Causes of False Positive NIPT Results

Biological Causes

The American College of Medical Genetics and Genomics notes that confined placental mosaicism is a common biological cause of false positive Non-Invasive Prenatal Testing (NIPT) results, as NIPT analyzes cell-free DNA primarily derived from placental trophoblasts rather than the fetus itself, leading to discordant results 2
Maternal copy number variations can be detected in cell-free DNA and misinterpreted as fetal abnormalities, according to the American College of Medical Genetics and Genomics 2
Maternal mosaicism, particularly involving sex chromosomes, can lead to false positive results, as noted by the American College of Medical Genetics and Genomics 1
Maternal malignancy can cause false positive NIPT results, as tumors can release abnormal DNA into maternal circulation, as reported by the American College of Medical Genetics and Genomics 3, 4

The American College of Obstetricians and Gynecologists states that low fetal fraction, often seen in obese women, can lead to unreliable NIPT results, with test failure rates of 20% in women over 250 lbs and 50% in women over 350 lbs 5
Algorithm variations, such as different cutoffs, z-scores, and normalization controls, can lead to inconsistent NIPT results, according to the American College of Medical Genetics and Genomics 1
Statistical limitations, including the design of screening algorithms to prioritize high detection rates of true positives, can result in false positives, as noted by the American College of Medical Genetics and Genomics 2

The Society for Maternal-Fetal Medicine reports that higher failure rates and potentially lower detection rates are observed in twin pregnancies, with limited data available on NIPT performance in multifetal gestations 5
The American College of Medical Genetics and Genomics notes that NIPT for microdeletions and smaller copy-number variants has lower positive predictive values (PPVs) compared to common trisomies, with false positive rates higher for rare conditions due to their lower prevalence 2

The American College of Medical Genetics and Genomics states that NIPT is a screening test, not a diagnostic test, and positive results require confirmation through invasive diagnostic testing, with the positive predictive value (PPV) varying by condition and maternal age 6, 2
The positive predictive value (PPV) is highest for trisomy 21 (91.8%) and lower for trisomy 18 (65.8%) and trisomy 13 (37.2%), as reported by the American College of Medical Genetics and Genomics 7
When multiple or rare aneuploidies are detected, consideration of maternal malignancy may be warranted, according to the American College of Medical Genetics and Genomics 4

The American College of Medical Genetics and Genomics recommends diagnostic testing (amniocentesis or CVS) following any positive NIPT result, with follow-up amniocentesis potentially needed to distinguish between confined placental mosaicism and true fetal mosaicism 6, 8
For cases with unexplained false positive results involving sex chromosomes, maternal karyotyping may be considered to rule out maternal mosaicism, as noted by the American College of Medical Genetics and Genomics 3