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Cell Free DNA (cfDNA) Prenatal Screening

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1. INTRODUCTION

  • Definition: A non-invasive prenatal screening (NIPS) test that analyzes circulating cell-free DNA in maternal blood to estimate the risk of fetal chromosomal aneuploidies.
  • Source: cffDNA (cell-free fetal DNA) originates from the apoptosis of placental trophoblasts (not the fetus directly).
  • Clearance: Rapidly cleared from maternal circulation (undetectable 2 hours postpartum).

2. TIMING & PREREQUISITES

  • Timing: Can be performed from 9–10 weeks of gestation onwards.
  • Fetal Fraction (FF): The proportion of cffDNA in maternal plasma.
    • Requires >4% FF for a reliable result.
    • Low FF causes: Maternal obesity (dilution), early gestation, LMWH use.

3. INDICATIONS (ACOG Guidelines)

Initially restricted to high-risk pregnancies, now recommended as an option for all pregnant women regardless of risk status.

  • High-Risk Indications:
    • Advanced Maternal Age (>35 years).
    • Abnormal serum screen (Positive Combined/Quad test).
    • Ultrasound soft markers.
    • Previous history of trisomy.

4. SCOPE OF DETECTION

  1. Core Panel: Trisomy 21 (Down), Trisomy 18 (Edwards), Trisomy 13 (Patau).
  2. Sex Chromosome Aneuploidies (SCA): Turner (45,X), Klinefelter (47,XXY).
  3. Expanded Panels (Variable):
    • Microdeletions (e.g., 22q11.2 deletion / DiGeorge).
    • Some single-gene disorders (e.g., Achondroplasia).

5. PERFORMANCE METRICS

  • Sensitivity: Highest for Down Syndrome (>99%). Slightly lower for T18 and T13.
  • False Positive Rate: Very low (<0.1%).
  • Superiority: Outperforms standard serum screening (Quad/Combined test) in sensitivity and specificity.

6. LIMITATIONS & PITFALLS (Crucial for Exam)

  • Screening ONLY: It is NOT diagnostic. A “High Risk” result must be confirmed by invasive testing (Amniocentesis/CVS) before termination of pregnancy.
  • False Positives:
    • Confined Placental Mosaicism (CPM): DNA is placental; if placenta is abnormal but fetus is normal, NIPT is false positive.
    • Vanishing Twin: DNA from a demised co-twin.
    • Maternal Malignancy: Tumors shed cell-free DNA.
  • Test Failure: Usually due to low Fetal Fraction (high BMI).

7. SUMMARY

  • Gold Standard Screening: Most accurate screening method for Trisomy 21.
  • Safety: Zero risk of miscarriage (non-invasive).
  • Limitation: Does not detect NTDs (still requires USG/AFP) and is cost-prohibitive in some settings.

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