Repeated measurement of pregnancy-associated plasma protein-A (PAPP-A) in Down syndrome screening: a validation study.

Objectives: To confirm that measuring pregnancy-associated plasma protein-A (PAPP-A) in both first- and second-trimester serum samples improves Down syndrome screening.

Methods: We selected paired first- and second-trimester stored serum samples from 34 Down syndrome pregnancies (cases) and 514 unaffected pregnancies (controls) and tested the second-trimester samples for PAPP-A and dimeric inhibin-A (DIA). First-trimester PAPP-A measurements were already available, as were second-trimester measurements of alpha-fetoprotein, unconjugated estriol (uE3), and human chorionic gonadotrophin (hCG).

Results: PAPP-A was lower among cases than controls (0.47 MoM) in the first trimester (at an average of 12.5 weeks); in the second trimester, it was not different (0.91 MoM). Using repeated measures of PAPP-A alone, 21 of 34 cases were detected (62%, 95%CI 44% to 78%) with 5% false positives. At an observed 2% false-positive rate, the detection rates (DR) for the quadruple (69%) and serum integrated (69%) tests were lower than for the repeated measures test (75%). Modelled performance at 12 weeks was similar to these observed findings (70, 75, and 82%, respectively). If the first-trimester samples were collected at 10 weeks, however, DR would be higher (70, 81, and 91%, respectively).

Conclusions: Adding a repeated measure of PAPP-A to existing serum markers improves Down syndrome screening to levels that are currently obtainable only by including ultrasound measurement of nuchal translucency (NT). Serum-based screening has the advantages of higher availability and reliability at a lower cost, resulting in a more effective screening strategy. A serum-based repeated measures test has a place in routine Down syndrome screening.