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Background: Late-onset sepsis (LOS) in preterm infants is a leading cause of mortality and morbidity. Timely recognition and initiation of antibiotics are important factors for improved outcomes. Identification of risk factors could allow selection of infants at an increased risk for LOS. Objectives: The aim was to identify risk factors for LOS. Methods: In this multicenter case-control study, preterm infants born at ≤30 weeks of gestation were included at 9 neonatal intensive care units. Detailed demographical and clinical data were collected daily up to day 28 postnatally. Clinical and demographic risk factors were identified using univariate and multivariate regression analyses in a 1: 1 matched case-control cohort. Results: In total, 755 infants were included, including 194 LOS cases (41 gram-negative cases, 152 gram-positive cases, and 1 fungus). In the case-control cohort, every additional day of parenteral feeding increased the risk for LOS (adjusted OR = 1.29; 95% CI 1.07–1.55; p = 0.006), whereas antibiotics administration decreased this risk (OR = 0.08; 95% CI 0.01–0.88; p = 0.039). These findings could largely be attributed to specific LOS-causative pathogens, since these predictive factors could be identified for gram-positive, but not for gram-negative, LOS cases. Specifically cephalosporins administration prior to clinical onset was inversely related to coagulase-negative staphylococcus LOS (CoNS-LOS) development. Formula feeding was an independent risk factor for development of CoNS-LOS (OR = 3.779; 95% CI 1.257–11.363; p = 0.018). Conclusion: The length of parenteral feeding was associated with LOS, whereas breastmilk administration was protective against CoNS-LOS. A rapid advancement of enteral feeding, preferably with breastmilk, may proportionally reduce the number of parenteral feeding days and consequently the risk for LOS. [ABSTRACT FROM AUTHOR]

Necrotizing enterocolitis (NEC) is a relatively common disease in very-low-birth-weight infants and is associated with high mortality and morbidity. In survivors, neurodevelopmental impairment is frequently seen. The exact etiology remains largely to be elucidated, but microbiota are considered to play a major role in the development of NEC. Furthermore, emerging evidence exists that the microbiota is also of importance in brain function and development. Therefore, microbiota characterization has not only potential as a diagnostic or even preventive tool to predict NEC, but may also serve as a biomarker to monitor and possibly even as a target to manipulate brain development. Analysis of fecal volatile organic compounds, which shape the volatile metabolome and reflect microbiota function and host interaction, has been shown to be of interest in the diagnosis of NEC and late-onset sepsis. In this review, we discuss evidence of the role of the complex interplay between microbiota, NEC, and brain development, including the brain-gut axis in preterm infants. [ABSTRACT FROM AUTHOR]

Background: The identification of independent clinical risk factors for necrotizing enterocolitis (NEC) may contribute to early selection of infants at risk, allowing for the development of targeted strategies aimed at the prevention of NEC. Objective: The objective of this study was to identify independent risk factors contributing to the development of NEC in a large multicenter cohort. Methods: This prospective cohort study was performed in 9 neonatal intensive care units. Infants born at a gestational age ≤30 weeks were included. Demographic and clinical data were collected daily until day 28 postnatally. Factors predictive of the development of NEC were identified using univariate and multivariable analyses in a 1: 5 matched case-control cohort. Results: In total, 843 infants (56 NEC cases) were included in this study. In the case-control cohort, univariate analysis identified sepsis prior to the onset of NEC and formula feeding to be associated with an increased risk of developing NEC, whereas the administration of antibiotics directly postpartum was inversely associated with NEC. In a multivariable logistic regression model, enteral feeding type and the number of days parenterally fed remained statistically significantly associated with NEC, whereas the administration of antibiotics directly after birth was associated with a lower risk of developing NEC. Conclusions: Formula feeding and prolonged (duration of) parenteral feeding were associated with an increased risk of NEC. Contrary to expectations, the initiation of treatment with antibiotics within 24 h after birth was inversely associated with NEC. [ABSTRACT FROM AUTHOR]

Background: Antenatal corticosteroids (ACS) improve preterm neonatal outcomes. However, uncertainty remains regarding the safety of ACS exposure for the developing fetus, particularly its neurosensory development. Objectives: We investigated the effect of single and multiple ACS exposures on auditory nerve development in an ovine model of pregnancy. Methods: Ewes with a single fetus (gestational age [GA] 100 days) received an intramuscular injection of 150 mg medroxyprogesterone-acetate, followed by intramuscular (i) betamethasone (0.5 mg/kg) on days 104, 111, and 118 GA; (ii) betamethasone on day 104 and saline on days 111 and 118 GA; or (iii) saline on days 104, 111, and 118 GA, with delivery on day 125 GA. Transmission electron microscope images of lamb auditory nerve preparations were digitally analyzed to determine auditory nerve morphology and myelination. Results: Relative to the control, mean auditory nerve myelin area was significantly increased in the multiple-treatment group (p < 0.001), but not in the single-treatment group. Increased myelin thickness was significantly changed only in a subgroup analysis for those axons with myelin thickness greater than the median value (p < 0.001). Morphological assessments showed that the increased myelin area was due to an increased likelihood of decompacted areas (p = 0.005; OR = 2.14, 95% CI 1.26–3.63; 31.6 vs. 18.2% in controls) and irregular myelin deposition (p = 0.001; OR = 5.91, 95% CI 2.16–16.19; 49.0 vs. 16.8% in controls) in the myelin sheath. Conclusions: In preterm sheep, ACS exposure increased auditory nerve myelin area, potentially due to disruption of normal myelin deposition. [ABSTRACT FROM AUTHOR]

In the last 4 decades, advances in neonatology have led to a significant increase in the survival of preterm infants. One of the biggest advances was the introduction of surfactant replacement therapy for the treatment of respiratory distress syndrome. This is the main cause of respiratory insufficiency in preterm infants and is one of the major causes of perinatal morbidity and mortality. Surfactant replacement therapy is already a well-investigated and established therapy in neonatology. However, surfactant replacement therapy has progressed and been refined over recent decades, especially with the increasing care for preterm infants born before 26 weeks' gestational age and the recent clinical focus on avoiding mechanical ventilation. Clinical evidence is evolving on new types of surfactant, surfactant dosages, co-medication given before, with, or after surfactant replacement, and new technical advances regarding the mode of administration. [ABSTRACT FROM AUTHOR]

Background: Bronchopulmonary dysplasia (BPD) is one of the most common complications after preterm birth and is associated with intrauterine exposure to bacteria. Transforming growth factor-β (TGFβ) is implicated in the development of BPD. Objectives: We hypothesized that different and/or multiple bacterial signals could elicit divergent TGFβ signaling responses in the developing lung. Methods: Time-mated pregnant Merino ewes received an intra-amniotic injection of lipopolysaccharide (LPS) and/or Ureaplasma parvum serovar 3 (UP) at 117 days' and/or 121/122 days' gestational age (GA). Controls received an equivalent injection of saline and or media. Lambs were euthanized at 124 days' GA (term = 150 days' GA). TGFβ1, TGFβ2, TGFβ3, TGFβ receptor (R)1 and TGFβR2 protein levels, Smad2 phosphorylation and elastin deposition were evaluated in lung tissue. Results: Total TGFβ1 and TGFβ2 decreased by 24 and 51% after combined UP+LPS exposure, whereas total TGFβ1 increased by 31% after 7 days' LPS exposure but not after double exposures. Alveolar expression of TGFβR2 decreased 75% after UP, but remained unaltered after double exposures. Decreased focal elastin deposition after single LPS exposure was prevented by double exposures. Conclusions: TGFβ signaling components and elastin responded differently to intrauterine LPS and UP exposure. Multiple bacterial exposures attenuated TGFβ signaling and normalized elastin deposition. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Chorioamnionitis is a major risk factor for preterm birth in multifetal pregnancies. However, there is little clinical data whether chorioamnionitis is restricted to one amniotic compartment in multifetal pregnancies. Objective: To explore whether chorioamnionitis is confined to the exposed compartment and does not cross to the unaffected fetus in twin pregnancy. Methods: In twin pregnant sheep, one of the twins was exposed to either 2 or 14 days of intra-amniotic lipopolysaccharide (LPS) while the co-twin was exposed to either 2 or 14 days of intra-amniotic saline (n = 3 for each exposure). Singletons were included in this study to compare the grade of inflammation with twins. All fetuses were delivered at 125 days of gestation (term = 150 days). Chorioamnionitis was confirmed by histological examination. Lung inflammation was assessed by cell count in bronchoalveolar lavage. Lung compliance was assessed at 40 cm H2O. Results were compared using analysis of variance (ANOVA) with a post-hoc Tukey analysis. Results: Inflammation in placenta, membranes and lung of LPS-exposed twins was significantly higher after 2 and 14 days of exposure when compared to the saline-exposed co-twins. Lung compliance in LPS-exposed twins was significantly increased after 14 days when compared to saline-exposed co-twins. Intrauterine LPS exposure increased lung compliance and inflammation in the membranes, placenta and lung to the same extent in twins as in singletons. Conclusion: In twin pregnant sheep, inflammation of the membranes, placenta and fetal lung was strictly limited to the exposed fetus in the amniotic compartment in which the LPS was injected. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

AbstractWe review information about how the preterm lung can be injured with the initiation of mechanical ventilation at birth. Although multiple variables such as pressure, tidal volume, positive end expiratory pressure, and the gas used for ventilation may contribute to the injury, the relative contribution of each is not known. Recent studies demonstrate that injury caused by initial high tidal volume is amplified by subsequent mechanical ventilation. A model for gas inflation of the fluid-filled lung may explain why even low tidal volumes may injure the preterm lung, and why the injury may initially occur to the small airways. Ventilation strategies that minimize injury need to be developed.Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Fetal lung maturation occurs after both maternal corticosteroid administration and chorioamnionitis. The effectors of this antenatally-induced lung maturation are not understood. Matrix metalloproteinases (MMPs) 2 and 9 are type-IV collagenases that can degrade alveolar basement membranes. Objectives: We hypothesized that the structural changes of lung maturation by both antenatal corticosteroid treatment and chorioamnionitis would be associated with increases in these MMPs. Methods: 64 pregnant ewes were randomly assigned to one of four treatment groups: intra-amniotic injection of 10 mg endotoxin, maternal intramuscular injection of 0.5 mg/kg betamethasone, both treatments combined or saline-treated controls. We quantified MMP-2 which is derived from connective tissue and MMP-9 which is predominantly derived from neutrophils in fetal lung fluid of lambs after maternal corticosteroid therapy and induction of chorioamnionitis and the combination of both therapies given at 109-111 days' gestational age with delivery 1, 5 or 15 days later. Results: Betamethasone, endotoxin and the combined treatments increased both surfactant pool size, lung gas volume and reduced alveolar wall thickness at 15 days. MMP-2 concentration was increased after betamethasone. MMP-9 concentration increased after endotoxin-induced chorioamnionitis but decreased by the combined treatments. Conclusion: Lung maturation via different pathways may use different forms of collagenases for remodelling lung structure. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]