PRENATAL DIAGNOSIS Prenat Diagn 2007; 27: 611–615. Published online 30 April 2007 in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/pd.1750 ADAM 12 as a second-trimester maternal serum marker in screening for Down syndrome Michael Christiansen 1 , Kevin Spencer 2 *, Jennie Laigaard 1,3 , Nicholas J. Cowans 2 , Severin Olesen Larsen 1 and Ulla M. Wewer 3 1 Department of Clinical Biochemistry, Statens Serum Institut, Copenhagen, Denmark 2 Prenatal Screening Unit, Clinical Biochemistry Department, Harold Wood Hospital, Romford, UK 3 Institute of Molecular Pathology, University of Copenhagen, Denmark Background ADAM 12 is a placenta-derived glycoprotein that is involved in growth and differentiation. The maternal serum concentration of ADAM 12 is a potential first-trimester maternal serum marker of Down syndrome (DS). Here we examine the potential of ADAM 12 as a second-trimester maternal serum marker of DS. Materials and Methods The concentration of ADAM 12 was determined in gestational week 14–19 in 88 DS pregnancies and 341 matched control pregnancies. Medians of normal pregnancies were established by polynomial regression and the distribution of log 10 MoM ADAM 12 values in DS pregnancies and controls determined. Correlations with alpha-fetoprotein (AFP) and free β -human chorionic gonadotrophin (free β -hCG) were established and used to model the performance of maternal serum screening with ADAM 12 in combination with other second-trimester serum markers. Results The ADAM 12 maternal serum concentration was significantly increased with a median MoM of 1.85 and a mean log 10 MoM (SD) of 0.268 (0.2678) compared to a mean log 10 MoM (SD) of 0.013 (0.4318) in controls. ADAM 12 correlated with maternal weight and ethnicity (with the serum concentration increased in Afro-Caribbeans), but neither with maternal age nor gestational age, and only marginally with AFP (r (DS) = 0.078, r (controls) = 0.093) and free β -hCG (r (DS) = 0.073, r (controls) = 0.144. The increase in detection rate—for a false positive rate of 5%—by adding ADAM 12 to the double test (AFP + free β -hCG) was 4%, similar to that of adding uE3 to the double test. Conclusion ADAM 12 is an efficient second-trimester marker for DS. Further studies should be conducted to determine whether it may be a useful additonal or alternative marker to those currently used in the second- trimester. Copyright  2007 John Wiley & Sons, Ltd. KEY WORDS: prenatal screening; PAPP-A; free β -hCG; growth factors; integrins; ADAM12; aneuploidy; trisomy 21 INTRODUCTION Maternal serum screening for chromosomal disorders in the second-trimester is a well established technique (Benn, 2002) and is commonly offered either as the triple test (employing the markers alpha-fetoprotein (AFP), total human chorionic gonadotrophin (hCG) or the free β -form of hCG (free β -hCG) and unconjugated estriol (uE3)) or the quadruple test where the triple test is supplemented with inhibin A (Benn et al., 2003). Second-trimester markers are also offered as part of integrated screening (Wald et al., 1999a) and contingent (Christiansen and Larsen, 2002; Benn et al., 2005) and sequential screening programes (Benn, 2002; Benn et al., 2005). The identification of new second-trimester markers will make it possible to reduce the false positive rate of screening, and thus, the number of invasive procedures associated with a 1% risk of aborting an otherwise healthy fetus (Tabor et al., 1986). *Correspondence to: Kevin Spencer, Department of Clinical Bio- chemistry, King George Hospital, Barley Lane, Goodmayes IG4 8YB, UK. E-mail: KevinSpencer1@aol.com The short and secreted spliceform of ADAM 12—A D isintegrin A nd M etalloprotease 12-S (Gilpin et al., 1998) (in brief ADAM 12)—is a glycoprotein synthe- sized by the placenta (Gilpin et al., 1998; Shi et al., 2000) and found in increasing concentration in mater- nal serum through gestation (Laigaard et al., 2003). ADAM 12 has proteolytic activity against insulin-like growth factor binding proteins 3 (IGFBP-3) (Shi et al., 2000) and insulin-like growth factor binding proteins 5 (IGFBP-5) (Loechel et al., 2000) and is probably respon- sible for at least part of the increased IGFBP-3 and IGFBP-5 protease activity seen in pregnancy (Giudice et al., 1990; Hossenlopp et al., 1990). ADAM 12 is involved in cell adhesion (Huang et al., 2005), myogenic and adipogenic transformation (Kawaguchi et al., 2003; Lafuste et al., 2005; Yi et al., 2005), apoptosis (Kvei- borg et al., 2005), and cell fusion, and modulation of the local effect, and bioavailability of IGF-I and IGF-II, and other growth factors (Rosenfeld and Roberts, 1999). ADAM 12 is probably of importance for placental and fetal growth. A reduced first-trimester maternal serum level of ADAM 12 has been described in pregnancies with fetuses with Down (Laigaard et al., 2003; 2006a,b) and Copyright  2007 John Wiley & Sons, Ltd. Received: 26 January 2007 Revised: 13 March 2007 Accepted: 20 March 2007 Published online: 30 April 2007