In a pregnant woman with a body mass index (BMI) of 41 who has had two non‑invasive prenatal testing (NIPT) draws with low fetal fraction, what are the risks and recommended next steps?

Pregnancy Risks with Two Low Fetal Fraction NIPT Results in a Patient with BMI 41

A pregnant woman with BMI 41 who has had two NIPT draws with low fetal fraction faces a modestly increased risk of placental compromise (particularly hypertensive disorders of pregnancy) and should proceed directly to diagnostic testing (amniocentesis) rather than attempting a third NIPT draw. 1, 2, 3

Understanding the Clinical Significance

Why Low Fetal Fraction Occurs with High BMI

• Maternal obesity is the strongest predictor of low fetal fraction, with women who have BMI ≥40 experiencing no-call rates ranging from 5.4% to 70.1% compared to 0-4.2% in normal-weight women. 4
• High BMI dilutes the fetal cell-free DNA in maternal circulation, making it technically difficult to achieve the minimum 4% fetal fraction threshold needed for reliable NIPT analysis. 2, 5
• After two failed attempts, the likelihood of a successful third draw remains low—repeat testing provides results in only 75-80% of cases with insufficient fetal fraction. 1, 2

Pregnancy Risks Associated with Low Fetal Fraction

Low fetal fraction itself is associated with adverse pregnancy outcomes, independent of BMI:

• Hypertensive disorders of pregnancy (HDP) occur significantly more frequently in the low fetal fraction group (5.17% vs. 1.91% in normal fetal fraction). 3
• The composite outcome of placental compromise (HDP, small for gestational age, placental abruption) is significantly elevated (7.76% vs. 3.64%, adjusted odds ratio 1.946). 3
• Low fetal fraction may reflect placental dysfunction, as the cell-free DNA originates from apoptotic trophoblast cells. 3

Regarding aneuploidy risk specifically:

• The association between low fetal fraction and fetal aneuploidy is marginal and not statistically significant in most studies. 6
• When NIPT is repeated after initial low fetal fraction failure, 66% are successful and most results are negative for trisomy. 6
• Low fetal fraction has been associated with trisomies 13 and 18 more than trisomy 21, but this association is weak. 2

Recommended Next Steps

Proceed Directly to Diagnostic Testing

The American College of Obstetricians and Gynecologists recommends offering diagnostic testing to individuals with persistent no-call results. 1, 2

• Amniocentesis is the preferred diagnostic test at this gestational age (typically second trimester after two failed NIPT attempts). 7
• Amniocentesis provides definitive karyotype analysis and can include chromosomal microarray (CMA) if indicated. 7
• This approach avoids further delays and provides conclusive information about fetal chromosomal status. 7

Alternative Screening Approaches

• Traditional serum screening (quad screen at 15-20 weeks) is not affected by maternal BMI in the same way as NIPT, though it has lower detection rates (75-80% for trisomy 21 vs. 99% for NIPT). 8
• However, given two failed NIPT attempts, proceeding directly to diagnostic testing is more efficient than attempting alternative screening methods. 1, 2

Enhanced Pregnancy Surveillance

Given the association between low fetal fraction and placental compromise:

• Implement increased surveillance for hypertensive disorders of pregnancy, including regular blood pressure monitoring and assessment for preeclampsia symptoms. 3
• Consider earlier and more frequent growth ultrasounds to monitor for fetal growth restriction. 3
• Discuss the modestly elevated risk of placental complications during prenatal counseling. 3

Common Pitfalls to Avoid

• Do not attempt a third NIPT draw—the success rate remains low and further delays definitive diagnosis. 1, 2
• Do not assume high aneuploidy risk based solely on low fetal fraction—the association is weak and most repeat tests are negative. 6
• Do not dismiss the low fetal fraction as purely technical—it carries independent prognostic information about placental function. 3
• Do not forget genetic counseling—patients with screen-positive or no-call NIPT results require access to genetic counseling by a genetics professional. 7

Important Caveats

• NIPT analyzes placental-derived DNA, which may not be 100% representative of the fetus due to confined placental mosaicism. 7, 9
• Even if amniocentesis shows normal results, the association between low fetal fraction and placental compromise persists and warrants enhanced surveillance. 3
• Sources of discordant NIPT results include confined placental mosaicism, vanishing twin, maternal chromosomal abnormalities, or maternal malignancy. 7