Scopeas the leading cause of perinatal mortality and morbidity worldwide, the impact of premature delivery is undisputable. Thus far, non-invasive, cost-efficient and accurate biochemical markers to predict preterm delivery are scarce. The aim of this systematic review is to investigate the potential of non-invasive metabolomic biomarkers for the prediction of preterm delivery.Methods and ResultsDatabases were systematically searched from March 2019 up to May 2020 resulting in 4062 articles, of which 45 were retrieved for full-text assessment. The resulting metabolites used for further analyses, such as ferritin, prostaglandin and different vitamins were obtained from different human anatomical compartments or sources (vaginal fluid, serum, urine and umbilical cord) and compared between groups of women with preterm and term delivery. None of the reported metabolites showed uniform results, however, a combination of metabolomics biomarkers may have potential to predict preterm delivery and need to be evaluated in future studies.

Early detection of late-onset sepsis (LOS) in preterm infants is crucial since timely treatment initiation is a key prognostic factor. We hypothesized that fecal volatile organic compounds (VOCs), reflecting microbiota composition and function, could serve as a non-invasive biomarker for preclinical pathogen-specific LOS detection. Fecal samples and clinical data of all preterm infants (≤30 weeks’ gestation) admitted at nine neonatal intensive care units in the Netherlands and Belgium were collected daily. Samples from one to three days before LOS onset were analyzed by gas chromatography—ion mobility spectrometry (GC-IMS), a technique based on pattern recognition, and gas chromatography—time of flight—mass spectrometry (GC-TOF-MS), to identify unique metabolites. Fecal VOC profiles and metabolites from infants with LOS were compared with matched controls. Samples from 121 LOS infants and 121 matched controls were analyzed using GC-IMS, and from 34 LOS infants and 34 matched controls using GC-TOF-MS. Differences in fecal VOCs were most profound one and two days preceding Escherichia coli LOS (Area Under Curve; p-value: 0.73; p = 0.02, 0.83; p < 0.002, respectively) and two and three days before gram-negative LOS (0.81; p < 0.001, 0.85; p < 0.001, respectively). GC-TOF-MS identified pathogen-specific discriminative metabolites for LOS. This study underlines the potential for VOCs as a non-invasive preclinical diagnostic LOS biomarker.

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Objective: Prediction of preterm birth is currently not feasible, resulting in maternal and fetal overexposure to prenatal corticosteroids and unnecessary hospital admittance. Novel biomarkers seem to hold potential for predictive applicability, including non-invasive volatile organic compounds. In this study, we aimed to assess the potential of urinary volatile organic compound profiles (VOCs) in the identification of pregnant women at risk for preterm birth. Design, setting, population: We prospectively collected urine of women admitted for imminent preterm birth (≧ 24+0 weeks until 36+6 weeks), collected data on maternal characteristics, including urine cultures, time between admission and delivery and mode of delivery. Methods and main outcome measures: Urine samples were analyzed using gas chromatography coupled to an ion mobility spectrometer (GC-IMS). VOCs of women delivering preterm and term were compared. Results: Urinary VOCs differed between women delivering between 28+0 until 36+6 weeks compared to women admitted for imminent preterm birth but delivering at term (area under the curve: 0.70). We identified women with either chorioamnionitis (area under the curve: 0.72) and positive bacterial cultures (area under the curve: 0.97) based on their urinary VOCs. Conclusions: Urinary VOCs hold potential for non-invasive prediction of preterm birth. Furthermore, they may allow for detection of chorioamnionitis and urinary tract infections in the investigated population. These observations need to be validated in a larger population prior to clinical implementation. Funding: This study was funded by the Department of Obstetrics and Prenatal diagnosis. Keywords: preterm birth, premature delivery, volatile organic compounds, chorioamnionitis, urinary tract infection, infection