# Untargeted 1H-NMR Urine Metabolomic Analysis of Preterm Infants with Neonatal Sepsis
###### Abstract  
One of the most critical medical conditions occurring after preterm birth is neonatal sepsis, a systemic infection with high rates of morbidity and mortality, chiefly amongst neonates hospitalized in Neonatal Intensive Care Units (NICU). Neonatal sepsis is categorized as early-onset sepsis (EOS) and late-onset sepsis (LOS) regarding the time of the disease onset. The accurate early diagnosis or prognosis have hurdles to overcome, since there are not specific clinical signs or laboratory tests. Herein, a need for biomarkers presents, with the goals of aiding accurate medical treatment, reducing the clinical severity of symptoms and the hospitalization time. Through nuclear magnetic resonance (NMR) based metabolomics, we aim to investigate the urine metabolomic profile of septic neonates and reveal those metabolites which could be indicative for an initial discrimination between the diseased and the healthy ones. Multivariate and univariate statistical analysis between NMR spectroscopic data of urine samples from neonates that developed EOS, LOS, and a healthy control group revealed a discriminate metabolic profile of septic newborns. Gluconate, myo-inositol, betaine, taurine, lactose, glucose, creatinine and hippurate were the metabolites highlighted as significant in most comparisons. metabolomics; NMR spectroscopy; neonatal sepsis; EOS; LOS; preterm birth +
Footnote †: journal: Medical Imaging and Clinical  
and late-onset sepsis [17]. Among the EOS risk factors are fetal distress, low APGAR score, resuscitation of the neonate and multiple pregnancies. Additionally, for low-income countries, as EOS seems to be enhanced from factors such as inadequate antenatal care, unhealthy birth and late recognition of conditions that might induce infections to the mother or the neonate [18]. Factors that can increase risk of LOS are considered mainly invasive procedures, such as surgical interventions, intubation, mechanical ventilation, catheter/probe insertion, long-term parenteral nutrition, frequent blood sampling, low stomach acid and/or insufficient breastfeeding [1]. The pathogenesis of EOS is taking place during the intrapartum period, during which the responsible pathogens are transmitted from mother to neonate [19]. Pathogens causing EOS are usually colonized in maternal genitourinary tract and with the amniotic membrane rupture are transmitted to the fetus or during the labor to neonate [20]. Most frequent EOS's pathogens are the Gram (+) group B Streptococcus (GBS) followed by the Gram (-) _E. Coli_ bacteria [21]. Pathogens causing LOS can be transmitted during labor or from the environment. LOS is usually caused by nosocomial or environmental pathogens, specifically Coagulase-negative staphylococci (CONS), Gram (-) bacilli and Fungi, especially _C. albicans_. Apart from differences in the pathogenesis and the time of onset, EOS and LOS have different clinical manifestations [22]. A combination of clinical signs and laboratory findings constitute the diagnosis procedure, with blood culture considered as the \"gold\" standard [23]. For the physicians, the diagnosis of sepsis is a challenge. The limited diagnostic accuracy of common laboratory tests, such as white blood cell indices and acute phase reactants contribute poorly to the early diagnosis of neonatal sepsis. The diagnostics' accuracy limitations, in combination with the neonate's prematurity and survival status as well as the ambiguity of early clinical signs, urge neonatologists to shut out sepsis [24]. Hence, the discovery of new biomarkers, which can easily be detected at an early stage, has occupied the medical and scientific community, with many studies already having been carried out [25]. In this scope, metabolomic analysis could take upon a fundamental role. Detecting and quantifying a wide variety of small molecules, intermediate or final components of metabolic pathways, metabolomics aim to identify the alterations caused by the condition of biological and medical interest.