False-negative results in non-invasive prenatal testing are rare but clinically significant, particularly in the presence of biological factors such as feto-placental mosaicism. This report describes a pregnancy affected by fetal trisomy 18 in which three consecutive non-invasive prenatal tests reported low risk despite abnormal first-trimester ultrasound findings (increased nuchal translucency, hydrops fetalis, and tricuspid regurgitation). Amniocentesis subsequently confirmed trisomy 18 in the fetus. Post-termination placental analysis revealed mosaicism, with high trisomy 18 levels on the fetal side (up to 76%) and lower levels on the maternal side (20%) of the placenta. This distribution resulted in an estimated “effective fetal fraction” below the standard detection threshold for a non-invasive prenatal test (~4%). These findings highlight the limitations of non-invasive prenatal testing as a screening test and underscore the importance of invasive diagnostic testing when structural abnormalities are detected. Consideration of biological variables such as placental mosaicism is essential for accurate interpretation and clinical decision-making. • Feto-placental mosaicism may lead to false-negative NIPT. • Uneven placental mosaicism masked trisomy 18 in cfDNA. • Repeated NIPT does not exclude false-negative results. • Diagnostic testing remains essential with structural anomalies.
Andová et al. (Wed,) studied this question.