to screen or diagnose affected pregnancies. I just had to choose which, if any, to undergo. Amniocentesis — accomplished by inserting a needle through my abdomen to collect amniotic fluid? Or chorionic villus sampling — also carried out with a needle in my abdomen or a catheter through my cervix to gather pieces of my placenta? These diagnostic tests would give a solid answer as to whether my baby had an abnormal number of chromosomes (the most common genetic problem seen in pregnant women of my age and the cause of Down syndrome), or carried the gene for cystic fibrosis or sickle cell anemia, for example. But neither of these procedures is risk-free: About one in a few hundred women (depending on the procedure and where it is performed) experience a miscarriage as a result.
Or maybe I wanted to go with noninvasive screening methods based on blood samples and ultrasound scans. These are safer for the baby, but give answers in likelihoods, rather than yeses and nos.
Currently, every pregnant woman in California is offered prenatal screening through a combination of blood tests and ultrasounds for genetic abnormalities through the California Department of Public Health. The $162 cost is often covered by insurance. If the preliminary screen indicates an elevated risk, the woman is offered follow-up genetic counseling, ultrasounds and amniocentesis at no additional charge.
Screening was important to me: It would help me prepare if my baby were to have a severe health problem. And some women choose to abort a fetus if the child would have a serious health condition.
The stakes of my choice felt very high. Get a firm answer while risking my baby’s life? Or stick with a safer, less accurate bet? As many as 5 percent of women taking these traditional screens receive a false-positive result — resulting in weeks of unnecessary worry. I still get a little anxious thinking about it.
Things have changed. It’s now possible to deduce the entire fetal genome from a single sample of a woman’s blood (although this is not yet offered clinically), and new, noninvasive blood tests can identify about 99 percent of Down syndrome cases as early as 10 weeks of pregnancy. False-positive rates reported by the companies hover at around 0.1 percent for detecting Down syndrome, and false negatives for the condition appear to be even more rare. The tests can also identify several other chromosomal abnormalities that would affect a baby’s health, although with slightly less accuracy. The me of 10 years ago would have jumped at the chance for such screening.
This new type of prenatal screen, called cell-free fetal DNA testing, stands to significantly reduce the need for invasive, costly and risky diagnostic procedures. Not surprisingly, these cffDNA tests have become hugely popular since they were introduced two years ago, and will undoubtedly transform prenatal genetic screening — an estimated billion-dollar market — in the United States.
Most woman who have been pregnant are familiar with how the growing fetus takes over the mother’s body — slowly, at first, and then with increasing ferocity as bladder and lungs and belly are stretched and pounded. The process is quite humbling.
So when I learned that up to 10 percent of free-floating genetic material in a mother’s blood actually comes from the fetus, I rolled my eyes and snorted. First my body, and then my blood? Does the indignity never end?
It turns out, though, that those bits of fetal DNA carry vital information about the genetic make-up of the fetus that could affect not just whether a woman chooses to carry it to term, but also how she and her family prepare for the birth of an affected child. Recent research suggests it may even be possible one day to treat a fetus with conditions like Down syndrome before birth. But it’s been difficult to tease out the fetal DNA from the mother’s.
In 2008, however, Stanford professor of bioengineering and applied physics Stephen Quake, PhD, published a new approach based on combining a molecular counting principle with advances in DNA sequencing technology. By simply comparing the relative levels of each chromosome in the mother’s blood, Quake, a Howard Hughes Medical Institute investigator, could identify women carrying a fetus that was contributing more or less than the expected ratio (a sign of an abnormal number of chromosomes, or aneuploidy). For example, a fetus with Down syndrome has an extra copy of chromosome 21, which would be reflected as a higher-than-normal ratio of chromosome 21 to other, unaffected chromosomes. The same approach works, although it is slightly less accurate, for other chromosomes like 18 and 13 as well as the sex chromosomes X and Y. (Abnormal ratios of these chromosomes can also cause serious, sometimes life-threatening, developmental disabilities.)
The test is much more accurate, and can be performed earlier in a pregnancy, than traditional screening tests for aneuploidies in chromosomes 21, 18 and 13. These traditional tests have sensitivities ranging from 75 to 95 percent and false-positive rates around 5 percent. Finally, the cffDNA test devised by Quake can be performed at any point after 10 weeks of pregnancy; traditional screens are accurate only when performed at very specific windows of time after conception.
“There’s no question that the cffDNA screens are more sensitive and more specific than conventional screening,” says Louanne Hudgins, MD, a professor of obstetrics and gynecology and of pediatrics, and director of perinatal genetics at Stanford. “They will also enable us to make accurate genetic diagnoses in the third trimester without the risk of preterm labor.” Hudgins is a co-author of Quake’s first paper describing the cffDNA analysis.
Stanford patented Quake’s test and licensed it to Verinata Health, but other companies have developed similar technology. San Diego-based Sequenom was the first to begin to offer the test in October 2011; since then Verinata, Ariosa Diagnostics and Natera have begun offering similar screens.
“This is the fastest adoption of medical technology that anyone has seen in our lifetime,” says Quake, who serves as an unpaid advisor to Verinata and receives a small percentage of Stanford’s royalties from the patent. “It’s truly amazing. In 2008, I thought it could take a decade to fully enter the clinic. But within days of publication I started to get emails from people around the world asking where they could get it done.”
Currently the cost of cffDNA tests ranges from about $795 to $2,700, depending on the company, and insurance coverage for the tests varies. The four companies are engaged in lawsuits, battling for the exclusive right to the approximately $1.3 billion market.
The American Congress of Obstetricians and Gynecologists currently recommends cffDNA tests only for women already shown by established screening methods or age to be at higher-than-normal risk, and they urge women to confirm any positive result with an invasive procedure such as amniocentesis or chorionic villus sampling.
Illumina, the company that owns Verinata, estimates that around half a million women will use a cffDNA prenatal test this year. “If 500,000 women are choosing this test, rather than invasive procedures like amnio or CVS,” says Quake, “that means in 2013 we will have avoided around 1,600 unnecessary fetal deaths. I find it absolutely remarkable, and it’s something of which I’m personally quite proud.”
Despite its rapid uptake, the cffDNA test is still in its infancy. Questions remain as to how the test performs when a woman is carrying more than one fetus, or how to deal with the fact that as many as 5 percent of women (usually those with high body mass index) will have too little fetal DNA in their blood for analysis. Furthermore, different companies use different DNA sequencing techniques for their analysis, which can vary in their sensitivity and outcome, and the way they report their results varies widely.
Many observers expect the U.S. Food and Drug Administration to step in within the next year to establish ground rules for providing the tests.
“We’ve taken the whole phenomenon of cffDNA testing and commercialized it at a time when there is very little regulation or oversight,” says bioethicist Mildred Cho, PhD, a Stanford professor of pediatrics.
‘I thought it could take a decade to fully enter the clinic. But within days of publication I started to get emails from people around the world asking where they could get it done.’
Until the tests are proven to have clinical utility in large groups of low-risk women (most were tested on women at high risk for these types of disorders), and until it’s certain that women and their providers thoroughly understand the strengths and weaknesses of the tests, it may be best to use them in combination with other, more traditional types of screens, some say.
“We’re in a very early stage right now with these tests,” says associate professor of genetics Kelly Ormond, a Stanford medical ethicist and certified genetic counselor. “I’m concerned that clinicians and patients who are jumping straight to the cffDNA tests may be overestimating what they can learn from them at this point.”
In an era when genetic information is touted as the key to personalized health care, it’s hard to argue that it can be better to know less. But Ormond and others say it’s important that women consider and discuss with family members and their clinicians what information, if any, they would like to receive from prenatal tests. They are concerned that the ease of the cffDNA test may mean that women will undergo the procedure without considering its implications.
“Women may not give a lot of thought as to whether they want the cffDNA test, whereas, someone presented with the possibility of an amnio will think long and hard about whether she wants a needle in her stomach,” says maternal and fetal medicine expert Mary Norton, MD, a former professor of obstetrics and gynecology at Stanford. Norton has recently taken a position as the vice chair for clinical and translational genetics at the University of California-San Francisco.
Cho cites studies indicating that physicians’ attitudes toward informed consent — that is, making sure that a patient fully understands and agrees before undergoing medical tests — may be more lax if the method is noninvasive. She and others recommend against combining the blood draw for the cffDNA test with any other routine blood sampling procedures to avoid confusion, and urge that the patient be offered genetic counseling before and after testing.
“It’s clear that the cffDNA tests have some tremendous advantages and strengths,” says Norton. “And, if all you care about is Down syndrome, it’s a really great option. But I think it’s important to step back and realize that the current recommended screening tests do pick up things that cffDNA doesn’t.”
For example, traditional screening, which combines a maternal blood test with prenatal ultrasounds in the first or second trimester, can detect a variety of problems including the likelihood of preterm delivery, structural abnormalities of the fetus and pre-eclampsia, which can result in a dangerously high blood pressure. Combining cffDNA testing with ultrasounds and blood tests for signs of these other conditions may be an effective approach, Quake believes.
Norton is an investigator on a large, multicenter clinical trial comparing the cffDNA test offered by Ariosa Diagnostics with traditional, first-trimester prenatal screening in 19,000 low- or average-risk women. Conventional first-trimester screens use a blood test and a specialized ultrasound measurement of the back of the fetal neck to estimate aneuploidy risk. They deliver results earlier than other conventional screens, but are less accurate than those that also incorporate a second-trimester blood test. Results from that trial are expected in early 2014.
There’s every reason to expect that cffDNA tests will one day be used to recognize fetuses with problems other than abnormal numbers of chromosomes. For instance, if a fetus is likely (because of the family’s medical history) to carry a mutation for a specific disease, it’s possible to sequence only the relevant genes.
“This is potentially very clinically important,” says Quake. “We could create a screen that would identify metabolic disorders, immune deficiencies and other problems. In principle we could learn this before the child is born, and be prepared to offer treatment right after birth rather than finding it out when the baby gets sick.”
Most experts agree cffDNA screening technology has the potential to revolutionize prenatal care, particularly if fetal whole-genome sequencing ever becomes commonplace. (Last year, Quake and another research group at the University of Washington independently showed that it is possible to sequence a fetus’ entire genome from a maternal blood sample.)
“Ultimately it is likely that anything we can figure out by studying an adult’s genetic sequence, we will be able to figure out for a 10-week-old fetus,” says Stanford law professor and bioethicist Hank Greely, JD. But do parents want to know whether their child will have a higher-than-normal risk for Alzheimer’s disease? How about obesity? Gum disease?
“No technology is all good or all bad,” says Greely. “In every instance, a new advance can be used well, or it can be used poorly. But it’s clear this test is spreading rapidly all over the world. It’s useful and it’s likely to play a bigger and bigger role in prenatal care in the coming years.” For instance, the cffDNA test for abnormal numbers of chromosomes 21, 18 and 13 will soon be part of the California prenatal screening panel as a way to follow up on troubling results from initial screens.
“Eventually we will be able to use this approach to ask any genetic question we want about a fetus,” says Quake, “and learn about any mutation we might be interested in.”
Ten years ago, I didn’t have this option. I finally decided on just the standard blood tests and ultrasounds when I was pregnant with my son. They didn’t indicate any increased risk, so, like every other pregnant woman for centuries, I held my breath and hoped until the day he was born.
He was fine.
E-mail Krista Conger