Combined first-trimester screening and invasive diagnostics for atypical chromosomal aberrations: Danish nationwide data on prenatal profiles and detection compared with NIPT.

OBJECTIVE: To examine the prenatal profiles of pregnancies affected by an atypical chromosomal aberration, focusing on pathogenic copy number variants (pCNVs). Further, we wanted to quantify the performance of combined first-trimester screening (cFTS) and a second-trimester anomaly scan in detecting these conditions. Finally, we aimed to estimate the consequences of a policy of using non-invasive prenatal testing (NIPT) rather than invasive testing with chromosomal microarray (CMA) to manage pregnancies identified as high risk from cFTS. METHODS: A retrospective review of the Danish fetal medicine database identified all pregnant women who had cFTS and a trisomy 21 risk-assessment between January 1, 2008, and December 31, 2018. Chromosomal aberrations diagnosed prenatally, postnatally, or from fetal tissue following pregnancy loss or termination of pregnancy (TOP) were identified. Chromosomal aberrations were grouped into one of six categories: 1) Triploidy; 2) Common trisomies (trisomies 21, 18, and 13); 3) Monosomy X; 4) Other sex chromosome aberrations (SCAs); 5) pCNVs; and 6) Rare autosomal trisomies (RATs) and mosaicisms. The prevalence of each aberration-category was stratified by the individual cFTS markers and risk estimate, and the size of each pCNV diagnosed from CMA was calculated. RESULTS: We included data on 565,708 pregnancies of which 3,982 were diagnosed with a fetal chromosomal aberration (0.70%). cFTS performed well in identifying triploidies (86%), monosomy X (92%), atypical SCAs (58%), and RATs and mosaicisms (70%). pCNVs comprised 28% (n = 1,091) of the chromosomal aberrations diagnosed overall, and the prevalence increased during the study period with more prenatal chromosomal microarray analysis being performed. In pregnancies with maternal age <30 years, NT <95th percentile, PAPP-A MoM ≥ 1, or trisomy 21 risk ≥1 in 1000, the prevalence of pCNVs significantly exceeded the prevalence of trisomies 21, 18, and 13. Pregnancies affected by a pCNV had significantly increased nuchal translucency thickness (NT) and decreased maternal biomarkers pregnancy associated plasma protein-A (PAPP-A) and ß-human chorionic gonadotropin (ß-hCG) compared with unaffected pregnancies. However, only 23% of these pregnancies screened positive from cFTS and 51% were not detected until after birth. Amongst high-risk pregnancies diagnosed with a chromosomal aberration, pCNVs comprised 14% and when other atypical aberrations were considered, conventional NIPT (screening for trisomies 21, 18, and 13, and monosomy X) would miss 28% of all pathogenic aberrations diagnosed following a high-risk cFTS result. Thus, 1 in 26 pregnancies at high-risk following cFTS would be affected by a chromosomal aberration despite a normal conventional NIPT result. In a contingent screening model with NIPT provided for the "intermediate" risk group (T21 risk of 1 in 100-300), 50% of the aberrations would be missed. In our cohort, 80% of the pCNVs diagnosed were <5Mb and therefore not detectable using current forms of "genome wide" NIPT. CONCLUSION: As a by-product to screening for trisomies 21, 18, and 13, most triploidies and the majority of atypical SCAs, RATs, and mosaicisms are detected before birth. However, only 23% of pCNVs are high-risk from cFTS and only half are diagnosed before birth. Replacing invasive testing with NIPT for high-risk pregnancies would substantially decrease the first-trimester detection of pathogenic chromosomal anomalies. This article is protected by copyright. All rights reserved.

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

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 ß-human chorionic gonadotropin (ß-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 < 1 in 100 and/or trisomy 18/13 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 with 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, 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 provide reassurance, whereas atypical profiles may warrant specialist referral and further investigation. In pregnancies identified as low risk on cFTS but with a highly atypical distribution of NT, PAPP-A and ß-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. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.