Chromosomal Hits and Misses of Noninvasive Prenatal Testing

Caroline Helwick

February 10, 2014

NEW ORLEANS — A review of prenatal genetic screening options in a population of pregnant women in California showed that noninvasive prenatal testing (NIPT) would detect 83% of chromosome abnormalities, but miss approximately 17%.

"Undetected aneuploidies ranged from relatively mild to those associated with significant disability," said Mary Norton, MD, from the University of California, San Francisco. "This is important information to be considered by patients, providers, and screening programs" when evaluating the utility of the different screening methods.

Dr. Norton presented the study results here at the Society for Maternal-Fetal Medicine (SMFM) 34th Annual Meeting.

Since NIPT was introduced into clinical practice in 2011, there has been tremendous uptake because of its high sensitivity and specificity for trisomy 21. It also has a high sensitivity for trisomies 13 and 18 (approximately 99%), but yields no information about other rare aneuploidies.

Integrated screening (such as serum markers and ultrasound) has a lower sensitivity and specificity for trisomies 13, 18, and 21, but does detect additional disorders (i.e., all chromosome abnormalities larger than 5 to 10 mb). Trisomies 13, 18, and 21 account for about 65% of all prenatal aneuploidies, Dr. Norton noted.

Currently, the American College of Obstetrics and Gynecology and other specialty organizations recommend NIPT only for high-risk women. In fact, NIPT is often used as an alternative to invasive testing when integrated screening identifies a woman as high risk.

Study Population

California provides integrated screening — including first- or second-trimester serum markers plus nuchal translucency ultrasound — for all pregnant women. This yields a risk estimate for trisomies 18 and 21, neural tube defects, and SCD (a composite of Smith–Lemli–Opitz syndrome, congenital anomalies, and fetal demise). Comprehensive follow-up is provided for all patients with positive results.

In their study, Dr. Norton and colleagues evaluated all karyotype results from invasive prenatal testing after any positive prenatal screen for singleton pregnancies from 2009 to 2012. Abnormal karyotypes were characterized by type of abnormality and whether the abnormality was detectable with current NIPT methods.

Of the more than 1.3 million women screened, 68,990 (5.2%) were positive for trisomy 18 or 21. Of these, 26,059 (37.8%) underwent invasive diagnostic testing. The 2993 women with an abnormal result (11.5%) made up the study cohort.

Overall, 88.2% were positive for trisomy 21, 9.8% were positive for trisomy 18, 1.4% had neural tube defects, and 0.6% were positive for SCD.

"Similar to previous reports, trisomy 21 accounted for more than 50% of the total abnormalities found by invasive testing, but rare and uncommon aneuploidies accounted for 16.9% of the total," Dr. Norton reported.

"This was 2% of the women — 1 in 50 — who had invasive testing," she emphasized.

Of the 511 abnormal karyotypes that were not detectable with NIPT, 369 (72%) were considered pathogenic for unfavorable conditions and 142 (28%) were considered benign.

Table. Pathogenic Abnormalities Not Likely to Be Detected With NIPT

Abnormality n Percent
Other trisomies 130 4.3
Duplications or deletions 90 3.0
Mosaic sex chromosomal abnormality 63 2.1
Common mosaics (trisomies 13, 18, 21) 32 1.1
Marker 14 0.5
Unbalanced translocations 9 0.3


NIPT failed to detect 22% of abnormalities in women younger than 25 years, but this dropped to 8% for women older than 45, "whose risk is driven by the high rate of common age-related aneuploidies for trisomies 18 and 21," Dr. Norton explained.

In 81% of undetectable chromosome abnormalities, the nuchal translucency measurement was less than 3.5 mm. It was at least 0.5 mm in 44% of patients with common (detectable) defects but in just 19% of those with rare (undetectable) defects. "Cases with rare aneuploidies are unlikely to have enlarged nuchal translucency," she said.

Abnormal second-trimester serum screening was more frequently associated with rare aneuploidies than with common aneuploidies, she added.

Dr. Norton acknowledged several limitations of the study. Because it included only screen-positive patients, it might not be generalizable to the unscreened population. In addition, it was based on potential detection with current NIPT techniques, only 38% of screen-positive women underwent invasive testing, and not all NIPT laboratories report the same abnormalities.

"Comparable data in unscreened patients would be useful," Dr. Norton said. Nevertheless, she suggested that these data could inform the expansion of NIPT targets.

"As the technology evolves, appropriate counseling should discuss the detection of all chromosomal abnormalities," she advised.

"Stick to the Guidelines"

Susan Tran, MD, from Oregon Health and Sciences University in Portland, spoke to Medscape Medical News about the use of NIPT.

"From what I see in my community, and from speaking to my colleagues, it seems there is some inappropriate employment of this test. For one thing, some generalists are offering this test without pre- or post-test counseling," she explained.

However, "NIPT is only screening for a finite number of conditions, and it's for screening, not diagnosis. Unfortunately, this takes a lot of time to explain to patients, and there are constraints in terms of time and resources," Dr. Tran noted.

According to the SMFM Choosing Wisely recommendations, NIPT should not be offered to low-risk patients and irreversible decisions should not be based on the results of this screening test. "At this point, we should go with the guidelines," said Dr. Tran, although she said she welcomes scrutiny of the test that might lead to different recommendations in the future.

Jerome Yankowitz, MD, the James M. Ingram professor and chair of obstetrics and gynecology at the University of South Florida in Tampa, said he agrees on the need to "stick with the guidelines," although he predicts they will ultimately change.

"A lot of people think NIPT is a vast improvement, but it's really an incremental improvement. It depends on where the cost of the test ends up. Cost-effectiveness is important," he explained.

He also noted that there are ways to improve the detection of Down's syndrome with conventional screening. "With standard screening in the first trimester — if we do the blood work, do nuchal translucency, and also get a nasal bone and a ductus venosus [Doppler image] — you can get the detection of Down's up to as high as 95%," he said.

Dr. Norton reports receiving research funding from Ariosa Diagnostics and CellScape Corporation. Dr. Tran has disclosed no relevant financial relationships. Dr. Yankowitz reports receiving honoraria from Verinata, which manufactures an NIPT.

Society for Maternal-Fetal Medicine (SMFM) 34th Annual Meeting: Abstract 5. Presented February 4, 2014.


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