What are the causes of false positive results in Non-Invasive Prenatal Testing (NIPT)?

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Causes of False Positive NIPT Results

The primary causes of false positive Non-Invasive Prenatal Testing (NIPT) results include confined placental mosaicism, vanishing twin, maternal copy number variations, maternal malignancies, and technical/statistical factors related to testing algorithms. 1

Biological Causes

Placental Factors

  • Confined Placental Mosaicism (CPM): The most common biological cause of false positive results. Since NIPT analyzes cell-free DNA primarily derived from placental trophoblasts rather than the fetus itself, chromosomal abnormalities confined to the placenta can lead to discordant results 1, 2
  • Fetoplacental Mosaicism: True fetal mosaicism that may be present in varying degrees between the fetus and placenta can cause discrepant results 3

Maternal Factors

  • Maternal Copy Number Variations: Maternal genomic variations can be detected in cell-free DNA and misinterpreted as fetal abnormalities 1
  • Maternal Mosaicism: Low-level maternal chromosomal mosaicism, particularly involving sex chromosomes, can lead to false positive results 1
  • Maternal Malignancy: Multiple or rare aneuploidies (especially autosomal monosomies) detected by NIPT may indicate an underlying maternal malignancy, as tumors can release abnormal DNA into maternal circulation 1
  • Maternal Obesity: High maternal weight (>250 lbs) is associated with low fetal fraction, which can increase the risk of test failure or inaccurate results 1

Pregnancy-Related Factors

  • Vanishing Twin/Demised Co-twin: DNA from a non-viable twin with chromosomal abnormalities can persist in maternal circulation and lead to false positive results 1
  • Empty Second Sac: The presence of a second gestational sac has been associated with false positive results 1

Technical and Statistical Factors

  • Low Fetal Fraction: Insufficient fetal DNA in the maternal circulation can lead to unreliable results. This is more common in obese women, with test failure rates of 20% in women >250 lbs and 50% in women >350 lbs 1
  • Algorithm Variations: Different testing platforms use different cutoffs, z-scores, and normalization controls, which can lead to inconsistent results 1
  • Statistical Limitations: By design, screening algorithms include some false positives to ensure high detection rates of true positives 1

Special Considerations

Multiple Gestations

  • Higher failure rates and potentially lower detection rates are observed in twin pregnancies 1
  • Limited data is available on NIPT performance in multifetal gestations 1

Microdeletion Testing

  • NIPT for microdeletions and smaller copy-number variants has lower positive predictive values (PPVs) compared to common trisomies 1
  • False positive rates are higher for rare conditions due to their lower prevalence 1

Clinical Implications

  • NIPT is a screening test, not a diagnostic test; positive results require confirmation through invasive diagnostic testing 1
  • The positive predictive value (PPV) varies by condition and maternal age - a 35-year-old woman with a positive NIPT result has a higher PPV than a 25-year-old woman 1
  • PPV is highest for trisomy 21 (91.8%) and lower for trisomy 18 (65.8%) and trisomy 13 (37.2%) 1
  • When multiple or rare aneuploidies are detected, consideration of maternal malignancy may be warranted 1

Follow-up Recommendations

  • Diagnostic testing (amniocentesis or CVS) is recommended following any positive NIPT result 1
  • For CVS with discordant results, follow-up amniocentesis may be needed to distinguish between confined placental mosaicism and true fetal mosaicism 1
  • For cases with unexplained false positive results involving sex chromosomes, maternal karyotyping may be considered to rule out maternal mosaicism 1

References

1
Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

2
Research

Confined placental mosaicism and its impact on confirmation of NIPT results.

American journal of medical genetics. Part C, Seminars in medical genetics, 2016

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Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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