Severe brain injury and trends of gestational-age-related neurodevelopmental outcomes in infants born very preterm: A population cohort study.

AIM: To investigate the impact of severe neonatal brain injury (SNBI) on gestational age-related trends in neurodevelopmental impairment (NDI) outcome in infants born very preterm. METHOD: A population-based cohort study recruited 1091 infants born at a gestational age of less than 31 weeks between 2011 and 2020. The trends in neonatal morbidities, mortality, and 24-month NDI severity (no/mild, moderate, severe) by epoch (2011-2015, 2016-2020) and gestational age (22-25 weeks, 26-28 weeks, 29-30 weeks) were determined in infants with and without SNBI inclusion. RESULTS: There was increased antenatal steroid use and higher maternal education and socioeconomic status over time. The rates of neonatal morbidities and mortality had no temporal changes. Among 825 infants with follow-up, those in the 22 to 25 weeks gestational age group had declining trends in cerebral palsy and severe cognitive impairment, with decreased rates of severe NDI from 19% to 8% across epochs, particularly in those without SNBI (from 16% to 2%). Relative to its occurrence in epoch 2011 to 2015, risk of severe NDI was significantly reduced in epoch 2016 to 2020 (adjusted relative risk 0.39, 95% confidence interval 0.16-0.96) for infants born at 22 to 25 weeks gestational age, and the risk dropped even lower in these infants without SNBI (0.12, 0.02-0.84). INTERPRETATION: Infants born at 22 to 25 weeks gestational age had decreased rates of severe NDI in the decade between 2011 and 2020, particularly those without SNBI. The improvement might be attributed to better perinatal/neonatal and after-discharge care.

The Quartile Levels of Thyroid-Stimulating Hormone by Newborn Screening Stratified Risks of Neurodevelopmental Impairment in Extremely Preterm Infants - A Population Cohort Study.

BACKGROUND: To evaluate whether thyroid-stimulating hormone (TSH) by newborn screening (NBS) at birth and at discharge can be surrogate markers for neurodevelopmental impairment (NDI) in extremely preterm infants. METHODS: The population cohort enrolled infants born <29 weeks' gestation in 2008 - 2020 in southern Taiwan. Infants with a maternal history of thyroid disorders and infants who required thyroxine supplementation during hospitalization were excluded. TSH levels by NBS at birth and at term-equivalent age (TEA)/discharge were respectively categorized into the lowest quartile, the interquartile range, and the highest quartile, which were correlated to NDI outcomes. RESULTS: Among 392 patients with paired TSH data, 358 (91%) were prospectively followed until corrected age 24 months. At birth, infants with lowest-quartile TSH had higher NDI risks (OR 2.3, 95% CI 1.3 - 4.1, P = 0.004) compared to infants with interquartile-range TSH. Conversely, by TEA/discharge, infants with highest-quartile TSH had increased NDI (OR 1.9, 1.0 - 3.4, P = 0.03). By paired TSH categories, infants persistently in the lowest TSH quartile (48%, aOR 4.4, 1.4 - 14.5, P = 0.01) and those with a shift from interquartile range to the highest quartile (32%, aOR 2.7, 1.0 - 7.4, P = 0.046) had increased NDI risks compared with the reference with consistent interquartile-range TSH. CONCLUSIONS: Extremely preterm infants persistently in the lowest-quartile TSH level at birth and at discharge had the highest NDI risk. TSH quartile levels by NBS may serve as a population surrogate biomarker for assessing NDI risks in infants born extremely preterm.

Trends in Gestational Age-Related Intelligence Outcomes of School-Age Children Born Very Preterm from 2001 to 2015 in Taiwan.

OBJECTIVE: To investigate whether gestational age (GA)-related intelligence outcomes of children born very preterm improved over time. STUDY DESIGN: A multicenter cohort study recruited 4717 infants born at GA <31 weeks and admitted to neonatal intensive care units between 2001 and 2015 in Taiwan. Intelligence outcomes at age 5.5 years were classified by intelligent quotient (IQ) into no cognitive impairment (IQ > -1 SD), mild cognitive impairment (IQ = -1∼-2 SD), and moderate/severe cognitive impairment (IQ < -2 SD). Trends were assessed for neonatal morbidities, mortality, and intelligence outcomes by birth epoch (2001-2003, 2004-2006, 2007-2009, 2010-2012, 2013-2015) and GA (23-24, 25-26, 27-28, 29-30 weeks). RESULTS: Maternal education levels increased and rates of brain injury and mortality decreased over time. Among the 2606 children who received IQ tests, the rates of no, mild, and moderate/severe cognitive impairment were 54.5%, 30.5%, and 15.0%, respectively. There were significant trends in the increasing rates of no cognitive impairment and declining rates of mild and moderate/severe cognitive impairment in all GA groups across the 5 birth epochs. Relative to the occurrence in 2001-2003, the odds were significantly reduced for moderate/severe cognitive impairment from 2007-2009 (aOR 0.49, 95% CI 0.30-0.81) to 2013-2015 (0.35, 0.21-0.56) and for mild cognitive impairment from 2010-2012 (0.54, 0.36-0.79) to 2013-2015 (0.36, 0.24-0.53). CONCLUSIONS: For children born very preterm between 2001 and 2015 in Taiwan, the improvement of maternal education levels and improvements in neonatal brain injury and mortality were temporally associated with trends of decreasing intellectual impairment at school age across all GA groups.

Preceding risks and mortality outcomes of different neonatal acute kidney injury in preterm infants.

BACKGROUND: The aim of the study was to examine preceding risks and mortality outcomes of oliguric and non-oliguric acute kidney injury (AKI) in very preterm infants. METHODS: Infants born ≤30 weeks' gestation were included. AKI was diagnosed based on neonatal Kidney Disease: Improving Global Outcomes criteria and was classified as oliguric and non-oliguric according to the urine-output criteria. We used modified Poisson and Cox proportional-hazards models for statistical comparisons. RESULTS: Of 865 enrolled infants (gestational age 27.2 ± 2.2 weeks and birth weight 983 ± 288 gm), 204 (23.6%) developed AKI. Before AKI, the oliguric AKI group had significantly higher prevalence of small-for-gestational age (p = 0.008), lower 5-min Apgar score (p = 0.009) and acidosis (p = 0.009) on admission, and hypotension (p = 0.008) and sepsis (p = 0.001) during admission than the non-oliguric AKI group. Oliguric (adjusted risk ratio 3.58, 95% CI 2.33-5.51; adjusted hazard ratio 4.93, 95% CI 3.14-7.72) instead of non-oliguric AKI had significantly higher mortality risks than no AKI. Oliguric AKI showed significantly higher mortality risks than non-oliguric AKI, irrespective of serum creatinine and severity of AKI. CONCLUSIONS: Categorizing AKI as oliguric and non-oliguric was crucial because of the distinct preceding risks and mortality outcomes of these two types of AKI in very preterm neonates. IMPACT: The differences of the underlying risks and prognosis between oliguric and non-oliguric AKI in very preterm infants remain unclear. We found that oliguric AKI, but not non-oliguric AKI, carries higher mortality risks than infants without AKI. Oliguric AKI possessed higher mortality risks than non-oliguric AKI, irrespective of concomitant serum creatinine elevation and severe AKI. Oliguric AKI is more associated with prenatal small-for-the-gestational age and perinatal and postnatal adverse events, while non-oliguric AKI is associated with nephrotoxins exposures. Our finding highlighted the importance of oliguric AKI and is helpful in developing future protocol in neonatal critical care.

Risk patterns associated with transient hearing impairment and permanent hearing loss in infants born very preterm: A retrospective study.

AIM: To determine the risk patterns associated with transient hearing impairment (THI) and permanent hearing loss (PHL) of infants born very preterm who failed hearing screenings. METHOD: We enrolled 646 infants (347 males, 299 females) born at no more than 30 weeks' gestation between 2006 and 2020 who received auditory brainstem response screening at term-equivalent age. Audiological examinations of infants who failed the screening revealed THI, when hearing normalized, or PHL, defined as a persistent unilateral or bilateral hearing threshold above 20 dB. Principal component analysis (PCA) was used to characterize risk patterns. RESULTS: Among the 646 infants, 584 (90.4%) had normal hearing, 42 (6.5%) had THI, and 20 (3.1%) had PHL. Compared with the group with normal hearing, the THI and PHL groups had significantly higher rates of neurodevelopmental impairment at 24 months corrected age. PCA of risk patterns showed the THI group and especially the PHL group had more severe haemodynamic and respiratory instability. Moreover, severe intraventricular haemorrhage (IVH) was also a risk for PHL. Propensity score matching revealed an association of haemodynamic and respiratory instability with PHL. INTERPRETATION: In infants born preterm, the severity and duration of haemodynamic and respiratory instability are risk patterns for both THI and PHL; severe IVH is an additional risk for PHL. WHAT THIS PAPER ADDS: Neurodevelopmental delay was more common in infants born preterm who failed hearing screening. Principal component analysis revealed the risk patterns associated with hearing impairment. Haemodynamic-respiratory instability was associated with transient and permanent hearing impairment outcomes. Severe haemodynamic-respiratory instability and intraventricular haemorrhage was associated with permanent hearing loss.

Early-life respiratory trajectories and neurodevelopmental outcomes in infants born very and extremely preterm: A retrospective study.

AIM: To determine whether early-life respiratory trajectories are associated with neurodevelopmental impairment (NDI) in infants born very and extremely preterm. METHOD: The daily type of respiratory supports in the first 8 weeks after birth were analysed in 546 infants (285 males, 261 females; median gestational age = 28.0 weeks, interquartile range = 3 weeks), comprising 301 infants born very preterm (gestation = 28-30 weeks) and 245 infants born extremely preterm (gestation <28 weeks), who survived to discharge from 2004 to 2018 and received follow-up assessment by Bayley Scales of Infant and Toddler Development at a corrected age of 24 months. NDI included cognition or motor impairment, moderate and severe cerebral palsy, or visual and hearing impairment. RESULTS: Clustering analysis identified three respiratory patterns with increasing severity: improving; slowly improving; and delayed improvement. These were significantly associated with increasing rates of NDI in infants born very and extremely preterm and smaller head circumference in infants born extremely preterm (both p < 0.001). By day 28, the proportion of infants who were under different categories of ventilation support significantly differed according to the three trajectory groups in infants born very and extremely preterm (both p < 0.05). Models that included adverse respiratory trajectories demonstrated more negative impacts on neurodevelopment than those without. INTERPRETATION: An adverse early-life respiratory trajectory was associated with NDI at follow-up, especially in infants born extremely preterm, suggesting a lung-brain axis of preterm birth. WHAT THIS PAPER ADDS: Clustering analysis identified three respiratory trajectories with increasing severity in infants born preterm. Increasing severity of respiratory trajectories was associated with increasing rates of neurodevelopmental impairment. Adverse respiratory trajectories had a significantly negative impact on neurodevelopmental outcomes.

OBJETIVO: Determinar se as trajetórias respiratórias no início da vida estão associadas ao comprometimento do neurodesenvolvimento (CND) em bebês nascidos muito e extremamente prematuros. MÉTODOS: O tipo diário de suporte respiratório nas primeiras 8 semanas após o nascimento foi analisado em 546 bebês (285 meninos, 261 meninas; idade gestacional mediana = 28,0 semanas, intervalo interquartil = 3 semanas), compreendendo 301 bebês nascidos muito prematuros (gestação = 28-30 semanas) e 245 bebês nascidos extremamente prematuros (gestação < 28 semanas), que sobreviveram à alta entre 2004 e 2018 e receberam avaliação de seguimento por meio da Bayley Scales of Infant and Toddler Development na idade corrigida de 24 meses. O CND incluiu deficiência cognitiva ou motora, paralisia cerebral moderada e grave ou deficiência visual e auditiva. RESULTADOS: A análise de agrupamento identificou três padrões respiratórios com gravidade crescente: melhorando; melhorando lentamente; e melhora tardia. Estes foram significativamente associados com taxas crescentes de CND em bebês nascidos muito e extremamente prematuros e menor perímetro cefálico em bebês nascidos extremamente prematuros (ambos p < 0,001). No dia 28, a proporção de bebês que estavam sob diferentes categorias de suporte ventilatório diferiu significativamente de acordo com os três grupos de trajetória em bebês nascidos muito prematuros e extremamente prematuros (ambos p < 0,05). Os modelos que incluíram trajetórias respiratórias adversas demonstraram mais impactos negativos no neurodesenvolvimento do que aqueles sem. INTERPRETAÇÃO: Uma trajetória respiratória adversa no início da vida foi associada ao CND no seguimento, especialmente em bebês nascidos extremamente prematuros, sugerindo um eixo pulmão-cérebro de nascimento prematuro.

Effect of first-month head-size growth trajectory on cognitive outcomes in preterm infants.

BACKGROUND: To examine whether the patterns of head-size growth trajectory in the first month after birth are associated with different susceptibility to cognitive impairment outcomes at age 24 months. METHODS: This retrospective cohort study included 590 infants of very-preterm survivors born between 2001 and 2016 receiving neurodevelopmental assessment at age 24 months. 403 children were enrolled for analysis after excluding infants with small-for-gestational age and severe brain injury. The head circumference (HC) growth evaluated weekly in the first month after birth compared to the at-birth HC was analyzed using group-based trajectory modeling. Neurocognition outcomes were determined as normal, borderline delay, or impaired using the Bayley Scales of Infant Development. RESULTS: The HC growth dynamics in the first month after birth showed three trajectory patterns: delayed catch-up (31.5%), slow catch-up (54.0%), and fast catch-up (14.5%), which significantly corresponded to different rates of impaired cognition at 19.5%, 6.0%, and 8.5%, respectively (p < 0.001). While 60% of the fast catch-up group had normal cognition, only one-third of the delayed catch-up group showed normal cognition. Three neonatal risk factors, gestational age (p = 0.006), respiratory distress syndrome requiring surfactant therapy (p = 0.012), and hemodynamically significant patent ductus arteriosus requiring intervention (p = 0.047) significantly affected HC growth trajectory patterning that led to cognitive impairment outcomes at follow-up. CONCLUSION: Preterm infants with delayed catch-up of head-size growth in the first month of age is susceptible to cognitive impairment outcome.

Trends in survival, neonatal morbidity and neurodevelopmental outcome of very preterm infants in Tainan, Southern Taiwan, 1995-2016.

BACKGROUND: Using regression modeling analysis to investigate the breakpoints of the trends in survival-without-major-neonatal-morbidities (MNM) or -without-neurodevelopmental- impairment (NDI) by year and gestational age (GA) in preterm infants. METHODS: We enrolled 2237 preterm infants (GA < 32 weeks) in Tainan, Taiwan. The trends in survival-without-MNM or -without-NDI by year (1995-2016) and GA (23-31 weeks), and the epochs and GA ranges with distinct changes were examined. Adjusted rate ratios (aRR) (95% confidence interval [CI]) were calculated using the rates in infants born at 23 weeks in 1995 as the reference. RESULTS: For yearly trend, there were three epochs (1995-2000, 2001-2006, 2007-2016) with distinct changes in the rates of survival-without-MNM (aRR [95% CI] 1.07 [1.02-1.12], 1.04 [1.02-1.07], 1.02 [1.01-1.04]) and -without-NDI (1.03 [1.02-1.07], 1.02 [1.01-1.04], 1.01 [0.98-1.04]). For GA trend, the three GA ranges with different increases in the rates of survival-without-MNM were 23+0-26+6 (1.60 [1.31-1.94]), 27+0-28+6 (1.24 [1.14-1.34]) and 29+0-31+6 weeks (1.17 [1.02-1.34]), while those in the rates of survival-without-NDI were 23+0-25+6 (1.14 [1.03-1.25]), 26+0-28+6 (1.06 [1.02-1.12]) and 29+0-31+6 weeks (1.04 [1.02-1.07]). The trends in survival-without-MNM and -without-NDI increased over years in infants with GA 25-31 but not < 25 weeks. CONCLUSION: The yearly trends in survival-without-MNM and -without-NDI had steady increases from 1995 to 2016 with distinct changes in three epochs, and the GA trends also increased with different rates per week in three GA ranges. Infants with GA < 25 weeks did not improve on the rates of survival-without-MNM or -without-NDI per year from 1995 to 2016.

Serum brain-derived neurotrophic factor and neurocognitive function in children with type 1 diabetes.

BACKGROUND/PURPOSE: This study aimed to clarify whether brain-derived neurotrophic factor (BDNF) is a biomarker for cognitive dysfunction in children with type 1 diabetes. METHODS: We conducted a cross-sectional case-control study of children aged between 6 and 18 years with type 1 diabetes and healthy volunteers. Serum BDNF level was measured in all of the studied children, and they all underwent intelligence tests with the Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV). We further compared the cognitive function and BDNF levels in the diabetic children with positive glutamic acid decarboxylase 65 antibody (GAD65-Ab) and those with negative GAD65-Ab. RESULTS: Forty-five children with type 1 diabetes (mean age 14.0 ± 2.6 years, 42% male) and 50 normal controls (mean age 13.2 ± 2.3 years, 54% male) were recruited. The serum BDNF level was significantly lower in the diabetes group than in the controls (15.92 ± 7.2 vs. 18.5 ± 5.1 ng/mL, respectively, t = -2.03, p = 0.045) and much lower in the subgroup with GAD65-Ab positive type 1 diabetes. The average Full-Scale IQ, verbal comprehension, perceptual reasoning and working memory scores in the diabetes group were significantly lower than in the controls (all p < 0.05). Among the children with type 1 diabetes, poor glycemic control was related to lower general cognitive abilities (r = -0.34, p < 0.02), lower verbal comprehension (r = -0.305, p < 0.05), and lower perceptual reasoning scores (r = -0.346, p = 0.02). CONCLUSION: The children with type 1 diabetes had a lower serum BDNF level and poorer neurocognitive function than normal healthy children, especially those with GAD65-Ab positive diabetes. Poor glycemic control was correlated with worse cognitive performance.

Quantitative analysis of intraoperative electrocorticography mirrors histopathology and seizure outcome after epileptic surgery in children.

BACKGROUND: Epileptic surgery is the potentially curative treatment for children with refractory seizures. The study aimed to quantify and analyze high frequency oscillation (HFO) ripples and interictal epileptiform discharges (EDs) in intraoperative electrocorticography (ECoG) between malformation of cortical dysplasia (MCD) and non-MCD children with MRI-lesional focal epilepsy, and evaluate of seizure outcomes after epileptic surgery. METHODS: The intraoperative ECoG was performed before and after lesionectomy. Quantifications of HFO ripples and interictal EDs of ECoG by frequency, amplitude, and foci of intraoperative ECoG were performed based on electrode location, and the characteristics of ECoG recordings were analyzed in each patient based on their histopathology. Seizure outcome after surgery according to their quantitative ECoG findings was analyzed. RESULTS: Frequency of EDs and HFO ripple rates in preresection ECoG were significantly higher in children with MCD compared with non-MCD (p = 0.018 and p = 0.002, respectively). Higher frequencies of EDs and ripple rates in preresection ECoG were observed in residual seizures than in seizure-free children (p = 0.045 and p = 0.005, respectively). Clinically, children with residual seizures after surgery were significantly younger at the onset, had a trend of higher seizure frequency and higher spike frequency of presurgical videoEEG. CONCLUSION: Our results suggested that quantification of intraoperative ECoG predicted seizure outcomes and reflected different ED pattern and frequencies between MCD and non-dysplastic histopathology among children who underwent resective epileptic surgery. The results of our study were encouraging and indicated that intraoperative ECoG improved the outcomes of surgery in children with epilepsy.

Early Blood Biomarkers Distinguish Inflammation from Neonatal Hypoxic-Ischemia Encephalopathy.

Neonatal hypoxic-ischemic encephalopathy is the most common cause of neurological disability in infancy. Superimposed inflammation may further worsen neurological outcomes. Reliable biomarkers which are both sensitive to hypoxic-ischemia and inflammation are critically needed. We tested plasma osteopontin (OPN) and glial fibrillary astrocytic protein (GFAP) within the reported therapeutic window (90 min after hypoxic-ischemic (HI) injury) in neonatal rats with different HI severity and inflammation. Two different HI severity groups (mild-HI with 75 min hypoxia and severe-HI with 150 min hypoxia) were established. Inflammation-sensitized HI brain injury induced by lipopolysaccharide (LPS) further increased apoptotic neurons and infarct volumes. In HI alone groups, OPN was significantly decreased (p < 0.001) but GFAP was slightly increased (p < 0.05) at 90 min after HI either in mild-HI or severe-HI compared with naïve group. In LPS-sensitized HI groups, both OPN and GFAP were significantly increased either in LPS-mild-HI or LPS-severe-HI groups compared with the naïve group (all p < 0.05). Induced inflammation by LPS exaggerated neonatal HI brain injury. The plasma OPN and GFAP levels may be useful to differentiate HI alone groups from inflammation-sensitized HI groups or naïve group.

Epilepsy occurrence after neonatal morbidities in very preterm infants.

OBJECTIVE: This study investigated the incidence of epilepsy and identified neonatal risk morbidities for epilepsy in children born extremely preterm. METHODS: Of the 806 very preterm infants (birth weight < 1500 g, gestational age < 32 weeks) who survived and were discharged from the four neonatal intensive care units in southern Taiwan between 2003 and 2012, 686 (85.1%) had longitudinal neurodevelopmental follow-up assessments up to 5 years of age. RESULTS: Among the 686 very preterm children, 19 (2.8%) exhibited epilepsy at a mean age of 19 ± 14 months. The incidence of epilepsy was highest among infants with neonatal seizure (33%), followed by cystic periventricular leukomalacia (cPVL, 27%), high-grade intraventricular hemorrhage (IVH, 21%), and necrotizing enterocolitis (NEC) stage III (20%). NEC stage III, neonatal seizure, high-grade IVH, and cPVL were also independent neonatal risk morbidities for epilepsy. Furthermore, the incidence of epilepsy was 21.6% in preterm children with significant neonatal brain injury (SNBI; ie, high-grade IVH and cPVL), but only 1% in preterm children without SNBI. Among preterm children with SNBI, neonatal seizure was higher in preterm children with epilepsy than in those without epilepsy (23.1% vs 2.1%, P = .03). Among preterm children without SNBI, NEC stage III was higher in preterm children with epilepsy than in those without epilepsy (33.3% vs 1.8%, P < .01). The preterm children with epilepsy were prone to have neurodevelopmental disability regardless of whether they had neonatal brain injury, and drug-resistant epilepsy (42%), particularly those with neonatal high-grade IVH. SIGNIFICANCE: There is an elevated incidence of epilepsy among very preterm children, and particularly those with significant brain injury and/or severe NEC during the neonatal period. Very preterm children with epilepsy are prone to have neurodevelopmental disability and drug-resistant epilepsy.

CXCL5 signaling is a shared pathway of neuroinflammation and blood-brain barrier injury contributing to white matter injury in the immature brain.

BACKGROUND: In very preterm infants, white matter injury is a prominent brain injury, and hypoxic ischemia (HI) and infection are the two primary pathogenic factors of this injury. Microglia and microvascular endothelial cells closely interact; therefore, a common signaling pathway may cause neuroinflammation and blood-brain barrier (BBB) damage after injury to the immature brain. CXC chemokine ligand 5 (CXCL5) is produced in inflammatory and endothelial cells by various organs in response to insults. CXCL5 levels markedly increased in the amniotic cavity in response to intrauterine infection and preterm birth in clinical studies. The objective of this study is to determine whether CXCL5 signaling is a shared pathway of neuroinflammation and BBB injury that contributes to white matter injury in the immature brain. METHODS: Postpartum day 2 (P2) rat pups received lipopolysaccharide (LPS) followed by 90-min HI. Immunohistochemical analyses were performed to determine microglial activation, neutrophil infiltration, BBB damage, and myelin basic protein and glial fibrillary acidic protein expression. Immunofluorescence experiments were performed to determine the cellular distribution of CXCL5. Pharmacological tests were performed to inhibit or enhance CXCL5 activity. RESULTS: On P2, predominant increases in microglial activation and BBB damage were observed 24 h after LPS-sensitized HI induction, and white matter injury (decreased myelination and increased astrogliosis) was observed on P12 compared with controls. Immunohistochemical analyses revealed increased CXCL5 expression in the white matter 6 and 24 h after insult. Immunofluorescence experiments revealed upregulated CXCL5 expression in the activated microglia and endothelial cells 24 h after insult. CXCL5 inhibition by SB225002, a selective nonpeptide inhibitor of CXCR2, significantly attenuated microglial activation and BBB damage, increased myelination, and reduced astrogliosis in the white matter after LPS-sensitized HI. In addition, CXCL5-sensitized HI or CXCL5 alone significantly induced BBB damage and white matter injury in association with different neuroinflammation mechanisms. CXCL5-sensitized HI-induced microglial activation and neutrophil infiltration, whereas CXCL5 alone predominately caused neutrophil infiltration. CONCLUSIONS: CXCL5 is a potential biomarker for white matter injury in preterm infants. Pharmacological blockade of CXCL5 signaling that attenuates dysregulated neuroinflammation can be used a therapeutic strategy against white matter injury in the immature brain.

Association of traumatic brain injury in childhood and attention-deficit/hyperactivity disorder: a population-based study.

BACKGROUND: We evaluated the risk of attention-deficit hyperactivity disorder (ADHD) following childhood traumatic brain injury (TBI). METHODS: Using Taiwan's National Health Insurance Research Database, we included 10,416 newly diagnosed TBI children (aged ≤12 y) between 2001 and 2002 and 41,664 children without TBI, who were frequency matched by sex, age, and year of the index medical service with each TBI child, as controls. Children who had been diagnosed with ADHD prior to their medical service index were excluded. Each individual was followed for 9 y to identify ADHD diagnosis. We also compared the ADHD risk in children who were treated for fractures but not TBI as sensitivity analysis. RESULTS: During the 9-y follow-up period, children with TBI had a higher ADHD risk (adjusted hazard ratio (AHR) = 1.32, 95% confidence interval (CI) = 1.19, 1.45) than did those without TBI. Furthermore, children with mild and severe TBI had higher AHRs for ADHD than did those without TBI (AHR = 1.30; 95% CI = 1.10, 1.53; and AHR = 1.37; 95% CI = 1.22, 1.55). However, no significant association was observed between fractures and ADHD. CONCLUSION: TBI in childhood is associated with a greater likelihood of developing ADHD.

TNFR1-JNK signaling is the shared pathway of neuroinflammation and neurovascular damage after LPS-sensitized hypoxic-ischemic injury in the immature brain.

BACKGROUND: Hypoxic-ischemia (HI) and inflammation are the two major pathogenic mechanisms of brain injury in very preterm infants. The neurovascular unit is the major target of HI injury in the immature brain. Systemic inflammation may worsen HI by up-regulating neuroinflammation and disrupting the blood-brain barrier (BBB). Since neurons and oligodendrocytes, microvascular endothelial cells, and microglia may closely interact with each other, there may be a common signaling pathway leading to neuroinflammation and neurovascular damage after injury in the immature brain. TNF-α is a key pro-inflammatory cytokine that acts through the TNF receptor (TNFR), and c-Jun N-terminal kinases (JNK) are important stress-responsive kinases. OBJECTIVE: To determine if TNFR1-JNK signaling is a shared pathway underlying neuroinflammation and neurovascular injury after lipopolysaccharide (LPS)-sensitized HI in the immature brain. METHODS: Postpartum (P) day-5 mice received LPS or normal saline (NS) injection before HI. Immunohistochemistry, immunoblotting and TNFR1- and TNFR2-knockout mouse pups were used to determine neuroinflammation, BBB damage, TNF-α expression, JNK activation, and cell apoptosis. The cellular distribution of p-JNK, TNFR1/TNFR2 and cleaved caspase-3 were examined using immunofluorescent staining. RESULTS: The LPS + HI group had significantly greater up-regulation of activated microglia, TNF-α and TNFR1 expression, and increases of BBB disruption and cleaved caspase-3 levels at 24 hours post-insult, and showed more cortical and white matter injury on P17 than the control and NS + HI groups. Cleaved caspase-3 was highly expressed in microvascular endothelial cells, neurons, and oligodendroglial precursor cells. LPS-sensitized HI also induced JNK activation and up-regulation of TNFR1 but not TNFR2 expression in the microglia, endothelial cells, neurons, and oligodendrocyte progenitors, and most of the TNFR1-positive cells co-expressed p-JNK. Etanercept (a TNF-α inhibitor) and AS601245 (a JNK inhibitor) protected against LPS-sensitized HI brain injury. The TNFR1-knockout but not TNFR2-knockout pups had significant reduction in JNK activation, attenuation of microglial activation, BBB breakdown and cleaved caspase-3 expression, and showed markedly less cortical and white matter injury than the wild-type pups after LPS-sensitized HI. CONCLUSION: TNFR1-JNK signaling is the shared pathway leading to neuroinflammation and neurovascular damage after LPS-sensitized HI in the immature brain.

The developmental phenotype of motor delay in extremely preterm infants following early-life respiratory adversity is influenced by brain dysmaturation in the parietal lobe.

BACKGROUND: Research indicates that preterm infants requiring prolonged mechanical ventilation often exhibit suboptimal neurodevelopment at follow-up, coupled with altered brain development as detected by magnetic resonance imaging (MRI) at term-equivalent age (TEA). However, specific regions of brain dysmaturation and the subsequent neurodevelopmental phenotype following early-life adverse respiratory exposures remain unclear. Additionally, it is uncertain whether brain dysmaturation mediates neurodevelopmental outcomes after respiratory adversity. This study aims to investigate the relationship between early-life adverse respiratory exposures, brain dysmaturation at TEA, and the developmental phenotype observed during follow-up in extremely preterm infants. METHODS: 89 infants born < 29 weeks' gestation from 2019 to 2021 received MRI examinations at TEA for structural and lobe brain volumes, which were adjusted with sex-and-postmenstrual-age expected volumes for volume residuals. Assisted ventilation patterns in the first 8 postnatal weeks were analyzed using kmlShape analyses. Patterns for motor, cognition, and language development were evaluated from corrected age 6 to 12 months using Bayley Scales of Infant Development, third edition. Mediation effects of brain volumes between early-life respiratory exposures and neurodevelopmental phenotypes were adjusted for sex, gestational age, maternal education, and severe brain injury. RESULTS: Two distinct respiratory trajectories with varying severity were identified: improving (n = 35, 39%) and delayed improvement (n = 54, 61%). Compared with the improving group, the delayed improvement group exhibited selectively reduced brain volume residuals in the parietal lobe (mean - 4.9 cm3, 95% confidence interval - 9.4 to - 0.3) at TEA and lower motor composite scores (- 8.7, - 14.2 to - 3.1) at corrected age 12 months. The association between delayed respiratory improvement and inferior motor performance (total effect - 8.7, - 14.8 to - 3.3) was partially mediated through reduced parietal lobe volume (natural indirect effect - 1.8, - 4.9 to - 0.01), suggesting a mediating effect of 20%. CONCLUSIONS: Early-life adverse respiratory exposure is specifically linked to the parietal lobe dysmaturation and neurodevelopmental phenotype of motor delay at follow-up. Dysmaturation of the parietal lobe serves as a mediator in the connection between respiratory adversity and compromised motor development. Optimizing respiratory critical care may emerge as a potential avenue to mitigate the consequences of altered brain growth and motor developmental delay in this extremely preterm population.

Association of Neonatal Antibiotic Exposure with Long-Term Growth Trajectory Faltering in Preterm-Birth Children.

INTRODUCTION: Preterm neonates often receive a variety of duration of antibiotic exposure during admission. The aim of the study was to evaluate whether neonatal antibiotic exposure is relevant with longitudinal growth problems in preterm-birth children. METHODS: This prospective study enrolled 481 infants who were born <32 weeks of gestation, discharged, and longitudinally followed from corrected age (CA) 6-60 months. After excluding 153 infants with blood culture-confirmed bacteremia, necrotizing enterocolitis, severe cerebral palsy, intestinal ostomy, and congenital anomaly, 328 infants were included for analysis. Covariates included perinatal demographics, neonatal morbidities, extrauterine growth restriction, and antibiotic exposure accumulated by term equivalent age. The primary outcome was the anthropometric trajectories in z-score of bodyweight (zBW), body height (zBH), and body mass index (zBMI) from CA 6-60 months. RESULTS: Antibiotic exposure duration was significantly negatively associated with zBW and zBH at CA 6, 12, and 60 months, and zBMI at CA 60 months. Multivariate generalized estimating equation analyses showed antibiotic exposure duration had significantly faltering z-score increment from CA 6 to 60 months in zBW and zBH (adjusted mean [95% CI]; ΔzBW: -0.021 [-0.041 to -0.001], p = 0.042; ΔzBH: -0.019 [-0.035 to -0.002], p = 0.027) after adjustment. Children with neonatal antibiotic exposure duration >15 days were significantly lower in the mean anthropometric zBW, zBH, and zBMI at CA 6, 12, 24, and 60 months compared with children with neonatal antibiotic exposure ≤15 days (all p < 0.01). CONCLUSIONS: Growth increments were negatively associated with antibiotic exposure duration in preterm neonates implicating that antibiotic stewardship and growth follow-up for preterm neonates are thus warranted.

Ischemic preconditioning reduces neurovascular damage after hypoxia-ischemia via the cellular inhibitor of apoptosis 1 in neonatal brain.

BACKGROUND AND PURPOSE: The neurovascular unit is a major target of hypoxia-ischemia (HI) injury in the neonatal brain. Although neurons are the cellular target of ischemic preconditioning (IP), vessel tolerance also contributes greatly to protection. Nerves and vessels cross-talk and use common signals during development. Cellular inhibitor of apoptosis 1 (cIAP1) is an important regulator that inhibits apoptosis. This study hypothesized that cIAP1 is a shared molecule underlying IP-mediated neurovascular protection against HI in the neonatal brain. METHODS: In vivo IP was induced by 2-hour reversible occlusion of right carotid artery 24 hours before HI on postpartum day 7 in rat pups. In vitro oxygen-glucose deprivation (OGD) preconditioning was established in SH-SY5Y neuronal cells and in human microvascular endothelial cell-1 vascular endothelial cells. cIAP1 expression was inhibited by cIAP1 small interfering RNA in vivo or by lentivirus-mediated short hairpin RNA in vitro, or was upregulated by the lentiviral expression system. RESULTS: IP reduced apoptosis, selectively increased cIAP1 in neurons and vascular endothelial cells, and provided long-term neuroprotection against HI. Intracerebroventricular delivery of cIAP1 small interfering RNA significantly attenuated IP-mediated cIAP1 upregulation and neuroprotection in vivo. In vitro, OGD preconditioning induced cIAP1 and protected against OGD cell death in SH-SY5Y neuronal and human microvascular endothelial cells-1. Knockdown of cIAP1 by lentivirus-mediated short hairpin RNA decreased the protective effect of OGD preconditioning in SH-SY5Y and human microvascular endothelial cell-1, whereas overexpression of cIAP1 by lentivirus protected against OGD in these cells. CONCLUSIONS: cIAP1 is a shared molecule underlying IP-induced protection in neurons and vascular endothelial cells against HI in the neonatal brain.

Thyroxin treatment protects against white matter injury in the immature brain via brain-derived neurotrophic factor.

BACKGROUND AND PURPOSE: Low level of thyroid hormone is a strong independent risk factor for white matter (WM) injury, a major cause of cerebral palsy, in preterm infants. Thyroxin upregulates brain-derived neurotrophic factor during development. We hypothesized that thyroxin protected against preoligodendrocyte apoptosis and WM injury in the immature brain via upregulation of brain-derived neurotrophic factor. METHODS: Postpartum (P) day-7 male rat pups were exposed to hypoxic ischemia (HI) and intraperitoneally injected with thyroxin (T4; 0.2 mg/kg or 1 mg/kg) or normal saline immediately after HI at P9 and P11. WM damage was analyzed for myelin formation, axonal injury, astrogliosis, and preoligodendrocyte apoptosis. Neurotrophic factor expression was assessed by real-time polymerase chain reaction and immunohistochemistry. Neuromotor functions were measured using open-field locomotion (P11 and P21), inclined plane climbing (P11), and beam walking (P21). Intracerebroventricular injection of TrkB-Fc or systemic administration of 7,8-dihydroxyflavone was performed. RESULTS: On P11, the HI group had significantly lower blood T4 levels than the controls. The HI group showed ventriculomegaly and marked reduction of myelin basic protein immunoreactivities in the WM. T4 (1 mg/kg) treatment after HI markedly attenuated axonal injury, astrocytosis, and microgliosis, and increased preoligodendrocyte survival. In addition, T4 treatment significantly increased myelination and selectively upregulated brain-derived neurotrophic factor expression in the WM, and improved neuromotor deficits after HI. The protective effect of T4 on WM myelination and neuromotor performance after HI was significantly attenuated by TrkB-Fc. Systemic 7,8-dihydroxyflavone treatment ameliorated hypomyelination after HI injury. CONCLUSIONS: T4 protects against WM injury at both pathological and functional levels via upregulation of brain-derived neurotrophic factor-TrkB signaling in the immature brain.

Human umbilical vein endothelial cells protect against hypoxic-ischemic damage in neonatal brain via stromal cell-derived factor 1/C-X-C chemokine receptor type 4.

BACKGROUND AND PURPOSE: Agents that protect against neurovascular damage provide a powerful neuroprotective strategy. Human umbilical vein endothelial cells (HUVECs) may be used to treat neonates with hypoxic-ischemia (HI) because of its autologous capability. We hypothesized that peripherally injected HUVECs entered the brain after HI, protected against neurovascular damage, and provided protection via stromal cell-derived factor 1/C-X-C chemokine receptor type 4 pathway in neonatal brain. METHODS: Postpartum day 7 rat pups received intraperitoneal injections of low-passage HUVEC-P4, high-passage HUVEC-P8, or conditioned medium before and immediately after HI. HUVECs were transfected with adenovirus-green fluorescent protein for cell tracing. Oxygen-glucose deprivation was established by coculturing HUVEC-P4 with mouse neuroblastoma neuronal cells (Neuro-2a) and with mouse immortalized cerebral vascular endothelial cells (b.End3). RESULTS: HUVEC-P4-treated group had more blood levels of green fluorescent protein-positive cells than HUVEC-P8-treated group 3 hours postinjection. Intraperitoneally injected HUVEC-P4, but not HUVEC-P8, entered the cortex after HI and positioned closed to the neurons and microvessels. Compared with the condition medium-treated group, the HUVEC-P4-treated but not the HUVEC-P8-treated group showed significantly less neuronal apoptosis and blood-brain barrier damage and more preservation of microvessels in the cortex 24 hours after HI. On postpartum day 14, the HUVEC-P4-treated group showed significant neuroprotection compared with the condition medium-treated group. Stromal cell-derived factor 1 was upregulated in the ipsilateral cortex 3 hours after HI, and inhibiting the stromal cell-derived factor 1/C-X-C chemokine receptor type 4 reduced the protective effect of HUVEC-P4. In vitro transwell coculturing of HUVEC-P4 also significantly protected against oxygen-glucose deprivation cell death in neurons and endothelial cells. CONCLUSIONS: Cell therapy using HUVECs may provide a powerful therapeutic strategy in treating neonates with HI.