Causes of Low Fetal Fraction in Non-Invasive Prenatal Testing (NIPT)
Low fetal fraction in NIPT is most commonly associated with maternal obesity, early gestational age, certain maternal conditions including autoimmune disorders and use of anticoagulants, and potential fetal chromosomal abnormalities. Understanding these factors is crucial as approximately 1% of NIPT samples result in "no-call" results, primarily due to insufficient fetal fraction 1.
Maternal Factors Associated with Low Fetal Fraction
- Obesity: Maternal high body mass index (BMI) is strongly associated with low fetal fraction, with studies showing that NIPT may fail to provide results in 20% of women >250 lb and 50% of women >350 lb 1
- Use of certain anticoagulants: Medications that affect blood coagulation can interfere with cell-free DNA analysis 1
- Autoimmune disorders: Maternal autoimmune conditions have been linked to higher rates of no-call results 1
- Maternal weight: There is an inverse relationship between maternal weight and fetal fraction, with heavier women having lower fetal fractions 2, 3
Gestational Age Factors
- Early gestational age: Fetal fraction is typically lower at <10 weeks gestation, making NIPT less likely to provide a result at very early gestational ages 1
- Non-linear development: Contrary to conventional understanding, fetal fraction does not consistently rise with gestational age; studies have identified a drop around 15 weeks of gestation 4
- Timing of blood draw: The interval between blood draws can significantly affect fetal fraction, with rapid increases observed over the first 8 days after an initial draw 3
Fetal and Placental Factors
- Fetal chromosomal abnormalities: Low fetal fraction has been associated with a higher than expected rate of certain fetal chromosome disorders, particularly trisomies 13 and 18, and triploidy 1
- Fetal gender: Male fetuses tend to have lower fetal fraction than female fetuses, possibly due to smaller gonosomal chromosomes 4
- Placental compromise: Low fetal fraction is associated with adverse pregnancy outcomes related to placental dysfunction, particularly hypertensive disorders of pregnancy 5
- Multiple gestations: The presence of multiple fetuses can affect fetal fraction measurements 1
- Vanishing twin or unrecognized twin: The presence of a second gestational sac has been associated with false-positive NIPT results 1
Technical Factors
- Laboratory methodology: Different NIPT platforms have varying minimum fetal fraction requirements and technical approaches to analyzing cell-free DNA 1
- Fragment size selection: Sequencing shorter cfDNA fragments (107-145 bp versus traditional 160 bp) can improve fetal fraction detection, especially in women with higher BMI 2
Clinical Implications of Low Fetal Fraction
- Increased risk of adverse outcomes: Low fetal fraction in NIPT during first and early second trimesters is associated with adverse pregnancy outcomes, particularly hypertensive disorders of pregnancy 5
- Redraw success rates: For cases with insufficient fetal fraction, repeat testing provides a result in approximately 75-80% of cases 1
- Predictive factors for successful redraw: The likelihood of obtaining a result on redraw depends on initial fetal fraction, maternal weight, and interval between blood draws 3, 6
Management Considerations
- Diagnostic testing: The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine recommend offering diagnostic testing (amniocentesis or CVS) to individuals with a no-call result 1
- Repeat testing: Repeat NIPT testing at a later gestational age may be considered, with success rates of 62.9-70.6% for obtaining a result on redraw 3
- Alternative screening: For women with high BMI or other factors predisposing to low fetal fraction, alternative screening methods may be more appropriate 1
Understanding these factors can help in counseling patients about the limitations of NIPT and appropriate follow-up when low fetal fraction results occur.