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Noninvasive test identifies more than 98% of Down syndrome cases

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But is it ready for prime time? Three critical questions remain unanswered, an expert says.



The first noninvasive maternal blood test for Down syndrome is available to physicians on request in 20 major metropolitan regions in the United States, with more widespread availability planned in the coming months.

According to manufacturer Sequenom, Inc., the MaterniT21 assay is indicated for use in pregnant women at “high risk” of carrying a fetus with Down syndrome and can accurately test maternal blood as early as 10 weeks of gestation.

The test is based on the presence of cell-free fetal nucleic acids in maternal plasma. The health provider draws a small sample of whole blood from a pregnant woman and ships the sample to the Sequenom Center for Molecular Medicine in San Diego, California, where massively parallel sequencing (MPS) is used to measure a possible overabundance of chromosome 21, or Trisomy 21 (Down syndrome).

Down syndrome affects approximately 6,000 infants or 1 in every 691 pregnancies each year in the United States.1

Currently, identification of Trisomy 21 requires assessment of several maternal serum screening markers and sonographic measurement of nuchal translucency. If these tests identify a high risk of Trisomy 21, chorionic villus sampling (CVS) or amniocentesis follows. First-trimester screening identifies as many as 90% of all cases of Down syndrome, with a false-positive rate of 2%.1 Because CVS and amniocentesis are invasive, however, they carry a small risk of pregnancy loss.

All MaterniT21 tests must be interpreted at one of the manufacturer’s laboratories. Approximate cost: $1,900—roughly equivalent to the cost of amniocentesis. Sequenom expects the out-of-pocket cost for patients with insurance to be no more than $235.

The test is not approved by the US Food and Drug Administration, which does not regulate tests when only one laboratory is involved.

Similar tests for Down syndrome are reportedly being developed by other laboratories.

Data on the new test

MaterniT21 was evaluated in a validation study of 4,664 women who had a high risk of Down syndrome.2 Fetal karyotyping was compared with the MaterniT21 test in 212 cases of Down syndrome and 1,484 matched euploid cases. The Down syndrome detection rate for the MaterniT21 test was 98.6% (209 of 212 cases); the false-positive rate was 0.20% (three of 1,471 cases); and testing failed in 13 pregnancies (0.8%), all of which were euploid. Researchers concluded that the new test “can substantially reduce the need for invasive diagnostic procedures and attendant procedure-related fetal losses.”2

“The results of this large clinical validation study are extremely promising,” said Allan T. Bombard, MD, laboratory director of Sequenom Center for Molecular Medicine and one of the authors of the study. “We believe perinatal specialists and obstetricians will appreciate the introduction of a test that is noninvasive and highly specific.”

The manufacturer is planning outreach to clinicians through its sales force, medical science liaisons, managed care team, and genetic counselors.

Is the test ready for widespread use?

“I certainly think this test needs to be confirmed by other studies before it becomes ready for prime time,” says Jeffrey A. Kuller, MD, a maternal-fetal medicine specialist and clinical geneticist at Duke University Medical Center in Durham, NC. Dr. Kuller notes that the MaterniT21 test detects only Trisomy 21, whereas conventional first-trimester screening assesses Trisomy 18 and, usually, Trisomy 13 as well. Dr. Kuller is professor of obstetrics and gynecology in the division of maternal-fetal medicine at Duke.

“Another big question mark is what does one do with an abnormal result? We have a pretty standardized algorithm for what we do if a patient has an abnormal first-trimester screen,” he points out—”they’re offered invasive testing.” But it’s unclear whether this test is intended to be diagnostic if it detects Trisomy 21.

“Can we essentially tell a patient, ‘You’re carrying a fetus with Down syndrome?’ Or do we need to do invasive testing like we do right now?”

Another unresolved issue is whether the test can be used reliably in a “low-risk” population. The creators of the MaterniT21 assay tested the product only in a “high-risk” population, Dr. Kuller notes. “I don’t think we know whether this would be a reasonable test for all patients.”

These three issues remain unresolved, says Dr. Kuller:

  • confirmation of the test’s efficacy in additional studies
  • clarification of whether it is diagnostic of Down syndrome
  • evaluation of the test in a population at low risk of Trisomy 21.

Panel offers recommendations for genetic counseling

The International Society for Prenatal Diagnosis (ISPD) issued a “rapid response statement” on the new test on October 24: “At this time, individual women who might be considering the MPS test need to receive detailed genetic counseling that explains the benefits and limitations of the test. Testing should only be provided after an informed consent.”3

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