Infection/inflammation-associated preterm delivery within 14 days of presentation with symptoms of preterm labour: A multivariate predictive model.

Emmanuel Amabebe,Steven Reynolds,Xiaoya He,Robyn Wood,Dilly O C Anumba,Victoria Stern,Luca Giannella

doi:10.1371/journal.pone.0222455

Abstract

Multi-marker tests hold promise for identifying symptomatic women at risk of imminent preterm delivery (PTD, <37 week’s gestation). This study sought to determine the relationship of inflammatory mediators and metabolites in cervicovaginal fluid (CVF) with spontaneous PTD (sPTD) and delivery within 14 days of presentation with symptoms of preterm labour (PTL). CVF samples from 94 (preterm = 19, term = 75) singleton women with symptoms of PTL studied between 19+0–36+6 weeks’ gestation were analysed for cytokines/chemokines by multiplexed bead-based immunoassay, while metabolites were quantified by enzyme-based spectrophotometry in a subset of 61 women (preterm = 16, term = 45). Prevalence of targeted vaginal bacterial species was determined for 70 women (preterm = 14, term = 66) by PCR. Overall, 10 women delivered within 14 days of sampling. Predictive capacities of individual biomarkers and cytokine-metabolite combinations for sPTD and delivery within 14 days of sampling were analysed by logistic regression models and area under the receiver operating characteristic curve. Fusobacterium sp., Mubiluncus mulieris and Mycoplasma hominis were detected in more preterm-delivered than term women (P<0.0001), while, M. curtisii was found in more term-delivered than preterm women (P<0.0001). RANTES (0.91, 0.65–1.0), IL-6 (0.79, 0.67–0.88), and Acetate/Glutamate ratio (0.74, 0.61–0.85) were associated with delivery within 14 days of sampling (AUC, 95% CI). There were significant correlations between cytokines and metabolites, and several cytokine-metabolite combinations were associated with sPTD or delivery within 14 days of sampling (e.g. L/D-lactate ratio+Acetate/Glutamate ratio+IL-6: 0.84, 0.67–0.94). Symptomatic women destined to deliver preterm and within 14 days of sampling express significantly higher pro-inflammatory mediators at mid to late gestation. In this cohort, IL-6, Acetate/Glutamate ratio and RANTES were associated with delivery within 14 days of sampling, consistent with their roles in modulating infection-inflammation-associated preterm labour in women presenting with symptoms of preterm birth. Replication of these observations in larger cohorts of women could show potential clinical utility.

Highlights

Preterm delivery (PTD, before 37 weeks of gestation) remains the dominant global cause of perinatal morbidity and mortality
The most commonly employed clinical test for predicting imminent preterm delivery (PTD) are quantitative fetal fibronectin and insulin-like growth factor binding protein-1 (Actim Partus) [4,5,6,7], due to the heterogeneity of the pathophysiology of PTD, several studies have explored other maternal clinical, inflammation and biochemical markers to predict PTD within 7–14 days in women presenting with symptoms of Preterm labour (PTL) [3, 8]
To determine whether cervicovaginal fluid (CVF) metabolites and cytokines/chemokines assessment enhanced the prediction of spontaneous PTD (sPTD) and delivery within 14 days of presentation with symptoms suggestive of PTL, we investigated the relationship between these markers of infection/inflammatory and sPTD and delivery within 14 days of presentation

Summary

Introduction

Preterm delivery (PTD, before 37 weeks of gestation) remains the dominant global cause of perinatal morbidity and mortality. Majority of women presenting with symptoms of PTL do not eventually deliver preterm and would benefit from better prognostication of those most likely to imminently deliver preterm [3]. Accurate identification of these pregnant women facilitates prompt clinical decision-making, maternal treatment with steroids to aid fetal lung maturation, minimises unnecessary hospitalisations, and improves triaging of patients to centres with optimal neonatal care facilities. We have recently demonstrated the predictive value of several CVF proinflammatory mediators, either singly or in combination with qfFN for spontaneous PTD (sPTD) in high risk women without symptoms of PTL [15]. Combining multiple potential markers implicated in the pathogenesis of sPTD may provide a more accurate clinical screening approach [7, 16, 17]

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Conclusion