1. The current diagnostic paradigm in surgical pathology classifies chorioamnionitis (CA) into acute and chronic. CA has been described as a rare lesion of the extraplacental membranes and chorionic plate. In an attempt to elucidate the pathologic basis of late preterm birth in which acute CA is rare, we systematically examined the placentas of patients with preterm labor (PTL) and preterm prelabor rupture of membranes (pPROM).(1) The frequency of chronic CA was 34% in PTL and 39% in pPROM, which is higher than that observed in normal term placentas (8%). The median gestational age of cases with preterm chronic CA was higher than those with acute CA, suggesting that acute and chronic CA represent different pathologic clusters of the preterm parturition syndrome. We also found that the mRNA expression of CXCL9, CXCL10, and CXCL11 (T-cell chemokines) was increased in the membranes with chronic CA, and that the median amniotic fluid (AF) CXCL10 concentration was significantly higher in patients with chronic CA than in those without this lesion in the PTL and pPROM groups. The absence of microorganisms by culture and molecular methods suggests that this lesion does not have a bacterial origin. Our observations suggest that chronic CA may account for the pathology of a large number of spontaneous preterm deliveries. The infiltration of lymphocytes into a semi-allograft suggests an immunological mechanism akin to that of transplantation rejection and graft-versus-host disease in the chorioamniotic membranes.(1) 2. The prevalence of microbial invasion of the amniotic cavity (MIAC) has been based largely on cultivation techniques. The limitations of such methods have been demonstrated based on the detection of conserved microbial sequences (16S rDNA), discovering a substantially greater diversity of Bacteria and Archaea than previously recognized. We analyzed the AF of 204 consecutive women with pPROM using both cultivation and molecular methods.(2) The prevalence of MIAC was 34% by culture, 45% by PCR, and 50% by both methods combined. The number of bacterial species revealed by PCR was greater than that by culture (44 vs. 14 species), including as-yet uncultivated taxa. Some taxa detected by PCR have been previously identified in the gastrointestinal tract and the mouth. Bacterial rDNA abundance exhibited a dose relationship with gestational age at delivery, and a positive PCR was associated with a lower gestational age at delivery and higher rates of respiratory distress syndrome and necrotizing enterocolitis. This study suggests that MIAC in pPROM is more common than previously recognized and, in some cases, associated with uncultivated taxa.(2) Infection has also been implicated in the pathogenesis of preeclampsia and as a potential cause of fetal growth restriction;yet, the association between MIAC, preeclampsia and small-for-gestational-age (SGA) fetuses is unknown. AF from 62 subjects with preeclampsia(3) and 52 subjects with an SGA neonate,(4) not in labor, was analyzed with both cultivation and molecular methods. The rate of MIAC in preeclampsia was 1.6% based on culture, 8% based on PCR, and 9.6% based on both methods.(3) All AF samples of patients with an SGA neonate were negative for microorganisms based on cultivation techniques, whereas 6% were positive based on PCR.(4) These studies(3,4) demonstrate that the prevalence of MIAC in preeclampsia and in SGA is low, suggesting that intra-amniotic infection plays a limited role in their pathophysiology. 3. The role of genomics in the study of PTL is aimed at determining if there is a genetic predisposition to spontaneous PTL and delivery. We conducted a series of studies(5-7) to determine whether maternal/fetal single nucleotide polymorphisms (SNPs) in candidate genes are associated with spontaneous PTL/delivery, pPROM and SGA. Genetic association studies were conducted in 223 mothers and 179 fetuses with PTL/delivery,(5) 225 mothers and 155 fetuses with pPROM,(6) 530 mothers and 436 fetuses that were SGA,(7) and 599 mothers and 628 fetuses with a normal pregnancy. We studied 190 candidate genes and 775 SNPs. Single locus/haplotype association analyses were performed. The strongest single locus associations with PTL/delivery were IL-6 receptor 1 (fetus) and TIMP-2 (mother), which remained significant after correction for multiple comparisons. Global haplotype analysis indicated an association between a fetal DNA variant in insulin-like growth factor F2 and maternal alpha 3 type IV collagen isoform 1.(5) Similarly, a SNP in TIMP-2 in mothers was significantly associated with pPROM. This association remained significant after correction for multiple comparisons. Haplotypes for Alpha 3 type IV collagen isoform precursor in the mother were associated with pPROM and multilocus analysis identified a 3-locus model for pPROM, which included maternal SNPs in collagen type I alpha 2, defensin alpha 5 gene, and endothelin 1.(6) Among patients with an SGA fetus, the most significant single-locus association in mothers was a SNP in TIMP-2, while in the fetus it was a SNP in fibronectin 1 isoform 3 preproprotein (FN1). Haplotype analyses resulted in associations in alpha 1 type I collagen preproprotein in mothers and FN1 in fetuses. Multi-locus analyses identified a two SNP model with maternal variants COL5A2 and PLAU predicting SGA outcome correctly 59% of the time.(7) These studies support the hypothesis that DNA variants can partially explain the risk of PTL, pPROM and SGA.(5-7) 4. Changes in the maternal plasma concentrations of angiogenic (PlGF and VEGF) and anti-angiogenic factors (sEng and sVEGFR-1) precede the clinical presentation of preeclampsia. We conducted a longitudinal cohort study(8) including 1622 consecutive singleton pregnant women to examine the role of maternal plasma PlGF, sEng, and sVEGFR-1 concentrations in early pregnancy and midtrimester in the identification of patients destined to develop preeclampsia. Higher likelihood ratios were provided by ratios of midtrimester plasma concentrations of PlGF, sEng, and sVEGFR-1 than single analytes. Individual angiogenic and anti-angiogenic factors did not perform well in the identification of preeclampsia as a whole. In contrast, a combination of these analytes such as the PlGF/sEng ratio, its delta and slope had the best predictive performance with a sensitivity of 100%, a specificity of 98-99%, and likelihood ratios for a positive test of 57.6, 55.6 and 89.6, respectively, for predicting early-onset preeclampsia (<34 weeks).(8) 5. Biomarkers for PTL and delivery can be discovered through the analysis of the metabolic network of cells (metabolome). Characterization of the global changes of the metabolome is now possible by using a metabolomics approach.
Our aim was to determine if metabolomic profiling of the AF can identify women with spontaneous PTL at risk for preterm delivery, regardless of the presence or absence of intra-amniotic infection/inflammation (IAI). Two retrospective cross-sectional studies were conducted including pregnant women with PTL who delivered at term, PTL without IAI who delivered preterm, and PTL with IAI.(9) AF metabolic profiling was performed by combining gas and liquid chromatography, and mass spectrometry. Compounds were identified by using authentic standards. In the exploratory study, metabolomic profiling of the AF was able to identify patients as belonging to the correct clinical group with an overall accuracy of 96.3%. In the validation study, metabolomic profiling was able to identify patients as belonging to the correct clinical group with an accuracy of 88.5%. The metabolites responsible for the classification of patients in different clinical groups were identified. A preliminary draft of the human AF metabolome was generated (e.g. xenobiotic compounds).(9)
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