ADAM12 as a marker of trisomy 18 in the first and second trimester of pregnancy.
BACKGROUND
ADAM12 (a disintegrin and metalloprotease 12) is a placentally derived glycoprotein that appears to be involved in growth and differentiation. The maternal serum concentration of ADAM12 appears to be a very good marker of trisomy 21 in the early first trimester when levels are reduced, and in the second trimester around 16-18 weeks levels are elevated. One small preliminary study of first trimester pregnancies with trisomy 18 found reduced levels in the maternal serum, and we examine herein the potential of ADAM12 as a marker of trisomy 18 in both the first and second trimester of pregnancy.


METHODS
The concentration of ADAM12 was determined by a time-resolved immunofluorometric assay in 132 first and 12 second trimester cases of trisomy 18, and 389 first and 341 second trimester gestational age-matched control pregnancies. Medians of normal pregnancies were established by polynomial regression and used to determine the population distribution parameters for the trisomy 18 and control groups. Correlation with previously established pregnancy-associated plasma protein-A (PAPP-A) and free beta-human chorionic gonadotropin (beta-hCG) multiples of the median (MoMs) and nuchal translucency thickness (NT) MoM were determined and used to model the performance of first trimester screening with ADAM12 in combination with other first trimester markers.


RESULTS
The maternal serum concentration of ADAM12 in the first trimester was significantly reduced with a median MoM of 0.829 (p < 0.001) and a mean log10 MoM SD of 0.2663 compared to 0.3353 in the controls. In the second trimester small series ADAM12 was significantly increased with a median MoM of 2.09 (p = 0.001) and a mean log10 MoM SD of 0.2607 compared to 0.4318 in controls. There was a significant correlation of ADAM12 MoM with gestational age (r = 0.510) in trisomy 18 cases, and the median MoM increased from 0.51 at 10 weeks to 1.28 at 13 weeks and 2.09 across the 14-18 week window. ADAM12 was correlated with PAPP-A (r = 0.1918) in the first trimester of cases with trisomy 18 but less so with NT (r = 0.1594) and free beta-hCG (r = 0.0938). Modeled detection rates incorporating ADAM12, free beta-hCG, and NT were 92% at 1% false positive rate (88% at 0.5%) A combination of all four markers had a detection rate of 96.5% at a false positive rate of 1% (95% at 0.5%).


CONCLUSIONS
ADAM12 may be a useful addition to early screening for trisomy 18 alongside other chromosomal anomalies, particularly if biochemical screening can occur before 10 weeks.
Spencer
Kevin
K
Prenatal Screening Unit, Clinical Biochemistry Department, Harold Wood Hospital, Romford, UK. KevinSpencer1@aol.com
Cowans
Nicholas J
NJ
D051722:ADAM Proteins / Q000097:blood* / Q000235:genetics; D000072199:ADAM12 Protein; D015415:Biomarkers / Q000097:blood*; D002887:Chromosomes, Human, Pair 18; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000097:blood* / Q000235:genetics; D011247:Pregnancy; D011262:Pregnancy Trimester, Second / Q000097:blood* / Q000235:genetics*; D011296:Prenatal Diagnosis; D014314:Trisomy / Q000235:genetics*
D015415:Biomarkers; D008565:Membrane Proteins; D051722:ADAM Proteins; D000072199:ADAM12 Protein; C000606480:ADAM12 protein, human