Noninvasive prenatal tests used to screen for trisomies 13, 18, and 21 have specific advantages and limitations that should be thoroughly explained to pregnant women so they can carefully consider this option, according to a recent policy statement from the American College of Medical Genetics and Genomics (ACMG).

The recommendation from ACMG is the fifth guidance statement about these tests, which are marketed in the U.S. by four companies. It follows statements from the American College of Obstetricians and Gynecologists (ACOG)/Society for Maternal-Fetal Medicine (SMFM), two from the International Society for Prenatal Diagnosis (ISPD), and the National Society of Genetic Counselors (NSGC).

While the ACMG generally agrees with advice from these other groups, their statement makes important departures. Namely, the ACMG calls these tests—which detect cell-free fetal DNA (cfDNA) in maternal blood—“noninvasive prenatal screening” (NIPS) tests to emphasize that they are not diagnostic. Likewise, the ACMG statement places no limits on who should be offered NIPS and goes into greater detail about what patients should know about it [Gregg et al., 2013].

“ACMG's statement emphasizes that NIPS is a screening test, not the be-all and end-all. There are certain caveats with [these] tests,” says Diana Bianchi, MD, Professor of Pediatrics, Obstetrics, and Gynecology at Tufts University School of Medicine in Boston, Massachusetts, an ISPD Past President, Editor-in-Chief of Prenatal Diagnosis, and a consultant to the prenatal testing company, Verinata Health in Redwood City, California, which markets a NIPS test.

Figure 1.

Noninvasive prenatal screening tests have some advantages over certain other testing methods for fetal aneuploidy

A Big Difference

However, the ACMG tatement differs by what it does not say. Other organizations recommend that obstetricians offer NIPS only to women at high risk of aneuploidy because published studies on the methodology have not focused on women at average risk. But ACMG makes no mention of offering these tests based on risk, implying that offering these tests to all women is appropriate.

“ACMG believes there is no reason to believe that the test will not have performance characteristics (detection rate, positive predictive value, and negative predictive value) that exceed those of currently available screening [tests],” says ACMG statement senior author Anthony Gregg, MD, a B.L. Stalnaker Professor, Chief of Maternal Fetal Medicine (MFM), and Director of Obstetrics at Shands Hospital in Gainesville, Florida.

Indeed, a study by Ariosa Diagnostics in San Jose, California found that in 2,049 average-risk women, a NIPS test identified trisomies 21 and 18 with a false-positive rate of 0.1%, which is comparable to studies in high-risk women [Nicolaides et al., 2012].

ACMG's stance is consistent with an ACOG recommendation in 2007 that all pregnant women be offered aneuploidy screening, regardless of age or risk profile, Dr. Gregg adds.

NIPS is an attractive alternative to the current screening scenario, which can lead to confusion among patients who have negative screens in their first or second trimester for aneuploidy, but have a subsequent ultrasound that may reveal fetal anatomic concerns or ultrasound markers of fetal aneuploidy, he notes.

ACMG's stance reflects reality, notes Jennifer Hoskovec, MS, President-Elect of NSGC and Assistant Professor of Obstetrics, Gynecology, and Reproductive Services at University of Texas Medical School at Houston. Many centers now make NIPS clinically available to women at average risk, Ms. Hoskovec points out.

A Focus on Counseling

In its statement, ACMG stipulates that qualified professionals should provide patients with pretest information and explain the advantages of NIPS over other screening methods, including ultrasound paired with combinations of tests for hormones, estrogens, and proteins from the fetus, placenta, and ovaries. NIPS offers higher detection rates, higher rates of negative predictive values, lower false positive rates, and risk assessments less dependent on gestational age than some other methods.

However, there are limitations. Since NIPS uses DNA from the placenta, not the fetus itself, the test “may not reflect the true fetal karyotype” and will not detect as many conditions as do amniocentesis and chronic villus sampling. Nor will NIPS identify abnormalities that can affect severity of symptoms and recurrence risk, such as unbalanced translocations, deletions, and duplications, the statement notes.

Additionally, NIPS has not been shown reliable in pregnancies with more than one fetus, and doesn't screen for single gene defects. Also, NIPS will not spot open neural tube defects, so ACMG recommends maternal serum-fetoprotein testing at 15–20 weeks' gestation.

Although one laboratory now offers NIPS for multiple gestations, the statement notes that limited data are currently available on the use of NIPS in twins and higher-order pregnancies, and its accuracy may depend on specific laboratory platforms, proprietary bioinformatics, and clinical validation studies.

High body mass index (BMI) can interfere with NIPS accuracy, the statement notes, and placental mosaicism and malignancy in the mother can produce unexplained abnormal NIPS results, researchers suggest [Futch et al., 2013; Osborne et al., 2013].

While many of these points may serve to educate practitioners unfamiliar with genetic testing, they are standard aspects of genetic counseling, says Ms. Hoskovec. “It's nice to see the necessary information outlined specifically, especially for other practitioners, if they are new to the technology and are the ones having the conversation with the patient.”

“Screening and testing for chromosomal abnormalities during pregnancy isn't mandatory, it's optional,” she adds. “There are many options, and they should be discussed with every patient to make sure testing gives information she wants to have. Noninvasive testing technology is great, but it may not be appropriate for everyone.”