Limitations of fixed risk thresholds in first-trimester combined screening for trisomy 21

OBJECTIVES: To evaluate the limitations of fixed risk thresholds in first-trimester CST for T21, with a focus on age-related inflation of false-positive results, and to assess whether alternative threshold strategies can mitigate this effect. MATERIAL AND METHODS: This retrospective study included 13,668 singleton pregnancies with first-trimester CST and confirmed prenatal or postnatal karyotype (13,540 euploid; 128 T21). Screening performance was evaluated using the standard 1:300 high-risk cut-off and two strategies targeting an approximately 5% FPR - a global threshold (5th percentile of euploid risk denominators, approximately 1:55) and an age-dependent threshold derived from age-specific 5th percentiles smoothed using locally estimated scatterplot smoothing. DR and FPR were calculated overall and stratified by maternal age (≤ 34, 35-39, and ≥ 40 years), with paired comparisons performed using McNemar's test. RESULTS: The standard 1:300 cut-off yielded an overall FPR of 16.1% (2,181/13,540), increasing from 9.7% in individuals aged ≤ 34 years to 38.5% in those aged ≥ 40 years. The global 5% FPR strategy substantially reduced false-positive classifications but decreased DR from 90.6% (116/128) to 79.7% (102/128) (p < 0.001). The age-dependent strategy-maintained a near-constant FPR across age groups (overall 5.4%), achieved a DR of 81.3% (104/128), and demonstrated higher diagnostic efficiency than the 1:300 threshold (diagnostic odds ratio 75.23; 95% confidence interval 48.15-117.55). CONCLUSIONS: Fixed risk thresholds in first-trimester CST lead to pronounced age-related inflation of false-positive results. Thresholds targeting an approximately 5% FPR - particularly age-dependent calibration - substantially reduce unnecessary screen-positive classifications with only moderate loss in detection. However, threshold adjustment alone does not address the fundamental limitation of binary classification based on a single posterior risk estimate. In contingent screening pathways where CST serves as triage before cell-free DNA or invasive testing, age-adapted thresholds offer a pragmatic approach to reducing avoidable escalation among pregnant individuals of advanced maternal age.