Interleukin-6 as a predictor of subclinical chorioamnionitis in preterm premature rupture of membranes

Citation Gulati S, Bhatnagar S, Raghunandan C, Bhattacharjee J. Interleukin‐6 as a predictor of subclinical chorioamnionitis in preterm premature rupture of membranes. Am J Reprod Immunol 2012; 67: 235–240 Problem One of the major challenges faced by the clinicians in preterm premature rupture of the membranes (PPROM) is to correctly identify when a significant chorioamnionitis is evolving and decide timely delivery of the fetus. Measuring interleukin‐6 levels in maternal serum can be useful for the identification of asymptomatic intrauterine infections in subjects with PPROM. Method of study A total of 75 pregnant women, of which 45 pregnant women presenting with PPROM between 24 and 34 weeks gestation and 30 healthy pregnant women without PPROM, were included in the study. Serum IL‐6 levels were determined by solid‐phase sandwich enzyme‐linked immunosorbent assay (Diaclone Research, Besancon, France). Results The mean serum IL‐6 value at admission in the control group was 2.48 ± 2.7 pg/mL and in the study group was 11.86 ± 14.5 pg/mL (P = 0.001). Mean serum IL‐6 concentrations at admission in subjects without histological chorioamnionitis were 3.98 ± 3.9 pg/mL and in those who had histological chorioamnionitis were 20.09 ± 16.8 pg/ml (P < 0.001). Conclusion Maternal serum IL‐6 levels were significantly elevated in subjects with PPROM with infectious morbidity as compared to those without infectious morbidity in the present study. There was a significant rise in maternal serum IL‐6 levels with increased duration of rupture of membranes and with evidence of histological chorioamnionitis and funisitis in the placenta.     

Matrix metalloproteinases in preterm prelabor rupture of membranes in the setting of chorioamnionitis: A scoping review

Fetal or gestational membranes extend from the placenta to enclose the fetus and amniotic fluid. While the membranes spontaneously rupture at term in normal pregnancies, they can rupture prematurely before the onset of labor, termed preterm prelabor rupture of membranes (PPROM). PPROM can be triggered by bacterial infection or sterile inflammation in the membranes, known as chorioamnionitis (CAM). The membranes derive their tensile strength from a collagen-rich extracellular matrix (ECM); as such, understanding the enzymes and processes that can degrade the membrane ECM are of paramount importance. Matrix metalloproteinases (MMPs) are a class of enzymes capable of degrading collagen and other components of the ECM, and can be induced by inflammation. We used a scoping review to address the question of how MMP activity is associated with PPROM, particularly their induction due to sterile or nonsterile CAM. We have found that the most studied MMPs in PPROM were MMPs 2, 8, and 9. Additionally, some MMPs are constitutively active, while others are induced by inflammation. Mechanistic studies of the pathways that induce MMP activation are sparse, and this area is ripe for future studies. Targeting MMP activation could be a future strategy to delay or prevent PPROM.     

Preterm labor and preterm premature rupture of membranes have a different pattern in the involved compartments of acute histologoic chorioamnionitis and/or funisitis: Patho‐physiologic implication related to different clinical manifestations

It is unknown whether histo‐topographic findings about the involved compartments (i.e., choriodecidua, amnion, chorionic‐plate) of acute‐histologic chorioamnionitis (acute‐HCA) and/or funisitis according to the presence or absence of intra‐amniotic inflammation (IAI) and/or fetal inflammatory response syndrome (FIRS) are different between preterm labor and intact membranes (PTL) and preterm premature rupture of membranes (preterm‐PROM). The involved compartments of acute‐HCA and/or funisitis were examined in 161 singleton preterm‐births (<34 weeks) due to PTL (n = 88) and preterm‐PROM (n = 73). The study‐population was divided into IAI(?)/FIRS(?), IAI(+)/FIRS(?), and IAI(+)/FIRS(+) groups according to the presence or absence of IAI (amniotic‐fluid MMP‐8 ≥ 23 ng/ml) and/or FIRS (umbilical‐cord plasma CRP ≥ 200 ng/ml). Histological inflammation was not detected in any‐compartment except choriodecidua in IAI(?)/FIRS(?) group with PTL while inflammation appeared in all‐compartment0s (choriodeciduitis‐46.2 %; amnionitis‐23.1 %; funisitis‐30.8 %; chorionic‐plate inflammation‐7.7 %) in IAI(?)/FIRS(?) group with preterm‐PROM. IAI(+)/FIRS(?) group had a significantly higher frequency of inflammation in each‐compartment than IAI(?)/FIRS(?) group in PTL (each‐for P < 0.01), but not preterm‐PROM (each‐for P > 0.1). However, IAI(+)/FIRS(+) group had a significantly higher rate of inflammation in each compartment than IAI(+)/FIRS(?) group in both PTL and preterm‐PROM (each‐for P < 0.05). We first demonstrated that PTL and preterm‐PROM had a different pattern in the involved compartments of acute‐HCA and/or funisitis in the IAI(?)/FIRS(?‐) group and in the change of involved compartments from IAI(?)/FIRS(?) to IAI(+)/FIRS(?)     

Macrophage inhibitory cytokine 1 in fetal membranes and amniotic fluid from pregnancies with and without preterm labour and premature rupture of membranes

The placenta and fetal membranes are the site of expression of macrophage inhibitory cytokine (MIC-1), a member of the transforming growth factor (TGF)-beta superfamily. We hypothesized that MIC-1 may act as an immune regulator in pregnancy complications associated with intrauterine inflammation. Decidual cells, chorionic trophoblasts and amnion epithelial cells were identified by immunohistochemistry as the predominant MIC-1-containing cell type in term membranes. Amnion and choriodecidual explants all produced MIC-1 in culture, the latter having the greatest production rate (206 +/- 74.5 pg/mg tissue/24 h, n=6; mean +/- SEM). Production was not responsive to stimulation by pro-inflammatory cytokines. MIC-1 was detectable in 217 transabdominal amniotic fluid (AF) samples taken from 15 to 41 weeks gestation, concentrations ranging from 0.9-51.1 ng/ml. AF MIC-1 concentrations in pregnancies with premature rupture of membranes (PROM) or preterm labour, either with or without microbial invasion of the amniotic cavity, were not significantly different from those delivered at term either with or without labour. Treatment with MIC-1 (0.25-25 ng/ml) did not alter production of interleukin-6 or -8 by amnion or choriodecidual cells in vitro. We conclude that AF MIC-1 is derived from the fetal membranes and decidua, but that MIC-1 is unlikely to be involved in the pathophysiology of preterm birth or PROM.     

Maternal plasma homocysteine levels in women with preterm premature rupture of membranes

Homocysteine is a sulfur-containing amino acid produced by the breakdown of methionine. Plasma homocysteine levels can be elevated due to a variety of genetic and nutritional factors. Poor nutrition from diets low in folate and vitamin B12 can lead to hyperhomocysteinemia. Mildly elevated levels of homocysteine have been implicated in a number of disease processes such as atherosclerotic vascular disease and adverse obstetrical outcomes. High levels of plasma homocysteine are also associated with abnormal collagen cross-linking. Due to homocysteine's effects on connective tissue integrity, it is hypothesized that hyperhomocysteinemia in pregnancy is associated with preterm premature rupture of membranes (PPROM). Hyperhomocysteinemia, therefore, could be a treatable cause of this important public health concern.     

Non-Invasive Prediction of Histologic Chorioamnionitis in Women with Preterm Premature Rupture of Membranes

PurposeTo develop a model based on non-invasive clinical and ultrasonographic parameters for predicting the likelihood of subsequent histologic chorioamnionitis in women with preterm premature rupture of membranes (PPROM) and to determine whether the inclusion of invasive test results improves the predictive value of the model.ResultsRisk scores based on serum CRP concentrations and gestational age (model 1) were calculated for each patient. The model was shown to have adequate goodness of fit and an area under the receiver operating characteristic curve (AUC) of 0.742. When including AF test results (e.g., AF IL-6 levels) in model 1, serum CRP concentrations were found to be insignificant, and thus, were excluded from model 2, comprising AF IL-6 levels and gestational age. No significant difference in AUC was found between models 1 and 2.ConclusionFor women with PPROM, the newly developed model incorporating non-invasive parameters (serum CRP and gestational age) was moderately predictive of histologic chorioamnionitis. The inclusion of invasive test results added no predictive information to the model in this setting.     

探讨影响早产胎膜早破母儿预后的危险因素

目的探讨胎膜早破对早产母儿的影响,以及影响早产儿预后的危险因素。方法对141例除外其它合并症、并发症的早产母儿临床资料进行回顾性分析(85例合并胎膜早破,56例无胎膜早破)。结果(1)78.82%早产胎膜早破发生在孕35w以后。(2)早产胎膜早破组与早产无胎膜早破组相比,母儿并发症无显著差异。(3)早产儿有并发症组、死亡组的新生儿窒息率均明显高于早产儿无并发症组及存活组,且新生儿出生体重、分娩孕周均明显降低。结论早产胎膜早破多发生在孕35w以后,对其进行合理治疗后胎膜早破并不是影响早产母儿预后的主要因素,早产儿并发症、死亡主要与新生儿窒息、出生体重、分娩孕周密切相关。     

母血IL-2在胎膜早破中的变化

目的探讨胎膜早破时母血中Th1因子IL-2水平的变化趋势及意义。方法酶联免疫吸附方法检测20例胎膜早破（PROM）其中8例合并重度妊娠高血压疾病、12例无合并症者,20例正常孕妇组并比较两组孕妇血清IL-2含量。结果PROM组IL-2在母血中含量高于对照组（P〈0.05）。PROM无合并症组低于合并妊娠高血压疾病组（P〈0.05）。结论PROM中孕妇血清中IL-2含量升高。     

Modulation of amniotic fluid activin-a and inhibin-a in women with preterm premature rupture of the membranes and infection-induced preterm birth

Citation Rosenberg VA, Buhimschi IA, Dulay AT, Abdel‐Razeq SS, Oliver EA, Duzyj CM, Lipkind H, Pettker CM, Buhimschi CS. Modulation of amniotic fluid activin‐A and inhibin‐A in women with preterm premature rupture of the membranes and infection‐induced preterm birth. Am J Reprod Immunol 2012; 67: 122–131 Problem Activins and inhibins are important modulators of inflammatory processes. We explored activation of amniotic fluid (AF) activin‐A and inhibin‐A system in women with intra‐amniotic infection and preterm premature rupture of the membranes (PPROM). Method of study We analyzed 78 AF samples: ‘2nd trimester‐control’ (n = 12), ‘3rd trimester‐control’ (n = 14), preterm labor with intact membranes [positive‐AF‐cultures (n = 13), negative‐AF‐cultures (n = 13)], and PPROM [positive‐AF‐cultures (n = 13), negative‐AF‐cultures (n = 13)]. Activin‐A levels were evaluated ex‐vivo following incubation of amniochorion and placental villous explants with Gram‐negative lipopolysaccharide (LPS) or Gram‐positive (Pam3Cys) bacterial mimics. Ability of recombinant activin‐A and inhibin‐A to modulate inflammatory reactions in fetal membranes was explored through explants’ IL‐8 release. Results Activin‐A and inhibin‐A were present in human AF and were gestational age‐regulated. Activin‐A was significantly upregulated by infection. Lower inhibin‐A levels were seen in PPROM. LPS elicited release of activin‐A from amniochorion, but not from villous explants. Recombinant activin‐A stimulated IL‐8 release from amniochorion, an effect that was not reversed by inhibin‐A. Conclusion Human AF activin‐A and inhibin‐A are involved in biological processes linked to intra‐amniotic infection/inflammation‐induced preterm birth.     

Cluster analysis of placental inflammatory proteins can distinguish preeclampsia from preterm labor and premature membrane rupture in singleton deliveries less than 28 weeks of gestation

Citation Faupel‐Badger JM, Fichorova RN, Allred EN, Hecht JL, Dammann O, Leviton A, McElrath TF. Cluster analysis of placental inflammatory proteins can distinguish preeclampsia from preterm labor and premature membrane rupture in singleton deliveries less than 28 weeks of gestation. Am J Reprod Immunol 2011; 66: 488–494 Problem Inflammation within the preterm placenta is common and leads to adverse outcomes for premature infants. The risks of complications are different between iatrogenic (e.g. PE) and spontaneous (e.g. PL and membrane rupture) causes of preterm delivery, suggesting different underlying biology contributes to these placental conditions. Method of study Thirty preterm singleton placentas from the following groups were analyzed: (i) severe PE, (ii) preterm premature membrane rupture (pPROM), and (iii) PL. Proinflammatory and anti‐inflammatory cytokines, adhesion and angiogenic molecules were measured in placental lysates using a multiplex assay. K‐means cluster analysis was used to generate patterns of protein level intensity. Results Three cluster patterns were apparent. Placentas from PE had high levels of vascular endothelial growth factor (VEGF) combined with low levels of acute inflammatory proteins (IL‐1β, IL‐18, IL‐6, TNF‐α), low IL‐1 RA, and high transforming growth factor β (TGF‐β). PL and pPROM had higher anti‐inflammatory IL‐1 RA and thrombomodulin combined with lower VEGF, regardless of proinflammatory cytokines and adhesion molecules. Half of the PL and pPROM cases had clusters of heightened inflammatory responses (lower TGF‐β clustered with higher intensity of inflammatory mediators). Conclusion Discriminating protein patterns were elucidated and may serve as a foundation from which to understand the biologic mechanisms underlying these pregnancy complications.     

解脲支原体感染在胎膜早破中的作用

目的探讨解脲支原体感染与胎膜早破的关系.方法采用培养法分别对52例胎膜早破和30例正常妊娠妇女的宫颈分泌物、胎膜组织进行UU检测,并对两组胎盘胎膜组织进行常规病理检查.结果观察组宫颈分泌物和胎膜组织中,UU检出率明显高于对照组,两组比较,差异有显著性(P＜0.05,P＜0.005).观察组胎盘绒毛膜羊膜炎明显高于对照组,差异有显著性(P＜0.005).结论UU感染与胎盘绒毛膜羊膜炎和胎膜早破有关.     

The role of CD4+CD25bright regulatory T cells in the maintenance of pregnancy, premature rupture of membranes, and labor

PURPOSE: The aim of this study was to evaluate the changes of the regulatory T cell subset in peripheral blood caused by gestational age and premature rupture of membranes (PROM) with or without labor to verify the role of regulatory T cells in pregnancy. PATIENTS AND METHODS: We investigated regulatory T cell distribution in the peripheral blood of pregnancies during the first trimester (group I, n=2), the second trimester (group II, n=12), and the third trimester without PROM and labor (group III, n=15). In addition, we evaluated pregnancies in the third trimester complicated by PROM (group IV, n=4) and labor with no complication by PROM (Group V, n=5). Comparisons were made with non-pregnant controls (group VI, n=4) using flow cytometry. RESULTS: During uncomplicated pregnancy, the CD4(+)CD25(bright) regulatory T cell population decreased with advancing gestational age (group I=3.35+/-0.47, group II=2.91+/-1.44, group III=2.81+/-1.36, group VI=2.52+/-0.71, p=NS). When we compared group IV with group III and V to evaluate the changes of the regulatory T cells with PROM, the CD4(+)CD25(bright) regulatory T cell population was significantly decreased in group IV compared to group III (p=0.001) and group V (p=0.026). CONCLUSION: The present results revealed that the regulatory T cell population increased in early pregnancy but decreased in pregnancies complicated by PROM, indicating that regulatory T cells might be related to the maintenance of pregnancy.     

MMP-9和iNOS在胎膜早破胎膜组织中的表达及相关性研究

目的: 探讨基质金属蛋白酶-9(MMP-9)和诱导型一氧化氮合酶(iNOS)在胎膜早破胎膜组织中的表达及相关性。 方法: 选择2010年4月-2011年1月我院在临产前行剖宫产终止妊娠的孕妇60例,分为早产胎膜早破组(pPROM)、足月胎膜早破组(tPROM)和正常足月妊娠组(对照组),每组各20例,采用免疫组织化学方法检测胎膜中MMP-9和iNOS的 表达,分析其差异性及相关性;同时取静脉血及羊水,应用ELISA法进行MMP-9 定量检测;采用HE染色检测胎膜,分析MMP-9、iNOS与绒毛膜羊膜炎的关系。结果: MMP-9在tPROM组和pPROM组胎膜组织、母血及羊水中的表达水平均高于对照组(P<0.01),iNOS在pPROM组胎膜中的表达水平高于对照组(P<0.01)。绒毛膜羊膜炎孕妇胎膜中的MMP-9(P<0.05)和iNOS(P<0.01)表达水平均高于非绒毛膜羊膜炎,二者呈正相关(P<0.01)。结论: MMP-9和iNOS表达升高与pPROM及绒毛膜羊膜炎的发生相关;MMP-9和iNOS在PROM发病机制中存在关联作用。     

胎膜早破对妊娠结局的影响及干预效果

目的探讨胎膜早破的分娩方式及早期干预效果。方法对2004年1月1日至2005年12月31日在我院住院分娩的1979例产妇资料进行回顾性分析。结果初产妇胎膜早破的发生率较经产妇明显增高(P<0.01),胎膜早破组早产发生率高(P<0.01),两组分娩方式比较无差异(P>0.05),胎膜早破组手术指征中头盆不称的发生率明显高于对照组(P<0.01),两组新生儿窒息、产后出血及产妇感染的发生率均无明显差异(P>0.05)。结论对胎膜早破患者预防性使用抗生素、适时终止妊娠等积极干预措施,可以减少母儿并发症发生。     

75例胎膜早破患者阴道液FFN与绒毛膜羊膜炎的临床分析

目的通过检测胎膜早破患者中的胎儿纤连蛋白（FFN）,探讨其与绒毛膜羊膜炎的关系,为预测胎膜早破中绒毛膜羊膜炎的发生提供较灵敏的检测方法。方法采用固相免疫吸附法对胎膜早破患者75例,健康孕妇50例进行血清C-反应蛋白定量检测、阴道液FFN定性检测,分娩后胎盘胎膜行病理检查。结果研究组CRP阳性率为37.33%,对照组为2%;FFN阳性率为85.33%,对照组为4%,差异有显著性（P〈0.01）。研究组中FFN阳性者绒毛膜羊膜炎发生率明显高于阴性者,敏感性及特异性分别高达93.02%、75.00%,差异亦有显著性（P〈0.01）。结论FFN与绒毛膜羊膜炎关系密切,可用于胎膜早破中预测绒毛膜羊膜炎的发生。     

血清IL-6水平与胎膜早破合并宫内感染的关系

目的探讨血清IL-6水平与胎膜早破合并宫内感染的关系.方法选取胎膜早破孕妇46例(其中早产早破组22例,足月早破组24例),和产科门诊定期产检的正常孕妇50例为对照组(其中未足月对照组22例,足月对照组28例),用酶联免疫法测定血清IL-6含量,分娩时取部分胎盘胎膜组织送病检.结果胎膜早破孕妇组织学绒毛膜羊膜炎的发生率为52.4%(24/46).早产早破组与足月早破组血清IL-6水平相比无差异(P>0.05),但均高于对照组(P<0.05=),无论是早产早破组还是足月早破组,有组织学绒毛膜羊膜炎者血清IL-6水平均高于无组织学绒毛膜羊膜炎者及对照组(P<0.05=).结论血清IL-6水平升高可作为早期诊断胎膜早破合并宫内感染的指标.     

联合检测C反应蛋白和降钙素原在创伤后脓毒症患者早期预警中的作用

目的评估血清C反应蛋白(CRP)和降钙素原(PCT)联合检测对创伤后脓毒症患者的预警价值。方法纳入严重创伤患者235例,其中110例脓毒症患者和125例非脓毒症患者。采集入院24 h内血样,检测血清中CRP和PCT。采用ROC曲线比较CRP和PCT对创伤后脓毒症的预警价值,同时采用NRI和IDI分析联合使用后的提高能力。结果脓毒症患者血清CRP和PCT水平均显著高于非脓毒症患者(P<0.001),ROC分析显示血清CRP和PCT的AUC分别为0.766(0.707~0.819)和0.744(0.684~0.799);将CRP和PCT联合较单指标预警创伤脓毒症的AUC提高了5.1%,7.3%。NRI和IDI分析结果证实PCT和CPR的联合使用较单独使用的预警效能显著提高(P<0.001)。结论CRP和PCT对严重创伤后脓毒症发生风险具有早期预警作用,二者联合能够显著提高早期预警能力。