Mary Norton, MD, advises her pregnant patients to think carefully about whether they want to have prenatal cell-free DNA screening, also commonly known as noninvasive prenatal testing (NIPT).
The screening, which is done by analyzing the pregnant person’s blood to look for the more common chromosomal abnormalities, can detect if a baby is at higher risk for trisomy 21 (also known as Down syndrome), trisomy 18 (Edwards syndrome), and trisomy 13 (Patau syndrome), and can also screen for several rare disorders, as early as 10 weeks of pregnancy.
But Norton, who is a professor and division chief of obstetrics, gynecology, and reproductive sciences, and chief of maternal-fetal medicine at the University of California, San Francisco School of Medicine, points out that the screening results for some patients may lead to unnecessary anxiety or false reassurance.
“The test itself is very good,” Norton says. “The biggest problem that I see is that patients and their providers lack a complete understanding of the limitations of the test.”
For one, the screening is currently only reliably available for a handful of conditions.
“It is an extremely accurate test for a couple of conditions, but pregnancy can be affected by hundreds of genetic conditions,” Norton says. “There’s no guarantee of a healthy baby.”
On the other hand, for several extremely rare conditions, the NIPT results produce more false positives than true positives, as the New York Times reported in January.
It’s a fact that the American College of Obstetricians and Gynecologists (ACOG) emphasizes should be clearly communicated when counseling a pregnant person about the screening results. In its guidelines, “cell-free DNA testing is not equivalent to diagnostic testing,” is written in bold type.
Still, the screening can provide important clinical information, provided it is given along with thorough, accurate, and non-directive counseling, says Diana W. Bianchi, MD, a geneticist, researcher, and director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, who has received international recognition for her contributions to prenatal diagnosis and therapies.
“If the pretest counseling occurs, [the screening] gives the prospective parents an opportunity to think about what they want to know ahead of time,” Bianchi says. “How it would influence their care.”
Prenatal screening and diagnosis have existed in some form since the development of the ultrasound in the 1950s, but has become more advanced in the last decade. NIPT became available in 2011 and has gained traction because of its accuracy for detecting a high risk of Down syndrome and because it can also determine the baby’s sex.
The screening is performed in a laboratory, where technicians search for fragments of DNA in the blood and use them to piece together genomic sequences for both the pregnant parent and the baby, though they can’t distinguish one from the other with certainty unless there is a Y chromosome present, indicating a male fetus, Bianchi explains.
Because of this, the screening can sometimes identify unknown issues in the parent, including genetic conditions or cancer, a phenomenon the National Institutes of Health is currently studying, she says.
Before NIPT, pregnant people who were considered at high risk of having a child with a chromosomal abnormality — particularly those age 35 and older — would likely be advised to have a diagnostic test, such as an amniocentesis or chorionic villus sampling, which take samples from the amniotic fluid and placental tissue, respectively, and carry small risks of pregnancy loss (about 1 in 300-500).
“There’s a big difference between a screening test and a diagnostic test,” says Susan D. Klugman, MD, a professor of reproductive and medical genetics at the Albert Einstein College of Medicine in the Bronx, New York, and president-elect of the American College of Medical Genetics and Genomics. “The screening test is offered to detect potential disease. If the screen is positive, it is appropriate to consider a diagnostic test.”
Since NIPT became available, the number of patients who choose an invasive diagnostic test has dropped significantly. One study found that at Mount Sinai West Hospital in Manhattan, the percentage of patients who had prenatal diagnostic tests dropped from 38% in 2010 to just 2% in 2015.
“Many people, especially if they had difficulty conceiving, don’t want any risk [of pregnancy loss],” Bianchi says. “Many also don’t want a needle in their womb or a catheter [to perform the diagnostic tests].”
In these cases, receiving a negative noninvasive screening result can be a great relief to the parents, she adds.
“There’s a big difference between a screening test and a diagnostic test. … The screening test is offered to detect potential disease. If the screen is positive, it is appropriate to consider a diagnostic test.”
Susan D. Klugman, MD
Albert Einstein College of Medicine in the Bronx, New York
On the other hand, a positive screening result that leads to a positive diagnostic result can give the parents an opportunity to plan.
“I discuss [the options] with my patients,” says Cara Heuser, MD, an assistant professor of obstetrics and gynecology at the University of Utah Health Sciences Center in Salt Lake City. “I tell them some people do not want this information and that’s totally fine. They feel like it would make them anxious and would rather find out when the baby [is born]. Other people find that information would be helpful in being prepared for a baby that might have special needs or might end the pregnancy.”
For those planning to continue the pregnancy, a diagnosis can help physicians look for potential health problems associated with chromosomal abnormality, such as heart defects. It can influence where the parents deliver the baby and what kind of specialists will be involved in the child’s care. If the diagnosis is for trisomy 18 or 13, which are both associated with perinatal mortality, they can meet with palliative and hospice care coordinators.
“In some situations, there is fetal treatment available,” Bianchi says. “My lab is working on [experimental] prenatal treatments that could be taken by a pregnant person [to treat] neurocognition for a fetus with Down syndrome.”
While prenatal screening and diagnosis has helped advance pregnancy care, some scientists, bioethicists, and disability rights advocates worry that without proper regulation and education, the practices could reinforce stereotypes and further marginalize people with disabilities.
“Responsible scientists are very concerned about the ethics,” Bianchi says. “Not only for identifying fetal [abnormalities, but] for subsequent care.”
In a 2015 article for the European Society of Human Genetics and the American Society of Human Genetics that Bianchi co-authored with more than a dozen other scientists, the experts raised the concern that the use of selective abortions for fetuses with genetic conditions makes the screening practice “morally sensitive” because it could lead to subtle pressure on the parent to terminate the pregnancy and it could send “a discriminatory message about the worth of the lives of people living with the relevant conditions.”
The National Council on Disability, an independent advisory agency of the U.S. government, published a report in 2019 titled “Genetic Testing and the Rush to Perfection,” which called for the government to further regulate the commercial use of NIPT and its marketing, increase education on disabilities, and ensure neutral genetic counseling is provided to patients along with screening, among other recommendations.
“Responsible scientists are very concerned about the ethics … not only for identifying fetal [abnormalities, but] for subsequent care.”
Diana W. Bianchi, MD
Eunice Kennedy Shriver National Institute of Child Health and Human Development
“Genetic testing in itself, and even the genetic editing potential that has arisen ... has not changed the fundamental truth that we cannot predetermine how our children will turn out,” the report states. “There is also the contradiction inherent in wielding choice for women as the motivation for increasing genetic testing, but failing to support and implement policies that would achieve equal opportunities for employment, meet long-term care needs, and ensure effective healthcare to people with disabilities, as well as increase support for families of children with disabilities.”
Even apart from these issues, some experts worry that the commercial marketing materials for NIPT are misleading and may cause undue anxiety for the parents or even pregnancy termination when there is no confirmed diagnosis.
“From the beginning, circa 2011, the marketing took the approach that this is so good, it is almost diagnostic,” Bianchi says. “It contributed to a decade of confusion between screening and diagnosis.”
In response to the New York Times article about the high rate of false positive screenings for rare conditions, the American Clinical Laboratory Association (ACLA) released a statement emphasizing the regulatory requirements that labs certified by the Clinical Laboratory Improvement Amendments must meet.
“These tests, like all screening tests, are optional and intended to provide a preliminary assessment of potential risk for certain health issues and are not equivalent to, nor intended to be used as, diagnostic tests for specific fetal conditions,” reads the statement, attributed to Tom Sparkman, JD, senior vice president of government affairs and policy for the ACLA. “Additionally, screening tests are an important precursor to identify individuals with elevated risk who are most suitable for subsequent diagnostic testing, which is typically more invasive and more expensive.”
A need for genetic counseling
In health care settings, many people are used to their doctors taking the lead in directing care plans, but genetics experts say that prenatal screening and diagnosis is one field where the patient should be directing the conversation.
“There’s not really any role for paternalism here,” Heuser says. “[Unlike with] cancer, when a physician might say, ‘I really think you should have chemotherapy,’ that’s not going to happen in this situation unless there’s some risk to the mom. … It’s more of a giving of information and exploring patient wishes and values rather than a recommendation.”
But patients sometimes do not receive proper counseling, particularly when the screenings are performed outside of a health care setting that includes geneticists or genetic counselors in the conversation.
“There’s not a national standard for counseling in this area,” Bianchi says. When she was a professor at Tufts University School of Medicine in Boston, Bianchi says that medical students completed 12 hours of general education on genetics. “That’s not enough to prepare people for the evolution in genetic medicine.”
Academic medical centers are playing a key role in the advancement of prenatal screening and diagnosis.
But as technology advances, it’s important that physician education keeps up, Norton says.
“I do think the best thing academic centers can do is train future physicians so they have a good understanding of the benefits and limitations of prenatal screening.