【摘要】：研究背景:妊娠高血壓疾病是妊娠期最為常見的并發(fā)癥之一,是孕婦、胎兒和新生兒的發(fā)病率和死亡率的主要原因,而該疾病的治療取決于很多因素,包括血壓水平、孕齡、癥狀的存在和相關(guān)的危險因素。除了蛋白尿,妊娠高血壓的孕婦還有很高罹患心血管疾病以及死亡的風險。相比正常孕婦,妊娠期高血壓具有更高的胎盤早剝、心腦血管意外、器官衰竭和彌散性血管內(nèi)凝血風險。而這些妊娠高血壓母親的胎兒則具有更高相關(guān)病癥的發(fā)病風險,例如胎兒宮內(nèi)發(fā)育遲緩,早產(chǎn)和胎兒宮內(nèi)死亡。早期診斷、密切的產(chǎn)前監(jiān)測以及及時的干預治療是處理妊娠期引發(fā)的高血壓的關(guān)鍵。目前,經(jīng)濟、可重復、值得信賴的臨床檢測預測方法仍十分欠缺。妊娠高血壓疾病會發(fā)生胰島素抵抗、交感神經(jīng)異常興奮以及過度的系統(tǒng)性炎癥等一系列綜合征。性激素結(jié)合球蛋白(SHBG)對高胰島素血癥、胰島素抵抗均有著密切關(guān)系,雄激素可增強血管對血管活性物質(zhì)的反應(yīng)性,降低前列環(huán)素水平并增加血栓素的產(chǎn)生,直接增加血小板凝集誘導微血栓形成,此外,炎癥在妊娠高血壓疾病中發(fā)病過程中起重要作用,因為妊娠高血壓疾病孕婦胎盤中慢性血管炎的癥狀顯著增加。已有研究表明血清睪酮、性激素結(jié)合球蛋白(SHBG)、超敏C反應(yīng)蛋白(hs-CRP)的水平與妊娠期高血壓發(fā)生可能相關(guān),本課題的目的即是要從妊娠高血壓疾病患者體內(nèi)的特殊表現(xiàn)找到評估妊娠高血壓疾病的高危因素和更有效的潛在標志物分子。β-痕跡蛋白是一種前列腺素D2合成酶,屬于脂質(zhì)運載蛋白家族成員,其蛋白分子量很小,僅有23-29 kDa。最近對于β-痕跡蛋白的研究主要集中在其作為血清肌酸酐的替代標志物用來評價腎功能,以及心血管疾病的新的標志物。β-痕跡蛋白已被發(fā)現(xiàn)是比血清肌酸酐更加靈敏的用于監(jiān)測腎功能損傷的標志物。β-痕跡蛋白可以作為糖尿病引發(fā)的腎功能異常的理想標志物。研究表明β-痕跡蛋白與許多生物學過程有關(guān),包括炎癥反應(yīng)、心絞痛、動脈粥樣化形成、血管舒縮性反應(yīng)以及系統(tǒng)性動脈高壓,具有抗炎癥、抗血栓形成、抗細胞凋亡、抗動脈粥樣硬化等心血管保護作用,可顯著聚集在人冠狀動脈粥樣硬化性狹窄的病變的纖維斑塊中,有多個研究報道,血清β-痕跡蛋白的水平在長期冠心病患者中是顯著升高的,并且血清β-痕跡蛋白的升高程度與其受損血管的數(shù)量、年齡、高血壓的情況密切相關(guān)。高水平的β-痕跡蛋白的能夠預測心房纖維性顫動接受抗凝治療的病人的不良的心血管事件、死亡率以及主要出血的發(fā)生,也可能用來反應(yīng)心血管疾病的發(fā)病進程。Hirawa等人比較了正常人和高血壓患者的β-痕跡蛋白的水平,發(fā)現(xiàn)在高血壓病人體內(nèi)β-痕跡蛋白的水平顯著高于正常對照組,說明β-痕跡蛋白在高血壓中發(fā)揮著重要的作用,然而,循環(huán)中的β-痕跡蛋白水平與妊娠高血壓之間的關(guān)系目前仍是未知。本研究著眼于檢測正常妊娠孕婦以及患有妊娠高血壓的孕婦體內(nèi)的血清β-痕跡蛋白的水平,探尋血清β-痕跡蛋白的水平與妊娠高血壓之間的聯(lián)系。據(jù)我們所知,這是首個揭示血清β-痕跡蛋白的水平與妊娠高血壓之間關(guān)聯(lián)的研究。研究目的:通過對比正常孕婦組和患有妊娠高血壓疾病組(簡稱妊娠高血壓組)的年齡、孕前BMI、妊娠史、血壓、體重、左心室射血分數(shù)(LVEF)、尿蛋白,檢測血清睪酮、性激素結(jié)合球蛋白(SHBG)、超敏C反應(yīng)蛋白(hs-CRP)和β-痕跡蛋白(BTP)的水平,調(diào)查研究孕婦發(fā)生妊娠期高血壓的高危因素及血清睪酮、性激素結(jié)合球蛋白(SHBG)、超敏C反應(yīng)蛋白(hs-CRP)的水平與妊娠期高血壓的發(fā)生是否具有相關(guān)性。探究正常孕婦和妊娠高血壓的孕婦在不同孕期的血清中β-痕跡蛋白(BTP)的水平變化情況,比較兩組孕婦血清BTP水平有無差異性,并通過ROC分析,評估血清β-痕跡蛋白(BTP)的水平與妊娠期高血壓發(fā)生是否具有相關(guān)性,能否反應(yīng)該疾病的嚴重程度,能否作為新的更有效的預測妊娠高血壓疾病的標志物以及對妊娠高血壓疾病的診斷識別能力。研究對象及方法:選取2014年在齊魯醫(yī)院和淄博市中心醫(yī)院產(chǎn)檢分娩的1206名孕婦,從中選擇孕齡以及孕婦年齡匹配的57名正常妊娠的孕婦,設(shè)為正常對照組(血壓140/90 mmHg,且孕期無蛋白尿);46名患有妊娠高血壓疾病的孕婦,設(shè)為妊娠高血壓組(妊娠高血壓疾病是指在懷孕前20周無高血壓癥狀,而在懷孕20周之后兩次以上血壓測量顯示,收縮壓≥140 mmHg或者舒張壓≥90 mmHg,且測量間隔至少4小時,伴有先兆子癇或者無蛋白尿癥)。46名妊娠高血壓孕婦按有無蛋白尿分為單純高血壓組和子癇前期組,按左心室射血分數(shù)60%為界分為LVEF60%組和LVET≥60%組。所有的孕婦都是單胎妊娠,兩組孕齡和胎齡匹配。排除標準主要包括:妊娠高血壓組可能還伴隨患有其他疾病如第二種類型的高血壓,冠狀動脈心臟病,腎臟疾病,或者是糖尿病等。首先收集整理所有孕婦的各項臨床指標,如產(chǎn)婦平均年齡(歲)、孕前身高質(zhì)量指數(shù)BMI(kg/m2)、貧血(n,%)、種族(n,%)、PIH家族史(n,%)、自然流產(chǎn)史(3)(n,%)、妊娠次數(shù)(3)(n,%)等,并且比較分析了收縮壓(毫米汞柱)、舒張壓(毫米汞柱)、出生時胎齡(天數(shù))、分娩方式(n,%,正常陰道分娩或計劃CS)以及胎盤重量(g),新生兒性別(n,%)與出生體重(g)等數(shù)據(jù)。妊娠高血壓組孕婦于終止妊娠行超聲心動圖監(jiān)測左心室射血分數(shù)(LVEF)。采集所有孕婦不同懷孕階段孕早期(1-12周)、孕中期(13-27周)、孕晚期(28-40周)的血液樣品備用,4℃,7000 rpm離心10分鐘后-80℃保存?zhèn)溆�。孕期各階段均檢測尿蛋白。采用酶聯(lián)免疫測定分析法測定血清SHBG濃度,免疫發(fā)光法測定睪酮和超敏C反應(yīng)蛋白水平,血清β-痕跡蛋白的水平采用酶聯(lián)免疫吸附(ELISA)試劑盒進行檢測。收集兩組孕婦尿蛋白、hs-CRP(mg/1)(孕中期、孕晚期)、睪酮(孕中期、孕晚期)、SHBG(nmol/l)(孕中期、孕晚期)和BTP(孕早期、孕中期、孕晚期)等實驗數(shù)據(jù),ELISA檢測結(jié)果采用非參數(shù)檢驗法。潛在風險評估通過繪制ROC曲線進行分析。研究結(jié)果:(1)與孕齡及產(chǎn)婦年齡相符的正常對照組孕婦相比,患有妊娠高血壓的孕婦具有更高的孕前身高質(zhì)量指數(shù)(BMI)(p0.05)、更高的貧血發(fā)病率(p0.001),以及明顯的妊娠高血壓家族遺傳史(p0.001);在出生時胎齡相同的前提下,對于其他參數(shù)如分娩方式,胎盤重量和出生體重等,妊娠高血壓組孕婦與正常健康對照組孕婦之間沒有明顯差異;(2)通過對比分析兩組孕婦中晚期血清睪酮、性激素結(jié)合球蛋白(SHBG)、C反應(yīng)蛋白(hs-CRP)的水平提示在妊娠期高血壓組和正常妊娠組差異無統(tǒng)計學意義;(3)在正常妊娠孕婦的各階段血清β-痕跡蛋白的水平之間無明顯差異,而患有妊娠高血壓的孕婦其血清β-痕跡蛋白的水平隨著不同的懷孕階段呈現(xiàn)逐漸上升的趨勢,但是妊娠高血壓的孕婦在孕中期和孕晚期的血清β-痕跡蛋白的水平相比并沒有顯著性差異;(4)與正常孕婦相比,患有妊娠高血壓的孕婦,其血清β-痕跡蛋白的水平在孕中期和孕晚期時顯著高于正常對照組孕婦(p0.05),而在孕早期兩組間血清β-痕跡蛋白的水平之間的差異并不明顯;(5)妊娠晚期子癇前期組血清β—痕跡蛋白的水平較單純高血壓組升高,差異具有統(tǒng)計學意義;妊娠高血壓組左心室射血分數(shù)LVET60%的孕婦血清中BTP的水平明顯高于LVET≥60%的孕婦;(6)通過ROC分析評估血清β-痕跡蛋白的水平用于預測妊娠高血壓疾病的潛在價值,結(jié)果顯示使用血清BTP量321.3ng/mL作為截斷值,對妊娠高血壓疾病的預測靈敏度可達91.3%,特異性可達89.5%。研究結(jié)論:1、孕婦有妊娠期高血壓病家族遺傳史、孕前身高質(zhì)量指數(shù)偏高、孕期貧血者應(yīng)納入本次妊娠高血壓發(fā)生的高危監(jiān)測人群。2、本研究未發(fā)現(xiàn)妊娠中晚期血清睪酮、性激素結(jié)合球蛋白(SHBG)、C反應(yīng)蛋白(hs-CRP)的水平與妊娠期高血壓發(fā)生具有相關(guān)性,因此該指標不能作為預測妊娠高血壓疾病的標志物。3、高水平的血清β-痕跡蛋白與妊娠高血壓的發(fā)生具有相關(guān)性,可以用來反映妊娠高血壓疾病的疾病進程,此外,血清β-痕跡蛋白也可作為妊娠高血壓累及腎臟或心臟功能的預測指標,與其它研究發(fā)現(xiàn)B-痕跡蛋白可以作為心腎功能異常的標志物結(jié)論一致,可以用來反應(yīng)妊娠期高血壓孕婦的疾病嚴重程度。4、通過ROC分析顯示β-痕跡蛋白的水平用于預測妊娠高血壓疾病具有較高的靈敏度和特異性,因此,血清β-痕跡蛋白的水平有望成為妊娠高血壓疾病的新型診斷標志物,在具有高危因素的孕婦中進行檢測可提高預測靈敏度,用于妊娠高血壓疾病的預測。
[Abstract]:Background: pregnancy induced hypertension is one of the most common complications of pregnancy. It is the main cause of the incidence and mortality of pregnant women, fetus and newborn, and the treatment of the disease depends on many factors, including blood pressure, gestational age, symptoms and related risk factors. Besides proteinuria and pregnant women, pregnant women also have high blood pressure. There is a high risk of cardiovascular disease and death. Compared to normal pregnant women, pregnancy induced hypertension has higher placental abruption, cardio cerebrovascular accident, organ failure, and diffuse intravascular coagulation risk. Intrauterine and fetal death. Early diagnosis, close antenatal monitoring and timely intervention are the key to the treatment of hypertension induced by pregnancy. Currently, the economy, repeatability, reliable clinical detection and prediction methods are still very short. Sex hormone binding globulin (SHBG) has a close relationship with hyperinsulinemia and insulin resistance. Androgen can enhance the responsiveness of blood vessels to vasoactive substances, reduce the level of prostacyclin and increase the production of thromboxane, directly add platelet agglutination to induce microthrombus formation, in addition, inflammation. There is an important role in the pathogenesis of pregnancy induced hypertension because the symptoms of chronic vasculitis in placenta are significantly increased in pregnant women with pregnancy induced hypertension. The level of serum testosterone, sex hormone binding globulin (SHBG) and hypersensitivity C reactive protein (hs-CRP) may be related to the occurrence of hypertension in pregnancy. The high risk factors of pregnancy induced hypertension and a more effective potential marker are found from the special manifestations of the patients with pregnancy induced hypertension. Beta trace protein is a prostaglandin D2 synthetase, a member of the lipid carrying protein family, whose protein molecular weight is very small. Only 23-29 kDa. has recently been studied for beta trace protein. It is mainly focused on the marker of serum creatinine as an alternative marker for the evaluation of renal function and a new marker of cardiovascular disease. Beta trace protein has been found to be a more sensitive marker for monitoring renal impairment than serum creatinine. Beta trace protein can be an ideal sign of renal dysfunction caused by glycuria. Research shows that beta trace protein is related to many biological processes, including inflammatory reaction, angina, atheromatous formation, vasoconstrictive reaction and systemic arterial pressure, with anti inflammation, antithrombotic formation, anti apoptosis, anti atherosclerosis and other cardiovascular protective effects, which can be significantly aggregated in human coronary atherosclerosis. Many studies have reported that the level of serum beta trace protein in patients with chronic coronary artery disease is significantly increased in patients with chronic coronary artery disease, and the level of serum beta trace protein is closely related to the number of damaged vessels, age, and hypertension. The high level of beta trace protein can predict atrial fibrillation The adverse cardiovascular events, mortality, and major bleeding of patients receiving anticoagulant therapy may also be used to respond to the progression of cardiovascular disease,.Hirawa et al. Compared the level of beta trace protein in normal and hypertensive patients, and found that the level of beta trace protein in high blood pressure patients is significantly higher than that in high blood pressure patients. The normal control group shows that beta trace protein plays an important role in hypertension. However, the relationship between the level of circulating beta trace protein and pregnancy induced hypertension is still unknown. This study aims to detect the level of serum beta trace protein in normal pregnant women and pregnant women with pregnancy induced hypertension and to explore the serum levels. The relationship between the level of beta trace protein and pregnancy induced hypertension. To our knowledge, this is the first study to reveal the association between serum level of beta trace protein and pregnancy induced hypertension. Objective: To compare the age of normal pregnant women with pregnancy induced hypertension (gestation hypertension group), prepregnancy BMI, pregnancy history, blood pressure, Weight, left ventricular ejection fraction (LVEF), urine protein, serum testosterone, sex hormone binding globulin (SHBG), hypersensitive C reactive protein (hs-CRP) and beta trace protein (BTP) were investigated to investigate the high risk factors of pregnancy induced hypertension in pregnant women and the level of serum testosterone, sex hormone binding globulin (SHBG) and hypersensitive C reactive protein (hs-CRP). Whether there is a correlation between the occurrence of pregnancy induced hypertension and the level of serum beta trace protein (BTP) in the serum of normal pregnant women and pregnant women during pregnancy at different stages of pregnancy, the level of serum BTP in the two groups of pregnant women was compared, and the level of serum beta trace protein (BTP) and pregnancy induced hypertension were evaluated by ROC analysis. Whether it is relevant, can the severity of the disease be counter to the severity of the disease, can be used as a new and more effective marker for predicting pregnancy induced hypertension and the ability to diagnose and identify pregnancy induced hypertension. Research objects and methods: select 1206 pregnant women who were born in Qilu Hospital and Zibo Central hospital in 2014 and choose pregnancy from them. 57 pregnant women of normal pregnancy age and pregnant age matched the normal control group (blood pressure 140/90 mmHg, and no proteinuria during pregnancy); 46 pregnant women with pregnancy induced hypertension were set up as pregnancy hypertension group (gestational hypertension disease was a symptom of no high blood pressure at 20 weeks before pregnancy, and the blood pressure was measured over two times after 20 weeks of pregnancy. " The results showed that the systolic pressure was more than 140 mmHg or the diastolic pressure was more than 90 mmHg, and the measurement interval was at least 4 hours, accompanied by preeclampsia or no proteinuria. The pregnant women of.46 pregnant hypertension were divided into simple hypertension group and preeclampsia group according to non albuminuria. The left ventricular ejection fraction was divided into group LVEF60% and LVET more than 60% groups according to the left ventricular ejection fraction 60%. All pregnant women were Single pregnancy, two groups of gestational age and gestational age matching. The exclusion criteria include: pregnancy induced hypertension may also accompany other diseases such as second types of hypertension, coronary heart disease, kidney disease, or diabetes. First, collect all the clinical indicators of all pregnant women, such as the average age of the pregnant women (age), and the height and quality before pregnancy. Volume index BMI (kg/m2), race (n,%), PIH family history (n,%), natural abortion history (3) (n,%), pregnancy times (3) (n,%) and so on, and compared and analyzed systolic pressure (millimeter mercury column), diastolic pressure (millimeter mercury column), birth gestational age (days), birth mode (n,%, normal vaginal delivery or CS), and placental weight (g), neonatal sex (n,%) and out of birth. Maternal weight (g) and other data. Pregnant women in pregnancy induced hypertension were monitored by echocardiography to monitor left ventricular ejection fraction (LVEF). All pregnant women were collected at different stages of pregnancy (1-12 weeks), mid trimester (13-27 weeks), late pregnancy (28-40 weeks) of blood samples, 4, 7000 RPM centrifugation and -80 C after 10 minutes. All stages of pregnancy were examined. The serum concentration of SHBG was measured by enzyme immunoassay. The level of testosterone and hypersensitive C reaction protein was measured by immunoluminescence. The level of serum beta trace protein was detected by enzyme linked immunosorbent assay (ELISA) kit. Two groups of pregnant women's urine protein, hs-CRP (mg/1) (mid trimester, late trimester), testosterone (mid trimester, late trimester), S were collected, S HBG (nmol/l) (mid trimester, late trimester of pregnancy) and BTP (early pregnancy, mid trimester, late pregnancy) and other experimental data, the results of the ELISA test were tested by non parametric test. The potential risk assessment was analyzed by plotting the ROC curve. (1) pregnant women with pregnancy induced hypertension were higher than the pregnant women in the normal control group that was in line with the age of pregnancy and the maternal age. The preconception height mass index (BMI) (P0.05), the higher anemia incidence (p0.001), and the family hereditary history of pregnancy induced hypertension (p0.001); under the premise of the same gestational age at birth, for other parameters such as delivery mode, placental weight, and birth weight, pregnant women with pregnancy and normal health control group have no obvious difference between pregnant women and pregnant women. (2) the level of serum testosterone, SHBG, and C reactive protein (hs-CRP) in the two groups of pregnant women showed no significant difference between the pregnancy induced hypertension group and the normal pregnancy group; (3) there was no significant difference between the levels of serum beta trace protein in the normal pregnant women and the pregnancy induced pregnancy. The level of serum beta trace protein in pregnant women with pregnancy induced hypertension increased gradually with different pregnancy stages, but there was no significant difference in the level of serum beta trace protein in the middle pregnancy and late trimester of pregnancy. (4) the serum beta mark of pregnant women with pregnancy induced hypertension compared with normal pregnant women. The level of trace protein in the middle and late pregnancy was significantly higher than that of the normal control group (P0.05), but there was no significant difference between the levels of serum beta trace protein between the two groups in the early pregnancy. (5) the level of serum beta trace protein in the pre eclampsia group was higher than that of the Dan Chungao blood pressure group, and the difference was statistically significant. The level of BTP in the serum of pregnant women with left ventricular ejection fraction LVET60% was significantly higher than that of pregnant women with LVET more than 60%. (6) the potential value of serum beta trace protein was assessed by ROC analysis to predict the potential value of pregnancy induced hypertension. The results showed that the use of serum BTP 321.3ng/mL as a truncated value and the predictive sensitivity for pregnancy induced hypertension Up to 91.3%, the specificity can reach the 89.5%. research conclusion: 1, pregnant women have the family history of pregnancy induced hypertension, the height mass index is high before pregnancy, the pregnant anemia should be included in the high risk monitoring group of the pregnancy hypertension,.2. This study did not find the middle and late pregnancy serum testosterone, sex hormone binding globulin (SHBG), C reactive protein (hs-CRP). The level is associated with the occurrence of pregnancy induced hypertension, so the index can not be used as a marker for predicting pregnancy induced hypertension. The high level of serum beta trace protein is associated with the occurrence of pregnancy induced hypertension, which can be used to reflect the progression of pregnancy induced hypertension. In addition, serum beta trace protein can also be used as a pregnancy.3. The predictors of hypertension involving the function of the kidney or heart are consistent with the conclusion that B- trace protein can be used as a marker of abnormal heart and kidney function. It can be used to respond to the severity of.4 in pregnant women with pregnancy induced hypertension. The level of beta trace protein can be used to predict high blood pressure in pregnancy by ROC analysis. It is sensitive and specific, so the level of serum beta trace protein is expected to be a new diagnostic marker for pregnancy induced hypertension. Detection in pregnant women with high risk factors can improve the predictive sensitivity and be used to predict pregnancy induced hypertension.
【學位授予單位】：山東大學
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R714.246

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