摘要
第一章孕早期血清指标与子痫前期、FGR的关系研究
目的：探讨ADAM12-S、PAPP-A、PP13、β-hCG与子痫前期、FGR的关系,并选出候选指标,以备建立孕早期筛查子痫前期、FGR的多参数模型。
方法：选取2008年12月至2010年9月在圣路易斯华盛顿大学Barnes-Jewish医院产科门诊于孕11-14周就诊的307例单胎妊娠孕妇作系统研究。询问病史,测量并计算BMI。抽取静脉血,利用时间分辨荧光免疫分析法检测解整合素样金属蛋白酶12-S(ADAM12-S)、胎盘蛋白13(PP13)、妊娠相关血浆蛋白A(PAPP-A)、β-人绒毛膜促性腺激素(β-hCG),并进行子宫动脉多普勒和胎盘四维能量多普勒检测。对参与研究的孕妇进行随访,记录妊娠并发症、分娩孕周、新生儿出生体重等信息。随访孕妇中27例发生子痫前期,12例发生FGR,148例为正常妊娠。120例发生其它妊娠并发症的病例、4例发生胎儿畸形的病例予以排除。对在Barnes-Jewish医院分娩的孕妇,收集其胎盘进行体视学分析。将子痫前期和FGR病例作为研究组,正常妊娠作为对照组对其血清、超声、胎盘体视学测值进行总结研究。ADAM12-S、PP13、PAPP-A、β-hCG测值转换为MoM(中位数倍数)。采用Wilcoxon秩和检验比较分析研究组与对照组各项血清指标的MoM值。
结果：子痫前期组PP13MoM显著低于对照组(p<0.05), FGR组PAPP-AMoM显著低于对照组(p<0.05)。研究组ADAM12-S、β-hCGMoM与对照组无显著差异(p>0.05)。
结论：孕早期PP13、PAPP-A降低分别与子痫前期、FGR相关,可能成为孕早期预测子痫前期、FGR的指标。
第二章孕早期超声指标测定及与血清指标、临床危险因素联合筛查子痫前期、FGR研究
目的：探讨孕早期四维能量多普勒及子宫动脉多普勒指标与子痫前期、FGR的关系,并将临床危险因素、血清、超声指标结合建立孕早期筛查子痫前期、FGR的多参数模型。
方法：利用彩色多普勒测量子宫动脉搏动指数(P1)、阻力指数(R1)、舒张早期切迹,利用四维能量多普勒测量胎盘体积和血管指数(包括血管化指数(vascularization index,VI)、血流指数(flow index,FI)、血管化-血流指数(vascularization-flow index,VFI)。胎盘商(PQ)=胎盘体积/头臀长(CRL)。PI、RI、PQ、VI、FI、VFI测值转化为MoM。采用Wilcoxon秩和检验比较分析研究组与对照组各项超声指标的MoM值。利用直线回归分析各项超声指标之间及超声指标与血清指标之间的相关性。利用Logistic回归分析建立孕早期筛查子痫前期、FGR的多参数模型。回归模型的筛查效能用受试者工作特征曲线下面积(AUC)、灵敏度、假阳性率(FPR)表示。
结果：1、子痫前期组FIMoM显著低于对照组(p<0.05)。研究组PIMoM、RIMoM、舒张早期切迹、VIMoM、VFIMoM、PQMoM与对照组无显著差异(p>0.05)。2、所有血清指标均存在相互关联。超声指标之间、超声指标与血清指标之间的关联性较小。3、临床危险因素、血清、超声单项指标预测子痫前期、FGR时,对预测子痫前期有显著贡献的临床危险因素为BMI、初产妇和既往子痫前期病史,对预测FGR有显著作用的为吸烟和慢性高血压。PAPP-A预测FGR的灵敏度(33.3%)高于临床危险因素预测FGR的灵敏度(30.1%),PP13、FI预测子痫前期的灵敏度分别为3.8%及7.7%,低于临床危险因素预测子痫前期的灵敏度(47.7%)。4、将临床危险因素、血清和超声指标联合预测子痫前期或FGR时,对预测子痫前期有显著贡献的为BMI、初产妇和既往子痫前期病史,AUC为0.885(95%C10.803-0.926),FPR为5%时的灵敏度为47.7%,FPR为10%时的灵敏度为67.7%。对预测FGR有显著作用的为慢性高血压及PAPP-A,AUC为0.806(95%CI0.736-0.864),FPR为5%时的灵敏度为25%,FPR为10%时的灵敏度为50%。
结论：孕早期PAPP-A可用于预测FGR,且灵敏度高于临床危险因素,可与临床危险因素联用预测FGR。孕早期PP13、FI预测子痫前期的灵敏度低,不能增进临床危险因素预测子痫前期的效能。
第三章子痫前期、FGR孕晚期胎盘体视学变化及其与孕早期血清、超声指标的关系
目的：探讨子痫前期、FGR患者孕晚期胎盘体视学变化是否与孕早期血清、超声指标相关。
方法：收集子痫前期13例、FGR7例、正常妊娠20例胎盘进行体视学分析。用排水法测量胎盘体积并随机取样5处,组织块经福尔马林固定后行苏木精—伊红染色。对染色后的切片进行体视学分析,计算胎盘绒毛和绒毛毛细血管的体积、表面积、长度。利用t检验和方差分析进行统计学分析。
结果：FGR组和子痫前期组胎盘体积、末梢绒毛体积、表面积较对照组显著降低(p<0.05)。胎盘体视学测值与超声指标、ADAM12-S、PP13、β-hCG均无显著性联系。PAPP-A与末梢绒毛体积关联的p值为0.05。胎盘体视学异常组PAPP-A(MoM)(0.7±0.5)低于对照组(1.1±0.5)(p=0.03)。
结论：孕早期PAPP-A降低影响胎盘末梢绒毛体积,可能是导致FGR发生的原因。
Chapter1The relationship of first trimester serum markers with preeclampsia and fetal growth restriction
Object:To evaluate the association of ADAM12-S, PAPP-A, PP13, P-hCG with preeclampsia and fetal growth restriction(FGR), and select candidate markers for a multi-parameter model to predict preeclampsia and fetal growth restrction.
Method:This is a systematical study of307singleton pregnancies who attended Medical Center of Washington University in St. Louis for routine assessment at11-14weeks of gestation from2008to2010. Medical history was recorded and body mass index (BMI) calculated. Venous blood was drawn. A disintegrin and metalloprotease12-S (ADAM12-S), placental protein13(PP13), pregnancy-associated plasma protein A (PAPP-A) and3-human chorionic gonadotrophin (P-hCG) concentration were measured by a time-resolved fluorescent immunoassay. Color Doppler and4-dimensional (4-D) power Doppler assessement were also applied. All the women included were followed up and pregnancy complications, gestational weeks of delivery, infant birthweight were recorded. There were27preclampsia,12FGR and148pregnancies.124pregnancies with other complications or fetal abnormality were excluded. Preclampsia and FGR cases were used as study group while normal pregnancy as control group. The results of serum analyte, sonographic and stereological assessment were summarized. Placentas were collected for stereological analysis from women who delivered in Barnes-Jewish Hospital. Multiples of the median (MoM) were calculated from the concentration of ADAM12-S、 PP13、PAPP-A、 β-hCG. Comparisons of serum analytes MoM between pregnancy outcomes were performed using Wilcoxon rank-sum test.
Result:PP13MoM was significantly lower for preeclampsia (p<0.05). PAPP-A MoM was significantly reduced for FGR (p<0.05). ADAM12-S MoM, β-hCG MoM was not significantly different between any adverse outcome and control.
Conclusion:First trimester reduced PP13, PAPP-A were associated with preeclampisa and FGR, respectively, and may become candidates to predict preclampsia and FGR in first trimester.
Chapter2The assessement of first trimester sonographic markers and its combination with serum analytes and clinical risk factors in predicting preeclmapsia and fetal growth restriciton
Object:To investigate the relationship of first trimester sonographic markers with preeclampsia and FGR, and combining serum analytes, sonographic makers and clinical risk factors to predict preeclampsia and FGR.
Method:Uterine artery pulsatility index (PI), resistance indices (RI) and notching were measured by color Doppler. Placental volume, vascularization index (VI), flow index (FI), and vascularization flow index (VFI) were obtained from4-dimensional (4-D) power Doppler. The placental quotient (PQ) was calculated by dividing placental volume by crown rump length (CRL). Multiples of the median (MoM) were calculated from the parameters. MoMs between pregnancy outcomes were compared using Wilcoxon rank-sum test. Regression analysis was then used to determine the significance of association between markers. Multivariable Logistic analysis was applied to establish moedel to predict preeclampsia and FGR. The performance of screening was demonstrated by area under receiver operating characteristic curves (AUC), sensitivity and false positive rates (FPR).
Result:1. FI MoM was significantly lower for preeclampsia compared to control (p<0.05). None of PIMoM, RIMoM, notching, VIMoM, VFIMoM, or PQMoM was significantly different between any adverse outcome and control (p>0.05).2. All serum markers were significantly correlated with each other. Sonographic markers were less correlated with each other. Maternal serum markers also correlated less with sonographic markers.3. When clinical risk factors, serum and songographic markers were used alone in prediction, BMI, nulliparity, previous preeclampisa showed significant contribution to the prediction of preeclampsia, while smoking, hypertension showed significant contribution to the prediciton of FGR. The sensitivity of PAPP-A to predict FGR(33.3%) was higer than that of clinical risk factors(30.1%), while the sensitivity of PP13,FI to predict preeclampsia(3.8%and7.7%respectively) was lower than that of clinical risk factors(47.7%).4. When clinical risk factors, serum and sonographic markers were combined to predict preeclampsia and FGR, there were significant contribution from BMI, nulliparity and previous preeclampsia in the prediction of preeclampsia. The AUC yielded by the ROC of the model was0.885(95%CI,0.803-0.926). At a5%FPR, the sensitivity was47.7%. At a10%FPR, the sensitivity was67.7%. In the prediction of FGR, there were significant contributions from hypertension and PAPP-A. The AUC yielded by the ROC of the model was0.806(95%CI,0.736-0.864). At a5%FPR, the sensitivity was25%. At a10%FPR, the sensitivity was50%.
Conclusion:First trimester PAPP-A contribute to the prediction of FGR. The sensitivity of PAPP-A to predict preeclampsia is higher than clinical risk factors and can be combined with clinical risk factors to predict FGR. PP13、FI and ADAM12-S failed to show their contribution to the screening model because of their low sensitivities.
Chapter3Placenta stereological change in preeclampsia and fetal growth restriction and its association with first-trimester serum analytes and sonographic evaluation
Objective:To test whether placenta stereological change is associated with first-trimester serum analytes and sonographic evaluation in preeclampsia and FGR.
Method:Placentas were collected from13preeclampsia,7FGR and20uncomplicated pregnancies. The volume of each placenta was tested by water replacement and random samples taken from5sites, and fixed in formalin within1hour of delivery. Hematoxylin&Eosin stained slides were analyzed by stereology to quantify linear dimensions, surface areas and volumes of placental villi and villi vessels. Paired t-test and Analysis of Variance (ANOVA) were used for comparison.
Results:The volume of placenta and volume and surface areas of terminal villi were significantly smaller in placentas from pregnancies complicated by FGR and preeclampsia (p<0.05). Placental stereology was not related with sonographic markers, ADAM12-S, PP13or P-hCG. The statistic significance of the relationship between PAPP-A and volume of terminal villi was0.05. Compared with the control group, the PAPP-A (MoM) was lower in the pregnancies with abnormal placenta stereology (1.1±0.5versus0.7±0.5, p=0.03).
Conclusion:The reduction of first-trimester PAPP-A levels affects volume of terminal villi, which might result in FGR.
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