Risks of Low Fetal Fraction in Cell-Free DNA Testing

Primary Risk: Increased Aneuploidy Risk

Women with low fetal fraction cfDNA results face a significantly increased risk of fetal aneuploidy, particularly trisomies 13, 18, and triploidy, with an odds ratio of 9.2, and should be offered diagnostic testing with amniocentesis or CVS, as recommended by the American College of Obstetricians and Gynecologists 1
Test failure occurs in 8% of all patients overall, but this rate doubles to 16% in pregnancies with fetal aneuploidy, according to the American College of Obstetricians and Gynecologists 1, 2
The odds ratio for aneuploidy in cases with failed tests due to low fetal fraction is 9.2, as reported by the American College of Obstetricians and Gynecologists 1, 3

Repeat testing is successful in only 50-80% of cases, potentially delaying critical diagnostic information, as noted by the American College of Obstetricians and Gynecologists 1, 4
At advanced gestational ages, patients may not wish to delay obtaining definitive information given the increased aneuploidy risk, according to the American College of Obstetricians and Gynecologists 1

cfDNA screening fails to provide results in 20% of women with high body mass index and 50% of women with very high body mass index, as reported by the American College of Obstetricians and Gynecologists 1, 3
Maternal high body mass index is a strong predictor of low fetal fraction, according to the American College of Obstetricians and Gynecologists 5
In women with high body mass index or obesity, cfDNA screening may not be the best screening option, as recommended by the American College of Obstetricians and Gynecologists 1, 6

The American College of Obstetricians and Gynecologists recommends counseling patients about the 9.2-fold increased odds of aneuploidy, particularly trisomies 13, 18, and triploidy, and offering diagnostic testing (amniocentesis or CVS) as the primary option 1
Consider repeat cfDNA testing as an alternative, understanding the 50-80% success rate, as noted by the American College of Obstetricians and Gynecologists 1
Factor in gestational age when deciding between repeat testing versus proceeding directly to diagnostic testing, as recommended by the American College of Obstetricians and Gynecologists 1
Consider maternal weight and whether alternative screening methods would be more appropriate, according to the American College of Obstetricians and Gynecologists 1, 5

Low fetal fraction causes test failure in approximately 0.9 %–8.1 % of all cfDNA screens; the failure rate rises to ≈16 % in pregnancies that ultimately have chromosome abnormalities【7】.

A failed cfDNA result due to insufficient fetal fraction confers a 9.2‑fold increased odds of fetal aneuploidy (especially trisomies 13, 18, and triploidy) compared with a successful test【7】.

Maternal body weight markedly affects success: test failure occurs in ≈20 % of women weighing >250 lb and ≈50 % of women weighing >350 lb【7】.
Early gestational age (<10 weeks) is associated with lower fetal fraction, reducing the likelihood of a valid result【7】.

Given the elevated aneuploidy risk, professional guidance recommends offering diagnostic testing (amniocentesis or chorionic villus sampling) to obtain definitive chromosomal information【7】.

Success rates for a repeat cfDNA draw range from 50 %–80 % (more precisely 62.9 %–70.6 % in studied cohorts)【7】.
Failure persists in 20 %–50 % of repeat attempts, especially among women with higher body weight【7】.
Optimal timing: drawing a second sample 8–14 days after the first, or waiting until ≥10 weeks gestation if the initial draw was <10 weeks, improves the chance of a successful repeat【7】.

Traditional serum (quad) screening can be performed in the second trimester without requiring fetal fraction, but it is less accurate than cfDNA and does not mitigate the increased aneuploidy risk associated with a failed cfDNA test【7】.

Key factors influencing the choice of testing strategy include gestational age, maternal weight, and the 9.2‑fold increased aneuploidy risk identified after the initial failure【7】.