Grand Rounds
CMECNE

What Is the Best Follow-Up Diagnostic Test After a High-Risk NIPT Result?

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Learning Objectives and CME/Disclosure Information

BACKGROUND AND PURPOSE:

  • DNA that circulates in the maternal compartment is mostly derived from placenta (cytotrophoblast layer) and not the fetus
  • Fetal and placental cells both originate from the fertilized oocyte, but diverge early in pregnancy into distinct tissues
    • Placenta can tolerate different cell lines (mosaicism) and may not perfectly match the fetal chromosomal complement, resulting in false positive and negative NIPS results
  • There are other causes that may result in false positive and negative NIPS reports, such as vanishing twin or maternal chromosomal anomalies
  • Therefore, there is universal agreement that a positive cfDNA report requires confirmation based on invasive testing with either CVS or amniocentesis
  • Grati et al. (Prenatal Diagnosis, 2015) used an extensive database to determine how often placental DNA (CVS results) matched fetal DNA (amniocentesis results), broken out by chromosome and cellular layer, to determine whether amniocentesis and/or CVS is the more appropriate confirmatory test.

METHODS:

  • Data on 52,673 karyotypes were analyzed to determine frequency of mosaicism involving cytophoblasts, for trisomies 21 (T21), 18 (T18), 13 (T13) and monsomy X (MX)
  • Karyotypes were obtained from cytorophoblast (outer layer, DNA source for NIPS), mesenchyme and confirmatory amniocentesis

RESULTS:

Using cytotrophoblast karyotype as a proxy for NIPS, authors posited the following

  • After a high-risk NIPS result, mosaicism on confirmatory CVS requiring a follow up amniocentesis would be:
    • 2% in T21
    • 4% in T18
    • 22% in T13
    • 59% in MX
  • When mosaicism is detected by CVS, the likelihood of fetal confirmation by amniocentesis would be:
    • 44% in T21
    • 14% in T18
    • 4% in T13
    • 26% in MX

CONCLUSION:

  • For T21/18, confirmatory CVS may still be an option, especially if there is a clinical indication to obtain early results
    • Small but still real risk for inconclusive results
  • For MX/T13, amniocentesis seems most appropriate for follow-up after high risk cfDNA result due to high likelihood of a mosaic result on confirmatory CVS
  • The authors state “If an ultrasound anomaly suggesting the suspected karyotype anomaly is found, CVS could be offered to the patient regardless of risk of need for a secondary procedure because an early diagnosis may be preferable.”

Learn More – Primary Sources:

The type of feto-placental aneuploidy detected by cfDNA testing may influence the choice of confirmatory diagnostic procedure

Diagnostic cytogenetic testing following positive noninvasive prenatal screening results: a clinical laboratory practice resource of the American College of Medical Genetics and Genomics (ACMG)

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Related ObG Topics:

Practical info on evidence based medicine for your women's healthcare practice
cfDNA vs. Routine Screening – How Do They Compare?
Does cfDNA in First Trimester Signal Subsequent Preeclampsia?
NIPS vs. Microarray for Pathogenic Results
Should Amniocentesis or Chorionic Villus Sampling Be Offered to All Pregnant Women?
How Accurate is NIPT as a Screening Test for Chromosomal Aneuploidies?
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