Premature birth is the leading cause of perinatal mortality and morbidity worldwide. The Perinatology Research Branch has defined preterm labor as a syndrome and determined that at least 25% of preterm neonates are born to women with sub-clinical intrauterine infection. The Branch has also provided evidence that many premature neonates are critically ill before birth and proposed that, in the context of intrauterine infection, the onset of premature labor has survival value. The goal of this project is to understand the pathophysiology of premature labor and delivery. This year, our research focused on the following studies:? ? 1. Gene expression signature of spontaneous term labor without histologic chorioamnionitis. Human parturition involves a common pathway manifested clinically by uterine contractions, cervical ripening and chorioamniotic membrane/decidual activation, culminating in membrane rupture. Previous studies have linked parturition to an inflammatory process. Investigators at the Branch analyzed both the transcriptome in the chorioamniotic membranes and maternal blood in order to identify the biological processes in normal spontaneous labor using an unbiased genome-wide approach. Transcriptional profiles for chorioamniotic membranes and blood were generated from patients at term with no labor and patients at term in labor. All placentas were subjected to histologic examination, and a criterion for inclusion was the absence of histologic chorioamnionitis. An increased expression of multiple chemokines and transcripts associated with neutrophil and monocyte recruitment was observed among patients in term labor. The results of this study indicate that labor induces gene expression changes consistent with localized inflammation despite the absence of histological chorioamnionitis. ? ? 2. Uterine transcriptomes of bacteria-induced and ovariectomy-induced preterm labor (PTL) in mice are characterized by differential expression of arachidonate metabolism genes. PTL is a syndrome with multiple etiologies. In this study, the Branch focused on two well established mechanisms of PTL: intrauterine infection and the requirement of progesterone for pregnancy maintenance. To investigate the role of intrauterine infection and progesterone in human PTL, investigators analyzed the uterine transcriptome of mice using two models: the first was the induction of PTL by intrauterine infection with Escherichia coli, and the second was the induction of PTL by ovariectomy and progesterone withdrawal. Quantitative reverse transcriptase?polymerase chain reaction measurements demonstrated that bacteria-induced PTL substantially increased the expression of genes involved in prostaglandin synthesis. In contrast, ovariectomy-induced PTL increased the expression of genes involved in lipoxin, leukotriene, and hydroxyeicosatetraenoic acid synthesis. The results of this study indicate that bacteria-induced and ovariectomy-induced PTL each express a different balance of genes that are involved in prostaglandin synthesis and the synthesis of lipoxins, leukotrienes, and HETEs. This balance may be important to PTL and is amenable to experimental investigation.? ? 3. The transcriptome of the uterine cervix before and after spontaneous term parturition. Cervical ripening is one of the components of the common pathway for parturition. Therefore, determining the expression profile of genes involved in this process is crucial for the understanding of mechanisms leading to premature cervical ripening and preterm delivery. This study provided an unbiased and comprehensive description of the changes in the cervical transcriptome before and after spontaneous term labor. The transcriptome of cervical tissue from patients at term not in labor and after spontaneous labor were characterized using Affymetrix microarrays. Results of this study revealed that the cervical transcriptome of term patients who underwent labor is dramatically different from that of patients without labor, with 1192 differentially expressed genes. Among the up-regulated genes were those involved in neutrophil chemotaxis, apoptosis, extracellular matrix regulation, and steroid metabolism. Genes involved in neutrophil chemotaxis were up-regulated in specimens from women after spontaneous labor, and an increased expression of IL-8, IL-6, and scular endothelial growth factor was confirmed by real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Toll-like receptor (TLR)-3 and TLR-5 showed decreased gene expression in patients after spontaneous labor in the microarray analysis and this was confirmed by qRT-PCR.? ? 4. A rapid bedside test for the prediction of preterm delivery (PTD). Intra-amniotic infection (IAI) and inflammation have been causally linked to preterm labor (PTL), PTD and fetal injury. Intra-amniotic inflammation can be detected by performing an amniocentesis and measuring cytokines (e.g. IL-6 and MMP-8), white blood cell count, and glucose concentrations in the amniotic fluid. It has been previously demonstrated that elevated MMP-8 concentrations in the amniotic fluid of patients with PTL and intact membranes can diagnose intra-amniotic inflammation with 95% sensitivity and 93% specificity. This year, the Branch conducted a study to investigate the diagnostic indices, predictive values, efficiency and likelihood ratios of the MMP-8 PTD Check test for the detection of IAI, inflammation, spontaneous PTD and severe neonatal morbidity among patients with increased uterine contractions and intact membranes. The MMP-8 PTD Check Test (SK Pharma Co, Ltd, Kyunggi-do, Korea) is a rapid bedside test (configured similarly to a rapid pregnancy test) designed to provide a quick bedside assessment for elevated concentrations of MMP-in a small amount of amniotic fluid. A positive MMP-8 rapid test correctly predicted 70% of the spontaneous PTDs within 48 hrs, and 94% of those occurring within 7 days and 14 days of the amniocentesis. The efficiency of a positive MMP-8 rapid test in the identification of IAI and inflammation was 94% (311/331) and 93% (308/331), respectively. We concluded that this rapid test gives clinicians a fast and accurate assessment of the inflammatory status of the amniotic cavity, and allows for better identification of patients at risk for impending PTD. Follow-up clinical trials are required to determine the role of the MMP-8 rapid test for the identification of inflammation at the time of amniocentesis, as well as determine whether, based on the rapid test results, treatment with antibiotics and/or anti-inflammatory agents may improve pregnancy outcome.? ? 5. Phylogenetic analysis reveals the evolution of the mammalian placenta. The placenta is the lifeline for mammalian reproduction and a complex organ that provides clues about natural selection and evolution. Through phylogenetic analysis of molecular and anatomical data, investigators at the Branch presented evidence describing the evolutionary history of the placenta of eutherian mammals?the group that includes all mammal species except marsupials and the egg laying monotremes (for example, the duck billed platypus). In contrast to most theories, the study found that the disc-shaped, hemochorial placenta of many primates, including humans, existed throughout the eutherian lineage from the last common ancestor of placental mammals to the emergence of humans. That intimate contact between fetal and maternal blood was established in the last common ancestor of the crown group of Eutheria gives credence to the hypothesis that successful pregnancy requires appropriate allorecognition and tolerance at the maternal-fetal interface.
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