Second-trimester Down's syndrome serum screening: double, triple or quadruple marker testing?

Prior research has established that second-trimester maternal serum screening is a widely used method for Down's syndrome detection. The UK National Screening Committee has set benchmarks for detection rates and false-positive rates based on the SURUSS study. However, no prior work had resolved whether these findings could be replicated in local clinical settings. While it was already known that the double test provides moderate detection rates, the addition of further markers like inhibin-A and unconjugated oestriol had not been thoroughly evaluated in routine practice. The lack of clarity around assay performance for these markers created a gap in understanding their reliability. This uncertainty drove the need to assess whether the inclusion of these markers improved detection without increasing false positives. No prior work had specifically examined the imprecision of the inhibin-A assay in this context. That uncertainty motivated the current study to evaluate the feasibility of achieving national screening targets using different marker combinations.

This study aimed to determine if the detection and false-positive rates of second-trimester Down's syndrome screening, as reported in the SURUSS study, could be replicated locally. The researchers focused on assessing the performance of the double, triple, and quadruple marker tests in a real-world setting. They specifically examined the impact of adding inhibin-A and unconjugated oestriol to the existing double test protocol. The goal was to evaluate whether these additional markers improved detection rates without increasing false positives. The study also sought to assess the reliability of the inhibin-A assay, which had not been previously evaluated in this context. The researchers wanted to determine if the UK National Screening Committee’s 2005 and 2007 targets for detection and false-positive rates were achievable using current screening methods. They aimed to provide evidence to guide local screening practices in light of national benchmarks. The study was designed to inform clinical decision-making by comparing the effectiveness of different screening strategies.

The researchers conducted a retrospective analysis of 1000 control pregnancies and 128 affected pregnancies. They evaluated the detection rates and false-positive rates for the double, triple, and quadruple marker tests. The study used a cut-off of 1 in 250 for risk assessment. The performance of the inhibin-A assay was assessed for precision and drift. They measured intrabatch percent coefficient of variation to evaluate assay variability. The team compared detection rates across the three test combinations. They also analyzed false-positive rates to determine consistency between test types. The study included a review of the UK National Screening Committee’s benchmark program to contextualize findings.

At a cut-off of 1 in 250, the quadruple test achieved a detection rate of 72%. The triple test had a detection rate of 70%, and the double test reached 63%. All three tests had false-positive rates between 6.6% and 7.0%. The inhibin-A assay showed significant within-batch imprecision, with an intrabatch percent coefficient of variation of 17%. The assay drift was considered too high for reliable screening use. The researchers found no significant differences in false-positive rates across test types. The 2005 NSC target of 60% detection with less than 5% false positives was achievable using triple testing. The 2007 target of 75% detection with less than 3% false positives was not met using current methods.

The researchers suggest that the 2005 NSC benchmark for Down's syndrome screening is achievable using triple testing in the second trimester. They propose that universal scan dating can help meet this target. The 2007 target of 75% detection with less than 3% false positives is unachievable with current screening methods. The inhibin-A assay is not recommended due to poor performance in precision and drift. The team concludes that the current quadruple test does not significantly improve detection rates over the triple test. They emphasize that assay reliability is essential for effective screening. Their findings support the use of triple testing as a practical and reliable method. The study highlights the need for improved assays to meet future screening targets.