Fetal Fraction of Cell‐Free DNA in the Prediction of Adverse Pregnancy Outcomes: A Nationwide Retrospective Cohort Study

ABSTRACT Objective To assess the added value of fetal fraction of cell‐free DNA in the maternal circulation in the prediction of adverse pregnancy outcomes. Design Retrospective cohort study. Setting Nationwide implementation study on non‐invasive prenatal testing (NIPT; TRIDENT‐2 study). Population Pregnant women in the Netherlands opting for NIPT between June 2018 and June 2019. Methods Two logistic regression prediction models were constructed for each adverse pregnancy outcome. The first model (base model) included prognostic clinical parameters that were selected from existing first‐trimester prediction models for adverse pregnancy outcomes. The second model (fetal fraction model) included fetal fraction as a predictor on top of the prognostic clinical parameters included in the base model. The added prognostic value of fetal fraction was assessed by comparing the base and fetal fraction models in terms of goodness of fit and predictive performance. Main Outcome Measures Likelihood ratio test (LRT), area under the curve (AUC) and Integrated Discrimination Improvement (IDI) index. Results The study cohort consisted of 56 110 pregnancies. The incidence of adverse pregnancy outcomes was 5.7% for hypertensive disorders of pregnancy (HDP; n = 3207), 10.2% for birthweight < p10 ( n = 5726), 3.2% for birthweight < p2.3 ( n = 1796), 3.4% for spontaneous preterm birth (sPTB; n = 1891), 3.4% for diabetes ( n = 1902) and 1.3% for congenital anomalies ( n = 741). Adding fetal fraction to the base model improved model fit for HDP, birthweight < p10, birthweight < p2.3, all sPTB, and diabetes, but not for congenital anomalies (LRT p < 0.05). For HDP, the AUC improved from 0.67 to 0.68 by adding fetal fraction to the base model ( p = 0.14) with an IDI of 0.0018 ( p < 0.0001). For birthweight < p10, the AUC improved from 0.65 to 0.66 ( p < 0.0001) with an IDI of 0.0023 ( p < 0.0001). For birthweight < p2.3, the AUC improved from 0.67 to 0.69 ( p < 0.0001) with an IDI of 0.0011 ( p < 0.0001). For all sPTB, the AUC was similar for both models (AUC 0.63, p = 0.021) with an IDI of 0.00028 ( p = 0.0023). For diabetes, the AUC was similar (AUC 0.72, p = 0.35) with an IDI of 0.00055 ( p = 0.00015). Conclusions Fetal fraction has statistically significant but limited prognostic value in the prediction of adverse pregnancy outcomes in addition to known prognostic clinical parameters.