What are the risks of a low fetal fraction in cell-free DNA (cfDNA) testing?

Risks of Low Fetal Fraction in Cell-Free DNA Testing

Women with low fetal fraction cfDNA results face a significantly increased risk of fetal aneuploidy (odds ratio 9.2), particularly trisomies 13,18, and triploidy, and should be offered diagnostic testing with amniocentesis or CVS. 1

Primary Risk: Increased Aneuploidy Risk

Low fetal fraction is strongly associated with fetal chromosomal abnormalities:

• Test failure occurs in 8% of all patients overall, but this rate doubles to 16% in pregnancies with fetal aneuploidy 1
• The odds ratio for aneuploidy in cases with failed tests due to low fetal fraction is 9.2 1
• Trisomies 13 and 18, as well as triploidy, are particularly associated with low fetal fraction results 1, 2

Secondary Risk: Test Failure and Delayed Diagnosis

Low fetal fraction results in test failure in 0.9-8.1% of cases, potentially delaying critical diagnostic information:

• Repeat testing is successful in only 50-80% of cases 1
• At advanced gestational ages, patients may not wish to delay obtaining definitive information given the increased aneuploidy risk 1
• The test failure rate varies depending on whether laboratories measure fetal fraction and require minimum concentrations 1

Associated Maternal and Pregnancy Factors

Low fetal fraction is associated with specific maternal characteristics that affect test reliability:

Maternal Obesity

• cfDNA screening fails to provide results in 20% of women >250 lb and 50% of women >350 lb 1, 3
• Maternal high BMI is the strongest predictor of low fetal fraction 3, 4
• In obese or morbidly obese women, cfDNA screening may not be the best screening option 1

Gestational Age

• Fetal fraction is lower at <10 weeks gestation and less likely to provide a result 1, 3
• Fetal fraction remains relatively constant from 10-22 weeks of gestation 1

Multiple Gestations

• Higher failure rates occur in multifetal gestations 1, 3
• Vanishing twin or empty second gestational sac is associated with false-positive results 1, 2
• Detection rates may be lower in twin pregnancies, though data are limited 1

Risk of Adverse Pregnancy Outcomes

Emerging evidence suggests low fetal fraction may indicate abnormal placentation and predict pregnancy complications:

• Low fetal fraction is associated with hypertensive disorders of pregnancy, small for gestational age neonates, and preterm birth 5
• Inverse correlation exists between fetal fraction and mean arterial pressure and uterine artery pulsatility index 6
• Lower fetal fraction correlates with higher risks for preeclampsia <34 weeks, preeclampsia <37 weeks, and fetal growth restriction <37 weeks 6

Important Caveats

Not all low fetal fraction results indicate increased risk:

• One large study of >1,100 patients with low fetal fraction showed no enrichment of aneuploidy upon redraw (84.2% yielded reportable results) 7
• In this cohort, almost all pregnancies with repeated low fetal fraction failure resulted in apparently healthy liveborns 7
• This suggests that proceeding directly to diagnostic testing may be unwarranted for most patients, and redrawing may be appropriate 7

However, the ACOG guideline recommendation remains that diagnostic testing should be offered given the overall increased risk 1, 3, particularly because the association with trisomies 13,18, and triploidy is well-established across multiple studies.

Clinical Management Algorithm

For patients with low fetal fraction results:

1. Counsel about 9.2-fold increased odds of aneuploidy, particularly trisomies 13,18, and triploidy 1
2. Offer diagnostic testing (amniocentesis or CVS) as the primary option 1, 3
3. Consider repeat cfDNA testing as an alternative, understanding 50-80% success rate 1
4. Factor in gestational age when deciding between repeat testing versus proceeding directly to diagnostic testing 1
5. Consider maternal weight and whether alternative screening methods would be more appropriate 1, 3

1, 3