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      Neurodevelopmental Outcomes at 18–24 Months of Corrected Age in Very Low Birth Weight Infants with Late-onset Sepsis

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          Abstract

          Background

          Preterm infants are prone to sepsis owing to their immature innate immunity and prolonged hospitalization. We aimed to evaluate the association between late-onset sepsis (LOS) during hospitalization and neurodevelopmental delay at 18–24 months of corrected age in very low birth weight infants (VLBWIs), and to ascertain this association when adjusted for perinatal risk factors.

          Methods

          This is a population-based study of VLBWIs born at 23–32 weeks of gestation between January 2014 and December 2017 who were enrolled in the Korean Neonatal Network. Bayley scales of infant development were evaluated at 18–24 months of corrected age in 2,098 infants. To test for LOS as a risk factor for neurodevelopmental delay, multiple logistic regression was used and adjusted for parental education status and clinical variables.

          Results

          Blood culture positive LOS was identified in 419 (20.0%) infants. Cognitive and motor delays were found in 392 (18.7%) and 347 (16.5%) infants, respectively. When multivariate analysis was performed, LOS had a significant association with cognitive delay (odds ratio, 1.48; 95% confidence interval, 1.02–2.16), but no association with motor delay in VLBWIs. Both delays were significantly more frequent in cases of intraventricular hemorrhage (IVH) ≥ grade 3, periventricular leukomalacia (PVL), and intrauterine growth restriction (IUGR) and duration of mechanical ventilation. Male sex and necrotizing enterocolitis ≥ grade 2 had an effect on motor delay, whereas paternal college graduation affected cognitive delay.

          Conclusion

          In VLBWIs with LOS, there is a heightened risk of cognitive delays at 18–24 months of corrected age. Brain injury, such as severe IVH and PVL, duration of mechanical ventilation, and IUGR, were also associated with cognitive and motor delays.

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          Most cited references38

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          A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants

          Background The aim of this study was to revise the 2003 Fenton Preterm Growth Chart, specifically to: a) harmonize the preterm growth chart with the new World Health Organization (WHO) Growth Standard, b) smooth the data between the preterm and WHO estimates, informed by the Preterm Multicentre Growth (PreM Growth) study while maintaining data integrity from 22 to 36 and at 50 weeks, and to c) re-scale the chart x-axis to actual age (rather than completed weeks) to support growth monitoring. Methods Systematic review, meta-analysis, and growth chart development. We systematically searched published and unpublished literature to find population-based preterm size at birth measurement (weight, length, and/or head circumference) references, from developed countries with: Corrected gestational ages through infant assessment and/or statistical correction; Data percentiles as low as 24 weeks gestational age or lower; Sample with greater than 500 infants less than 30 weeks. Growth curves for males and females were produced using cubic splines to 50 weeks post menstrual age. LMS parameters (skew, median, and standard deviation) were calculated. Results Six large population-based surveys of size at preterm birth representing 3,986,456 births (34,639 births < 30 weeks) from countries Germany, United States, Italy, Australia, Scotland, and Canada were combined in meta-analyses. Smooth growth chart curves were developed, while ensuring close agreement with the data between 24 and 36 weeks and at 50 weeks. Conclusions The revised sex-specific actual-age growth charts are based on the recommended growth goal for preterm infants, the fetus, followed by the term infant. These preterm growth charts, with the disjunction between these datasets smoothing informed by the international PreM Growth study, may support an improved transition of preterm infant growth monitoring to the WHO growth charts.
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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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              Neonatal sepsis.

              Neonatal sepsis is the cause of substantial morbidity and mortality. Precise estimates of neonatal sepsis burden vary by setting. Differing estimates of disease burden have been reported from high-income countries compared with reports from low-income and middle-income countries. The clinical manifestations range from subclinical infection to severe manifestations of focal or systemic disease. The source of the pathogen might be attributed to an in-utero infection, acquisition from maternal flora, or postnatal acquisition from the hospital or community. The timing of exposure, inoculum size, immune status of the infant, and virulence of the causative agent influence the clinical expression of neonatal sepsis. Immunological immaturity of the neonate might result in an impaired response to infectious agents. This is especially evident in premature infants whose prolonged stays in hospital and need for invasive procedures place them at increased risk for hospital-acquired infections. Clinically, there is often little difference between sepsis that is caused by an identified pathogen and sepsis that is caused by an unknown pathogen. Culture-independent diagnostics, the use of sepsis prediction scores, judicious antimicrobial use, and the development of preventive measures including maternal vaccines are ongoing efforts designed to reduce the burden of neonatal sepsis.
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                Author and article information

                Journal
                J Korean Med Sci
                J Korean Med Sci
                JKMS
                Journal of Korean Medical Science
                The Korean Academy of Medical Sciences
                1011-8934
                1598-6357
                13 July 2021
                06 September 2021
                : 36
                : 35
                : e205
                Affiliations
                Division of Neonatology, Department of Pediatrics, Ewha Womans University College of Medicine, Seoul, Korea.
                Author notes
                Address for Correspondence: So-Yeon Shim, MD, PhD. Division of Neonatology, Department of Pediatrics, Ewha Womans University College of Medicine, 260 Gonghang-daero, Gangseo-gu, Seoul 07804, Korea. simso@ 123456ewha.ac.kr
                Author information
                https://orcid.org/0000-0001-7627-6802
                https://orcid.org/0000-0002-3851-9073
                https://orcid.org/0000-0002-1685-4276
                Article
                10.3346/jkms.2021.36.e205
                8422039
                34490752
                a3a0f745-36a2-4dea-9858-d850df5b5cbe
                © 2021 The Korean Academy of Medical Sciences.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 25 December 2020
                : 09 July 2021
                Funding
                Funded by: Korea Centers for Disease Control and Prevention, CrossRef https://doi.org/10.13039/501100003669;
                Award ID: 2019ER710301
                Funded by: Ministry of Education of the Republic of Korea, CrossRef https://doi.org/10.13039/501100002701;
                Funded by: National Research Foundation of Korea, CrossRef https://doi.org/10.13039/501100003725;
                Award ID: NRF-2016S1A3A2925502
                Funded by: Ewha Womans University Medical Center
                Award ID: 201900560001
                Categories
                Original Article
                Pediatrics

                Medicine
                late-onset sepsis,very low birth weight infant,developmental delay
                Medicine
                late-onset sepsis, very low birth weight infant, developmental delay

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