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: 9150098
• 负责人: ROBERTO ROMERO
• 金额: $ 2080.52万
• 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/9150098
• 关键词: Abdomen; Accounting; Acute; Adipose tissue; Affect; Age; Amniotic Fluid; Ampicillin; Anaerobic Bacteria; Angiogenic Factor; Antibiotic Therapy; Antibiotics; Bedside Testings; Biological Markers; Biological Process; Biometry; Birth; Blood; Ceftriaxone; Cephalosporins; Clarithromycin; Clinical; Combined Antibiotics; Data; Deposition; Development; Diagnosis; Differential Diagnosis; Disease; Endoglin; Energy Metabolism; Enzyme-Linked Immunosorbent Assay; Exons; Fetal Death; Fetal Growth Retardation; Fetal Weight; Fetus; Fibrin; Floor; Gene Chips; Gene Expression; Gene Expression Profile; Genes; Glucose; Goals; Histologic; Human; Immunoassay; Infant; Infarction; Infection; Inflammation; Inflammatory; Injury; Interleukin-6; Intervention; Ketone Bodies; Lactic acid; Lateral; Lesion; Live Birth; Malnutrition; Measures; Messenger RNA; Metabolic; Metabolism; Methods; Metronidazole; Molecular; Morbidity - disease rate; Mothers; Neonatal; Nonesterified Fatty Acids; Nutrient; Outcome; Pathologic Processes; Patients; Performance; Perinatal; Perinatology; Physicians; Placenta; Plasma; Play; Pravastatin; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pregnant Women; Premature Birth; Premature Labor; Premature Rupture Fetal Membranes; Prevention; Problem Solving; Process; Production; Proteins; RNA Splicing; Recurrence; Regimen; Regulation; Reporting; Research; Retrospective Studies; Risk; Risk Assessment; Role; Rupture; Science; Second Labor Stage; Small for Gestational Age Infant; Specificity; Spliced Genes; Staging; Syndrome; Techniques; Time; Ureaplasma; Visceral; Woman; adverse outcome; amniotic cavity; antimicrobial; antimicrobial drug; base; clinical practice; cost; cytokine; differential expression; fetal; improved; indexing; intraamniotic infection; microbial; mortality; myometrium; neonatal sepsis; perinatal outcomes; premature; preterm premature rupture of membranes; prevent; rapid diagnosis; subcutaneous; therapy design; time use

Antibiotic Treatment of Patients with Preterm Prelabor Rupture of Membranes: Premature rupture of membranes (PROM) affects 10% of all pregnant women and preterm PROM occurs in 1% of all gestations. PROM in the preterm gestation accounts for 30% of all preterm births. The administration of antibiotics to patients with preterm PROM has become the standard of practice and is effective in increasing the duration of the latency period and reducing the rate of clinical chorioamnionitis and neonatal sepsis. Studies reported by our Branch have provided evidence that antibiotics administration do not eradicate subclinical intra-amniotic infection in patients with preterm PROM or prevent subsequent infection. This led us to conduct a retrospective study of the outcome of pregnancy in patients given conventional antimicrobial vs. a new combination of antibiotics effective against ureaplasma species and anaerobic bacteria. We compared perinatal outcomes in 314 patients with PROM <34 weeks receiving antimicrobial regimen 1 (ampicillin and/or cephalosporins; n=195) vs. regimen 2 (ceftriaxone, clarithromycin and metronidazole; n=119). The outcomes of preterm PROM treated with standard antibiotic administration vs. a new combination proved that the new combination consisting of ceftriaxone, clarithromycin, and metronidazole prolonged the latency period, reduced acute histologic chorioamnionitis and funisitis and improved neonatal outcomes in patients with preterm PROM. These studies call for a reexamination of the current clinical practice and suggest that alternative antimicrobial agents may be more effective in this common complication of pregnancy (1). Biomarkers to Predict Induced Preterm Delivery: Inducted or induced preterm delivery account for 30% of all preterm births and occur because of maternal and/or fetal indications such as preeclampsia or intrauterine growth restriction. Small-for-gestational-age (SGA) fetuses could be constitutionally small or be the result of intrauterine malnutrition. The differential diagnosis between these two conditions has been a challenge. This year, we reported a study which determined whether maternal plasma concentrations of specific biomarkers (angiogenic and anti-angiogenic factors) can predict which mothers diagnosed with suspected SGA will develop preeclampsia or require an indicated early preterm delivery (&#8804;34 weeks of gestation); and whether risk assessment performance is improved using these proteins in addition to clinical factors and Doppler parameters. This study included women with singleton pregnancies diagnosed with suspected SGA (estimated fetal weight <10th percentile) between 24 and 34 weeks of gestation (n=314). We found that the biomarkers measured in maternal blood between 24-34 weeks of gestation can indeed identify the majority of mothers diagnosed with suspected SGA who subsequently developed preeclampsia or those who required preterm delivery &#8804; 34 weeks of gestation. Moreover, the addition of these biomarkers to other clinical parameters improved the prediction of preterm delivery (2). A Point of Care Test for Interleukin-6 in Amniotic Fluid: Preterm PROM accounts for 30-40% of spontaneous deliveries <37 weeks of gestation and is a major cause of perinatal morbidity and mortality. Amniotic fluid (AF) interleukin-6 (IL-6) concentrations can identify patients with intra-amniotic inflammation, at risk of impending preterm delivery and adverse pregnancy outcome. The conventional method to determine IL-6 concentrations in AF is an enzyme-linked immunosorbent assay (ELISA). However, this technique is not available in clinical settings and the results may take several days to acquire. A lateral flow-based immunoassay, or point of care (POC) test, has been developed to solve these problems. We conducted a study to compare the performance of AF IL-6 determined by the POC test to that determined by ELISA for the identification of intra-amniotic inflammation, and for assessing risk of spontaneous preterm delivery in patients with preterm PROM. This study included 56 women with singleton pregnancies who presented with preterm PROM. The findings were: 1) a positive POC test for AF IL-6 concentrations had 97% sensitivity and 96% specificity for the identification of intra-amniotic inflammation, as defined by ELISA; and 2) results of the POC test were equivalent to those determined by ELISA in identifying patients with microbial invasion of amniotic cavity, as well as those with acute inflammatory lesions of the placenta. These findings suggest that a POC test for AF concentrations of IL-6 can be used in place of ELISA for the identification of intra-amniotic inflammation in women with preterm PROM. Results can be available within 20 minutes this makes it possible to implement interventions designed to treat intra-amniotic inflammation and improve pregnancy outcome (3). Prevention of Fetal Death with the Use of Statins: Massive perivillous fibrin deposition of the placenta or maternal floor infarction is a serious condition associated with recurrent complications including fetal death and severe fetal growth restriction. There is no method to evaluate the risk of adverse outcomes in subsequent pregnancies, or effective prevention. Recent observations reported by our Branch discovered that maternal floor infarction is characterized by an imbalance in angiogenic/anti-angiogenic factors in early pregnancy. Statins can increase the production of angiogenic factors and inhibit anti-angiogenic forces. We report for the first time the use of statins to prevent recurrent fetal death. Abnormalities of the anti-angiogenic factor, sVEGFR-1, and soluble endoglin were detected early in the index pregnancy, and treatment with pravastatin corrected the abnormalities. Treatment resulted in a live birth infant near term who had normal biometric parameters and development milestones at the age of 2. This is the first reported successful use of pravastatin to reverse an angiogenic/anti-angiogenic imbalance and prevent fetal death. Whether other interventions can reverse the anti-angiogenic state associated with massive perivillous fibrin deposition of the placenta remains to be established (4). Characterization of Visceral and Subcutaneous Adipose Tissue Transcriptome: Parturition imposes an increased energy demand on the laboring woman. Labor is characterized by increased concentrations of nutrients including glucose, free fatty acids, ketone bodies, and lactic acid. There is an approximately 3-fold increase in whole body glucose utilization during labor and delivery and, as expected, energy expenditure of the parturient women in the second stage of labor is 40% higher compared to the first stage. Examination of the human myometrium transcriptome revealed that biological processes related to metabolism were among the molecular functions enriched in the differentially expressed genes between pregnant women with and without spontaneous term labor. We undertook a study to determine gene expression and splicing changes associated with parturition and regions (visceral vs. subcutaneous) of the adipose tissue of pregnant women. The transcriptome of visceral and abdominal subcutaneous adipose tissue from pregnant women at term with (n=15) and without (n=25) spontaneous labor was profiled with Affymetrix GeneChip Human Exon 1.0 ST array. Overall gene expression changes and differential exon usage rate were compared between patient groups and adipose tissue regions (paired analyses). We showed, for the first time, evidence that mRNA splicing and processing in the subcutaneous adipose tissue of women in labor compared to those without labor. Collectively, our data indicate that adipose tissue may play a role in metabolic regulation in human parturition (5).

早产胎膜破裂患者的抗生素治疗：胎膜早破（PROM）影响10%的孕妇，早产胎膜早破发生率为1%。早胎早破占所有早产的30%。对早产胎膜早破患者应用抗生素已成为惯例，可有效延长潜伏期，降低临床绒毛膜羊膜炎和新生儿败血症的发生率。我们分会报告的研究提供了证据，表明抗生素的使用并不能根除早产儿羊膜早破患者的亚临床羊膜内感染，也不能预防随后的感染。因此，我们进行了一项回顾性研究，比较了使用常规抗菌药物的患者与使用对脲原体和厌氧菌有效的新型抗生素组合的妊娠结局。我们比较了314例胎膜早破<34周的患者接受抗菌方案1（氨苄西林和/或头孢菌素，n=195）和方案2（头孢曲松、克拉霉素和甲硝唑，n=119）的围产儿结局。标准抗生素与甲硝唑联合治疗早产儿胎膜早破的结果证明，头孢曲松、克拉霉素和甲硝唑联合治疗可延长胎膜早破患者的潜伏期，减少急性组织学绒毛膜羊膜炎和羊膜炎，改善新生儿预后。这些研究要求对目前的临床实践进行重新检查，并建议替代抗菌药物可能对这种常见的妊娠并发症更有效(1)。