Screening of Chorioamnionitis Using Volatile Organic Compound Detection in Exhaled Breath: A Pre-clinical Proof of Concept Study.

Daan R M G Ophelders,Owen B Spiller,Tim G A M Wolfs,Reint K Jellema,Frederik-Jan Van Schooten,Matthias C Hütten,Agnieszka Smolinska,Agnes W Boots,Salwan Al-Nasiry

doi:10.3389/fped.2021.617906

Daan R M G Ophelders, Owen B Spiller + Show 7 more

Open Access

https://doi.org/10.3389/fped.2021.617906

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Abstract

Chorioamnionitis is a major risk factor for preterm birth and an independent risk factor for postnatal morbidity for which currently successful therapies are lacking. Emerging evidence indicates that the timing and duration of intra-amniotic infections are crucial determinants for the stage of developmental injury at birth. Insight into the dynamical changes of organ injury after the onset of chorioamnionitis revealed novel therapeutic windows of opportunity. Importantly, successful development and implementation of therapies in clinical care is currently impeded by a lack of diagnostic tools for early (prenatal) detection and surveillance of intra-amniotic infections. In the current study we questioned whether an intra-amniotic infection could be accurately diagnosed by a specific volatile organic compound (VOC) profile in exhaled breath of pregnant sheep. For this purpose pregnant Texel ewes were inoculated intra-amniotically with Ureaplasma parvum and serial collections of exhaled breath were performed for 6 days. Ureaplasma parvum infection induced a distinct VOC-signature in expired breath of pregnant sheep that was significantly different between day 0 and 1 vs. day 5 and 6. Based on a profile of only 15 discriminatory volatiles, animals could correctly be classified as either infected (day 5 and 6) or not (day 0 and 1) with a sensitivity of 83% and a specificity of 71% and an area under the curve of 0.93. Chemical identification of these distinct VOCs revealed the presence of a lipid peroxidation marker nonanal and various hydrocarbons including n-undecane and n-dodecane. These data indicate that intra-amniotic infections can be detected by VOC analyses of exhaled breath and might provide insight into temporal dynamics of intra-amniotic infection and its underlying pathways. In particular, several of these volatiles are associated with enhanced oxidative stress and undecane and dodecane have been reported as predictive biomarker of spontaneous preterm birth in humans. Applying VOC analysis for the early detection of intra-amniotic infections will lead to appropriate surveillance of these high-risk pregnancies, thereby facilitating appropriate clinical course of action including early treatment of preventative measures for pre-maturity-associated morbidities.

Highlights

Chorioamnionitis, inflammation associated with an intra-uterine infection of the amniotic fluid and fetal membranes is a major risk factor for preterm birth and an independent risk factor for postnatal disorders such as chronic lung disease, necrotizing enterocolitis, and periventricular leukomalacia [1,2,3]
Incidences of chorioamnionitis are inversely related to gestational age (GA) at birth ranging from an incidence of >70% at 24 weeks GA to 16% at 34 weeks GA [4]
In accordance with several earlier studies [12, 33,34,35], intraamniotic infection following intra-amniotic Ureaplasma parvum (UP) administration was confirmed by the presence of UP in amniotic fluid during Cesarean section

Summary

Introduction

Chorioamnionitis, inflammation associated with an intra-uterine infection of the amniotic fluid and fetal membranes is a major risk factor for preterm birth and an independent risk factor for postnatal disorders such as chronic lung disease, necrotizing enterocolitis, and periventricular leukomalacia [1,2,3]. A small proportion of pregnant women with preterm birth show clinical signs of chorioamnionitis such as maternal fever, uterine fundal tenderness, maternal tachycardia, fetal tachycardia, and purulent or foul amniotic fluid [5]. Preterm birth is most frequently the result of a clinically unapparent histological chorioamnionitis [6, 7]. In these cases, evidence for the presence of chorioamnionitis becomes available only after delivery. Post-partum histological examination of the placenta with evidence of inflammation and necrosis throughout the chorionic plate and amnion is currently the gold standard to diagnose chorioamnionitis [5]

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