Clinical Implications of Noninvasive Prenatal Testing Failures Due to Low Fetal Fraction: Associations With Adverse Maternal and Fetal Outcomes

ABSTRACT Objective To identify risk factors associated with noninvasive prenatal testing (NIPT) failures due to a low fetal fraction (LFF, < 4%) and to evaluate appropriate management strategies. Methods This was a single retrospective cohort study conducted on consecutive NIPT procedures performed at a national prenatal diagnosis center between April 2016 and June 2022. Results Among the 41,693 NIPT procedures conducted at Peking Union Medical College Hospital, 524 cases (1.3%) failed due to LFF. Testing failures were associated with an increased risk of rare fetal chromosomal abnormalities (OR 18.9). Independent risk factors for NIPT failure included antiphospholipid syndrome (OR 19.7), rare fetal chromosomal abnormalities (OR 17.9), body mass index ≥ 25 kg/m 2 (OR 8.1), low molecular weight heparin administration (OR 7.7), systemic lupus erythematosus (OR 6.1), and dichorionic twins (OR 2.1). NIPT failure was also associated with a higher incidence of gestational hypertension (2.9% vs. 0.7%; OR 4.0), preeclampsia (9.1% vs. 1.0%; OR 10.4), gestational diabetes mellitus (26.0% vs. 11.8%; OR 2.6), fetal growth restriction (4.7% vs. 0.9%; OR 5.4), spontaneous abortion (2.4% vs. 0.6%; OR 4.1), and preterm birth (10.0% vs. 3.6%; OR 3.0). Conclusions Pregnancies with NIPT failures are at a heightened risk for fetal chromosomal abnormalities and placenta‐mediated complications, highlighting the need for enhanced monitoring and individualized management during perinatal care.