Total pregnancy‐associated plasma protein A—a first trimester maternal serum marker for Down's syndrome: clinical and technical assessment of a poly‐monoclonal enzyme immunoassay

Abstract

Pregnancy-associated plasma protein A (PAPP-A) is a maternal serum marker of fetal chromosomal disease and a risk marker for adverse outcome. PAPP-A in the circulation exists both as a 2:2 complex (PAPP-A/proMBP) with the proform of eosinophil major basic protein (proMBP) and as dimeric PAPP-A. Non-PAPP-A containing proMBP complexes constitute the bulk of proMBP in maternal serum. We developed and characterized a sandwich enzyme immunoassay for PAPP-A using a polyclonal rabbit anti-PAPP-A/proMBP antibody (SSI 6823) and a monoclonal murine anti-PAPP-A/proMBP antibody (HYB 234-3), reactive with the PAPP-A part of PAPP-A/proMBP. The assay range was 2 mIU/L-500 mIU/L, intra- and inter-assay coefficients of variation <10%. The immunoreactivity eluted ahead of thyroglobulin, Mr 669 kDa, in gel filtration and bound to a heparin column. Serum concentrations of PAPP-A were determined in gestational weeks 5-13 in 167 pregnant women with normal fetuses and 39 women with Down's syndrome (DS) fetuses. The median PAPP-A MoM (multiples of the median in normal controls) in DS pregnancies was 0.30 (quartile range: 0.17-0.54). The PAPP-A logMoMs in DS pregnancies were normally distributed with a mean of -0.5927 and SD of 0.3639. When simulating the performance of PAPP-A and age as markers for DS in population screening a detection rate (DR) of 62% was found for a screen positive rate (SPR) of 5%. Together with beta-HCG and nuchal translucency, two other first trimester markers for fetal DS, a DR 90% could be obtained for an SPR of 5%.

Screening for fetal trisomy 21 in gestational weeks 6 and 7

“…As previously shown, free β‐hCG has the best discriminative ability after 10 weeks gestation (4,5,9). Our findings are consistent with results from a previous study (10). This study only covered PAPP‐A and not free β‐hCG, and showed a PAPP‐A median MoM for fetal T21 affected pregnancies of 0.27 (range: 0.2–0.55) in weeks 6–8 compared to 0.33 (0.01–1.03) in weeks 9–12.…”

ADAM 12 as a first‐trimester maternal serum marker in screening for Down syndrome

“…However, ADAM 12 has the best discriminatory efficiency early in the first trimester ( Table 2). In that respect, the marker behaves in a manner similar to PAPP-A (Spencer et al, 2002(Spencer et al, , 2003dChristiansen and Jaliashvili, 2003), ProMBP (Christiansen et al, 1999(Christiansen et al, , 2004 and SP1 (Qin et al, 1997).…”

Improved first‐trimester Down syndrome screening performance by lowering the false‐positive rate: a prospective study of 9941 low‐risk women

“…Analyses for PAPP‐A and β‐hCG were performed prospectively during the study period in small batches without knowledge of the clinical data, and were not acted upon. Maternal serum PAPP‐A was determined by an in‐house manual enzyme‐linked immunoassay technique using a polyclonal–monoclonal sandwich assay29. Maternal free β‐hCG was determined using the AFP/β‐hCG AutoDelfia ™ kit (EG&G Life Sciences, Turku, Finland).…”