Low Fetal Fraction of Cell Free DNA at Non-Invasive Prenatal Screening Increases the Subsequent Risk of Preterm Birth in Uncomplicated Singleton Pregnancy

Objective: To examine the association between low fetal fraction (FF) of cell free DNA determined at non-invasive prenatal screening (NIPS) and the subsequent risk of preterm birth in uncomplicated singleton pregnancy. Methods: We retrospectively interrogated NIPS System and hospitalization records from April 2018 to August 2019 and obtained results from 1521 consecutive and uncomplicated women with singleton pregnancy in which plasma FF of cell free DNA at NIPS had been investigated together with birth outcomes. We examined the association between FF and preterm birth (PTB) by regression analysis. Results: The incidence of preterm birth, low birthweight, and macrosomia in the study population was 5.06%, 2.89%, and 7.17%, respectively. FF at NIPS in the second to fourth quartiles (8.40-11.07, 11.08-13.70, and > 13.70%, respectively) was associated with higher gestational age at delivery relative to the lowest quartile (< 8.40%), with estimated mean increases of 0.27 weeks (95% CI: 0.05-0.49), 0.29 weeks (95% CI: 0.06-0.51), and 0.28 weeks (95% CI: 0.05-0.51), respectively (P for trend = 0.027). Low FF (< the 5th percentile) was associated with an increased risk of PTB (adjusted OR: 2.23, 95% CI: 1.01-4.98, P = 0.047) compared to normal FF (>= the 5th and <= the 95th percentiles). In addition, when compared to women with normal FF and body mass index (BMI) < 25 at NIPS, the risk of early PTB (< 34 weeks gestation) was remarkably significantly higher among those with low FF and BMI >= 25 (adjusted OR: 6.29, 95% CI: 1.71-23.15, P = 0.006). Conclusion: Our study supports the association of low FF at NIPS with PTB (especially early PTB) for uncomplicated singleton pregnancy.