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

• Published in: Prenatal diagnosis 2006-10, Vol.26 (10), p.973-979
• Main Authors: Laigaard, Jennie, Spencer, Kevin, Christiansen, Michael, Cowans, Nicholas J., Larsen, Severin Olesen, Pedersen, Bent Norgaard, Wewer, Ulla M.
• Format: Article
• Language: English
• Subjects: ADAM 12; ADAM Proteins - blood; ADAM12 Protein; aneuploidy; Biological and medical sciences; Biomarkers - blood; Chorionic Gonadotropin, beta Subunit, Human - blood; Chromosome aberrations; Disintegrins - blood; Down Syndrome - diagnosis; Female; free β-hCG; Gestational Age; growth factors; Gynecology. Andrology. Obstetrics; Humans; Management. Prenatal diagnosis; Medical genetics; Medical sciences; Membrane Proteins - blood; Normal Distribution; PAPP-A; Placenta - metabolism; Pregnancy; Pregnancy Trimester, First; Pregnancy-Associated Plasma Protein-A - analysis; Pregnancy. Fetus. Placenta; prenatal screening; trisomy 21
• ISSN: 0197-3851; 1097-0223
• DOI: 10.1002/pd.1540

Background A Disintegrin And Metalloprotease 12 (ADAM 12) is a glycoprotein synthesised by placenta and it has been shown to be a potential first‐trimester maternal serum marker for Down syndrome (DS) in two small series. Here we analyse further, the potential of ADAM 12 as a marker for DS in a large collection of first‐trimester serum samples. Materials and Methods The concentration of ADAM 12 was determined in 10–14‐week pregnancy sera from 218 DS pregnancies and 389 gestational age‐matched control pregnancies, which had been collected as part of routine prospective first‐trimester screening programs (DS = 105) or as part of previous research studies (DS = 113). ADAM 12 was measured using a semi‐automated time resolved immunofluorometric assay and median values for normal pregnancies were established by polynomial regression. These medians were then used to determine population distribution parameters for DS and normal pregnancy groups. Correlation with previously established PAPP‐A and free β‐hCG multiple of the medians (MoMs) and delta nuchal translucency (NT) were determined and used to model the performance of first‐trimester screening with ADAM 12 in combination with other first‐trimester markers at various time periods across the first trimester. The benefits of a contingent testing model incorporating early measurement of PAPP‐A and ADAM 12 were also explored. Results The maternal serum concentration of ADAM 12 was significantly reduced (p = 0.0049) with an overall median MoM of 0.79 in the DS cases and a log10 MoM SD of 0.3734 in the DS cases and 0.3353 in the controls. There was a significant correlation of ADAM 12 MoM in DS cases with gestational age (r = 0.375) and the median MoM increased from 0.50 at 10–11 weeks to 1.38 at 13 weeks. ADAM 12 was correlated with maternal weight (r(controls) = 0.283), PAPP‐A (r(controls) = 0.324, r(DS) = 0.251) but less so with free β‐hCG (r(controls) = 0.062, r(DS) = 0.049) and delta NT (r(controls) = 0.110, r(DS) = 0.151). ADAM 12 was significantly (p = 0.026) lower in smokers (0.87 vs 1.00) and elevated in Afro‐Caribbean women compared to Caucasian women (1.34 vs 1.00). Population modelling using parameters from this and an earlier study showed that a combination of ADAM 12 and PAPP‐A measured at 8–9 weeks and combined with NT and free β‐hCG measured at 12 weeks could achieve a detection rate of 97% at a 5% false‐positive rate or 89% at a 1% false‐positive rate. PAPP‐A and ADAM 12 alone at 8–9 weeks could id