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ObjectiveWe compared mortality and morbidity of inborn versus outborn very preterm infants <32 weeks’ gestation in Western Australia (WA) between 2005 and 2018.DesignRetrospective cohort study.PatientsInfants <32 weeks’ gestation who were born in WA.Main outcome measuresMortality was assessed as death before discharge home from the tertiary neonatal intensive care unit. Short-term morbidities included combined brain injury (intracranial haemorrhage grade ≥3 and cystic periventricular leukomalacia) and other major neonatal outcomes. Developmental assessments at age 2, 3 and 5 years were evaluated. We performed multivariable logistic regression analysis of outborn status on outcomes, controlling for gestational age, birth weight z-score, sex and multiple birth.ResultsA total of 4974 infants were born in WA between 22 and 32 weeks’ gestation between 2005 and 2018 of which 4237 (89.6%) were inborn and 443 (10.4%) were outborn. Overall mortality to discharge was higher in outborn infants (20.5% (91/443) vs 7.4% (314/4237); adjusted OR (aOR) 2.44, 95% CI 1.60 to 3.70, p<0.001). Outborn infants had higher rates of combined brain injury than those inborn (10.7% (41/384) vs 6.0% (246/4115); aOR 1.98, 95% CI 1.37 to 2.86), p<0.001). No difference in up to 5-year developmental measures was detected. Follow-up data were available for 65% of outborn and 79% of inborn infants.ConclusionsOutborn preterm infants <32 weeks in WA had increased odds of mortality and combined brain injury than those inborn. Developmental outcomes up to 5 years were similar between groups. Loss to follow-up may have impacted the long-term comparison.

Very preterm infants are at increased risk of adverse outcomes in early childhood. We assessed whether delayed clamping of the umbilical cord reduces mortality or major disability at 2 years in the APTS Childhood Follow Up Study.

Neonatal sepsis remains one of the key challenges of neonatal medicine, and together with preterm birth, causes almost 50% of all deaths globally for children younger than 5 years. Compared with advances achieved for other serious neonatal and early childhood conditions globally, progress in reducing neonatal sepsis has been much slower, especially in low-resource settings that have the highest burden of neonatal sepsis morbidity and mortality. By contrast to sepsis in older patients, there is no universally accepted neonatal sepsis definition. This poses substantial challenges in clinical practice, research, and health-care management, and has direct practical implications, such as diagnostic inconsistency, heterogeneous data collection and surveillance, and inappropriate treatment, health-resource allocation, and education. As the clinical manifestation of neonatal sepsis is frequently non-specific and the current diagnostic standard blood culture has performance limitations, new improved diagnostic techniques are required to guide appropriate and warranted antimicrobial treatment. Although antimicrobial therapy and supportive care continue as principal components of neonatal sepsis therapy, refining basic neonatal care to prevent sepsis through education and quality improvement initiatives remains paramount.

ObjectiveTo investigate the physical and chemical compatibility of pentoxifylline (PTX) with a wide range of parenteral medications used in the neonatal intensive care setting.DesignPTX and drug solutions were combined in glass phials and inspected visually for physical incompatibility. The chemical compatibility was evaluated on the basis of PTX concentrations.ResultsPrecipitation, colour change or turbidity was not visible in any of the test mixtures, indicating no observed physical incompatibility or apparent risk of blockage in narrow-bore intravenous tubing. The PTX concentration was approximately 2.5% and 4.5% lower when combined with dopamine and amoxicillin, respectively. The PTX concentration ratios for all other combinations were in the range of 99%–102%.ConclusionIn simulated Y-site conditions, physical compatibility testing of PTX and 30 parenteral medications revealed no evidence of precipitation. Based on PTX concentration tests, it could be prudent to avoid mixing PTX with dopamine or amoxicillin.

ObjectiveTo investigate the physical and chemical compatibility of pentoxifylline (PTX) with a range of parenteral medications used in neonatal intensive care.DesignPTX and drug solutions were combined in glass vials, inspected for physical incompatibility and evaluated on the basis of PTX concentrations for chemical compatibility.ResultsNo precipitation, colour change or turbidity was observed in any of the test mixtures. The PTX concentration was approximately 5.5% lower when combined with undiluted calcium gluconate injection (100 mg/mL). The PTX concentration ratios for all other combinations, including diluted calcium gluconate injection (50 mg/mL), were in the range of 99.5%–102%.ConclusionIn simulated Y-site conditions, PTX was found to be compatible with 15 parenteral medications and six total parenteral nutrition solutions. Based on PTX concentration tests, it would be prudent to avoid mixing PTX with undiluted calcium gluconate injection.

Review on preterm infant monocytes and how developmental immaturity of these cells may contribute to preterm infants' susceptibility to infections. The extreme vulnerability of preterm infants to invasive microbial infections has been attributed to “immature” innate immune defenses. Monocytes are important innate immune sentinel cells critical in the defense against infection in blood. They achieve this via diverse mechanisms that include pathogen recognition receptor- and inflammasome-mediated detection of microbes, migration into infected tissues, and differentiation into M?s and dendritic cells, initiation of the inflammatory cascade by free radicals and cytokine/chemokine production, pathogen clearance by phagocytosis and intracellular killing, and the removal of apoptotic cells. Relatively little is known about these cells in preterm infants, especially about how their phenotype adapts to changes in the microbial environment during the immediate postnatal period. Overall, preterm monocytes exhibit attenuated proinflammatory cytokine responses following stimulation by whole bacterial or specific microbial components in vitro. These attenuated cytokine responses cannot be explained by a lack of intracellular signaling events downstream of pattern recognition receptors. This hyporesponsiveness also contrasts with mature, term-like phagocytosis capabilities detectable even in the most premature infant. Finally, human data on the effects of fetal chorioamnionitis on monocyte biology are incomplete and inconsistent. In this review, we present an integrated view of human studies focused on monocyte functions in preterm infants. We discuss how a developmental immaturity of these cells may contribute to preterm infants’ susceptibility to infections.

Background:Deficiencies in phagocytosis may contribute to the increased susceptibility of infants to early life infections. Data on phagocytosis of the major neonatal pathogens Staphylococcus epidermidis (SE), Staphylococcus aureus (SA), and Escherichia coli (EC) by preterm infant leukocytes are inconsistent.Methods:Cord and <24-h peripheral blood were collected from very preterm (<30.1 wks gestational age (GA)) and term (37–42 wks GA) infants. Monocyte and neutrophil phagocytosis of pHrodo-labeled SE, SA, and EC were analyzed using a small-volume flow cytometry assay, with simultaneous characterization of surface activation marker expression.Results:Preterm infants had lower proportions of monocytes and neutrophils capable of phagocytosis than term infants, but preterm infant phagocytes had higher phagocytic capacity. Phagocytosis was strongly correlated between cord and <24-h peripheral blood. Supplementation with exogenous complement significantly increased phagocytosis of EC but not of SE or SA. Monocyte human leukocyte antigen (HLA)-DR expression was lower in preterm infants but did not correlate with phagocytosis.Conclusion:There is no defect in phagocytosis by monocytes and neutrophils from preterm compared with term infants, although preterm infants possess fewer phagocytes, possibly contributing to susceptibility to bacterial infection. Further investigation into the development of postnatal phagocytic competence is warranted.

This review aims to interpret the current literature on the role of genetic and epigenetic factors in susceptibility to neonatal infection, a leading cause of early life mortality and morbidity.

Introduction:Staphylococcus epidermidis (SE) rarely causes infection in term infants but is a leading cause of late-onset sepsis in preterm infants. We hypothesized that the innate immune responses to SE in preterm infants are impaired in a gestational age (GA)-dependent manner.Methods:Cord and peripheral blood mononuclear cells (MNCs) were stimulated with SE bacteria, and a range of innate immune responses were assessed, including phagocytosis, intracellular killing, Toll-like receptor (TLR) pathway transcriptional activation, cytokine production, TLR2 and TLR4 expression, and cell signaling.Results:Phagocytosis and intracellular killing of SE bacteria were similar in neonatal and adult monocytes. Cytokine gene expression and protein synthesis increased in a GA-dependent manner, which was confirmed at the single-cell level. These GA-related effects were not associated with differences in expression of TLR2 or TLR4, nor with downstream activation of nuclear factor-?B or mitogen-activated protein kinase pathways.Discussion:The expression of TLRs, phagocytic capacity, and intracellular killing by monocytes develops early in fetal development, whereas the ability to mount a bacteria-induced cytokine response requires further maturation. The functional immaturity of monocyte activation pathways in the preterm infant may underpin their particular susceptibility to sepsis with commensal bacteria.

Background:In vitro investigations of human innate immune responses to extracellular bacteria commonly utilise killed preparations in preference to live organisms. The effects of the bacterial preparation method on the activation of innate signalling pathways by the common opportunistic pathogen Staphylococcus epidermidis (SE) are unknown.Materials and methods: Mononuclear cell cytokine expression patterns induced by live (LSE), heat-killed (HKSE) and ethanol-killed SE (EKSE) were characterized at the transcriptional and translational level. Toll-like receptor (TLR)-activating capacity of the preparations was analysed using TLR-transfected human embryonic kidney cells.Results: Live SE activated NF-κB, STAT1, type I interferon, and inflammasome pathways. Killed preparations engaged the NF-κB pathway, but had significantly lower capacity to activate other innate immune pathways.Conclusions: Killing of extracellular bacteria has significant qualitative and quantitative effects on key aspects of innate responses in vitro. Interpretation of in vitro data and extrapolation of findings should take into account the potential effects of bacterial preparation and should not assume that responses to killed bacteria are predictive of responses to live organisms.

ABSTRACTGroup B streptococcus (GBS) is an important cause of early- and late-onset sepsis in the newborn. Preterm infants have markedly increased susceptibility and worse outcomes, but their immunological responses to GBS are poorly defined. We compared mononuclear cell and whole-blood cytokine responses to heat-killed GBS (HKGBS) of preterm infants (gestational age [GA], 26 to 33 weeks), term infants, and healthy adults. We investigated the kinetics and cell source of induced cytokines and quantified HKGBS phagocytosis. HKGBS-induced tumor necrosis factor (TNF) and interleukin 6 (IL-6) secretion was significantly impaired in preterm infants compared to that in term infants and adults. These cytokines were predominantly monocytic in origin, and production was intrinsically linked to HKGBS phagocytosis. Very preterm infants (GA, <30 weeks) had fewer cytokine-producing monocytes, but nonopsonic phagocytosis ability was comparable to that for term infants and adults. Exogenous complement supplementation increased phagocytosis in all groups, as well as the proportion of preterm monocytes producing IL-6, but for very preterm infants, responses were still deficient. Similar defective preterm monocyte responses were observed in fresh whole cord blood stimulated with live GBS. Lymphocyte-associated cytokines were significantly deficient for both preterm and term infants compared to levels for adults. These findings indicate that a subset of preterm monocytes do not respond to GBS, a defect compounded by generalized weaker lymphocyte responses in newborns. Together these deficient responses may increase the susceptibility of preterm infants to GBS infection.

Group B streptococcus (GBS) is an important cause of early- and late-onset sepsis in the newborn. Preterm infants have markedly increased susceptibility and worse outcomes, but their immunological responses to GBS are poorly defined. We compared mononuclear cell and whole-blood cytokine responses to heat-killed GBS (HKGBS) of preterm infants (gestational age [GA], 26 to 33 weeks), term infants, and healthy adults. We investigated the kinetics and cell source of induced cytokines and quantified HKGBS phagocytosis. HKGBS-induced tumor necrosis factor (TNF) and interleukin 6 (IL-6) secretion was significantly impaired in preterm infants compared to that in term infants and adults. These cytokines were predominantly monocytic in origin, and production was intrinsically linked to HKGBS phagocytosis. Very preterm infants (GA, <30 weeks) had fewer cytokine-producing monocytes, but nonopsonic phagocytosis ability was comparable to that for term infants and adults. Exogenous complement supplementation increased phagocytosis in all groups, as well as the proportion of preterm monocytes producing IL-6, but for very preterm infants, responses were still deficient. Similar defective preterm monocyte responses were observed in fresh whole cord blood stimulated with live GBS. Lymphocyte-associated cytokines were significantly deficient for both preterm and term infants compared to levels for adults. These findings indicate that a subset of preterm monocytes do not respond to GBS, a defect compounded by generalized weaker lymphocyte responses in newborns. Together these deficient responses may increase the susceptibility of preterm infants to GBS infection.

Coagulase-negative staphylococci have emerged as the most common nosocomial pathogen in neonatal intensive care units worldwide. Our understanding of the interactions between coagulase-negative staphylococci and the immune system is incomplete, especially in the newborn. This review summarizes current knowledge on the human immune response to coagulase-negative staphylococci, with particular emphasis on the neonatal innate immune system.

Lately, we reported that topical application of coconut oil is safe and feasible in very preterm infants and that this intervention has beneficial effects on skin condition and may be associated with improved neonatal outcomes 1−3. This prophylactic measure is predominantly a nursing intervention; neonatal nurses apply the coconut oil and educate and supervise parents in its use as part of family integrated care. Here, we complement our published observations with the results of a detailed survey assessing neonatal nurses' perceptions and experiences in the application of topical coconut oil. This survey characterises neonatal nurses’ experiences with topical application of coconut oil to very preterm infants in a busy intensive care unit. The results clearly support the feasibility and general acceptability of this prophylactic intervention and highlight that this is easily integrated into the daily workflow without significant effects on workload.

To review current data on genetic factors contributing to the striking susceptibility of neonates to infectious diseases and other adverse outcomes.

Newborns and especially preterm infants show a unique susceptibility to severe bacterial infections that cause significant morbidity and mortality. As very few data are available on innate immune functions in human fetuses, we conducted a comprehensive study to investigate the expression of several adhesion molecules essentially involved in migration (CD11a, CD11b, CD11c, CD18, and CD62L). Furthermore, phagocytic activity, generation of respiratory burst products, and production of several proinflammatory cytokines were assessed. Various functions of the fetal innate immune system were demonstrated to be essentially different from those observed in term neonates or adults. Expression of several surface markers was significantly diminished on fetal granulocytes. Furthermore, a significantly reduced phagocytic activity of fetal granulocytes and monocytes was found, contrasted by an enhanced generation of reactive oxygen products. In addition, we demonstrate that significant numbers of fetal monocytes are capable of the production of proinflammatory cytokines in response to stimulation. However, the pattern of cytokine production is different from the more mature individuals the number of IL-6 – and tumor necrosis factor-–positive monocytes were significantly diminished, whereas more IL-8 –producing monocytes were found compared with adults. The results of our study add significantly to our understanding of the maturation and impairment of the innate immune response.

Newborns and especially preterm infants show a unique susceptibility to severe bacterial infections that cause significant morbidity and mortality. As very few data are available on innate immune functions in human fetuses, we conducted a comprehensive study to investigate the expression of several adhesion molecules essentially involved in migration (CD11a, CD11b, CD11c, CD18, and CD62L). Furthermore, phagocytic activity, generation of respiratory burst products, and production of several proinflammatory cytokines were assessed. Various functions of the fetal innate immune system were demonstrated to be essentially different from those observed in term neonates or adults. Expression of several surface markers was significantly diminished on fetal granulocytes. Furthermore, a significantly reduced phagocytic activity of fetal granulocytes and monocytes was found, contrasted by an enhanced generation of reactive oxygen products. In addition, we demonstrate that significant numbers of fetal monocytes are capable of the production of proinflammatory cytokines in response to stimulation. However, the pattern of cytokine production is different from the more mature individuals: the number of IL-6 – and tumor necrosis factor-a–positive monocytes were significantly diminished, whereas more IL-8 –producing monocytes were found compared with adults. The results of our study add significantly to our understanding of the maturation and impairment of the innate immune response.

To determine the frequency of in vivo activated TH1 lymphocytes, T‐cell subsets of 9 multiple sclerosis patients with active disease and 17 healthy controls were analyzed by immunostaining for CCR5, CD26, and their expression of interleukin‐2, interferon‐γ, and tumor necrosis factor‐α. The numbers of CCR5+interferon‐γ– and tumor necrosis factor‐α–producing T cells were significantly increased in the peripheral blood of multiple sclerosis patients. CCR5 expression may be a useful marker to identify effector cells in multiple sclerosis and could be used as a tool for monitoring disease activity. Ann Neurol 2000;47:269–273

To determine the frequency of in vivo activated TH1 lymphocytes, T-cell subsets of 9 multiple sclerosis patients with active disease and 17 healthy controls were analyzed by immunostaining for CCR5, CD26, and their expression of interleukin-2, interferon-γ, and tumor necrosis factor-α. The numbers of CCR5⁺ interferon-γ– and tumor necrosis factor-α–producing T cells were significantly increased in the peripheral blood of multiple sclerosis patients. CCR5 expression may be a useful marker to identify effector cells in multiple sclerosis and could be used as a tool for monitoring disease activity. Ann Neurol 2000;47:269–273

Infection is correlated with increased risk of neurodevelopmental sequelae in preterm infants. In modeling neonatal brain injury, Toll-like receptor agonists have often been used to mimic infections and induce inflammation. Using the most common cause of bacteremia in preterm infants, Staphylococcus epidermidis, we present a more clinically relevant neonatal mouse model that addresses the combined effects of bacterial infection together with subsequent hypoxic-ischemic brain insult.

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