妊娠肝内胆汁淤积症胎盘细胞凋亡与Fas、FasL的研究

目的　探讨妊娠肝内胆汁淤积症 (intrahepatic cholestasis of pregnancy,ICP)胎盘组织Fas及 Fas L (Fasligand)表达在细胞凋亡中的作用。　方法　采用 d U TP缺口末端标记法 (TU NEL )和免疫组化技术对 31例 ICP患者胎盘组织中的细胞凋亡、Fas、Fas L的基因表达进行检测 ,并以正常妊娠胎盘组织 31例作为对照组。　结果　 ICP组胎盘组织中细胞滋养细胞、合体滋养细胞、蜕膜细胞及绒毛间质细胞的凋亡指数 (AI)分别为 4 9.0 9± 9.13(t=13.4 1)、4 6 .6 4± 9.77(t=12 .16 )、35 .0 9±9.4 9(t=8.4 3)、38.74± 9.70 (t=11.2 8) ,明显高于对照组 (P<0 .0 0 5 )。 ICP组细胞滋养细胞和合体滋养细胞 Fas表达明显增强 (P<0 .0 0 5 ) ,Fas L在细胞滋养细胞、合体滋养细胞、蜕膜细胞及绒毛间质细胞中的表达明显低于对照组 (P<0 .0 0 5 )。　结论　 ICP患者胎盘组织中 Fas表达增强 ,Fas L表达减弱 ,可导致母胎间免疫耐受的破坏 ,胎盘细胞凋亡增加 ,可能与 ICP患者胎盘功能减退有关。     

妊娠期肝内胆汁淤积症胎盘病理的研究

妊娠期肝内胆汁淤积症胎盘病理的研究上海市第六人民医院妇产科病理研究室（２００２３３）刘伯宁有关妊娠期肝内胆汁淤积症（ｉｎｔｒａｈｅｐａｔｉｃｃｈｏｌｅｓｔａｓｉｓｏｆｐｒｅｇｎａｎｃｙ，ＩＣＰ）胎盘病理的研究较少，虽曾有文献报道在ＩＣＰ胎盘中，发现...     

中西医结合治疗妊娠肝内胆汁淤积症患者的胎盘形态学观察

70年代中期以来 ,妊娠肝内胆汁淤积症 (ｉｎｔｒａｈｅｐａｔｉｃｃｈｏｌｅｓｔａｓｉｓｏｆｐｒｅｇｎａｎｃｙ ,ＩＣＰ)因其围产儿病死率、围产儿病率、产后出血率、早产率高被列为高危妊娠。有报道 ,半数不明原因的死胎死产由ＩＣＰ引起[1] 。还有学者均认为 ,ＩＣＰ时胎盘绒毛间隙狭窄 ,从而导致围产儿不良结局[2 ,3] 。我们采用中西医结合治疗ＩＣＰ ,取得了较好的效果。并通过胎盘形态学变化得以证实 ,现报道如下。一、资料与方法1.研究对象 :(1)治疗组 :1993年 9月至 1995年 9月 ,我院收治的ＩＣＰ患者 8例 ;(2 )未治疗组 :随机按入…     

妊娠肝内胆汁淤积症胎盘超微结构及其表皮生长因子受体表达的研究

目的　观察妊娠肝内胆汁淤积症 (intrahepaticcholestasisofpregnancy ,ICP)胎盘超微结构病理改变和表皮生长因子受体 (EGFR)的表达 ,研究胆汁酸对滋养细胞的毒性作用及其对胎儿生长发育的影响。　方法　透射电镜观察 2 2例ICP患者胎盘组织 ,其中ICP合并胎儿生长受限 (fetalgrowthrestriction ,FGR) 7例、ICP未合并FGR 15例 ,应用免疫组化方法和逆转录 聚合酶链反应 (RT PCR)技术测定胎盘滋养细胞表皮生长因子受体 (EGFR)的表达 ,并和 15例正常晚期胎盘比较。　结果　电镜显示 ,ICP胎盘合体滋养细胞较对照组微绒毛减少、内质网扩张、线粒体肿胀或髓鞘样改变 ,核染色质异常分布。ICP合并FGR组上述病理改变更为明显 ,绒毛间质毛细血管减少 ,并出现大量胶原原纤维。ICP合并FGR组胎盘EGFR免疫组化的平均A值 (0 .2 39± 0 .0 17)和ICP未合并FGR组EGFR免疫组化的平均A值 (0 .2 5 3± 0 .0 15 )均比对照组 (0 .384± 0 .0 16 )低 ,差异具非常显著性 (P<0 .0 1)。ICP合并FGR组胎盘EGFRmRNA指数 (0 .2 30± 0 .0 4 8)和ICP未合并FGR组EGFRmRNA指数 (0 .2 31± 0 .0 4 2 )表达均比对照组 (0 .4 6 0± 0 .0 5 1)低 ,差异具非常显著性 (P <0 .0 1) ,ICP合并FGR组与ICP未合并FGR组之间胎盘EGFR的表达无显著性差异 (P     

促肾上腺皮质激素释放激素在妊娠肝内胆汁淤积症胎盘组织的表达及意义

目的探讨促肾上腺皮质激素释放激素(corticotropin-releasing hormone,CRH)在妊娠肝内胆汁淤积症(intrahepatic cholestasis of pregnancy,ICP)患者胎盘组织中的表达及意义。方法 2008年10月至2009年1月在四川大学华西第二医院应用Western blot和实时荧光定量PCR(Real-time PCR)分别检测10例ICP与10例正常胎盘组织中CRH在蛋白及mRNA的表达。结果灰度分析显示,ICP组胎盘组织中CRH蛋白表达水平为1.70±0.36,明显低于正常组的2.42±0.57,两组差异有统计学意义(P<0.05);但ICP胎盘组织CRH mRNA水平为2.62±2.25与正常对照组2.19±1.58相比差异无统计学意义(P>0.05)。结论 CRH可能参与了ICP胎儿急性缺氧的病理生理过程,推测ICP胎盘组织CRH表达可能存在翻译水平障碍。     

妊娠肝内胆汁淤积症患者血清甘胆酸水平变化与胎盘细胞凋亡调节基因表达的关系

目的　探讨妊娠肝内胆汁淤积症 (ICP)患者血清甘胆酸水平变化与胎盘细胞凋亡的关系 ,进一步分析ICP患者胎盘功能减退的可能机制。方法　应用放射免疫方法 ,测定 30例ICP患者(ICP组 )及 2 7例正常孕妇 (对照组 )分娩前血清甘胆酸水平 ,应用免疫组化方法测定两组孕妇胎盘细胞凋亡调节基因bax和bcl 2的表达。结果　 (1)ICP组甘胆酸水平为 (5 1 8± 5 9) μmol/L ,对照组为(9 4± 5 6 ) μmol/L ,两组比较 ,差异有显著性 (P <0 0 5 )。 (2 )ICP组胎盘合体滋养细胞bax阴性 2例 ,弱阳性 9例 ,中等阳性 11例 ,强阳性 8例 ;bcl 2弱阳性 12例 ,中等阳性 12例 ,强阳性 6例。对照组bax阴性 9例 ,弱阳性 13例 ,中等阳性 4例 ,强阳性 1例 ;bcl 2弱阳性 3例 ,中等阳性 4例 ,强阳性 2 0例。两组比较 ,ICP组bax表达阳性率显著高于对照组 (P <0 0 0 0 5 ) ,而bcl 2的表达阳性率又显著低于对照组 (P <0 0 0 0 5 )。 (3)孕妇血甘胆酸水平与胎盘bax表达阳性率呈线性正相关 (P <0 0 0 5 ) ,与胎盘bcl 2表达呈线性负相关 (P <0 0 0 5 )。结论　ICP患者血中高水平的甘胆酸使胎盘合体滋养细胞bax基因过度表达 ,这可能是ICP患者胎盘功能减退的机制之一。     

妊娠期肝内胆汁淤积症

妊娠期肝内胆汁淤积症徐先明综述庄依亮审校（上海医科大学妇产科医院）妊娠期肝内胆汁淤积症（Ｉｎｔｒａｈｅｐａｔｉｃｃｈｏｌｅｓｔａｓｉｓｏｆｐｒｅｇｎａｎｃｙ，ＩＣＰ）易引起早产和胎儿窘迫、死胎、死产，近年来受到产科医生的重视，被列为高危妊娠之一，目前...     

Fas和FasL在妊娠肝内胆汁淤积症患者胎盘绒毛组织中的表达及其意义

妊娠肝内胆汁淤积症 (intrahepaticcholestasisofpregnancy ,ICP)患者的早产率及围产儿死亡率高。该病的病因和发病机理尚不明确。近年来的研究表明 ,其发病与免疫耐受 免疫排斥平衡紊乱密切相关。而Fas诱导的细胞凋亡被认为是妊娠免疫耐受的机制之一 [1] 。在多种妊娠并发症 ,如妊娠高血压综合征 (妊高征 )及流产等患者体内和胎盘组织中都存在Fas系统表达异常及功能紊乱的现象[2 ,3 ] 。本研究检测了ICP患者和正常妊娠妇女胎盘组织中Fas和FasL的表达 ,旨在探讨Fas、FasL与ICP发病的关系。一、资料与方法1.研究对象及标本处理 :选择 …     

妊娠肝内胆汁淤积症

本文综述妊娠肝内胆汁淤积症的流行病学、临床表现、实验室检查、肝脏病理变化，对肥儿的、发病机理、雌激素引起肝汁淤积的实验模型、诊断和治疗的进展。     

胎盘MDR3的表达及其与妊娠期肝内胆汁淤积症关系的研究

目的探讨妊娠期肝内胆汁淤积症(intrahepatic cholestasis of pregnancy,ICP)胎盘中胆盐载体磷脂输出泵(multidrug resistance p-plycoprotein,MDR3)的表达,以及母、胎血中总胆汁酸(total bile acids,TBA)和甘胆酸(cholylglycine,CG)水平的变化;进一步分析胎盘胆盐载体对胆汁酸水平的调节作用及其与ICP的关系。方法ICP(ICP组)及正常妊娠(对照组)孕妇各20例。母血、胎儿脐静脉血中TBA、CG水平的测定分别采用放射免疫法和速率法;胎盘组织中胆盐载体MDR3 mRNA的表达采用荧光定量PCR法。结果(1)ICP组母血、脐血中的TBA、CG水平均高于对照组(P<0.05)。ICP组母血TBA水平高于脐血(25.8±16.6和8.6±5.5)μmol/L,CG水平高于脐血(3416.1±1986.0和821.8±673.2)μg/dL(P<0.05);对照组母血和脐血TBA水平(3.4±2.5和4.4±3.3)μmol/L,CG水平(342.7±234.9和309.3±145.2)μg/dL比较,差异无统计学意义(P>0.05)。(2)ICP和正常妊娠各期胎盘组织中均有MDR3 mRNA的表达。ICP组MDR3 mRNA表达量低于对照组(0.80±0.67和162.63±334.33)拷贝/ng(P<0.05)。(3)ICP组、对照组胎盘中MDR3 mRNA表达量与母血、脐血中TBA和CG水平均无相关性(r=-0.60~0.165,P>0.05)。结论ICP胎盘胆盐载体MDR3 mRNA表达降低,可能引起ICP胎盘对胆汁酸的转运障碍、胎儿体内胆汁淤积,可能是引起ICP胎儿窘迫的原因。     

妊娠肝内胆汁淤积症分度诊断和处理的临床意义

目的　探讨妊娠肝内胆汁淤积症 (ICP)分度诊断和处理的临床意义。方法　将 1999年1月至 2 0 0 3年 5月 ,在我院产前检查并诊为ICP的 2 78例患者 ,应用我院 1999年自订的ICP分度标准 ,根据ICP患者的血清胆红素、肝转氨酶和甘胆酸水平分为轻度与重度ICP。并进行分度诊断和分度处理 ,观察其妊娠结局与分度诊断前后的围产儿死亡率。结果　 (1)轻度ICP患者为 192例 (轻度组 ) ,重度ICP患者为 86例 (重度组 )。 (2 )重度组和轻度组ICP患者终止妊娠的平均孕周分别为(35 8± 1 6 )周和 (37 7± 1 9)周 ,两组比较 ,差异有极显著性 (P <0 0 1)。 (3)重度组和轻度组ICP分度诊断后 ,期待治疗的时间为 (10± 5 )d和 (19± 6 )d ,两组比较 ,差异有极显著性 (P <0 0 0 1)。 (4)重度组ICP患者羊水粪染、新生儿窒息和新生儿转入重症监护室的发生率分别为 38 4 % (33/ 86 )、12 8% (11/ 86 )、30 2 % (2 6 / 86 ) ,明显高于轻度组的 9 4 % (18/ 192 )、4 2 % (8/ 192 )、9 4 % (18/ 192 )。(5 )采用分度诊断前围产儿死亡率为 3 9%～ 6 0 % ,分度诊断后围产儿死亡率为 0 7%～ 1 2 % ,两者比较 ,差异有极显著性 (P <0 0 1)。结论　对ICP患者进行分度诊断和处理 ,有助于改善围产儿预后。     

妊娠肝内胆汁淤积症1241例发病特点分析

目的探讨妊娠肝内胆汁淤积症(ICP)的发病特点。方法采用回顾性分析的方法,对我院1991年1月至2000年12月收治的1241例ICP患者的临床资料进行回顾性系统分析。结果1241例ICP患者中,多胎妊娠44例(3．5％),合并妊娠高血压综合征(妊高征)。101例(8．1％);。126例经产妇中,38例(30．2％)为ICP复发;有发病时间记录的1230例患者的平均发病孕周为32．6周,孕晚期发病有1100例(88．6％);1201例(96．8％)以皮肤瘙痒为首发症状,也有以黄疸(8例,占0．6％)、肝功能异常(28例,占2．3％)等为起始表现者;生化指标中主要以血清总胆汁酸(TBA)、丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)升高为主,但大多为轻、中度升高;也有患者TBA、ALT或AST正常(分别占17．7％、15．6％、17．1％),少数患者(35例,3．2％)白蛋白／球蛋白比值倒置。结论 (1)ICP具有复发性,多胎妊娠孕妇更易发病,瘙痒常是ICP显著而且首发的症状,TBA和肝脏转氨酶升高有助于该病的诊断。(2)少数患者发病时临床表现及实验室检查结果均不典型,对此要引起警惕。     

凋亡相关基因survivin在子宫颈癌组织中的

目的 探讨新的凋亡抑制基因survivin在宫颈癌组织中的表达,及其与bcl-2和p53表达的相关性。方法 应用免疫组织化学链霉菌抗生物素蛋白－过氧化酶连接法（SP法）,检测survivin、bcl-2、p53基因在10例正常宫颈组织及59例宫颈癌组织中的表达。结果 survivin基因在正常宫颈组织中不表达,59例宫颈癌组织中,41例表达阳性,占69．5％。病理分级为G1－G2级的宫颈癌的survivin基因表达阳性率为58．1％（18／31）,G3级为82．1％（23／28）,两者比较,差异有显著性（P＜0．05）;临床分期Ⅱ期的宫颈癌的survivin基因表达阳性率为8例中有4例,Ⅲ期者为81．8％（36／44）,两者比较,差异有显著性（P＜0．05）,survivin基因表达阳性率与宫颈癌的病理分级和临床分期呈正相关。宫颈癌组织中p53蛋白表达阳性、阴性者中,survivin基因表达阳性率分别为76．7％（33／43）、16例中有8例,两者比较,差异有显著性（P＜0．05）;bcl-2蛋白表达阳性、阴性者中,survivin基因表达阳性率分别为80．0％（36／45）、14例中有5例,两者比较,差异有显著性（P＜0．005）,survivin基因表达阳性率与宫颈癌组织中p53、bcl-2蛋白表达密切相关。结论 survivin基因的异常表达而引起的细胞凋亡抑制,在宫颈癌的发生中起一定作用,其过度表达提示宫颈癌预后不良。survivin基因的表达与宫颈癌组织中p53、bcl-2蛋白的异常表达密切相关。     

辅助性T淋巴细胞亚型与妊娠期肝内胆汁淤积症发病的关系

目的　探讨辅助性T淋巴细胞 (TH) 1型细胞因子 [γ干扰素 (IFN γ)、肿瘤坏死因子α(TNF α) ]及TH2 型细胞因子 [白细胞介素 4(IL 4) ]与妊娠期肝内胆汁淤积症 (ICP)发病的关系 ,从分子免疫学角度探讨ICP的发病机理。方法　采用双抗体夹心酶联免疫吸附法 ,检测 2 0例ICP孕妇 (研究组 )和 2 0例正常妊娠妇女 (对照组 )外周血单个核细胞在植物血凝素刺激下产生TH1型细胞因子(IFN γ ,TNF α)及TH2 型细胞因子 (IL 4)的水平 ,并对TH1型细胞因子与ICP患者血清总胆汁酸的相关性进行分析。结果　 ( 1)研究组孕妇的IFN γ、TNF α水平分别为 ( 63 9± 15 6)ng/L、( 10 2 1± 2 3 1)ng/L ;明显高于对照组孕妇的 ( 464± 147)ng/L、( 72 8± 175 )ng/L ,两组比较 ,差异有极显著性 (P <0 0 0 1)。研究组孕妇的IL 4水平为 ( 2 2± 4)ng/L ,明显低于对照组孕妇的 ( 2 7± 6)ng/L ,两组比较 ,差异有显著性(P <0 0 5 )。 ( 2 )研究组孕妇的TNF α/IL 4比值为 48± 11,明显高于对照组孕妇的 3 0± 8;研究组孕妇的IFN γ/IL 4比值为 3 0± 8,明显高于对照组的 19± 6,两组分别 ,差异均有极显著性 (P <0 0 0 1)。( 3 )研究组孕妇的IFN γ、TNF α水平与ICP患者血清胆汁酸水平呈正相关 ,相关系数 (r)分别为 0 45 8,0     

p53、bcl-2和bax基因表达与IUGR胎盘细胞凋亡的相关性研究

目的：研究胎儿宫内发育迟缓（ｉｎｔｒａｕｔｅｒｉｎｅ　ｇｒｏｗｔｈ　ｒｅｔａｒｄａｔｉｏｎ,ＩＵＧＲ)患者的胎盘细胞凋亡,以ｐ５３、ｂｃｌ－２和ｂａｘ相关性。方法：收集ＩＵＧＲ ２０份和正常足月分娩１２例的胎盘组织,应用原位末端标记(TUNEL)法检测其胎盘组织中的细胞凋亡,免疫组化法（ＩＨＣＡ）检测胎盘组织中ｐ５３、ｂｃｌ－２和ｂａｘ基因表达。结果：①正常和ＩＵＧＲ胎盘组织中均可见凋亡细胞,但ＩＵＧＲ胎盘中细胞凋亡指数（ａｐｏｐｔｏｓｉｓ　ｉｎｄｅｘ,ＡＩ）为１６．７～６８．３１,明显高于正常胎盘中的９．２～３０．４／高倍视野（平均２０．６７／高倍视野）,差异有显著性（Ｐ＜０．０５）;②ＩＵＧＲ ２０例胎盘组织中均有ｂａｘ过表达（４０％～９０％),高于正常组织（１０％～４０％）,差异有显著性（Ｐ＜０．０５）;③正常及ＩＵＧＲ胎盘组织中均未见ｂｃｌ－２表达;④ｐ５３在ＩＵＧＲ胎盘组织中的表达为５０％～８０％,而在正常组织中为５５％～８０％（Ｐ＞０．０５）;⑤ＩＵＧＲ２０例胎盘组织中细胞ＡＩ与ｂａｘ的表达呈正相关,与ｐ５３表达无关,ｂａｘ与ｐ５３之间无相关性。结论：①正常孕妇和ＩＵＧＲ患者胎盘组织中均有细胞凋亡,但ＩＵＧ     

克拉玛依地区妊娠肝内胆汁淤积症流行病学调查结果分析

目的　了解本地区妊娠肝内胆汁淤积症(intrahepatic cholestasis of pregnancy, ICP)的发病率及发病特点。　方法　从妊娠20~24周开始普查,动态观察至36周以上,以总胆汁酸酶循环法测定血清总胆汁酸(total bile acid,TBA),TBA>28.5μmol /L为异常,同时复查肝功能加以确诊。　结果　共普查1275例,确诊为ICP 的患者102 例,发病率为8.00%。妊娠33~36 周ICP的发病率(66/351,18.80%)明显高于其他不同孕龄组(P<0.01)。少数民族孕妇ICP的发病率(47/328,14.33%)高于汉族孕妇(55/947, 5. 81%) (P< 0. 01)。有ICP 高危因素的患者ICP 发病(10/67,14.93%)高于无高危因素组(92/208,7.62%)(P<0.01)。　结论　克拉玛依地区ICP的发病率为8 00%,为ICP的高发地区。少数民族孕妇ICP的发病率明显高于汉族发病率。ICP的发病与孕周、孕妇年龄、家族、服药史等有一定的相关性。TAB在整个孕期的波动范围较大。     

妊娠期肝内胆汁淤积症发生死胎的临床因素分析

目的 探讨妊娠期肝内胆汁淤积症(ICP)孕妇发生胎儿死亡的临床特点、实验室指标及胎儿监护手段.方法 对1999年1月至2010年12月浙江大学医学院附属妇产科医院收治的发生死胎的21例ICP孕妇的临床资料进行回顾性分析.结果 (1)21例ICP孕妇的平均年龄(30.2±4.6)岁,其中＞35岁者4例;经产妇6例,1例2年前因ICP发生死胎而引产1次;20例单胎妊娠,1例双胎妊娠.(2)21例ICP孕妇的死胎均发生在孕晚期,胎儿死亡的孕周为29～41周,平均(33.8±4.2)周.12例发生在孕29～37周,9例发生在孕37周后.9例为门诊B超检查时确诊胎死宫内;9例因诊断ICP入院治疗期间发生胎心消失;2例临产后胎心消失;1例胎心监护提示V型减速,拟行急诊刮宫产术于麻醉期间胎心消失.在所有ICP孕妇中围产儿死亡率为0.148%(21/14 184).(3)21例ICP孕妇均有皮肤瘙痒,其中11例有全身皮肤瘙痒.10例在发生死胎前自觉胎动减少或消失.21例ICP孕妇血清甘胆酸水平均升高,其中21.49～64.48 μmol/L 11例,t≥64.48 μmol/L 10例.血清总胆汁酸水平升高16例(另5例未检查),最高达270μmoL/L.血清丙氨酸氨基转移酶和天冬氨酸氨基转移酶水平升高14例,总胆红素＞21μmol/L 7例,直接胆红素升高12例.21例ICP孕妇中,重度15例,轻度6例.(4)9例孕妇门诊即确诊宫内死胎未做胎心监护,其余12例住院检查结果 为:胎心监护结果 可疑2例,无应激试验(NST)提示胎心轻度V型减速1例,B超提示脐动脉舒张期血流缺如3例,胎儿生物物理指标评分低值1例.(5)21例ICP孕妇均经阴道分娩.6例为自然宫缩娩出死胎,其余15例予米非司酮配合依沙吖啶羊膜腔注射或缩宫素引产,14例在48 h内成功娩出死胎,仅1例追加地诺前列酮栓后引产成功.所有死胎外观无异常,脐带长度均在正常范围,有4例脐带绕颈或绕体.胎盘胎膜外观无异常,18例羊水Ⅲ度胎粪污染,2例合并羊水过少.10例行死胎及胎盘病理检查,其中1例合并多发畸形,其余死胎病理检查未见明显异常,10例胎盘病理检查均有绒毛膜周围或底蜕膜、大血管周围的纤维蛋白沉积,同时伴有钙化、退行性变、红色梗死及局灶性合体细胞结节增多.结论 ICP孕妇发生死胎的孕周常在孕晚期,时间常在正常宫缩后,ICP重度可能是发生死胎的关键因素;尚无有效的胎儿监护指标可预测死胎的发生.因此,应综合评估病情,加强胎儿监护,适时终止妊娠.

Abstract：

Objective To investigate the clinical features,critical laboratory parameters,and fetal monitoring methods in intrahepatic cholestasis of pregnancy(ICP).Methods A retrospective analysis of 21 cases of ICP suffered with fetal death in Women's hospital.School of Medicine.Zhejiang University from January 1999 to December 2010 were discussed.Results(1)The average age of ICP patients suffered with fetal death were(30.2±4.6)years old.Among them,4 cases were older than 35 years,six cases were multipara.oneo of them suffered stillbirth 2 year before.Twenty cases were singleton pregnancies and 1 cage was twin pregnancy.(2)All 21 cases of fetal death occurred in the third trimester,12 cases occurred before 37 weeks,9 cases after 37 weeks.Nine cases were diagnosed by ultrasound in outpatient clinics,fetal heart beat disappeared in 9 patients after admission because of ICP, two disappeared after labor, one during anesthesia before emergent surgery. Perinatal mortality rate of ICP was 0. 148% (21/14 184), and fetal death occurred from 29 to 41 weeks with an average gestational age of ( 33.8 ± 4. 2 ) weeks, ( 3 ) Puritus occurred in all 21 cases while 11 of them had pruritus all over the body. Ten pregnant women felt the fetal movement decreased or disappeared before diagnosis of fetal death. The glycocholic acid levels increased in all of the 21 cases. Among them, glycocholic acid levels in 11 cases were (21.49 -64. 48) μmol/L, while in 10 cases were ≥64. 48 μmol/L Serum bile acid levels elevated in 16 cases which had been analyzed ( the other 5 cases had not been checked ), and the highest level reached 270 μmol/L Serum alanine aminotransferase and aspartate aminotransferase were increased in 14 cases. Seven cases had their total bilirubin ＞21 μmoL/L, and 12 cases had their direct bilirubin levels significantly elevated. Among the 21 cases of ICP, 15 cases were in severe status, while the other 6 cases were mild. (4) Nine patients had no antepartum surveillance since fetal death were diagnosed before admission. The results of antepartum surveillance were as follows: 2 cases had nonreassuring nonstress test (NST), one had mild "V" type deceleration. Absence of diastolic flow in umbilical artery were found in 3 cases, and low fetal biophysical score was got in one case. ( 5 ) All 21 patients had vaginal delivery. Six of them delivered after natural contraction, and the remaining 14 cases delivered after oral intake of mifepristone and amniotic injection of ethacridine, or oxytocin induced labor within 48 hours, only one case delivered after additional dinoprostone suppositories. The appearance of fetus, placentas and membranes were normal, the lengths of umbilical cord were average. Four cases were found with cords binding the necks or the bodies. Eighteen cases had grade Ⅲ amniotic fluid with meconium-stained, and 2 cases complicated by oligohydramnios. Ten cases had their fetuses and placentas examined by pathologist. Among them, one case had multiple malformations, no more obvious pathological abnormalities were found in other fetuses. Pathologic examination showed that fibrin deposited around chorion and deciduas basalis, large vessels accompanied by calcification, degeneration,hemorrhagic infarction, and increased focal syncytial nodules could be seen in all of the ten placentas. Conclusions Fetal death in pregnant women with ICP of ten occurs after the contractions, Severe ICP may be a key factor that involved in the occurrence of fetal death. Up to now, there is no valid indicators in fetal monitoring, which can predict fetal death. Extensive assessment of the severity and careful antepartum surveillance should be achieved before timely termination of pregnancy.     

妊娠期肝内胆汁淤积症胎儿胆汁酸水平与肺表面活性物质的相关性研究

目的 探讨妊娠期肝内胆汁淤积症(ICP)胎儿总胆汁酸水平与胎儿肺表面活性物质(PS)的关系.方法 选择2008年4月至2010年2月在中南大学湘雅二医院住院行剖宫产分娩的ICP孕妇55例(ICP组),记录ICP组孕妇的新生儿出生至产后7 d的一般情况,凡符合胎儿窘迫、新生儿窒息、新生儿呼吸窘迫综合征其中1项者为病理围产儿,无上述情况为正常围产儿.另选同期健康孕妇23例为对照组.采用循环酶法测定两组孕妇血、脐血及羊水中总胆汁酸水平;ELISA法测定两组胎儿脐血肺表面活性蛋白A(SP-A)水平;高效液相色谱法测定两组羊水中磷脂酰胆碱(PC)、磷脂酰肌醇(PI)、溶血卵磷脂(LPC)、神经鞘磷脂(SM)的含量.结果 (1)ICP组孕妇血、脐血及羊水中总胆汁酸水平分别为(30.1±7.9)、(9.3±3.3)及(4.4 ±1.5)mmol/L,明显高于对照组的(4.8±2.2)、(4.9±0.9)及(1.4±1.1)mmol/L,两组分别比较,差异均有统计学意义(P＜0.05).(2)ICP 组胎儿脐血SP-A水平为(29.5±6.4)μg/L,明显高于对照组的(22.6±7.4)μg/L,两组比较,差异均有统计学意义(P＜0.05).(3)ICP组中病理围产儿20例,健康围产儿35例,病理围产儿脐血总胆汁酸及SP-A水平分别为(10.9±2.2)mmol/L及(37.0±5.9)μg/L,健康围产儿分别为(8.0±2.8)mmol/L及(26.7±4.8)μg/L,两者比较,差异有统计学意义(P＜0.05).(4)脐血总胆汁酸水平分别与孕妇血、羊水总胆汁酸水平呈正相关(r1=0.706,r2=0.763,P＜0.05);脐血SP-A水平与脐血总胆汁酸水平呈正相关(r3=0.494,P＜0.05).(5)ICP组羊水中PC及PI的含量分别为(65.4±7.2)及(3.8±0.6)mg/L,均明显低于对照组的(69.7±3.7)及(4.3±0.7)mg/L,两组比较,差异有统计学意义(P＜0.05);ICP组羊水LPC的含量为(4.8±0.9)mg/L,明显高于对照组的(4.2±0.6)mg/L,两组比较,差异有统计学意义(P＜0.05);ICP组羊水SM的含量为(3.5±0.8)mg/L,与对照组的(4.0±0.5)mg/L比较,差异无统计学意义(P＞0.05).(6)ICP组羊水PC/LPC比值(14.2±3.2)明显低于对照组(16.9±2.5),差异有统计学意义(P＜0.05).(7)脐血总胆汁酸水平与羊水PC、PI的含量均呈负相关(r1=-0.561,r2=-0.407,P＜0.05);与LPC含量无相关性(r3=0.260,P＞0.05).结论 ICP孕妇的胎儿脐血及羊水中总胆汁酸水平均明显高于健康孕妇,其胎儿PS的改变与胎儿体内高总胆汁酸水平有关.

Abstract：

Objective To explore the relationship between total bile acid(TBA)concentration and fetal pulmonary surfactant in intrahepatic cholestasis of pregnancy(ICP).Methods Fifry five patients with ICP(ICP group)who received cesarean section from April 2008 to February 2010 in Second Xiangya Hospital,Central South University,were recruited.The general conditions of the neonates within 7 days after birth in ICP group were recorded.Those with fetal distress,neonatal asphyxia,or neonatal respiratory distress syndrome were referred as pathological neonates, others were referred as normal neonates. Over the same period, 23 healthy gravidas were recruited as control group. Enzymatic method was used to detect the TBA concentrations in maternal blood, cord blood and amniotic fluid. ELISA was employed to measure the urfactant protein A (SP-A) concentration in cord blood. High performance liquid chromatography system was used to detect the concentrations of phesphatidylcholine (PC),phosphatidylinositol (PI),lysophosphatidylcholine ( LPC), and sphingomyelin(SM) in amniotic fluid. Results ( 1 ) The concentrations of TBA in maternal blood, cord blood and amniotic fluid were ( 30. 1 ± 7.9 ), (9. 3± 3. 3 ) and (4. 4 ± 1.5 ) mmol/L in ICP group, (4. 8 ± 2. 2), (4. 9 ± 0. 9) and ( 1.4 v 1.1 ) mmol/L in control group, respectively. The differences between the two groups were significant ( P ＜ 0. 05 ). ( 2 ) The SP-A concentration in cord blood in ICP group was ( 29. 5 ± 6. 4 ) μg/L, significantly higher than that in control group, which was ( 22. 6 ± 7. 4 )μg/L ( P＜ 0. 05 ). ( 3 ) There were 20 pathological neonates and 35 normal neonates in ICP group. In pathological neonates, the concentrations of TBA and SP-A in cord blood were (10.9 ± 2.2) mmol/L,(37.0 ± 5.9 ) μg/L, respectively; and were ( 8.0 ± 2. 8 ) mmol/L, ( 26. 7 ± 4. 8 ) μg/L in normal neonates. The differences were significant (P＜ 0. 05 ). (4) There was a positive correlation between TBA concentration in cord blood and in maternal blood ( r1 = 0. 706, P＜0. 05 ). The TBA concentration in cord blood was positively correlated with SP-A concentration as well ( r3 = 0. 494,P ＜ 0. 05 ). (5) The PC and PI concentrations in amniotic fluid were (65.4 ± 7.2) mg/L and ( 3. 8 ± 0. 6 ) mg/L in ICP group, ( 69. 7 ±3.7) mg/L and (4. 3 ± 0. 7 ) mg/L in control group, respectively. The differences were significant (P ＜0. 05 ). The concentration of LPC in amniotic fluid in ICP group was (4. 8 ±0. 9) mg/L, significantly higher than that in control group (P＜0. 05), which was (4. 2 ±0. 6) mg/L. The concentration of SM in amniotic fluid was (3.5±0. 8) mg/L in ICP group, (4. 0 ± 0. 5 ) mg/L in control group, with no significant difference ( P＞0. 05 ). (6) The ratio of PC/LPC in ICP group ( 14. 2± 3. 2 ) was significantly lower than that in control group ( 16. 9 ± 2. 5 ) ( P＜ 0. 05 ). ( 7 ) The TBA concentration in cord blood was negatively correlated with PC and PI concentrations (r1 = -0. 561, r2 = -0. 407, P ＜ 0. 05 ), and had no correlation with LPC concentration (r3 = 0. 260, P＞ 0. 05). Conclusions ( 1 ) The fetal TBA concentrations in both cord blood and amniotic fluid of patients with ICP was higher than those of healthy gravidas, they were also positively correlated with maternal TBA concentration. (2) ICP resulted in the change of fetal pulmonary surfactant and this change was associated with TBA concentrations in both cord blood and amniotic fluid.