Non-invasive prenatal testing (NIPT) is a screening method used during pregnancy to assess the risk of certain chromosomal conditions in the fetus. This test analyzes small fragments of cell-free DNA (cfDNA) found in the pregnant person’s blood. The cfDNA includes genetic material from both the pregnant individual and the placenta, which reflects the fetus’s genetic makeup. NIPT primarily screens for conditions like Down syndrome (Trisomy 21), Edwards syndrome (Trisomy 18), and Patau syndrome (Trisomy 13), providing an early indication of potential genetic abnormalities.
Understanding Fetal Fraction
Fetal fraction refers to the percentage of cell-free DNA in the pregnant person’s bloodstream that originates from the placenta and the fetus. This measurement is important for NIPT quality control, as sufficient fetal DNA is necessary for accurate and reliable results. Cell-free fetal DNA (cffDNA) enters the maternal circulation primarily through the breakdown of placental cells.
For most NIPT methods, a fetal fraction typically greater than 4% is considered necessary to provide dependable results. If the fetal fraction is too low, the test may return an inconclusive result because there isn’t enough fetal DNA to analyze accurately. The average fetal fraction generally ranges from 10% to 15% between 10 and 20 weeks of gestation.
Common Causes of Low Fetal Fraction
Several factors can contribute to a low fetal fraction. Early gestational age is a primary reason, as the amount of fetal DNA in the maternal bloodstream increases as pregnancy progresses. While fetal cfDNA is detectable as early as five weeks, the concentration is often too low for NIPT until around 9 or 10 weeks of gestation, when the fetal fraction typically reaches a level suitable for testing.
Maternal body mass index (BMI) is another factor influencing fetal fraction. Higher maternal BMI can lead to a lower fetal fraction because increased maternal weight may result in a larger maternal blood volume, diluting the concentration of fetal DNA. This effect occurs because a greater amount of maternal cell-free DNA is present, potentially due to increased adipose tissue necrosis, which can obscure the fetal DNA. Studies have shown an inverse relationship, where higher maternal weight correlates with lower fetal fraction.
Certain maternal medical conditions can also impact cffDNA levels. Autoimmune disorders or specific treatments might affect the total amount of cell-free DNA in the maternal circulation, leading to a lower fetal fraction.
Fetal aneuploidy, though less common, can sometimes be associated with a lower fetal fraction. Pregnancies affected by conditions like Trisomy 13 (Patau syndrome) or Trisomy 18 (Edwards syndrome) may exhibit reduced fetal DNA levels.
Finally, technical or laboratory factors can occasionally contribute to an insufficient sample. Issues with sample collection or degradation of maternal white blood cells can increase the maternal cfDNA fraction, inadvertently diluting the fetal cfDNA.
Impact of Low Fetal Fraction Results
When an NIPT returns an “insufficient fetal fraction” or “no result,” it indicates the test could not be completed reliably due to inadequate fetal DNA. This outcome does not necessarily mean there is an issue with the pregnancy or the fetus. It signifies that the sample did not meet the minimum fetal fraction threshold required for accurate analysis.
Receiving an inconclusive NIPT result can be a source of anxiety for expectant parents. The uncertainty can lead to worry about the baby’s health, even when the underlying reason for the low fetal fraction is often related to factors like early testing or maternal characteristics. The most common reason for a “no-call” result is insufficient fetal fraction.
Addressing Low Fetal Fraction
When an NIPT yields an insufficient fetal fraction, healthcare providers typically recommend next steps. Often, a repeat blood draw for NIPT is offered, sometimes scheduled for a later gestational age to allow the fetal fraction to naturally increase. Approximately 50% to 60% of individuals who initially receive a failed NIPT result due to low fetal fraction will obtain a successful result on a second attempt.
If a second NIPT also yields an insufficient fetal fraction or if a repeat test is not recommended, alternative screening or diagnostic options may be discussed. These options can include traditional first-trimester screening, which combines ultrasound measurements with maternal blood work. More definitive diagnostic tests, such as amniocentesis or chorionic villus sampling (CVS), may also be considered if there are clinical indications or if the patient desires a conclusive diagnosis. Individuals should consult with their healthcare provider or a genetic counselor to discuss the specific results and determine the most appropriate course of action for their pregnancy.