Contingent screening for trisomy 21 using non‐invasive prenatal testing has the potential to reduce invasive diagnostic testing and increase the detection of trisomy 21.

To describe the diagnostic and economic performance of prenatal screening models for trisomy 21 that use non‐invasive prenatal testing as a contingent screen across a range of combined first trimester screening risk cut‐offs from a public health system perspective.

Using a hypothetical cohort of 300 000 pregnancies, we modelled the outcomes of 25 contingent non‐invasive prenatal testing screening models and compared these to conventional screening, offering women with a high‐risk (1 > 300) combined first trimester screening result an invasive test. The 25 models used a range of risk cut‐offs. High‐risk women were offered invasive testing. Intermediate‐risk women were offered non‐invasive prenatal testing. We report the cost of each model, detection rate, costs per diagnosis, invasive tests per diagnosis and the number of fetal losses per diagnosis.

The cost per prenatal diagnosis of trisomy 21 using the conventional model was $51 876 compared to the contingent models which varied from $49 309–66 686. The number of diagnoses and cost per diagnosis increased as the intermediate‐risk threshold was lowered. Results were sensitive to trisomy 21 incidence, uptake of testing and cost of non‐invasive prenatal testing.

Contingent non‐invasive prenatal testing models using more sensitive combined first trimester screening risk cut‐offs than conventional screening improved the detection rate of trisomy 21, reduced procedure‐related fetal loss and could potentially be provided at a lower cost per diagnosis than conventional screening.