【摘要】：目的：近年來(lái)，早產(chǎn)兒出生率仍然在不斷的升高。隨著新生兒重癥監(jiān)護(hù)病房(NICU)的發(fā)展，早產(chǎn)兒的存活率有了明顯提高。但早產(chǎn)兒各器官發(fā)育尚不成熟，其并發(fā)癥及后遺癥的發(fā)生嚴(yán)重影響早產(chǎn)兒遠(yuǎn)期生活質(zhì)量。有效地防治早產(chǎn)是降低早產(chǎn)發(fā)生率、改善預(yù)后的關(guān)鍵。因此如何預(yù)防早產(chǎn)的發(fā)生已成為亟待解決的問題。首先必需明確早產(chǎn)的原因。目前已知的早產(chǎn)原因包括：感染、母親年齡、子宮因素、孕期合并癥及并發(fā)癥、社會(huì)生活環(huán)境、經(jīng)濟(jì)狀態(tài)等。其次，明確相應(yīng)疾病狀態(tài)下導(dǎo)致的早產(chǎn)分娩發(fā)動(dòng)機(jī)制。雖然目前公認(rèn)前列腺素是導(dǎo)致分娩發(fā)動(dòng)的最后的共同通路[1]，但是具體調(diào)節(jié)機(jī)制至今仍未完全清楚。而且研究認(rèn)為分娩發(fā)動(dòng)是一個(gè)復(fù)雜的綜合作用的結(jié)果，必須綜合各種因素考慮[2]。近些年以來(lái)，Challis.et al等學(xué)者通過(guò)對(duì)綿羊以及哺乳動(dòng)物模型的研究發(fā)現(xiàn)，胎兒的下丘腦-垂體-腎上腺軸（hypothalamic-pituitary-adrenal，HPA軸）的激活是分娩發(fā)動(dòng)的中心機(jī)制[3]。HPA軸激活的直接結(jié)果是胎兒體內(nèi)皮質(zhì)醇增多。皮質(zhì)醇可以直接影響胎盤前列腺素合成酶的表達(dá)，導(dǎo)致前列腺素的合成增多[3]。前列腺素作用于宮頸，使宮頸軟化；作用于子宮平滑肌，使子宮收縮，最終促使分娩發(fā)動(dòng)。由此推測(cè)皮質(zhì)醇作為前列腺素合成酶的誘導(dǎo)因子，間接地促進(jìn)前列腺素的合成而啟動(dòng)分娩。胎兒體內(nèi)皮質(zhì)醇的合成受多種因素的影響，不同病因狀態(tài)胎兒體內(nèi)皮質(zhì)醇表達(dá)水平亦不同。尤其在胎兒應(yīng)激狀態(tài)下，皮質(zhì)醇作為應(yīng)激激素將會(huì)大量分泌。而皮質(zhì)醇作為誘導(dǎo)因子，由其所形成的皮質(zhì)醇-前列腺素合成酶-前列腺素的級(jí)聯(lián)反應(yīng)，在妊娠分娩中起重要作用。因此通過(guò)測(cè)定新生兒血中皮質(zhì)醇及其相關(guān)因子水平，可以了解胎兒內(nèi)分泌活動(dòng)在妊娠分娩中的作用，為有效地預(yù)防早產(chǎn)的發(fā)生提供新思路。另外，雖然有效地預(yù)防是降低早產(chǎn)發(fā)生率的根本，然而合理的評(píng)價(jià)及干預(yù)是改善其遠(yuǎn)期預(yù)后的重要手段。有學(xué)者曾提出產(chǎn)前及產(chǎn)后皮質(zhì)醇的水平影響新生兒大腦關(guān)鍵區(qū)域神經(jīng)纖維的表達(dá)。這些區(qū)域包括海馬以及與記憶相關(guān)的區(qū)域[4]。此外，前列腺素有維持胎兒動(dòng)脈導(dǎo)管不閉的作用，從血流動(dòng)力學(xué)上保證了胎兒重要器官得到含氧豐富的血供[5]。前列腺素還可調(diào)節(jié)胎兒下丘腦-垂體-腎上腺軸（HPA）的功能[6、7]，促進(jìn)胎兒發(fā)育成熟。因此通過(guò)檢測(cè)新生兒皮質(zhì)醇、前列腺素水平，還可以指導(dǎo)新生兒疾病的防治，為改善其遠(yuǎn)期預(yù)后提供理論依據(jù)。 方法：選擇邢臺(tái)市人民醫(yī)院新生兒科收治的新生兒55例，首先根據(jù)胎齡分為足月新生兒對(duì)照組；早產(chǎn)兒組。其中足月新生兒對(duì)照組15例，其胎齡平均為37.6±0.50周、體重平均為3000g±430.43g、男8例，女7例；其次早產(chǎn)兒組根據(jù)分娩原因分為：特發(fā)性早產(chǎn)組、妊高癥分娩組。其中特發(fā)性早產(chǎn)組20例，其胎齡平均為33.58±1.28周，體重平均為1990.59±408.68g，男13例，女7例；妊高癥分娩組20例，其胎齡平均為33.83±3.10周，體重平均為1794.41±414.80g，男12例，女8例。各組內(nèi)新生兒胎齡、出生體重、性別均無(wú)統(tǒng)計(jì)學(xué)差異，P0.05。所選新生兒母親均為適齡產(chǎn)婦、無(wú)不良生活習(xí)慣、未使用抗生素、產(chǎn)前無(wú)感染病史、無(wú)胎膜早破、產(chǎn)前未使用促肺成熟藥物；新生兒無(wú)宮內(nèi)窘迫、窒息史、Apgar評(píng)分正常。 55例新生兒均在出生30min內(nèi)采集外周靜脈血并離心留取上清液，采用酶聯(lián)免疫吸附法檢測(cè)新生兒血清中皮質(zhì)醇、前列腺素合成酶、前列腺素三者的含量。結(jié)合相關(guān)臨床資料對(duì)比分析，并進(jìn)行統(tǒng)計(jì)學(xué)處理。 結(jié)果： 13組新生兒血清皮質(zhì)醇水平變化（Fig1，Table1） 足月新生兒對(duì)照組血清皮質(zhì)醇水平高于特發(fā)性早產(chǎn)組，差異有統(tǒng)計(jì)學(xué)意義（P0.05）；足月新生兒對(duì)照組及特發(fā)性早產(chǎn)組血清皮質(zhì)醇水平顯著低于妊高癥早產(chǎn)組，差異有統(tǒng)計(jì)學(xué)意義（P0.05）。 23組新生兒血清前列腺素合成酶水平變化（Fig2，Table2） 足月新生兒對(duì)照組血清前列腺素合成酶水平高于特發(fā)性早產(chǎn)組，差異有統(tǒng)計(jì)學(xué)意義（P0.05）；足月新生兒對(duì)照組及特發(fā)性早產(chǎn)組血清前列腺素合成酶水平顯著低于妊高癥早產(chǎn)組，差異有統(tǒng)計(jì)學(xué)意義（P0.05）。 33組新生兒血清前列腺素的水平變化（Fig3，Table3） 足月新生兒對(duì)照組血清前列腺素水平高于特發(fā)性早產(chǎn)組，差異有統(tǒng)計(jì)學(xué)意義（P0.05）；足月新生兒對(duì)照組及特發(fā)性早產(chǎn)組血清前列腺素水平顯著低于妊高癥早產(chǎn)組，差異有統(tǒng)計(jì)學(xué)意義（P0.05）。 4相關(guān)性分析 4.1新生兒血清皮質(zhì)醇、前列腺素合成酶相關(guān)性分析（見Fig4、7、10,Table4） 足月新生兒對(duì)照組血清皮質(zhì)醇、前列腺素合成酶呈正相關(guān)，差異有統(tǒng)計(jì)學(xué)意義（r=0.895，P0.01）；特發(fā)性早產(chǎn)組新生兒血清皮質(zhì)醇、前列腺素合成酶無(wú)相關(guān)性，差異無(wú)統(tǒng)計(jì)學(xué)意義（r=-0.349，P0.05）；妊高癥早產(chǎn)組新生兒血清皮質(zhì)醇、前列腺素合成酶呈正相關(guān)，差異有統(tǒng)計(jì)學(xué)意義（r=0.876，P0.01）。 4.2新生兒血清前列腺素合成酶、前列腺素相關(guān)性分析（見Fig5、8、11,Table5） 足月新生兒對(duì)照組血清前列腺素合成酶、前列腺素呈正相關(guān)，差異有統(tǒng)計(jì)學(xué)意義（r=0.818，P0.01）；特發(fā)性早產(chǎn)組新生兒血清前列腺素合成酶、前列腺素?zé)o相關(guān)性，差異無(wú)統(tǒng)計(jì)學(xué)意義（r=-0.354，P0.05）；妊高癥早產(chǎn)組新生兒血清前列腺素合成酶、前列腺素呈正相關(guān)，差異有統(tǒng)計(jì)學(xué)意義（r=0.770，P0.01）。 4.3新生兒血清皮質(zhì)醇、前列腺素相關(guān)性分析（見Fig6、9、12, Table6） 足月新生兒對(duì)照組血清皮質(zhì)醇、前列腺素呈正相關(guān)，差異有統(tǒng)計(jì)學(xué)意義（r=0.761，P0.01）；特發(fā)性早產(chǎn)組血清皮質(zhì)醇、前列腺素?zé)o相關(guān)性，差異無(wú)統(tǒng)計(jì)學(xué)意義（r=-0.139，P0.05）；妊高癥早產(chǎn)組新生兒血清皮質(zhì)醇、前列腺素呈正相關(guān)，差異有統(tǒng)計(jì)學(xué)意義（r=0.863，P0.01）。 結(jié)論： 1足月新生兒對(duì)照組與特發(fā)性早產(chǎn)組相比，新生兒血清皮質(zhì)醇水平足月新生兒對(duì)照組高于特發(fā)性早產(chǎn)組（P0.05），提示隨著孕周的增加胎兒分泌皮質(zhì)醇的能力增強(qiáng)。表明其水平變化反應(yīng)胎兒腎上腺功能。 2足月新生兒對(duì)照組與妊高癥早產(chǎn)組相比，新生兒血清皮質(zhì)醇水平足月新生兒對(duì)照組小于妊高癥早產(chǎn)組（P0.05），提示早產(chǎn)兒腎上腺具有良好的調(diào)節(jié)功能。妊高癥時(shí)胎兒處于應(yīng)激狀態(tài)，皮質(zhì)醇大量分泌。 3足月新生兒對(duì)照組血清皮質(zhì)醇、前列腺素合成酶、前列腺素三者水平呈正相關(guān)關(guān)系。表明在正常妊娠過(guò)程中，胎兒內(nèi)分泌活動(dòng)參與妊娠分娩的過(guò)程。隨著孕周的增加，胎兒腎上腺分泌的皮質(zhì)醇逐漸增高。當(dāng)皮質(zhì)醇增高到一定程度時(shí)，其作為前列腺素的上游因子，，通過(guò)誘導(dǎo)前列腺素合成酶的表達(dá)，促進(jìn)前列腺素的合成，從而啟動(dòng)分娩。三者之間的相互作用在維持妊娠及分娩發(fā)動(dòng)中起重要作用。 4妊高癥早產(chǎn)組新生兒血清皮質(zhì)醇、前列腺素合成酶、前列腺素三者水平均同時(shí)升高，呈正相關(guān)性。表明胎兒在應(yīng)激狀態(tài)下，分泌較多皮質(zhì)醇，并通過(guò)上述級(jí)聯(lián)反應(yīng)，使分娩提前啟動(dòng)，導(dǎo)致早產(chǎn)。 5特發(fā)性早產(chǎn)組新生兒血清皮質(zhì)醇與足月新生兒對(duì)照組相比，其水平并未升高；在特發(fā)性早產(chǎn)組皮質(zhì)醇、前列腺素合成酶、前列腺素三者之間無(wú)相關(guān)性。故推測(cè)皮質(zhì)醇及其相關(guān)因子所形成的級(jí)聯(lián)反應(yīng)并未參與特發(fā)性早產(chǎn)的分娩發(fā)動(dòng)。 6監(jiān)測(cè)新生兒血清皮質(zhì)醇水平，有利于評(píng)價(jià)新生兒腎上腺功能。 7深入研究皮質(zhì)醇、前列腺素合成酶和前列腺素，應(yīng)用分子生物學(xué)技術(shù)研究三者之間精密的調(diào)控機(jī)制，找到促發(fā)級(jí)聯(lián)反應(yīng)的扳機(jī)點(diǎn)，為妊高癥早產(chǎn)的早期防治開拓新的途徑。
[Abstract]:OBJECTIVE: In recent years, the birth rate of premature infants is still rising. With the development of neonatal intensive care unit (NICU), the survival rate of premature infants has been significantly improved. However, the organ development of premature infants is still immature. The complications and sequelae of premature infants seriously affect the long-term quality of life. So how to prevent the occurrence of preterm labor has become an urgent problem to be solved. First of all, it is necessary to clarify the causes of preterm labor. Although prostaglandins are currently recognized as the last common pathway leading to the onset of labor, the specific regulatory mechanism is still unclear. Moreover, studies have shown that the onset of labor is the result of a complex and comprehensive effect, and various factors must be taken into account. The activation of hypothalamic-pituitary-adrenal axis (HPA axis) is the central mechanism of labor initiation [3]. The direct result of HPA axis activation is the increase of fetal cortisol. Cortisol can directly affect the placental prostaglandin synthase surface. Prostaglandin acts on the cervix, softening the cervix; acts on the smooth muscle of the uterus, causing contraction of the uterus, and ultimately promoting the initiation of labor. The levels of cortisol expression in fetuses with different etiological factors are also different. Especially in fetal stress, cortisol, as a stress hormone, will be secreted in large quantities. As an inducer, cortisol, the cascade of cortisol-prostaglandin synthase-prostaglandin, plays an important role in pregnancy and childbirth. Therefore, by measuring the levels of cortisol and its related factors in the blood of newborns, we can understand the role of fetal endocrine activities in pregnancy and childbirth, and provide new ideas for effectively preventing the occurrence of premature delivery. Prenatal and postnatal cortisol levels have been suggested to affect the expression of nerve fibers in key brain regions of newborns. These regions include the hippocampus and memory-related areas [4]. Prostaglandin can also regulate the function of fetal hypothalamus-pituitary-adrenal axis (HPA) and promote fetal development and maturation.Therefore, the detection of neonatal cortisol and prostaglandin levels can also guide the prevention and treatment of neonatal diseases and provide theoretical basis for improving long-term prognosis.
Methods: Fifty-five neonates were selected from the Department of Neonatology, Xingtai People's Hospital, and divided into two groups according to gestational age: full-term neonate control group and preterm neonate group. Idiopathic premature delivery group, pregnancy-induced hypertension delivery group, including 20 cases of idiopathic premature delivery group, the average gestational age was 33.58 + 1.28 weeks, the average weight was 1990.59 + 408.68 g, 13 males, 7 females; pregnancy-induced hypertension delivery group, 20 cases, the average gestational age was 33.83 + 3.10 weeks, the average weight was 1794.41 + 414.80 g, 12 males, 8 females. There was no significant difference between the two groups, P 0.05. The mothers of the newborns were all puerperas of the right age, without unhealthy living habits, antibiotics, prenatal infection, premature rupture of membranes, and pulmonary maturation drugs. The newborns had no history of intrauterine distress, asphyxia and normal Apgar score.
The serum cortisol, prostaglandin synthase and prostaglandin were detected by enzyme-linked immunosorbent assay (ELISA). The clinical data were compared and analyzed.
Result:
Changes of serum cortisol levels in 13 groups of neonates (Fig1, Table1)
The level of serum cortisol in full-term neonate control group was higher than that in idiopathic preterm delivery group (P 0.05). The level of serum cortisol in full-term neonate control group and idiopathic preterm delivery group was significantly lower than that in PIH preterm delivery group (P 0.05).
Changes of serum prostaglandin synthetase levels in 23 groups of neonates (Fig2, Table2)
The level of serum prostaglandin synthase in term neonate control group was higher than that in idiopathic preterm delivery group (P 0.05). The level of serum prostaglandin synthase in term neonate control group and idiopathic preterm delivery group was significantly lower than that in pregnancy induced hypertension preterm delivery group (P 0.05).
Changes of serum prostaglandin levels in 33 groups of neonates (Fig3, Table3)
The level of serum prostaglandin in term neonate control group was higher than that in idiopathic preterm delivery group, the difference was statistically significant (P 0.05); the level of serum prostaglandin in term neonate control group and idiopathic preterm delivery group was significantly lower than that in pregnancy induced hypertension preterm delivery group, the difference was statistically significant (P 0.05).
4 Correlation Analysis
Correlation analysis of serum cortisol and prostaglandin synthetase in 4.1 neonates (see Fig4,7,10, Table4)
Serum cortisol and prostaglandin synthase were positively correlated in term neonate control group (r = 0.895, P 0.01); serum cortisol and prostaglandin synthase were not correlated in idiopathic premature infant group (r = - 0.349, P 0.05); serum cortisol and prostaglandin synthase were not correlated in idiopathic premature infant group (r = - 0.349, P 0.05); serum cortisol and The enzyme was positively correlated, and the difference was statistically significant (r=0.876, P0.01).
4.2 neonatal serum prostaglandin synthase, prostaglandin correlation analysis (see Fig5,8,11, Table5)
Serum prostaglandin synthase and prostaglandin were positively correlated in term neonate control group (r = 0.818, P 0.01); serum prostaglandin synthase and prostaglandin were not correlated in idiopathic premature infant group (r = - 0.354, P 0.05); serum prostaglandin synthase was not correlated in pregnancy induced hypertension premature infant group (P 0.354, P 0.05). Prostaglandin was positively correlated, and the difference was statistically significant (r=0.770, P0.01).
Correlation analysis of serum cortisol and prostaglandin in 4.3 neonates (see Fig6,9,12, Table6)
Serum cortisol and prostaglandin were positively correlated in full-term neonate control group (r = 0.761, P 0.01); serum cortisol and prostaglandin were not correlated in idiopathic preterm delivery group, and there was no significant difference (r = - 0.139, P 0.05); serum cortisol and prostaglandin were positively correlated in preterm pregnancy induced hypertension group, and the difference was statistically significant. Meaning (r=0.863, P0.01).
Conclusion:
1. Compared with the idiopathic preterm birth group, the serum cortisol level of the full-term neonate control group was higher than that of the idiopathic preterm birth group (P 0.05), suggesting that the ability of the fetus to secrete cortisol increased with the increase of gestational age.
Compared with the preterm group of PIH, the serum cortisol level of full-term neonates in the control group was lower than that in the preterm group of PIH (P 0.05), suggesting that the adrenal gland of preterm infants has a good regulatory function.
There was a positive correlation between the levels of serum cortisol, prostaglandin synthase and prostaglandin in the control group of full-term neonates, indicating that fetal endocrine activity was involved in the process of pregnancy and childbirth during normal pregnancy. As the upstream factor of prostaglandin, the synthesis of prostaglandin is promoted by inducing the expression of prostaglandin synthetase, thus initiating labor.
4. The levels of serum cortisol, prostaglandin synthase and prostaglandin in preterm infants with PIH were all increased at the same time, showing a positive correlation.
5. The serum cortisol level of neonates in idiopathic preterm delivery group was not higher than that of full-term neonate control group, and there was no correlation among cortisol, prostaglandin synthase and prostaglandin in idiopathic preterm delivery group.
6 monitoring the serum cortisol level of newborns is beneficial to evaluate adrenal function in neonates.
7. Deeply study cortisol, prostaglandin synthase and prostaglandin, study the precise regulation mechanism among them by molecular biology technology, find the trigger point of cascade reaction, and open up a new way for early prevention and treatment of pregnancy induced hypertension.
【學(xué)位授予單位】：河北醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2012
【分類號(hào)】：R722.1

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