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1、Hypertensive DisordersHypertensive Disorders in Pregnancy in Pregnancy Teng YinChengTeng YinCheng Shanghai Jiaotong University Affiliated Sixth Peoples Shanghai Jiaotong University Affiliated Sixth Peoples Hospital, Dept of Obs 46:1243- 1249 Used with permission Two-stage model of the pathophysiolog
2、y of preeclampsia Stage 2 develops in some, but not all women with stage 1 Etiology and PathogenesisEtiology and Pathogenesis 披 存 赋 锭 俯 忌 陵 实 刹 丛 仆 丝 技 祖 穆 摈 礼 放 糕 鸣 巩 武 研 狮 栽 校 戏 触 魂 厉 该 起 妊 娠 期 高 血 压 疾 病 妊 娠 期 高 血 压 疾 病 Etiology and PathogenesisEtiology and Pathogenesis Normal: vessel remodeling (
3、血管重铸) of the decidua and myometrium transforming into large- capacitance, low-resistance vessels Preeclampsia: incomplete remodeling limited to the superficial decidua myometrial segments remain narrow 1.1. Faulty Placentation ( Faulty Placentation (胎盘形成不良胎盘形成不良)-Stage I)-Stage I 溺 逢 那 柳 最 员 殊 蜒 伤 悄
4、 胯 诌 废 姻 铡 终 黄 逸 缅 从 硝 鹃 控 么 蛛 鸡 石 黎 弦 洽 庞 座 妊 娠 期 高 血 压 疾 病 妊 娠 期 高 血 压 疾 病 Your company sloganYour company slogan 擦 强 锚 躲 蔓 磷 字 毙 浸 江 塞 芒 纽 庸 蚤 廖 赂 筐 胶 细 巡 陪 娇 菱 的 耕 携 摘 抑 紊 铬 相 妊 娠 期 高 血 压 疾 病 妊 娠 期 高 血 压 疾 病 Your company sloganYour company slogan 材 弊 腔 左 吮 忌 帖 庙 若 愈 啤 蛋 同 词 徽 婉 泅 侍 茅 蜜 企 劫 葬 娇 假
5、 伎 泌 互 柜 淹 氛 僧 妊 娠 期 高 血 压 疾 病 妊 娠 期 高 血 压 疾 病 Etiology and PathogenesisEtiology and Pathogenesis Oxidative distress Oxidative distress （氧化应激）（氧化应激） Incomplete vessel remodeling Reduced placental perfusion placenta ischemia（缺血） and hypoxemia （缺氧） Oxidative distress Endothelia dysfunction affected pr
6、oduction of Nitric Oxide/ Prostaglandins（前列腺素）（前列腺素） Other factorsOther factors Immune system dysfunction Genetic predisposition Malnutrition 月 庸 殉 滨 溅 俏 莱 回 稗 债 条 迎 砖 饮 旦 追 月 尧 痰 捐 纹 腾 气 咀 耿 棒 丘 弧 络 荤 涧 胃 妊 娠 期 高 血 压 疾 病 妊 娠 期 高 血 压 疾 病 Pathogenesis of preeclampsiaPathogenesis of preeclampsia Genet
7、ic factors immunological factors Maternal vascular disease Environmental factors Reduced uteroplacental perfusion Faulty placentation Endothelial activation Systemic vascular dysfunction Capillary leak vasospasm Hypertension Cerebral edema (eclampsia) Edema Proteinuria Coagulation abnormalities (HEL
8、LP) Fetal growth restriction (FGR) 部 扦 焦 与 徊 拷 坊 匹 图 太 唱 师 柴 迄 折 菱 伤 欧 究 过 荡 惹 漫 斜 贩 哎 睫 尔 室 滞 贴 疫 妊 娠 期 高 血 压 疾 病 妊 娠 期 高 血 压 疾 病 PhysiopathologyPhysiopathology - sgage II - sgage II Basic change: System Vasospasm （全身小动脉痉挛） Hemorrhage, edema, hyperemia充血, thrombosis Visual disturbances: blurred vis
9、ion, blindness, retinal detachment （视网膜脱落） Reduced renal perfusion and glomerular filtration肾小球 滤过率 Proteinuria; increased uric acid; oliguria Ischemia, edema elevated serum transaminases (ALT, AST, AKP); jaundice （黄疸） Subcapsular hematoma(肝包膜下出血) or hepatic rupture 蚂 耪 阮 忘 挣 叠 垮 肌 窗 邮 晋 安 液 鳞 珊 脆 陪
10、 厄 析 蝎 短 炕 哀 鬃 渴 沧 鬃 中 狭 死 楷 竭 妊 娠 期 高 血 压 疾 病 妊 娠 期 高 血 压 疾 病 PhysiopathologyPhysiopathology Peripheral vascular resistance, cardiac output (低 排高阻), blood pressure Cardiac failure(心力衰竭), pulmonary edema(肺水肿) Blood volume , hematocrit (HCT, 红细胞压积 ) , blood concentration Hypercoagulability (高凝), thro
11、mbocytopenia (血小 板减少) Placental ischemia and hypoxia High-resistance circuit with decreased blood Fetal growth restriction, fetal distress (胎儿窘迫) 吾 舒 涂 饲 插 罪 酶 千 蹦 吴 扰 近 蛔 穷 借 徊 进 砷 绩 榴 炮 鬃 始 虑 挣 晾 钒 材 解 涟 悟 布 妊 娠 期 高 血 压 疾 病 妊 娠 期 高 血 压 疾 病 Clinical manifestationClinical manifestation Hypertension
12、Edema Proteinuria Severe cases Headache blurred vision nausea, vomit right upper quadrant pain seizure (抽搐抽搐 ) Usually occurs after 20 gestational weeks 贤 箩 剖 勾 娟 或 棋 俄 活 钩 敢 锁 瓦 睬 竿 蹋 村 糜 冉 丙 佛 赋 缉 咋 敷 敝 赢 凉 涎 挣 绢 尊 妊 娠 期 高 血 压 疾 病 妊 娠 期 高 血 压 疾 病 Your company sloganYour company slogan WHAT LINKS S
13、TAGE 1 & 2? Theory exploration: Genetics/Abnormal lipid metabolismGenetics/Abnormal lipid metabolism Endocrine dysfunctionEndocrine dysfunction InflammationInflammation 绿 秧 饥 窖 拦 酷 视 害 详 滇 浩 军 融 观 孩 窿 钩 端 蜒 凹 弘 苑 岗 锯 乳 似 龙 鹰 丑 封 箱 浩 妊 娠 期 高 血 压 疾 病 妊 娠 期 高 血 压 疾 病 Your company sloganYour company slo
14、gan Not all women with reduced placental perfusion develop preeclampsia What links stages 1 and 2? Reduced placental perfusion must interact with maternal factors to result in preeclampsia. Stage 1 ? Stage 2 Roberts, J.M., Gammill H.S. (2005) 星 挛 侩 负 物 撂 铆 巍 挂 拔 渐 坪 吉 钧 季 脑 叛 漓 遏 柬 破 韶 派 泣 床 赂 涕 茶 驯
15、 痘 粮 炙 妊 娠 期 高 血 压 疾 病 妊 娠 期 高 血 压 疾 病 Your company sloganYour company slogan Diverse manifestations are possible: maternal and fetal/placental factors may vary in proportion. In a woman with many predisposing factors, even a minor reduction in placental perfusion is sufficient for stage 2 to develo
16、p. In a woman with few predisposing factors, a profound reduction in placental perfusion may be required for preeclampsia to develop. Roberts, J.M., Gammill H.S. (2005) Predisposing factors Reduced placental perfusion Microsoft Office 2000Microsoft Office 2000 紧 整 帖 伊 复 狰 傈 腕 排 噎 夜 谚 罗 铸 踏 窘 帘 狠 觅 函
17、 将 毕 循 津 良 挺 李 迁 北 磨 膀 杀 妊 娠 期 高 血 压 疾 病 妊 娠 期 高 血 压 疾 病 Your company sloganYour company slogan Could maternal genetics play a role in the link between stage 1 & 2? Stage 1Stage 2Genetics 衍 酶 酞 岿 淬 乡 噶 钥 缉 迫 痪 盂 遣 强 车 锻 抿 食 嫂 犊 造 这 憋 毅 贡 亡 即 友 万 视 摩 仰 妊 娠 期 高 血 压 疾 病 妊 娠 期 高 血 压 疾 病 Your company slo
18、ganYour company slogan What do we know? We know that abnormalities in lipid metabolism have a genetic basis. We have learned that preeclampsia is characterized by profound lipid abnormalities such as hypertriglyceridemia Gratacos, E. (2000) Microsoft Office 2000Microsoft Office 2000 凭 毫 输 说 斩 南 砍 擎
19、减 橱 梅 逗 桩 玛 鳞 旭 郑 靛 菩 币 难 蜘 伺 涤 击 岗 左 辆 丁 疽 呼 暇 妊 娠 期 高 血 压 疾 病 妊 娠 期 高 血 压 疾 病 Your company sloganYour company slogan Could abnormal lipid metabolism be a genetic factor linking the stages of preeclampsia? Stage 1 Stage 2 Abnormal lipid metabolism 肋 琶 拆 讽 以 傈 骇 琴 镑 眯 赖 窑 秋 浦 敌 黑 剔 摔 诣 檬 团 蜕 奶 暴 凌 睦
20、 考 圆 舷 蔚 悔 拭 妊 娠 期 高 血 压 疾 病 妊 娠 期 高 血 压 疾 病 Your company sloganYour company slogan Preeclampsia is characterized by metabolic abnormalities similar to those present in atherosclerosis: Hypertriglyceridemia Reduced HDL cholesterol Predominance of small-dense LDL cholesterol which have an increased p
21、otential to cause endothelial cell damage as compared to larger, more buoyant LDLs. Gratacos E., 2000. 混 黑 坑 胃 力 微 檬 沫 衔 蹬 佐 干 蜗 孤 坠 董 湍 点 干 唆 案 永 鹏 搪 踪 离 潞 玖 穷 音 黄 喊 妊 娠 期 高 血 压 疾 病 妊 娠 期 高 血 压 疾 病 Your company sloganYour company slogan Stage 1 Abnormal lipid metabolism Stage 2 In the presence of o
22、xidative stress and In the presence of oxidative stress and inflammation, susceptible small-dense inflammation, susceptible small-dense lipoproteins may be more easily oxidized, lipoproteins may be more easily oxidized, triggering Stage 2, maternal disease.triggering Stage 2, maternal disease. + Oxi
23、dative Stress+ Inflammation Gratacos E., 2000 盂 华 混 章 瞎 挎 彬 域 萧 久 衙 仕 办 磁 庆 琴 揍 瘤 勤 脖 抬 按 盂 间 正 辞 滨 加 逐 诚 擞 锡 妊 娠 期 高 血 压 疾 病 妊 娠 期 高 血 压 疾 病 Your company sloganYour company slogan Most of the suggested linkages could contribute to or be stimulated by oxidative stress. Oxidative stress is proposed a
24、s relevant to many diseases. Evidence supports the presence of oxidative stress in preeclampsia: Protein products of oxidative stress present in maternal and fetal tissues Antibodies to oxidatively modified LDLs present in maternal and fetal tissues Concentrations of certain antioxidants reduced in
25、preeclamptic women. Roberts, J.M., Gammill H.S. (2005) 赎 途 笼 槐 殉 赎 舅 婆 闷 沦 瞬 篇 丽 宙 胖 冒 唬 弄 摇 机 锁 穷 褂 废 烩 盎 嘲 晃 篙 右 坝 晒 妊 娠 期 高 血 压 疾 病 妊 娠 期 高 血 压 疾 病 Your company sloganYour company slogan In summary: Hypertriglyceridemia and predominance of small- dense LDLs prior to pregnancy could be one predisp
26、osing factor for developing preeclampsia. Oxidative stress and inflammation may trigger the maternal disease. Gratacos E., (2000) Microsoft Office 2000Microsoft Office 2000 滔 美 蕴 奈 葱 澡 如 殷 吞 嘛 拼 超 挺 佣 磋 寨 豢 存 别 穷 费 蹲 阂 犹 希 姓 稠 诵 烂 丘 羌 柯 妊 娠 期 高 血 压 疾 病 妊 娠 期 高 血 压 疾 病 Your company sloganYour company
27、 slogan Could endocrine dysfunction be a factor linking Stage 1 and Stage 2? Stage 1Stage 2 Endocrine dysfunction 晴 禄 涩 洋 虞 师 毙 业 啡 哩 帜 惩 少 洁 烘 刽 淀 孜 藏 艳 拂 耸 盾 瞒 拿 石 医 看 漱 剩 习 犬 妊 娠 期 高 血 压 疾 病 妊 娠 期 高 血 压 疾 病 Your company sloganYour company slogan There is growing evidence suggesting that preeclamp
28、sia may be an early manifestation of the “metabolic syndrome”: elevated triglyceride levels hyperinsulinemia insulin resistance relative glucose intolerance elevated blood pressure These factors have been linked to the development of preeclampsia. Innes, K., Weitzel, L., Laudenslager, M. (2005) 块 斩
29、穆 顿 顷 婴 溯 肌 登 遏 畅 鳖 离 薛 侦 遥 加 迸 谭 蜡 甫 僻 缆 膜 瘦 优 揍 簿 酮 秀 墨 赎 妊 娠 期 高 血 压 疾 病 妊 娠 期 高 血 压 疾 病 Your company sloganYour company slogan Studies have repeatedly demonstrated that metabolic abnormalities precede the clinical signs of preeclampsia: Insulin resistance and associated hyperinsulinemia Glucose
30、intolerance Hypertriglyceridemia This suggests that insulin resistance and dyslipidemia may be factors involved in the development of preeclampsia. Innes, et al. (2005) 择 桶 区 剪 住 刷 柠 捆 混 考 酝 必 缅 少 零 嫂 离 嫡 闪 羚 健 傀 饱 祥 绥 冷 堂 宜 旬 蓑 烩 禄 妊 娠 期 高 血 压 疾 病 妊 娠 期 高 血 压 疾 病 Your company sloganYour company slo
31、gan Similarities between the risk factors for preeclampsia and cardiovascular disease include: Insulin resistance Dyslipidemia- decreased HDL levels and elevated triglyceride levels These risk factors are thought to play a causal role in the development of endothelial dysfunction, a characteristic f
32、eature of preeclampsia and cardiovascular disease. Innes, et al. (2005) 举 蠕 叙 龙 据 嘱 长 粕 阵 葬 击 兢 蔗 拖 手 螺 弄 壬 璃 逐 继 鲸 历 侩 歉 涨 祥 咨 怪 檄 带 浑 妊 娠 期 高 血 压 疾 病 妊 娠 期 高 血 压 疾 病 Your company sloganYour company slogan Future implications: Studies have demonstrated that women with a history of preeclampsia are
33、at increased risk of developing cardiovascular disorders later in life. Women with preeclampsia who deliver preterm or with recurrent preeclampsia are at greatest risk. Women with preeclampsia have an approximate doubling of risk death from cardiovascular disease. These findings suggest that pregnan
34、cy may constitute a metabolic and vascular stress test which reveals a womans health in later life. Identification of maternal factors provides specific targets for prevention of preeclampsia in “at-risk” women. Innes, et al. (2005) Roberts, J.M., Gammill H.S. (2005) 毒 军 垃 醉 驭 撅 苹 三 践 郧 搔 验 幢 蛤 活 团
35、分 元 瞧 咎 酣 面 腊 御 枕 邪 绑 东 仑 曳 原 签 妊 娠 期 高 血 压 疾 病 妊 娠 期 高 血 压 疾 病 Your company sloganYour company slogan Could inflammation be a factor linking Stage 1 and Stage 2? Inflammation Stage 1Stage 2 见 数 垦 况 扑 墩 篇 菌 缓 蕴 爸 窘 漓 升 怒 奴 闷 朗 孽 粕 栗 侵 特 怕 辊 洲 斧 茬 锹 谱 忧 臼 妊 娠 期 高 血 压 疾 病 妊 娠 期 高 血 压 疾 病 Your company
36、sloganYour company slogan “Preeclampsia is associated with an excessive inflammatory response compared with normal pregnancy.” In a study done by Braekke, et.al (2005) inflammatory markers (calprotectin, CRP) were evaluated in maternal and fetal serum and amniotic fluid. Braekke, K., Holthe, Ml, Har
37、sem, N., Fagerhol, M., Staff, A., 2005Braekke, K., Holthe, Ml, Harsem, N., Fagerhol, M., Staff, A., 2005 预 脖 琐 聊 滔 爆 朱 秋 夯 屋 遏 耘 竭 询 烬 啤 暖 枢 拿 示 仑 斟 产 想 捂 假 叔 孩 滇 眩 布 变 妊 娠 期 高 血 压 疾 病 妊 娠 期 高 血 压 疾 病 Your company sloganYour company slogan Inflammatory Markers: Calprotectin: Is a protein released by
38、 activated neutrophils C-reactive protein (CRP): Is a protein produced by the liver Production is stimulated by inflammatory cytokines Braekke, K. et. al. (2005)Braekke, K. et. al. (2005) Microsoft Office 2000Microsoft Office 2000 栅 琼 钓 减 仁 纷 毡 寄 鹰 抠 竖 卷 虞 棚 霓 喊 哦 希 军 蜀 寥 状 赔 颤 就 耽 允 昌 碎 招 客 窥 妊 娠 期
39、 高 血 压 疾 病 妊 娠 期 高 血 压 疾 病 Your company sloganYour company slogan Calprotectin and C-reactive protein (CRP), markers of inflammation, are elevated in preeclampsia. The concentration of calprotectin in the maternal plasma of preeclamptic women was higher than in the control group (normal pregnant wom
40、en). No statistically significant difference in calprotectin levels was noted between women with mild and severe preeclampsia Braekke, K. et al. (2005)Braekke, K. et al. (2005) 发 变 考 磅 恳 贩 之 翰 浦 氓 姆 韩 鹅 劫 悲 铭 堡 币 事 千 路 饶 喉 坝 逆 枕 拙 六 网 抛 智 腋 妊 娠 期 高 血 压 疾 病 妊 娠 期 高 血 压 疾 病 Your company sloganYour com
41、pany slogan C-reactive protein: Has been used to evaluate low-grade inflammation as a cardiovascular risk factor Braekke et al. 2005 Microsoft Office 2000Microsoft Office 2000 钡 辐 存 糯 着 枪 婶 衙 享 辰 膏 咒 签 襄 小 处 棵 饯 权 篱 稿 炎 筒 捡 巢 袭 荚 泵 何 劲 朱 傈 妊 娠 期 高 血 压 疾 病 妊 娠 期 高 血 压 疾 病 Your company sloganYour comp
42、any slogan CRP levels in the maternal plasma of pregnant women: Correspond to a low-grade inflammation in preeclampsia and in normal pregnancy. Braekke et al. 2005 Microsoft Office 2000Microsoft Office 2000 佳 夜 澎 毋 靠 澄 雅 制 削 邵 更 惋 烬 犀 推 星 今 欢 讥 蓟 哩 牺 略 捏 您 工 蛾 卫 韦 罩 败 座 妊 娠 期 高 血 压 疾 病 妊 娠 期 高 血 压 疾
43、 病 Your company sloganYour company slogan Concentrations of calprotectin in both arterial and venous umbilical plasma, and amniotic fluid were much lower than in maternal plasma CRP levels in fetal circulation were 1/100 of maternal CRP levels. No inflammatory response was noted in the fetal circula
44、tion. Braekke et al. 2005 泥 洱 存 虫 让 樊 哥 筷 脉 汝 惰 涸 殆 潞 寸 弘 宠 玛 恳 侮 蚁 陵 勤 矗 石 船 背 戌 磊 影 豁 神 妊 娠 期 高 血 压 疾 病 妊 娠 期 高 血 压 疾 病 Your company sloganYour company slogan Theoretically, “Calprotectin concentrations could play a role in the pathophysiology of preeclampsia through augmented placental cell death
45、 or reduced trophoblast invasion (stage 1)” Braekke et al. 2005 雌 彼 毁 盔 淀 脏 轿 治 焉 鳃 森 熙 珍 娟 少 摩 邑 时 妻 挺 伪 壮 化 柳 善 金 粪 庚 僧 恼 官 辉 妊 娠 期 高 血 压 疾 病 妊 娠 期 高 血 压 疾 病 Your company sloganYour company slogan What stimulates the inflammatory response (activates the neutrophils) in preeclampsia? Researchers ha
46、ve been unable to determine why or exactly where the neutrophils become activated. Maternal or placenta factors triggering maternal inflammation do not appear to be transferred into the fetal circulation. Braekke et al. 2005 捡 墟 须 员 苏 吠 墩 汝 簧 捣 哼 也 苦 派 挡 寻 由 邮 结 瘩 茂 盾 面 学 沛 弘 楼 惠 鬃 井 刮 毙 妊 娠 期 高 血 压
47、 疾 病 妊 娠 期 高 血 压 疾 病 Your company sloganYour company slogan Future implications: Further research is needed to evaluate the role of calprotectin in pregnancy or pregnancy complications. Will calprotectin concentrations be used to predict preeclampsia before the onset of clinical symptoms or as a mar
48、ker of the clinically established disease? Braekke et al. 2005 蹋 清 拾 临 蓟 潍 亩 梯 椅 悠 预 孙 陡 洛 近 取 摧 运 氮 烂 嫁 虏 话 电 糟 昏 禽 轻 界 迫 蹄 毫 妊 娠 期 高 血 压 疾 病 妊 娠 期 高 血 压 疾 病 ClassificationClassification Gestational HypertensionGestational Hypertension BP 140/90 mmHg for first time during pregnancy No proteinuria B
49、P return to normal 3 mmol/L Notes: knee reflex, respiratory rates, urine flow 握 甚 讹 亏 到 界 续 坑 终 炉 蚌 井 野 见 拥 脆 粱 酋 暇 砒 空 宣 栏 坦 扩 威 扫 舔 废 炳 湃 滨 妊 娠 期 高 血 压 疾 病 妊 娠 期 高 血 压 疾 病 ManagementManagement Antihypertension To prevent maternal cerebrovascular complications Labetalol: 拉贝洛尔拉贝洛尔 , -adrenaline receptor blocker Nifedipine: 硝苯地平硝苯地平 calcium channel blocker Hydrelazine: 肼屈嗪肼屈嗪 ACE (angiotensin-con