解整合素金属蛋白酶12分泌型在中孕期唐氏综合征胎儿筛查中的应用研究

Second trimester screening for trisomy 21 using ADAM12-S as a maternal serum marker

目的探讨解整合素金属蛋白酶12分泌型（adisintegrinandmetalloprotease12secreting-form，ADAM12-S）在中孕期筛查唐氏综合征（Downsyndrome，DS）胎儿的应用价值和适宜的筛查方案。方法应用时间分辨荧光免疫法检测参与中孕期筛查的53名DS胎儿和621名孕龄和体重匹配的正常新生儿孕母血清样本的ADAM12-S水平，通过加权回归曲线拟合等统计学处理，选择最佳筛查模型，建立ADAM12-S筛查DS胎儿的方法，并分析ADAM12-S单独或联合中孕期二联筛查方案的检出率及假阳性率。结果DS妊娠组的ADAM12-S中位数倍数（multipleofthemedian，MoM）的中位数水平要高于正常妊娠对照组（P〈0．01）。在5％的筛查假阳性率时，ADAM12-S筛查的检出率为28．3％，其阳性似然比为5．66，阴性似然比为0．75。采用三联筛查方案（ADAM12-S＋血清甲胎蛋白＋游离伊绒毛膜促性腺激素）可将检出率从二联筛查方案（血清甲胎蛋白＋游离β绒毛膜促性腺激素）的39．62％提高到52．80％；对于在二联筛查风险率在1／3001／1000的孕妇，进一步用ADAM12-S进行酌情筛查可将检出率从39．62％提高到47．12％，而假阳性率仅从5％增加到5．8％。结论ADAM12-S是中孕期筛查DS妊娠的一个有效标记物。对中孕期二联筛查风险率在1／300～1／1000的孕妇采用ADAM12-S进行酌情筛查有更高的费效比。

Objective To investigate the value of a disintegrin and metalloproteinase 12 secreting form （ADAM12-S） as a maternal serum marker in second trimester screening for trisomy 21 （Down syndrome, DS）, and to develop an appropriate prenatal DS screening protocol. Methods Serum samples were collected from 53 pregnant women carrying a trisomy 21 fetus and 621 pregnant women with matched gestational age and weight carrying a healthy fetus. ADAM12-S concentrations were determined with a time-resolved fluorescence immunoassay （TRFIA）. Curve fitting by weighted regression and other statistical methods were conducted, and the model was optimized for prenatal trisomy 21 screening program in second trimester. ADAM12-S alone or in combination with other two-or three-combination test was selected as a serum marker for prenatal second-trimester screening of trisomy 21 by calculation of detection rate （DR） and false positive rate （FPR）. Results By comparison, the median multiple of the median （MoM） value of ADAM12-S in DS pregnancy group was higher than that of the control group （P〈0.01）. When FPR= 50%, the DR of ADAM12-S was 28. 3%, and the positive and negative likelihood ratios were 5. 66 and 0. 75, respectively. The DR of three-combination test of ADAM12-S, alpha fetoprotein（AFP） and free beta subunit of human chorionic gonadotropin （I3-HCG） has increased to 52. 80% from 39. 62% of the conventional two-combination test （AFP and free β-HCG）. For women with a risk between 1/300 and 1/ 1000 by two-combination test for DS, the DR has increased from 39. 62% to 47. 12%, but FPR only increased by 0. 8% after adding ADAM12-S as a maternal serum marker. Conclusion Considering the increased DR of pregnancies with a risk between 1/300 and 1/1000 in second trimester, ADAM12-S may provide a feasible maternal serum maker when combined with AFP and free β-hCG. The cost-effectiveness ratio is reasonable.