【作者】 成春苹；

【导师】 戎小平；

【作者基本信息】 河北医科大学 ， 儿科学， 2012， 硕士

【摘要】 目的：近年来，早产儿出生率仍然在不断的升高。随着新生儿重症监护病房(NICU)的发展，早产儿的存活率有了明显提高。但早产儿各器官发育尚不成熟，其并发症及后遗症的发生严重影响早产儿远期生活质量。有效地防治早产是降低早产发生率、改善预后的关键。因此如何预防早产的发生已成为亟待解决的问题。首先必需明确早产的原因。目前已知的早产原因包括：感染、母亲年龄、子宫因素、孕期合并症及并发症、社会生活环境、经济状态等。其次，明确相应疾病状态下导致的早产分娩发动机制。虽然目前公认前列腺素是导致分娩发动的最后的共同通路[1]，但是具体调节机制至今仍未完全清楚。而且研究认为分娩发动是一个复杂的综合作用的结果，必须综合各种因素考虑[2]。近些年以来，Challis.et al等学者通过对绵羊以及哺乳动物模型的研究发现，胎儿的下丘脑-垂体-肾上腺轴（hypothalamic-pituitary-adrenal，HPA轴）的激活是分娩发动的中心机制[3]。HPA轴激活的直接结果是胎儿体内皮质醇增多。皮质醇可以直接影响胎盘前列腺素合成酶的表达，导致前列腺素的合成增多[3]。前列腺素作用于宫颈，使宫颈软化；作用于子宫平滑肌，使子宫收缩，最终促使分娩发动。由此推测皮质醇作为前列腺素合成酶的诱导因子，间接地促进前列腺素的合成而启动分娩。胎儿体内皮质醇的合成受多种因素的影响，不同病因状态胎儿体内皮质醇表达水平亦不同。尤其在胎儿应激状态下，皮质醇作为应激激素将会大量分泌。而皮质醇作为诱导因子，由其所形成的皮质醇-前列腺素合成酶-前列腺素的级联反应，在妊娠分娩中起重要作用。因此通过测定新生儿血中皮质醇及其相关因子水平，可以了解胎儿内分泌活动在妊娠分娩中的作用，为有效地预防早产的发生提供新思路。另外，虽然有效地预防是降低早产发生率的根本，然而合理的评价及干预是改善其远期预后的重要手段。有学者曾提出产前及产后皮质醇的水平影响新生儿大脑关键区域神经纤维的表达。这些区域包括海马以及与记忆相关的区域[4]。此外，前列腺素有维持胎儿动脉导管不闭的作用，从血流动力学上保证了胎儿重要器官得到含氧丰富的血供[5]。前列腺素还可调节胎儿下丘脑-垂体-肾上腺轴（HPA）的功能[6、7]，促进胎儿发育成熟。因此通过检测新生儿皮质醇、前列腺素水平，还可以指导新生儿疾病的防治，为改善其远期预后提供理论依据。方法：选择邢台市人民医院新生儿科收治的新生儿55例，首先根据胎龄分为足月新生儿对照组；早产儿组。其中足月新生儿对照组15例，其胎龄平均为37.6±0.50周、体重平均为3000g±430.43g、男8例，女7例；其次早产儿组根据分娩原因分为：特发性早产组、妊高症分娩组。其中特发性早产组20例，其胎龄平均为33.58±1.28周，体重平均为1990.59±408.68g，男13例，女7例；妊高症分娩组20例，其胎龄平均为33.83±3.10周，体重平均为1794.41±414.80g，男12例，女8例。各组内新生儿胎龄、出生体重、性别均无统计学差异，P>0.05。所选新生儿母亲均为适龄产妇、无不良生活习惯、未使用抗生素、产前无感染病史、无胎膜早破、产前未使用促肺成熟药物；新生儿无宫内窘迫、窒息史、Apgar评分正常。55例新生儿均在出生30min内采集外周静脉血并离心留取上清液，采用酶联免疫吸附法检测新生儿血清中皮质醇、前列腺素合成酶、前列腺素三者的含量。结合相关临床资料对比分析，并进行统计学处理。结果：13组新生儿血清皮质醇水平变化（Fig1，Table1）足月新生儿对照组血清皮质醇水平高于特发性早产组，差异有统计学意义（P<0.05）；足月新生儿对照组及特发性早产组血清皮质醇水平显著低于妊高症早产组，差异有统计学意义（P<0.05）。23组新生儿血清前列腺素合成酶水平变化（Fig2，Table2）足月新生儿对照组血清前列腺素合成酶水平高于特发性早产组，差异有统计学意义（P<0.05）；足月新生儿对照组及特发性早产组血清前列腺素合成酶水平显著低于妊高症早产组，差异有统计学意义（P<0.05）。33组新生儿血清前列腺素的水平变化（Fig3，Table3）足月新生儿对照组血清前列腺素水平高于特发性早产组，差异有统计学意义（P<0.05）；足月新生儿对照组及特发性早产组血清前列腺素水平显著低于妊高症早产组，差异有统计学意义（P<0.05）。4相关性分析4.1新生儿血清皮质醇、前列腺素合成酶相关性分析（见Fig4、7、10,Table4）足月新生儿对照组血清皮质醇、前列腺素合成酶呈正相关，差异有统计学意义（r=0.895，P<0.01）；特发性早产组新生儿血清皮质醇、前列腺素合成酶无相关性，差异无统计学意义（r=-0.349，P>0.05）；妊高症早产组新生儿血清皮质醇、前列腺素合成酶呈正相关，差异有统计学意义（r=0.876，P<0.01）。4.2新生儿血清前列腺素合成酶、前列腺素相关性分析（见Fig5、8、11,Table5）足月新生儿对照组血清前列腺素合成酶、前列腺素呈正相关，差异有统计学意义（r=0.818，P<0.01）；特发性早产组新生儿血清前列腺素合成酶、前列腺素无相关性，差异无统计学意义（r=-0.354，P>0.05）；妊高症早产组新生儿血清前列腺素合成酶、前列腺素呈正相关，差异有统计学意义（r=0.770，P<0.01）。4.3新生儿血清皮质醇、前列腺素相关性分析（见Fig6、9、12, Table6）足月新生儿对照组血清皮质醇、前列腺素呈正相关，差异有统计学意义（r=0.761，P<0.01）；特发性早产组血清皮质醇、前列腺素无相关性，差异无统计学意义（r=-0.139，P>0.05）；妊高症早产组新生儿血清皮质醇、前列腺素呈正相关，差异有统计学意义（r=0.863，P<0.01）。结论：1足月新生儿对照组与特发性早产组相比，新生儿血清皮质醇水平足月新生儿对照组高于特发性早产组（P<0.05），提示随着孕周的增加胎儿分泌皮质醇的能力增强。表明其水平变化反应胎儿肾上腺功能。2足月新生儿对照组与妊高症早产组相比，新生儿血清皮质醇水平足月新生儿对照组小于妊高症早产组（P<0.05），提示早产儿肾上腺具有良好的调节功能。妊高症时胎儿处于应激状态，皮质醇大量分泌。3足月新生儿对照组血清皮质醇、前列腺素合成酶、前列腺素三者水平呈正相关关系。表明在正常妊娠过程中，胎儿内分泌活动参与妊娠分娩的过程。随着孕周的增加，胎儿肾上腺分泌的皮质醇逐渐增高。当皮质醇增高到一定程度时，其作为前列腺素的上游因子，通过诱导前列腺素合成酶的表达，促进前列腺素的合成，从而启动分娩。三者之间的相互作用在维持妊娠及分娩发动中起重要作用。4妊高症早产组新生儿血清皮质醇、前列腺素合成酶、前列腺素三者水平均同时升高，呈正相关性。表明胎儿在应激状态下，分泌较多皮质醇，并通过上述级联反应，使分娩提前启动，导致早产。5特发性早产组新生儿血清皮质醇与足月新生儿对照组相比，其水平并未升高；在特发性早产组皮质醇、前列腺素合成酶、前列腺素三者之间无相关性。故推测皮质醇及其相关因子所形成的级联反应并未参与特发性早产的分娩发动。6监测新生儿血清皮质醇水平，有利于评价新生儿肾上腺功能。7深入研究皮质醇、前列腺素合成酶和前列腺素，应用分子生物学技术研究三者之间精密的调控机制，找到促发级联反应的扳机点，为妊高症早产的早期防治开拓新的途径。更多还原

【Abstract】 Objective：Recently,the birthrate of preterm is incrasing.With the develo-pment of the NICU, the survival rate is significantly inproved.However,theorgans of premature infants do not mature enough,and the occurrence ofcomplication affects the quality of their life forward seriously. It is critical thatprevent preterm effectively for reducing the birthrate of preterm andimproving prognosis.Hence,it is urgent to solve the problem that how toprevent the occurrence of preterm.First we must know the reason ofpreterm.Currently the reasons known include:infection、age of the mother、uterine factors、pregnant complications、the environment of the social life、statement of the economy and so on.Second,we should make clear themechanisms of the preterm with the corresponding diseases.Althoughprostaglandin leads to preterm at last in public,the regulation is not knowncompletely at present.Studies believe that the parturition is a complex andcomprehensive result,so we must consider all kinds of factors.Recently,bystudy the model of sheep and mammal, Challis et.al.find that the activity ofthe HPA of the fetal is the central parturition mechanism.The activity of fetalHPA directly results to the increase of cortisol in fetuses.Then cortisol directlyaffects the expression of placental prostaglandin synthetase,which leads to theincrease of prostaglandin(PG).PG can make cervical soft, make uterinecontraction so that start the parturition. Therefore,we could infer cortisol as aninducing factor of prostaglandin synthesis promotes the synthesis of PG tostart the parturition indirectly. Many factors affect the synthesis of cortisol,anddifferent pathogenies lead to different expression of cortisol.Especially at thestate of stress,it may be secreted much. Cortisol as a stress hormone is aimportant role in the delivery by the cascade reaction which can be describedcortisol-prostaglandin synthetase（cox-2）-prostaglandin（PG）.Hence,we can understand the role of secretion in pregnancy through detecting the expressionlevel of cortisol in newborn blood,so that provide a new way for effectivelypreventing preterm.In addition,rational evaluation is an important way toimprove the prognosis in long term while prevention effectively isfundamental to deduce the birthrate of preterm.Some researchers pointed outthat the level of cortisol before and after affected the expression of thenewborn’s nerve fiber in brain key regions.These regions include hippocampusand some related remember.Furthermore,PG plays a role in remaining the fetalarteriosus ductus not closed so provides oxygen rich blood to vital organs.Itcan also regulate HPA axis to promote fetal maturity.consequently,detectingthe level of cortisol and PG can guide the prevention of disease and providethe evidence of improving prognosis.Methods: Fifty-five neonates were selected from neonatology in ThePeople’s Hospital of Xingtai who were divided to two groups according togestational age:full term infant group and premature group. There are15informer37.6±0.50in average gestational age and3000g±430.43g in averageweight, containing8boys and7girls. The premature group is divided into twogroups according to the etiology of birth:idiopathic preterm andpregnancy-induced hypertension preterm. In idiopathic preterm, the averagegestational age of twenty newborns are33.58±1.28, and their average weightis1990.59±408.68g, containing13boys and7girls. In Pregnancy-inducedhypertension preterm group, the average gestational age of twenty newbornsare33.83±3.10, and their average weight is1794.41±414.80g, containing12boys and8girls. All newborns in every group have no statistics differences ingestational age、weight and sex(P>0.05). And all mothers conform to thesecriterions: at the right age of pregnant、have no adverse habits、not use ofantibiotics、have no infection of prenatal、have no premature rupture ofmembranes(PROM)、not use drugs to promote lung maturity.All neonateswithout intrauterine distress、asphyxia、Apgar score is normal.All newborns were collected blood of peripheral vein within30mins, andthen obtained serum by centrifuge. The levels of serum cortisol、cox-2and PG were ditected by enzyme-linked immunosorbent assay (ELISA).Combinedwith comparative analysis of relevant clinical data, a statistical treatment wasconducted.Results:1The change of serum cortisol levels of newborns in three groupsSerum cortisol level of full term infant group is higher than idiopathicpreterm group, there is a statistically difference (P＜0.05);Serum cortisol levelof full term infant group and idiopathic preterm group are significantly lowerthan Pregnancy-induced hypertension preterm group,there is an obviousstatistically difference (P＜0.05).2The change of serum cox-2levels of newborns in three groupsSerum cox-2level of full term infant group is higher than idiopathicpreterm group, there is a statistically difference (P＜0.05);Serum cox-2levelof full term infant group and idiopathic preterm group are significantly lowerthan Pregnancy-induced hypertension preterm group, there is an obviousstatistically difference (P＜0.05).3The change of serum PG levels of newborns in three groupsSerum PG level of full term infant group is higher than idiopathic pretermgroup, there is a statistically difference (P＜0.05);Serum PG level of full terminfant group and idiopathic preterm group are significantly lower thanPregnancy-induced hypertension syndrome preterm group,there is an obviousstatistically difference (P＜0.05).4The correlation analysis4.1The correlation analysis of serum cortisol and cox-2In full term infant group, serum cortisol and cox-2has correlation, there isa statistically difference（r=0.895，P<0.01）.In idiopathic preterm group, serumcortisol and cox-2has no correlation, there is no statistically difference（r=-0.349，P>0.05）.In Pregnancy-induced hypertension preterm group,serum cortisol and cox-2has correlation, there is a statistically difference（r=0.876，P<0.01）.4.2The correlation analysis of serum cox-2and PG In full term infant group, serum cox-2and PG has correlation, there is astatistically difference（r=0.818，P<0.01）. In idiopathic preterm group, serumcox-2and PG has no correlation, there is no statistically difference（r=-0.354，P>0.05）.In Pregnancy-induced hypertension preterm group, serum cox-2andPG has correlation, there ia a statistically difference（r=0.770，P<0.01）.4.3The correlation analysis of serum cortisol and PGIn full term infant group, serum cortisol and PG has correlation, there is astatistically difference（r=0.761，P<0.01）.In idiopathic preterm group, serumcortisol and PG has no correlation, there is no statistically difference（r=-0.139，P>0.05）.In Pregnancy-induced hypertension preterm group,serum cortisol and PG has correlation, there is a statistically difference（r=0.863，P<0.01）.Conclusion:1The level of serum cortisol full term infant group is higher than idiopathicpreterm group, the change of it suggests that the ability of secretion of cortisolof fetus strengthened as gestational age increased,which indicates that it canreflect the function of fetal adrenal gland.2The level of serum cortisol of full term infant group is lower thanpregnancy-induced hypertension preterm group, the change of it suggests thatadrenal gland has a good regulation function of preterm infant. Therefore, thefetus at the state of stress response in pregnancy induced hypertensionsyndrome will increase the secrete of cortisol.3In full term infant group serum cortisol、cox-2and PG is in positivecorrelation,which indicates that the endocrine activity of fetal take part in theprocess of normal delivery.With the increase of gestational age,the secretion ofcortisol of fetal adrenal gradually increased. When it achieves a point, as aupper factor of prostate,it can increase the level of PG by induce theexpression of cox-2.The interaction of the three factors play an important rolein remaining pregnancy and starting delivery.4In Pregnancy-induced hypertension preterm group,the level of cortisol、cox-2and PG rises at the same time,which in positive correlation. It’s indicate that more cortisol were secreted at the state of stress response,and then launchdelivery by cascade reaction.5The level of serum cortisol is not increased in idiopathic preterm groupthan full term infant group;In idiopathic preterm group, serum cortisol、cox-2and PG are in no Correlation.So it can be indicate that cortisol and relatedfactors take no participate in idiopathic preterm.6It is helpful for evaluation function of neonatal adrenal gland bymonitoring the level of cortisol of neonates.7Studying the regulation mechanism of cortisol、cox-2and PG by thetechnology in molecular biology, finding out the trigger point will provide anew way in preventing Pregnancy-induced hypertension preterm birth.更多还原