未足月胎膜早破发病机制研究进展

未足月胎膜早破（PPROM）是一种常见且棘手的产科并发症,是早产的常见原因,若不能及时处理,会严重威胁母儿生命。在许多低、中等收入国家,PPROM产生的最大影响是早产所导致新生儿死亡。许多因素与PPROM的发生有关,如感染、子宫过度增大、吸烟、遗传相关疾病等,它们所导致胎膜降解和破裂的通路是重叠的。PPROM的发病机制十分复杂,最近的研究表明炎性细胞因子和基质金属蛋白酶（MMPs）的激活、氧化应激和羊膜细胞凋亡是导致PPROM的主要途径。综述PPROM发病机制的研究进展,通过讨论导致胎膜弱化的危险因素以及机制,为降低PPROM发生率提供线索和方法。     

胎膜早破与MMPs、TIMP-2、TNF-α基因多态性相关性研究

目的:探讨胎膜早破患者基质金属蛋白酶(MMPs)、金属蛋白酶类组织抑制剂2(TIMP-2)、肿瘤坏死因子-α(TNF-α)等系列基因的多个单核苷酸多态性(SNP)位点与胎膜早破的相关性。方法:选择早产胎膜早破患者47例(PPROM组),足月胎膜早破67例(PROM组),足月自然临产120例(正常足月产组)作为研究对象。抽取各组孕妇外周血提取DNA。以PCR方法扩增带有目的 SNP的基因片段,对产物进行测序。结果:MMP-1(rs1799750),MMP-2(rS2285053),MMP-3(rs617819,rs35068180),MMP-7(rs11568818),MMP-8(rs11225395),TIMP-2(rs2277698)各基因型在PPROM组,PROM组,正常足月产组中的分布差异显著,具有统计学意义。结论:TIMP-2、MMPs等基因的SNP类型与胎膜早破有一定的相关性。     

细胞间黏附分子-1在早产胎膜早破中的表达及临床意义

目的:研究细胞间黏附分子-1(ICAM-1)在早产胎膜早破中的表达及临床意义.方法:选取38例早产胎膜早破(PPROM)孕妇为研究组(PPROM组),36例与PPROM组孕周相对应之胎膜完整的自发早产(PTL)孕妇为对照组(PTL组),应用sP法检测各组胎膜ICAM-1的表达,并进行临床病理的相关性分析.结果:PPROM组中有55.26%(21/38)存在绒毛膜羊膜炎,PIL组中为36.11%(13/36),两组比较差异有统计学意义(P<0.05);两组胎膜中均存在不同程度的ICAM-1阳性表达,两组比较差异有统计学意义(P<0.05),PPROM组和PTL组ICAM-1的阳性表达与绒毛膜羊膜炎的相关系数分别为0.90和0.72,且病理结果中炎症越重的患者其胎膜上ICAM-1的阳性表达越明显.结论:ICAM-1的表达与感染相关,异常表达在早产胎膜早破的发病过程中起一定作用.感染越重的患者,ICAM-1的表达越明显,提示妊娠结局的严重化.     

细胞应激和危险相关分子模式在未足月胎膜早破的研究进展

未足月胎膜早破(PPROM)易导致母儿感染,诱发自发性早产。 PPROM 发生机制尚不明确, 胎膜细胞的无菌性或细菌性炎症反应导致局部胎膜薄弱、发生破裂是其组织病理学特征。 胎膜细胞应 激引起机体产生具有免疫调节作用的危险相关分子模式(DAMPs),引起炎症免疫应答,在 PPROM 中发 挥重要作用。 在感染、细胞拉伸等作用下,高迁移率族蛋白 B1(HMGB1)、热休克蛋白 70(HSP70)、S100 蛋白、细胞外基质(ECM)分解产物等 DAMPs 分子,激发免疫反应、弱化胎膜结构。 本文对近年来细胞 应激和 DAMPs 在 PPROM 的发生机制进行综述,为 PPROM 的研究提供新思路。     

人胎膜组织中E26转录因子1的表达及其与胎膜早破的关系

目的 检测人胎膜组织中E26转录因子1(Ets-1)的表达及定位,探讨其与胎膜早破发生的关系.方法 选择2007年2-11月在重庆医科大学附属第一医院住院分娩的产妇100例为研究对象,按足月与否、有无胎膜早破、分娩方式将其分为早产临产、未足月胎膜早破(PPROM)、足月临产、足月胎膜早破(TPROM)组,以足月择期刮宫产产妇为对照组,每组各20例,分娩后采集其胎膜组织,用免疫组化链霉菌抗生物素蛋白-过氧化物酶连接(SP)法检测Ets-1蛋白的表达水平及定位,每组选取6例以逆转录(RT)-PCR技术检测Ets-1 mRNA的表达水平,并进行半定量分析.结果 (1)各组胎膜组织中Ets-1 mRNA的表达:早产临产、PPROM、足月临产、TPROM、对照组胎膜组织中Ets-1mRNA表达水平分别为0.342±0.016、0.603±0.027、0.325±0.013、0.582±0.075、0.139±0.012,PPROM组和TPROM组均高于对照组.分别比较,差异均有统计学意义(P<0.05);早产临产组与足月临产组,PPROM组与TPROM组比较,差异均无统计学意义(P>0.05).(2)Ets-1蛋白在胎膜组织的定位:Ets-1蛋白集中在羊膜和绒毛膜的间质层、滋养层细胞的胞质和胞核中表达;细胞内可见清晰的棕黄色颗粒.在羊膜上皮细胞中未见Ets-1蛋白表达.(3)各组胎膜组织中Ets-1蛋白的表达:早产临产、PPROM、足月临产、TPROM、对照组胎膜组织中Ets-1蛋白表达水平分别为0.552±0.018、2.853±0.174、0.538±0.042、2.731±0.090、0.214±0.013,PPROM组与TPROM组均高于对照组,分别比较,差异均有统计学意义(P<0.05);但早产临产组与足月临产组,PPROM组与TPROM组胎膜组织分别比较,差异均无统计学意义(P>0.05).结论 Ets-1在人类胎膜组织中有表达,且在胎膜早破时表达水平升高.     

基质金属蛋白酶与早产的关系

由于早产机制未完全阐明,故早产发生率及早产儿发病率和死亡率一直无明显下降,感染和胎膜早破是早产的主要原因,近来研究认为感染和胎膜早破引起的早产和妊娠妇女体内基质金属蛋白酶(MMPs)的含量变化有关,这两种情况引起的早产发生前,母体血、尿及羊水中的MMPs含量将升高,从而降解妊娠组织的细胞外基质(ECM),引起胎膜破裂及宫颈成熟扩张,而导致早产,且测定妊娠妇女体内MMPs的含量变化可进行早产预测以及应用其抑制剂在动物实验中可降低早产的发生率.     

未足月胎膜早破的处理

<正>未足月胎膜早破(preterm premature rupture of the membranes,PPROM)是指妊娠未满37周胎膜在临产前发生破裂。单胎妊娠PPROM的发生率为2%～4%,双胎妊娠为7%～20%[1]。PPROM导致的早产占早产的1/3,同时可能并发绒毛膜羊膜炎、     

早产与胎膜早破

早产胎膜早破 (preterm prem ature rupture of mem-branes,PPROM)是指发生在妊娠 2 0～ 37周内的胎膜破裂且最终为早产者。据文献报道〔1 ,2〕,PPROM约占妊娠总数的 2 %～ 3% ,约占整个早产的 1/ 3。其中 70 %～ 80 %的孕妇在一周内分娩。与胎膜完整的妊娠相比 ,PPROM的围产儿死亡比、新生儿发病率及母亲感染率较高 ,围产儿死亡数占整个围产儿死亡数的 2 0 %左右 ,其围产儿死亡比的高低与 PPROM的分娩孕周及其处理有关。因此 ,早产合并胎膜早破应引起产科工作者的高度重视。1　病因与发病机理1.1　感染 :目前多数学者认为 ,下生殖…     

松弛素与早产胎膜早破的相关性研究

目的探讨松弛素(relaxin,RLN)与早产胎膜早破(preterm prematu rerupture of membranes,PPROM)的相关性。方法 ELISA法分别检测25例PPROM、32例足月胎膜早破(TPROM)及31例正常足月分娩孕妇分娩前血清RLN2水平;免疫组化SP法检测以上三组孕产妇胎盘和胎膜组织中松弛素受体LGR7蛋白的表达。结果①三组血清RLN2水平比较,PPROM组(372.26±143.13)pg/ml显著高于TPROM组(292.73±96.01)pg/ml及对照组(241.71±91.57)pg/ml(P<0.05);②三组孕妇的胎盘、胎膜组织中均有LGR7蛋白的表达,PPROM组胎盘、胎膜组织中松弛素受体LGR7蛋白强阳性表达率(96.00%)高于另两组,TPROM组(75.00%)高于正常组(58.06%);③胎盘、胎膜组织中松弛素受体LGR7蛋白表达水平与血清RLN2水平呈正相关关系(rs=0.453,P=0.0001)。结论孕晚期血清RLN2水平及胎盘、胎膜组织中松弛素受体LGR7蛋白表达水平的增高可能与PPROM的发病有关。     

《2022年加拿大妇产科医师协会“未足月胎膜早破的诊断与管理”指南》解读

<正>未足月胎膜早破(preterm prelabour rupture of membranes, PPROM)的定义为临产前胎膜自发破裂,且发生于妊娠37周前。PPROM的发生率约为3%,在所有早产的病因中约占三分之一。在加拿大,早产的发生率为8%,在过去10年中增长了近25%。尽管PPROM后早产的发生率较高,但PPROM的最佳管理仍是一个有争议的话题,这受限于证据不足。     

Role of cytokines in preterm labour and brain injury

Intrauterine infection induces an intra-amniotic inflammatory response involving the activation of a number of cytokines and chemokines which, in turn, may trigger preterm contractions, cervical ripening and rupture of the membranes. Infection and cytokine-mediated inflammation appear to play a prominent role in preterm birth at early gestations (<30 weeks). The role of infection/inflammation in preterm birth in Europe has been incompletely characterised. The rate of preterm birth in Sweden is lower, and the rate of chorioamnionitis, bacterial vaginosis (BV), neonatal sepsis, and urinary tract infections during pregnancy is lower compared with the USA. In a Swedish population of women with preterm labour or preterm premature rupture of the membranes (PPROM) <34 weeks of gestation, microorganisms were detected in the amniotic fluid in 25% of women with PPROM and in 16% of those in preterm labour. Nearly half of these women had intra-amniotic inflammation defined as elevated interleukin-6 (IL-6) and IL-8, and there was a high degree of correlation between cytokine levels and preterm birth or the presence of microbial colonisation. These data do not support the hypothesis that infection-related preterm birth is less frequent in northern Europe than elsewhere. The intra-amniotic inflammatory response has also been associated with white matter injury and cerebral palsy. We find that in experimental models, induction of a systemic inflammatory response using lipopolysaccharide activates toll-like receptors (TLRs), which produce either white matter lesions or increase brain susceptibility to secondary insults. Recently, IL-18 in umbilical blood was shown to correlate with brain injury in preterm infants and IL-18 deficiency in mice decreases CNS vulnerability.     

Matrix metalloproteinases and their tissue inhibitors in preterm perinatal complications

The objective of this article is to review the role of matrix metalloproteinases (MMPs) in fetomaternal/neonatal complications of preterm birth. The function of MMPs as proteolytic enzymes involved in tissue remodeling/destruction is reviewed in preterm labor, preeclampsia, premature rupture of membranes, intrauterine growth restriction, chronic lung disease, necrotizing enterocolitis, intraventricular hemorrhage, cystic periventricular leukomalacia, and retinopathy of prematurity. Cytokines, steroid hormones, and reactive oxygen species all regulate MMP labor and expression/activity. In labor, activation follows an inflammatory response, which results in fetal membrane rupture and cervical dilation/ripening, particularly when premature. Expression/activation is elevated during parturition, particularly when premature. While fetal membrane rupture is preceded by increases in tissue-specific MMPs, neonatal complications also ensue from an imbalance between MMPs and their tissue inhibitors. These e fects implicate environmental triggers and a genetic predisposition. MMPs are involved in the perinatal complications of prematurity and are potential targets for therapeutic intervention. Functional MMP genetic polymorphisms may assist in identifying patients at risk of complications.     

Classification and heterogeneity of preterm birth

Three main conditions explain preterm birth: medically indicated (iatrogenic) preterm birth (25%; 18.7–35.2%), preterm premature rupture of membranes (PPROM) (25%; 7.1–51.2%) and spontaneous (idiopathic) preterm birth (50%; 23.2–64.1%). The majority of multiple pregnancies (10% of all preterm births) are delivered preterm (50% for medical reasons). Although medical indications relate more to feto-maternal conditions, PPROM to infections and idiopathic preterm birth to lifestyle, these risk factors are identified in any category, emphasising that preterm birth has a multifactorial origin. Still, several incidences of preterm birth are not completely explained with a plausible cause for PPROM or spontaneous preterm labour suggesting that other causes have yet to be identified. In addition, preterm birth is associated with unrecognised severe congenital anomalies. Variability within the main categories may be explained by the studied population, ethnic group, social class and preventive interventions towards reducing spontaneous preterm birth where the proportion of medically-indicated preterm birth is increased. Despite being retrospective a classification according to gestational age at birth is important for neonatal prognosis. Preterm birth is stratified into mild preterm (32–36 weeks), very preterm (28–31 weeks) and extremely preterm (<28 weeks) with increasing neonatal mortality and morbidity. Recent studies suggested that infection was mostly responsible for extreme preterm birth, while stress and lifestyle accounted for mild preterm birth, and a mixture of both conditions contributed to very preterm birth.     

Plasma levels of thrombin-antithrombin complexes predict preterm premature rupture of the fetal membranes.

OBJECTIVE: Decidual hemorrhage (abruption) is strongly associated with preterm premature rupture of fetal membranes (PPROM). Moreover, thrombin enhances decidual matrix metalloproteinase (MMP) expression, and MMP has been strongly linked to PPROM. The current study sought to determine whether increased thrombin activation, as assessed by circulating maternal plasma thrombin-antithrombin (TAT) complexes, predicted subsequent PPROM. STUDY DESIGN: We conducted a nested, case-control study of plasma TAT levels, measured by sensitive immunoassay, among 27 women with a singleton preterm birth preceded by PPROM and 54 matched, term controls. Receiver operating characteristic curve analysis was performed to identify the optimal TAT cut-off level predicting PPROM. RESULTS: Mean gestational age at delivery in cases was 33.3 weeks, compared to 39.7 weeks in controls (p < 0.001). Compared with controls, women with PPROM had increased median plasma TAT levels in both the second trimester (5.1 microg/l (range 2.2-26.3 microg/l) vs. 3.2 microg/l (range 1.3-7.3 microg/l); p = 0.001) and third trimester (7.0 microg/l (range 2.6-85.8 microg/dl) vs. 4.8 microg/l (range 1.7-15.4 microg/dl); p = 0.01). In the PPROM group, 16.0% of the women exhibited bleeding during the pregnancy, while the corresponding value among controls was 3.6% (p = 0.07). In the second trimester, the odds ratio for PPROM with a TAT level of > 3.9 microg/l was 6.0 (95% CI 1.67-21.1). This value predicted PPROM with a sensitivity of 88%, specificity of 68% and positive and negative predictive values of 82% and 97%, respectively. CONCLUSION: Second-trimester elevated plasma TAT concentrations are predictive of subsequent PPROM. These data provide further evidence that PPROM is associated with decidual thrombin activation.     

Maternal serum concentrations of s-Endoglin and IL-6 in pregnancy complicated by preterm premature membrane rupture

Objective: This study aimed to investigate maternal serum concentrations of s-Endoglin and compare s-Endoglin with other inflammatory markers in prediction of time to delivery, in pregnancies complicated by preterm premature rupture of membranes (PPROM).

Materials and methods: Fifty five patients complicated by PPROM whose gestational age were between 2433 weeks and 44 matched healthy pregnant women were included in present study. Maternal concentrations of s-Endoglin concentrations were measured by an enzyme-linked immunosorbent assay (ELISA) and compared with maternal inflammatory markers including interleukin-6 (IL-6), white blood cell (WBC) count and serum C-reactive protein (CRP). The best variable for prediction of preterm birth was computed.

Results: Mean s-Endoglin levels in PPROM were lower than control groups (0.24?±?0.12?pg/ml and 0.69?±?0.25?pg/ml, respectively, p?<?0.01). Besides IL-6 (p?<?0.01), WBC (p?=?0.016) and CRP (p?=?0.010) levels were higher in PPROM group. In PPROM group, ROC analysis results of s-Endoglin for prediction of preterm delivery <48 h, <7 days, <32 weeks were not different (p?>?0.05). For predicting preterm birth before 48 h and 7 days, only IL-6 at cut off value >0.70 (pg/ml) and >0.55 (pg/ml) had area under curve (AUC); 0.871 (0.7750.965), p?<?0.01, AUC; 0.925 (0.8560.993), p?<?0.001, respectively.

Conclusion: s-Endoglin as an anti-angiogenic marker seemed to have a role in pathogenesis but results of present study showed that, unlike IL-6, it was unsatisfactory for estimating time to delivery in PPROM.     

Interleukin-6 in preterm premature rupture of membranes as an indicator of neonatal outcome

BACKGROUND: The aim of this study was to investigate whether the levels of interleukin-6 (IL-6) can be used as markers of adverse outcome in preterm neonates born after preterm premature rupture of membranes (PPROM). METHODS: This study involved 109 preterm neonates and their mothers. The PPROM group consisted of 58 neonates who were born after PPROM, and the control group consisted of 51 neonates. IL-6 levels were measured in umbilical cord blood, maternal blood sampled during delivery and in neonatal blood taken on the fourth day of life. RESULTS: In the PPROM group, IL-6 concentrations in maternal blood, cord blood, and neonatal blood were significantly higher in neonates with sepsis, compared with those without sepsis (P < 0.001). Choosing 108.5 pg/ml as a cut-off concentration of IL-6 in umbilical cord blood for neonatal sepsis resulted in sensitivity 95%, specificity 100%, positive predictive value 100%, and negative predictive value 97.4%. Concerning IL-6 in maternal blood, a cut-off concentration of 81 pg/ml showed sensitivity 90%, specificity 97.4%, positive predictive value 94.7%, and negative predictive value 94.9%. Eighteen of 20 neonates with early sepsis and seven of nine neonates, who died in the PPROM group, were born of mothers with IL-6 levels above the cut-off concentration in their blood during delivery. CONCLUSIONS: IL-6 in umbilical cord blood was the most significant variable for predicting early onset sepsis in preterm neonates. IL-6 in maternal blood was indicative of intrauterine environmental threats and might be used to identify pregnancies where intervention would be appropriate.     

Role of matrix metalloproteinases in preterm labour

Extracellular matrix homeostasis is a key process in the maintenance of the tensile strength of the amniochorion. This tensile strength guarantees the role of the membranes as a physical and functional boundary for the fetus during human pregnancy. Pathological rupture of these structures before 37 completed weeks of gestation is known as preterm prelabour rupture of the membranes (PPROM) and it is a major cause of spontaneous preterm labour and preterm birth. A mechanism involving the activation of matrix metalloproteinases (MMP)-9, a 92-kDa type IV collagenase, as an essential mediator of tissue damage is under investigation. The proposed mechanism involves the abnormal expression and activity of MMP-9 with subsequent connective tissue degradation taking place at a time that does not synchronise with other events of labour. The local physiological signal by amniochorion cells to induce MMP-9 expression is not known, but bacterial products and/or the proinflammatory cytokines, IL-1β and TNF-α, as paracrine or autocrine signals may trigger these processes in pregnancies complicated with intra-amniotic infection. These signalling pathways indicate complex cooperative and bidirectional communications between amnion and choriodecidua in response to bacterial products, which include intermembranous cytokine traffic and signalling between tissues. Products secreted in culture by amniochorion and choriodecidual leucocytes, obtained from women who delivered following normal labour in the absence of infection, condition a specific microenvironment that induces collagen degradation in fetal membranes. Further characterisation of the role of choriodecidual leucocytes in the control of extracellular matrix degradation in amniochorion is currently under way.     

Relaxin Stimulates Interleukin-6 and Interleukin-8 Secretion from the Extraplacental Chorionic Cytotrophoblast

In the absence of infection, decidual relaxin (RLN) expression is increased in patients with preterm premature rupture of the membranes (PPROM) resulting in preterm birth, but it is not known whether inflammation stimulates RLN expression or vice versa. This study examined the effect of lipopolysaccharide (LPS) on the expression of RLN mRNA and secreted protein and whether RLN treatment influences secretion of proinflammatory cytokines from the fetal membranes. Explants of human fetal membranes in vitro and rhesus monkey fetal membranes in vivo were treated with LPS, which increased expression of IL-6 but had no effect on RLN. RLN treatment stimulated IL-6 and IL-8 secretion from choriodecidual explants in a subset of patients, as well as from isolated chorionic cytotrophoblast cells but not decidual cells. In vivo results obtained in rhesus monkeys after intra-amniotic infusion of RLN demonstrated increased IL-6 and IL-8 concentrations in amniotic fluid. Our results indicate that increased decidual RLN expression is independent of LPS but may induce a local sterile inflammatory process which potentially contributes to extracellular matrix degradation and weakening of the fetal membranes.     

孕产妇血清中MMP-3、TNF-α、IL-10的表达与早产和早产胎膜早破的关系

目的探讨基质金属蛋白酶-3（MMP-3）、肿瘤坏死因子-α（TNF-α）、白细胞介素-10（lL-10）在孕产妇血清中的表达与早产、胎膜早破的关系。方法选择单胎头位初产妇80例作为研究对象,按孕周、胎膜是否破裂和产妇是否临产分为早产临产组（sPTD）、早产胎膜早破组（PPROM）、先兆早产组（TPL）和妊娠28～36＋6周无产兆组（对照组）,每组各20例。用ELISA法检测孕妇血清中MMP-3及TNF-α、lL-10的水平。结果①早产临产组、早产胎膜早破组、先兆早产组和对照组血清中MMP-3的浓度分别为（242.25±72.40）ng/ml、（225.95±85.43）ng/ml、（197.85±57.08）ng/ml、（186.80±54.33）ng/ml;TNF-α的浓度分别为（1332.35±346.65）pg/ml、（1365.00±211.80）pg/ml、（1188.15±269.43）pg/ml、（1061.85±210.02）pg/ml;IL-10的浓度分别为（563.65±116.50）pg/ml、（566.80±123.03）pg/ml、（521.00±105.14）pg/ml、（483.50±119.17）pg/ml;②早产组血清中MMP-3,TNF-α浓度高于对照组,以TNF-α升高更明显（P〈0.01）;而IL-10在前两组中有增高趋势,但与后两组相比差异无统计学意义（P〉0.05）;③血清中MMP-3、TNF-α、IL-10浓度呈两两正相关。结论①孕产妇血清中MMP-3及TNF-α浓度与早产、胎膜早破密切相关;②孕产妇血清中MMP-3、TNF-α及IL-10在临产、胎膜早破中可能起协同作用。