Fetal fraction of cell-free DNA in non-invasive prenatal testing and adverse pregnancy outcomes: a nationwide retrospective cohort study of 56,110 pregnant women

Abstract

BackgroundNon-invasive prenatal testing by cell-free DNA analysis is offered to pregnant women worldwide to screen for fetal aneuploidies. In non-invasive prenatal testing, the fetal fraction of cell-free DNA in the maternal circulation is measured as a quality control parameter. Since fetal cell-free DNA originates from the placenta, the fetal fraction might also reflect placental health and maternal pregnancy adaptation. ObjectiveTo assess the association between the fetal fraction and adverse pregnancy outcomes. Study DesignWe performed a retrospective cohort study of women with singleton pregnancies opting for non-invasive prenatal testing between June 2018 and June 2019 within the Dutch nationwide implementation study (TRIDENT-2). Multivariable logistic regression analysis was used to assess associations between fetal fraction and adverse pregnancy outcomes. Fetal fraction was assessed as a continuous variable and as <10th percentile, corresponding to a fetal fraction below 2.5%. ResultsThe cohort comprised 56,110 pregnancies. In the analysis of fetal fraction as a continuous variable, a decrease in fetal fraction was associated with an increased risk of hypertensive disorders of pregnancy (adjusted OR [aOR] 2.27 [95% CI 1.89 to 2.78]), small for gestational age neonates <p10 (aOR 1.37 [1.28 to 1.45]) and <p2.3 (aOR 2.63 [1.96 to 3.57]), and spontaneous preterm birth from 24 to 37 weeks of gestation (aOR 1.02 [1.01 to 1.03]). No association was found for fetal congenital anomalies (aOR 1.02 [1.00 to 1.04]), stillbirth (aOR 1.02 [0.96 to 1.08]), or neonatal death (aOR 1.02 [0.96 to 1.08]). Similar associations were found for adverse pregnancy outcomes when fetal fraction was <10th percentile. ConclusionsIn early pregnancy, a low fetal fraction is associated with an increased risk of adverse pregnancy outcomes. These findings can be utilized to expand the potential of non-invasive prenatal testing in the future, enabling the prediction of pregnancy complications and facilitating tailored pregnancy management through intensified monitoring or preventive measures.