A Fetal Development

Prenatal DNA testing of a small sample of blood reduces the need for invasive procedures to detect Down syndrome and other genetic disorders. But that’s only the beginning of what these tests will be able to do.

By Aimee Swartz

Illustration by Shout

When Abby Brown became pregnant at 35 with her first child, in 2012, she knew that her age put her fetus at an elevated risk for Down syndrome. At age 25, a woman’s odds of having a baby with the disorder are 1 in 1,200. Those odds climb to 1 in about 350 by the age of 35 and to 1 in about 40 by age 44.

Blood tests typically used to screen for Down syndrome had raised no red flags for Brown, now 37 and living in New York City, but still she wanted to be certain that her fetus was healthy. Each year in the United States, an estimated 6,000 babies are born with Down syndrome, a chromosomal abnormality that causes lifelong mental disabilities, developmental delays, and, often, heart defects and other health problems.

Until recently, ruling out a diagnosis of Down syndrome and other chromosomal abnormalities prenatally required amniocentesis or chorionic villus sampling — invasive procedures that require the insertion of a needle or tube into the womb or placenta and cause 1 to 2 percent of women to have a miscarriage.

Brown and her husband faced a complicated decision: risk a healthy pregnancy to find out for sure if there was something wrong with their child or live with a degree of uncertainty? Then Brown learned about a new option that had come on the market just weeks before: a screening test that is about as accurate as amniocentesis and chorionic villus sampling but as low-risk as a routine blood draw.

Known as fetal cell-free DNA testing (cfDNA), the test can detect Down syndrome and other chromosomal abnormalities through a sample of blood drawn from the mother.

Chromosomal abnormalities are caused by a missing, extra, or irregular chromosome. Typically, humans have 46 chromosomes in every cell of their body — 23 inherited from their mother and 23 inherited from their father. People with Down syndrome have three copies (trisomy) of chromosome 21 instead of the usual two.

The cfDNA tests rely on DNA fragments shed by the placenta that, in nearly all pregnancies, are equivalent to fetal DNA. These short fragments of DNA, along with fragments from the pregnant woman, float in the woman’s bloodstream. This mixture of fragments can be extracted and analyzed for extra material from specific chromosomes.

“If more than the expected proportion of fragments for chromosome 21 are found, for example, it would indicate that the fetus may have Down syndrome,” says Glenn Palomaki, a scientist specializing in prenatal screening at Women & Infants Hospital and Alpert Medical School at Brown University in Providence, Rhode Island.

In addition to screening for Down syndrome, cfDNA tests can also screen for Edwards syndrome (trisomy 18) and Patau syndrome (trisomy 13), both of which can cause serious developmental and medical issues. Some insurance plans cover the tests, which cost anywhere from $500 to $2,000, but most patients wind up paying out of pocket.

Though prenatal screening tests vary by clinic, the current standard often includes a blood test and an ultrasound during the first trimester. The blood test measures certain hormone and protein levels that are associated with chromosomal abnormalities. The ultrasound, called a nuchal translucency test, measures the fluid that accumulates in the back of a fetus’s neck — a characteristic that is strongly associated with an elevated risk of Down syndrome.

These standard screening tests estimate the chance of the fetus having Down syndrome, but they neither confirm nor rule out the disorder. Women deemed to be at high risk based on the screening are advised to undergo either amniocentesis or chorionic villus sampling for a definitive answer.

The problem with routinely used tests, says Diana Bianchi, executive director of Tufts Medical Center’s Mother Infant Research Institute, is that “they are far from definitive.” Large studies have shown that these tests pick up only about 79 to 90 percent of all cases of Down syndrome and incorrectly detect the disorder — an occurrence known as a “false positive” — in about 3 to 6 percent of all cases.

In contrast, cfDNA tests are “extremely accurate,” Palomaki says. Recent data show that cfDNA tests can identify 99 of every 100 fetuses with Down syndrome. Just as important, he notes, is that cfDNA tests incorrectly identify Down syndrome in only 1 in 200 normal pregnancies — much lower than typical screening methods, which incorrectly identify Down syndrome in as many as 12 in every 200 normal pregnancies.

At the time of Abby Brown’s pregnancy, the technology was so new that only a few clinics in London, where she lived at the time, offered cfDNA testing. Once she located a clinic near her that offered the tests, she did not hesitate to make an appointment. Within a week, Brown learned that she had less than a 1 in 10,000 chance of having a child born with Down syndrome.

Fetal cell-free DNA testing is not perfect, however. If blood samples do not include sufficient placental DNA, the results may be inconclusive. And a rare form of Down syndrome called mosaicism, in which abnormalities can vary between the placenta and the fetus, can be missed by cfDNA tests.

Bianchi points to the fact that cfDNA testing can be done as early as the seventh to ninth week of pregnancy as one of the technology’s “greatest advantages,” saying it gives women and their partners “more time to grapple with the difficult choice of terminating a pregnancy or preparing for a special-needs child.”

Others say that the ability to detect a problem so much earlier than amniocentesis — typically performed between the 15thand 20th weeks of pregnancy — could result in more women choosing an abortion. “It may seem more acceptable to women than having an abortion much later in their pregnancy,” says Arthur Caplan, a professor of bioethics at New York University’s Langone Medical Center.

Because of the chance of a false positive, women are advised not to base their decision to terminate their pregnancies on results of cfDNA testing alone. Rather, Bianchi says, “Those who test positive are very strongly urged to undergo an amniocentesis or chorionic villus sampling before taking irreversible action.”

Though cfDNA testing cannot completely replace invasive diagnostics, Caplan says, “It won’t be long before it becomes standard of care for all women.”

Bianchi estimates that well over 100,000 tests have been performed. And in late 2012, the American College of Obstetricians and Gynecologists began recommending cfDNA testing as a screening tool for women at high risk of delivering a baby with Down syndrome.

The rapid uptake of cfDNA tests suggests they are likely just the beginning when it comes to prenatal DNA screening. Though sequencing the fetus’s entire genome using cell-free DNA fragment is still too expensive to be done under normal conditions, with the costs of genome sequencing continuing to fall, some foresee a future in which information about a fetus extends well beyond a handful of known fetal conditions to any human trait that has a major genetic component.

“What if we are able to detect a gene that increases the risk of a disease — for example, breast cancer? What if we can detect deafness or short-staturedness?” Caplan says. “This really has the potential to change the way people think about pregnancy in general. Genetic counselors are going to become very, very important.”