Non-Invasive Prenatal Testing (NIPT) screens for specific chromosomal conditions by analyzing cell-free DNA (cfDNA) circulating in a pregnant person’s bloodstream. The quality and reportability of the NIPT result are determined by the Fetal Fraction (FF), which represents the proportion of the total genetic material in the blood sample that originated from the pregnancy itself.
Defining Fetal Fraction
The Fetal Fraction is the percentage of the total cell-free DNA (cfDNA) in the blood sample that is of fetoplacental origin. During pregnancy, fragmented DNA molecules are released into the plasma from cells undergoing natural cell death. This cfDNA is a mixture of the pregnant person’s genetic material and the genetic material from the placenta, which is genetically identical to the fetus. The placental cells are the source of the fetal DNA fragments, while the remaining, larger portion of the cfDNA is of maternal origin.
Why Fetal Fraction is Key to NIPT Reliability
The Fetal Fraction functions as a quality control measure, directly impacting the ability of the NIPT to accurately screen for aneuploidies like Down syndrome (Trisomy 21). For the test to work, the laboratory must distinguish the fetal signal (excess or deficiency of DNA fragments) from the noise (the bulk of the maternal cfDNA). Most laboratories require a minimum Fetal Fraction threshold, typically ranging between 2% and 4%, to generate a reliable result. If the Fetal Fraction falls below this cutoff, the fetal signal is too weak to be statistically separated from the maternal background. An insufficient Fetal Fraction significantly increases the risk of a false negative result or leads to a non-reportable result.
Factors Influencing Fetal Fraction Levels
The amount of placental DNA circulating in the blood is influenced by several biological and clinical factors. The most significant factor is Gestational Age, as the Fetal Fraction naturally increases as the pregnancy progresses. NIPT is typically performed after 10 weeks of gestation, when the Fetal Fraction is usually sufficient for testing.
Maternal Body Mass Index (BMI) is another major determinant, showing an inverse relationship with Fetal Fraction. In individuals with a higher BMI, a larger volume of maternal cfDNA is released, which effectively dilutes the placental DNA, lowering the overall Fetal Fraction percentage. Other influences include multiple gestations and certain maternal medications, such as anticoagulants, which can interfere with cfDNA analysis.
Understanding Low Fetal Fraction Results
When the Fetal Fraction is below the laboratory’s minimum threshold, the result is classified as a “no-call” or test failure, and no screening result can be provided. The most common immediate step is to advise a repeat blood draw, usually a week or two later, allowing the Fetal Fraction time to rise. Approximately 50% to 80% of repeat samples yield a reportable result, especially if the initial test was performed close to the 10-week mark.
In cases of persistently low Fetal Fraction, the patient might be offered alternative screening options or diagnostic testing. While a low Fetal Fraction is often due to benign factors like early testing or maternal BMI, it has also been associated with a slightly increased risk for certain fetal aneuploidies, such as Trisomy 13 and 18, and placental dysfunction. If NIPT repeatedly fails, definitive diagnostic tests like amniocentesis or chorionic villus sampling (CVS) are available, which analyze fetal cells directly to provide a conclusive answer.