CN118348258A - 早孕期母血清甲胎蛋白异质体l2预测胎儿21三体、18三体和神经管畸形的方法 - Google Patents
早孕期母血清甲胎蛋白异质体l2预测胎儿21三体、18三体和神经管畸形的方法 Download PDFInfo
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Abstract
本发明公开了一种早孕期母血清甲胎蛋白异质体L2预测胎儿21三体、18三体和神经管畸形的方法,包括如下步骤:针对早孕期孕妇,将研究对象分为病例组和对照组,检测两组孕妇血清的AFP‑L2、PAPP‑A和freeβ‑hCG水平,通过早孕期母血清AFP‑L2预测神经管畸形NTD,同时使用AFP‑L2、PAPP‑A和freeβ‑hCG构建风险计算模型,以分布似然作为胎儿21三体、18三体和神经管畸形NTD风险,再根据ROC曲线计算出AFP‑L2、PAPP‑A和freeβ‑hCG筛查胎儿21三体、18三体和神经管畸形NTD的最佳临界值、曲线下面积。本发明的有益效果为:早孕期母血清甲胎蛋白异质体AFP‑L2、PAPP‑A和freeβ‑hCG对筛查胎儿21三体、18三体和神经管畸形NTD胎儿具有较高的灵敏度和特异度,是筛查胎儿21三体、18三体和神经管畸形NTD的较好标志物。
Description
技术领域
本发明涉及医学检测领域,主要是一种早孕期母血清甲胎蛋白异质体L2预测胎儿21三体、18三体和神经管畸形的方法。
背景技术
甲胎蛋白(alpha-fetoprotein,AFP)是一种含有N-连接的双糖链分子结构的糖蛋白,可来源于胎儿肝脏和卵黄囊。不同来源的AFP在糖链结构上存在一定的区别,这种分子结构上的差别可通过植物凝集素-小扁豆素(lens culinaris agglutinin,LCA)与其不同的亲和力将其检出为AFP-L1、AFP-L2和AFP-L3[1],这三种AFP亚型通常被称为甲胎蛋白异质体(alpha-fetoprotein variants),其中AFP-L2(alpha-fetoprotein variants L2,AFP-L2)与LCA结合较弱,主要来自孕妇,有研究表明其在监测孕妇怀孕期间盆腔恶性肿瘤复发中发挥重要作用[2]。
21-三体(Trisomy 21)、18-三体综合征(18三体)和神经管缺陷(neural tubedefects,NTD)是新生儿出生缺陷最常见的遗传性染色体异常和结构异常疾病,其存在严重的智力低下,存活时间很短,往往有多器官畸形,是环境和遗传共同作用的结果,可导致流产、死胎或死产等临床症状,在新生儿中的发病率约为1‰[3-5]。这些患儿出生后尚无有效的治疗方法,NTD患儿需要多次手术治疗,给家庭和社会增加负担,因此早期开展对胎儿21三体、18三体和NTD的产前筛查和产前诊断尤为重要。
早孕期(11周至13周6天)非整倍体筛查标志物如:妊娠血浆相关蛋白A(pregnancyassociated plasma protein-A,PAPP-A)、游离人绒毛膜促性腺激素β亚基(freeβsubunitof human chorionic gonadotropin,freeβ-hCG)和胎儿颈部透明层(Nuchaltranslucency,NT)厚度的联合检查被广泛应用于胎儿21三体、18三体产前筛查[6,7],理论上在假阳性率为5%时,可检测80%~90%的胎儿染色体非整倍体[8]。可实际临床工作中,筛查的检测灵敏度和特异度并不理想。与中孕期筛查相比,早孕期产前筛查具有筛查时间早,给孕妇的提供决策时间早,临床早干预等优点,但早孕期筛查的缺点是不能筛查NTD。超声影像学能够准确检测NTD,但也受孕龄、胎儿位置及超声医师技术水平的影响,因此,急需寻找新的早孕期产前筛查标志物或制定新的筛查方案。
NTD由于神经管的裸露,胎儿的AFP会大幅度转运到羊水中,而对羊水进行AFP检测对于早期妊娠的无脑和开放性脊柱裂的产前诊断至关重要[9,10]。有研究报道孕21三体、18三体母体血清中AFP值降低,21三体、18三体胎儿由于胎肝发育不全,AFP合成相应减少,还有可能由于AFP的胎盘转运缺陷,引起母体血清AFP水平相应减少[10,11],针对AFP水平在21三体、18三体母体中变化机制仍不明确。
本发明的研究前期结果显示,中孕期母血清AFP-L2和AFP-L3筛查21三体、18三体和开放性神经管缺陷(Open neural tube defects,ONTD)和胎儿腹壁缺陷(Abdominalwall defects,AWD)胎儿具有较高的灵敏度和特异度,是筛查21三体、18三体和NTD的良好标志物,联合筛查结果优于单独筛查,并以AFP-L2+AFP-L3+freeβ-hCG联合筛查效率最高[12-16],而对早孕期母血清AFP-L2预测胎儿21三体、18三体和NTD的风险模型构建方面研究较少,前期结果表明,病例组的早孕期母血清AFP-L2水平高于对照;AFP-L2预测21三体的AUC为0.797,95%CI(0.601-948,P=0.009),敏感度、特异度分别为0.805、0.695[17]。
为了解AFP-L2可否可以同时预测21三体、18三体和NTD的诊断价值,并提高对这三种疾病的预测效率,本发明采用病例对照研究方法,在早孕期血清学二联筛查+NT的基础之上,采用酶联免疫吸附试验(ELISA),分别检测病例组(21三体、18三体和NTD)和对照组(妊娠正常胎儿的孕妇)孕妇血清中AFP-L2的水平,通过构建AFP-L2单指标或多指标联合的风险模型,研究其对21三体、18三体和NTD筛查效率。
发明内容
本发明的目的在于克服现有技术存在的不足,而提供一种早孕期母血清甲胎蛋白异质体L2预测胎儿21三体、18三体和神经管畸形的方法。
本发明的目的是通过如下技术方案来完成的。一种早孕期母血清甲胎蛋白异质体L2预测胎儿21三体、18三体和神经管畸形的方法,该方法包括如下步骤:
(1)、针对早孕期孕妇,根据有无胎儿21三体、18三体和神经管畸形NTD,将研究对象分为病例组和对照组,病例组是指经羊水细胞染色体核型分析或影像学确诊为21三体、18三体和NTD胎儿的孕妇,对照组为随机抽取同时期胎儿发育正常的孕妇;
(2)、检测两组孕妇血清的AFP-L2、PAPP-A和freeβ-hCG水平,通过早孕期母血清AFP-L2预测神经管畸形NTD,同时使用AFP-L2、PAPP-A和freeβ-hCG构建风险计算模型,该模型假设AFP-L2、PAPP-A和freeβ-hCG的浓度值服从多元正态分布,计算得出各指标分布的对应参数,以分布似然作为胎儿21三体、18三体和神经管畸形NTD风险,再根据ROC曲线计算出AFP-L2、PAPP-A和freeβ-hCG筛查胎儿21三体、18三体和神经管畸形NTD的最佳临界值、曲线下面积。
更进一步的,检测孕妇血清的AFP-L2、PAPP-A和freeβ-hCG水平时,需要对各项标志物的浓度值进行校准,以MGM表示母体的预产年龄、孕周和体重。
本发明的有益效果为:早孕期母血清甲胎蛋白异质体AFP-L2、、PAPP-A和freeβ-hCG对筛查胎儿21三体、18三体和神经管畸形NTD胎儿具有较高的灵敏度和特异度,是筛查胎儿21三体、18三体和神经管畸形NTD的较好标志物,使用AFP-L2、、PAPP-A和freeβ-hCG联合构建的风险计算模型比单独使用AFP、AFP-L2、AFP-L3浓度值筛查有更好的筛查效率。
附图说明
图1为不同组别早孕期母血清AFP-L2,freeβ-hCG和PAPP-A水平示意图。
图2为单个或多个标志物联合构建的风险模型对21三体、18三体和NTD胎儿诊断价值示意图。
具体实施方式
下面将结合附图和实施例对本发明做详细的介绍:
实施例:
1.方法
1.1病例组和对照组入选标准
1.1.1确定病例组和对照组回顾性分析了2015年至2021年在杭州市妇产科医院和杭州市临平区妇幼保健院,产前筛查门诊进行检测的321,400例孕妇血清标本,随访结果为妊娠21三体、18三体和NTD胎儿的所有孕妇被列入确诊病例中,再从这些确诊病例中随机抽取妊娠21三体、18三体、NTD胎儿的孕妇各83例、21例和51例作为病例组,共155例;同时按21三体病例1:3随机抽取同时期妊娠正常胎儿的265例孕妇血清标本作为对照组,所有病例共计420例。所有研究对象均为妊娠10~13+6周的单胎孕妇。本研究经本院伦理委员会批准,批准号为[2023]-医伦审A第(002)号。
1.1.2病例诊断:采用中国出生缺陷监测网制定的诊断标准进行,病例组为经羊水或脐血细胞染色体核型分析,超声或MRI诊断,确诊妊娠有21三体、18三体和NTD胎儿的孕妇。21三体、18三体以核型47,XX(或XY)+21;47,XX(或XY)+18来确诊。NTD根据受累的神经组织是否暴露于体表,分ONTD和闭合性神经管畸形,其中ONTD比较常见,包括开放性脊柱裂、无脑儿和脑膨出,依据其缺陷部位和严重程度而临床表现不同[5,18-19]。
1.1.3排除标准:双胎、多胎妊娠孕妇;排除合并其他内科疾病如胰岛素依赖性糖尿病及严重妊娠并发症孕妇;吸烟;试管婴儿;随访结果为其它出生缺陷。
1.2仪器
1235Auto时间分辨荧光免疫分析仪(美国PerkinElmer公司);RT-6100酶标仪(Rayto公司),988洗板机(北京Tianshi公司)。检测试剂:PAPP-A,freeβ-hCG采试剂盒(PAPP-A/freeβ-hCG)(美国PerkinElmer公司);AFP-L2试剂(美国BIM公司)
1.3病例组和对照组血清AFP-L2水平检测
1.3.1检测原理
PAPP-A,freeβ-hCG测定采用时间分辨荧光法(DELFIA);AFP-L2采用双抗体一步夹心法酶联免疫吸附试验(ELISA)。往预先包被AFP-L2捕获抗体的包被微孔中,依次加入标本、标准品、HRP标记的检测抗体,经过温育并彻底洗涤。用底物TMB显色,TMB在过氧化物酶的催化下转化成蓝色,在酸的作用下转化成最终的黄色。颜色的深浅和样品中的AFP-L2呈正相关。用酶标仪在450nm波长下测定吸光度(OD值),计算样品浓度。
2.3.2样本采集和保存
在抽血前,每位孕妇到有资质筛查的定点医院,签署知情同意后,抽取空腹肘静脉血2~3mL,静置30min后,以2 500r/min速度离心10min并分离血清,低温运输至产前筛查实验室,经过早孕期二联(PAPP-A+freeβ-hCG)血清学检测后,多余血清标本,储存于-80℃冰箱,建立血清标本库。PAPP-A、freeβ-hCG、AFP-L2的检测按说明书进行。
1.4采用二元logistic回归分析对AFP-L2预测21三体、T18和ONTD分别构建10个模型模型一:AFP-L2;
模型二:freeβ-hCG;
模型三:PAPP-A;
模型四:AFP-L2+MGM;
模型五:freeβ-hCG+MGM;
模型六:PAPP-A+MGM;
模型七:PAPP-A+freeβ-hCG+MGM;
模型八:AFP-L2+freeβ-hCG+MGM;
模型九:AFP-L2+PAPP-A+MGM;
模型十:PAPP-A+freeβ-hCG+AFP-L2+MGM。
为了减少母体的预产年龄、孕周和体重因素不同而造成的偏差,需要对各项标志物的浓度值进行校准,为计算方便,以MGM(maternal age+gestational age+maternalweight)表示母体的预产年龄、孕周和体重。
1.5统计学处理
采用IBM-SPSS21.0statisties(IBM-SPSS,Chicago,USA)进行统计学处理。数据正态性检验采用One-sample Kolmogorov-Smirnov检验,偏态数据以中位数及四分位数M(Q)表示,两组间的比较采用Mann-Whitney U检验。利用ROC曲线确定cut-off、AUC指标AFP-L2浓度的诊断价值进行评价。并计算最佳cut-off、AUC、约登指数。使用灵敏度(Sensitivity,Se)、特异度(Specificity,Sp)、假阴性率(false negative rate,FNR)、假阳性率(falsepositive rate,FPR)、阳性似然比(positive likelihood ratio,+LR)和阴性似然比(negative likelihood ratio,-LR)值来评估模型的性能。AUC最大且灵敏度较高的风险模型具有更优的诊断价值,P<0.05时认为差异具有统计学意义。
2.结果
2.1四组孕妇早孕期人口基础资料比较
21三体,18三体组和对照组早孕期孕妇的体重间比较,差异均无统计学意义(均P≥0.05),但NTD组孕妇的体重高于对照组(56.00(52.00-62.00)kg vs.52.00(49.00-56.45)kg),组间差异均有统计学意义(P<0.05);21三体和NTD组孕妇年龄高于对照组,组间差异有统计学意义(P=0.004),18三体组孕妇年龄略高于对照组,组间差异无统计学意义(P≥0.05);21三体、18三体和NTD组孕龄均低于对照组(87.50days、87days和86daysvs.90days),组间差异均有统计学意义(P<0.05),见表1。
2.2各组AFP-L2、PAPP-A和freeβ-hCG水平比较
孕有21三体、18三体和NTD胎儿的早孕期母血清AFP-L2水平均高于对照组[6.64(4.56-8.09)ng/mL、6.17(3.96-8.37)ng/mL、6.87(5.29-8.68)ng/mL vs.3.71(2.71-4.64)ng/mL],组间差异有统计学意义(P<0.001);孕有21三体、18三体和NTD胎儿的孕妇的PAPP-A水平均低于对照组(1595(839-2153)mU/L、365(215-744)mU/L和2800(1580-4700)mU/Lvs.4200(2825-6400)mU/L),组间差异均有统计学意义(均P<0.001);freeβ-hCG在21三体组高于对照组(87.90(63.70-132.00)ng/mL vs.48.30(33.60-74.50)ng/mL),18三体组低于对照组(7.53(4.55-13.05)ng/mL vs.48.30(33.60-74.50)ng/mL),组间差异均有统计学意义(均P<0.001),而NTD组孕妇的freeβ-hCG低于对照组,但组间差异无统计学意义(P≥0.05),见图1和表2。
2.3AFP-L2、PAPP-A和freeβ-hCG预测21三体胎儿的价值
早孕期母血清AFP-L2、PAPP-A和freeβ-hCG预测21三体胎儿的AUC分别为0.831(95%CI:0.775~0.886)、0.884(95%CI:0.840~0.928)和0.764(95%CI:0.704~0.825),均P<0.001,AUC大小顺序是PAPP-A>AFP-L2>freeβ-hCG,但三种标志物中AFP-L2的灵敏度最低(0.639),但特异度最高(0.943)。当AFP-L2筛查21三体最佳临界值为5.819ng/mL时,对应的敏感度、特异度分别为0.639和0.943。各标志物经预产年龄、孕周和体重校准后,AUC有所提高,并以三联的AFP-L2+PAPP-A+freeβ-hCG+MGM为最佳(AUC=0.959、灵敏度=0.892和特异度=0.928),双联指标的AUC大小排序是AFP-L2+PAPP-A+MGM(AUC=0.951)>PAPP-A+freeβ-hCG+MGM(AUC=0.923)>AFP-L2+freeβ-hCG+MGM(AUC=0.902),见图2D。
2.4早孕期母血清AFP-L2、PAPP-A和freeβ-hCG预测18三体胎儿的价值早孕期母血清AFP-L2、PAPP-A和freeβ-hCG预测18三体胎儿的AUC分别为0.783(95%CI:0.671~0.896),0.971(95%CI:0.927~1)和0.971(95%CI:0.942~1),均P<0.001,在三种单种标志物中AFP-L2的AUC最小,灵敏度最低(0.524),但特异度最高(0.955)。当AFP-L2筛查18三体的最佳临界值为6.083ng/mL时,对应的敏感度和特异度分别为52.4%和95.50%。联合标志物组合中,以二联PAPP-A+freeβ-hCG+MGM(AUC=0.994)为最佳,其次是AFP-L2+freeβ-hCG+MGM(AUC=0.992),两模型的灵敏度均为0.952,但特异度是后者高于前者(0.992>0.989),见图2E。
2.5早孕期母血清AFP-L2、PAPP-A和freeβ-hCG预测NTD胎儿的价值早孕期母血清AFP-L2预测NTD胎儿的AUC分别为0.876(95%CI:0.816~0.937),P<0.001,当cut-off=5.282mg/mL时,AFP-L2的灵敏度为0.766,特异度为0.898;PAPP-A可预测NTD胎儿(AUC=0.684(95%CI:0.599~0.768)均P<0.001);但freeβ-hCG预测NTD的效果不佳[AUC=0.544(95%CI:0.449~0.639),P≥0.05],AFP-L2经母体的预产年龄、孕周和体重校准后AUC有所提高,但联合PAPP-A和freeβ-hCG后,没有提高其预测价值,灵敏度均为0.830,见图2F和表3。
2.6AFP-L2单指标或联合指标模型预测21三体、18三体和NTD的效果评价对于21三体和NTD,AFP-L2的阳性预测值大于freeβ-hCG与PAPP-A,AFP-L2+PAPP-A+freeβ-hCG+MGM的阳性预测值大于单项标志物;对于18三体,AFP-L2的阳性预测值略小于PAPP-A,AFP-L2+PAPP-A+freeβ-hCG+MGM的阳性预测值大于单项标志物,AFP-L2对于21三体,18三体的假阳性最低(0.057,0.045),见表4。
本发明研究结果表明,孕有21三体、18三体和NTD胎儿的早孕期母血清AFP-L2水平均升高,早孕期AFP-L2筛查21三体、18三体和NTD胎儿具有较高特异度,联合多种标志物筛查优于单指标。
甲胎蛋白(AFP)是胎儿发育过程中产生的一种糖蛋白,其功能可能与配体结合与转运、发育生长、免疫系统的调节及抗氧化作用有关,表明其对胎儿的发育至关重要[20]。本研究结果显示,孕21三体、18三体和NTD胎儿的早孕期母血清AFP-L2水平均升高,与以往孕21三体,18三体患儿的母血清AFP水平降低不同[21]。AFP水平主要有胎儿肝脏产生,经胎盘循环到母体血清中,母体血清中AFP水平在多种妊娠并发症中有所升高,包括NTD、先兆子痫和胎儿死亡等[20],母体血清AFP的变化在不同疾病中不同,可能与胎儿蛋白产生量、胎盘发育异常、转运障碍有关。本研究表明,孕有21三体胎儿的早孕期母血清AFP-L2水平均高于对照组,差异有统计学意义;同样前期研究结果也表明早孕期和中孕期病例组母体血清AFP-L2水平均高于对照组[17,13],与本研究结果相似。Newby等[22]认为21三体综合症孕妇的胎盘组织匀浆中的AFP水平显著升高,而肝组织匀浆中的AFP水平则未发生变化,母体血清中的AFP水平却降低了,他表明这可能存在AFP的特定运输缺陷。Yamamoto等[23]研究也表明在21三体胎儿妊娠中,胎儿肝脏中AFP-L3与母体血清中的百分比有统计学差异,他们认为孕21三体胎儿妇女的胎盘中AFP-L3组分的转移较高,这可能是母体血清中AFP-L3增加的原因之一。早孕期21三体胎儿的孕妇血清AFP-L2水平升高可能与AFP-L3类似,也可能存在特定于AFP的运输缺陷造成母体中AFP-L2升高[17]。
申请人首次报导了早孕期母血清AFP-L2可以预测NTD的产前筛查标志物。表3显示,早孕期母血清AFP-L2预测21三体、18三体和NTD胎儿的AUC分别为0.831,0.783和0.876,AFP-L2预测21三体、18三体和NTD胎儿的最佳临界值分别为5.819ng/mL、6.083ng/mL和5.282ng/mL,此时对应的敏感度、特异度分别为:63.90%、52.40%和76.60%;94.30%、95.50%和89.80%。结果表明早孕期母血清AFP-L2预测NTD的效果高于21三体,18三体,早孕期母血清AFP-L2预测21三体、18三体和NTD胎儿的特异度高于敏感度。早孕期AFP-L2浓度值预测21三体,18三体胎儿的AUC=0.831和0.783略高于上中孕期的AUC=0.785和0.775[13],是否与早孕期AFP-L2浓度相对低于中孕期有关,有待进一步研究。
本发明研究还表明,在单个标志物与多个标志物联合筛查比较中,AFP-L2+PAPP-A+freeβ-hCG+MGM对21三体和NTD的筛查价值高于单项标志物,申请人前期研究也表明,在考虑增加母体血清AFP-L2后,PAPP-A+freeβ-hCG+NT+AFP-L2和PAPP-A+freeβ-hCG+AFP-L2两种模型分别对预测21三体和18三体胎儿的综合区分改善度(Integrated DiscriminationImprovement,IDI),净重分类改善度(Net Reclassification Improvement,NRI),分别提高(1.10%和5.27%;11.07%和2.78%)(1.10%和5.27%;11.07%和2.78%)[17]。这表明早孕期母血清AFP-L2联合其它非整位体标志物可提高对21三体、18三体和NTD胎儿筛查价值。
综上所述,本发明首次报导了早孕期母血清AFP-L2可以预测NTD,早孕期母血清AFP-L2升高,可以筛查21三体、18三体和NTD胎儿,有别于21三体,18患儿AFP水平降低不同;早孕期AFP-L2筛查21三体、18三体和NTD胎儿具有较高的特异度,联合多种标志物筛查优于单指标,并且将为早孕期产前筛查提供新的标志物。
表1.不同组别孕妇人口基本信息
NTD,neural tube defects;Data are presented as M(Q);*P<0.001.
表2.不同组别AFP-L2、freeβ-hCG和PAPP-A水平比较
NTD,neural tube defects;AFP-L2,alpha-fetoprotein variants L2;PAPP-A:pregnancy-associated
plasma protein A;freeβ-hCG:free beta-subunit of human chorionicgonadotropin;Data are
presented as M(Q);*P<0.001.
表3.不同标志物的单指标或多指标组合预测21三体、18三体和NTD的价值
NTD,neural tube defects;AFP-L2,alpha-fetoprotein variants L2;PAPP-A:pregnancy-associated plasma protein A;freeβ-hCG:free beta-subunit of humanchorionic gonadotropin;MGM:maternal age+gestational age+maternal weight;*P<0.001.
表4.不同标志物的单指标或多指标组合预测21三体、18三体和NTD的诊断效果
NTD,neural tube defects;AFP-L2,alpha-fetoprotein variants L2;PAPP-A:pregnancy-associated plasma protein A;freeβ-hCG:free beta-subunit of humanchorionic gonadotropin;MGM:maternal age+gestational age+maternal weight;AUC,area under curve;CI,confidence interval.;Se,Sensitivity;Sp,Specificity;FNR,false negative rate;FPR,false positive rate;PPV,Positive predictive value;NPV,Negative predictive value;+LR,positive likelihood ratio;-LR,negativelikelihood ratio;*P<0.001.
参考文献
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可以理解的是,对本领域技术人员来说,对本发明的技术方案及发明构思加以等同替换或改变都应属于本发明所附的权利要求的保护范围。
Claims (2)
1.一种早孕期母血清甲胎蛋白异质体L2预测胎儿21三体、18三体和神经管畸形的方法,其特征在于:该方法包括如下步骤:
(1)、针对早孕期孕妇,根据有无胎儿21三体、18三体和神经管畸形NTD,将研究对象分为病例组和对照组,病例组是指经羊水细胞染色体核型分析或影像学确诊为21三体、18三体和NTD胎儿的孕妇,对照组为随机抽取同时期胎儿发育正常的孕妇;
(2)、检测两组孕妇血清的AFP-L2、PAPP-A和freeβ-hCG水平,通过早孕期母血清AFP-L2预测神经管畸形NTD,同时使用AFP-L2、PAPP-A和freeβ-hCG构建风险计算模型,该模型假设AFP-L2、PAPP-A和freeβ-hCG的浓度值服从多元正态分布,计算得出各指标分布的对应参数,以分布似然作为胎儿21三体、18三体和神经管畸形NTD风险,再根据ROC曲线计算出AFP-L2、PAPP-A和freeβ-hCG筛查胎儿21三体、18三体和神经管畸形NTD的最佳临界值、曲线下面积。
2.根据权利要求1所述早孕期母血清甲胎蛋白异质体L2预测胎儿21三体、18三体和神经管畸形的方法,其特征在于:检测孕妇血清的AFP-L2、PAPP-A和freeβ-hCG水平时,需要对各项标志物的浓度值进行校准,以MGM表示母体的预产年龄、孕周和体重。
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