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Development of a New Biomarker Model for Predicting Preterm Birth in Cervicovaginal Fluid.

ABSTRACT: Preterm birth (PTB) is a social problem that adversely affects not only the survival rate of the fetus, but also the premature babies and families, so there is an urgent need to find accurate biomarkers. We noted that among causes, eubiosis of the vaginal microbial community to dysbiosis leads to changes in metabolite composition. In this study, short chain fatty acids (SCFAs) representing dysbiosis were derivatized using (N-tert-butyldimethylsilyl-N-methyltrifluoroacetamide, MTBSTFA) and targeted analysis was conducted in extracted organic phases of cervicovaginal fluid (CVF). In residual aqueous CVF, polar metabolites produced biochemistry process were derivatized using methoxyamine and N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA), and non-targeted analysis were conducted. Nine SCFAs were quantified, and 58 polar metabolites were detected in 90 clinical samples using gas chromatography/mass spectrometry (GC/MS). The criteria of statistical analysis and detection rate of clinical sample for development of PTB biomarkers were presented, and 19 biomarkers were selected based on it, consisting of 1 SCFA, 2 organic acids, 4 amine compounds, and 12 amino acids. In addition, the model was evaluated as a suitable indicator for predicting PTB without distinction between sample collection time. We hope that the developed biomarkers based on microbiota-derived metabolites could provide useful diagnostic biomarkers for actual patients and pre-pregnancy.

SUBMITTER: Lee JY

PROVIDER: S-EPMC9416165 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Development of a New Biomarker Model for Predicting Preterm Birth in Cervicovaginal Fluid.

Lee Ji-Youn JY Seo Sumin S Shin Bohyun B Hong Se Hee SH Kwon Eunjin E Park Sunwha S Hur Young Min YM Lee Dong-Kyu DK Kim Young Ju YJ Han Sang Beom SB

Metabolites 20220809 8

Preterm birth (PTB) is a social problem that adversely affects not only the survival rate of the fetus, but also the premature babies and families, so there is an urgent need to find accurate biomarkers. We noted that among causes, eubiosis of the vaginal microbial community to dysbiosis leads to changes in metabolite composition. In this study, short chain fatty acids (SCFAs) representing dysbiosis were derivatized using (<i>N-tert</i>-butyldimethylsilyl-<i>N</i>-methyltrifluoroacetamide, MTBST ...[more]

PMID: 36005605

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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: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.

Dataset Information

Development of a New Biomarker Model for Predicting Preterm Birth in Cervicovaginal Fluid.

Publications

Development of a New Biomarker Model for Predicting Preterm Birth in Cervicovaginal Fluid.

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