产前筛查母血清标志物水平与产科并发症或病理妊娠的研究
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摘要
唐氏综合征(Down's syndrome，DS)又称21三体综合征，是活产新生儿最常见的染色体疾病，是死胎、流产以及胎儿出生缺陷中最常见的原因之一。近年来，随着社会的文明和进步，人们对优生优育的认识有了进一步的提高，唐氏综合征的血清学产前筛查正在普及。
大量的研究已经显示妊娠中期应用甲胎蛋白(alpha fetoprotein，AFP)和游离β人绒毛膜促性腺激素(human chorionic gonadotropin，hCG)进行唐氏综合征筛查是发现21三体患儿的有效手段。而国人正常孕妇各孕周AFP和游离β-hCG中位数的建立将有助于提高21三体的检出率，但现用软件中的内嵌中位数与国人在种族等方面存在差异，因此有必要建立本地区孕妇各孕周的中位数水平。
目的：
1、研究孕中期孕妇的年龄、孕周、体重、孕次、产次对孕中期母血清标志物的影响。
2、通过大样本的人群血清学筛查，确立本地区各孕周的血清AFP、游离β-hCG的中位数；比较各年龄组的唐氏综合征的高危比例，探讨高危人群范围。
3、研究本地区孕妇孕中期母血清中高水平游离β-hCG或AFP与某些产科并发症或病理妊娠的关系。以期早期发现、早期诊断产科并发症或病理妊娠。
方法：
1、取材和筛查指标：妊娠15-20周期间，孕妇由就诊医院抽血并分离血清，标本保存于-20℃冰箱，于一周内送至浙江大学医学院附属妇产科医院浙江省产前诊断中心进行血清学标志物检测。筛查指标为孕中期母血清AFP和游离β-hCG。
2、试剂和仪器：测定方法采用时间分辨荧光免疫分析法(DELFIA，Wallac)。双标记试剂盒(AFP/游离-βhCG)购自美国PerkinElmer公司，检测仪器采用Wallac全自动免疫分析系统，并严格按照试剂说明书进行操作。风险率由Wallac公司提供的产前筛查21三体风险计算软件计算。
3、统计学方法：采用SPSS 11.0软件包进行统计分析，统计学方法有t-检验、相关分析、正态性检验。
结果：
第一部分母血清标志物中位数的确立及其影响因素研究
1、孕中期母血清AFP测定值、体重校正值与孕周均成正相关，相关系数分别为r=0.281，P＜0.001及r=0.048，P＜0.001；而孕中期血清游离β-hCG测定值、体重校正值与孕周均成负相关，相关系数分别为r=0.231，P＜0.001；r=0.037，P=0.004；
2、孕中期母血清AFP测定值及游离β-hCG测定值与孕妇体重均成负相关，相关系数分别为为-0.160，和-0.130，P值均小于0.001；
3、孕中期血清AFP和游离β-hCG测定值、校正值与孕妇的年龄均无相关性，P值均大于0.05；
4、孕中期母血清AFP中位数的倍数(multiple of median，MoM)值与孕次成正相关，相关系数为r=0.062，P＜0.001；而孕中期母血清游离β-hCG MoM值与孕次成负相关，相关系数为r=-0.028，P=0.02；
5、孕中期母血清AFP MoM值和游离β-hCG MoM值与产次均无相关性，P值均大于0.05；
6、本地区孕中期母血清中各孕周的游离β-hCG、AFP的中位数与软件内嵌值比较
(1) AFP中位数的测定值比分析软件内嵌值要高。两者比较没有统计学差异，t=0.889，P=0.395；
(2)游离β-hCG中位数的测定值比分析软件内嵌值要高。两者比较没有统计学差异，t=1.234，P=0.245；
7、唐氏综合征的高危检出率随着年龄的增长有逐渐增高的趋势，且唐氏征筛查高危检出率与年龄有明显相关性(相关系数r=0.918，P＜0.001)。
第二部分孕中期高水平血清标志物与产科并发症或病理妊娠的关系
1、当游离β-hCG MoM值≥2.0时
(1)孕1次组孕中期高水平AFP MoM值与早产、早产低体重儿有关，P值分别为0.017和0.001，相对危险度(relative risk，RR)值分别为7.059和33.545；
(2)孕2次组孕中期高水平AFP MoM值与早产、足月低体重儿有关，P值分别为0.021和0.010，RR值分别为6.696和25.667；
(3)孕3次及以上组高水平AFP MoM值与妊娠合并重度贫血有关，P=0.039；
(4)不按孕次分组时，孕中期血清高水平AFP MoM值与完全性前置胎盘、新生儿轻度窒息有关，P值分别为0.001和0.002，RR值分别为21.525和17.631；
2、当AFP MoM值在0.5-2.0时
(1)孕1次组高水平游离β-hCG MoM值与羊水过少有关，P=0.009，RR=5.588；
(2)孕3次及以上组，高水平游离β-hCG MoM值与过期妊娠、羊水Ⅲ°浑浊及胎儿宫内窘迫有关，P值分别为0.004、0.004和小于0.001，RR值分别为4.297、2.088和2.427；
(3)不按孕次分组时，高水平游离β-hCG MoM值与胎盘植入有关，P=0.040，RR=5.581；
3、当游离β-hCG MoM值在0.5-2.0时
(1)孕1次组孕中期高水平AFP MoM值与胎膜早破有关，P=0.046，RR=2.483；
(2)孕2次组孕中期高水平AFP MoM值与重度子痫前期有关，P值分别为0.005，RR值为10.904；
(3)孕3次及以上组孕中期高水平AFP MoM值与重度子痫前期有关，P值分别为0.035，RR值为8.103；
(4)不按孕次分组时，孕中期血清高水平AFP MoM值与完全性前置胎盘有关，P=0.001，RR=25.3。
结论：
1、影响孕中期血清AFP测定值与游离β-hCG测定值的因素有：孕周、孕妇体重和孕次；因此要正确建立本地区孕中期血清标志物的中位数，就必须对这些影响因素进行校正；
2、AFP中位数的测定值及游离β-hCG中位数的测定值比分析软件内嵌值要高；
3、当孕妇年龄小于35岁时，唐氏征筛查高危检出率与年龄有明显相关性；
4、孕中期高水平血清标志物与一些产科并发症或病理妊娠如：早产、早产低体重儿、完全性前置胎盘、新生儿轻度窒息、羊水过少、过期妊娠、羊水Ⅲ°浑浊、胎盘植入、胎儿宫内窘迫、胎膜早破、重度子痫前期和胎儿生长受限(fetal growth restriction，FGR)有关。
Down' s syndrome is entitled trisomy 21 syndrome. It is the most common chromosomal disease in live birth newborns. Down' s syndrome is one of the most common causes which leads to the still-birth the abortion and the fetus birth defect. Along with social improvement and civilized development, people make further acquaintanceship with aristogenesis, so the serum prenatal screeing of Down' s syndrome has become widespread.
Massive research has showed that we could detect the trisomy 21 syndrome effectively if we has carried out the prenatal screening with AFP and free β -hCG. If we could establish the different gestational weeks-median of AFP and β -hCG of the normal pregnant women in our country, we could increase the detection rate of trisomy 21 syndrome efficiencily. The median of the software applied has been different from the exact median of the countrymen because of the race, so it is necessary to establish the median of the pregnant women in our district.
Objective
1. To investigate the relationship between the pregnant women' s age, gestational week body weight gravidity .. parity and the maternal serum markers in the second trimester.
2. To establish the different gestational weeks-median of serum AFP and free
β-hCG in the district by serum screening of large samples and compare the high risk-proportion of different age groups to discuss the range of high risk-people.
3. To investigate the relationship of maternal serum high level AFP or free β -hCG and the obstetric complications or pathological gestation for the early detection and diagnosis.
Methods
1. Material and Screening Index: In the course of 15-20 gestational weeks of pregnancy duration, the pregnant women accepted hemospasia in the local hospital and then the blood-serum were segregated. The samples were conserved in the condition of -20℃ by the refrigerator and delivered to the antenatal diagnosis center of the women' s hospital school of Medicine Zhejiang University to test the maternal serum markers in the second trimster including AFP and free β-hCG.
2. Reagent and Apparatus: We used time-resolved fluorescence immunoassay (DELFIA ,Wallac).The double labeling kit (AFP/free-β hCG) was purchased from American Perkin Elmer Company. The checking instrument adopted Wallac fully automated immunoassay. We underwent the operation according to reagent specification critically. The risk ratios were caculated by prenatal screening risk-caculated software of trisomy 21 syndrome which was supplied was supplied by the Wallac Company.
3. Statistical Methods: We utilized the SPSS 11.0 software to analyze. The statistical methods include t-test correlation analysis and the test of normality.
Rusults
Part I the Establishment of the Median of Maternal Serum Markers Including AFP and Free β -hCG and the Research of its Influencing Factors
1. The measured value and adjusted value of serum AFP in second trimester are
positively related to gestational weeks. The correlation coefficients are 0. 281 and 0. 048, and the P values are both less than 0. 001. But the measured value and adjusted value of serum free β -hCG in second trimester are negatively related to gestational weeks. The correlation coefficients are -0.231 and -0. 037, and the P values are both less than 0.001.
2. The measured values of serum AFP and the serum free β -hCG in the second
trimester are negatively related to pregnant woman' s weight. The correlation coefficients are respectively -0.160 and -0. 130, and the P values are both less than 0.001.
3. The measured and adjusted value of the serum AFP and the serum free β -hCG are not related to the age of pregnant women, and the P values are all more than 0. 05.
4. The serum AFP MoM in the second trimester is positively related to gravidity. The correlation coefficient is 0. 062, and the P value is less than 0. 001. The serum β-hCG MoM in the second trimester is negatively related to gravidity. The correlation coefficient is -0. 028, and the P value is 0.02.
5. The serum AFP MoM and free β -hCG MoM in second trimester are not related to parity, and the P values are both more than 0.05.
6. We compare the median of the serum AFP value and free β -hCG value in different gestation weeks in the research with the median of both in the statistical software.
(1) The measured value of AFP median in this research is higher than the intrinsic value in the software. And both comparison is not significantly different. The t value is 0. 889, and the P value is 0.395.
(2) The measured value of free β -hCG median is higher than the intrinsic value
in the software. And both comparison is not significantly different. The t value is 1. 234, and the P value is 0.245.
7. The detection rate of high risk in Down' s syndrome is gradually raised along with the increased age. And the detection rate of high risk in DS is
obviously related to the pregnant women age. The correlation coefficient is 0.918, and the P value is less than 0.001.
Part II the Relationgship of High Level Serum Markers in the Second Trimester and Pregnancy Complications or Pathological Gestation 1 When free β-hCG MoM value is not less than 2.0
(1) When the first gestation, the MoM value of high level AFP in the second trimester is related to premature birth and infant of low-birth weight of premature birth. The P values are 0.017 and 0.001 separately. The RR values are 7. 059 and 33.545 separately.
(2) When the second gestation, the MoM value of high level AFP in the second trimester is related to premature birth and mature infant of low-birth weight. The P values are 0. 021 and 0. 010 separately. The RR values are 6. 696 and 25. 667 separately.
(3) When the third gestation and more, the MoM value of high level AFP in the second trimester is related to pregnancy with severe anemia. The P value is 0. 039.
(4) Regardless of gravidity, the MoM value of high level AFP in the second trimester is related to complete placenta praevia and mild apnea of infant. The P values are 0. 001 and 0. 002 separately. The RR values are 21. 525 and 17.631 separately.
2 When free AFP MoM value is between 0.5 and 2.0:
(1) When the first gestation, the MoM value of high level free β-hCG in the
second trimester is related to oligoamnios. The P value is 0. 009. The RR value is 5. 588.
(2) When the third gestation and more, the MoM value of high level free β -hCG in the second trimester is related to prolonged pregnancy III~° nephelium of amniotic fluid and fetal distress in uterus. The P values are separately 0. 004 0. 004 and less than 0. 001, and the RR values are 4. 297 2. 088 and 2. 427 separately;
(3) The MoM value of high level free β -hCG in the second trimester is related to the placenta implantation regardless of gravidity. The P value is 0.04, and the RR value is 5.581;
3, When free β-hCG MoM value is between 0.5-2.0
(1) When the first gestation , the MoM value of high level AFP in the second trimester is related to premature rupture of fetal membranes. The P value is 0.046. The RR value is 2.483.
(2) When the second gestation , the MoM value of high level AFP in the second trimester is related to severe preeclampsia. The P value is 0. 005. The RR value is 10.904.
(3) When the third gestation and more, the MoM value of high level AFP in the second trimester is related to severe preeclampsia and the P value is 0. 035. The RR value is 8.103.
(4) Regardless of gravidity, the MoM value of the high second-trimester maternal serum AFP is related to complete placenta praevia. And the P value is 0. 001. The RR value is 25. 3.
Conclusions
1 The influencing factors of the measured values of serum AFP and free β -hCG in the second trimester are: gestational week, the pregnant women' s weight and gravidity. We should ajust the median with these influencing factors in order to establish the right median of the serum markers in the second trimester of the district.
2, The measured values of the AFP MoM and free β -hCG MoM are higher than the intrinic median in the analyzed software.
3 When the pregnant women' s age is younger than 35, the detection rate of the high risk of Down' s syndrome is related to the age obviously.
4 The high level serum markers in the second trimester are related to some obstetric complications or pathological pregnancies including premature
labor, infant of low-birth weight when premature labor, complete placenta praevia, infant with mild apnea oligoamnios successful tocolysis of threatened premature labor prolonged pregnancy III° nephelium of amniotic fluid, placenta implantation, fetal distress in uterus, premature rupture of fetal membranes, severe preeclampsia and FGR.
大量的研究已经显示妊娠中期应用甲胎蛋白(alpha fetoprotein，AFP)和游离β人绒毛膜促性腺激素(human chorionic gonadotropin，hCG)进行唐氏综合征筛查是发现21三体患儿的有效手段。而国人正常孕妇各孕周AFP和游离β-hCG中位数的建立将有助于提高21三体的检出率，但现用软件中的内嵌中位数与国人在种族等方面存在差异，因此有必要建立本地区孕妇各孕周的中位数水平。
目的：
1、研究孕中期孕妇的年龄、孕周、体重、孕次、产次对孕中期母血清标志物的影响。
2、通过大样本的人群血清学筛查，确立本地区各孕周的血清AFP、游离β-hCG的中位数；比较各年龄组的唐氏综合征的高危比例，探讨高危人群范围。
3、研究本地区孕妇孕中期母血清中高水平游离β-hCG或AFP与某些产科并发症或病理妊娠的关系。以期早期发现、早期诊断产科并发症或病理妊娠。
方法：
1、取材和筛查指标：妊娠15-20周期间，孕妇由就诊医院抽血并分离血清，标本保存于-20℃冰箱，于一周内送至浙江大学医学院附属妇产科医院浙江省产前诊断中心进行血清学标志物检测。筛查指标为孕中期母血清AFP和游离β-hCG。
2、试剂和仪器：测定方法采用时间分辨荧光免疫分析法(DELFIA，Wallac)。双标记试剂盒(AFP/游离-βhCG)购自美国PerkinElmer公司，检测仪器采用Wallac全自动免疫分析系统，并严格按照试剂说明书进行操作。风险率由Wallac公司提供的产前筛查21三体风险计算软件计算。
3、统计学方法：采用SPSS 11.0软件包进行统计分析，统计学方法有t-检验、相关分析、正态性检验。
结果：
第一部分母血清标志物中位数的确立及其影响因素研究
1、孕中期母血清AFP测定值、体重校正值与孕周均成正相关，相关系数分别为r=0.281，P＜0.001及r=0.048，P＜0.001；而孕中期血清游离β-hCG测定值、体重校正值与孕周均成负相关，相关系数分别为r=0.231，P＜0.001；r=0.037，P=0.004；
2、孕中期母血清AFP测定值及游离β-hCG测定值与孕妇体重均成负相关，相关系数分别为为-0.160，和-0.130，P值均小于0.001；
3、孕中期血清AFP和游离β-hCG测定值、校正值与孕妇的年龄均无相关性，P值均大于0.05；
4、孕中期母血清AFP中位数的倍数(multiple of median，MoM)值与孕次成正相关，相关系数为r=0.062，P＜0.001；而孕中期母血清游离β-hCG MoM值与孕次成负相关，相关系数为r=-0.028，P=0.02；
5、孕中期母血清AFP MoM值和游离β-hCG MoM值与产次均无相关性，P值均大于0.05；
6、本地区孕中期母血清中各孕周的游离β-hCG、AFP的中位数与软件内嵌值比较
(1) AFP中位数的测定值比分析软件内嵌值要高。两者比较没有统计学差异，t=0.889，P=0.395；
(2)游离β-hCG中位数的测定值比分析软件内嵌值要高。两者比较没有统计学差异，t=1.234，P=0.245；
7、唐氏综合征的高危检出率随着年龄的增长有逐渐增高的趋势，且唐氏征筛查高危检出率与年龄有明显相关性(相关系数r=0.918，P＜0.001)。
第二部分孕中期高水平血清标志物与产科并发症或病理妊娠的关系
1、当游离β-hCG MoM值≥2.0时
(1)孕1次组孕中期高水平AFP MoM值与早产、早产低体重儿有关，P值分别为0.017和0.001，相对危险度(relative risk，RR)值分别为7.059和33.545；
(2)孕2次组孕中期高水平AFP MoM值与早产、足月低体重儿有关，P值分别为0.021和0.010，RR值分别为6.696和25.667；
(3)孕3次及以上组高水平AFP MoM值与妊娠合并重度贫血有关，P=0.039；
(4)不按孕次分组时，孕中期血清高水平AFP MoM值与完全性前置胎盘、新生儿轻度窒息有关，P值分别为0.001和0.002，RR值分别为21.525和17.631；
2、当AFP MoM值在0.5-2.0时
(1)孕1次组高水平游离β-hCG MoM值与羊水过少有关，P=0.009，RR=5.588；
(2)孕3次及以上组，高水平游离β-hCG MoM值与过期妊娠、羊水Ⅲ°浑浊及胎儿宫内窘迫有关，P值分别为0.004、0.004和小于0.001，RR值分别为4.297、2.088和2.427；
(3)不按孕次分组时，高水平游离β-hCG MoM值与胎盘植入有关，P=0.040，RR=5.581；
3、当游离β-hCG MoM值在0.5-2.0时
(1)孕1次组孕中期高水平AFP MoM值与胎膜早破有关，P=0.046，RR=2.483；
(2)孕2次组孕中期高水平AFP MoM值与重度子痫前期有关，P值分别为0.005，RR值为10.904；
(3)孕3次及以上组孕中期高水平AFP MoM值与重度子痫前期有关，P值分别为0.035，RR值为8.103；
(4)不按孕次分组时，孕中期血清高水平AFP MoM值与完全性前置胎盘有关，P=0.001，RR=25.3。
结论：
1、影响孕中期血清AFP测定值与游离β-hCG测定值的因素有：孕周、孕妇体重和孕次；因此要正确建立本地区孕中期血清标志物的中位数，就必须对这些影响因素进行校正；
2、AFP中位数的测定值及游离β-hCG中位数的测定值比分析软件内嵌值要高；
3、当孕妇年龄小于35岁时，唐氏征筛查高危检出率与年龄有明显相关性；
4、孕中期高水平血清标志物与一些产科并发症或病理妊娠如：早产、早产低体重儿、完全性前置胎盘、新生儿轻度窒息、羊水过少、过期妊娠、羊水Ⅲ°浑浊、胎盘植入、胎儿宫内窘迫、胎膜早破、重度子痫前期和胎儿生长受限(fetal growth restriction，FGR)有关。
Down' s syndrome is entitled trisomy 21 syndrome. It is the most common chromosomal disease in live birth newborns. Down' s syndrome is one of the most common causes which leads to the still-birth the abortion and the fetus birth defect. Along with social improvement and civilized development, people make further acquaintanceship with aristogenesis, so the serum prenatal screeing of Down' s syndrome has become widespread.
Massive research has showed that we could detect the trisomy 21 syndrome effectively if we has carried out the prenatal screening with AFP and free β -hCG. If we could establish the different gestational weeks-median of AFP and β -hCG of the normal pregnant women in our country, we could increase the detection rate of trisomy 21 syndrome efficiencily. The median of the software applied has been different from the exact median of the countrymen because of the race, so it is necessary to establish the median of the pregnant women in our district.
Objective
1. To investigate the relationship between the pregnant women' s age, gestational week body weight gravidity .. parity and the maternal serum markers in the second trimester.
2. To establish the different gestational weeks-median of serum AFP and free
β-hCG in the district by serum screening of large samples and compare the high risk-proportion of different age groups to discuss the range of high risk-people.
3. To investigate the relationship of maternal serum high level AFP or free β -hCG and the obstetric complications or pathological gestation for the early detection and diagnosis.
Methods
1. Material and Screening Index: In the course of 15-20 gestational weeks of pregnancy duration, the pregnant women accepted hemospasia in the local hospital and then the blood-serum were segregated. The samples were conserved in the condition of -20℃ by the refrigerator and delivered to the antenatal diagnosis center of the women' s hospital school of Medicine Zhejiang University to test the maternal serum markers in the second trimster including AFP and free β-hCG.
2. Reagent and Apparatus: We used time-resolved fluorescence immunoassay (DELFIA ,Wallac).The double labeling kit (AFP/free-β hCG) was purchased from American Perkin Elmer Company. The checking instrument adopted Wallac fully automated immunoassay. We underwent the operation according to reagent specification critically. The risk ratios were caculated by prenatal screening risk-caculated software of trisomy 21 syndrome which was supplied was supplied by the Wallac Company.
3. Statistical Methods: We utilized the SPSS 11.0 software to analyze. The statistical methods include t-test correlation analysis and the test of normality.
Rusults
Part I the Establishment of the Median of Maternal Serum Markers Including AFP and Free β -hCG and the Research of its Influencing Factors
1. The measured value and adjusted value of serum AFP in second trimester are
positively related to gestational weeks. The correlation coefficients are 0. 281 and 0. 048, and the P values are both less than 0. 001. But the measured value and adjusted value of serum free β -hCG in second trimester are negatively related to gestational weeks. The correlation coefficients are -0.231 and -0. 037, and the P values are both less than 0.001.
2. The measured values of serum AFP and the serum free β -hCG in the second
trimester are negatively related to pregnant woman' s weight. The correlation coefficients are respectively -0.160 and -0. 130, and the P values are both less than 0.001.
3. The measured and adjusted value of the serum AFP and the serum free β -hCG are not related to the age of pregnant women, and the P values are all more than 0. 05.
4. The serum AFP MoM in the second trimester is positively related to gravidity. The correlation coefficient is 0. 062, and the P value is less than 0. 001. The serum β-hCG MoM in the second trimester is negatively related to gravidity. The correlation coefficient is -0. 028, and the P value is 0.02.
5. The serum AFP MoM and free β -hCG MoM in second trimester are not related to parity, and the P values are both more than 0.05.
6. We compare the median of the serum AFP value and free β -hCG value in different gestation weeks in the research with the median of both in the statistical software.
(1) The measured value of AFP median in this research is higher than the intrinsic value in the software. And both comparison is not significantly different. The t value is 0. 889, and the P value is 0.395.
(2) The measured value of free β -hCG median is higher than the intrinsic value
in the software. And both comparison is not significantly different. The t value is 1. 234, and the P value is 0.245.
7. The detection rate of high risk in Down' s syndrome is gradually raised along with the increased age. And the detection rate of high risk in DS is
obviously related to the pregnant women age. The correlation coefficient is 0.918, and the P value is less than 0.001.
Part II the Relationgship of High Level Serum Markers in the Second Trimester and Pregnancy Complications or Pathological Gestation 1 When free β-hCG MoM value is not less than 2.0
(1) When the first gestation, the MoM value of high level AFP in the second trimester is related to premature birth and infant of low-birth weight of premature birth. The P values are 0.017 and 0.001 separately. The RR values are 7. 059 and 33.545 separately.
(2) When the second gestation, the MoM value of high level AFP in the second trimester is related to premature birth and mature infant of low-birth weight. The P values are 0. 021 and 0. 010 separately. The RR values are 6. 696 and 25. 667 separately.
(3) When the third gestation and more, the MoM value of high level AFP in the second trimester is related to pregnancy with severe anemia. The P value is 0. 039.
(4) Regardless of gravidity, the MoM value of high level AFP in the second trimester is related to complete placenta praevia and mild apnea of infant. The P values are 0. 001 and 0. 002 separately. The RR values are 21. 525 and 17.631 separately.
2 When free AFP MoM value is between 0.5 and 2.0:
(1) When the first gestation, the MoM value of high level free β-hCG in the
second trimester is related to oligoamnios. The P value is 0. 009. The RR value is 5. 588.
(2) When the third gestation and more, the MoM value of high level free β -hCG in the second trimester is related to prolonged pregnancy III~° nephelium of amniotic fluid and fetal distress in uterus. The P values are separately 0. 004 0. 004 and less than 0. 001, and the RR values are 4. 297 2. 088 and 2. 427 separately;
(3) The MoM value of high level free β -hCG in the second trimester is related to the placenta implantation regardless of gravidity. The P value is 0.04, and the RR value is 5.581;
3, When free β-hCG MoM value is between 0.5-2.0
(1) When the first gestation , the MoM value of high level AFP in the second trimester is related to premature rupture of fetal membranes. The P value is 0.046. The RR value is 2.483.
(2) When the second gestation , the MoM value of high level AFP in the second trimester is related to severe preeclampsia. The P value is 0. 005. The RR value is 10.904.
(3) When the third gestation and more, the MoM value of high level AFP in the second trimester is related to severe preeclampsia and the P value is 0. 035. The RR value is 8.103.
(4) Regardless of gravidity, the MoM value of the high second-trimester maternal serum AFP is related to complete placenta praevia. And the P value is 0. 001. The RR value is 25. 3.
Conclusions
1 The influencing factors of the measured values of serum AFP and free β -hCG in the second trimester are: gestational week, the pregnant women' s weight and gravidity. We should ajust the median with these influencing factors in order to establish the right median of the serum markers in the second trimester of the district.
2, The measured values of the AFP MoM and free β -hCG MoM are higher than the intrinic median in the analyzed software.
3 When the pregnant women' s age is younger than 35, the detection rate of the high risk of Down' s syndrome is related to the age obviously.
4 The high level serum markers in the second trimester are related to some obstetric complications or pathological pregnancies including premature
labor, infant of low-birth weight when premature labor, complete placenta praevia, infant with mild apnea oligoamnios successful tocolysis of threatened premature labor prolonged pregnancy III° nephelium of amniotic fluid, placenta implantation, fetal distress in uterus, premature rupture of fetal membranes, severe preeclampsia and FGR.
引文
1、lomaki GE, Kinight GJ, Mccartly JE et al. Maternal serum screening for Down syndrome in the United States: a 1995 survey. Am J Obstet Gynecol. 1997 May;176(5):1046-51
2、仇杭佳，彭健桥．孕妇血清标志物中位数在Down综合症筛查中的应用．国际医药卫生导报．2004，10(10)107-109
3、张丽，周助人，冯光．妊娠中期不同孕周妇女外周血清标记物中位数及出生缺陷筛查标准．中国妇幼保健。2005，20，2324-2325
4、王长本，丁显平，郭定以，魏祥松，夏庆杰．唐氏综合征产前筛查、诊断的研究，国外
5、医学临床生物化学与检验学分册，2004，5，25(3)，200-202．
6、Hsu JJ, Hsieh TT, Hsieh FJ. Down syndrome screening in an Asian population using alpha-fetoprotein and free beta-HCG:A report of the Taiwan Down Syndrome Sreening Group[J].Obstet Gynecol, 1996,87:387-947.
7、Muller F, Dreux S, Oury JF, et al. Down syndrome maternal serum marker after 18 weeks' gestation[J].Prenat Diagn, 2002 Nov, 22(11):1001-1004.
1 Wald NJ, George L, Smith D, et al. Serum screening for Down' s syndrome between 8 and 14 weeks of pregnancy. Br J Obstet,1996,103:407
2 David L. Walton, Carol T. Norem, et al. Second-Trimester serum Chorionic Gonadotropin concentrations and complications and outcome of pregnancy. The New Eengland Journal of Medicine., 1999, 341(27):2033-2038
3 Odibo AO, Sehdev HM, Stamilio DM, et al. Evaluating the thresholds of abnormal second trimester multiple marker screening tests associated with intra-ute -rine Growth Restriction. Am J Perinatol. 2006. Aug, 23(6):363-367.
4 Celentano C, Guanciali-Franchi PE, Liberati M, et al. Lack of correlation betw -een elevated maternal serum HCG during second-trimester biochemical scree -ning and fetal enital anomaly. Prenat Diagn, 2005,25(3):220-222
5 Geralyn M, Helayne M, Felice P, et al. Second-Trimester Leverls of Maternal Serum Human Chorionic Gonadotropin and Inhibin A as Predictors of Preeclamp -sia in the Third Trimester of Pregnancy. J Soc Gynecol Invest, 2000, 7(3): 170-174
6 Brajenovic-Milic B, Trislaric D, Zuvic-Butorac M, et al. Elevated Second-Tri -meste -r Free β -HCG as an Isolated Finding and Pregnancy Outcomes. Fetal Diagn Ther, 2004,19 (6):483-487
7, Jou H, Wu SC, Lu YM, et al. Weight-correction formula for maternal serum screen -ing for Down syndrome in TaiWall.J Formos Med Assoc. 2000, 99:931-935.
8 Salone R. Maternal serums screening for Down' s syndrome on population basis[J]. Ac -ta Gynecology Scand 1997,76:81-87.
9 Holsing S. Current state of screening for Down' s syndrome. Ann Clin Biochem, 2002,39:1
10 Pavin CA, Gray DL, Kessler G. Influence of assay method diferenceson multiple of the median distributions: maternal serum alpha-fetoprotein as all exapl -le. Clin Chem, 1991, 37(5):637-642
1 Nathalie Lepage ,Davie Chitayat, John Kingdom, et al. Association between second -trimester is omplications in singleton and twin pregnancies. Am J Obstet Gynecol, 2003,188 (5):1354-1359
2 Chandra S, Scott H, Dodds L, Watts C, Blight C, Van Den Hof M. Unexplained elevated maternal serum alpha-fetroprotein and/or human chorionic gonadotropin and the risk of adverse outcomes. AM J Obstet Gynecol, 2003, 189(3):775-781
3 Cuckle HS, Wald NJ, Densem JW. The effect of smoking in pregnancy on maternal serum AFP estriol hCG progesterone, and dehydroepiandroepiandrosterone sulfate levels. Br J Obstet Gynaecol 1990:97:272-276.
4 David L. Walton, Carol T. Norem, et al. Second-Trimester serum Chorionic Gonadotrop -in concentrations and complications and outcome of pregnancy. The New England Journal of Medicine., 1999,341(27):2033-2038
5 Geralyn M, Helayne M, Felice P, et al. Second-Trimester Leverls of Maternal Serum Human Chorionic Gonadotropin and Inhibin A as Predictors of Preeclampsia in the Third Trimester of Pregnancy. J Soc Gynecol Investing, 2000, 7(3):170-174
6 Bojana BraMil, Dubravka Ti, et al. Elevated Second-Trimester Free β -hCG as an Isol -ated Finding and Pregnancy Outcomes. Fetal Diagn Ther, 2004,19 (6):483-487
7 Kevin Spencer. Second-trimester prenatal screening for Down syndrome and the relationship of maternal serum biochemical markers to pregnancy complications with adverse outcome. Prenat Diagn, 2000, 20(8):652-656
8 Robert Ogle, Eric Jauniaux, et al. Serum screening for Down syndrome and adverse pregnancy outcomes:a case-controlled study. Prenat Diagn, 2000, 20(2):96-99
9 Raquel Romero-Carmona, Miguel Escobar-Liompart et al . Human chorionic gonadotrop -in and vascular endothelial growth factor in normal and complicated pregnancies Obstetric and Gynecology, 2003, 102(5):995-999
10 Spencer K. Second-trimester prenatal screening for Down syndrome and the relation -ship of ma ternal serum biochemical markers to pregnancy complications with advers -e outcome. Prenat Dia -gn, 2000, 20(8):652-656
1 Celentano C, Guanciali-Franchi PE, Liberati M, et al. Lack of correlation between elevated maternal serum HCG during second-trimester biochemical screening and fetal enital anomaly. Prenat Diagn, 2005, 25(3):220-222
2 Kharfi A, Giguere Y, Grandre PD, et al. Human chorionic gonadotropin (HCG) may be a marker of systemic oxidative stress in normotensive and preeclamptic term pregna -ncies. Clin Biochem, 2005, 195(7): 236-240
3 Geralyn M, Helayne M, Felice P, et al. Second-Trimester Leverls of Maternal Serum Human Chorionic Gonadotropin and Inhibin A as Predictors of Preeclampsia in the Third Trimester of Pregnancy. J Soc Gynecol Invest, 2000,7(3):170-174
4 Brajenovic-Milic B, Trislaric D, Zuvic-Butorac M, et al. Elevated Second-Trimeste -r Free β-HCG as an Isolated Finding and Pregnancy Outcomes. Fetal Diagn Ther, 2004,19 (6): 483-487
5 Spencer K. Second-trimester prenatal screening for Down syndrome and the relatio -nship of maternal serum biochemical markers to pregnancy complications with adverse outcome. Prenat Diagn, 2000, 20(8):652-656
6 Ogle R, Jauniaux E, Pahal GS. et al. Serum screening for Down syndrome and adverse pregnancy outcomes:a case-controlled study. Prenat Diagn, 2000,20 (2):96-99
7 Lepage N, Chitayat D, Kingdom J, et al. Association between second-trimester isolated high maternal serum maternal serum human chorionic gonadotropin levels and obstetric complications in singleton and twin pregnancies. Am J Obstet Gyneco -1,2003, 188(5):1354-1359
8 Chandra S, Scott H, Dodds L, et al. Unexplained elevated maternal serum alpha-fetro -prtein and/or human chorionic gonadotropin and the risk of adverse outcomes. AM J Obstet Gynecol, 2003, 189(3):775-781
9 Bartha JL, Romero-Carmona R, Escobar-Liompart M, et al . Human chorionic gonadotr -opin and vascular endothelial growth factor in normal and complicated pregnanci -es. Obstet & Gynecol, 2003,102(5):995-999
10 Audibert F, Benchimol Y, Benattar C, et al. Prediction of Preeclampsia or Intraute -rine Growth Restriction by Second Trimester Serum Screening and Uterine Doppler Velocimetry. Fetal Diagn Ther, 2005, 20(1):48-53
11 De Leon J, Sifuentes G, Hopkins C, et al. Maternal serum free beta-HCG levels in uncomplicated pregnancies at the 10th-15th week of gestation and the development of obstetric complications.J Reprod Med, 2004,49(2):89-92
12 Liu SS, Lee FK, Lee JK, et al. Pregnancy outcomes in unselected singleton pregnant women with an increased risk of first-trimester Down' s syndrome. Acta Obstet Gynecol Scand, 2004, 83(12):1130-1134
13 Yaron Y, Heifetz S, Ochshorn Y, et al. Decreased first trimester PAPP-A is a predec -tor of adverse pregnancy outcome. Prenat Diagn, 2002, 22(9):778-782
14 Leporrier N, Herrou M, morrello R, et al. Fetuses with Down' s syndrome detected by prenatal screening are more likely to abort spontaneously than fetuses with Down' s syndrome not detected by prenatal screening. Br J Obstet Gynecol, 2003, 110(1) :18-21
15 Endres LK, Krotz S, Grobman WA, et al. Isolated low second-trimester maternal serum β -human chorionic gonadotropin is not associated with adverse pregnancy outcom -e.Am J Obstet Gynecol, 2003, 189(3):755-757
16 Lambert-Messerlian M, Silver HM, Petraglia F, et al. Second-Trimester Levels of Maternal Serum Human Chorionic Gonadotropin and Inhibin A as Predictors of Preec -lampsia in the Third Trimester of Pregnancy. J Soc Gynecol Invest, 2000, 7(3): 170 -174
17 Hauzman E, Fedorcsak P, Klinga K, et al. Use of serum inhibin A and human chorionic gonadotropin measurements to predict the outcome of in vitro fertilization pregnancpregnancies. Fertility and sterility,2004, 81(1):66-72
18 Davidson EJ, Riley SC,Roberts SA, et al. Maternal serum activin, inhibin, human chorionic gonadotrophin and a -fetoprotein as second trimester predictors of preeclampsia. Br J Obstet Gynaecol, 2003, 110(1):46-52
19 Morssink LP, Heringa MP, Beekhuis JR, et al. The Association Between Hypertensive Disorders of Pregnancy and Abnormal Second-Trimester Maternal Serum Levels of HCG and Alpha-Fetoprotein. Obstet & Gynecol, 1997, 89(5) :666-670
2、仇杭佳，彭健桥．孕妇血清标志物中位数在Down综合症筛查中的应用．国际医药卫生导报．2004，10(10)107-109
3、张丽，周助人，冯光．妊娠中期不同孕周妇女外周血清标记物中位数及出生缺陷筛查标准．中国妇幼保健。2005，20，2324-2325
4、王长本，丁显平，郭定以，魏祥松，夏庆杰．唐氏综合征产前筛查、诊断的研究，国外
5、医学临床生物化学与检验学分册，2004，5，25(3)，200-202．
6、Hsu JJ, Hsieh TT, Hsieh FJ. Down syndrome screening in an Asian population using alpha-fetoprotein and free beta-HCG:A report of the Taiwan Down Syndrome Sreening Group[J].Obstet Gynecol, 1996,87:387-947.
7、Muller F, Dreux S, Oury JF, et al. Down syndrome maternal serum marker after 18 weeks' gestation[J].Prenat Diagn, 2002 Nov, 22(11):1001-1004.
1 Wald NJ, George L, Smith D, et al. Serum screening for Down' s syndrome between 8 and 14 weeks of pregnancy. Br J Obstet,1996,103:407
2 David L. Walton, Carol T. Norem, et al. Second-Trimester serum Chorionic Gonadotropin concentrations and complications and outcome of pregnancy. The New Eengland Journal of Medicine., 1999, 341(27):2033-2038
3 Odibo AO, Sehdev HM, Stamilio DM, et al. Evaluating the thresholds of abnormal second trimester multiple marker screening tests associated with intra-ute -rine Growth Restriction. Am J Perinatol. 2006. Aug, 23(6):363-367.
4 Celentano C, Guanciali-Franchi PE, Liberati M, et al. Lack of correlation betw -een elevated maternal serum HCG during second-trimester biochemical scree -ning and fetal enital anomaly. Prenat Diagn, 2005,25(3):220-222
5 Geralyn M, Helayne M, Felice P, et al. Second-Trimester Leverls of Maternal Serum Human Chorionic Gonadotropin and Inhibin A as Predictors of Preeclamp -sia in the Third Trimester of Pregnancy. J Soc Gynecol Invest, 2000, 7(3): 170-174
6 Brajenovic-Milic B, Trislaric D, Zuvic-Butorac M, et al. Elevated Second-Tri -meste -r Free β -HCG as an Isolated Finding and Pregnancy Outcomes. Fetal Diagn Ther, 2004,19 (6):483-487
7, Jou H, Wu SC, Lu YM, et al. Weight-correction formula for maternal serum screen -ing for Down syndrome in TaiWall.J Formos Med Assoc. 2000, 99:931-935.
8 Salone R. Maternal serums screening for Down' s syndrome on population basis[J]. Ac -ta Gynecology Scand 1997,76:81-87.
9 Holsing S. Current state of screening for Down' s syndrome. Ann Clin Biochem, 2002,39:1
10 Pavin CA, Gray DL, Kessler G. Influence of assay method diferenceson multiple of the median distributions: maternal serum alpha-fetoprotein as all exapl -le. Clin Chem, 1991, 37(5):637-642
1 Nathalie Lepage ,Davie Chitayat, John Kingdom, et al. Association between second -trimester is omplications in singleton and twin pregnancies. Am J Obstet Gynecol, 2003,188 (5):1354-1359
2 Chandra S, Scott H, Dodds L, Watts C, Blight C, Van Den Hof M. Unexplained elevated maternal serum alpha-fetroprotein and/or human chorionic gonadotropin and the risk of adverse outcomes. AM J Obstet Gynecol, 2003, 189(3):775-781
3 Cuckle HS, Wald NJ, Densem JW. The effect of smoking in pregnancy on maternal serum AFP estriol hCG progesterone, and dehydroepiandroepiandrosterone sulfate levels. Br J Obstet Gynaecol 1990:97:272-276.
4 David L. Walton, Carol T. Norem, et al. Second-Trimester serum Chorionic Gonadotrop -in concentrations and complications and outcome of pregnancy. The New England Journal of Medicine., 1999,341(27):2033-2038
5 Geralyn M, Helayne M, Felice P, et al. Second-Trimester Leverls of Maternal Serum Human Chorionic Gonadotropin and Inhibin A as Predictors of Preeclampsia in the Third Trimester of Pregnancy. J Soc Gynecol Investing, 2000, 7(3):170-174
6 Bojana BraMil, Dubravka Ti, et al. Elevated Second-Trimester Free β -hCG as an Isol -ated Finding and Pregnancy Outcomes. Fetal Diagn Ther, 2004,19 (6):483-487
7 Kevin Spencer. Second-trimester prenatal screening for Down syndrome and the relationship of maternal serum biochemical markers to pregnancy complications with adverse outcome. Prenat Diagn, 2000, 20(8):652-656
8 Robert Ogle, Eric Jauniaux, et al. Serum screening for Down syndrome and adverse pregnancy outcomes:a case-controlled study. Prenat Diagn, 2000, 20(2):96-99
9 Raquel Romero-Carmona, Miguel Escobar-Liompart et al . Human chorionic gonadotrop -in and vascular endothelial growth factor in normal and complicated pregnancies Obstetric and Gynecology, 2003, 102(5):995-999
10 Spencer K. Second-trimester prenatal screening for Down syndrome and the relation -ship of ma ternal serum biochemical markers to pregnancy complications with advers -e outcome. Prenat Dia -gn, 2000, 20(8):652-656
1 Celentano C, Guanciali-Franchi PE, Liberati M, et al. Lack of correlation between elevated maternal serum HCG during second-trimester biochemical screening and fetal enital anomaly. Prenat Diagn, 2005, 25(3):220-222
2 Kharfi A, Giguere Y, Grandre PD, et al. Human chorionic gonadotropin (HCG) may be a marker of systemic oxidative stress in normotensive and preeclamptic term pregna -ncies. Clin Biochem, 2005, 195(7): 236-240
3 Geralyn M, Helayne M, Felice P, et al. Second-Trimester Leverls of Maternal Serum Human Chorionic Gonadotropin and Inhibin A as Predictors of Preeclampsia in the Third Trimester of Pregnancy. J Soc Gynecol Invest, 2000,7(3):170-174
4 Brajenovic-Milic B, Trislaric D, Zuvic-Butorac M, et al. Elevated Second-Trimeste -r Free β-HCG as an Isolated Finding and Pregnancy Outcomes. Fetal Diagn Ther, 2004,19 (6): 483-487
5 Spencer K. Second-trimester prenatal screening for Down syndrome and the relatio -nship of maternal serum biochemical markers to pregnancy complications with adverse outcome. Prenat Diagn, 2000, 20(8):652-656
6 Ogle R, Jauniaux E, Pahal GS. et al. Serum screening for Down syndrome and adverse pregnancy outcomes:a case-controlled study. Prenat Diagn, 2000,20 (2):96-99
7 Lepage N, Chitayat D, Kingdom J, et al. Association between second-trimester isolated high maternal serum maternal serum human chorionic gonadotropin levels and obstetric complications in singleton and twin pregnancies. Am J Obstet Gyneco -1,2003, 188(5):1354-1359
8 Chandra S, Scott H, Dodds L, et al. Unexplained elevated maternal serum alpha-fetro -prtein and/or human chorionic gonadotropin and the risk of adverse outcomes. AM J Obstet Gynecol, 2003, 189(3):775-781
9 Bartha JL, Romero-Carmona R, Escobar-Liompart M, et al . Human chorionic gonadotr -opin and vascular endothelial growth factor in normal and complicated pregnanci -es. Obstet & Gynecol, 2003,102(5):995-999
10 Audibert F, Benchimol Y, Benattar C, et al. Prediction of Preeclampsia or Intraute -rine Growth Restriction by Second Trimester Serum Screening and Uterine Doppler Velocimetry. Fetal Diagn Ther, 2005, 20(1):48-53
11 De Leon J, Sifuentes G, Hopkins C, et al. Maternal serum free beta-HCG levels in uncomplicated pregnancies at the 10th-15th week of gestation and the development of obstetric complications.J Reprod Med, 2004,49(2):89-92
12 Liu SS, Lee FK, Lee JK, et al. Pregnancy outcomes in unselected singleton pregnant women with an increased risk of first-trimester Down' s syndrome. Acta Obstet Gynecol Scand, 2004, 83(12):1130-1134
13 Yaron Y, Heifetz S, Ochshorn Y, et al. Decreased first trimester PAPP-A is a predec -tor of adverse pregnancy outcome. Prenat Diagn, 2002, 22(9):778-782
14 Leporrier N, Herrou M, morrello R, et al. Fetuses with Down' s syndrome detected by prenatal screening are more likely to abort spontaneously than fetuses with Down' s syndrome not detected by prenatal screening. Br J Obstet Gynecol, 2003, 110(1) :18-21
15 Endres LK, Krotz S, Grobman WA, et al. Isolated low second-trimester maternal serum β -human chorionic gonadotropin is not associated with adverse pregnancy outcom -e.Am J Obstet Gynecol, 2003, 189(3):755-757
16 Lambert-Messerlian M, Silver HM, Petraglia F, et al. Second-Trimester Levels of Maternal Serum Human Chorionic Gonadotropin and Inhibin A as Predictors of Preec -lampsia in the Third Trimester of Pregnancy. J Soc Gynecol Invest, 2000, 7(3): 170 -174
17 Hauzman E, Fedorcsak P, Klinga K, et al. Use of serum inhibin A and human chorionic gonadotropin measurements to predict the outcome of in vitro fertilization pregnancpregnancies. Fertility and sterility,2004, 81(1):66-72
18 Davidson EJ, Riley SC,Roberts SA, et al. Maternal serum activin, inhibin, human chorionic gonadotrophin and a -fetoprotein as second trimester predictors of preeclampsia. Br J Obstet Gynaecol, 2003, 110(1):46-52
19 Morssink LP, Heringa MP, Beekhuis JR, et al. The Association Between Hypertensive Disorders of Pregnancy and Abnormal Second-Trimester Maternal Serum Levels of HCG and Alpha-Fetoprotein. Obstet & Gynecol, 1997, 89(5) :666-670