阿司匹林及低分子肝素在子痫前期中应用的研究进展

子痫前期是妊娠中晚期常见的一种特发疾病,其病情变化快,发生HELLP综合征、胎盘早剥、子痫、早产、胎儿窘迫等严重并发症的概率高,是导致发展中国家孕妇不良妊娠结局的主要原因之一,目前缺乏有效的防治措施。子痫前期的基本病理改变为全身小动脉痉挛,致滋养细胞受损、侵蚀不良,胎盘浅着床,合体滋养细胞缺血、缺氧,炎性因子、促凝物质释放,使血压升高、凝血与纤溶系统失衡,血液早期处于高凝状态。低分子肝素(low molecular weight heparin,LMWH)和阿司匹林是产科常用的两种具有抗凝作用的药物,由于子痫前期患者与正常孕妇的凝血状态存在差异,这两种药物在子痫前期中的应用引起了国内外学者的关注。现就其在子痫前期防治过程中的有效性及安全性的研究进展进行综述。     

子痫前期患者胎盘组织中Rho激酶Ⅱ表达与滋养细胞凋亡的研究

目的探讨Rho激酶Ⅱ(Rho-associatedProteinKinaseⅡ,ROCKⅡ)在正常妊娠和子痫前期患者胎盘的分布和表达及与滋养细胞凋亡的关系。方法采用免疫组织化学法检测30例子痫前期(轻、重度)孕妇和15例正常妊娠妇女胎盘中ROCKⅡ的分布和表达,采用TUNEL法检测三组胎盘滋养细胞的凋亡情况。结果ROCKⅡ在正常妊娠和子痫前期患者胎盘的滋养细胞、内皮细胞、基质细胞中均有表达,以滋养细胞表达为主。子痫前期重度和轻度组以及正常妊娠组ROCKⅡ的免疫组化积分分别为(4.53±0.58)、(3.18±0.59)和(2.06±0.63),P<0.01。正常妊娠和子痫前期患者胎盘的滋养细胞、内皮细胞、基质细胞均存在凋亡,以滋养细胞凋亡为主。重度子痫前期组胎盘滋养细胞凋亡(0.28±0.03)%显著高于子痫前期轻度组(0.22±0.04)%,子痫前期轻度组显著高于正常妊娠组(0.16±0.05)%(P<0.01)。滋养细胞ROCKⅡ表达和滋养细胞凋亡具有相关性(r=0.96,P<0.01)。结论子痫前期患者胎盘组织中Rho激酶Ⅱ的高表达可能与其滋养细胞凋亡增加有关。     

低分子肝素在子痫前期中应用的回顾与展望

<正>子痫前期综合征是导致孕产妇和围产儿不良预后重要原因之一,为多因素致病,促凝和抗凝机制的失衡是某些病例发病主要影响因素之一,尤其与早发子痫前期的发生发展和严重并发症的发生密切相关~([1])。正常妊娠时,孕妇血液处于凝血和抗凝系统平衡的血栓前状态(pre-thrombotic state,PTS)。重度子痫前期患者,特别是早发重度子痫前期患者,凝血和抗凝系统失衡,凝血系统处于病理性高凝状态。失衡的PTS为抗凝治疗提供了理     

HO在子痫前期患者胎盘组织和滋养细胞中的表达及青心酮的干预

目的探讨血红素氧合酶（heme oxygenase，HO）在子痫前期胎盘中的表达和作用机制，以及青心酮（DHAP）治疗子痫前期的理论依据。方法应用半定量反转录一聚合酶链反应法检测正常孕妇和妊娠期高血压疾病子痫前期患者胎盘组织以及青心酮干预的滋养细胞中HOmRNA表达水平。结果与正常孕妇组比较，子痫前期组胎盘中HO-1、2mRNA表达明显降低（P〈0．05，P〈0．01）；青心酮能上调滋养细胞中HO-1mRNA的表达水平（P〈0．05），并呈浓度依赖关系。结论子痫前期患者胎盘组织中HO-1、2表达降低，可能系子痫前期疾病发病的重要机制之一。青心酮能够上调滋养细胞中HO-1基因表达，其作用机制可能为通过改善HO—CO系统防治子痫前期。     

解整合素金属蛋白酶10在重度子痫前期胎盘中的表达及其意义

目的通过对孕妇胎盘组织中解整合素金属蛋白酶10（a disintegrin and metalloproteinase 10,ADAM10）的检测,探讨ADAM10与子痫前期发病的关系。方法选择2009年9月至2012年3月在北京大学人民医院产科住院分娩的30例重度子痫前期（子痫前期组）和30例正常孕妇（正常妊娠组）,采用反转录聚合酶链反应（RT—PCR）方法检测两组孕妇胎盘组织中ADAM10 mRNA的表达,并采用免疫组化二步法和蛋白质印迹法（Western Blot）检测胎盘组织中ADAM10蛋白的表达。结果ADAM10表达于胎盘组织的细胞滋养细胞和合体滋养细胞的细胞浆和细胞核中。子痫前期组中ADAM10 mRNA及蛋白的表达均明显高于正常妊娠组（P〈0．05）。结论重度子痫前期胎盘组织中ADAM10的过度表达可能与子痫前期的发生和发展有关。     

叶酸、体质指数及凝血指标与子痫前期的相关性分析

目的分析叶酸、体质指数(BMI)及凝血指标与子痫前期的相关性。方法选取子痫前期孕妇(86例)和正常孕妇(55例),分析孕前BMI、妊娠早期(孕周11～12周)叶酸、凝血酶原时间(PT)、活化部分凝血活酶时间(APTT)、纤维蛋白原(FIB)与子痫前期及妊娠结局的关系。结果与对照组比较,子痫前期孕妇血清叶酸、凝血指标PT、APTT水平降低,而孕前BMI和FIB升高(P 0.05);受试者工作特征(ROC)曲线分析显示,叶酸、孕前BMI及凝血指标联合检测预测子痫前期,曲线下面积(AUC)为0.853(95%置信区间为0.778～0.905);与良好妊娠结局组相比,不良妊娠结局组血清叶酸水平降低,FIB升高(P 0.05),而两组孕前BMI、PT、APTT水平比较,差异均无统计学意义(P0.05)。结论孕前BMI、妊娠早期叶酸、凝血指标(PT、APTT、FIB)联合检测对子痫前期有较高的预测价值,并可评估患者妊娠结局。     

子痫前期凝血状态评估及抗凝治疗

<正>正常妊娠时,孕妇血液处于凝血和抗凝系统平衡的血栓前状态(PTS)。重度子痫前期患者,特别是早发型重度子痫前期患者,凝血和抗凝系统失衡,凝血系统处于病理性高凝状态。失衡的PTS,为抗凝治疗提供了依据。近年对小剂量阿司匹林和低分子肝素(LMWH)在子痫前期的应用进行了大量的临床研究,表明有子痫前期高危因素的患者使用小剂量阿司匹林和LMWH,可预防子痫前期的发生,改善妊娠结局和新生儿预后。     

蛋白质组学技术与妊娠相关疾病的研究进展

蛋白质组学（pmteomics）是从整体水平研究细胞内动态变化的蛋白质组成成分、表达水平与修饰状态．了解蛋白质之间的相互作用与联系，解释蛋白质功能与细胞生命活动的规律。蛋白质组学技术在临床医学研究领域主要侧重于疾病的发生机制、预防、早期诊断和治疗、寻找疾病的生物标志物以及治疗靶点的研究。就其在妊娠相关疾病如妊娠合并感染、早产、子痫前期、妊娠滋养细胞疾病的研究进展作综述。关键词蛋白质组学技术妊娠合并感染早产子痫前期妊娠滋养细胞疾病     

免疫调控在子痫前期早期干预中的作用和评价

子痫前期的发生与免疫失调有一定的关系。母胎界面免疫耐受异常使滋养细胞侵袭性下降,子宫螺旋小动脉的“重铸障碍”,导致病理性胎盘形成;自身免疫异常如抗磷脂抗体通过干扰依赖磷脂的各种凝血与抗凝血因子的功能,使凝血功能紊乱,胎盘微血栓形成,导致胎盘灌注量的下降。子痫前期的早期干预措施包括：对于有子痫前期高危因素的孕妇妊娠中期开始服用小剂量阿司匹林,有较好的预防作用;妊娠早期和中期应用低分子肝素治疗也有一定的疗效;各种免疫治疗和抗氧化治疗的效果缺乏循证医学证据。     

缺氧诱导因子1α与肾上腺髓质素在子痫前期胎盘中的表达及意义

目的探讨子痫前期(preeclampsia,PE)患者胎盘中缺氧诱导因子1α(hypoxia-inducible factor1α,HIF-1α)及其靶基因肾上腺髓质素(adrenomedullin,ADM)的表达及与子痫前期发病和围产儿预后的关系。方法应用免疫组化链霉素抗生物素蛋白-过氧化酶连接法(SP法)和逆转录聚合酶链反应(RT-PCR)检测2009年12月至2010年9月福建医科大学附属第一医院31例子痫前期孕妇和27例正常妊娠妇女胎盘中HIF-1α、ADM的表达;同时分析子痫前期、正常妊娠孕妇及围产儿的临床资料。结果 (1)HIF-1α蛋白及ADM蛋白主要表达在胎盘的合体滋养细胞、细胞滋养细胞、血管内皮细胞胞浆及少量胞核中。子痫前期组胎盘中HIF-1α、ADM蛋白及HIF-1α、ADM mRNA表达均强于正常组(P<0.05);子痫前期组孕妇并发症及围产儿不良结局发生率均高于正常组(P<0.05);(2)子痫前期组胎盘HIF-1α、ADM的mRNA表达水平呈正相关(r=0.826,P<0.01);ADM mRNA的表达水平与平均动脉压(r=0.662,P<0.01)、孕妇并发症(r=0.365,P<...     

Expression imbalance of IL-17/IL-35 in peripheral blood and placental tissue of pregnant women in preeclampsia

ObjectivesThe possible mechanism of preeclampsia is investigated in this study to facilitate the exploration of the future remediation of this disease by analysing the changes of IL-17 and IL-35 in peripheral blood and placental tissue of pregnant women with preeclampsia (PE).Materials and methodsThe study was conducted using 45 healthy pregnant women as the control group and 90 pregnant women in the preeclampsia group, including 45 cases with severe preeclampsia and 45 cases with mild preeclampsia. All of 135 pregnant women underwent caesarean delivery. IL-17 and IL-35 concentrations in the serum were measured by ELISA, and IL-17 and IL-35 expression in placental specimens was detected by immunohistochemistry.ResultsThere were no statistically significant differences in age among the three study groups. Serum IL-17 levels were significantly higher in PE patients than in healthy pregnant women (P < 0.01). The ratio of positive staining for IL-17 was markedly higher in mild PE tissues (84.44%; 38/45) and severe PE tissues (86.67%; 39/45) than in healthy pregnant tissues (35.56%; 16/45) (P < 0.01). The strong positive rates for IL-17 were markedly higher in mild PE tissues (48.89%; 22/45) and severe PE tissues (68.89%; 31/45) than in healthy pregnant tissues (13.33%; 6/45) (P < 0.01). No differences between mild PE tissues and severe PE tissues were noted in both positive case rates and strong positive rates. Consistent with this finding, the ratio of strong positive staining for IL-35 was higher in healthy pregnant tissues (66.67%; 30/45) than in mild PE tissues (33.11%; 14/45) and severe PE tissues (26.67%; 12/45) (P < 0.01).ConclusionsThe abnormal increase in serum and placental of IL-17 has an association with the formation and development of PE. IL-35 expression is significantly lower in severe PE placenta tissue and serum compared with normal pregnant women. These results suggested that IL-17/IL-35 imbalance may play a role in the pathophysiology of PE.     

低分子肝素在产科常见疾病中的应用

低分子肝素（LMWH）在达到有效的抗凝血作用的同时,可以减少肝素所致的出血等不良反应,在临床上具有一定的应用价值。目前LMWH广泛应用于产科临床,其不仅能预防妊娠期和产褥期深静脉血栓形成（DVT）,还能预防、治疗易栓症引起的子痫前期（PE）、胎儿生长受限（FGR）等产科常见并发症。对妊娠期及产褥期DVT的危险因素进行评估后,可考虑使用LMWH。研究发现,LMWH也能改善非易栓症孕妇的不良妊娠结局,降低高危人群（有胎盘早剥、早发型PE病史的孕妇）患早发型PE、重度PE、FGR及晚期流产的风险,延长妊娠时间,提高新生儿存活率和出生体质量。现综述近年来LMWH应用于产科DVT、PE和FGR的相关研究进展。     

Decreased Pathological Placental Findings in Aspirin-Treated Pregnant Women at Risk of Hypertensive Complications

Objective: The small controlled trials reporting large reductions in the incidence of preeclampsia and intrauterine growth restriction (IUGR) in highrisk pregnant women treated with low-dose aspirin have recently been followed by large clinical trials suggesting less beneficial results. The effect of low-dose aspirin on placental lesions associated with preeclampsia and IUGR has not yet been studied.

Methods: We participated in the large multicenter randomized collaborative low-dose aspirin study in pregnancy (CLASP) trial of low-dose aspirin for the prevention and treatment of preeclampsia and intrauterine growth restriction. As part of this study, we evaluated placentae submitted from 25 women treated with aspirin and 28 with placebo.

Results: More of the pathological findings classically described in preeclampsia and IUGR were demonstrated in the placentae from the placebo group than from the aspirin group (54% vs. 16%, P = 0.02). The placental findings did not correlate with clinical pregnancy outcome or Doppler flow parameters of the fetal umbilical artery in either group.

Conclusions: Our results support the assumption that aspirin may have some inhibitory effect on the uteroplacental circulatory ischemic changes typically occurring in preeclampsia and IUGR.     

子(癎)前期患者血清TPA、HCG测定的对比意义

目的:探讨子癎前期患者及正常妊娠晚期妇女血清TPA、HCG的变化特点及临床意义。方法:将51例子癎前期患者设为实验组,分为轻度(A组)、重度(B组),33例正常晚孕者设为对照组,测定实验组、对照组TPA及HCG变化,并进行比较。结果:实验组TPA的浓度与对照组比较差异有显著性(P<0.05),实验B组与对照组比较差异有非常显著性(P<0.01),且与病情严重程度呈正相关;实验组HCG浓度与对照组比较差异有显著性(P<0.05)。实验A组与对照组比较差异非常显著(P<0.01)。结论:子癎前期患者外周血TPA增高与滋养细胞凋亡增加有关,而HCG分泌增加与缺氧状态下滋养细胞反应性增生有关,提示子癎前期患者有明显的滋养细胞增生与分化异常存在。TPA作为外周血滋养细胞凋亡的标志物,可间接反映胎盘功能的变化。     

Circulating and placental endoglin concentrations in pregnancies complicated by intrauterine growth restriction and preeclampsia

Inadequate trophoblast invasion and spiral artery remodeling leading to poor placental perfusion and hypoxia are believed to underlie preeclampsia (PE) and intrauterine growth restriction (IUGR). Recent studies implicate increased circulating endoglin as a contributor to the pathogenesis of PE. The objective of this study was to determine whether placental and circulating endoglin concentrations are altered in pregnancies complicated by intrauterine growth restricted (IUGR) infants and to address the role of hypoxia on the regulation of placental endoglin. We analyzed 10 placentas each from normal pregnant (NP), PE, and IUGR subjects. Endoglin levels were 2.5-fold higher in preeclamptic placentas compared to NP (15.4+/-2.6 versus 5.7+/-1.0, p<0.01). In contrast, endoglin levels were similar in NP and IUGR placentas (5.7+/-1.0 vs 5.9+/-1.1, p=NS). Placentas from pregnancies with both PE and IUGR exhibited endoglin levels comparable to the PE group and significantly different from normotensive pregnancies with and without IUGR pregnancies (mean 14.9+/-4.0, n=9, p=0.013). Soluble endoglin concentrations in maternal plasma were comparable in NP and IUGR, but higher in women with PE (n=10 per group, p<0.05). Despite a 2-fold increase in hypoxia inducible factor, HIF-1alpha, we did not observe endoglin upregulation in NP, PE, or IUGR placental villous explants exposed to hypoxia (2% oxygen). In contrast to PE, placental or circulating endoglin is not increased in normotensive women delivering small, asymmetrically grown (IUGR) infants at term. The placentas of women with IUGR appear to be fundamentally different from PE women with respect to endoglin, despite the proposed common pathology of deficient trophoblast invasion/spiral artery remodeling and poor placental perfusion.     

低分子肝素治疗前后子痫前期患者血清γ干扰素及白介素-4的变化

目的:通过检测低分子肝素(LMWH)治疗前后子痫前期(PE)患者血清中γ干扰素(INF-γ)及白介素-4(IL-4)含量变化,探讨LMWH治疗PE的作用机制。方法:选取2012年6月至2014年5月我院收治的72例PE患者,其中28例早发型重度PE、26例晚发型重度PE和18例轻度PE患者,给予低分子肝素钙0.4ml皮下注射,1次/d×7d,ELISA法检测治疗前和治疗第3天、7天患者血清中INF-γ和IL-4含量变化。选取同期门诊住院孕周分别为28~33+6周、34~36+6和37周正常孕妇各20例作为对照。结果:正常孕妇随着孕周的增长,INF-γ和IL-4含量均无明显变化。LMWH治疗前,PE患者随着病情加重血清INF-γ呈上升趋势、IL-4呈下降趋势,各组间两两比较差异均有统计学意义。治疗后,PE患者的血清INF-γ均呈下降趋势、IL-4均呈上升趋势,治疗前后比较差异均有统计学意义,轻度PE治疗前后比较差异无统计学意义。结论:LMWH可通过调节PE患者免疫失衡,减少患者血管内皮细胞损伤,缓解PE症状。     

Placental expression and serum levels of cytokeratin-18 are increased in women with preeclampsia

OBJECTIVE: To evaluate placental expression and serum cytokeratin-18 in women with preeclampsia. METHODS: Serum cytokeratin-18 was evaluated in 44 women with preeclampsia and 44 healthy pregnant women using an immunoradiometric assay. Placental expression of cytokeratin-18 was investigated in specimens from 23 women with preeclampsia and 20 healthy pregnant women by immunohistochemistry. RESULTS: Median serum cytokeratin-18 in women with preeclampsia and healthy pregnant women was 106.7 and 76.0 U/L, respectively (P =.02). Among women with preeclampsia, serum cytokeratin-18 was significantly associated with severity of disease (P =.001) and showed a sensitivity (standard error) and specificity (standard error) of 85% (7%) and 65% (12%), respectively. In placental specimens, the cytoplasm of the syncytiotrophoblast stained positive for cytokeratin-18 with strong and widespread staining in 83% and 45% of placental specimens of women with preeclampsia and healthy pregnant women, respectively (P =.01). CONCLUSION: Elevated serum cytokeratin-18 values are associated with disease severity in women with preeclampsia. Our data provide additional evidence that the placenta might be the source of the elevated serum cytokeratin-18 values in women with preeclampsia.     

Placental and serum levels of carotenoids in preeclampsia

OBJECTIVE: We compared placental tissue, maternal serum, and umbilical cord venous blood levels of four dietary carotenoids (alpha-carotene, beta-carotene, lycopene, and canthaxanthin) in normal pregnant women and those with preeclampsia. METHODS: Levels of alpha-carotene, beta-carotene, lycopene, and canthaxanthin were measured in placental tissue, maternal serum, and umbilical cord venous blood from 22 normal pregnant women and 19 women with preeclampsia. The criteria for recruitment included gestational age of 30-42 weeks, singleton pregnancy, intact membranes, absence of labor contractions, and absence of any other medical complication concurrent with preeclampsia. Carotenoids were measured using high-pressure liquid chromatography. RESULTS: All four carotenoids were detectable in human placental tissue, maternal serum, and umbilical cord venous blood samples. The levels of beta-carotene, lycopene, and canthaxanthin in placentas from preeclamptic women were significantly lower (P =.032, .009, and .013, respectively, by Mann-Whitney test) than those from normal pregnant women. Maternal serum levels of beta-carotene and lycopene were significantly lower (P =.004 and .008, respectively, by Mann-Whitney test) in women with preeclampsia. However, umbilical cord venous blood levels of these carotenoids were not significantly different between the two groups. CONCLUSION: Lower placental tissue and maternal serum carotenoid levels in women with preeclampsia suggest that oxidative stress or a dietary antioxidant influence might have an effect on the pathophysiology of preeclampsia.     

Effects of aspirin on placenta and perinatal outcomes in patients with poor obstetric history

Objective: The aim of this study was to compare a low-dose aspirin treatment on placental and perinatal effects in the patients with poor obstetric history such as preeclampsia, intrauterine growth retardation (IUGR) in previous pregnancy. Study design: This retrospective study of 86 pregnant women was conducted between April 2002 and June 2005. In this study period 364 placentas were examined and the patients with poor obstetric history such as IUGR and preeclampsia were selected. Then the patients were assigned to three groups; group 1 (n = 30) was composed of women with no risk in previous pregnancy; group 2 (n = 27) was composed of patients with poor obstetric history (e.g., preeclampsia, IUGR) who were treated with aspirin and patients in group 3 (n = 29) had poor obstetric history without any treatment (patients who were started to follow-up after 14 weeks of gestation). Patients in group 2 were treated with a low-dose aspirin (80 mg/day) as soon as a urinary pregnancy test was positive. Treatment was usually stopped at 34 completed weeks of gestation. On histopathologic examination of the placenta, uteroplacental vascular pathologic features and secondary villous damage (such as fibrinoid necrosis of desidual vessels, villous infarct, severely increased villous fibrosis, severely increased syncytiotrophoblast knotting, obliteration of the vessel lumen, severely increased villous hypervascularity) and also lesions involving coagulation (such as excessive perivillous fibrin deposition, multiple occlusive thrombi in uteroplacental vessels, avascular villi ) were examined. Results: There were no significant differences between the groups with respect to maternal age, body mass index at the first trimester and delivery. Also there were no significant differences among groups with respect to placental weight, fetal height, weight, gestational week, umbilical artery pH, pO2, pCO2 and base excess status. The incidences of preeclampsia were 3.3, 7.4, 6.8% and the incidences of IUGR were 6.7, 11.1, 6.8% in the groups, respectively (P > 0.05 for both). Although the percentages of all pathologic findings were higher in groups 2 and 3, these differences were not statistically important. Conclusion: When low-dose aspirin is taken, starting at the beginning of pregnancy in patients with poor obstetric history, there are still high frequencies of uteroplacental vascular and related villous lesions persisted on placental bed. Also it has no beneficial effects on perinatal outcomes in these patients.