Non-Invasive Prenatal Testing (NIPT) is a blood test performed during pregnancy to screen for the likelihood of certain chromosomal abnormalities. This screening method has become widely adopted because it poses no physical risk to the pregnancy. NIPT assesses the probability of conditions like Trisomy 21, Trisomy 18, and Trisomy 13. The reliability of this test is measured by specific scientific metrics and influenced by various biological factors.
Understanding How NIPT Works
NIPT analyzes cell-free DNA (cfDNA) circulating in the mother’s bloodstream. Fragments of DNA from both the mother and the placenta enter the maternal circulation, and the placental DNA largely reflects the genetic makeup of the fetus.
The test isolates and sequences these cfDNA fragments to count the number of copies of specific chromosomes. Detecting an extra copy—such as more than the expected amount of chromosome 21 material—indicates an increased likelihood of a trisomy condition. Standard NIPT screens primarily focus on Trisomy 21 (Down Syndrome), Trisomy 18 (Edwards Syndrome), and Trisomy 13 (Patau Syndrome).
A key determinant of the test’s success is the fetal fraction, which is the percentage of the total cfDNA originating from the placenta. A minimum fetal fraction, typically around 4%, is required for a valid result. If the fetal fraction is too low, the test cannot be completed, leading to a “no-call” result.
Key Metrics Defining NIPT Accuracy
The accuracy of NIPT is defined by four statistical measures describing its performance. Sensitivity measures the test’s ability to correctly identify a fetus that has the condition. For Trisomy 21, NIPT demonstrates high sensitivity, often exceeding 99% in clinical studies.
Specificity measures the ability to correctly identify a fetus that does not have the condition. NIPT shows high specificity for common trisomies, frequently reported as over 99.9%, meaning it rarely gives a positive result when the fetus is unaffected.
The Positive Predictive Value (PPV) is the most relevant metric for an individual with a positive result, representing the probability that a high-risk result is genuinely correct. While sensitivity and specificity are high, the PPV varies significantly based on the condition’s prevalence in the population. For example, the PPV for Trisomy 21 is higher in older mothers because the underlying risk increases with maternal age.
The Negative Predictive Value (NPV) is the probability that a low-risk result is genuinely correct, often approaching 100% for the common trisomies. A negative NIPT result is highly reliable for indicating the fetus does not have the screened condition. Conversely, the PPV for rarer conditions, like Trisomy 13 or sex chromosome aneuploidies, is substantially lower, even with high sensitivity and specificity.
Why NIPT is a Screening Tool, Not a Diagnosis
NIPT is classified as a screening test because its results are not considered definitive. The biological source of the cell-free DNA introduces uncertainty, as the placental cfDNA being analyzed may not perfectly match the genetic makeup of the fetus itself.
This discrepancy often occurs due to confined placental mosaicism. This happens when the chromosomal abnormality is present in the placental tissue, which generates the cfDNA, but is not present in the fetus. Confined placental mosaicism is a primary cause of false-positive NIPT results.
In rare instances, NIPT can yield a false-negative result if the placenta is chromosomally typical while the fetus carries a mosaic or partial aneuploidy. Consequently, a positive NIPT result must be confirmed with an invasive diagnostic procedure. Confirmatory testing, such as Chorionic Villus Sampling (CVS) or Amniocentesis, analyzes cells directly from the fetus to establish a definitive diagnosis.
Individual Factors That Affect Test Reliability
Gestational Age and Fetal Fraction
The percentage of fetal fraction is highly dependent on gestational age. Testing performed too early can result in a low fetal fraction and a subsequent “no-call” result. Testing is recommended after the tenth week of gestation to ensure sufficient fetal DNA is present.
Maternal BMI
Maternal Body Mass Index (BMI) has an inverse correlation with fetal fraction. Higher maternal BMI can dilute the concentration of fetal cfDNA in the bloodstream, increasing the likelihood of a failed test or a false-negative result. The increased maternal blood volume means the fetal DNA makes up a smaller proportion of the total cfDNA.
Multiple Gestations and Maternal Conditions
NIPT results are less reliable for multiple gestations, such as twin pregnancies, because the test cannot differentiate between the cfDNA contributions of individual fetuses. Maternal conditions, including pre-existing genetic mosaicism or certain cancers, can also interfere with the cfDNA analysis. These conditions may lead to spurious results, as the test might detect a maternal chromosomal abnormality instead of a fetal one.