The Significance of Test Failures in Noninvasive Prenatal Screening for Fetal Aneuploidy Using Cell-free DNA

Abstract

AbstractNoninvasive prenatal screening (NIPS) for fetal aneuploidy is less effective when there is a small fraction of fetal cell-free DNA in the maternal plasma. In this study, modeling was used to assess the impact of a low fetal fraction (FF) in NIPS when (a) FF is not measured; (b) low FF cases receive invasive testing; (c) low FF cases receive the combined test; (d) low FF cases receive the quadruple test. Modeling was based on expected performance of NIPS, invasive testing, and conventional screening. NIPS failure rates of 0–6% due to low FF were considered under the assumption that aneuploidy rates were the same in successful and unsuccessful cases. In a secondary analysis, the effect of higher rates of aneuploidy in failed cases was assessed. Failure to measure FF can result in lower detection rates. Providing invasive tests to all women with low FF restores a high level of detection but at the expense of many unnecessary invasive tests. Utilization of conventional screening results in only a modest loss in detection and limited deterioration in the false-positive rate. These trends are more apparent when higher rates of fetal aneuploidy are present in low FF women. Recognizing those cases where an NIPS result is invalid due to low FF is important from both the individual patient and overall population screening perspectives. When there is a NIPS test failure due to low FF, utilization of conventional maternal serum marker screening and ultrasound should be considered for women who have previously not received conventional screening.