Non-Invasive Prenatal Testing (NIPT) has become a common method for screening for certain chromosomal conditions during pregnancy, such as Down syndrome. This test analyzes small fragments of cell-free DNA (cfDNA) circulating in the pregnant person’s bloodstream, which includes both maternal and placental genetic material. The fetal fraction (FF) is a measurement representing the percentage of the total cfDNA that originates from the placenta, serving as a proxy for the developing fetus. A sufficient fetal fraction is a requirement for the test to be reliable, directly impacting the laboratory’s ability to generate an accurate result.
What is Fetal Fraction and Why is it Essential for NIPT?
The bloodstream of a pregnant person contains a mix of DNA fragments from their own cells and fragments released from the placenta, which is genetically identical to the fetus. Fetal fraction is the ratio quantifying the placental DNA proportion relative to the total cfDNA present in the maternal plasma. This measurement reflects the genetic makeup of the pregnancy.
Fetal fraction calculation serves as an inherent quality control measure for NIPT. The testing method relies on having enough fetal-derived material to accurately count chromosomes and detect subtle numerical variations that indicate conditions like trisomy 21. Without a sufficient amount of placental DNA, the ability of the statistical algorithms to distinguish between normal and abnormal results is significantly compromised.
Most commercial NIPT platforms require a minimum fetal fraction threshold to ensure the reliability of the analysis. This minimum is typically set between 2% and 4%, although it can vary slightly depending on the specific technology used by the laboratory. If the measured fetal fraction falls below this cut-off, the test may be considered inconclusive or a “no call” result is issued. A higher fetal fraction provides greater statistical confidence in the final screening result.
What is Considered a Normal Fetal Fraction at 12 Weeks?
Fetal fraction is not a fixed number but a dynamic value that increases as the pregnancy progresses. The average fetal fraction generally rises by about 0.1% to 0.2% per week of gestation. Due to this steady increase, 12 weeks of pregnancy is a common and opportune time for NIPT, as the fetal fraction is reliably above the minimum threshold for most assays.
At 12 weeks of gestation, a typical fetal fraction is often cited as being around 8% to 10%. This range indicates that the sample contains enough placental DNA to allow for a statistically robust and reportable result from the NIPT. While this is a common mean value, a result anywhere above the minimum 4% threshold is generally sufficient for analysis. The fraction continues to rise throughout the second and third trimesters.
Factors That Influence Fetal Fraction Measurement
Gestational age is the most significant factor affecting the fetal fraction, but other biological variables also play a role. The primary non-gestational factor is the pregnant person’s maternal weight or Body Mass Index (BMI). There is an inverse relationship between maternal weight and fetal fraction.
A higher maternal weight is associated with a greater volume of maternal cfDNA released into the bloodstream, which effectively dilutes the fixed amount of placental cfDNA. This means that for two people at the same gestational age, the one with a higher BMI will likely have a lower reported fetal fraction. Certain medications, such as low molecular weight heparin (LMWH) or other anticoagulants, have also been linked to reduced fetal fraction in some studies.
Pregnancies involving twins or other multiple gestations also influence the fetal fraction, as the total amount of placental DNA is increased. However, interpreting the results in a multiple gestation is more complex, as the reported fraction is the sum of DNA contributions from all placentas. Certain fetal chromosomal abnormalities, particularly Trisomy 13 (Patau syndrome) and Trisomy 18 (Edwards syndrome), have been associated with lower average fetal fractions due to issues with placental development.
Understanding a Low Fetal Fraction Result
When a test returns a low fetal fraction, it means the sample did not contain enough placental DNA to meet the laboratory’s minimum confidence threshold. This is often termed a “no call” or a test failure, signifying that the result is inconclusive. A low fetal fraction is a limitation of the test sample and not a definitive diagnosis of a fetal problem.
The most common follow-up step after an initial low fetal fraction is to repeat the blood draw, usually after waiting one to two weeks. This delay allows the pregnancy to advance, which typically increases the fetal fraction to a sufficient level for a successful retest. A significant percentage of people who receive a low FF result on the first attempt will receive a reportable result upon a second draw.
If the repeat NIPT also fails due to a persistently low fetal fraction, alternative options are discussed with a healthcare provider. These alternatives may include pursuing diagnostic procedures, such as chorionic villus sampling (CVS) or amniocentesis, which analyze fetal cells directly. While low fetal fraction is not diagnostic, studies have noted a statistical association between repeated low FF results and a slightly elevated risk for certain placental complications and aneuploidies.