Extremes of Fetal Fraction on Noninvasive Prenatal Screening and Placental Histopathology: Is There an Association?

Objective: To evaluate the association between low and high fetal fraction (FF) of cell-free fetal DNA on non-invasive prenatal screening (NIPS) and placental pathology. Methods: We undertook a prospective cohort study of patients undergoing NIPS between July 2022 and July 2023 through Natera Inc. Based on the FF percentile, the study cohort was divided into three groups: high FF (≥95th%), low FF (≤5th%), and a control group (FF 6th-94th%). Our primary study outcome was a composite of high-risk placental lesions. We compared the occurrence of the primary study outcome across the study groups using the chi² test. Multivariable regression analyses were performed to predict the likelihood of the primary outcome based on the FF percentile. Selected obstetric and neonatal outcomes were assessed as secondary outcomes. Results: The primary outcome was present in 11 (50.0%), 19 (48.7%), and 11 (35.5%) of participants in the low FF, high FF, and control cohorts, respectively (p = 0.46). In an adjusted model, the FF percentile was not associated with the primary outcome (aOR 2.41 (0.72-8.42) for low FF, aOR 1.55 (0.51-4.82) for high FF). Chorangiosis (p = 0.02) and fetal inflammatory response (p = 0.002) were seen more commonly in the low and high FF groups. Spontaneous preterm birth was more common in the low FF group (p = 0.04). Conclusions: Our study did not identify a correlation between high-risk histopathological patterns and extremely low or high FF when compared to a control cohort. Chorangiosis and fetal inflammatory response were found more commonly in the low and high FF groups.