Study Highlights Limitations of NIPS in Detecting Hidden Fetal Chromosomal Abnormalities

The Dilemma: Non-Invasive or Invasive Testing for Mild NT Thickening?

With the rise of non-invasive prenatal screening (NIPS), many expectant parents hope for safe, accurate answers about their baby’s health—especially when faced with mildly increased nuchal translucency (NT) on ultrasound. But can NIPS truly rule out all important chromosomal abnormalities in these borderline cases?

A new study in the Archives of Gynecology and Obstetrics set out to answer this question by comparing NIPS to the gold standard, chromosomal microarray analysis (CMA), in over 900 pregnancies where fetuses had isolated mild NT thickening.

What the Research Explored

Researchers analyzed 936 fetuses with NT between 2.5 and 3.5 mm, a range considered “mildly increased.” All underwent invasive CMA testing. They then calculated how many significant chromosomal issues would be detected—or missed—by four common types of NIPS, including the most advanced genome-wide options.

Key Findings: Residual Risk Remains

Basic NIPS (trisomy 13/18/21 only) detected 10 out of 44 significant cases, leaving a residual risk of 3.63% (1 in 28).

Adding sex chromosome analysis (NIPS-5) caught 7 more cases, but the residual risk was still 2.88% (1 in 35).

Expanded NIPS (microdeletions included) picked up one more case, barely lowering risk to 2.78%.

The best-case scenario, genome-wide NIPS, detected a few more large abnormalities, but residual risk persisted at 2.35% (1 in 43).

No matter the NIPS panel, a substantial risk of missing clinically significant copy-number variations (CNVs) remained—risks higher than many guidelines use to recommend invasive testing.

What Does This Mean for Expecting Parents?

Despite its appeal, NIPS can’t catch everything in cases of mildly increased NT. The study urges caution and thorough counseling. Even a “low-risk” NIPS result cannot fully rule out important chromosomal problems that only invasive CMA can detect.

Couples should be aware of these limitations and understand the real, though small, chance that a significant issue might go undetected without invasive testing. Knowing the residual risk empowers families to make truly informed decisions about proceeding with further testing.

Key Takeaways:

NIPS may leave a 2–4% residual risk of major chromosomal abnormalities in mild NT thickening cases.

Genome-wide NIPS is better but still not perfect; many smaller CNVs are missed.

Invasive testing (CMA) remains the most comprehensive diagnostic tool for these pregnancies.

Thorough pre-test counseling is essential to ensure families understand what NIPS can—and cannot—detect.

Guidelines suggest invasive testing when NT is increased, even mildly, due to the limitations of NIPS.

Citation:

Su L, Zhao W, Huang H, et al. Can cell-free fetal DNA screening be utilized for the assessment of chromosomal abnormalities in fetuses with mildly increased nuchal translucency? Archives of Gynecology and Obstetrics. 2025;312:1977–1984. doi:10.1007/s00404-025-08143-y