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Identifying metabolite markers for preterm birth in cervicovaginal fluid by magnetic resonance spectroscopy.

ABSTRACT: INTRODUCTION:Preterm birth (PTB) may be preceded by changes in the vaginal microflora and metabolite profiles. OBJECTIVES:We sought to characterise the metabolite profile of cervicovaginal fluid (CVF) of pregnant women by 1H NMR spectroscopy, and assess their predictive value for PTB. METHODS:A pair of high-vaginal swabs was obtained from pregnant women with no evidence of clinical infection and grouped as follows: asymptomatic low risk (ALR) women with no previous history of PTB, assessed at 20-22 gestational weeks, g.w., n = 83; asymptomatic high risk (AHR) women with a previous history of PTB, assessed at both 20-22 g.w., n = 71, and 26-28 g.w., n = 58; and women presenting with symptoms of preterm labor (PTL) (SYM), assessed at 24-36 g.w., n = 65. Vaginal secretions were dissolved in phosphate buffered saline and scanned with a 9.4 T NMR spectrometer. RESULTS:Six metabolites (lactate, alanine, acetate, glutamine/glutamate, succinate and glucose) were analysed. In all study cohorts vaginal pH correlated with lactate integral (r = -0.62, p < 0.0001). Lactate integrals were higher in the term ALR compared to the AHR (20-22 g.w.) women (p = 0.003). Acetate integrals were higher in the preterm versus term women for the AHR (20-22 g.w.) (p = 0.048) and SYM (p = 0.003) groups; and was predictive of PTB < 37 g.w. (AUC 0.78; 95 % CI 0.61-0.95), and delivery within 2 weeks of the index assessment (AUC 0.84; 95 % CI 0.64-1) in the SYM women, whilst other metabolites were not. CONCLUSION:High CVF acetate integral of women with symptoms of PTL appears predictive of preterm delivery, as well as delivery within 2 weeks of presentation.

SUBMITTER: Amabebe E

PROVIDER: S-EPMC4783437 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Identifying metabolite markers for preterm birth in cervicovaginal fluid by magnetic resonance spectroscopy.

Amabebe Emmanuel E Reynolds Steven S Stern Victoria L VL Parker Jennifer L JL Stafford Graham P GP Paley Martyn N MN Anumba Dilly O C DO

Metabolomics : Official journal of the Metabolomic Society 20160308

<h4>Introduction</h4>Preterm birth (PTB) may be preceded by changes in the vaginal microflora and metabolite profiles.<h4>Objectives</h4>We sought to characterise the metabolite profile of cervicovaginal fluid (CVF) of pregnant women by 1H NMR spectroscopy, and assess their predictive value for PTB.<h4>Methods</h4>A pair of high-vaginal swabs was obtained from pregnant women with no evidence of clinical infection and grouped as follows: asymptomatic low risk (ALR) women with no previous history ...[more]

PMID: 27065760

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Project description:Changes in vaginal microbiota that is associated with preterm birth (PTB) leave specific metabolite fingerprints that can be detected in the cervicovaginal fluid (CVF) using metabolomics techniques. In this study, we characterize and validate the CVF metabolite profile of pregnant women presenting with symptoms of threatened preterm labor (PTL) by both 1H-nuclear magnetic resonance spectroscopy (NMR) and enzyme-based spectrophotometry. We also determine their predictive capacity for PTB, singly, and in combination, with current clinical screening tools - cervicovaginal fetal fibronectin (FFN) and ultrasound cervical length (CL). CVF was obtained by high-vaginal swabs from 82 pregnant women with intact fetal membranes presenting between 24 and 36?weeks gestation with symptoms of threatened, but not established, PTL. Dissolved CVF samples were scanned with a 400?MHz NMR spectrometer. Acetate and other metabolites were identified in the NMR spectrum, integrated for peak area, and normalized to the total spectrum integral. To confirm and validate our observations, acetate concentrations (AceConc) were also determined from a randomly-selected subset of the same samples (n?=?57), by spectrophotometric absorption of NADH using an acetic acid assay kit. CVF FFN level, transvaginal ultrasound CL, and vaginal pH were also ascertained. Acetate normalized integral and AceConc were significantly higher in the women who delivered preterm compared to their term counterparts (P?=?0.002 and P?=?0.006, respectively). The 1H-NMR-derived acetate integrals were strongly correlated with the AceConc estimated by spectrophotometry (r?=?0.69; P?<?0.0001). Both methods were equally predictive of PTB <37?weeks (acetate integral: AUC?=?0.75, 95% CI?=?0.60-0.91; AceConc: AUC?=?0.74, 95% CI?=?0.57-0.90, optimal predictive cutoff of >0.53?g/l), and of delivery within 2?weeks of the index assessment (acetate integral: AUC?=?0.77, 95% CI?=?0.58-0.96; AceConc: AUC?=?0.68, 95% CI?=?0.5-0.9). The predictive accuracy of CVF acetate was similar to CL and FFN. The combination of CVF acetate, FFN, and ultrasound CL in a binary logistic regression model improved the prediction of PTB compared to the three markers individually, but CVF acetate offered no predictive improvement over ultrasound CL combined with CVF FFN. Elevated CVF acetate in women with symptoms of PTL appears predictive of preterm delivery, as well as delivery within 2?weeks of presentation. An assay of acetate in CVF may prove of clinical utility for predicting PTB.

Project description:OBJECTIVES:Perturbation of the choriodecidual space before the onset of spontaneous preterm birth (sPTB) could lead to a concomitant rise in both cervicovaginal fluid (CVF) cytokine and fetal fibronectin (FFN), and assessing the concentrations of both markers could improve the prediction of sPTB (delivery before 37 completed weeks of gestation). Therefore, we prospectively determined mid-trimester changes in CVF cytokine and FFN concentrations, and their predictive capacity for sPTB in asymptomatic pregnant women. STUDY DESIGN:CVF collected at 20+0-22+6 weeks (n?=?47: Preterm-delivered?=?22, Term-delivered?=?25) and 26+0-28+6 weeks (n?=?50: Preterm-delivered?=?17, Term-delivered?=?33) from 63 asymptomatic pregnant women at risk of sPTB were examined. Cytokine and FFN concentrations were determined by multiplexed bead-based immunoassay and 10Q Rapid analysis (Hologic, MA, USA) respectively. The 20+0-22+6/26+0-28+6 weeks ratios of cytokines and FFN concentrations were compared between preterm- and term-delivered women using Receiver Operating Characteristics curves to predict sPTB. Also, bacterial 16S rDNA from 64 samples (20+0-22+6 weeks n?=?36, 26+0-28+6 weeks n?=?28) was amplified by polymerase chain reaction to determine associations between vaginal microflora, cytokine and FFN concentrations. RESULTS:Changes in RANTES and IL-1? concentrations between 20+0-22+6 and 26+0-28+6 weeks, expressed as a ratios, were predictive of sPTB, RANTES (AUC?=?0.82, CI?=?0.62-0.94) more so than IL-1? (AUC?=?0.71, CI?=?0.53-0.85) and FFN (not predictive). Combining these markers (AUC?=?0.83, CI?=?0.63-0.95) showed similar predictive capacity as RANTES alone. FFN concentrations at 26+0-28+6 weeks correlated with IL-1? (r?=?0.4, P?=?0.002) and RANTES (r?=?0.3, P?=?0.03). In addition, there was increased prevalence of vaginal anaerobes including Bacteroides, Fusobacterium and Mobiluncus between gestational time points in women who experienced sPTB compared to the term women (P?=?0.0006). CONCLUSIONS:CVF RANTES and IL-1? in mid-trimester of pregnancy correlate with quantitative FFN. The levels of CVF RANTES and IL-1? decline significantly in women who deliver at term unlike women who deliver preterm. This observation suggests that sPTB may be characterised by sustained choriodecidual inflammation and may have clinical value in serial screening for sPTB if confirmed by larger studies.

Project description:Spontaneous preterm birth (PTB) before 37 completed weeks of gestation resulting from preterm labor (PTL) is a leading contributor of perinatal morbidity and mortality. Early identification of at-risk women by reliable screening tests could alleviate this health issue; however, conventional methods such as obstetric history and clinical risk factors, uterine activity monitoring, biochemical markers, and cervical sonography for screening women at risk for PTB have proven unsuccessful in lowering the rate of PTB. Cervicovaginal fluid (CVF) might prove to be a useful, readily available biological fluid for identifying diagnostic PTB biomarkers. Human columnar epithelial endocervical-1 (End1) and vaginal (Vk2) cell secretomes were employed to generate a stable isotope labeled proteome (SILAP) standard to facilitate characterization and relative quantification of proteins present in CVF. The SILAP standard was prepared using stable isotope labeling by amino acids in cell culture (SILAC) of End1 and Vk2 through seven passages. The labeled secreted proteins from both cell lines were combined and characterized by liquid-chromatography-tandem mass spectrometry (LC-MS/MS). In total, 1211 proteins were identified in the End1-Vk2 SILAP standard, with 236 proteins being consistently identified in each of the replicates analyzed. Individual proteins were found to contain <0.5% of the endogenous unlabeled forms. Identified proteins were screened to provide a set of 15 candidates that have either previously been identified as potential PTB biomarkers or could be linked mechanistically to PTB. Stable isotope dilution LC-multiple reaction monitoring (MRM/MS) assays were then developed for conducting relative quantification of the 15 candidate biomarkers in human CVF samples from term and PTB cases. Three proteins were significantly elevated in PTB cases (desmoplakin isoform 1, stratifin, and thrombospondin 1 precursor), providing a foundation for further validation in larger patient cohorts.

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Identifying metabolite markers for preterm birth in cervicovaginal fluid by magnetic resonance spectroscopy.

Publications

Identifying metabolite markers for preterm birth in cervicovaginal fluid by magnetic resonance spectroscopy.

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