Down syndrome screening: suitability of a WHO 5 standardized total hCG assay

To determine how the adoption of the new WHO 5th International Standard (IS 07/364) will affect the suitability of total βhCG as a marker for second trimester Down syndrome screening, compared to the current WHO 3rd IS (75/537).

Assays employing both standards were evaluated on the Beckman Coulter DxI platform. Matched βhCG results from 232 fresh second trimester maternal serum samples were compared. In addition, stored samples from 51 Down syndrome and 251 matched control sera were also tested with both assays and results converted to weight-adjusted multiples of the median (MoMs). These results were combined with maternal age and the existing alpha-fetoprotein, unconjugated estriol and inhibin-A MoM levels to compute patient-specific Down syndrome risk.

Correlation between the two sets of results on fresh samples was high (r=0.993), but showed a proportional increase of 33% (95% CI 31% to 35%) in results using the new versus old assay across the range of measurements. βhCG results in the case/control dataset were also highly correlated (0.994) and showed a similar proportional increase (34%). After computing assay-specific MoMs, the resulting 'triple' and 'quadruple' Down syndrome risks were highly correlated, and resulted in no difference in either of the two detection rates (78% and 88%, respectively) or false positive rates (6.4%, 6.8%).

Laboratories using the DxI platform with the new total βhCG 5th IS assay will need to compute new reference (medians), but can expect no impact on the clinical validity of the associated Down syndrome screening programs.