Can Non-Invasive Prenatal Testing (NIPT) detect the Kell antigen in the fetus?

NIPT for Kell Antigen Detection in the Fetus

Yes, NIPT can reliably detect the fetal Kell (KEL1) antigen from maternal plasma using cell-free DNA analysis, with validated sensitivity and specificity of 100% as early as 10 weeks gestation. 1

Clinical Validation and Performance

NIPT for fetal Kell antigen detection has been extensively validated using next-generation sequencing (NGS) and digital PCR platforms:

• NGS-based NIPT demonstrated 100% sensitivity (95% CI 99-100%) and 100% specificity (95% CI 99-100%) in detecting fetal Kell antigen status across 1,061 preclinical samples in the ethnically diverse U.S. population. 1

• The no-results rate was essentially zero (0.1%) in clinical practice, including 769 alloimmunized pregnancies, making it highly reliable for clinical decision-making. 1

• Digital PCR protocols can detect as little as 0.05-0.5% KEL1 target allele in maternal plasma, providing exceptional sensitivity even in early pregnancy. 2

• Clinical validation showed 100% concordance between NIPT results and neonatal antigen genotype/serology in alloimmunized pregnancies. 1

Optimal Timing and Technical Considerations

• Testing can be performed as early as 10 weeks gestation without requiring a sample from the biological partner, which is a significant advantage over traditional paternal genotyping approaches. 1

• Both chip-based digital PCR and droplet digital PCR platforms provide highly reliable results with no false KEL1-negative results, though some inconclusive reads may occur requiring repeat testing. 3

• The test does not require knowledge of paternal phenotype, eliminating issues related to non-paternity that can complicate traditional management approaches. 1

Clinical Applications and Management Impact

For K-negative pregnant women with anti-Kell antibodies, NIPT enables early identification of Kell-positive fetuses who require intensive monitoring, while sparing Kell-negative fetuses from unnecessary interventions. 1, 4

Risk Stratification Algorithm:

1. If NIPT confirms Kell-negative fetus: No further specialized monitoring needed beyond routine prenatal care 1

2. If NIPT confirms Kell-positive fetus with anti-Kell titer ≥4: Intensive ultrasonographic monitoring for fetal anemia is warranted, as this threshold has 100% sensitivity (95% CI 91-100%) for identifying fetuses requiring transfusion therapy 5

3. Serial antibody-dependent cellular cytotoxicity testing is NOT informative for risk stratification and should not be used to guide clinical decisions 5

Critical Advantages Over Current Practice

• NIPT may identify more at-risk fetuses than current clinical practice, which relies on paternal genotyping with adherence rates that are often suboptimal and results that can be incorrect due to non-paternity. 1

• Clinical adoption streamlines care by reducing unnecessary RhIG administration, intensive monitoring of Kell-negative fetuses, and patient anxiety in cases where the fetus is confirmed Kell-negative. 1

• The first anti-Kell titer measurement combined with fetal Kell status from NIPT is sufficient for risk stratification; repeated titer measurements during pregnancy do not provide additional predictive value. 5

Important Caveats

• While NIPT for common aneuploidies is considered screening and requires diagnostic confirmation, NIPT for fetal Kell antigen has demonstrated diagnostic-level accuracy (100% sensitivity and specificity) in validation studies. 1

• However, as with all NIPT applications, pre-test and post-test genetic counseling should be provided to discuss test limitations and clinical implications. 6

• In pregnancies with anti-Kell antibodies and confirmed Kell-positive fetus, approximately 53% of fetuses will require intrauterine or postnatal transfusion therapy, emphasizing the importance of intensive monitoring in this population. 5