Atypicality index as an add‐on to combined first‐trimester screening for chromosomal aberrations

ABSTRACT Objectives To compute a set of atypicality indices based on combined first‐trimester screening (cFTS) markers and second‐trimester estimated fetal weight (EFW), and to demonstrate their potential in identifying pregnancies at reduced or increased risk of chromosomal aberrations following a low‐risk cFTS result. Methods The atypicality index quantifies the unusualness of an individual set of measurements relative to a reference distribution and can be computed from any variables or measurements available. A score of 0% on the atypicality index represents the most typical profiles, while a score of 100% indicates the highest level of atypicality. From the Danish Fetal Medicine Database, we retrieved data on all pregnant women seen for cFTS in the Central Denmark Region between January 2008 and December 2018. All pregnancies with a cytogenetic or molecular analysis obtained prenatally, postnatally or following pregnancy loss or termination were identified. A first‐trimester atypicality index (AcFTS) was computed based on nuchal translucency (NT) thickness, maternal serum free β‐human chorionic gonadotropin (β‐hCG) and pregnancy‐associated plasma protein‐A (PAPP‐A). Furthermore, a second‐trimester index (AcFTS + EFW) was computed from cFTS markers and EFW from a routine second‐trimester anomaly scan. All pregnancies were stratified into subgroups based on their atypicality levels and their cFTS risk estimates. The risk of chromosomal aberrations in each subgroup was then compared with the overall prevalence, and a graphical presentation of the multivariate measurement profiles was developed. Results We retrieved data on 145 955 singleton pregnancies, of which 9824 (6.7%) were genetically examined. Overall, 1 in 122 (0.82% (95% CI, 0.77–0.87%)) of all pregnancies seen for cFTS were affected by a fetal chromosomal aberration, and in screen‐negative pregnancies (cFTS trisomy 21 risk