解整合素金属蛋白酶12在产前诊断唐氏综合征中应用的研究
|
摘要
第一部分高龄孕妇中孕期血清学产前筛查价值探讨
1研究背景
唐氏综合征(Down syndrome, DS)在活产新生儿中的发生率为1/600-1/800,是最常见的一种染色体病。以智力低下、发育迟缓和特殊的多发小畸形为主要表现,由于缺乏有效地治疗措施,这种患儿出生后将会给家庭和社会带来沉重的经济和精神负担,通过产前诊断和选择性人工流产来减少患儿的出生是目前国内外较好的预防措施。细胞遗传学产前诊断是确诊胎儿患有唐氏综合征或其它染色体疾病的方法,但因为需要介入性手术取材和检测成本高昂,仅适用于高风险孕妇。血清学产前筛查具有无创、快捷、服务成本相对低廉的优点,可以从接受筛查的人群中发现唐氏综合征高风险的孕妇,已被广大孕妇所接受。当筛查结果出现高风险阳性时,即建议进行羊膜腔穿刺,采集羊水进行胎儿细胞的染色体核型分析以明确诊断。产前筛查常用的血清标记物有妊娠相关血浆蛋白(PAPP-A)、甲胎蛋白(AFP)、人绒毛膜促性腺激素β亚基(β-hCG)、游离雌三醇(uE3)、抑制素A (Inhibin-A)等,多项血清标志物联合,结合孕妇的年龄、体重等参数计算胎儿患唐氏综合征风险的产前筛查方法有很多。基于我国国情和筛查方案的社会成本效益,目前国内主要采用中孕期二联筛查(AFP+freeβ-hCG)或三联筛查(AFP+freeβ-hCG+uE3),我们产前诊断中心采用的是中孕期二联筛查(AFP+freeβ-hCG)方案。随着社会经济发展进步,高龄孕妇正逐渐成为庞大的一个受人关注的群体。由于唐氏综合征的发病率与年龄明显相关,因此国内外很多协会和组织都在产前诊断的适应症中规定有年龄大于35岁的高龄孕妇,即只要怀孕妇女属于高龄范畴,都被建议直接进行羊膜腔穿刺和染色体核型分析。近年国际上有学者提出应改变将高龄孕妇作为羊膜腔穿刺常规的观念。
我们对中孕期二联筛查方案筛查效果以及对于高龄孕妇中孕期产前筛查的价值进行研究,以期探索和完善符合我国国情的有效的产前筛查策略,提高唐氏综合征及其它染色体异常患儿的检出率。
2研究目的
2.1回顾性分析唐氏综合征二联产前筛查工作效果；
2.1对高龄孕妇中孕期血清学产前筛查的价值进行研究。
3研究方法
方法：用时间分辨荧光免疫分析技术测定对孕15+0-20+6周的孕妇进行血清学筛查,筛查标记物为甲胎蛋白(AFP)、游离绒毛膜促性腺激素p亚基(freeβ-hCG),应用Multi-cal软件计算唐氏综合征风险,风险切割值(cut off)为1/270,高风险者建议其进行侵入即羊膜腔穿刺行羊水细胞染色体检查以确诊。随访孕妇的妊娠结局,计算血清学二联筛查的检出率,假阳性率,阳性预测值。
4结果
妊娠中期血清学二联筛查对胎儿唐氏综合征的检出率为85.21%(98/115),假阳性率为3.41%(3218/94307),阳性预测值为2.96%(98/3316)。高龄组检出唐氏综合征3例,发病率为(0.16%,3/1886)是低龄组(0.12%,112/92519)的1.33倍,两组比较,差异显著(p<0.05)。高龄组的检出率为100%(3/3),假阳性率为8.13%(153/1883),阳性预测值为1.92%(3/156)；低龄组中共有112例唐氏综合征,17例为假阴性,检出率为84.8%(95/112),假阳性率为3.32%(3065/92407),阳性预测值为3.01%(95/3160),高龄组与低龄组两者之间假阳性率差别明显,p<0.05。
5结论
二联血清学筛查检出率偏低,且筛查不等同于确诊,假阴性病例的出现不可完全避免,对所有采用胎儿唐氏综合征的妊娠中期血清学二联产前筛查孕妇的筛查后遗传咨询和确诊不容忽视。对于高龄孕妇,血清学筛查仍是有效筛查手段,故对高龄产妇应采取个体化胎儿唐氏综合征筛查和诊断策略,可降低侵入性产前诊断比例和风险。
6创新点
我们在长期原始数据积累和大样本统计分析的基础上,明确提出高龄孕妇产前诊断策略—血清学筛查仍是有效筛查手段。
第二部分解整合素金属蛋白酶12在中孕期产前诊断唐氏综合征中的应用
1研究背景
近几年产前筛查在产科领域发展迅速。产前筛查要求经济、简便、无创以及尽早应用。产前筛查常用的血清标记物有妊娠相关血浆蛋白(PAPP-A)、甲胎蛋白(AFP)、人绒毛膜促性腺激素β亚基(β-hCG)、游离雌三醇(uE3)、抑制素A(Inhibin-A)等。解整合素金属蛋白酶12(ADAM12)是新近发现的一个血清标志物,是一种与组织生长发育相关的蛋白,具有良好的妊娠特异性,国内外研究报道ADAM 12为高效的早孕期筛查唐氏综合征血清标志物,但将ADAM 12应用于中孕期产前筛查的相关研究较少。我国产前筛查工作起步较晚,目前在我国开展的产前筛查模式是中孕期血清学二联或三联筛查,结合年龄、体重等来评估孕妇孕有唐氏患儿的风险大小,而早孕筛查模式尚未被广泛接受及采用,因此,探讨ADAM 12在孕中期产前筛查胎儿唐氏综合征中的应用价值更为符合中国国情,为进一步提高产前筛查的检出率提供优化方案。
2研究目的
2.1研究中孕期ADAM 12在孕有唐氏综合征胎儿的孕妇血清中的变化规律。
2.2探讨ADAM 12在孕中期产前筛查胎儿唐氏综合征中的应用价值。
3方法
经染色体核型分析证实为唐氏综合征胎儿的孕妇静脉血血清样本共46例为研究组(24例为假阴性),随机选择同期经随访证实为正常新生儿孕妇静脉血血清样本184份为对照组(35例为假阳性),用时间分辨荧光免疫分析技术测定两组孕妇血清ADAM12浓度,比较ADAM12的MoM值在上述两组妊娠妇女外周血中的水平的变化,同时对ADAM12与其他血清标志物之间的相关性进行了研究。
4结果
从孕15+0周到19+6周,正常中孕期妊娠妇女血清ADAM12水平逐渐升高,其平均MoM值为1.0,唐氏综合征胎儿孕妇血清ADAM12的平均MoM值为1.26,两者之间差异有统计学意义。如果将ADAM12加入筛查方案,则检出率从48%上升到85%,同时可降低假阳性率和假阴性率。
5结论
ADAM12是中孕期唐氏综合征产前筛查的一个有效的血清学指标。
6创新点
将ADAM12应用于中孕期唐氏综合征产前诊断,建立中国人群ADAM12的参考值范围。对于ADAM12在提高检出率,降低假阳性率方面进行了研究,尤其是在假阴性病例中的研究国内鲜有报道。该部分研究结果已以论文形式正式发表于SCI收录期刊。
第三部分解整合素金属蛋白酶12在早孕期和中孕期产前筛查唐氏综合征中与其他血清标志物相关性的研究
1研究背景
通过产前筛查发现唐氏综合征高风险孕妇,结合产前诊断,对确诊为唐氏综合征妊娠孕妇尽可能早的终止妊娠,最大程度地降低妊娠唐氏综合征胎儿家庭的精神负担,因此越早进行产前筛查越好。唐氏综合征早孕期筛查是可行的、有效的,欧美等西方发达国家已开始普及。基于我国国情和筛查方案的社会成本效益,目前国内主要采用中孕期二联筛查(AFP+freeβ-hCG)或三联筛查(AFP+freeβ-hCG+uE3),筛查效率偏低。随着我国经济技术水平的提高,对早孕期筛查的需求将越来越迫切。早孕期产前筛查在我国刚刚起步,因为可以更早的检出唐氏综合征胎儿无疑是今后唐氏综合征产前筛查工作的发展趋势。
目前用于早孕和中孕期产前筛查的血清学标志物有妊娠相关血浆蛋白(PAPP-A)、甲胎蛋白(AFP)、人绒毛膜促性腺激素β亚基(β-hCG)、游离雌三醇(uE3)、抑制素A(Inhibin-A)等,筛查方案有早孕期筛查(first trimester screening)和中孕期筛查(second trimester screening),筛查模式多样：二联(AFP+freeβ-hCG)筛查、三联(AFP+freeβ-hCG+uE3)筛查和四联(AFP+freeβ-hCG+uE3+inh A)筛查,独立的序贯筛查(independent sequential screening)、酌情的序贯筛查(contingent sequential screening)以及结合早、中孕期筛查的联合筛查(integrated screening)等,筛查方案的发展趋势是个体化筛查及酎情筛查。为了提高产前筛查的效率,提高检出率,降低阳性率,尽可能避免假阴性病例的出现,人们在不断寻找新的更为有效的血清学筛查指标,不断优化产前筛查方案。
解整合素金属蛋白酶12(ADAM12)是新近发现的一个高效的产前筛查血清标志物,有望提高唐氏综合征的产前筛查效率。对ADAM12在早孕期和中孕期产前筛查唐氏综合征中与其他血清标志物相关性的研究,探讨ADAM12在产前筛查中的作用,以期优化现行产前筛查方案。
2研究目的
探索中国早孕期和中孕期正常单胎孕妇血清中ADAM12和freeβ-hCG、PAPP-A以及AFP水平的变化规律及相关性,为优化中国孕妇唐氏综合征血清学产前筛查方案提供理论依据。
3方法
早孕期(孕9+0-13+6周)单胎孕妇339例,中孕期(15+0-20+6)单胎孕妇1104例,用时间分辨荧光免疫分析技术测定孕妇血清ADAM12和freeβ-hCG、PAPP-A以及AFP的水平,统计分析ADAM 12与体重、孕周的关系及与其它血清标志物之间的相关性。
4结果
早孕期339例单胎妊娠中未检出唐氏综合征胎儿,中孕期胎儿染色体核型证实为唐氏综合征的妊娠妇女22例。ADAM12在正常单胎早孕期妊娠妇女血清中ADAM12与PAPP-A之间有显著性相关,与freeβ-hCG之间无相关性。在中孕期正常妊娠妇女血清中,ADAM12与孕周和孕妇体重之间均存在相关性(p均<0.05)。ADAM12与AFP之间相关性有统计学意义,而与freeβ-hCG之间无显著性相关。在胎儿为唐氏综合征的中孕期妊娠妇女血清中,ADAM 12的水平较正常妊娠妇女明显升高,其ADAM12MoM约为正常中孕妇女ADAM12MoM值的1.2倍,二者之间差异有统计学意义。
5结论
我国人群孕妇血清中ADAM12水平随孕周的增加而增高,胎儿为唐氏综合征的中孕期妊娠妇女ADAM12MoM约为正常中孕妇女ADAM12MoM值的1.2倍,二者之间差异有统计学意义。ADAM12与PAPP-A及AFP有相关性,与freeβ-hCG相关性无统计学意义。ADAM12是中孕期产前筛查唐氏综合征的一个有效指标。ADAM12与其他血清标志物之间存在相关性,因此对ADAM12在早孕期和中孕期唐氏综合征产前筛查中的特异性和灵敏度还有待于进一步研究。
6创新点
通过对早、中孕期孕妇血清ADAM12变化趋势的研究,建立了ADAM12在我国人群产前筛查中的参考范围。通过ADAM12在中孕期产前筛查唐氏综合征中的研究认为ADAM12是有效的中孕期产前筛查血清学筛查指标。通过ADAM12与其他血清标志物相关性的研究对ADAM12用于产前筛查的特异性进行了探讨。
第四部分解整合素金属蛋白酶12在中孕期正常双胎妊娠中应用的研究
1研究背景
近年来随着辅助生育技术的开展及妇女生育年龄后延,双胎妊娠发生率呈现升高趋势。双胎妊娠中至少一胎为染色体异常的发生率较同年龄组单胎妊娠高,但对于双胎妊娠进行产前筛查尚未在临床中正式开展,这是由于双胎妊娠的复杂性使得现有的血清学产前筛查方案在双胎妊娠中的应用价值一直备受争议。自从有研究首次报道ADAM12在早孕期妊娠妇女血清中显著降低以来,人们对于ADAM12应用于产前筛查给予了极大的关注。之前的研究表明,ADAM12可用于早孕期的单、双胎产前筛查,在中孕期的单胎妊娠的产前筛查中ADAM12的价值也得到肯定,但对于在中孕期双胎妊娠中应用ADAM12进行产前筛查目前尚无报道。我国产前筛查工作起步较晚,筛查模式较为单一,主要是中孕期二联或三联筛查,对于双胎妊娠孕妇中孕期血清学筛查的资料很少,缺乏大样本系统研究。
2研究目的
2.1探讨双胎妊娠中孕期孕妇血清ADAM12变化规律,建立中国人群中孕期双胎妊娠妇女ADAM12水平的正常参考范围；
2.2比较双胎妊娠孕妇与正常单胎妊娠妇女血清ADAM12水平之间的差异,对ADAM12在双胎妊娠产前筛查中的作用进行探讨。
3方法
收集孕15+0-19+6周正常双胎妊娠孕妇306例为研究组,随机选择同时期正常单胎妊娠孕妇932例作为对照组；用时间分辨荧光免疫分析技术测定两组孕妇血清freeβ-hCG、AFP和ADAM12浓度,观察中孕期双胎妊娠和单胎妊娠孕妇上述血清标志物的变化特点,比较两组间ADAM12水平差异。
4结果
所有病例经随访确定为非唐氏综合征妊娠。双胎中有31例是应用各种辅助生育技术后受孕,其余为自然受孕,其ADAM12的水平范围是465.69-1616.72ng/ml。双胎孕妇ADAM12MoM的中位数值约为1.33,而单胎的为1.0,二者之间差异有统计学意义。在单胎妊娠中ADAM1 2与AFP显著相关,与freeβ-hCG无显著相关,在双胎妊娠中ADAM12与AFP和freeβ-hCG皆无显著相关。
5结论
我们建立了正常中孕双胎ADAM12的参考范围465.69-1616.72ng/mL。双胎的ADAM12MoM较单胎升高,是单胎的1.33倍。ADAM12在双胎妊娠的产前筛查中是一个有效的血清学指标。
6创新点
双胎妊娠产前筛查目前尚未列入常规,这主要是现行的二联筛查方案不适于双胎妊娠的DS血清学产前筛查。ADAM12用于唐氏综合征产前筛查的研究方兴未艾,我们将ADAM12用于双胎妊娠中孕期产前筛查的研究更是走在世界的前列。
Chapter One Assessment of the value of maternal serum screening of Down syndrome for women with advanced maternal age
1 Background
Down syndrome (DS) is the most common cause of severe mental retardation in children. The rate of Down syndrome for live births is between 1/600～1/800. It is the result of trisomy of chromosome 21 which is usually a random event though it is commoner in older mothers. Such children will be a heavy financial and emotional burden for the family and society because of lacking effective treatment measures. Down syndrome can be diagnosed by chorionic villus sampling (CVS) and amniocentesis followed by karyotyping. Because of the risks associated with these invasive procedures, they can only be offered to a high-risk pregnant women. Non-invasive biochemical screening for Down syndrome is well established in the second trimester of pregnancy. Second-trimester screening traditionally consists of some combination of maternal serum analysis and maternal age. Screening programmes in Mainland of China involving the measurement of maternal serum alpha-fetoprotein (AFP), human chorionic gonadotropin (hCG) with or without unconjugated estriol (uE3)(double/triple screening test). Taking into account of the actual situation of economy & technology and the cost-effectiveness of program, We used double-screening (AFP+free P-hCG) test in our prenatal diagnosis center between the 14 to 20 weeks of gestation. Diagnostic amniocentesis was performed as routain in women over 35 years and in women with a previous affected child, but recently, some scholars proposed such opinion that amniocentesis may be offered on a selective rather than routine basis in women w ith advanced maternal age.
We had evaluated the double-screening programs in the second trimester, assessed the value of maternal serum screening (MSS) of Down syndrome for women with advanced maternal age (AMA, over 35 years) and tried to lessen the rate of amniocentesis.
2 Objectives
2.1 To evaluated the double-screening programs in the second trimester in our prenatal diagnosis center for Down syndrome.
2.2 To assess the value of maternal serum screening (MSS) of Down syndrome for women with advanced maternal age (AMA, over 35 years)in the second trimester.
3 Methods
From June 2004 to December 2009, pregnant women between 15+0 and 20-6 weeks of gestation, who received prenatal screening for Down syndrome in the Women's Hospital, College of Medicine, Zhejiang University were retrospectively analyzed. Levels of freeβ-hCG and AFP were measured by commercial time-resolved fluoroimmunoassay. Statistical analysis was performed using SPSS 16.0 software to evaluate the relationship between each serum marker and weight, gestational age, and the correlations between markers were analyzed too.
Down syndrome risk of each pregnancy was calculated by computer software. Screening positive pregnant women were offered genetic counseling and the option of amniocentesis and cordocentesis. The detection rate (DR), false positive rate (FPR), positive predictive value were calculated.
4 Results
In our study, there were 94405 pregnant women were tested, at a cut-off value of 1 in 270,3316 cases have positive results, in which 156 positive results belong to 1886 cases of women with advanced maternal age (AMA, over 35 years). The total positive MSS rate of Down is 3.5%,98 neonates were diagnosed as Down syndrome by amniocentesis, only 3 cases of Down syndrome was AMA. Other 17 cases of Down syndrome were confirmed as Down syndrome after birth (defined as fals negative cases). The detection rate (DR) was 85.21%(98/115), false positive rate (FPR) was 3.41%(3218/94307), and the positive predictive value (PPV) was 2.96%(98/3316). The detection rate and positive predictive value of AMA were similar with the younger. However, the false positive rate was significantly higher (8.13% vs. 3.32%) of AMA than the pregnancies younger than 35. There is no trisomy 21 in AMA group with negative results of MSS.
5 Conclusions
All pregnant women should be informed the screening test dosen't equal to diagnosis because of the false negative result. The screening test is effective for women with advanced maternal age. Because amniocentesis is of invaive, there is no necessar y to ask all AMA pregnant women to have amniocentesis and chromosome analysis for safety.
6 Inovations
The detection rate of double screening test for Down syndrome in second trimester is relatively low, all pregnant women should be informed the screening test dosen't equal to diagnosis because of the false negative result. For women with advanced maternal age, serum screening is still an effective method to reduce the the proportion of invasive prenatal diagnosis and lower the risks of fetal loss.
Chapter Two ADAM12 is an Effective Marker in the Second Trimester of Pregnancy for Prenatal Screening of Down Syndrome
1 Background
Prenatal screening developed rapidly in rencent years. Biochemical screening for Down syndrome (DS) is well established, and the serum marker involves maternal serum alpha-fetoprotein (AFP), unconjugated estriol (uE3), and human chorionic gonadotropin (hCG) inhibin-A (INH-A), and so on. A Disintegrin and metalloproteinase 12 (ADAM 12) is discovered recently, which is considered increasing the detection rate of DS screening significantly. Many studies have suggested that ADAM 12 is an useful serum marker for prenatal screening of Down syndrome during the first trimester, fewer scholars studied the effection of ADM 12 in second trimester for prenatal screening of Down syndrome. Taking into account of the actual situation of economy & technology and the cost-effectiveness of program, double screening(AFP+ freeβ-Hcg) in second trimester is the widely used screening mode in the mainland of China. First trimester prenatal screening has not been accepted in our country. So using ADAM 12 in the second trimester for prenatal screening of Down syndrome is more fit for China's national conditions.
2 Objectives
The study was designed to explore the changing trends of the levels of maternal serum ADAM12 used in second-trimester Down syndrome screening. To estimate the utility of maternal serum ADAM12 as a second trimester Down syndrome serum marker.
3 Methods
Samples from a total of 46 Down syndrome pregnancies(including 24 false negative cases) and 184 unaffected singleton pregnancies matched for gestational age and maternal weight were retrieved from storage and measured for ADAM 12 by time-resolved fluoroimmunoassay; 35 false positive pregnancies were included among the controls to assess reductions in false positive rates by inclusion of ADAM 12 in the risk calculation of an algorithm that utilized AFP and hCG (double screening).
4 Results
ADAM 12 was measured and expressed as multiple of the gestation-specific median (MoM) and corrected for maternal weight. The median ADAM 12 level in the affected pregnancies was 1.26 MoM compared with 1.0 MoM in the unaffected control pregnancies (p<0.05). In unaffected pregnancies, there was a significant correlation between ADAM 12 and AFP (r=0.314) but not hCG (r=0.018). Statistical modeling predicted that ADAM 12 as a second serum marker could increase the detection rate from 48% to 85%, while reducing the false-negative and false-positive rates.
5 Conclusions
ADAM 12 can be used as an effective second trimester serum marker for prenatal screen of Down syndrome.
6 Innovations
We used ADAM 12 in prenatal screening of Down syndrome in the second trimester, studied the distribution of ADAM 12 in the Chinese population. We evaluated the function of ADAM 12 in improving the detection rate and reducing the false positive rate. There were few reports about using AD AM12 in false negative cases. Our results has been published in SCI journal.
Chapter Three The correlations between ADAM12 and other serum markers in prennatal screening of Down Synrome during the first and second trimesters
1 Background
Prenatal screening for Down syndrome was performed by risk calculation based on biochemical and biometric parameters. The serum marker involves maternal serum alpha-fetoprotein (AFP), unconjugated estriol (uE3), pregnancy-associated plasma protein A (PAPP-A), the freeβ-subunit of human chorionic gonadotrophin (freeβ-hCG) and human chorionic gonadotropin (hCG), inhibin-A (INH-A), and so on. In mainland China, double-screening was the main method in second trimester for risk calculation, first trimester prenatal screening has not yet carried out widespread in China, but it is undoubtedly the tendency of the future clinical work with prenatal screening. A Disintegrin and metalloproteinase 12 (ADAM 12) is a recently discovered new serum marker, which is considered increasing the detection rate of Down syndrome screening significantly. Study the correlation between ADAM 12 and other serum markers in the first and second trimester for prenatal screening of Down syndrome to optimize the existing prenatal screening programs.
2 Objectives
To explore maternal serum freeβ-hCG, PAPP-A, AFP and ADAM 12 levels in the first and second trimester in local Chinese population, in order to evaluate whether ADAM 12 can be an independent marker for prenatal screening of Down synrome.
3 Methods
From August 2005 to October 2009, maternal serum samples were collected from women with singleton pregnancy younger than 35 years,339 from first trimester, 1104 from sceond trimester including 22 Down syndrome pregnancies in the Women's Hospital, College of Medicine, Zhejiang University. Levels of freeβ-hCG, PAPP-A, AFP and ADAM 12 were measured by commercial time-resolved fluoroimmunoassay. Statistical analysis was performed using SPSS 16.0 software to evaluate the relationship between each serum marker and weight, gestational age, and the correlations between markers were analyzed too.
4 Results
There was no significant differences were found between the maternal ages and weights in each gestational week, and no correlations were found between the maternal weights and gestational weeks either (P>0.01 for all). The ADAM12 levels increased with gestational age and correlated significantly with PAPP-A during the first trimester, with AFP during the second trimester, no significant correlation were found with freeβ-hCG levels. In the second trimester Down syndrome pregnancies, the median ADAM12 MoM was approximately 1.2 times increased compared to normal pregnancies.
5 Conclusion
The maternal serum ADAM 12 concentration was increased with the gestational age increased in local Chinese population and correlated significantly both with PAPP-A and AFP levels. No correlation was found between the levels of ADAM12 and freeβ-hCG. ADAM12 is an effective serum marker for prenatal diagnosis of Down syndrom during the second trimester. ADAM12 may not be an independent marker, but it might be used as an additional marker to strengthen the influence of other markers in prenatal screening for Down syndrome during the first and second trimesters.
6 Innovations
Our study revealed the changing trend of maternal serum PAPP-A, freeβ-hCG, AFP and ADAM 12 during the first and second trimester in local Chinese population. We studied the correlation between ADAM 12 and other serum markers and we suggest that ADAM 12 should not be an entirely independent marker for Down syndrome screening.
Chapter Four Second trimester maternal serum ADAM12 level in normal twin pregnancies
1 Background
Over the past decade, twin pregnancies are becoming more frequent due to the wide use of various ovulation induction drugs and assisted reproduction technology and advanced maternal age. The incidence of having at least one Down Syndrome-affected fetus in twin pregnancies was higher than that of singleton pregnancies, thus it is important to carry out prenatal screening for twin pregnancies. However, the value of maternal serum screening in twin pregnancies is still controversial. Many studies have shown ADAM 12 is an effective maternal serum marker sensitive and specific for prenatal screening of Down syndrome in singleton pregnancies during the first and second trimester, there is no report about using ADAM 12 in prenatal screening of Down syndrome in twins during the second trimester.
Double screening in second trimester is widely used in mainland of China, establishing reference values of ADAM 12 and trying to apply it for prenatal screening of the twin pregnancy during the second trimester has higher clinical value.
2 Objectives
2.1 To explore the changing trends of maternal serum AD AM12 levels in the second trimester for twin pregnancies.
2.2 Comparing the differences of ADAM12 levels between the twins and the singleton controls to see whether ADAM 12 can be used for Down syndrome screening in the second trimester for twins.
3 Methods
The concentrations of ADAM12 of normal twins and singleton controls at gestational weeks 15+0 to 19+6 were measured. The Wilcoxon rank sum test was performed to compare the differences of ADAM12 between twins and singletons at different gestational ages. Correlations were determined using Pearson's correlation coefficient for ADAM12 and other markers. Statistically significant differences were considered when p<0.05.
4 Results
The study group comprised 306 twin pregnancies,31 twins following various forms of ART. In this study,939 singleton pregnancies women in the 15 to 19 weeks of gestation were enrolled,932 women with normal singleton pregnancies were selected as model controls, other 7 Down syndrome affected pregnancies including 2 false-negative cases diagnosed after birth were all excluded. In twin pregnancies, ADAM12 concentrations ranged from 465.69 to 1616.72 ng/ml. The overall median ADAM12 MoM in twins was 1.33 MoM while 1.0 MoM in singleton, in twin pregnancies, no significant correlation were present between the ADAM12 and freeβ-hCG (r=-0.003, p=0.964) and AFP (r= 0.54, p=0.343).
5 Conclusions
The median ADAM12 MoM in euploid twins is significantly increased comparing with singletons, ADAM12 may be an useful marker to prenatal screening of twins during the second trimester.
6 Innovations
We established the distribution of maternal serum ADAM12 for twin pregnancies during the second trimester. Study for ADAM12 in Chinese twin pregnancies will help to establish specific second trimester Down syndrome screening model for Chinese twin-prenatal care.
1研究背景
唐氏综合征(Down syndrome, DS)在活产新生儿中的发生率为1/600-1/800,是最常见的一种染色体病。以智力低下、发育迟缓和特殊的多发小畸形为主要表现,由于缺乏有效地治疗措施,这种患儿出生后将会给家庭和社会带来沉重的经济和精神负担,通过产前诊断和选择性人工流产来减少患儿的出生是目前国内外较好的预防措施。细胞遗传学产前诊断是确诊胎儿患有唐氏综合征或其它染色体疾病的方法,但因为需要介入性手术取材和检测成本高昂,仅适用于高风险孕妇。血清学产前筛查具有无创、快捷、服务成本相对低廉的优点,可以从接受筛查的人群中发现唐氏综合征高风险的孕妇,已被广大孕妇所接受。当筛查结果出现高风险阳性时,即建议进行羊膜腔穿刺,采集羊水进行胎儿细胞的染色体核型分析以明确诊断。产前筛查常用的血清标记物有妊娠相关血浆蛋白(PAPP-A)、甲胎蛋白(AFP)、人绒毛膜促性腺激素β亚基(β-hCG)、游离雌三醇(uE3)、抑制素A (Inhibin-A)等,多项血清标志物联合,结合孕妇的年龄、体重等参数计算胎儿患唐氏综合征风险的产前筛查方法有很多。基于我国国情和筛查方案的社会成本效益,目前国内主要采用中孕期二联筛查(AFP+freeβ-hCG)或三联筛查(AFP+freeβ-hCG+uE3),我们产前诊断中心采用的是中孕期二联筛查(AFP+freeβ-hCG)方案。随着社会经济发展进步,高龄孕妇正逐渐成为庞大的一个受人关注的群体。由于唐氏综合征的发病率与年龄明显相关,因此国内外很多协会和组织都在产前诊断的适应症中规定有年龄大于35岁的高龄孕妇,即只要怀孕妇女属于高龄范畴,都被建议直接进行羊膜腔穿刺和染色体核型分析。近年国际上有学者提出应改变将高龄孕妇作为羊膜腔穿刺常规的观念。
我们对中孕期二联筛查方案筛查效果以及对于高龄孕妇中孕期产前筛查的价值进行研究,以期探索和完善符合我国国情的有效的产前筛查策略,提高唐氏综合征及其它染色体异常患儿的检出率。
2研究目的
2.1回顾性分析唐氏综合征二联产前筛查工作效果；
2.1对高龄孕妇中孕期血清学产前筛查的价值进行研究。
3研究方法
方法：用时间分辨荧光免疫分析技术测定对孕15+0-20+6周的孕妇进行血清学筛查,筛查标记物为甲胎蛋白(AFP)、游离绒毛膜促性腺激素p亚基(freeβ-hCG),应用Multi-cal软件计算唐氏综合征风险,风险切割值(cut off)为1/270,高风险者建议其进行侵入即羊膜腔穿刺行羊水细胞染色体检查以确诊。随访孕妇的妊娠结局,计算血清学二联筛查的检出率,假阳性率,阳性预测值。
4结果
妊娠中期血清学二联筛查对胎儿唐氏综合征的检出率为85.21%(98/115),假阳性率为3.41%(3218/94307),阳性预测值为2.96%(98/3316)。高龄组检出唐氏综合征3例,发病率为(0.16%,3/1886)是低龄组(0.12%,112/92519)的1.33倍,两组比较,差异显著(p<0.05)。高龄组的检出率为100%(3/3),假阳性率为8.13%(153/1883),阳性预测值为1.92%(3/156)；低龄组中共有112例唐氏综合征,17例为假阴性,检出率为84.8%(95/112),假阳性率为3.32%(3065/92407),阳性预测值为3.01%(95/3160),高龄组与低龄组两者之间假阳性率差别明显,p<0.05。
5结论
二联血清学筛查检出率偏低,且筛查不等同于确诊,假阴性病例的出现不可完全避免,对所有采用胎儿唐氏综合征的妊娠中期血清学二联产前筛查孕妇的筛查后遗传咨询和确诊不容忽视。对于高龄孕妇,血清学筛查仍是有效筛查手段,故对高龄产妇应采取个体化胎儿唐氏综合征筛查和诊断策略,可降低侵入性产前诊断比例和风险。
6创新点
我们在长期原始数据积累和大样本统计分析的基础上,明确提出高龄孕妇产前诊断策略—血清学筛查仍是有效筛查手段。
第二部分解整合素金属蛋白酶12在中孕期产前诊断唐氏综合征中的应用
1研究背景
近几年产前筛查在产科领域发展迅速。产前筛查要求经济、简便、无创以及尽早应用。产前筛查常用的血清标记物有妊娠相关血浆蛋白(PAPP-A)、甲胎蛋白(AFP)、人绒毛膜促性腺激素β亚基(β-hCG)、游离雌三醇(uE3)、抑制素A(Inhibin-A)等。解整合素金属蛋白酶12(ADAM12)是新近发现的一个血清标志物,是一种与组织生长发育相关的蛋白,具有良好的妊娠特异性,国内外研究报道ADAM 12为高效的早孕期筛查唐氏综合征血清标志物,但将ADAM 12应用于中孕期产前筛查的相关研究较少。我国产前筛查工作起步较晚,目前在我国开展的产前筛查模式是中孕期血清学二联或三联筛查,结合年龄、体重等来评估孕妇孕有唐氏患儿的风险大小,而早孕筛查模式尚未被广泛接受及采用,因此,探讨ADAM 12在孕中期产前筛查胎儿唐氏综合征中的应用价值更为符合中国国情,为进一步提高产前筛查的检出率提供优化方案。
2研究目的
2.1研究中孕期ADAM 12在孕有唐氏综合征胎儿的孕妇血清中的变化规律。
2.2探讨ADAM 12在孕中期产前筛查胎儿唐氏综合征中的应用价值。
3方法
经染色体核型分析证实为唐氏综合征胎儿的孕妇静脉血血清样本共46例为研究组(24例为假阴性),随机选择同期经随访证实为正常新生儿孕妇静脉血血清样本184份为对照组(35例为假阳性),用时间分辨荧光免疫分析技术测定两组孕妇血清ADAM12浓度,比较ADAM12的MoM值在上述两组妊娠妇女外周血中的水平的变化,同时对ADAM12与其他血清标志物之间的相关性进行了研究。
4结果
从孕15+0周到19+6周,正常中孕期妊娠妇女血清ADAM12水平逐渐升高,其平均MoM值为1.0,唐氏综合征胎儿孕妇血清ADAM12的平均MoM值为1.26,两者之间差异有统计学意义。如果将ADAM12加入筛查方案,则检出率从48%上升到85%,同时可降低假阳性率和假阴性率。
5结论
ADAM12是中孕期唐氏综合征产前筛查的一个有效的血清学指标。
6创新点
将ADAM12应用于中孕期唐氏综合征产前诊断,建立中国人群ADAM12的参考值范围。对于ADAM12在提高检出率,降低假阳性率方面进行了研究,尤其是在假阴性病例中的研究国内鲜有报道。该部分研究结果已以论文形式正式发表于SCI收录期刊。
第三部分解整合素金属蛋白酶12在早孕期和中孕期产前筛查唐氏综合征中与其他血清标志物相关性的研究
1研究背景
通过产前筛查发现唐氏综合征高风险孕妇,结合产前诊断,对确诊为唐氏综合征妊娠孕妇尽可能早的终止妊娠,最大程度地降低妊娠唐氏综合征胎儿家庭的精神负担,因此越早进行产前筛查越好。唐氏综合征早孕期筛查是可行的、有效的,欧美等西方发达国家已开始普及。基于我国国情和筛查方案的社会成本效益,目前国内主要采用中孕期二联筛查(AFP+freeβ-hCG)或三联筛查(AFP+freeβ-hCG+uE3),筛查效率偏低。随着我国经济技术水平的提高,对早孕期筛查的需求将越来越迫切。早孕期产前筛查在我国刚刚起步,因为可以更早的检出唐氏综合征胎儿无疑是今后唐氏综合征产前筛查工作的发展趋势。
目前用于早孕和中孕期产前筛查的血清学标志物有妊娠相关血浆蛋白(PAPP-A)、甲胎蛋白(AFP)、人绒毛膜促性腺激素β亚基(β-hCG)、游离雌三醇(uE3)、抑制素A(Inhibin-A)等,筛查方案有早孕期筛查(first trimester screening)和中孕期筛查(second trimester screening),筛查模式多样：二联(AFP+freeβ-hCG)筛查、三联(AFP+freeβ-hCG+uE3)筛查和四联(AFP+freeβ-hCG+uE3+inh A)筛查,独立的序贯筛查(independent sequential screening)、酌情的序贯筛查(contingent sequential screening)以及结合早、中孕期筛查的联合筛查(integrated screening)等,筛查方案的发展趋势是个体化筛查及酎情筛查。为了提高产前筛查的效率,提高检出率,降低阳性率,尽可能避免假阴性病例的出现,人们在不断寻找新的更为有效的血清学筛查指标,不断优化产前筛查方案。
解整合素金属蛋白酶12(ADAM12)是新近发现的一个高效的产前筛查血清标志物,有望提高唐氏综合征的产前筛查效率。对ADAM12在早孕期和中孕期产前筛查唐氏综合征中与其他血清标志物相关性的研究,探讨ADAM12在产前筛查中的作用,以期优化现行产前筛查方案。
2研究目的
探索中国早孕期和中孕期正常单胎孕妇血清中ADAM12和freeβ-hCG、PAPP-A以及AFP水平的变化规律及相关性,为优化中国孕妇唐氏综合征血清学产前筛查方案提供理论依据。
3方法
早孕期(孕9+0-13+6周)单胎孕妇339例,中孕期(15+0-20+6)单胎孕妇1104例,用时间分辨荧光免疫分析技术测定孕妇血清ADAM12和freeβ-hCG、PAPP-A以及AFP的水平,统计分析ADAM 12与体重、孕周的关系及与其它血清标志物之间的相关性。
4结果
早孕期339例单胎妊娠中未检出唐氏综合征胎儿,中孕期胎儿染色体核型证实为唐氏综合征的妊娠妇女22例。ADAM12在正常单胎早孕期妊娠妇女血清中ADAM12与PAPP-A之间有显著性相关,与freeβ-hCG之间无相关性。在中孕期正常妊娠妇女血清中,ADAM12与孕周和孕妇体重之间均存在相关性(p均<0.05)。ADAM12与AFP之间相关性有统计学意义,而与freeβ-hCG之间无显著性相关。在胎儿为唐氏综合征的中孕期妊娠妇女血清中,ADAM 12的水平较正常妊娠妇女明显升高,其ADAM12MoM约为正常中孕妇女ADAM12MoM值的1.2倍,二者之间差异有统计学意义。
5结论
我国人群孕妇血清中ADAM12水平随孕周的增加而增高,胎儿为唐氏综合征的中孕期妊娠妇女ADAM12MoM约为正常中孕妇女ADAM12MoM值的1.2倍,二者之间差异有统计学意义。ADAM12与PAPP-A及AFP有相关性,与freeβ-hCG相关性无统计学意义。ADAM12是中孕期产前筛查唐氏综合征的一个有效指标。ADAM12与其他血清标志物之间存在相关性,因此对ADAM12在早孕期和中孕期唐氏综合征产前筛查中的特异性和灵敏度还有待于进一步研究。
6创新点
通过对早、中孕期孕妇血清ADAM12变化趋势的研究,建立了ADAM12在我国人群产前筛查中的参考范围。通过ADAM12在中孕期产前筛查唐氏综合征中的研究认为ADAM12是有效的中孕期产前筛查血清学筛查指标。通过ADAM12与其他血清标志物相关性的研究对ADAM12用于产前筛查的特异性进行了探讨。
第四部分解整合素金属蛋白酶12在中孕期正常双胎妊娠中应用的研究
1研究背景
近年来随着辅助生育技术的开展及妇女生育年龄后延,双胎妊娠发生率呈现升高趋势。双胎妊娠中至少一胎为染色体异常的发生率较同年龄组单胎妊娠高,但对于双胎妊娠进行产前筛查尚未在临床中正式开展,这是由于双胎妊娠的复杂性使得现有的血清学产前筛查方案在双胎妊娠中的应用价值一直备受争议。自从有研究首次报道ADAM12在早孕期妊娠妇女血清中显著降低以来,人们对于ADAM12应用于产前筛查给予了极大的关注。之前的研究表明,ADAM12可用于早孕期的单、双胎产前筛查,在中孕期的单胎妊娠的产前筛查中ADAM12的价值也得到肯定,但对于在中孕期双胎妊娠中应用ADAM12进行产前筛查目前尚无报道。我国产前筛查工作起步较晚,筛查模式较为单一,主要是中孕期二联或三联筛查,对于双胎妊娠孕妇中孕期血清学筛查的资料很少,缺乏大样本系统研究。
2研究目的
2.1探讨双胎妊娠中孕期孕妇血清ADAM12变化规律,建立中国人群中孕期双胎妊娠妇女ADAM12水平的正常参考范围；
2.2比较双胎妊娠孕妇与正常单胎妊娠妇女血清ADAM12水平之间的差异,对ADAM12在双胎妊娠产前筛查中的作用进行探讨。
3方法
收集孕15+0-19+6周正常双胎妊娠孕妇306例为研究组,随机选择同时期正常单胎妊娠孕妇932例作为对照组；用时间分辨荧光免疫分析技术测定两组孕妇血清freeβ-hCG、AFP和ADAM12浓度,观察中孕期双胎妊娠和单胎妊娠孕妇上述血清标志物的变化特点,比较两组间ADAM12水平差异。
4结果
所有病例经随访确定为非唐氏综合征妊娠。双胎中有31例是应用各种辅助生育技术后受孕,其余为自然受孕,其ADAM12的水平范围是465.69-1616.72ng/ml。双胎孕妇ADAM12MoM的中位数值约为1.33,而单胎的为1.0,二者之间差异有统计学意义。在单胎妊娠中ADAM1 2与AFP显著相关,与freeβ-hCG无显著相关,在双胎妊娠中ADAM12与AFP和freeβ-hCG皆无显著相关。
5结论
我们建立了正常中孕双胎ADAM12的参考范围465.69-1616.72ng/mL。双胎的ADAM12MoM较单胎升高,是单胎的1.33倍。ADAM12在双胎妊娠的产前筛查中是一个有效的血清学指标。
6创新点
双胎妊娠产前筛查目前尚未列入常规,这主要是现行的二联筛查方案不适于双胎妊娠的DS血清学产前筛查。ADAM12用于唐氏综合征产前筛查的研究方兴未艾,我们将ADAM12用于双胎妊娠中孕期产前筛查的研究更是走在世界的前列。
Chapter One Assessment of the value of maternal serum screening of Down syndrome for women with advanced maternal age
1 Background
Down syndrome (DS) is the most common cause of severe mental retardation in children. The rate of Down syndrome for live births is between 1/600～1/800. It is the result of trisomy of chromosome 21 which is usually a random event though it is commoner in older mothers. Such children will be a heavy financial and emotional burden for the family and society because of lacking effective treatment measures. Down syndrome can be diagnosed by chorionic villus sampling (CVS) and amniocentesis followed by karyotyping. Because of the risks associated with these invasive procedures, they can only be offered to a high-risk pregnant women. Non-invasive biochemical screening for Down syndrome is well established in the second trimester of pregnancy. Second-trimester screening traditionally consists of some combination of maternal serum analysis and maternal age. Screening programmes in Mainland of China involving the measurement of maternal serum alpha-fetoprotein (AFP), human chorionic gonadotropin (hCG) with or without unconjugated estriol (uE3)(double/triple screening test). Taking into account of the actual situation of economy & technology and the cost-effectiveness of program, We used double-screening (AFP+free P-hCG) test in our prenatal diagnosis center between the 14 to 20 weeks of gestation. Diagnostic amniocentesis was performed as routain in women over 35 years and in women with a previous affected child, but recently, some scholars proposed such opinion that amniocentesis may be offered on a selective rather than routine basis in women w ith advanced maternal age.
We had evaluated the double-screening programs in the second trimester, assessed the value of maternal serum screening (MSS) of Down syndrome for women with advanced maternal age (AMA, over 35 years) and tried to lessen the rate of amniocentesis.
2 Objectives
2.1 To evaluated the double-screening programs in the second trimester in our prenatal diagnosis center for Down syndrome.
2.2 To assess the value of maternal serum screening (MSS) of Down syndrome for women with advanced maternal age (AMA, over 35 years)in the second trimester.
3 Methods
From June 2004 to December 2009, pregnant women between 15+0 and 20-6 weeks of gestation, who received prenatal screening for Down syndrome in the Women's Hospital, College of Medicine, Zhejiang University were retrospectively analyzed. Levels of freeβ-hCG and AFP were measured by commercial time-resolved fluoroimmunoassay. Statistical analysis was performed using SPSS 16.0 software to evaluate the relationship between each serum marker and weight, gestational age, and the correlations between markers were analyzed too.
Down syndrome risk of each pregnancy was calculated by computer software. Screening positive pregnant women were offered genetic counseling and the option of amniocentesis and cordocentesis. The detection rate (DR), false positive rate (FPR), positive predictive value were calculated.
4 Results
In our study, there were 94405 pregnant women were tested, at a cut-off value of 1 in 270,3316 cases have positive results, in which 156 positive results belong to 1886 cases of women with advanced maternal age (AMA, over 35 years). The total positive MSS rate of Down is 3.5%,98 neonates were diagnosed as Down syndrome by amniocentesis, only 3 cases of Down syndrome was AMA. Other 17 cases of Down syndrome were confirmed as Down syndrome after birth (defined as fals negative cases). The detection rate (DR) was 85.21%(98/115), false positive rate (FPR) was 3.41%(3218/94307), and the positive predictive value (PPV) was 2.96%(98/3316). The detection rate and positive predictive value of AMA were similar with the younger. However, the false positive rate was significantly higher (8.13% vs. 3.32%) of AMA than the pregnancies younger than 35. There is no trisomy 21 in AMA group with negative results of MSS.
5 Conclusions
All pregnant women should be informed the screening test dosen't equal to diagnosis because of the false negative result. The screening test is effective for women with advanced maternal age. Because amniocentesis is of invaive, there is no necessar y to ask all AMA pregnant women to have amniocentesis and chromosome analysis for safety.
6 Inovations
The detection rate of double screening test for Down syndrome in second trimester is relatively low, all pregnant women should be informed the screening test dosen't equal to diagnosis because of the false negative result. For women with advanced maternal age, serum screening is still an effective method to reduce the the proportion of invasive prenatal diagnosis and lower the risks of fetal loss.
Chapter Two ADAM12 is an Effective Marker in the Second Trimester of Pregnancy for Prenatal Screening of Down Syndrome
1 Background
Prenatal screening developed rapidly in rencent years. Biochemical screening for Down syndrome (DS) is well established, and the serum marker involves maternal serum alpha-fetoprotein (AFP), unconjugated estriol (uE3), and human chorionic gonadotropin (hCG) inhibin-A (INH-A), and so on. A Disintegrin and metalloproteinase 12 (ADAM 12) is discovered recently, which is considered increasing the detection rate of DS screening significantly. Many studies have suggested that ADAM 12 is an useful serum marker for prenatal screening of Down syndrome during the first trimester, fewer scholars studied the effection of ADM 12 in second trimester for prenatal screening of Down syndrome. Taking into account of the actual situation of economy & technology and the cost-effectiveness of program, double screening(AFP+ freeβ-Hcg) in second trimester is the widely used screening mode in the mainland of China. First trimester prenatal screening has not been accepted in our country. So using ADAM 12 in the second trimester for prenatal screening of Down syndrome is more fit for China's national conditions.
2 Objectives
The study was designed to explore the changing trends of the levels of maternal serum ADAM12 used in second-trimester Down syndrome screening. To estimate the utility of maternal serum ADAM12 as a second trimester Down syndrome serum marker.
3 Methods
Samples from a total of 46 Down syndrome pregnancies(including 24 false negative cases) and 184 unaffected singleton pregnancies matched for gestational age and maternal weight were retrieved from storage and measured for ADAM 12 by time-resolved fluoroimmunoassay; 35 false positive pregnancies were included among the controls to assess reductions in false positive rates by inclusion of ADAM 12 in the risk calculation of an algorithm that utilized AFP and hCG (double screening).
4 Results
ADAM 12 was measured and expressed as multiple of the gestation-specific median (MoM) and corrected for maternal weight. The median ADAM 12 level in the affected pregnancies was 1.26 MoM compared with 1.0 MoM in the unaffected control pregnancies (p<0.05). In unaffected pregnancies, there was a significant correlation between ADAM 12 and AFP (r=0.314) but not hCG (r=0.018). Statistical modeling predicted that ADAM 12 as a second serum marker could increase the detection rate from 48% to 85%, while reducing the false-negative and false-positive rates.
5 Conclusions
ADAM 12 can be used as an effective second trimester serum marker for prenatal screen of Down syndrome.
6 Innovations
We used ADAM 12 in prenatal screening of Down syndrome in the second trimester, studied the distribution of ADAM 12 in the Chinese population. We evaluated the function of ADAM 12 in improving the detection rate and reducing the false positive rate. There were few reports about using AD AM12 in false negative cases. Our results has been published in SCI journal.
Chapter Three The correlations between ADAM12 and other serum markers in prennatal screening of Down Synrome during the first and second trimesters
1 Background
Prenatal screening for Down syndrome was performed by risk calculation based on biochemical and biometric parameters. The serum marker involves maternal serum alpha-fetoprotein (AFP), unconjugated estriol (uE3), pregnancy-associated plasma protein A (PAPP-A), the freeβ-subunit of human chorionic gonadotrophin (freeβ-hCG) and human chorionic gonadotropin (hCG), inhibin-A (INH-A), and so on. In mainland China, double-screening was the main method in second trimester for risk calculation, first trimester prenatal screening has not yet carried out widespread in China, but it is undoubtedly the tendency of the future clinical work with prenatal screening. A Disintegrin and metalloproteinase 12 (ADAM 12) is a recently discovered new serum marker, which is considered increasing the detection rate of Down syndrome screening significantly. Study the correlation between ADAM 12 and other serum markers in the first and second trimester for prenatal screening of Down syndrome to optimize the existing prenatal screening programs.
2 Objectives
To explore maternal serum freeβ-hCG, PAPP-A, AFP and ADAM 12 levels in the first and second trimester in local Chinese population, in order to evaluate whether ADAM 12 can be an independent marker for prenatal screening of Down synrome.
3 Methods
From August 2005 to October 2009, maternal serum samples were collected from women with singleton pregnancy younger than 35 years,339 from first trimester, 1104 from sceond trimester including 22 Down syndrome pregnancies in the Women's Hospital, College of Medicine, Zhejiang University. Levels of freeβ-hCG, PAPP-A, AFP and ADAM 12 were measured by commercial time-resolved fluoroimmunoassay. Statistical analysis was performed using SPSS 16.0 software to evaluate the relationship between each serum marker and weight, gestational age, and the correlations between markers were analyzed too.
4 Results
There was no significant differences were found between the maternal ages and weights in each gestational week, and no correlations were found between the maternal weights and gestational weeks either (P>0.01 for all). The ADAM12 levels increased with gestational age and correlated significantly with PAPP-A during the first trimester, with AFP during the second trimester, no significant correlation were found with freeβ-hCG levels. In the second trimester Down syndrome pregnancies, the median ADAM12 MoM was approximately 1.2 times increased compared to normal pregnancies.
5 Conclusion
The maternal serum ADAM 12 concentration was increased with the gestational age increased in local Chinese population and correlated significantly both with PAPP-A and AFP levels. No correlation was found between the levels of ADAM12 and freeβ-hCG. ADAM12 is an effective serum marker for prenatal diagnosis of Down syndrom during the second trimester. ADAM12 may not be an independent marker, but it might be used as an additional marker to strengthen the influence of other markers in prenatal screening for Down syndrome during the first and second trimesters.
6 Innovations
Our study revealed the changing trend of maternal serum PAPP-A, freeβ-hCG, AFP and ADAM 12 during the first and second trimester in local Chinese population. We studied the correlation between ADAM 12 and other serum markers and we suggest that ADAM 12 should not be an entirely independent marker for Down syndrome screening.
Chapter Four Second trimester maternal serum ADAM12 level in normal twin pregnancies
1 Background
Over the past decade, twin pregnancies are becoming more frequent due to the wide use of various ovulation induction drugs and assisted reproduction technology and advanced maternal age. The incidence of having at least one Down Syndrome-affected fetus in twin pregnancies was higher than that of singleton pregnancies, thus it is important to carry out prenatal screening for twin pregnancies. However, the value of maternal serum screening in twin pregnancies is still controversial. Many studies have shown ADAM 12 is an effective maternal serum marker sensitive and specific for prenatal screening of Down syndrome in singleton pregnancies during the first and second trimester, there is no report about using ADAM 12 in prenatal screening of Down syndrome in twins during the second trimester.
Double screening in second trimester is widely used in mainland of China, establishing reference values of ADAM 12 and trying to apply it for prenatal screening of the twin pregnancy during the second trimester has higher clinical value.
2 Objectives
2.1 To explore the changing trends of maternal serum AD AM12 levels in the second trimester for twin pregnancies.
2.2 Comparing the differences of ADAM12 levels between the twins and the singleton controls to see whether ADAM 12 can be used for Down syndrome screening in the second trimester for twins.
3 Methods
The concentrations of ADAM12 of normal twins and singleton controls at gestational weeks 15+0 to 19+6 were measured. The Wilcoxon rank sum test was performed to compare the differences of ADAM12 between twins and singletons at different gestational ages. Correlations were determined using Pearson's correlation coefficient for ADAM12 and other markers. Statistically significant differences were considered when p<0.05.
4 Results
The study group comprised 306 twin pregnancies,31 twins following various forms of ART. In this study,939 singleton pregnancies women in the 15 to 19 weeks of gestation were enrolled,932 women with normal singleton pregnancies were selected as model controls, other 7 Down syndrome affected pregnancies including 2 false-negative cases diagnosed after birth were all excluded. In twin pregnancies, ADAM12 concentrations ranged from 465.69 to 1616.72 ng/ml. The overall median ADAM12 MoM in twins was 1.33 MoM while 1.0 MoM in singleton, in twin pregnancies, no significant correlation were present between the ADAM12 and freeβ-hCG (r=-0.003, p=0.964) and AFP (r= 0.54, p=0.343).
5 Conclusions
The median ADAM12 MoM in euploid twins is significantly increased comparing with singletons, ADAM12 may be an useful marker to prenatal screening of twins during the second trimester.
6 Innovations
We established the distribution of maternal serum ADAM12 for twin pregnancies during the second trimester. Study for ADAM12 in Chinese twin pregnancies will help to establish specific second trimester Down syndrome screening model for Chinese twin-prenatal care.
引文
[1]Down JL. Observations on an ethnic classification of idiots.1866. Ment Retard, 1995,33(1):54-56.
[2]Driscoll DA, Gross S. Clinical practice. Prenatal screening for aneuploidy. N Engl J Med,2009,360(24):2556-2562.
[3]Penrose LS. Maternal age in familial mongolism. J Ment Sci,1951,97(409): 738-747.
[4]Hook EB, Chambers GM. Estimated rates of Down syndrome in live births by one year maternal age intervals for mothers aged 20-49 in a New York State study-implications of the risk figures for genetic counseling and cost-benefit analysis of prenatal diagnosis programs. Birth Defects Orig Artic Ser,1977, 13(3A):123-141.
[5]Lamson SH, Hook EB. A simple function for maternal-age-specific rates of Down syndrome in the 20-to-49-year age range and its biological implications. Am J Hum Genet,1980,32(5):743-753.
[6]Domm ergues M, Audib ert F, Benatt ar C, et al. Is routine amniocentesis for advanced maternal age still indicated? Fetal Diagnosis therapy,2001,16: 372-377
[7]Audibert F, Mairovit z V, Frydman R. Alternatives to amniocentesis for advanced mat ernal age. Gynecol Obstet Fetil,2002,30:562-566.
[8]Merkatz IR, Nitowsky HM, Macri JN, Johnson WE. An association between low maternal serum alpha-fetoprotein and fetal chromosomal abnormalities. Am J Obstet Gynecol,1984,148(7):886-894.
[9]Bogart MH, M.R. Pandian, O.W. Jones. Abnormal maternal serum chorionic gonadotropin levels in pregnancies with fetal chromosome abnormalities. Prenat Diagn,1987,7(9):623-630.
[10]Wald NJ, Cuckle HS, Densem JW, Nanchahal K, Canick JA, Haddow JE, et al. Maternal serum unconjugated oestriol as an antenatal screening test for Down's syndrome. Br J Obstet Gynaecol,1988,95(4):334-341.
[11]Brizot ML, Hyett JA, McKie AT, Bersinger NA, Farzaneh F, Nicolaides KH. Gene expression of human pregnancy-associated plasma protein-A in placenta from trisomic pregnancies. Placenta,1996,17(1):33-36.
[12]Aitken DA, Wallace EM, Crossley JA, Swanston IA, van Pareren Y, van Maarle M, et al. Dimeric inhibin A as a marker for Down's syndrome in early pregnancy. N Engl J Med,1996,334(19):1231-1236.
[13]Debieve F, Bouckaert A, Hubinont C, Thomas K. Multiple screening for fetal Down's syndrome with the classic triple test, dimeric inhibin A and ultrasound. Gynecol Obstet Invest,2000,49(4):221-226.
[14]Tux en A, Keeling JW, Reintoft I, Fischer Hansen B, Nolting D, Kjaer I. A histological and radiological investigation of the nasal bone in fetuses with Down syndrome. Ultrasound Obstet Gynecol,2003,22(1):22-26.
[15]Cuckle HS, Wald NJ, Lindenbaum RH. Maternal serum alpha-fetoprotein measurement:a screening test for Down syndrome. Lancet,1984,1(8383):926-929.
[16]Haddow JE, Palomaki GE, Knight GJ, Williams J, Pulkkinen A, Canick JA, et al. Prenatal screening for Down's syndrome with use of maternal serum markers. N Engl J Med,1992,327(9):588-593.
[17]Malone FD, Canick JA, Ball RH, Nyberg DA, Comstock CH, Bukowski R, et al. First-trimester or second-trimester screening, or both, for Down's syndrome. N Engl J Med,2005,353(19):2001-2011.
[18]Snijders RJ, Thom EA, Zachary JM, Platt LD, Greene N, Jackson LG, et al. First-trimester trisomy screening:nuchal translucency measurement training and quality assurance to correct and unify technique. Ultrasound Obstet Gynecol, 2002,19(4):353-359.
[19]Wald NJ, Watt HC, Hackshaw AK. Integrated screening for Down's syndrome on the basis of tests performed during the first and second trimesters. N Engl J Med, 1999,341(7):461-467.
[20]Grant SS. Options for Down syndrome screening:what will women choose? J Midwifery Womens Health,2005,50(3):211-218.
[21]Rozenberg P, Malagrida L, Cuckle H, Durand-Zaleski I, Nisand I, Audibert F, et al. Down's syndrome screening with nuchal translucency at 12(+0)-14(+0) weeks and maternal serum markers at 14(+1)-17(+0) weeks:a prospective study. Hum Reprod,2002,17(4):1093-1098.
[22]Scott A. Nuchal translucency measurement in first trimester Down syndrome screening. Issues Emerg Health Technol,2007,100:1-6.
[23]Laigaard J, Sorensen T, Frohlich C, Pedersen BN, Christiansen M, Schiott K, et al. ADAM 12:a novel first-trimester maternal serum marker for Down syndrome. Prenat Diagn,2003,23(13):1086-1091.
[24]Laigaard J, Cuckle H, Wewer UM, Christiansen M. Maternal serum ADAM 12 levels in Down and Edwards'syndrome pregnancies at 9-12 weeks'gestation. Prenat Diagn,2006,26(8):689-691.
[25]Christiansen M, Pihl K, Hedley PL, Gjerris AC, Lind PO, Larsen SO, et al. ADAM 12 may be used to reduce the false positive rate of first trimester combined screening for Down syndrome. Prenat Diagn,2010,30(2):110-114.
[26]Makrydimas G, Sotiriadis A, Spencer K, et al. ADAM 122s in coelomic fluid and maternal serum in early p regnancy. Prenat Diagn.2006,26 (13):1197-1200.
[27]Loechel F, Fox JW, Murphy G, et al. ADAM 122S cleaves IGFBP-3 and IGFBP-5 and is inhibited by TIMP-3. Biochem Biophys Res Commun,2000,278: 511.
[28]Christiansen M, Spencer K, Laigaard J, et al. ADAM 12 as a second-trimester maternal serum marker in screening for Down syndrome. Prent Diagn,2007,27:611-5.
[29]郭淑惠,王婧岚,李慧丽.新生儿性别比及双胎率和畸形率调查结果分析.中国妇幼保健,2006,7：977-978
[30]Lam YH, Ghosh A, Tang MH, Tang LC, Lee CP, Sin SY, et al. Second-trimester maternal serum alpha-fetoprotein and human chorionic gonadotrophin screening for Down's syndrome in Hong Kong. Prenat Diagn,1998,18(6):585-589.
[31]Chao AS, Chung CL, Wu CD, Chang SD, Cheng PJ, Lin YT, et al. Second trimester maternal serum screening using alpha fetoprotein, free beta human chorionic gonadotropin and maternal age specific risk:result of chromosomal abnormalities detected in screen positive for Down syndrome in an Asian population. Acta Obstet Gynecol Scand,1999,78(5):393-397.
[32]Jou HJ, Shyu MK, Chen SM, Shih JC, Hsu JJ, Hsieh FJ. Maternal serum screening for down syndrome by using alpha-fetoprotein and human chorionic gonadotropin in an asian population.a prospective study. Fetal Diagn Ther,2000, 15(2):108-111.
[1]Driscoll DA, Gross S. Clinical practice. Prenatal screening for aneuploidy. N Engl J Med,2009,360(24):2556-2562.
[2]Korenberg JR, Chen XN, Schipper R, et al. Down syndrome phenotypes:the consequences of chromosomal imbalance.Proc Natl Acad Sci USA 1994;91:4997-5001.
[3]Shaw SW, Chen CP, Cheng PJ, et al. Gene dosage change of TPTE and BAGE2 and breakpoint analysis in Robertsonian Down syndrome. J Hum Genet 2008;53:136-43.
[4]Cuckle HS, Wald NJ, Lindenbaum RH. Maternal serum alpha-fetoprotein measurement:a screening test for Down syndrome. Lancet,1984,1(8383):926-929.
[5]Bogart MH, M.R. Pandian, O.W. Jones. Abnormal maternal serum chorionic gonadotropin levels in pregnancies with fetal chromosome abnormalities. Prenat Diagn,1987,7(9):623-630.
[6]Wald NJ, Cuckle HS, Densem JW, Nanchahal K, Canick JA, Haddow JE, et al. Maternal serum unconjugated oestriol as an antenatal screening test for Down's syndrome. Br J Obstet Gynaecol,1988,95(4):334-341.
[7]Brizot ML, Hyett JA, McKie AT, Bersinger NA, Farzaneh F, Nicolaides KH. Gene expression of human pregnancy-associated plasma protein-A in placenta from trisomic pregnancies. Placenta,1996,17(1):33-36.
[8]Aitken DA, Wallace EM, Crossley JA, Swanston IA, van Pareren Y, van Maarle M, et al. Dimeric inhibin A as a marker for Down's syndrome in early pregnancy. N Engl J Med,1996,334(19):1231-1236.
[9]Bindra R, Heath V, Liao A, Spencer K, Nicolaides KH. One-stop clinic for assessment of risk for trisomy 21 at 11-14 weeks:a prospective study of 15 030 pregnancies. Ultrasound Obstet Gynecol,2002,20(3):219-225.
[10]Cuckle HS, van Lith JM. Appropriate biochemical parameters in first-trimester screening for Down syndrome. Prenat Diagn,1999,19(6):505-512.
[11]Wald NJ, Watt HC, Hackshaw AK. Integrated screening for Down's syndrome on the basis of tests performed during the first and second trimesters. N Engl J Med, 1999,341(7):461-467.
[12]Grant SS. Options for Down syndrome screening:what will women choose? J Midwifery Womens Health,2005,50(3):211-218.
[13]Rozenberg P, Malagrida L, Cuckle H, Durand-Zaleski I, Nisand I, Audibert F, et al. Down's syndrome screening with nuchal translucency at 12(+0)-14(+0) weeks and maternal serum markers at 14(+1)-17(+0) weeks:a prospective study. Hum Reprod,2002,17(4):1093-1098.
[14]Saller DN, Jr., Canick JA. Current methods of prenatal screening for Down syndrome and other fetal abnormalities. Clin Obstet Gynecol,2008,51(1):24-36.
[15]Shaw SW, Hsu JJ, Lee CN, Hsiao CH, Chen CP, Hsieh TT, et al. First-and second-trimester Down syndrome screening:current strategies and clinical guidelines. Taiwan J Obstet Gynecol,2008,47(2):157-162.
[16]Platt LD, Greene N, Johnson A, Zachary J, Thom E, Krantz D, et al. Sequential pathways of testing after first-trimester screening for trisomy 21. Obstet Gynecol, 2004,104(4):661-666.
[17]Benn P, Wright D, Cuckle H. Practical strategies in contingent sequential screening for Down syndrome. Prenat Diagn,2005,25(8):645-652.
[18]Cuckle H, Benn P, Wright D. Down syndrome screening in the first and/or second trimester:model predicted performance using meta-analysis parameters. Semin Perinatol,2005,29(4):252-257.
[19]Wright D, Bradbury I, Cuckle H, Gardosi J, Tonks A, Standing S, et al. Three-stage contingent screening for Down syndrome. Prenat Diagn,2006,26(6): 528-534.
[20]Wald NJ, Rodeck C, Hackshaw AK, Rudnicka A. SURUSS in perspective. BJOG, 2004,111(6):521-531.
[21]Wald NJ, Rodeck C, Hackshaw AK, Rudnicka A. SURUSS in perspective. Semin Perinatol,2005,29(4):225-235.
[22]Wald NJ, Rodeck C, Hackshaw AK, Walters J, Chitty L, Mackinson AM. First and second trimester antenatal screening for Down's syndrome:the results of the Serum, Urine and Ultrasound Screening Study (SURUSS). Health Technol Assess,2003,7(11):1-77.
[23]Ball RH, Caughey AB, Malone FD, Nyberg DA, Comstock CH, Saade GR, et al. First- and second-trimester evaluation of risk for Down syndrome. Obstet Gynecol,2007,110(1):10-17.
[24]Cleary-Goldman J, Malone FD, Vidaver J, Ball RH, Nyberg DA, Comstock CH, et al. Impact of maternal age on obstetric outcome. Obstet Gynecol,2005,105(5 Pt 1):983-990.
[25]Malone FD, Ball RH, Nyberg DA, Comstock CH, Saade G, Berkowitz RL, et al. First-trimester nasal bone evaluation for aneuploidy in the general population. Obstet Gynecol,2004,104(6):1222-1228.
[26]Malone FD, Canick JA, Ball RH, Nyberg DA, Comstock CH, Bukowski R, et al. First-trimester or second-trimester screening, or both, for Down's syndrome. N Engl J Med,2005,353(19):2001-2011.
[27]Domm ergues M, Audib ert F, Benatt ar C, et al. Is routine amniocentesis for advanced maternal age still indicated? Fetal Diagnosis therapy,2001,16: 372-377
[28]Audibert F, Mairovit z V, Frydman R. Alternatives to amniocentesis for advanced mat ernal age. Gynecol Obstet Fetil,2002,30:562-566.
[29]Bian XM, Liu J T, Qi QW, et al. Second trimester maternal serum screening for Down's syndrome in mainland China:A multi-center prospective study. Chin J Obstet Gynecol,2008,43 (11):805-809.
[30]ACOG Practice Bulletin No.77:Screening for fetal chromosomal abnormalities. Obstet Gynecol,2007,109 (1):217-227.
[31]ACOG Practice bulletin. Clinical management guidelines for obstetrician gynecolostists. Invasive prenatal testing for aneuploidy. Obstet Gynecol,2007 110:1459-1466.
[1]Korenberg JR, Chen XN, Schipper R, et al.1994. Down syndrome phenotypes: the consequences of chromosomal imbalance. Proc Natl Acad Sci USA 91:4997-5001.
[2]Shaw SW, Chen CP, Cheng PJ, et al.2008. Gene dosage change of TPTE and BAGE2 and breakpoint analysis in Robertsonian Down syndrome. J Hum Genet 53:136-43.
[3]Merkatz IR, Nitowsky HM, Macri JN, Johnson WE. An association between low maternal serum alpha-fetoprotein and fetal chromosomal abnormalities. Am J Obstet Gynecol,1984,148(7):886-894.
[4]Cuckle HS, Wald NJ, Lindenbaum RH. Maternal serum alpha-fetoprotein measurement:a screening test for Down syndrome. Lancet,1984,1(8383):926-929.
[5]Bogart MH, M.R. Pandian, O.W. Jones. Abnormal maternal serum chorionic gonadotropin levels in pregnancies with fetal chromosome abnormalities. Prenat Diagn,1987,7(9):623-630.
[6]Wald NJ, Cuckle HS, Densem JW, Nanchahal K, Canick JA, Haddow JE, et al. Maternal serum unconjugated oestriol as an antenatal screening test for Down's syndrome. Br J Obstet Gynaecol,1988,95(4):334-341.
[7]Brizot ML, Hyett JA, McKie AT, Bersinger NA, Farzaneh F, Nicolaides KH. Gene expression of human pregnancy-associated plasma protein-A in placenta from trisomic pregnancies. Placenta,1996,17(1):33-36.
[8]Aitken DA, Wallace EM, Crossley JA, Swanston IA, van Pareren Y, van Maarle M, et al. Dimeric inhibin A as a marker for Down's syndrome in early pregnancy. N Engl J Med,1996,334(19):1231-1236.
[9]Laigaard J, Sorensen T, Frohlich C, Pedersen BN, Christiansen M, Schiott K, et al. ADAM 12:a novel first-trimester maternal serum marker for Down syndrome. Prenat Diagn,2003,23(13):1086-1091.
[10]Laigaard J, Cuckle H, Wewer UM, Christiansen M. Maternal serum ADAM 12 levels in Down and Edwards' syndrome pregnancies at 9-12 weeks' gestation. Prenat Diagn,2006,26(8):689-691.
[11]Christiansen M, Pihl K, Hedley PL, Gjerris AC, Lind PO, Larsen SO, et al. ADAM 12 may be used to reduce the false positive rate of first trimester combined screening for Down syndrome. Prenat Diagn,2010,30(2):110-114.
[12]Loechel F, Fox JW, Murphy G, et al. ADAM 12-S cleaves IGFBP-3 and IGFBP-5 and is inhibited by TIMP-3. B iochem B iophysRes Commun,2000,278:511.
[13]Shi Z, Xu W, Loechel F, et al.2000. ADAM 12, a disintegrin metalloprotease, interacts with insulin-like growth factor-binding protein-3. J Biol Chem 275:18574-80.
[14]Cowans NJ, Spencer K.2007. First-trimester ADAM12 and PAPP-A as markers for intrauterine fetal growth restriction through their roles in the insulin-like growth factor system.
[15]Makrydimas G, Sotiriadis A, Spencer K, et al. ADAM12-s in coelomic fluid and maternal serum in early p regnancy. PrenatDiagn.2006,26 (13):1197-1200.
[16]Jennie Laigaard, Kevin Spencer, Michael Christiansen, et al. ADAM 12 as a first-trimester maternal serum marker in screening for Down syndrome. Prenat Diagn, August 7,2006.
[17]边旭明,刘俊涛,戚庆炜,等.对孕中期妇女行血清学二联指标筛查胎儿唐氏综合征的多中心前瞻性研究.中华妇产科杂志,2008,43(11)：805-809.
[18]Spencer K.1996. Second trimester prenatal screening for Down's syndrome using alpha-fetoprotein and free beta hCG:a seven year review. Br J Obstet Gynaecol 106:1287-93.
[19]Liao C, Huang Y, Li D, et al.2006. Second-trimester maternal serum screening for Down syndrome in Mainland China. Prenat Diagn 26:1271-2.
[20]Lovgren T, Merio L, Mitrunen K, et al.1996. One-step all-in-one dry reagent immunoassays with fluorescent europium chelate label and time-resolved fluorometry. Clin Chem 42:1196-201.
[21]Reynolds TM, Vranken G, Van Nueten J.2006.Weight correction of MoM values: which method? J Clin Pathol 59:753-8.
[22]Christiansen M, Spencer K, Laigaard J, et al.2007. ADAM 12 as a second-trimester maternal serum marker in screening for Down syndrome. Prent Diagn 27:611-5.
[23]Parsons L, Richards J, Garlick R.1992.Screening for Down's syndrome. BMJ 305:1228.
[1]Ball RH, Caughey AB, Malone FD, Nyberg DA, Comstock CH, Saade GR, et al. First- and second-trimester evaluation of risk for Down syndrome. Obstet Gynecol,2007,110(1):10-17.
[2]ACOG Committee Opinion #296:first-trimester screening for fetal aneuploidy. Obstet Gynecol,2004,104(1):215-217.
[3]边旭明,刘俊涛,戚庆炜,等.对孕中期妇女行血清学二联指标筛查胎儿唐氏综合征的多中心前瞻性研究.中华妇产科杂志,2008,43(11)：805-809.
[4]Cuckle HS, Wald NJ, Lindenbaum RH. Maternal serum alpha-fetoprotein measurement:a screening test for Down syndrome. Lancet,1984,1(8383):926-929.
[5]Bogart MH, M.R. Pandian, O.W. Jones. Abnormal maternal serum chorionic gonadotropin levels in pregnancies with fetal chromosome abnormalities. Prenat Diagn,1987,7(9):623-630.
[6]Wald NJ, Cuckle HS, Densem JW, Nanchahal K, Canick JA, Haddow JE, et al. Maternal serum unconjugated oestriol as an antenatal screening test for Down's syndrome. Br J Obstet Gynaecol,1988,95(4):334-341.
[7]Brizot ML, Hyett JA, McKie AT, Bersinger NA, Farzaneh F, Nicolaides KH. Gene expression of human pregnancy-associated plasma protein-A in placenta from trisomic pregnancies. Placenta,1996,17(1):33-36.
[8]Aitken DA, Wallace EM, Crossley JA, Swanston IA, van Pareren Y, van Maarle M, et al. Dimeric inhibin A as a marker for Down's syndrome in early pregnancy. N Engl J Med,1996,334(19):1231-1236.
[9]Bindra R, Heath V, Liao A, Spencer K, Nicolaides KH. One-stop clinic for assessment of risk for trisomy 21 at 11-14 weeks:a prospective study of 15 030 pregnancies. Ultrasound Obstet Gynecol,2002,20(3):219-225.
[10]Cuckle HS, van Lith JM. Appropriate biochemical parameters in first-trimester screening for Down syndrome. Prenat Diagn,1999,19(6):505-512.
[11]Wald NJ, Watt HC, Hackshaw AK. Integrated screening for Down's syndrome on the basis of tests performed during the first and second trimesters. N Engl J Med, 1999,341(7):461-467.
[12]Grant SS. Options for Down syndrome screening:what will women choose? J Midwifery Womens Health,2005,50(3):211-218.
[13]Rozenberg P, Malagrida L, Cuckle H, Durand-Zaleski I, Nisand I, Audibert F, et al. Down's syndrome screening with nuchal translucency at 12(+0)-14(+0) weeks and maternal serum markers at 14(+1)-17(+0) weeks:a prospective study. Hum Reprod,2002,17(4):1093-1098.
[14]Saller DN, Jr., Canick JA. Current methods of prenatal screening for Down syndrome and other fetal abnormalities. Clin Obstet Gynecol,2008,51(1):24-36.
[15]Shaw SW, Hsu JJ, Lee CN, Hsiao CH, Chen CP, Hsieh TT, et al. First-and second-trimester Down syndrome screening:current strategies and clinical guidelines. Taiwan J Obstet Gynecol,2008,47(2):157-162.
[16]Platt LD, Greene N, Johnson A, Zachary J, Thom E, Krantz D, et al. Sequential pathways of testing after first-trimester screening for trisomy 21. Obstet Gynecol, 2004,104(4):661-666.
[17]Benn P, Wright D, Cuckle H. Practical strategies in contingent sequential screening for Down syndrome. Prenat Diagn,2005,25(8):645-652.
[18]Cuckle H, Benn P, Wright D. Down syndrome screening in the first and/or second trimester:model predicted performance using meta-analysis parameters. Semin Perinatol,2005,29(4):252-257.
[19]Wright D, Bradbury I, Cuckle H, Gardosi J, Tonks A, Standing S, et al. Three-stage contingent screening for Down syndrome. Prenat Diagn,2006,26(6): 528-534.
[20]Laigaard J, Sorensen T, Frohlich C, Pedersen BN, Christiansen M, Schiott K, et al. ADAM 12:a novel first-trimester maternal serum marker for Down syndrome. Prenat Diagn,2003,23(13):1086-1091.
[21]Laigaard J, Cuckle H, Wewer UM, Christiansen M. Maternal serum ADAM 12 levels in Down and Edwards'syndrome pregnancies at 9-12 weeks' gestation. Prenat Diagn,2006,26(8):689-691.
[22]Christiansen M, Pihl K, Hedley PL, Gjerris AC, Lind PO, Larsen SO, et al. ADAM 12 may be used to reduce the false positive rate of first trimester combined screening for Down syndrome. Prenat Diagn,2010,30(2):110-114.
[23]Loechel F, Fox JW, Murphy G, et al. ADAM 12-S cleaves IGFBP-3 and IGFBP-5 and is inhibited by TIMP-3. B iochem B iophysRes Commun,2000, 278:511.
[24]Shi Z, Xu W, Loechel F, et al.2000. ADAM 12, a disintegrin metalloprotease, interacts with insulin-like growth factor-binding protein-3. J Biol Chem 275:18574-80.
[25]Cowans NJ, Spencer K. First-trimester ADAM12 and PAPP-A as markers for intrauterine fetal growth restriction through their roles in the insulin-like growth factor system.2007 Prenat Diagn.2007,27(3):264-71.
[26]Makrydimas G, Sotiriadis A, Spencer K, et al. ADAM12-S in coelomic fluid and maternal serum in early p regnancy. PrenatDiagn.2006,26 (13):1197-1200.
[27]Laigaard J, Spencer K, Christiansen M, Cowans NJ, Larsen SO, Pedersen BN, et al. ADAM 12 as a first-trimester maternal serum marker in screening for Down syndrome. Prenat Diagn,2006,26(10):973-979.
[28]Christiansen M, Spencer K, Laigaard J, et al.2007. ADAM 12 as a second-trimester maternal serum marker in screening for Down syndrome. Prent Diagn 27:611-5
[29]Christiansen M, Pihl K, Hedley PL, Gjerris AC, Lind PO, Larsen SO, et al. ADAM 12 may be used to reduce the false positive rate of first trimester combined screening for Down syndrome. Prenat Diagn,2010,30(2):110-114.
[30]Cicero S, Longo D, Rembouskos G, Sacchini C, Nicolaides KH. Absent nasal bone at 11-14 weeks of gestation and chromosomal defects. Ultrasound Obstet Gynecol,2003,22(1):31-35.
[31]Leung TY, Spencer K, Leung TN, Fung TY, Lau TK. Higher median levels of free beta-hCG and PAPP-A in the first trimester of pregnancy in a Chinese ethnic group. Implication for first trimester combined screening for Down's syndrome in the Chinese population. Fetal Diagn Ther,2006,21(1):140-143.
[32]First-trimester or second-trimester screening, or both, for Down's syndrome. N Engl J Med,2005,353(19):2001-2011.
[33]Wald NJ, Watt HC, Hackshaw AK. Integrated screening for Down's syndrome on the basis of tests performed during the first and second trimesters. N Engl J Med, 1999,341(7):461-467.
[34]Rozenberg P, Malagrida L, Cuckle H, Durand-Zaleski I, Nisand I, Audibert F, et al. Down's syndrome screening with nuchal translucency at 12(+0)-14(+0) weeks and maternal serum markers at 14(+1)-17(+0) weeks:a prospective study. Hum Reprod,2002,17(4):1093-1098.
[35]Grant SS. Options for Down syndrome screening:what will women choose? J Midwifery Womens Health,2005,50(3):211-218.
[36]Wortelboer EJ, Linskens IH, Koster MP, et al. ADAM12s as a firsttrimester screening marker of trisomy. Prenat Diagn.2009.29:866-869.
[37]Wang M, Lu S, Zhu Y, Li H. ADAM 12 is an effective marker in the second trimester of pregnancy for prenatal screening of Down syndrome. Prenat Diagn. 2010.30:561-4.
[38]Valinen Y, Peuhkurinen S, Jarvela IY, Laitinen P, Ryynanen M. Maternal Serum ADAM 12 Levels Correlate with PAPP-A Levels during the First Trimester. Gynecol Obstet Invest,2010,70(1):60-63.
[39]Qin QP, Christiansen M, Pettersson K. Point-of-care time-resolved immunofluorometric assay for human pregnancy-associated plasma protein A: use in first-trimester screening for Down syndrome. Clin Chem,2002,48(3): 473-483.
[40]Hwa V, Oh Y, Rosenfeld RG. The insulin-like growth factor-binding protein (IGFBP) superfamily. Endocr Rev,1999,20(6):761-787.
[1]Spencer K. Screening for trisomy 21 in twin pregnancies in the first trimester using free beta-hCG and PAPP-A, combined with fetal nuchal translucency thickness. Prenat Diagn,2000,20(2):91-95.
[2]郭淑惠,王婧岚,李慧丽.新生儿性别比及双胎率和畸形率调查结果分析.中国妇幼保健,2006,7：977-978.
[3]Nicolaides KH SN, Snijders RJM. The 11-14 Week Scan. The Diagnosis of Fetal Abnormalities. London:Parthenon Publishing,1999,168-174.
[4]Kohl SG, Casey G. Twin gestation. Mt Sinai J Med,1975,42(6):523-539.
[5]Odibo AO, Lawrence-Cleary K, Macones GA. Screening for aneuploidy in twins and higher-order multiples:is first-trimester nuchal translucency the solution? Obstet Gynecol Surv,2003,58(9):609-614.
[6]Russell RB, Petrini JR, Damus K, Mattison DR, Schwarz RH. The changing epidemiology of multiple births in the United States. Obstet Gynecol,2003, 101(1):129-135.
[7]Neveux LM, Palomaki GE, Knight GJ, Haddow JE. Multiple marker screening for Down syndrome in twin pregnancies. Prenat Diagn,1996,16(1):29-34.
[8]ACOG Practice Bulletin No.77:screening for fetal chromosomal abnormalities. Obstet Gynecol,2007,109(1):217-227.
[9]Laigaard J, Sorensen T, Frohlich C, Pedersen BN, Christiansen M, Schiott K, et al. ADAM 12:a novel first-trimester maternal serum marker for Down syndrome. Prenat Diagn,2003,23(13):1086-1091.
[10]Laigaard J, Cuckle H, Wewer UM, Christiansen M. Maternal serum ADAM 12 levels in Down and Edwards' syndrome pregnancies at 9-12 weeks' gestation. Prenat Diagn,2006,26(8):689-691.
[11]Christiansen M, Pihl K, Hedley PL, Gjerris AC, Lind PO, Larsen SO, et al. ADAM 12 may be used to reduce the false positive rate of first trimester combined screening for Down syndrome. Prenat Diagn,2010,30(2):110-114.
[12]Laigaard J, Spencer K, Christiansen M, Cowans NJ, Larsen SO, Pedersen BN, et al. ADAM 12 as a first-trimester maternal serum marker in screening for Down syndrome. Prenat Diagn,2006,26(10):973-979.
[13]Christiansen M, Pihl K, Hedley PL, Gjerris AC, Lind PO, Larsen SO, et al. ADAM 12 may be used to reduce the false positive rate of first trimester combined screening for Down syndrome. Prenat Diagn,2010,30(2):110-114.
[14]Spencer K, Cowans NJ, Uldbjerg N, Torring N:First-trimester ADAM12s as early markers of trisomy 21:a promise still unfulfilled? Prenat Diagn,2008, 28:338-342.
[15]Valinen Y, Laitinen P, Ranta J, et al. Effect of a new marker, ADAM 12, on Down risk figures in first trimester screening. J Matern Fetal Neonatal Med,2009, 22:602-607.
[16]Laigaard J, Cuckle H, Wewer UM, Christiansen M:Maternal serum ADAM 12 levels in Down and Edwards' syndrome pregnancies at 9-12 weeks' gestation. Prenat Diagn,2006,26:689-691.
[17]Makrydimas G, Sotiriadis A, Spencer K, et al. ADAM 12-s in coelomic fluid and maternal serum in early pregnancy. Prenat Diagn,2006,26:1197-1200.
[18]Wortelboer EJ, Linskens IH, Koster MP, et al. ADAM12s as a firsttrimester screening marker of trisomy. Prenat Diagn,2009,29:866-869.
[19]Christiansen M, Spencer K, Laigaard J, et al. ADAM 12 as a second trimester maternal serum markers in screening for Down's syndrome. Prenat Diagn, 2007,27:611-615.
[20]Wang M, Lu S, Zhu Y, Li H. ADAM 12 is an effective marker in the second trimester of pregnancy for prenatal screening of Down syndrome. Prenat Diagn, 2010,30:561-4.
[21]M. P. H. Koster, E. J. Wortelboer, Ph. Stoutenbeek,et al.Distributions of current and new first-trimester Down syndrome screening markers in twin pregnancies. Prenat Diagn,2010,30:413-417
[22]边旭明,刘俊涛,戚庆炜,等.对孕中期妇女行血清学二联指标筛查胎儿唐氏综合征的多中心前瞻性研究.中华妇产科杂志,2008,43(11)：805-809.
[23]Nyboe Andersen A, Gianaroli L, Nygren KG. Assisted reproductive technology in Europe,2000. Results generated from European registers by ESHRE. Hum Reprod, 2004:490-503.
[24]Gjerris AC, Loft A, Pinborg A,et al. First-trimester screening markers are altered in pregnancies conceived after IVF/ICSI. Ultrasound Obstet Gynecol 2009; 33: 8-17.
[25]Amor DJ, Xu JX, Halliday JL,et al. Pregnancies conceived using assisted reproductive technologies (ART) have low levels of pregnancy-associated plasma protein-A (PAPP-A) leading to a high rate of false-positive results in first trimester screening for Down syndrome. Hum Reprod.2009,26(6):1330-8.
[26]Maymon R, Herman A, Shulman A, et al.First trimester embryo reduction:a medical solution to an iatrogenic problem. Hum Reprod.1995,10:668-73.
[27]Raty R, Virtanen A, Koskinen P, Laitinen P, Forsstrom J, Salonen R, et al. Maternal midtrimester serum AFP and free beta-hCG levels in in vitro fertilization twin pregnancies. Prenat Diagn,2000,20(3):221-223.
[28]Laigaard J, Pedersen NG, Larsen SO, et al. ADAM 12 in first trimester maternal serum from pregnancies conceived by assisted reproduction techniques (ART). Prenat Diagn,2009,29:628-629.
[29]Orlandi F, Rossi C, Allegra A, et al. First trimester screening with free beta-hCG, PAPP-A and nuchal translucency in pregnancies conceived with assisted reproduction. Prenat Diagn,2002,22:718-721.
[30]Raty R, Virtanen A, Koskinen P, et al. Maternal midtrimester serum AFP and free beta-hCG levels in in vitro fertilization twin pregnancies. Prenat Diagn,2000,20: 221-223.
[31]Monteagudo A, Timor-Tritsch IE, Sharma S. Early and simple determination of chorionic and amniotic type in multifetal gestations in the first fourteen weeks by high-frequency transvaginal ultrasonography. Am J Obstet Gynecol,1994,170(3): 824-829.
[32]Sepulveda W, Sebire NJ, Hughes K, Odibo A, Nicolaides KH. The lambda sign at 10-14 weeks of gestation as a predictor of chorionicity in twin pregnancies. Ultrasound Obstet Gynecol,1996,7(6):421-423.
[33]Fisk NM BP. Prenatal dtermination of chorionicity and zygosity.In Multiple Pregnancy.Ward RH,White M(eds). RCOG press:London,1995,56-67.
[34]Muller F, Dreux S, Dupoizat H, Uzan S, Dubin MF, Oury JF, et al. Second-trimester Down syndrome maternal serum screening in twin pregnancies: impact of chorionicity. Prenat Diagn,2003,23(4):331-335.
[35]Spencer K.Screening for trisomy 21 in twin pregnancies in the first trimester:does chorionicity impact on maternal serum free β-hCG or PAPP-A levels? Prenat Diagn,2001,21:715-717.
[36]Gonce A, Borrell A, Fortuny A, et al. First trimester screening for trisomy 21 in twin pregnancy:does the addition of biochemistry make an improvement? Prenat Diagn,2005.25:1156-1161.
[37]Wojdemann KR, Larsen SO, Shalmi A-C,Sundberg K, Tabor A,Christiansen M. Nuchal translucency measurements are highly correlated in both mono- and dichorionic twin pairs. Prenat Diagn,2006,26:218-220.
[38]Kevin Spencer, Karl O. Kagan and Kypros H. Nicolaides. Screening for trisomy 21 in twin pregnancies in the first trimester:an update of the impact of chorionicity on maternal serum markers Prenat Diagn,2008; 28:49-52.
[39]Linskens IH, Spreeuwenberg MD, Blankenstein MA, van Vugt JM. Early first-trimester free beta-hCG and PAPP-A serum distributions in monochorionic and dichorionic twins. Prenat Diagn,2009,29:74-78.
[1]Merkatz IR, Nitowsky HM, Macri JN, Johnson WE. An association between low maternal serum alpha-fetoprotein and fetal chromosomal abnormalities. Am J Obstet Gynecol,1984,148(7):886-894.
[2]Bogart MH, M.R. Pandian, O.W. Jones. Abnormal maternal serum chorionic gonadotropin levels in pregnancies with fetal chromosome abnormalities. Prenat Diagn,1987,7(9):623-630.
[3]Wald NJ, Cuckle HS, Densem JW, Nanchahal K, Canick JA, Haddow JE, et al. Maternal serum unconjugated oestriol as an antenatal screening test for Down's syndrome. Br J Obstet Gynaecol,1988,95(4):334-341.
[4]Brizot ML, Hyett JA, McKie AT, Bersinger NA, Farzaneh F, Nicolaides KH. Gene expression of human pregnancy-associated plasma protein-A in placenta from trisomic pregnancies. Placenta,1996,17(1):33-36.
[5]Aitken DA, Wallace EM, Crossley JA, Swanston IA, van Pareren Y, van Maarle M, et al. Dimeric inhibin A as a marker for Down's syndrome in early pregnancy. N Engl J Med,1996,334(19):1231-1236.
[6]Laigaard J, Sorensen T, Frohlich C, Pedersen BN, Christiansen M, Schiott K, et al. ADAM 12:a novel first-trimester maternal serum marker for Down syndrome. Prenat Diagn,2003,23(13):1086-1091.
[7]Laigaard J, Cuckle H, Wewer UM, Christiansen M. Maternal serum ADAM 12 levels in Down and Edwards' syndrome pregnancies at 9-12 weeks' gestation. Prenat Diagn,2006,26(8):689-691.
[8]Christiansen M, Pihl K, Hedley PL, Gjerris AC, Lind PO, Larsen SO, et al. ADAM 12 may be used to reduce the false positive rate of first trimester combined screening for Down syndrome. Prenat Diagn,2010,30(2):110-114.
[9]Loechel F, Fox JW, Murphy G, et al. ADAM 122S cleaves IGFBP-3 and IGFBP-5 and is inhibited by TIMP-3. Biochem Biophys Res Commun,2000,278: 511.
[10]Christiansen M, Spencer K, Laigaard J, et al. ADAM 12 as a second-trimester maternal serum marker in screening for Down syndrome. Prent Diagn,2007,27:611-5.
[11]Cuckle HS, Wald NJ, Lindenbaum RH. Maternal serum alpha-fetoprotein measurement:a screening test for Down syndrome. Lancet,1984,1(8383):926-929.
[12]Haddow JE, Palomaki GE, Knight GJ, Williams J, Pulkkinen A, Canick JA, et al. Prenatal screening for Down's syndrome with use of maternal serum markers. N Engl J Med,1992,327(9):588-593.
[13]Malone FD, Berkowitz RL, Canick JA, D'Alton ME. First-trimester screening for aneuploidy:research or standard of care? Am J Obstet Gynecol,2000,182(3): 490-496.
[14]Wald NJ, Watt HC, Hackshaw AK. Integrated screening for Down's syndrome on the basis of tests performed during the first and second trimesters. N Engl J Med, 1999,341(7):461-467.
[15]Shaw SW, Hsu JJ, Lee CN, Hsiao CH, Chen CP, Hsieh TT, et al. First- and second-trimester Down syndrome screening:current strategies and clinical guidelines. Taiwan J Obstet Gynecol,2008,47(2):157-162.
[16]Nicolaides KH, Azar G, Byme D, Mansur C, Marks K. Fetal nuchal translucency: ultrasound screening for chromosomal defects in first trimester of pregnancy. BMJ,1992,304(6831):867-869.
[17]Mol BW, Lijmer JG, van der Meulen J, Pajkrt E, Bilardo CM, Bossuyt PM. Effect of study design on the association between nuchal translucency measurement and Down syndrome. Obstet Gynecol,1999,94(5 Pt 2):864-869.
[18]Debieve F, Bouckaert A, Hubinont C, Thomas K. Multiple screening for fetal Down's syndrome with the classic triple test, dimeric inhibin A and ultrasound. Gynecol Obstet Invest,2000,49(4):221-226.
[19]Rosen T, D'Alton ME, Platt LD, Wapner R. First-trimester ultrasound assessment of the nasal bone to screen for aneuploidy. Obstet Gynecol,2007,110(2 Pt 1): 399-404.
[20]Moon MH, Cho JY, Lee YM, Jung SI, Yang JH, Kim MY, et al. First-trimester screening for Down syndrome; the role of nasal bone assessment in the Korean population. Prenat Diagn,2007,27(9):830-834.
[21]Stempfle N, Huten Y, Fredouille C, Brisse H, Nessmann C. Skeletal abnormalities in fetuses with Down's syndrome:a radiographic post-mortem study. Pediatr Radiol,1999,29(9):682-688.
[22]Tuxen A, Keeling JW, Reintoft I, Fischer Hansen B, Nolting D, Kjaer I. A histological and radiological investigation of the nasal bone in fetuses with Down syndrome. Ultrasound Obstet Gynecol,2003,22(1):22-26.
[23]Cicero S, Curcio P, Papageorghiou A, Sonek J, Nicolaides K. Absence of nasal bone in fetuses with trisomy 21 at 11-14 weeks of gestation:an observational study. Lancet,2001,358(9294):1665-1667.
[24]Gianferrari EA, Benn PA, Dries L, et al. Absent or shotened nasal bone length and the detection of Down syndrome in second trimester fetuses. Obstet Gynecol,2007,109(2):3712-3751.
[25]Nyberg DA, SouterVL. Use of genetic sonography for adjusting the risk for fetal Down syndrome. Semin Perinatol,2003,27(2):1302-1441.
[26]Gaglio P, Danelon D, Bontempo S,et al.Fetal cerebral ventriculomegaly: outcome in 176 cases.Utrasound Obstet Gynecol,2005,25:372-377.
[27]M Wyldes, M Watkinson. Isolated mild fetal lateral ventrieulomegaly. Arch.Dis. Child.Fetal Neonatal,20o4,89:92-103.
[28]Scott A. Nuchal translucency measurement in first trimester Down syndrome screening. Issues Emerg Health Technol,2007,100:1-6.
[29]吕时铭.我国产前诊断技术发展与质量控制.中华检验医学杂志,2010,33(2)：101-104.
[30]Bianchi D W,Simpson J L, Jackson L G, et al.Fetal gender and aneuploidy detection using fetal cells in maternal blood:Analysis of N IFTY data. Prenat Diagn.2002,22:609-615.
[31]Dan DA,Maria G,Tmjillo MJ,et al.Appficafion of quantitative fluorescent PCR with short tandem repeat markers to the study of aneuploidies in spontaneous miscarriages. Hum Reprod.2005,20(5):1235-1243.
[32]Schaefer AJ, Chung J, Heretis K,et al.Comparative genomic hybridization-array analysis enhances the detection of aneuploidies and submieroscopic imbalance in spontaneous miscarriages. Am H Hum Genet.2004,74(6):1168-1174.
[33]Parano E,Falcidia E,Grillo A, et al. Noninvasive prenatal diagnosis of chromosomal aneuploidies by isolation and analysis of fetal cells from maternal blood. Am J Med Genet,2001,101:262-267.
[34]Lo YM, Corbetta N, Chamberlain PF, et al. Presence of fetal DNA in maternal plasma and serum. Lancet,1997,350:485-487.
[35]Lo YM, Lau TK, Zhang J,et al. Increased fetal DNA concentrations in the plasma of pregnant women carrying fetuses with trisomy 21.Clin Chem,1999,45:1747-1751.
[36]Chinnapapagari SK, HolzgreveW,Lapaire O, et al. Treatment of maternal blood samples with formaldehyde does not alter the proportion of circulatory fetal nucleic acids (DNA and mRNA) in maternal plasma. Clin Chem,2005,51:652-655.
[37]Chung GT, Chiu RW, Chan KC, et al. Lack of dramatic enrichment of fetal DNA in maternal plasma by formaldehyde treatment. Clin Chem,2005,51:655-658.
[38]Tsui NB, et al. Systematic micro-array based identification of placental mRNA in maternal plasma:towards non-invasive prenatal gene expression profiling. J Med Genet,2004,41:461-467.
[2]Driscoll DA, Gross S. Clinical practice. Prenatal screening for aneuploidy. N Engl J Med,2009,360(24):2556-2562.
[3]Penrose LS. Maternal age in familial mongolism. J Ment Sci,1951,97(409): 738-747.
[4]Hook EB, Chambers GM. Estimated rates of Down syndrome in live births by one year maternal age intervals for mothers aged 20-49 in a New York State study-implications of the risk figures for genetic counseling and cost-benefit analysis of prenatal diagnosis programs. Birth Defects Orig Artic Ser,1977, 13(3A):123-141.
[5]Lamson SH, Hook EB. A simple function for maternal-age-specific rates of Down syndrome in the 20-to-49-year age range and its biological implications. Am J Hum Genet,1980,32(5):743-753.
[6]Domm ergues M, Audib ert F, Benatt ar C, et al. Is routine amniocentesis for advanced maternal age still indicated? Fetal Diagnosis therapy,2001,16: 372-377
[7]Audibert F, Mairovit z V, Frydman R. Alternatives to amniocentesis for advanced mat ernal age. Gynecol Obstet Fetil,2002,30:562-566.
[8]Merkatz IR, Nitowsky HM, Macri JN, Johnson WE. An association between low maternal serum alpha-fetoprotein and fetal chromosomal abnormalities. Am J Obstet Gynecol,1984,148(7):886-894.
[9]Bogart MH, M.R. Pandian, O.W. Jones. Abnormal maternal serum chorionic gonadotropin levels in pregnancies with fetal chromosome abnormalities. Prenat Diagn,1987,7(9):623-630.
[10]Wald NJ, Cuckle HS, Densem JW, Nanchahal K, Canick JA, Haddow JE, et al. Maternal serum unconjugated oestriol as an antenatal screening test for Down's syndrome. Br J Obstet Gynaecol,1988,95(4):334-341.
[11]Brizot ML, Hyett JA, McKie AT, Bersinger NA, Farzaneh F, Nicolaides KH. Gene expression of human pregnancy-associated plasma protein-A in placenta from trisomic pregnancies. Placenta,1996,17(1):33-36.
[12]Aitken DA, Wallace EM, Crossley JA, Swanston IA, van Pareren Y, van Maarle M, et al. Dimeric inhibin A as a marker for Down's syndrome in early pregnancy. N Engl J Med,1996,334(19):1231-1236.
[13]Debieve F, Bouckaert A, Hubinont C, Thomas K. Multiple screening for fetal Down's syndrome with the classic triple test, dimeric inhibin A and ultrasound. Gynecol Obstet Invest,2000,49(4):221-226.
[14]Tux en A, Keeling JW, Reintoft I, Fischer Hansen B, Nolting D, Kjaer I. A histological and radiological investigation of the nasal bone in fetuses with Down syndrome. Ultrasound Obstet Gynecol,2003,22(1):22-26.
[15]Cuckle HS, Wald NJ, Lindenbaum RH. Maternal serum alpha-fetoprotein measurement:a screening test for Down syndrome. Lancet,1984,1(8383):926-929.
[16]Haddow JE, Palomaki GE, Knight GJ, Williams J, Pulkkinen A, Canick JA, et al. Prenatal screening for Down's syndrome with use of maternal serum markers. N Engl J Med,1992,327(9):588-593.
[17]Malone FD, Canick JA, Ball RH, Nyberg DA, Comstock CH, Bukowski R, et al. First-trimester or second-trimester screening, or both, for Down's syndrome. N Engl J Med,2005,353(19):2001-2011.
[18]Snijders RJ, Thom EA, Zachary JM, Platt LD, Greene N, Jackson LG, et al. First-trimester trisomy screening:nuchal translucency measurement training and quality assurance to correct and unify technique. Ultrasound Obstet Gynecol, 2002,19(4):353-359.
[19]Wald NJ, Watt HC, Hackshaw AK. Integrated screening for Down's syndrome on the basis of tests performed during the first and second trimesters. N Engl J Med, 1999,341(7):461-467.
[20]Grant SS. Options for Down syndrome screening:what will women choose? J Midwifery Womens Health,2005,50(3):211-218.
[21]Rozenberg P, Malagrida L, Cuckle H, Durand-Zaleski I, Nisand I, Audibert F, et al. Down's syndrome screening with nuchal translucency at 12(+0)-14(+0) weeks and maternal serum markers at 14(+1)-17(+0) weeks:a prospective study. Hum Reprod,2002,17(4):1093-1098.
[22]Scott A. Nuchal translucency measurement in first trimester Down syndrome screening. Issues Emerg Health Technol,2007,100:1-6.
[23]Laigaard J, Sorensen T, Frohlich C, Pedersen BN, Christiansen M, Schiott K, et al. ADAM 12:a novel first-trimester maternal serum marker for Down syndrome. Prenat Diagn,2003,23(13):1086-1091.
[24]Laigaard J, Cuckle H, Wewer UM, Christiansen M. Maternal serum ADAM 12 levels in Down and Edwards'syndrome pregnancies at 9-12 weeks'gestation. Prenat Diagn,2006,26(8):689-691.
[25]Christiansen M, Pihl K, Hedley PL, Gjerris AC, Lind PO, Larsen SO, et al. ADAM 12 may be used to reduce the false positive rate of first trimester combined screening for Down syndrome. Prenat Diagn,2010,30(2):110-114.
[26]Makrydimas G, Sotiriadis A, Spencer K, et al. ADAM 122s in coelomic fluid and maternal serum in early p regnancy. Prenat Diagn.2006,26 (13):1197-1200.
[27]Loechel F, Fox JW, Murphy G, et al. ADAM 122S cleaves IGFBP-3 and IGFBP-5 and is inhibited by TIMP-3. Biochem Biophys Res Commun,2000,278: 511.
[28]Christiansen M, Spencer K, Laigaard J, et al. ADAM 12 as a second-trimester maternal serum marker in screening for Down syndrome. Prent Diagn,2007,27:611-5.
[29]郭淑惠,王婧岚,李慧丽.新生儿性别比及双胎率和畸形率调查结果分析.中国妇幼保健,2006,7：977-978
[30]Lam YH, Ghosh A, Tang MH, Tang LC, Lee CP, Sin SY, et al. Second-trimester maternal serum alpha-fetoprotein and human chorionic gonadotrophin screening for Down's syndrome in Hong Kong. Prenat Diagn,1998,18(6):585-589.
[31]Chao AS, Chung CL, Wu CD, Chang SD, Cheng PJ, Lin YT, et al. Second trimester maternal serum screening using alpha fetoprotein, free beta human chorionic gonadotropin and maternal age specific risk:result of chromosomal abnormalities detected in screen positive for Down syndrome in an Asian population. Acta Obstet Gynecol Scand,1999,78(5):393-397.
[32]Jou HJ, Shyu MK, Chen SM, Shih JC, Hsu JJ, Hsieh FJ. Maternal serum screening for down syndrome by using alpha-fetoprotein and human chorionic gonadotropin in an asian population.a prospective study. Fetal Diagn Ther,2000, 15(2):108-111.
[1]Driscoll DA, Gross S. Clinical practice. Prenatal screening for aneuploidy. N Engl J Med,2009,360(24):2556-2562.
[2]Korenberg JR, Chen XN, Schipper R, et al. Down syndrome phenotypes:the consequences of chromosomal imbalance.Proc Natl Acad Sci USA 1994;91:4997-5001.
[3]Shaw SW, Chen CP, Cheng PJ, et al. Gene dosage change of TPTE and BAGE2 and breakpoint analysis in Robertsonian Down syndrome. J Hum Genet 2008;53:136-43.
[4]Cuckle HS, Wald NJ, Lindenbaum RH. Maternal serum alpha-fetoprotein measurement:a screening test for Down syndrome. Lancet,1984,1(8383):926-929.
[5]Bogart MH, M.R. Pandian, O.W. Jones. Abnormal maternal serum chorionic gonadotropin levels in pregnancies with fetal chromosome abnormalities. Prenat Diagn,1987,7(9):623-630.
[6]Wald NJ, Cuckle HS, Densem JW, Nanchahal K, Canick JA, Haddow JE, et al. Maternal serum unconjugated oestriol as an antenatal screening test for Down's syndrome. Br J Obstet Gynaecol,1988,95(4):334-341.
[7]Brizot ML, Hyett JA, McKie AT, Bersinger NA, Farzaneh F, Nicolaides KH. Gene expression of human pregnancy-associated plasma protein-A in placenta from trisomic pregnancies. Placenta,1996,17(1):33-36.
[8]Aitken DA, Wallace EM, Crossley JA, Swanston IA, van Pareren Y, van Maarle M, et al. Dimeric inhibin A as a marker for Down's syndrome in early pregnancy. N Engl J Med,1996,334(19):1231-1236.
[9]Bindra R, Heath V, Liao A, Spencer K, Nicolaides KH. One-stop clinic for assessment of risk for trisomy 21 at 11-14 weeks:a prospective study of 15 030 pregnancies. Ultrasound Obstet Gynecol,2002,20(3):219-225.
[10]Cuckle HS, van Lith JM. Appropriate biochemical parameters in first-trimester screening for Down syndrome. Prenat Diagn,1999,19(6):505-512.
[11]Wald NJ, Watt HC, Hackshaw AK. Integrated screening for Down's syndrome on the basis of tests performed during the first and second trimesters. N Engl J Med, 1999,341(7):461-467.
[12]Grant SS. Options for Down syndrome screening:what will women choose? J Midwifery Womens Health,2005,50(3):211-218.
[13]Rozenberg P, Malagrida L, Cuckle H, Durand-Zaleski I, Nisand I, Audibert F, et al. Down's syndrome screening with nuchal translucency at 12(+0)-14(+0) weeks and maternal serum markers at 14(+1)-17(+0) weeks:a prospective study. Hum Reprod,2002,17(4):1093-1098.
[14]Saller DN, Jr., Canick JA. Current methods of prenatal screening for Down syndrome and other fetal abnormalities. Clin Obstet Gynecol,2008,51(1):24-36.
[15]Shaw SW, Hsu JJ, Lee CN, Hsiao CH, Chen CP, Hsieh TT, et al. First-and second-trimester Down syndrome screening:current strategies and clinical guidelines. Taiwan J Obstet Gynecol,2008,47(2):157-162.
[16]Platt LD, Greene N, Johnson A, Zachary J, Thom E, Krantz D, et al. Sequential pathways of testing after first-trimester screening for trisomy 21. Obstet Gynecol, 2004,104(4):661-666.
[17]Benn P, Wright D, Cuckle H. Practical strategies in contingent sequential screening for Down syndrome. Prenat Diagn,2005,25(8):645-652.
[18]Cuckle H, Benn P, Wright D. Down syndrome screening in the first and/or second trimester:model predicted performance using meta-analysis parameters. Semin Perinatol,2005,29(4):252-257.
[19]Wright D, Bradbury I, Cuckle H, Gardosi J, Tonks A, Standing S, et al. Three-stage contingent screening for Down syndrome. Prenat Diagn,2006,26(6): 528-534.
[20]Wald NJ, Rodeck C, Hackshaw AK, Rudnicka A. SURUSS in perspective. BJOG, 2004,111(6):521-531.
[21]Wald NJ, Rodeck C, Hackshaw AK, Rudnicka A. SURUSS in perspective. Semin Perinatol,2005,29(4):225-235.
[22]Wald NJ, Rodeck C, Hackshaw AK, Walters J, Chitty L, Mackinson AM. First and second trimester antenatal screening for Down's syndrome:the results of the Serum, Urine and Ultrasound Screening Study (SURUSS). Health Technol Assess,2003,7(11):1-77.
[23]Ball RH, Caughey AB, Malone FD, Nyberg DA, Comstock CH, Saade GR, et al. First- and second-trimester evaluation of risk for Down syndrome. Obstet Gynecol,2007,110(1):10-17.
[24]Cleary-Goldman J, Malone FD, Vidaver J, Ball RH, Nyberg DA, Comstock CH, et al. Impact of maternal age on obstetric outcome. Obstet Gynecol,2005,105(5 Pt 1):983-990.
[25]Malone FD, Ball RH, Nyberg DA, Comstock CH, Saade G, Berkowitz RL, et al. First-trimester nasal bone evaluation for aneuploidy in the general population. Obstet Gynecol,2004,104(6):1222-1228.
[26]Malone FD, Canick JA, Ball RH, Nyberg DA, Comstock CH, Bukowski R, et al. First-trimester or second-trimester screening, or both, for Down's syndrome. N Engl J Med,2005,353(19):2001-2011.
[27]Domm ergues M, Audib ert F, Benatt ar C, et al. Is routine amniocentesis for advanced maternal age still indicated? Fetal Diagnosis therapy,2001,16: 372-377
[28]Audibert F, Mairovit z V, Frydman R. Alternatives to amniocentesis for advanced mat ernal age. Gynecol Obstet Fetil,2002,30:562-566.
[29]Bian XM, Liu J T, Qi QW, et al. Second trimester maternal serum screening for Down's syndrome in mainland China:A multi-center prospective study. Chin J Obstet Gynecol,2008,43 (11):805-809.
[30]ACOG Practice Bulletin No.77:Screening for fetal chromosomal abnormalities. Obstet Gynecol,2007,109 (1):217-227.
[31]ACOG Practice bulletin. Clinical management guidelines for obstetrician gynecolostists. Invasive prenatal testing for aneuploidy. Obstet Gynecol,2007 110:1459-1466.
[1]Korenberg JR, Chen XN, Schipper R, et al.1994. Down syndrome phenotypes: the consequences of chromosomal imbalance. Proc Natl Acad Sci USA 91:4997-5001.
[2]Shaw SW, Chen CP, Cheng PJ, et al.2008. Gene dosage change of TPTE and BAGE2 and breakpoint analysis in Robertsonian Down syndrome. J Hum Genet 53:136-43.
[3]Merkatz IR, Nitowsky HM, Macri JN, Johnson WE. An association between low maternal serum alpha-fetoprotein and fetal chromosomal abnormalities. Am J Obstet Gynecol,1984,148(7):886-894.
[4]Cuckle HS, Wald NJ, Lindenbaum RH. Maternal serum alpha-fetoprotein measurement:a screening test for Down syndrome. Lancet,1984,1(8383):926-929.
[5]Bogart MH, M.R. Pandian, O.W. Jones. Abnormal maternal serum chorionic gonadotropin levels in pregnancies with fetal chromosome abnormalities. Prenat Diagn,1987,7(9):623-630.
[6]Wald NJ, Cuckle HS, Densem JW, Nanchahal K, Canick JA, Haddow JE, et al. Maternal serum unconjugated oestriol as an antenatal screening test for Down's syndrome. Br J Obstet Gynaecol,1988,95(4):334-341.
[7]Brizot ML, Hyett JA, McKie AT, Bersinger NA, Farzaneh F, Nicolaides KH. Gene expression of human pregnancy-associated plasma protein-A in placenta from trisomic pregnancies. Placenta,1996,17(1):33-36.
[8]Aitken DA, Wallace EM, Crossley JA, Swanston IA, van Pareren Y, van Maarle M, et al. Dimeric inhibin A as a marker for Down's syndrome in early pregnancy. N Engl J Med,1996,334(19):1231-1236.
[9]Laigaard J, Sorensen T, Frohlich C, Pedersen BN, Christiansen M, Schiott K, et al. ADAM 12:a novel first-trimester maternal serum marker for Down syndrome. Prenat Diagn,2003,23(13):1086-1091.
[10]Laigaard J, Cuckle H, Wewer UM, Christiansen M. Maternal serum ADAM 12 levels in Down and Edwards' syndrome pregnancies at 9-12 weeks' gestation. Prenat Diagn,2006,26(8):689-691.
[11]Christiansen M, Pihl K, Hedley PL, Gjerris AC, Lind PO, Larsen SO, et al. ADAM 12 may be used to reduce the false positive rate of first trimester combined screening for Down syndrome. Prenat Diagn,2010,30(2):110-114.
[12]Loechel F, Fox JW, Murphy G, et al. ADAM 12-S cleaves IGFBP-3 and IGFBP-5 and is inhibited by TIMP-3. B iochem B iophysRes Commun,2000,278:511.
[13]Shi Z, Xu W, Loechel F, et al.2000. ADAM 12, a disintegrin metalloprotease, interacts with insulin-like growth factor-binding protein-3. J Biol Chem 275:18574-80.
[14]Cowans NJ, Spencer K.2007. First-trimester ADAM12 and PAPP-A as markers for intrauterine fetal growth restriction through their roles in the insulin-like growth factor system.
[15]Makrydimas G, Sotiriadis A, Spencer K, et al. ADAM12-s in coelomic fluid and maternal serum in early p regnancy. PrenatDiagn.2006,26 (13):1197-1200.
[16]Jennie Laigaard, Kevin Spencer, Michael Christiansen, et al. ADAM 12 as a first-trimester maternal serum marker in screening for Down syndrome. Prenat Diagn, August 7,2006.
[17]边旭明,刘俊涛,戚庆炜,等.对孕中期妇女行血清学二联指标筛查胎儿唐氏综合征的多中心前瞻性研究.中华妇产科杂志,2008,43(11)：805-809.
[18]Spencer K.1996. Second trimester prenatal screening for Down's syndrome using alpha-fetoprotein and free beta hCG:a seven year review. Br J Obstet Gynaecol 106:1287-93.
[19]Liao C, Huang Y, Li D, et al.2006. Second-trimester maternal serum screening for Down syndrome in Mainland China. Prenat Diagn 26:1271-2.
[20]Lovgren T, Merio L, Mitrunen K, et al.1996. One-step all-in-one dry reagent immunoassays with fluorescent europium chelate label and time-resolved fluorometry. Clin Chem 42:1196-201.
[21]Reynolds TM, Vranken G, Van Nueten J.2006.Weight correction of MoM values: which method? J Clin Pathol 59:753-8.
[22]Christiansen M, Spencer K, Laigaard J, et al.2007. ADAM 12 as a second-trimester maternal serum marker in screening for Down syndrome. Prent Diagn 27:611-5.
[23]Parsons L, Richards J, Garlick R.1992.Screening for Down's syndrome. BMJ 305:1228.
[1]Ball RH, Caughey AB, Malone FD, Nyberg DA, Comstock CH, Saade GR, et al. First- and second-trimester evaluation of risk for Down syndrome. Obstet Gynecol,2007,110(1):10-17.
[2]ACOG Committee Opinion #296:first-trimester screening for fetal aneuploidy. Obstet Gynecol,2004,104(1):215-217.
[3]边旭明,刘俊涛,戚庆炜,等.对孕中期妇女行血清学二联指标筛查胎儿唐氏综合征的多中心前瞻性研究.中华妇产科杂志,2008,43(11)：805-809.
[4]Cuckle HS, Wald NJ, Lindenbaum RH. Maternal serum alpha-fetoprotein measurement:a screening test for Down syndrome. Lancet,1984,1(8383):926-929.
[5]Bogart MH, M.R. Pandian, O.W. Jones. Abnormal maternal serum chorionic gonadotropin levels in pregnancies with fetal chromosome abnormalities. Prenat Diagn,1987,7(9):623-630.
[6]Wald NJ, Cuckle HS, Densem JW, Nanchahal K, Canick JA, Haddow JE, et al. Maternal serum unconjugated oestriol as an antenatal screening test for Down's syndrome. Br J Obstet Gynaecol,1988,95(4):334-341.
[7]Brizot ML, Hyett JA, McKie AT, Bersinger NA, Farzaneh F, Nicolaides KH. Gene expression of human pregnancy-associated plasma protein-A in placenta from trisomic pregnancies. Placenta,1996,17(1):33-36.
[8]Aitken DA, Wallace EM, Crossley JA, Swanston IA, van Pareren Y, van Maarle M, et al. Dimeric inhibin A as a marker for Down's syndrome in early pregnancy. N Engl J Med,1996,334(19):1231-1236.
[9]Bindra R, Heath V, Liao A, Spencer K, Nicolaides KH. One-stop clinic for assessment of risk for trisomy 21 at 11-14 weeks:a prospective study of 15 030 pregnancies. Ultrasound Obstet Gynecol,2002,20(3):219-225.
[10]Cuckle HS, van Lith JM. Appropriate biochemical parameters in first-trimester screening for Down syndrome. Prenat Diagn,1999,19(6):505-512.
[11]Wald NJ, Watt HC, Hackshaw AK. Integrated screening for Down's syndrome on the basis of tests performed during the first and second trimesters. N Engl J Med, 1999,341(7):461-467.
[12]Grant SS. Options for Down syndrome screening:what will women choose? J Midwifery Womens Health,2005,50(3):211-218.
[13]Rozenberg P, Malagrida L, Cuckle H, Durand-Zaleski I, Nisand I, Audibert F, et al. Down's syndrome screening with nuchal translucency at 12(+0)-14(+0) weeks and maternal serum markers at 14(+1)-17(+0) weeks:a prospective study. Hum Reprod,2002,17(4):1093-1098.
[14]Saller DN, Jr., Canick JA. Current methods of prenatal screening for Down syndrome and other fetal abnormalities. Clin Obstet Gynecol,2008,51(1):24-36.
[15]Shaw SW, Hsu JJ, Lee CN, Hsiao CH, Chen CP, Hsieh TT, et al. First-and second-trimester Down syndrome screening:current strategies and clinical guidelines. Taiwan J Obstet Gynecol,2008,47(2):157-162.
[16]Platt LD, Greene N, Johnson A, Zachary J, Thom E, Krantz D, et al. Sequential pathways of testing after first-trimester screening for trisomy 21. Obstet Gynecol, 2004,104(4):661-666.
[17]Benn P, Wright D, Cuckle H. Practical strategies in contingent sequential screening for Down syndrome. Prenat Diagn,2005,25(8):645-652.
[18]Cuckle H, Benn P, Wright D. Down syndrome screening in the first and/or second trimester:model predicted performance using meta-analysis parameters. Semin Perinatol,2005,29(4):252-257.
[19]Wright D, Bradbury I, Cuckle H, Gardosi J, Tonks A, Standing S, et al. Three-stage contingent screening for Down syndrome. Prenat Diagn,2006,26(6): 528-534.
[20]Laigaard J, Sorensen T, Frohlich C, Pedersen BN, Christiansen M, Schiott K, et al. ADAM 12:a novel first-trimester maternal serum marker for Down syndrome. Prenat Diagn,2003,23(13):1086-1091.
[21]Laigaard J, Cuckle H, Wewer UM, Christiansen M. Maternal serum ADAM 12 levels in Down and Edwards'syndrome pregnancies at 9-12 weeks' gestation. Prenat Diagn,2006,26(8):689-691.
[22]Christiansen M, Pihl K, Hedley PL, Gjerris AC, Lind PO, Larsen SO, et al. ADAM 12 may be used to reduce the false positive rate of first trimester combined screening for Down syndrome. Prenat Diagn,2010,30(2):110-114.
[23]Loechel F, Fox JW, Murphy G, et al. ADAM 12-S cleaves IGFBP-3 and IGFBP-5 and is inhibited by TIMP-3. B iochem B iophysRes Commun,2000, 278:511.
[24]Shi Z, Xu W, Loechel F, et al.2000. ADAM 12, a disintegrin metalloprotease, interacts with insulin-like growth factor-binding protein-3. J Biol Chem 275:18574-80.
[25]Cowans NJ, Spencer K. First-trimester ADAM12 and PAPP-A as markers for intrauterine fetal growth restriction through their roles in the insulin-like growth factor system.2007 Prenat Diagn.2007,27(3):264-71.
[26]Makrydimas G, Sotiriadis A, Spencer K, et al. ADAM12-S in coelomic fluid and maternal serum in early p regnancy. PrenatDiagn.2006,26 (13):1197-1200.
[27]Laigaard J, Spencer K, Christiansen M, Cowans NJ, Larsen SO, Pedersen BN, et al. ADAM 12 as a first-trimester maternal serum marker in screening for Down syndrome. Prenat Diagn,2006,26(10):973-979.
[28]Christiansen M, Spencer K, Laigaard J, et al.2007. ADAM 12 as a second-trimester maternal serum marker in screening for Down syndrome. Prent Diagn 27:611-5
[29]Christiansen M, Pihl K, Hedley PL, Gjerris AC, Lind PO, Larsen SO, et al. ADAM 12 may be used to reduce the false positive rate of first trimester combined screening for Down syndrome. Prenat Diagn,2010,30(2):110-114.
[30]Cicero S, Longo D, Rembouskos G, Sacchini C, Nicolaides KH. Absent nasal bone at 11-14 weeks of gestation and chromosomal defects. Ultrasound Obstet Gynecol,2003,22(1):31-35.
[31]Leung TY, Spencer K, Leung TN, Fung TY, Lau TK. Higher median levels of free beta-hCG and PAPP-A in the first trimester of pregnancy in a Chinese ethnic group. Implication for first trimester combined screening for Down's syndrome in the Chinese population. Fetal Diagn Ther,2006,21(1):140-143.
[32]First-trimester or second-trimester screening, or both, for Down's syndrome. N Engl J Med,2005,353(19):2001-2011.
[33]Wald NJ, Watt HC, Hackshaw AK. Integrated screening for Down's syndrome on the basis of tests performed during the first and second trimesters. N Engl J Med, 1999,341(7):461-467.
[34]Rozenberg P, Malagrida L, Cuckle H, Durand-Zaleski I, Nisand I, Audibert F, et al. Down's syndrome screening with nuchal translucency at 12(+0)-14(+0) weeks and maternal serum markers at 14(+1)-17(+0) weeks:a prospective study. Hum Reprod,2002,17(4):1093-1098.
[35]Grant SS. Options for Down syndrome screening:what will women choose? J Midwifery Womens Health,2005,50(3):211-218.
[36]Wortelboer EJ, Linskens IH, Koster MP, et al. ADAM12s as a firsttrimester screening marker of trisomy. Prenat Diagn.2009.29:866-869.
[37]Wang M, Lu S, Zhu Y, Li H. ADAM 12 is an effective marker in the second trimester of pregnancy for prenatal screening of Down syndrome. Prenat Diagn. 2010.30:561-4.
[38]Valinen Y, Peuhkurinen S, Jarvela IY, Laitinen P, Ryynanen M. Maternal Serum ADAM 12 Levels Correlate with PAPP-A Levels during the First Trimester. Gynecol Obstet Invest,2010,70(1):60-63.
[39]Qin QP, Christiansen M, Pettersson K. Point-of-care time-resolved immunofluorometric assay for human pregnancy-associated plasma protein A: use in first-trimester screening for Down syndrome. Clin Chem,2002,48(3): 473-483.
[40]Hwa V, Oh Y, Rosenfeld RG. The insulin-like growth factor-binding protein (IGFBP) superfamily. Endocr Rev,1999,20(6):761-787.
[1]Spencer K. Screening for trisomy 21 in twin pregnancies in the first trimester using free beta-hCG and PAPP-A, combined with fetal nuchal translucency thickness. Prenat Diagn,2000,20(2):91-95.
[2]郭淑惠,王婧岚,李慧丽.新生儿性别比及双胎率和畸形率调查结果分析.中国妇幼保健,2006,7：977-978.
[3]Nicolaides KH SN, Snijders RJM. The 11-14 Week Scan. The Diagnosis of Fetal Abnormalities. London:Parthenon Publishing,1999,168-174.
[4]Kohl SG, Casey G. Twin gestation. Mt Sinai J Med,1975,42(6):523-539.
[5]Odibo AO, Lawrence-Cleary K, Macones GA. Screening for aneuploidy in twins and higher-order multiples:is first-trimester nuchal translucency the solution? Obstet Gynecol Surv,2003,58(9):609-614.
[6]Russell RB, Petrini JR, Damus K, Mattison DR, Schwarz RH. The changing epidemiology of multiple births in the United States. Obstet Gynecol,2003, 101(1):129-135.
[7]Neveux LM, Palomaki GE, Knight GJ, Haddow JE. Multiple marker screening for Down syndrome in twin pregnancies. Prenat Diagn,1996,16(1):29-34.
[8]ACOG Practice Bulletin No.77:screening for fetal chromosomal abnormalities. Obstet Gynecol,2007,109(1):217-227.
[9]Laigaard J, Sorensen T, Frohlich C, Pedersen BN, Christiansen M, Schiott K, et al. ADAM 12:a novel first-trimester maternal serum marker for Down syndrome. Prenat Diagn,2003,23(13):1086-1091.
[10]Laigaard J, Cuckle H, Wewer UM, Christiansen M. Maternal serum ADAM 12 levels in Down and Edwards' syndrome pregnancies at 9-12 weeks' gestation. Prenat Diagn,2006,26(8):689-691.
[11]Christiansen M, Pihl K, Hedley PL, Gjerris AC, Lind PO, Larsen SO, et al. ADAM 12 may be used to reduce the false positive rate of first trimester combined screening for Down syndrome. Prenat Diagn,2010,30(2):110-114.
[12]Laigaard J, Spencer K, Christiansen M, Cowans NJ, Larsen SO, Pedersen BN, et al. ADAM 12 as a first-trimester maternal serum marker in screening for Down syndrome. Prenat Diagn,2006,26(10):973-979.
[13]Christiansen M, Pihl K, Hedley PL, Gjerris AC, Lind PO, Larsen SO, et al. ADAM 12 may be used to reduce the false positive rate of first trimester combined screening for Down syndrome. Prenat Diagn,2010,30(2):110-114.
[14]Spencer K, Cowans NJ, Uldbjerg N, Torring N:First-trimester ADAM12s as early markers of trisomy 21:a promise still unfulfilled? Prenat Diagn,2008, 28:338-342.
[15]Valinen Y, Laitinen P, Ranta J, et al. Effect of a new marker, ADAM 12, on Down risk figures in first trimester screening. J Matern Fetal Neonatal Med,2009, 22:602-607.
[16]Laigaard J, Cuckle H, Wewer UM, Christiansen M:Maternal serum ADAM 12 levels in Down and Edwards' syndrome pregnancies at 9-12 weeks' gestation. Prenat Diagn,2006,26:689-691.
[17]Makrydimas G, Sotiriadis A, Spencer K, et al. ADAM 12-s in coelomic fluid and maternal serum in early pregnancy. Prenat Diagn,2006,26:1197-1200.
[18]Wortelboer EJ, Linskens IH, Koster MP, et al. ADAM12s as a firsttrimester screening marker of trisomy. Prenat Diagn,2009,29:866-869.
[19]Christiansen M, Spencer K, Laigaard J, et al. ADAM 12 as a second trimester maternal serum markers in screening for Down's syndrome. Prenat Diagn, 2007,27:611-615.
[20]Wang M, Lu S, Zhu Y, Li H. ADAM 12 is an effective marker in the second trimester of pregnancy for prenatal screening of Down syndrome. Prenat Diagn, 2010,30:561-4.
[21]M. P. H. Koster, E. J. Wortelboer, Ph. Stoutenbeek,et al.Distributions of current and new first-trimester Down syndrome screening markers in twin pregnancies. Prenat Diagn,2010,30:413-417
[22]边旭明,刘俊涛,戚庆炜,等.对孕中期妇女行血清学二联指标筛查胎儿唐氏综合征的多中心前瞻性研究.中华妇产科杂志,2008,43(11)：805-809.
[23]Nyboe Andersen A, Gianaroli L, Nygren KG. Assisted reproductive technology in Europe,2000. Results generated from European registers by ESHRE. Hum Reprod, 2004:490-503.
[24]Gjerris AC, Loft A, Pinborg A,et al. First-trimester screening markers are altered in pregnancies conceived after IVF/ICSI. Ultrasound Obstet Gynecol 2009; 33: 8-17.
[25]Amor DJ, Xu JX, Halliday JL,et al. Pregnancies conceived using assisted reproductive technologies (ART) have low levels of pregnancy-associated plasma protein-A (PAPP-A) leading to a high rate of false-positive results in first trimester screening for Down syndrome. Hum Reprod.2009,26(6):1330-8.
[26]Maymon R, Herman A, Shulman A, et al.First trimester embryo reduction:a medical solution to an iatrogenic problem. Hum Reprod.1995,10:668-73.
[27]Raty R, Virtanen A, Koskinen P, Laitinen P, Forsstrom J, Salonen R, et al. Maternal midtrimester serum AFP and free beta-hCG levels in in vitro fertilization twin pregnancies. Prenat Diagn,2000,20(3):221-223.
[28]Laigaard J, Pedersen NG, Larsen SO, et al. ADAM 12 in first trimester maternal serum from pregnancies conceived by assisted reproduction techniques (ART). Prenat Diagn,2009,29:628-629.
[29]Orlandi F, Rossi C, Allegra A, et al. First trimester screening with free beta-hCG, PAPP-A and nuchal translucency in pregnancies conceived with assisted reproduction. Prenat Diagn,2002,22:718-721.
[30]Raty R, Virtanen A, Koskinen P, et al. Maternal midtrimester serum AFP and free beta-hCG levels in in vitro fertilization twin pregnancies. Prenat Diagn,2000,20: 221-223.
[31]Monteagudo A, Timor-Tritsch IE, Sharma S. Early and simple determination of chorionic and amniotic type in multifetal gestations in the first fourteen weeks by high-frequency transvaginal ultrasonography. Am J Obstet Gynecol,1994,170(3): 824-829.
[32]Sepulveda W, Sebire NJ, Hughes K, Odibo A, Nicolaides KH. The lambda sign at 10-14 weeks of gestation as a predictor of chorionicity in twin pregnancies. Ultrasound Obstet Gynecol,1996,7(6):421-423.
[33]Fisk NM BP. Prenatal dtermination of chorionicity and zygosity.In Multiple Pregnancy.Ward RH,White M(eds). RCOG press:London,1995,56-67.
[34]Muller F, Dreux S, Dupoizat H, Uzan S, Dubin MF, Oury JF, et al. Second-trimester Down syndrome maternal serum screening in twin pregnancies: impact of chorionicity. Prenat Diagn,2003,23(4):331-335.
[35]Spencer K.Screening for trisomy 21 in twin pregnancies in the first trimester:does chorionicity impact on maternal serum free β-hCG or PAPP-A levels? Prenat Diagn,2001,21:715-717.
[36]Gonce A, Borrell A, Fortuny A, et al. First trimester screening for trisomy 21 in twin pregnancy:does the addition of biochemistry make an improvement? Prenat Diagn,2005.25:1156-1161.
[37]Wojdemann KR, Larsen SO, Shalmi A-C,Sundberg K, Tabor A,Christiansen M. Nuchal translucency measurements are highly correlated in both mono- and dichorionic twin pairs. Prenat Diagn,2006,26:218-220.
[38]Kevin Spencer, Karl O. Kagan and Kypros H. Nicolaides. Screening for trisomy 21 in twin pregnancies in the first trimester:an update of the impact of chorionicity on maternal serum markers Prenat Diagn,2008; 28:49-52.
[39]Linskens IH, Spreeuwenberg MD, Blankenstein MA, van Vugt JM. Early first-trimester free beta-hCG and PAPP-A serum distributions in monochorionic and dichorionic twins. Prenat Diagn,2009,29:74-78.
[1]Merkatz IR, Nitowsky HM, Macri JN, Johnson WE. An association between low maternal serum alpha-fetoprotein and fetal chromosomal abnormalities. Am J Obstet Gynecol,1984,148(7):886-894.
[2]Bogart MH, M.R. Pandian, O.W. Jones. Abnormal maternal serum chorionic gonadotropin levels in pregnancies with fetal chromosome abnormalities. Prenat Diagn,1987,7(9):623-630.
[3]Wald NJ, Cuckle HS, Densem JW, Nanchahal K, Canick JA, Haddow JE, et al. Maternal serum unconjugated oestriol as an antenatal screening test for Down's syndrome. Br J Obstet Gynaecol,1988,95(4):334-341.
[4]Brizot ML, Hyett JA, McKie AT, Bersinger NA, Farzaneh F, Nicolaides KH. Gene expression of human pregnancy-associated plasma protein-A in placenta from trisomic pregnancies. Placenta,1996,17(1):33-36.
[5]Aitken DA, Wallace EM, Crossley JA, Swanston IA, van Pareren Y, van Maarle M, et al. Dimeric inhibin A as a marker for Down's syndrome in early pregnancy. N Engl J Med,1996,334(19):1231-1236.
[6]Laigaard J, Sorensen T, Frohlich C, Pedersen BN, Christiansen M, Schiott K, et al. ADAM 12:a novel first-trimester maternal serum marker for Down syndrome. Prenat Diagn,2003,23(13):1086-1091.
[7]Laigaard J, Cuckle H, Wewer UM, Christiansen M. Maternal serum ADAM 12 levels in Down and Edwards' syndrome pregnancies at 9-12 weeks' gestation. Prenat Diagn,2006,26(8):689-691.
[8]Christiansen M, Pihl K, Hedley PL, Gjerris AC, Lind PO, Larsen SO, et al. ADAM 12 may be used to reduce the false positive rate of first trimester combined screening for Down syndrome. Prenat Diagn,2010,30(2):110-114.
[9]Loechel F, Fox JW, Murphy G, et al. ADAM 122S cleaves IGFBP-3 and IGFBP-5 and is inhibited by TIMP-3. Biochem Biophys Res Commun,2000,278: 511.
[10]Christiansen M, Spencer K, Laigaard J, et al. ADAM 12 as a second-trimester maternal serum marker in screening for Down syndrome. Prent Diagn,2007,27:611-5.
[11]Cuckle HS, Wald NJ, Lindenbaum RH. Maternal serum alpha-fetoprotein measurement:a screening test for Down syndrome. Lancet,1984,1(8383):926-929.
[12]Haddow JE, Palomaki GE, Knight GJ, Williams J, Pulkkinen A, Canick JA, et al. Prenatal screening for Down's syndrome with use of maternal serum markers. N Engl J Med,1992,327(9):588-593.
[13]Malone FD, Berkowitz RL, Canick JA, D'Alton ME. First-trimester screening for aneuploidy:research or standard of care? Am J Obstet Gynecol,2000,182(3): 490-496.
[14]Wald NJ, Watt HC, Hackshaw AK. Integrated screening for Down's syndrome on the basis of tests performed during the first and second trimesters. N Engl J Med, 1999,341(7):461-467.
[15]Shaw SW, Hsu JJ, Lee CN, Hsiao CH, Chen CP, Hsieh TT, et al. First- and second-trimester Down syndrome screening:current strategies and clinical guidelines. Taiwan J Obstet Gynecol,2008,47(2):157-162.
[16]Nicolaides KH, Azar G, Byme D, Mansur C, Marks K. Fetal nuchal translucency: ultrasound screening for chromosomal defects in first trimester of pregnancy. BMJ,1992,304(6831):867-869.
[17]Mol BW, Lijmer JG, van der Meulen J, Pajkrt E, Bilardo CM, Bossuyt PM. Effect of study design on the association between nuchal translucency measurement and Down syndrome. Obstet Gynecol,1999,94(5 Pt 2):864-869.
[18]Debieve F, Bouckaert A, Hubinont C, Thomas K. Multiple screening for fetal Down's syndrome with the classic triple test, dimeric inhibin A and ultrasound. Gynecol Obstet Invest,2000,49(4):221-226.
[19]Rosen T, D'Alton ME, Platt LD, Wapner R. First-trimester ultrasound assessment of the nasal bone to screen for aneuploidy. Obstet Gynecol,2007,110(2 Pt 1): 399-404.
[20]Moon MH, Cho JY, Lee YM, Jung SI, Yang JH, Kim MY, et al. First-trimester screening for Down syndrome; the role of nasal bone assessment in the Korean population. Prenat Diagn,2007,27(9):830-834.
[21]Stempfle N, Huten Y, Fredouille C, Brisse H, Nessmann C. Skeletal abnormalities in fetuses with Down's syndrome:a radiographic post-mortem study. Pediatr Radiol,1999,29(9):682-688.
[22]Tuxen A, Keeling JW, Reintoft I, Fischer Hansen B, Nolting D, Kjaer I. A histological and radiological investigation of the nasal bone in fetuses with Down syndrome. Ultrasound Obstet Gynecol,2003,22(1):22-26.
[23]Cicero S, Curcio P, Papageorghiou A, Sonek J, Nicolaides K. Absence of nasal bone in fetuses with trisomy 21 at 11-14 weeks of gestation:an observational study. Lancet,2001,358(9294):1665-1667.
[24]Gianferrari EA, Benn PA, Dries L, et al. Absent or shotened nasal bone length and the detection of Down syndrome in second trimester fetuses. Obstet Gynecol,2007,109(2):3712-3751.
[25]Nyberg DA, SouterVL. Use of genetic sonography for adjusting the risk for fetal Down syndrome. Semin Perinatol,2003,27(2):1302-1441.
[26]Gaglio P, Danelon D, Bontempo S,et al.Fetal cerebral ventriculomegaly: outcome in 176 cases.Utrasound Obstet Gynecol,2005,25:372-377.
[27]M Wyldes, M Watkinson. Isolated mild fetal lateral ventrieulomegaly. Arch.Dis. Child.Fetal Neonatal,20o4,89:92-103.
[28]Scott A. Nuchal translucency measurement in first trimester Down syndrome screening. Issues Emerg Health Technol,2007,100:1-6.
[29]吕时铭.我国产前诊断技术发展与质量控制.中华检验医学杂志,2010,33(2)：101-104.
[30]Bianchi D W,Simpson J L, Jackson L G, et al.Fetal gender and aneuploidy detection using fetal cells in maternal blood:Analysis of N IFTY data. Prenat Diagn.2002,22:609-615.
[31]Dan DA,Maria G,Tmjillo MJ,et al.Appficafion of quantitative fluorescent PCR with short tandem repeat markers to the study of aneuploidies in spontaneous miscarriages. Hum Reprod.2005,20(5):1235-1243.
[32]Schaefer AJ, Chung J, Heretis K,et al.Comparative genomic hybridization-array analysis enhances the detection of aneuploidies and submieroscopic imbalance in spontaneous miscarriages. Am H Hum Genet.2004,74(6):1168-1174.
[33]Parano E,Falcidia E,Grillo A, et al. Noninvasive prenatal diagnosis of chromosomal aneuploidies by isolation and analysis of fetal cells from maternal blood. Am J Med Genet,2001,101:262-267.
[34]Lo YM, Corbetta N, Chamberlain PF, et al. Presence of fetal DNA in maternal plasma and serum. Lancet,1997,350:485-487.
[35]Lo YM, Lau TK, Zhang J,et al. Increased fetal DNA concentrations in the plasma of pregnant women carrying fetuses with trisomy 21.Clin Chem,1999,45:1747-1751.
[36]Chinnapapagari SK, HolzgreveW,Lapaire O, et al. Treatment of maternal blood samples with formaldehyde does not alter the proportion of circulatory fetal nucleic acids (DNA and mRNA) in maternal plasma. Clin Chem,2005,51:652-655.
[37]Chung GT, Chiu RW, Chan KC, et al. Lack of dramatic enrichment of fetal DNA in maternal plasma by formaldehyde treatment. Clin Chem,2005,51:655-658.
[38]Tsui NB, et al. Systematic micro-array based identification of placental mRNA in maternal plasma:towards non-invasive prenatal gene expression profiling. J Med Genet,2004,41:461-467.