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      Neonatal sepsis definitions from randomised clinical trials

      review-article
      1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 2 , 1 , 3 , 1 , 3 , 1 , 3 , 4 , 1 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 21 , 22 , 23 , 24 , 25 , 1 , 3 , 4 , 26 , 27 , , On behalf of the Infection, Inflammation, Immunology and Immunisation (I4) section of the European Society for Paediatric Research (ESPR)
      Pediatric Research
      Nature Publishing Group US

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          Abstract

          Introduction

          Neonatal sepsis is a leading cause of infant mortality worldwide with non-specific and varied presentation. We aimed to catalogue the current definitions of neonatal sepsis in published randomised controlled trials (RCTs).

          Method

          A systematic search of the Embase and Cochrane databases was performed for RCTs which explicitly stated a definition for neonatal sepsis. Definitions were sub-divided into five primary criteria for infection (culture, laboratory findings, clinical signs, radiological evidence and risk factors) and stratified by qualifiers (early/late-onset and likelihood of sepsis).

          Results

          Of 668 papers screened, 80 RCTs were included and 128 individual definitions identified. The single most common definition was neonatal sepsis defined by blood culture alone ( n = 35), followed by culture and clinical signs ( n = 29), and then laboratory tests/clinical signs ( n = 25). Blood culture featured in 83 definitions, laboratory testing featured in 48 definitions while clinical signs and radiology featured in 80 and 8 definitions, respectively.

          Discussion

          A diverse range of definitions of neonatal sepsis are used and based on microbiological culture, laboratory tests and clinical signs in contrast to adult and paediatric sepsis which use organ dysfunction. An international consensus-based definition of neonatal sepsis could allow meta-analysis and translate results to improve outcomes.

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          Most cited references130

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          The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).

          Definitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathobiology (changes in organ function, morphology, cell biology, biochemistry, immunology, and circulation), management, and epidemiology of sepsis, suggesting the need for reexamination.
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            Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection.

            Neonatal infections are frequent complications of extremely low-birth-weight (ELBW) infants receiving intensive care. To determine if neonatal infections in ELBW infants are associated with increased risks of adverse neurodevelopmental and growth sequelae in early childhood. Infants weighing 401 to 1000 g at birth (born in 1993-2001) were enrolled in a prospectively collected very low-birth-weight registry at academic medical centers participating in the National Institute of Child Health and Human Development Neonatal Research Network. Neurodevelopmental and growth outcomes were assessed at a comprehensive follow-up visit at 18 to 22 months of corrected gestational age and compared by infection group. Eighty percent of survivors completed the follow-up visit and 6093 infants were studied. Registry data were used to classify infants by type of infection: uninfected (n = 2161), clinical infection alone (n = 1538), sepsis (n = 1922), sepsis and necrotizing enterocolitis (n = 279), or meningitis with or without sepsis (n = 193). Cognitive and neuromotor development, neurologic status, vision and hearing, and growth (weight, length, and head circumference) were assessed at follow-up. The majority of ELBW survivors (65%) had at least 1 infection during their hospitalization after birth. Compared with uninfected infants, those in each of the 4 infection groups were significantly more likely to have adverse neurodevelopmental outcomes at follow-up, including cerebral palsy (range of significant odds ratios [ORs], 1.4-1.7), low Bayley Scales of Infant Development II scores on the mental development index (ORs, 1.3-1.6) and psychomotor development index (ORs, 1.5-2.4), and vision impairment (ORs, 1.3-2.2). Infection in the neonatal period was also associated with impaired head growth, a known predictor of poor neurodevelopmental outcome. This large cohort study suggests that neonatal infections among ELBW infants are associated with poor neurodevelopmental and growth outcomes in early childhood. Additional studies are needed to elucidate the pathogenesis of brain injury in infants with infection so that novel interventions to improve these outcomes can be explored.
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              The global burden of paediatric and neonatal sepsis: a systematic review

              The incidence of sepsis is highest in neonates and children, yet the global burden of sepsis in these age groups has not been assessed. We reviewed available evidence from observational epidemiological studies to estimate the global burden and mortality of sepsis in neonates and children. We did a systematic review and meta-analysis of studies reporting population-based sepsis incidence in neonates and children, published between 1979 and 2016. Our search yielded 1270 studies, 23 of which met the inclusion criteria; 16 were from high-income countries and seven from middle-income countries. 15 studies from 12 countries reported complete data and were included in the meta-analysis. We found an aggregate estimate of 48 (95% CI 27-86) sepsis cases and 22 (14-33) severe sepsis cases in children per 100 000 person-years. Mortality ranged from 1% to 5% for sepsis and 9% to 20% for severe sepsis. The population-level estimate for neonatal sepsis was 2202 (95% CI 1099-4360) per 100 000 livebirths, with mortality between 11% and 19%. Extrapolating these figures on a global scale, we estimate an incidence of 3·0 million cases of sepsis in neonates and 1·2 million cases in children. Although these results confirm that sepsis is a common and frequently fatal condition affecting neonates and children globally, few population-based data are available from low-income settings and the lack of standardisation of diagnostic criteria and definition of sepsis in the reviewed studies are obstacles to the accurate estimation of global burden. Robust epidemiological monitoring to define global sepsis incidence and mortality in children is urgently needed.
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                Author and article information

                Contributors
                Eleanor.molloy@tcd.ie
                Journal
                Pediatr Res
                Pediatr Res
                Pediatric Research
                Nature Publishing Group US (New York )
                0031-3998
                1530-0447
                6 November 2021
                6 November 2021
                2023
                : 93
                : 5
                : 1141-1148
                Affiliations
                [1 ]GRID grid.8217.c, ISNI 0000 0004 1936 9705, Discipline of Paediatrics, Trinity College Dublin, , the University of Dublin & Children’s Hospital Ireland (CHI) at Tallaght, ; Dublin, Ireland
                [2 ]GRID grid.8217.c, ISNI 0000 0004 1936 9705, John Stearne Medical Library, , Trinity College Dublin, St. James’ Hospital, ; Dublin, Ireland
                [3 ]GRID grid.416409.e, ISNI 0000 0004 0617 8280, Trinity Translational Medicine Institute, , St James Hospital, ; Dublin, Ireland
                [4 ]GRID grid.8217.c, ISNI 0000 0004 1936 9705, Trinity Research in Childhood Centre (TRiCC), , Trinity College Dublin, ; Dublin, Ireland
                [5 ]GRID grid.413202.6, ISNI 0000 0004 0626 2490, Department of Paediatrics, , Tergooi Hospital, ; Blaricum, The Netherlands
                [6 ]GRID grid.7177.6, ISNI 0000000084992262, Department of Paediatrics, Amsterdam UMC, , University of Amsterdam, Emma Children’s Hospital, ; Amsterdam, The Netherlands
                [7 ]GRID grid.414659.b, ISNI 0000 0000 8828 1230, Neonatal Health and Development, , Telethon Kids Institute, ; Perth, WA Australia
                [8 ]GRID grid.415259.e, ISNI 0000 0004 0625 8678, Neonatal Directorate, King Edward Memorial Hospital for Women, ; Perth, WA Australia
                [9 ]GRID grid.461578.9, Radboud Institute for Health Sciences, Department of Neonatology, , Radboud University Medical Center, Amalia Children’s Hospital, ; Nijmegen, The Netherlands
                [10 ]GRID grid.239585.0, ISNI 0000 0001 2285 2675, Division of Neonatal-Perinatal Medicine, Department of Pediatrics, , Columbia University Medical Center, ; New York City, NY USA
                [11 ]GRID grid.15276.37, ISNI 0000 0004 1936 8091, Department of Pediatrics, , University of Florida, ; Gainesville, FL USA
                [12 ]GRID grid.15276.37, ISNI 0000 0004 1936 8091, Department of Pathology, Immunology, and Laboratory Medicine, , University of Florida, ; Gainesville, FL USA
                [13 ]GRID grid.78028.35, ISNI 0000 0000 9559 0613, Department of Neonatology, , Pirogov Russian National Research Medical University, ; Moscow, Russia
                [14 ]GRID grid.411984.1, ISNI 0000 0001 0482 5331, Neonatology, Clinic for Paediatric Cardiology, Intensive Care and Neonatology, , University Medical Centre Göttingen, ; Göttingen, Germany
                [15 ]GRID grid.412826.b, ISNI 0000 0004 0611 0905, Neonatal Unit, Department of Obstetrics and Gynecology, , Motol University Hospital and Second Faculty of Medicine, ; Prague, Czech Republic
                [16 ]GRID grid.4491.8, ISNI 0000 0004 1937 116X, Institute of Pathological Physiology, First Faculty of Medicine, , Charles University, ; Prague, Czech Republic
                [17 ]GRID grid.8515.9, ISNI 0000 0001 0423 4662, Clinic of Neonatology, Department Mother-Woman-Child, , Lausanne University Hospital and University of Lausanne, ; Lausanne, Switzerland
                [18 ]GRID grid.1003.2, ISNI 0000 0000 9320 7537, Paediatric Critical Care Research Group, , Child Health Research Centre, University of Queensland, ; Brisbane, Australia
                [19 ]GRID grid.240562.7, Paediatric Intensive Care Unit, , Queensland Children’s Hospital, ; Brisbane, Australia
                [20 ]GRID grid.5734.5, ISNI 0000 0001 0726 5157, Department of Pediatrics, , Bern University Hospital, University of Bern, ; Bern, Switzerland
                [21 ]GRID grid.416135.4, ISNI 0000 0004 0649 0805, Department of Pediatrics, Division of Neonatology, , Erasmus MC-Sophia Children’s Hospital, ; Rotterdam, The Netherlands
                [22 ]GRID grid.40263.33, ISNI 0000 0004 1936 9094, Department of Pediatrics, Women & Infants Hospital of Rhode Island, , Alpert Medical School of Brown University, ; Providence, USA
                [23 ]GRID grid.262962.b, ISNI 0000 0004 1936 9342, Division of Neonatology, , Saint Louis University, Edward Doisy Research Center, ; St. Louis, MO USA
                [24 ]GRID grid.415996.6, ISNI 0000 0004 0400 683X, Institute of Translational Medicine, , University of Liverpool, Centre for Women’s Health Research, Liverpool Women’s Hospital, ; Liverpool, UK
                [25 ]GRID grid.7445.2, ISNI 0000 0001 2113 8111, Neonatal Medicine, School of Public Health, Faculty of Medicine, Chelsea and Westminster campus, , Imperial College London, ; London, UK
                [26 ]GRID grid.411886.2, ISNI 0000 0004 0488 4333, Paediatrics, Coombe Women’s and Infant’s University Hospital, ; Dublin, Ireland
                [27 ]Neonatology, CHI at Crumlin, Dublin, Ireland
                Article
                1749
                10.1038/s41390-021-01749-3
                10132965
                34743180
                24897cb3-aad6-4d28-b3ba-848d4f6ca875
                © The Author(s) 2021

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 9 July 2021
                : 27 August 2021
                : 31 August 2021
                Categories
                Systematic Review
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                © International Pediatric Research Foundation, Inc 2023

                Pediatrics
                Pediatrics

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