The Role Of Subclinical Infection And Cytokines In Preterm Parturition

亚临床感染和细胞因子在早产中的作用

• 批准号: 8736857
• 负责人: ROBERTO ROMERO
• 金额: $ 2229.47万
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8736857
• 关键词: Acute; Address; Adverse event; Affect; Anesthesia procedures; Angiogenic Factor; Antibodies; Area; Benefits and Risks; Biological Markers; Birth; Blood; Blood Pressure; Blood Tests; CXCL10 gene; Cervical; Cervical Cerclage; Cervix Uteri; Chronic; Classification; Clinical; Cohort Studies; Complication; Deposition; Diagnosis; Disease; Effectiveness of Interventions; Endothelium; Etiology; Fetal Death; Fetal Growth Retardation; Fetus; Fibrin; Floor; Frequencies; Gene Expression Profile; Genes; Goals; Graft Rejection; HLA Antigens; Individual; Infant Mortality; Infarction; Infection; Infection of amniotic sac and membranes; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Length; Lesion; Longitudinal Studies; Maternal antibody; Medical; Meta-Analysis; Methods; Molecular Profiling; Morbidity - disease rate; Mothers; Neonatal; Operative Surgical Procedures; Organ Transplantation; Outcome; Pathologic; Pathologic Processes; Patients; Perinatal; Perinatology; Physicians; Placebos; Placenta; Placental Growth Factor; Plasma; Plasma Cells; Population; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Premature Birth; Premature Infant; Premature Labor; Prevalence; Prevention; Probability; Progesterone; Prospective Studies; Proteins; Proteome; Randomized Clinical Trials; Recording of previous events; Recurrence; Relative (related person); Reporting; Research; Retrospective Studies; Risk; Risk Factors; Role; Second Pregnancy Trimester; Small for Gestational Age Infant; Solid; Specificity; Symptoms; Syndrome; System; Testing; Therapeutic Intervention; Third Pregnancy Trimester; Time; Triage; Umbilical vein; United States; Vagina; Woman; Work; base; complement C4d; cost; cost effectiveness; cytokine; fetal; fetal blood; high risk; improved; intraamniotic infection; mortality; neonate; novel; preference; premature; prevent; prognostic; programs; prospective; respiratory distress syndrome; stillbirth; treatment effect

An individual patient meta-analysis conducted by our program showed that vaginal progesterone is effective in preventing preterm birth (PTB) in women with and without a history of a previous PTB. Cervical cerclage has been proposed to prevent preterm birth in women with a short cervix and a history of previous PTB. Which is preferable medical treatment with vaginal progesterone or a cervical cerclage, which requires anesthesia and surgery? No studies have compared the benefits and risks of these two interventions. To address this, we also conducted an indirect patient meta-analysis of randomized clinical trials to compare the treatment effects of vaginal progesterone vs cerclage to prevent PTB in asymptomatic women with a short cervix (<25 mm) in the midtrimester, singleton gestation, and previous spontaneous PTB. This method has emerged as an accepted and valid approach for comparing competing interventions with each other using a common comparator. 9 trials were included: 4 evaluated vaginal progesterone vs placebo (n=158) and 5 evaluated cerclage vs no cerclage (n=504). The use of either vaginal progesterone or cerclage was associated with a significant reduction in the risk of PTB <32 weeks of gestation and composite perinatal morbidity/mortality when compared with placebo and no cerclage, respectively. Treatment with vaginal progesterone was associated with a non-significant 29% reduction in the risk of PTB <32 weeks of gestation and a non-significant 33% decrease in the risk of composite perinatal morbidity and mortality when compared with cerclage. There were no significant differences between the efficacy of either in the prevention of PTB at <37, <35, and <28 weeks of gestation or adverse perinatal outcomes. The selection of the optimal treatment will depend upon adverse events and cost-effectiveness of the interventions, as well as patient/ physicians preferences.(1) However, medical treatment with vaginal progesterone is as efficacious as surgical treatment. Fetal death is a major obstetrical challenge with the prevalence of 3 million cases worldwide. An imbalance of angiogenic/anti-angiogenic factors has been implicated in the pathophysiologic description of preeclampsia, pregnancies with small-for-gestational-age (SGA) neonates, stillbirth, and other obstetrical complications. A prospective cohort study was conducted to determine whether maternal plasma concentrations of PlGF, sVEGFR-1 and sEng at 30-34 weeks of gestation can identify patients at risk for stillbirth, late preeclampsia, and delivery of small-for gestational-age neonates. The results showed that a plasma concentration of PlGF/sVEGFR-1 <0.12 MoM at 30-34 weeks of gestation had a sensitivity of 80%, a specificity of 94%, and a likelihood ratio of a positive test of 14 for the identification of subsequent stillbirth. This is the first test that can assess the risk of fetal death in mothers without risk factors at the beginning of the third trimester of pregnancy.(5) Massive perivillous fibrin deposition (MPFD) and maternal floor infarction (MFI) are related placental lesions often associated with recurrent fetal death and fetal growth restriction. The Branch conducted a study to determine whether this complication of pregnancy could reflect maternal anti-fetal rejection. We found that the prevalence of plasma cell deciduitis in the placenta was significantly higher in cases with MPFD than in those with uncomplicated term deliveries (40% vs 8.6%, P=0.01). Patients with MPFD had a significantly higher frequency of maternal anti-HLA class I positivity during the second trimester than those with uncomplicated term deliveries (80% vs 36%, P=0.01). Strongly positive C4d deposition was observed on umbilical vein endothelium in cases of MPFD. A specific maternal antibody against fetal HLA antigen class I or II was identified in all cases of MPFD. The mean maternal plasma concentration of CXCL-10, which has been reported to be increased in the maternal blood of patients with solid organ transplant rejection, was higher in patients with evidence of MPFD than in those without (P<0.001). These studies provide evidence that this serious placental lesion is associated with evidence of maternal anti-fetal rejection.(2) Since MPFD is associated with fetal death and fetal growth restriction, conditions reported to be associated with an imbalance of angiogenic/anti-angiogenic factors, we conducted a longitudinal study to examine whether maternal plasma concentrations of angiogenic/anti-angiogenic factors in MPFD differ from those of uncomplicated pregnancies prior to the time of diagnosis. Patients who eventually delivered placentas with MPFD had a lower mean plasma concentration of placental growth factor (PlGF), and higher mean plasma concentrations of sVEGFR-1 and sEng than controls. Differences in mean sVEGFR-1, sEng, and the ratios of PlGF to sVEGFR-1 and PlGF to sEng were observed before 20 weeks of gestation. This provides, for the first time, evidence that an imbalance of angiogenic/anti-angiogenic factors is present in patients with MPFD prior to the diagnosis and these changes may participate in the mechanisms responsible for adverse pregnancy outcomes.(3) These findings also open avenues for therapeutic intervention. Preeclampsia is a pregnancy-specific syndrome which affects 3-5% of all pregnancies. A frequent clinical challenge is to identify those patients who present to the obstetrical triage area with the suspicion of preeclampsia (based upon an elevation of blood pressure or other symptoms), and will require preterm delivery or develop maternal and/or neonatal complications. Having first reported that this may be feasible based upon a retrospective study, we have now completed a prospective study. The results confirm (in another population) that a classification system proposed by our Program, based upon the determination of biomarkers in maternal blood, has prognostic value in identifying patients at risk for preterm delivery or adverse maternal/neonatal outcome. Among patients presenting prior to 34 weeks of gestation, those classified as high risk had a 94% probability of preterm delivery, and 70% developed maternal and/or neonatal complications within 2 weeks. On the other hand, patients classified as low risk were unlikely to deliver within 2 weeks or develop maternal and/or neonatal complications.(4) This has practical implications for the management of this common complication of pregnancy. We first described the fetal inflammatory response syndrome (FIRS) as a condition associated with preterm labor or preterm PROM, intra-amniotic infection and acute inflammatory lesions of the placenta (funisitis). We discovered a different form of fetal systemic inflammation characterized by an elevation of CXCL10 in association with chronic placental inflammatory lesions, and termed this FIRS type II - associated lesions are chronic chorioamnionitis, villitis of unknown etiology, and plasma cell deciduitis. These lesions occur in the context of maternal anti-fetal rejection. We found that chronic placental inflammation correlates with maternal seropositivity for class I and class II HLA panel-reactive antibodies (PRA), and that maternal HLA PRA seropositivity during the second trimester of pregnancy is a risk factor for spontaneous preterm delivery, especially for late PTB, which represents 70% of all preterm births. Molecular profiling of fetal blood demonstrated distinct changes in the fetal blood transcriptome and proteome according to the presence or absence of FIRS type II. Differential expression of 128 genes and 20 proteins whose abundance differed between fetuses with and without FIRS type II were reported. Altogether, the findings suggest that maternal anti-fetal rejection can be a novel mechanism of disease in spontaneous preterm labor (6,7).

我们计划进行的一个个体患者的荟萃分析表明，阴道孕激素可有效预防有或没有先前PTB病史的女性早产（PTB）。已经提出了宫颈固定，以防止子宫颈短的女性和先前PTB史的女性早产。使用阴道孕激素或宫颈环链的哪种可取的治疗方法，需要麻醉和手术？没有研究比较这两种干预措施的益处和风险。为了解决这个问题，我们还对随机临床试验进行了间接的患者荟萃分析，以比较阴道孕酮与cerclage的治疗作用，以防止在中期中期的宫颈短宫颈短其中的无症状女性中PTB，中期中期，单胎妊娠，单身妊娠和先前的自发性PTB。 该方法已成为一种使用共同的比较器彼此比较的公认和有效方法。包括9次试验：4个评估的阴道孕酮与安慰剂（n = 158）和5个评估的固定固定剂与无固定的固定（n = 504）。与安慰剂相比，使用阴道孕酮或环链的使用与PTB <32周的妊娠和复合围产期发病率/死亡率的风险显着降低有关。与CERCLAGE相比，用阴道孕酮的治疗与PTB <32周的风险降低了29％的降低29％，而复合围产期发病率和死亡率的风险则降低了33％。在预防PTB <37，<35，<35和<28周的妊娠或不良围产期结局中，在PTB预防PTB方面的疗效之间没有显着差异。最佳治疗的选择将取决于干预措施的不良事件和成本效益，以及患者/医生的偏爱。（1）但是，使用阴道孕激素的药物治疗与手术治疗一样有效。 胎儿死亡是全球300万例案件的主要产科挑战。血管生成/抗血管生成因子的失衡已与先兆子痫的病理生理描述，妊娠妊娠妊娠（SGA）新生儿（SGA）新生儿，静止病和其他近亲并发症的妊娠有关。进行了一项前瞻性队列研究，以确定妊娠30-34周的母体血浆PLGF，SVEGFR-1和SENG的浓度是否可以鉴定出有潜伏，前倾斜晚期的患者，并提供小胎儿新生儿。结果表明，在妊娠30-34周时，PLGF/SVEGFR-1 <0.12 MOM的血浆浓度的灵敏度为80％，特异性为94％，阳性测试的可能性为14，以识别随后的静物。这是第一个可以评估母亲在怀孕三个月开始时没有危险因素的胎儿死亡风险的测试。（5） 大量的周围纤维蛋白沉积（MPFD）和母体地板梗死（MFI）是相关的胎盘病变，通常与复发性胎儿死亡和胎儿生长限制有关。该分支机构进行了一项研究，以确定这种怀孕并发症是否可以反映母亲的抗狂热排斥反应。我们发现，在MPFD病例中，胎盘中浆细胞骨的患病率明显高于单个术语递送的患者（40％vs 8.6％，p = 0.01）。 MPFD患者在妊娠中期的母体抗HLA I类阳性的频率明显高于单个递送的孕妇（80％vs 36％，p = 0.01）。在MPFD的情况下，在脐静脉内皮上观察到强烈的C4D沉积。在MPFD的所有情况下，都鉴定出针对胎儿HLA抗原I或II类的特异性母体抗体。 CXCL-10的平均母体血浆浓度在固体器官移植排斥反应的患者的孕妇血液中升高，MPFD迹象的患者高于没有的患者（p <0.001）。这些研究提供了证据，表明这种严重的胎盘病变与母体抗狂热排斥的证据有关。（2） 由于MPFD与胎儿死亡和胎儿生长限制有关，因此据报道，据报道与血管生成/抗血管生成因子的失衡有关，我们进行了一项纵向研究，以检查孕产妇血浆血浆浓度的血管生成/抗血管生成因子的MPFD在MMPFD之前是否与诊断时间不正常的怀孕之前的孕妇有不同。最终用MPFD递送胎盘的患者的平均血浆浓度较低，胎盘生长因子（PLGF）和SVEGFR-1和SENG的平均血浆浓度较高。在妊娠20周之前，观察到平均SVEGFR-1，SENG和PLGF与SVEGFR-1和PLGF与SENG的比率差异。这首先提供了证据表明，在诊断之前，MPFD患者存在血管生成/抗血管生成因子的失衡，这些变化可能参与负责不良妊娠结局的机制。 先兆子痫是一种特异性综合征，影响所有妊娠的3-5％。经常出现的临床挑战是​​确定那些怀疑先兆子痫的患者（根据血压或其他症状的升高），并需要早产或发展孕妇和/或新生儿并发症。首先报告说，根据回顾性研究，这可能是可行的，我们现在已经完成了一项前瞻性研究。结果（在另一个人群中）证实，根据孕产妇血液中生物标志物的确定，我们计划提出的分类系统具有预后的价值，可以识别有早产或不良母亲/新生儿结果的患者。在妊娠34周之前出现的患者中，被归类为高风险的患者的早产可能性为94％，而70％的患者在2周内出现了母体和/或新生儿并发症。另一方面，被归类为低风险的患者不太可能在2周内提供或发展母亲和/或新生儿并发症。（4）这对治疗这种常见的怀孕并发症具有实际意义。 我们首先将胎儿炎症综合征（FIR）描述为与早产或早产舞会，肿瘤内感染和胎盘急性炎症病变有关的疾病。我们发现了一种不同形式的胎儿全身性炎症，其特征是CXCL10与慢性胎盘炎性病变相关，并称这种FIRS II型 - 相关病变是慢性绒毛膜炎，未知病因学的病毒炎和血浆细胞结论性。这些病变发生在母亲的抗狂热排斥反应的背景下。我们发现，慢性胎盘炎症与I级和II级HLA面板反应性抗体（PRA）的母体血清阳性相关，并且在怀孕第二三个月期间，母体HLA PRA血清阳性是自发性预先分娩的危险因素，尤其是PTB的晚期PTB，代表了所有preterm preterm preterm birters of的较晚。胎儿血液的分子分析表明，根据II型FIRS的存在或不存在胎儿血液转录组和蛋白质组的明显变化。报道了128个基因和20种蛋白质的差异表达，其丰度在II型的胎儿之间有所不同。总的来说，发现表明，母体的抗狂欢排斥可以是自发性早产的新机理（6,7）。