OBJECTIVES: To compute a set of atypicality indices from combined first-trimester screening (cFTS) markers and second-trimester estimated fetal weight (EFW), and to demonstrate their potential in identifying pregnancies at either reduced or increased risks 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 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 of pregnancy were identified. A first-trimester atypicality index (AcFTS ) was computed from nuchal translucency (NT) thickness, maternal serum free β-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A). Further, a second trimester index (AcFTS+EFW ) was computed from cFTS markers and estimated fetal weight (EFW) estimated at 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 multivariate measurement profiles was introduced.

RESULTS: We retrieved data on 145,955 singleton pregnancies, of which 9824 (6.7%) were genetically examined. Overall, 1 in 122 of all pregnancies seen for cFTS (0.82% [95% CI 0.77-0.87%]) were affected by a fetal chromosomal aberration and in screen-negative pregnancies (cFTS T21 risk <1 in 100 and/or T18/13 risk <1 in 50), 0.41% [95% CI 0.38-0.44%] were affected. In screen-negative pregnancies with a typical first-trimester profile (AcFTS <80% ), the risk of chromosomal aberrations was significantly reduced (0.28%) compared to the overall risk. The risk of chromosomal aberrations increased with higher atypicality index to 0.49% (AcFTS [80-90%) ), 1.52% (AcFTS [90-99%) ), and 4.44% (AcFTS [>99%) ) and was significantly increased in the two most atypical subgroups. The same applied for the second trimester atypicality index (AcFTS+EFW ) with risks of chromosomal aberrations of 0.76% and 4.16% in the two most atypical subgroups (AcFTS+EFW [90-99%) and AcFTS+EFW >99% , respectively).

CONCLUSIONS: As an add-on to cFTS, the atypicality index identifies women with typical measurement profiles which may act as reassurance, whereas atypical profiles may warrant specialist referral and further investigations. In pregnancies at low risk from cFTS but with a highly atypical distribution of NT, PAPP-A, and β-hCG, the risk of a chromosomal aberration is substantially increased. The atypicality index optimizes the interpretation of pre-existing prenatal screening profiles and is not limited to cFTS markers or EFW. This article is protected by copyright. All rights reserved.