子痫前期孕妇孕中期血清sEng、sFlt-1水平与妊娠结局的关系研究

目的探究子痫前期(PE)孕妇孕中期血清可溶性内皮因子(sEng)、可溶性fms样酪氨酸激酶1(sFlt-1)水平与妊娠结局的关系。方法回顾性分析2018年1月至2019年1月在甘肃省天水市第一人民医院妇产科生产的98例PE孕妇(疾病组)和健康孕妇98例(健康组)临床资料,依据疾病组妊娠结局不同分为良好组和不良组,对比疾病组、健康组血清sEng、sFlt-1水平及妊娠结局,并对PE孕妇妊娠结局影响因素进行分析。结果疾病组血清sEng、sFlt-1水平较健康组明显高(P 0.05),疾病组不良妊娠结局总发生率明显高于健康组(P 0.05),不良组孕中期血清甘油三脂、总胆固醇、sEng、sFlt-1水平较良好组明显高(P 0.05),孕中期血清sEng、sFlt-1水平为PE孕妇妊娠结局的高危因素(P 0.05)。结论 PE孕妇孕中期血清s Eng、s Flt-1水平明显增高,孕中期PE孕妇血清sEng、sFlt-1水平增高可增加不良妊娠结局发生风险,积极监测孕中期血清sEng、sFlt-1水平对降低PE孕妇不良妊娠结局风险有积极意义。     

子痫前期孕妇血清及尿液中VEGF、PLGF、sFlt-1水平变化及意义

目的:研究子痫前期孕妇血清及尿液中血管内皮生长因子(VEGF)、胎盘生长因子(PLGF)、可溶性血管内皮生长因子受体1(sFlt-1)水平变化与病情程度的关系,以及对子痫前期的预测价值.方法:将妊娠28～40周的19例轻度子痫前期,13例重度子痈前期孕妇作为研究组,9例正常妊娠孕妇作为对照组.采用酶联免疫吸附法检测各组孕妇血清及尿液中VEGF、PLGF、sFlt-1水平.结果:轻度子痫前期组血清及尿液VEGF、PLGF、sFlt-1水平与重度子痫前期组比较,差异均有高度统计学意义(P＜0.01).轻度子痫前期组血清及尿液ⅦGF、PLGF、sFlt-1水平与对照组比较,差异均有高度统计学意义(P＜0.01).子痫前期组,血清PLGF及sFlt-1水平高于尿液中水平.而血清VEGF水平则低于尿液中的水平.在对照组,血清的VEGF、PLGF及sFlt-1水平均高于尿中的水平.结论:孕妇血清和尿液中ⅦGF、PLGF、sFlt-1水平与子痫前期病情程度呈相关性.检测孕妇尿液中的VEGF、PLGF及sFlt-1水平可能预测子痫前期的发生.     

子痫前期孕妇血浆蛋白酶Corin、PLGF、sEng、sFlt-1水平变化及临床意义

目的探讨子痫前期(PE)孕妇血浆蛋白酶Corin、胎盘生长因子(PLGF)、可溶性内皮因子(sEng)、可溶性血管内皮生长因子受体-1(sFlt-1)表达及其意义。方法将PE孕妇92例根据严重程度分为轻度PE组(M-PE组,n=53)和重度PE组(S-PE组,n=39),根据发病时间分为早发型PE组(n=57)和晚发型PE组(n=35)。另选同期健康孕妇50例为对照组。检测各组血浆Corin、PLGF、s Eng及sFlt-1。结果 PE组的血浆Corin、sEng、sFlt-1和sFlt-1/PLGF高于对照组,且S-PE组高于M-PE组(P 0.05);PE组的血浆PLGF低于对照组,且S-PE组低于M-PE组(P 0.05)。早发型PE组的血浆Corin、sEng、sFlt-1和sFlt-1/PLGF均高于晚发型PE组,PLGF低于晚发型PE组(P 0.05)。PE患者的血浆Corin与sEng、sFlt-1和sFlt-1/PLGF比值呈显著正相关性,与PLGF呈显著负相关性(P 0.05)。结论 PE患者血浆Corin、s Eng、s Flt-1呈明显高表达而PLGF呈低表达,且与发病时期、病情严重程度相关,早发型PE异常表达更明显。     

可溶性酪氨酸激酶受体1/胎盘生长因子比值在子痫前期诊断中的价值

目的:探讨血清、尿液可溶性酪氨酸激酶受体1/胎盘生长因子(sFlt-1/PLGF)比值在子痫前期的诊断价值.方法:检测及比较分析40例正常孕妇、38例轻度子痫前期与32例重度子痫前期孕妇血清及尿液中PLGF、sFlt-1及sFlt-1/PLGF比值的变化,将尿液PLGF、sFlt-1分别与血清PLGF、sFlt-1进行Person相关分析,并用ROC曲线分析血清、尿液中sFlt-1/PLGF比值对子痫前期的诊断价值.结果:轻度子痫前期组血清、尿液sFlt-1/PLGF比值高于正常对照组,重度子痫前期组sFlt-1/PLGF比值高于轻度子痫前期组,各组之间的差异均有统计学意义(均P＜0.01);尿液PLGF、sFlt-1分别与血清PLGF、sFlt-1具有正相关性(r=0.692,r=0.784,均P＜0.05);血清、尿液sFlt-1/PLGF比值对轻度子痫前期的ROC曲线下面积(AUC)分别为0.921、0.935,血清、尿液sFlt-1/PLGF比值对重度子痫前期的ROC的AUC分别为0.959、0.972.血清中sFlt-1/PLGF比值的AUC与尿液中sFlt-1/PLGF比值的AUC相比差异均无统计学意义(均P ＞0.05).结论:血清、尿液sFlt-1/PLGF比值在子痫前期患者中均有明显的升高,其为子痫前期的诊断提供了一个较理想的实验室指标,在临床中可以用尿液sFlt-1/PLGF比值替代血液sFlt-1/PLGF比值.     

可溶性血管内皮生长因子受体-1在子痫前期胎盘及在外周血的研究

目的研究可溶性血管内皮生长因子受体-1(sFlt-1) mRNA在正常妊娠和子痫前期胎盘中的表达差异及相应的母体外周血中sFlt-1水平的变化。方法选取15例子痫前期孕妇(子痫前期组)和14例孕周与之相匹配的血压正常妊娠孕妇(对照组),用ELISA方法测定其外周血中sFlt-1的水平;并应用实时荧光定量PCR测定两组胎盘组织中sFlt-1 mRNA水平。结果外周血中sFlt-1的水平子痫前期组明显高于对照组,分别为(16.9±8.32)μg/L、(5.48±2.09)μg/L,两者差异有显著性(P<0.05)。sFlt-1 mRNA在两组胎盘中均有表达,在子痫前期组的表达明显高于对照组的表达分别为(4.11±4.09)、(1.69±1.61),两者差异有显著性(P<0.05)。子痫前期组血清sFlt-1水平与24h尿蛋白定量呈明显正相关(r=0.741,P<0.05)。结论sFlt-1 mRNA在子痫前期组孕妇的外周血中及胎盘组织表达升高,可能与子痫前期的病因及病理生理有关。     

血清可溶性血管内皮生长因子受体与子痫前期发病的关系

目的探讨血清中可溶性血管内皮生长因子受体1(sFlt-1)的变化及其与子痫前期发病的关系。方法(1)应用半定量RT-PCR技术检测10例重度子痫前期患者(子痫前期组)及10例足月正常妊娠妇女(正常妊娠组)的胎盘组织中sFlt-1mRNA表达水平。(2)应用酶联免疫吸附试验(ELISA)法测定35例重度子痫前期患者(子痫前期1组)及35例正常足月妊娠妇女(正常妊娠1组)外周血中sFlt-1水平。(3)ELISA测定20例重度子痫前期患者(子痫前期2组)及20例正常足月妊娠妇女(正常妊娠2组)胎盘附着处子宫静脉血中sFlt-1水平。(4)ELISA测定10例早孕(早孕组)及10例中孕(中孕组)妇女外周血中sFlt-1水平。结果(1)子痫前期组胎盘组织中sFlt-1mRNA表达水平为0.95±0.04,明显高于正常妊娠组的0.64±0.15,两组比较,差异有统计学意义(P<0.01)。(2)子痫前期1组孕妇外周血清中sFlt-1水平为(5640±3191)ng/L,明显高于正常妊娠1组的(2194±635)ng/L,两组比较,差异有统计学意义(P<0.01)。(3)子痫前期2组孕妇子宫静脉血清中sFlt-1水平为(7673±2296)ng/L,明显高于正常妊娠2组的(3057±785)ng/L,两组比较,差异有统计学意义(P<0.01)。(4)早、中孕组孕妇外周血清中sFlt-1水平分别为(32±20)ng/L及(994±302)ng/L。结论(1)子痫前期患者外周血中sFlt-1水平明显增高;(2)血清中sFlt-1水平随孕周增加而升高,并可能与子痫前期的发病有关。     

子痫前期可溶性CD105的表达及变化意义

目的探讨子痫前期患者可溶性CD105(sCD105)表达的变化和意义,探索妊娠中期测定血清sCD105值预测子痫前期的可能性。方法选择2007年1月至2008年2月间绍兴市妇幼保健院子痫前期患者40例(子痫前期组),其中轻度子痫前期12例,重度子痫前期28例。选择同期在该院年龄、孕龄匹配且有正常妊娠结局的40例正常孕妇为对照组。两组孕妇在孕15～20周曾行产前筛查,保留有血液标本。采用酶联免疫吸附分析法(ELISA)测定各组血清sCD105水平。结果对照组和子痫前期组血清妊娠晚期sCD105水平的中位数分别为10.35μg/L和35.15μg/L,差异有统计学意义(P0.001)。轻度子痫前期组和重度子痫前期组血清妊娠晚期sCD105水平的中位数分别为20.99μg/L和51.68μg/L,差异有统计学意义(P=0.001)。对照组和子痫前期组妊娠中期sCD105水平的中位数分别为5.20μg/L和5.90μg/L,差异有统计学意义(P=0.032)。选择sCD1055.23μg/L为界限值,预测子痫前期的灵敏度为67.5%,特异度为52.5%,阳性预测值为58.7%,阴性预测值为61.8%。结论子痫前期患者sCD105水平显著增高,发生子痫前期的妊娠中期孕妇sCD105也显著增高,而且这种增高与疾病的严重程度呈正相关。     

血浆可溶性血管内皮生长因子受体1水平变化对子痫前期发病的早期预测价值

目的 探讨孕妇血浆中可溶性血管内皮生长因子受体1(sFlt-1)水平变化对子痫前期发病的早期预测价值.方法 采用前瞻性研究方法,应用酶联免疫吸附试验(ELISA)对146例妊娠20～26周最初血压正常孕妇的血浆中sFlt-1水平进行测定,并随访观察孕妇血压变化和妊娠结局.结果 (1)146例孕妇中,发展为子痫前期患者12例(子痫前期组),余134例孕妇妊娠结局正常(正常妊娠组).(2)子痫前期组孕妇血浆sFlt-1水平为(4135±699)ng/L,正常妊娠组为(1490±1033)ng/L,两组比较,差异有统计学意义(P＜0.01).子痫前期组患者临床诊断前10周即出现sFlt-1水平升高.(3)sFlt-1水平预测子痫前期,受试者工作曲线的曲线下面积为0.981.以sFlt-1≥3344 ng/L为切点,预测子痫前期的敏感度、特异度、阳性预测值及阴性预测值分别为100%、96%、67%、100%.结论 子痫前期患者血浆sFlt-1水平升高的变化早于临床诊断子痫前期10周以上,因此,血浆sFlt-1水平变化可作为子痫前期发病的早期预测指标.     

孕早期胎盘生长因子、同型半胱氨酸及血管内皮生长因子对妊娠期高血压疾病的预测价值

目的探讨孕早期胎盘生长因子(PLGF)、同型半胱氨酸(Hcy)及血管内皮生长因子(VEGF)对妊娠期高血压疾病(HDP)的预测价值。方法选取2015年1月至2018年6月于江苏省淮安市妇幼保健院行产前检查并分娩的220例孕妇,根据随访结果将其分为妊娠高血压组(n=33)、轻度子痫前期组(n=32)、重度子痫前期组(n=35)及正常对照组(n=120)。产检时记录受试孕妇一般资料,检测血清PLGF、Hcy及VEGF水平。分析孕早期血清指标与HDP的关系及对HDP的预测价值。结果 HDP组孕妇PLGF、VEGF水平均显著低于对照组,Hcy水平显著高于对照组;轻度子痫前期组及重度子痫前期组孕妇PLGF、VEGF均显著低于妊娠高血压组,Hcy水平显著高于妊娠高血压组(P0.05)。孕早期PLGF、VEGF与HDP呈负相关,Hcy与HDP呈正相关。孕早期PLGF、Hcy及VEGF预测HDP发生的ROC曲线下面积分别为0.804、0.609和0.755(P0.05)。结论 HDP孕妇在孕早期可出现PLGF、VEGF及Hcy水平改变,孕早期PLGF、VEGF及Hcy均与HDP相关且具有一定预测价值。     

妊娠期糖尿病患者孕期及产后血清VEGF、sFlt1水平的变化及意义

目的探讨妊娠期糖尿病(GDM)患者孕期及产后血清血管内皮生长因子(VEGF)及其可溶性受体1(sFlt-1)水平的变化及意义。方法对100例GDM患者(其中,FGR21例、巨大儿27例、胎儿正常52例)及30例正常孕妇(对照组),用ELISA法检测各孕妇孕28周、32周、36周、分娩前及产后24h血清VEGF及sFlt-1水平。结果三组GDM患者不同孕周VEGF水平均比同期对照组高(P<0.05);FGR组孕期及产后sFlt-1水平均比同期其余三组高(P<0.05);除巨大儿组外,其余三组孕期sFlt-1水平随孕周增加逐步升高(P<0.05)。结论 GDM患者孕中晚期VEGF水平变化平稳,总体水平高于正常妊娠者;GDM孕妇孕期sFlt-1水平的变化影响胎儿发育结局。     

外周血sFlt-1、PlGF、25-羟基维生素D、D-二聚体、vWF及P-选择素等指标预测子痫前期的价值

目的:分析可溶性血管内皮生长因子受体-1(s Flt-1)、胎盘生长因子(Pl GF)、25-羟基维生素D(25-OHVD)、D-二聚体、血管性假血友病因子(v WF)及P-选择素在子痫前期患者妊娠早期外周血中的表达,探讨其在子痫前期发生中的预测价值。方法:选择2013年1—12月在南方医科大学附属深圳妇幼保健院产科门诊进行产前检查的1 081例妊娠10~13~(+6)周的单胎孕妇作为研究对象,选取发生子痫前期者为病例组(50例),同期无妊娠并发症以及合并症的正常妊娠妇女352例作为对照组。采用酶联免疫吸附试验(ELISA)检测外周血中s Flt-1、Pl GF、25-OH-VD、D-二聚体、v WF及P-选择素的浓度。通过受试者工作特征(ROC)曲线分析这6个生化指标预测PE发生的敏感度和特异度。结果:1病例组外周血s Flt-1、D-二聚体、v WF及P-选择素平均值均高于对照组,差异有统计学意义(P0.05);外周血Pl GF及25-OH-VD平均值病例组均低于对照组,差异有统计学意义(P0.05);2ROC曲线结果显示,s Flt-1、Pl GF、25-OH-VD、D-二聚体、v WF及P-选择素的中位数倍数(Mo M)之和预测子痫前期,具有较高的敏感度(78%)和特异度(100%)。结论:妊娠早期联合检测外周血s Flt-1、Pl GF、25-OH-VD、D-二聚体、v WF及P-选择素多项生物学指标联合能提高子痫前期的预测价值。     

Serum sFlt1:PlGF Ratio,PlGF, and Soluble Endoglin Levels in Gestational Proteinuria

Objective: It was recently reported that both a high soluble fms-like tyrosine kinase 1 (sFlt1): placental growth factor (PlGF) ratio (sFlt1:PlGF ratio) and high soluble endoglin (sEng) levels are related to the later occurrence of preeclampsia. We compared the serum sFlt1:PlGF ratio, PlGF and sEng levels in women with gestational proteinuria (GP) to those in women with preeclampsia. Methods: Seven women with GP and 34 women with preeclampsia were recruited in this study. The 95^th percentile values in the reference curves of sFlt1, sFlt1:PlGF ratio and sEng, and the 5^th percentile values in the reference curve of PlGF were respectively set as the cutoff values. Results: The incidence rates of a high sFlt1:PlGF ratio, low PlGF and high sEng in women with GP were 57%, 29% and 86%, respectively, whereas those in women with preeclampsia were 94%, 77%, and 88%, respectively (p?=?0.028, p?=?0.024, and p?=?1.000, respectively). The incidence rates of a both high sFlt1:PlGF ratio and high sEng in women with GP and preeclampsia were 57% and 88%, respectively (p?=?0.082). Conclusion: The majority of women with GP showed both increases of the sFlt1:PlGF ratio and sEng, thus suggesting some women with GP may represent subclinical preeclampsia. In addition, women with GP showed a significantly lower sFlt1:PlGF ratio and higher PlGF level than those with preeclampsia, suggesting that the PlGF level is a key regulator for developing hypertension in some pregnant women, even with increases of both sFlt1:PlGF ratio and sEng levels.     

Failure of second-trimester measurement of soluble endoglin and other angiogenic factors to predict placental abruption

OBJECTIVE: High level of soluble endoglin (sEng), a potent antiangiogenic factor, predicts pre-eclampsia. We compared the serum levels of sEng in early second trimester in women with and without subsequent placental abruption. Proangiogenic placental growth factor (PlGF) and antiangiogenic soluble fms-like tyrosine kinase 1 (sFlt-1) were also studied. METHODS: Serum samples of 42 women with placental abruption and 50 control women, collected at 15 to 16 gestational weeks were analyzed for sEng, sFlt-1 and PlGF by immunoassays. RESULTS: The levels of sEng showed no difference between the cases and controls, but parous or smoking women with abruption had lower levels of sEng. Similarly, sFlt-1, PlGF, or sFlt-1/PlGF ratio showed no difference between the cases and the controls. CONCLUSION: Our data suggest that sEng, PlGF and sFlt-1 levels in early second trimester fail to predict placental abruption.     

Peripheral arterial tonometry and angiogenic biomarkers in preeclampsia

ABSTRACT

Objective: To evaluate changes in vascular function and serum biomarkers in women with and without preeclampsia (PE) to create a model for the easier and more precise diagnosis of PE in the future. Methods: Endothelial function and arterial stiffness were evaluated using peripheral arterial tonometry and concentrations of placental growth factor (PlGF), soluble fms like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng) were determined by immunoassay. Results: Arterial stiffness deteriorates and endothelial function is better in women with PE compared with a healthy pregnancy. Women who developed PE had a decreased PlGF and PlGF/(sFlt-1+ sEng) ratio and an increased sEng, and sFlt-1/PlGF ratio. Conclusion: Peripheral arterial analysis did provide additional information beyond serum biomarkers in the diagnosis of PE.     

Urinary angiogenic factors cluster hypertensive disorders and identify women with severe preeclampsia

OBJECTIVE: Serum levels of soluble fms-like tyrosine kinase 1 (sFlt-1), vascular endothelial growth factor (VEGF), and placental growth factor (PlGF) are altered in women with clinical preeclampsia. We sought to identify whether similar alterations in urinary levels of these proteins cluster hypertensive disorders in pregnancy, and identify women with severe preeclampsia (sPE). STUDY DESIGN: Free urinary levels of sFlt-1, VEGF, and PlGF were measured by immunoassay in 68 women enrolled prospectively in the following groups: nonpregnant reproductive age (NP-CTR n = 14), healthy pregnant control (P-CTR n = 16), pregnant hypertensive and proteinuric women who did not meet criteria for severe preeclampsia (pHTN n = 21), and women with sPE (n = 17). RESULTS: There was no difference in gestational age at the time of enrollment among groups (median [range]: sPE: 31 [24-40], pHTN: 34 [16-40], P-CTR: 28 [7-39] wks). Urinary excretion of VEGF was significantly increased in sPE women compared with NP-CTR (P = .023), but did not differ among pregnant groups. Urinary PlGF levels were significantly increased in pregnant compared with nonpregnant women, but were decreased in all hypertensive women compared with healthy P-CTR (P < .001). Urinary sFlt-1 concentrations were significantly increased in women with sPE relative to all other groups (P < .001). pHTN women had higher sFlt-1 urinary output compared with P-CTR group (P = .001). A cutoff >2.1 in the ratio log [sFlt-1/PlGF] had 88.2% sensitivity and 100% specificity in differentiating women with sPE from normotensive controls. We also described that the log[sFlt-1/PlGF] ratio identified women with sPE better than proteinuria alone (P = .03). Our regression model revealed that uric acid correlated best with log[sFlt-1/PlGF] ratio (r = 0.628; P = .005). CONCLUSION: sPE is associated with increased urinary output of the antiangiogenic factor sFlt-1 and a decreased output of PlGF at the time of clinical manifestation, providing a rapid noninvasive screening of hypertensive women based on a sFlt/PlGF ratio. This ratio may be used as representation for severity of the disease, and appears to be superior to random urinary protein measurements.     

Effective prediction of preeclampsia by a combined ratio of angiogenesis-related factors

OBJECTIVE: Imbalance between angiogenesis-related factors is closely related to the development of preeclampsia. The objective was to estimate the most effective and accurate predictive biomarker among levels and ratios of angiogenesis-related factors, including soluble fms-like tyrosine kinase 1 (sFlt-1), soluble endoglin, placental growth factor (PlGF), and transforming growth factor-beta1 (TGF-beta1), in women who subsequently developed preeclampsia. METHODS: A nested cohort study was conducted to estimate the levels of sFlt-1, soluble endoglin, PlGF, and TGF-beta1 in plasma collected in the second trimester from 40 women who subsequently developed preeclampsia and 100 contemporaneous normotensive women. RESULTS: Levels of sFlt-1 and soluble endoglin were significantly higher in women with preeclampsia than in normotensive women, whereas levels of PlGF and TGF-beta1 were lower (P<.001). In women with preeclampsia, sFlt-1/PlGF, soluble endoglin/TGF-beta1, and the combined ratio of (sFlt-1+soluble endoglin)/(PlGF+TGF-beta1) were significantly higher than in normotensive women (P<.001) and even greater in severe preeclampsia with preterm delivery compared with mild preeclampsia with term delivery (P<.05). At equivalent sensitivity (85%), the false-positive rate was 45% for sFlt-1, 41% for soluble endoglin, 33% for sFlt-1/PlGF, 21% for soluble endoglin/TGF-beta1, and 10% for the combined ratio. After adjusting for potential confounding factors, the risks for developing preeclampsia were as follows: odds ratio (OR) 6.9 [95% confidence interval 2.3-20.7] for sFlt-1 level, 7.1 [2.3-21.7] for soluble endoglin level, 6.8 [2.4-19.4] for sFlt-1/PlGF, 38.8 [9.8-154.3] for soluble endoglin/TGF-beta1, and 74.8 [17.6-316.7] for the combined ratio. CONCLUSION: The combined ratio of angiogenesis-related factors showed the lowest false-positive rate and the highest OR for prediction of preeclampsia, indicating that it may provide more effective prediction of development of preeclampsia. LEVEL OF EVIDENCE: II.     

Use of serum and urinary soluble sFlt-1 and PLGF in the diagnosis of preeclampsia

Objective: Preeclampsia (PE) is a disorder of pregnancy marked by hypertension and proteinuria with no known treatment aside from pregnancy termination. The pathogenesis of PE is poorly understood, but is thought to originate in the placenta. We assessed the value of measuring serum and urinary soluble deformylase-like tyrosine kinase receptor 1 (sFlt-1), a known target of placental factors, and placental growth factor (PLGF), a key placental signaling molecule, in the diagnosis of PE.

Methods: Eighty patients with PE were classified as either exhibiting mild (44 cases) or severe (36 cases) symptoms of PE. Forty normal pregnant women were selected as controls. Serum and urinary PLGF and sFlt-1 levels, along with the ratio of sFlt-1 to PLGF, were compared across groups.

Results: Serum and urinary sFlt-1 and sFlt-1/PLGF ratios in severe PE patients were significantly higher than those in the mild PE group, and measurements from mild PE patients were significantly higher than controls (all P values <0.01). The serum and urinary PLGF levels in severe PE patients were significantly lower than mild PE patients, and mild PE patients had significantly lower PLGF levels than controls (all P values <0.01). As expected, serum sFlt-1 and PLGF levels and ratios were highly correlated with urinary sFlt-1 and PLGF levels and ratios.

Conclusions: The severity of PE was closely correlated with these measurements, suggesting that they may be useful tools in the diagnosis and evaluation of PE.     

Mid-pregnancy levels of angiogenic markers as indicators of pathways to preterm delivery

Objective: To determine whether mid-pregnancy levels of angiogenic markers were associated with increased risk of preterm delivery (PTD). Methods: We studied a subcohort from the Pregnancy Outcomes and Community Health Study for whom mid-pregnancy angiogenic markers (soluble fms-like tyrosine kinase-1 [sFlt-1], soluble endoglin [sEng] and placental growth factor [PlGF]) and covariate data were available (N = 1301). Angiogenic marker levels were grouped as high/not high (sFlt-1 and sEng), low/not low (PlGF) and high/intermediate/low (sFlt-1). Associations between levels of angiogenic markers and PTD/PTD subtype were determined for women who were nonsmokers during pregnancy (N = 933). Results: Low PlGF and high sEng were associated with medically-indicated PTD and PTD <35 weeks, largely due to preeclampsia (PE). Excluding PE and small-for-gestational-age infants, low sFlt-1 was positively associated with medically-indicated PTD. Conclusions: Among nonsmokers, mid-pregnancy levels of angiogenic markers may mark multiple pathways leading to PTD, only one attributable to PE.     

Angiogenic biomarkers for prediction of maternal and neonatal complications in suspected preeclampsia

Objective: To determine if maternal serum angiogenic factors predict maternal and neonatal complications in women presenting to an acute care setting with suspected preeclampsia. Study design: Maternal serum samples were prospectively collected from women with suspected preeclampsia at the time of initial presentation to hospital triage with signs or symptoms of preeclampsia. Soluble fms-like tyrosine kinase-1 (sFlt1), placental growth factor (PlGF), and soluble endoglin (sEng) were measured by ELISA. The primary outcome was a composite of maternal and neonatal complications. Results: Of 276 women with suspected preeclampsia, 78 developed maternal or neonatal complications. Among women presenting prior to 37 weeks gestation, sFlt1, PlGF, and sEng were significantly different in women who developed maternal and neonatal complications as compared to women without complications. Higher levels of sFlt1, sEng, and the sFlt1:PlGF ratio were associated with an increased odds of complications among women presenting prior to 37 weeks. A multivariable model combining the sFlt1:PlGF ratio with clinical variables was more predictive of complications (AUC 0.91, 95% CI 0.85–0.97) than a model using clinical variables alone (AUC 0.82, 95% CI 0.79–0.90). Conclusion: Angiogenic biomarkers associate with maternal and neonatal complications in women with suspected preeclampsia, and may be useful for risk stratification.     

子痫前期胎盘中生长阻滞和DNA损伤45α基因及p38丝裂原活化蛋白激酶的表达

目的 探讨子痫前期胎盘组织中生长阻滞和DNA损伤45α(growth arrest and DNA damage-inducible 45 alpha,Gadd45α)基因和p38丝裂原活化蛋白激酶(p38 mitogen-activated protein kinase,p38 MAPK)信号分子的表达,及其与血清中可溶性血管内皮生长因子受体-1(soluble vascular endothelial growth factor receptor-1,sFlt-1)和可溶性endoglin(soluble endoglin,sEng)的相关性分析.方法 选择2009年9月至2010年3月在重庆医科大学附属第一医院住院分娩的孕妇54例为研究对象,按病情分为子痫前期轻度组20例、子痫前期重度组16例,以足月择期剖宫产孕妇18例为对照组.采用免疫组织化学SP法检测Gadd45α及磷酸化p38 MAPK(phospho-p38 MAPK,p-p38 MAPK)蛋白在各组胎盘组织中的定位;实时荧光定量PCR检测各组胎盘组织中Gadd45α mRNA水平;Western印迹法检测各组胎盘组织中Gadd45α蛋白的表达水平、p38 MAPK及p-p38 MAPK的蛋白表达差异;双抗体夹心酶联免疫吸附法检测各组孕妇血清样本中sFlt-1及sEng的含量,并进行单因素方差及LSD-t检验分析.结果 (1)免疫组织化学检测Gadd45α与p-p38 MAPK蛋白均定位于胎盘滋养层细胞胞质及胞核、血管内皮细胞胞核及少量间质细胞胞核.(2)子痫前期重度及轻度组Gadd45α mRNA相对表达水平(3.33±0.13和2.10±0.11)较正常对照组(1.01±0.18)明显上调,且子痫前期重度组高于轻度组,两两比较差异均有统计学意义(P＜0.05).(3)Western 印迹法检测正常对照组、子痫前期轻度组及重度组患者胎盘组织中Gadd45α蛋白表达水平分别为0.22±0.11、0.65±0.15、1.34±0.17;p-p38 MAPK蛋白的表达水平分别为0.32±0.08、0.72±0.12、1.45±0.21,两两比较差异均有统计学意义(P＜0.05);p38 MAPK蛋白水平组间比较差异无统计学意义(P＞0.05).(4)子痫前期轻度组、重度组孕妇血清sFlt-1、sEng水平明显高于正常对照组,且子痫前期重度组高于轻度组,两两比较差异均有统计学意义(P＜0.05).(5)各组Gadd45α蛋白水平与孕妇血清中的sFlt-1、sEng含量呈正相关(r分别为0.88和0.87,P均＜0.05).结论 Gadd45α在子痫前期患者胎盘组织中的表达明显升高,其可能通过调控p38 MAPK信号转导通路,诱使循环中的sFlt-1、sEng释放增加,从而加重胎盘血管重铸障碍和抑制滋养细胞浸润,参与子痫前期的发病.

Abstract：

Objective To evaluate the expression of Gadd45α and p38 MAPK in placentas and the correlations of Gadd45α protein and serum soluble vascular endothelial growth factor receptor-1 (sFlt-1) and soluble endoglin (sEng) in preeclampsia(PE). Methods Fifty-four pregnant women who delivered from September 2009 to March 2010 in the First Affiliated Hospital of Chongqing Medical University were chosen as the subjects. They were classified into mild preeclampsia group (n=20),severe preeclampsia group (n=16) and the control group (normal pregnant women underwent elective cesarean sections at term without labor and perinatal complications, n=18). Western blot and immunohistochemistry were employed to determine the expression and localization of Gadd45α and p-p38 MAPK protein respectively. Gadd45α mRNA level was determined by quantitative real-time PCR. The levels of seum sFlt-1 and sEng were measured by enzyme-linked immunosorbent assay (ELISA). One-way ANOVA and LSD-t test were applied for statistical analysis. Results (1)Immunohistochemistry identified that the positive stained cells were mostly located in trophoblast cells in normotensive placentas, whereas in preeclamptic placentas Gadd45α protein and p-p38 MAPK protein were detected in trophoblast and endothelial cells, as well as a few stromal cells at increased levels.(2)The mRNA levels of Gadd45α was significantly elevated in mild and severe preeclampsia groups compared to the control group (2.10±0.11 and 3.33±0.13 vs 1.01±0.18, P＜0.05), and Gadd45α mRNA level in severe group was significantly higher than in mild group (P＜0.05).(3)The data of Western blot revealed that the Gadd45α protein levels in each group were 0.22±0.11, 0.65±0.15 and 1.34±0.17, respectively, with significant differences between each group(P＜0.05). The p-p38 MAPK protein levels in each group were 0.32±0.08, 0.72±0.12 and 1.45±0.21, respectively, with significant differences between each group (P＜0.05). p38 MAPK protein levels in the total groups showed no difference(P＞0.05).(4)Compared with the control group, sFlt-1 and sEng concentrations in maternal circulation were significantly increasing in mild and severe preeclampsia groups, and concentrations in severe group were significantly higher than those in mild group (P＜0.05).(5) There were positive correlations between Gadd45α protein levels and the concentrations of serum sFlt-1 and sEng in each group( r=0.88 and 0.87, respectively all P＜0.05). Conclusions Upregulation of Gadd45α in preeclampsia placentas may play an important role in the pathogenesis of preeclampsia. It may induce the increased maternal serum levels of sFlt-l and sEng by activating p38 MAPK signaling pathway, leading to deficient cytotrophoblastic invasion and abnormal placental vascular reconstruction during pregnancy.