What have we learned about the new Down syndrome prenatal test?

Sequenom’s updated logo

In 2011, a new prenatal test for Down syndrome entered the market offering earlier, safer, and more accurate results. What have we learned about this new technology since then?

It’s non-invasive prenatal screening, not diagnostic.

On October 17, 2011, Sequenom, a San Diego biotech company, launched MaterniT21, a prenatal test for Down syndrome and other conditions with an extra chromosome. Competitors have since entered the market offering their own brand: Ariosa’s Harmony, Verinata’s verifi, and Natera’s Panorama. These tests promise very high detection rates and very low false negatives based only on a test of the mother’s blood.

When the testing was being developed, it was thought it would be diagnostic. When it came to market, however, it still had false positives and false negatives, rendering it not a diagnostic test, but a screening test. To emphasize this point, the American College of Medical Genetics & Genomics (ACMG) labeled the testing “Non-Invasive Prenatal Screening” or “NIPS.”

Tests placental DNA, not fetal DNA.

At the time of the launch, NIPS was described as testing cell free fetal DNA (cffDNA). It turns out the testing is of DNA from cells in the developing placenta, not the fetus. In 2015, the largest known clinical study of NIPS noted that false positives and false negatives are due to the testing of placental, not fetal, DNA. There is a phenomenon known as “placental mosaicism” where cells in the placenta can have a third copy of the 21^st Chromosome, the most common cause for Down syndrome, but the fetus does not have Down syndrome. This is one of the reasons these tests will have false positives and false negatives, because they are not testing DNA from the fetus.

Tests’ accuracy is limited to high-risk populations.

The study Sequenom relied on to take its test to market was of a population with an incidence rate as high as 1-in-8, meaning one out of every eight pregnancies was positive for Down syndrome. This high of a rate does not happen in the natural population. While the chance for Down syndrome increases with the age of the mother, even a 45-year-old mom’s chance of having a child with Down syndrome is 1-in-35. The other testing companies have also reported their accuracy levels in populations already designated as “high-risk,” usually women 35 and older or those who already had a prenatal test showing an increased chance for Down syndrome. In a study of the general population, receiving a “positive” NIPS result meant it had a 45.5% chance of being a true positive, or a greater than 50% chance of being a false positive. Similarly, in 2015, the largest known clinical study reported that the younger the mother, the less accurate a NIPS result was. As a result, the guidelines published by the National Society of Genetic Counselors (NSGC) and the American Congress of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine, recommend NIPS be offered only to women who are already considered “high-risk.” After the 45.5% result in the general population, the Society for Maternal-Fetal Medicine reiterated that NIPS should be offered as a second-tier screen, i.e. to women considered “high risk.”

Insurance coverage is limited to high-risk moms.

Due to the professional recommendations, while NIPS is increasingly being covered by more and more insurance plans, that coverage remains limited to tests performed on mothers considered “high-risk.” As shown in the charts below, this is because the clinical studies have yet to show that NIPS provides reliable results in low-risk moms.

When a “positive” means a 50/50 (or lower) chance.

The professional recommendations are supported by NIPS having a much lower predictive value in low-risk populations.

Positive predictive value (PPV) means how likely a “positive” test result actually means the tested-for condition is present. PPV is the number of true positives divided by the total number of positive tests returned, both true and false positives. When the new test is performed in populations considered low-risk, a positive result can have a PPV of less than 50%.

For example, a 30 year old mother has about a 1-in-1,000 chance of having a child with Down syndrome. At that incidence rate, the chart below shows the number of true and false positives the new tests would report at a detection rate of 99.5% and a specificity rate (the rate of ruling out unaffected pregnancies) of 99.9% for 100,000 30-year old pregnant women, 100 of which would actually be positive for Down syndrome:

Therefore, a 30-year old woman receiving a “positive” test result could be in the 99.5 who are actually carrying a child with Down syndrome or the 100 who were not. This gives her a 50/50 chance. With the chance for having a child with Down syndrome tied to a mother’s age, it is more likely that a woman under 30 receiving a “positive” NIPS result is not actually expecting a child with Down syndrome.

Imperceptible reassurance for younger women.

The overwhelming majority of pregnant women are not carrying a child with Down syndrome. Therefore, almost all women considering prenatal testing are not doing so because they expect to receive a positive result. Rather, they are seeking reassurance through a negative result. This is what is promised by NIPS’ low false negative rate. But, for younger mothers, Robert Resta, a genetic counselor and former editor of the Journal of Genetic Counseling, considered that level of reassurance “not exactly a great scientific achievement.”

This is because younger mothers already have close to, if not the same, chance of not having a child with Down syndrome as the test’s ability to screen out those pregnancies that are not affected.

The NIPS labs quote a specificity rate, the ability to rule out those unaffected pregnancies, of 99.9%. But, as the table for Negative Predictive Value (NPV) below shows, mothers under 30 are already at that 99.9% rate based solely on their age:

NPV maternal age

Therefore, the high accuracy rate is largely imperceptible in low-risk populations, particularly mothers under the age of 30.

NIPS is not the holy grail of Prenatal Testing.

A former chair of ACOG’s ethics committee recounted her experience of being an older mom—over 40—and expecting her fourth child. She reported how her obstetrician exulted with the new testing, “this is the Holy Grail. It’s what we’ve been waiting for all these years.” This reaction has been common to the new prenatal testing, but it is incorrect, and not even shared by the testing companies themselves.

The notion of a “holy grail” of prenatal testing is a test that can diagnose the fetus without exposing the pregnancy to the risk of miscarriage. Current diagnostic tests—a first-trimester chorionic villus sampling (CVS) or the more commonly performed second-trimester amniocentesis—both have a chance, however slight, of procedure-related miscarriage. This is due to a needle being inserted into the womb. However, these tests remain the only way still to receive a diagnosis, and, pursuant to guidance by the National Society of Genetic Counselors, because CVS tests placental DNA, it can have the same risk of returning a false result, making amniocentesis the more accurate diagnostic test.

Every professional organization’s statement on NIPS makes clear this point: that diagnostic testing is necessary to confirm results and women receiving a NIPS test should be offered diagnostic testing. Put another way, a NIPS result is never truly positive or truly negative. Therefore, because NIPS is still a screening test, and not a diagnostic test, it is not the holy grail of prenatal testing.

But, one of the predictions when Sequenom launched has proven true.

Dramatically fewer invasive diagnostic procedures.

Due to its high rates, it was predicted that mothers would choose to rely on their NIPS results and forego exposing their pregnancies to the risk of miscarriage from diagnostic testing. This is, in fact, what is happening.

Mothers receiving a negative NIPS result are choosing to avoid the needle of diagnostic testing. Those receiving a positive NIPS result who intend to continue their pregnancy similarly are relying on the NIPS result to prepare for having a child with Down syndrome rather than risk miscarriage to know for certain. The testing companies have found that the rate of diagnostic procedures has plummeted following the introduction of NIPS.

The need for educational materials for patients and providers persists.

When Sequenom launched its test, the study it relied upon recognized then that “educational materials for both patients and providers” were needed. Since 2008, in fact, federal law has recognized the need for patients to understand the accuracy of prenatal tests, to receive written materials about the tested-for condition, and to be referred to parent support organizations. In the summer before Sequenom launched, the NSGC and the American Academy of Pediatrics each published guidelines recognizing that patients receiving a positive prenatal test result for Down syndrome should also receive accurate written materials about Down syndrome and the chance to contact fellow parents. Since launching, all of the NIPS laboratories have emphasized their role in providing information to patients.

But, none of them have yet to provide information consistent with federal law and professional guidelines when they deliver a test result.

Instead, patients receive a one-sheeter that only reports the results of their tests. Whether the patient receives written materials or referral to support organizations is dependent upon their health care provider. But, when ACOG surveyed its own members after its guidelines changed to offering all women prenatal testing, less than 3-in-10 said they provided educational materials to their patients.

A mom shared how she received her test result over the phone. She sat in her car in the parking lot crying after hanging up. She wanted more information, but, as she said,

Nobody offered anything. Nobody told me about any resources.

The federal law has gone unfunded and unimplemented by the Department of Health & Human Services. Tired of waiting, Massachusetts, in 2012, then Kentucky in 2013, and then evermore states in each successive year,  passed a law requiring health care providers deliver with each test result for Down syndrome educational materials from the National Center for Prenatal & Postnatal Down Syndrome Resources and referral to the patient’s local parent support organization. The materials from the National Center are the only ones that have been both approved by the NSGC and recognized by the ACMG as resources that patients should receive with a test result. In 2015, the NSGC published a fact sheet for implementing these laws.

The NIPS market was estimated at $1.6 billion this year. Verinata was acquired by Illumnia for $350 million. By 2019, NIPS is expected to be the fastest growing offering of a prenatal testing global market valued at $8.3 billion. Increasingly the cost of testing is being covered by insurance and government health programs. Yet, none of the testing manufacturers are providing the recommended information to accompany their tests and insurance companies are not covering the costs for health care providers to provide this information.

Women are aborting based only on a NIPS result

While suspected, and single case studies being mentioned at conferences, in 2014 an investigative report shocked by sharing how 6 percent of surveyed termination decisions were made based solely on a NIPS result. In response, the Society for Maternal Fetal Medicine issued a statement emphasizing that a NIPS result is never diagnostic:

It is important for providers to remember that cell free DNA is a screening test, and does not have the diagnostic accuracy of amniocentesis.  By its very nature, a screening test does not tell with 100% certainty whether or not a fetus will be affected by a given disorder. Unfortunately, in part because of the high stakes in this very competitive market, the tests are being presented as having >99% accuracy, the same accuracy as is used to describe amniocentesis and CVS.

Links in the quote are to relevant posts on this blog expanding on those subjects, like how “99%” can constitute malpractice.

Yet, in 2015, the largest clinical study of NIPS reported that up to 16% of all terminations were based solely on a NIPS result. The decision to terminate a pregnancy should never be made based on a maybe, but the hyping of NIPS’ accuracy, coupled with the lack of information given to patients, is it any wonder that women are making uninformed, life-changing decisions?

What we’ve learned about NIPS.

Since 2011, much has been revealed about the new prenatal test for Down syndrome. It is not the holy grail of prenatal testing. Rather, it is a screening test of placental–not fetal–DNA, that has been shown to be effective in high-risk populations. NIPS is resulting in fewer invasive diagnostic procedures and is increasingly being covered by insurance. But the need identified when NIPS launched two years ago, and by federal law five years ago, and by laws in an ever growing number of states, for patients to receive educational materials about Down syndrome from their health care providers and from the testing companies remains, despite these resources being available and the laboratories being part of a billion-dollar industry.

This post was updated on June 24, 2015.