Clinical Implications of Low Cell‐Free DNA Fetal Fraction in Non‐Invasive Prenatal Testing: A Retrospective Cohort Study of 40,716 Pregnancies

Objective This study aimed to investigate the association between fetal fraction (FF) on non‐invasive prenatal testing (NIPT) and pregnancy‐related complications using a large sample to support improved prenatal management. Methods This retrospective cohort study included women with singleton pregnancies and negative NIPT results between January 2015 and March 2022 as part of the Japan Multicenter Study. Chi‐square tests and binary logistic regression analyses were used to assess the association between FF and pregnancy‐related complications. Results A total of 40,716 responses were analyzed. No significant association was found between FF and placental abruption (χ 2 (1) = 2.84, p = 0.09). Women in the low FF group (FF < 10.27%, < 25th percentile) had higher risks of fetal demise, adjusted OR = 1.79, 95% CI [1.31, 2.43]), preterm birth (adjusted OR = 1.63, 95% CI [1.30, 2.06]), fetal growth restriction (FGR) (adjusted OR = 1.50, 95% CI [1.10, 2.05]), and hypertensive disorders of pregnancy (HDP) (adjusted OR = 1.44, 95% CI [1.24, 1.66]). No significant differences were observed for gestational diabetes mellitus (GDM) (adjusted OR = 1.13, 95% CI [0.99, 1.30], p = 0.081). Conclusion Low FF on NIPT is associated with an increased risk of several pregnancy complications, highlighting the need for careful management.