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.

Investigation of New Psychoactive Substances (NPS), Other Illicit Drugs, and Drug-Related Compounds in a Taiwanese Wastewater Sample Using High-Resolution Mass-Spectrometry-Based Targeted and Suspect Screening.

The proliferation of new psychoactive substances (NPSs) in recent years has posed a significant challenge to public health. Traditional monitoring methods have proven insufficient in tracking these constantly evolving substances, leading to the development of alternative approaches such as wastewater-based epidemiology (WBE). The present study aims to utilize high-resolution mass spectrometry (HRMS)-based targeted and suspect screening to profile NPS, other illicit drugs, and drug-related compounds in a Taiwanese wastewater sample. For the targeted analysis, 8 out 18 standards of illicit drugs have been identified. The suspect screening approach based on approximately 3600 substances in the SWGDRUG library can further identify 92 compounds, including opiate analgesics, synthetic cathinones, phenylalkylamines derivatives, phenethylamine derivatives, tryptamine derivatives, steroids, and ephedrine-related compounds. Additionally, the presence of 5-methoxy-2-aminoindane (MEAI) in the wastewater indicates that drug dealers have recently sold this potential NPS to evade drug regulations. This study firstly reports the HRMS-based comprehensive profile of NPS, other illicit drugs, and drug-related compounds in Taiwan, which could be applied as biomarkers for estimating the consumption of drugs.

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.

The Association of Patent Ductus Arteriosus with Inflammation: A Narrative Review of the Role of Inflammatory Biomarkers and Treatment Strategy in Premature Infants.

Patent ductus arteriosus (PDA) is a common cardiovascular complication that complicates clinical care in the intensive care of premature infants. Prenatal and postnatal infections and the inflammation process can contribute to PDA, and intrauterine inflammation is a known risk factor of PDA. A variety of inflammatory biomarkers have been reported to be associated with PDA. Chorioamnionitis induces the fetal inflammatory process via several cytokines that have been reported to be associated with the presence of PDA and may have a role in the vascular remodeling process or vessel dilation of the ductus. On the other hand, anti-inflammatory agents, such as antenatal steroids, decrease PDA incidence and severity in patients born to those with chorioamnionitis. Proinflammatory cytokines, which are expressed more significantly in preterm neonates and chorioamnionitis, are associated with the presence of PDA. In this review, we focus on the pathogenesis of PDA in preterm infants and the role of biomarkers associated with the perinatal inflammatory process.

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.

Fricative productions of Mandarin-speaking children with cerebral palsy: the case of five-year-olds.

This study aimed at improving the understanding of speech characteristics of fricatives produced by five-year-old Mandarin-acquiring children with cerebral palsy (CP). Productions from nine CP children and nine gender-and-age-matched typically developing (TD) children were collected and analyzed. Results from transcription indicated that the CP group had lower production accuracy rates for all the five fricatives in Mandarin Chinese. Additionally, when the CP children failed to articulate the target fricative segments, they tended to delete them or convert them into non-continuant segments. Results from acoustic analyses indicated that the M2 values of the labiodental [f] and the M1 and M2 values of the alveolar [s] were higher among the CP children. The experimental results revealed that: (1) Observable differences were available once the age of the groups was properly controlled and acoustical measurements were adopted; (2) the lack of finer-grained speech motor control abilities among CP children were reflected in the M1 and M2 values; (3) for segments at the anterior places, the clinical group failed to extend the articulatory gestures to the desirable positions. It is suggested that future studies focusing on different age groups and children with different native languages would help to approach the nature of articulatory barriers among individuals with CP.

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.

Comparison of medical issues in antenatal and perinatal periods in early youth, adolescent, and young adult mothers in Taiwan: a 10-year nationwide study.

BACKGROUND: Limited information is available concerning investigating the separate effect of teenage childbirth on medical issues in the antenatal and perinatal periods. Therefore, this study aimed to assess medical problems in antenatal and perinatal periods among early youth, adolescent and young adult mothers in Taiwan. METHODS: This retrospective population-based cohort study was conducted by using data from Taiwan's National Health Insurance Research Database. A total of 335,590 mothers aged less than 25 years who had singleton births were identified between 2002 and 2011. Univariate and multivariate logistic regression analyses were conducted to estimate unadjusted and adjusted odds ratios (OR) and 95% confidence intervals (CI) of each medical problem category in the antenatal and perinatal periods. RESULTS: Compared with mothers aged 20-24 years, adolescents (16-19 years) and early youth mothers (≤ 15 years), particularly those aged 10-15, had a significantly higher risk of intrauterine growth retardation (IUGR, OR = 1.37, 95% CI: 1.00-1.89) and preterm delivery (OR = 2.98, 95% CI: 2.48-3.58) after adjusting for demographic characteristics and clinical factors. Additionally, adolescents mothers were at an increased risk of anemia (OR = 1.32, 95% CI: 1.24-1.40), oligohydramnios (OR = 1.21, 95% CI: 1.12-1.32), failed labor induction (OR = 1.33, 95% CI: 1.24-1.43), and fetal distress (OR = 1.20, 95% CI: 1.14-1.26) after adjustment. CONCLUSIONS: Not all young mothers in our study experienced the same magnitude of increased medical problems in the antenatal and perinatal periods. However, a sufficiently higher probability of having IUGR and preterm delivery was observed among early youth and adolescent mothers.

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.

Deep Learning Model for Prediction of Bronchopulmonary Dysplasia in Preterm Infants Using Chest Radiographs.

Bronchopulmonary dysplasia (BPD) is common in preterm infants and may result in pulmonary vascular disease, compromising lung function. This study aimed to employ artificial intelligence (AI) techniques to help physicians accurately diagnose BPD in preterm infants in a timely and efficient manner. This retrospective study involves two datasets: a lung region segmentation dataset comprising 1491 chest radiographs of infants, and a BPD prediction dataset comprising 1021 chest radiographs of preterm infants. Transfer learning of a pre-trained machine learning model was employed for lung region segmentation and image fusion for BPD prediction to enhance the performance of the AI model. The lung segmentation model uses transfer learning to achieve a dice score of 0.960 for preterm infants with ≤ 168 h postnatal age. The BPD prediction model exhibited superior diagnostic performance compared to that of experts and demonstrated consistent performance for chest radiographs obtained at ≤ 24 h postnatal age, and those obtained at 25 to 168 h postnatal age. This study is the first to use deep learning on preterm chest radiographs for lung segmentation to develop a BPD prediction model with an early detection time of less than 24 h. Additionally, this study compared the model's performance according to both NICHD and Jensen criteria for BPD. Results demonstrate that the AI model surpasses the diagnostic accuracy of experts in predicting lung development in preterm infants.

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.

Determining the Optimal Treatment for Idiopathic Clubfoot: A Network Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Clubfoot, or congenital talipes equinovarus deformity, is a common anomaly affecting the foot in infants. However, clinical equipoise remains between different interventions, especially those based on the Ponseti method. The aim of this study was to examine the clinical outcomes of the various interventions for treating idiopathic clubfoot. METHODS: Searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Scopus, and CINAHL were conducted. Randomized controlled trials comparing different interventions, including the Ponseti method, accelerated Ponseti method, Ponseti method with botulinum toxin type A (Botox) injection, Ponseti method with early tibialis anterior tendon transfer (TATT), Kite method, and surgical treatment, were included. Network meta-analyses (NMAs) were conducted according to the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) reporting guidelines. The primary outcomes were the change in total Pirani score and maximal ankle dorsiflexion. Secondary outcomes were the number of casts, time in casts, and rates of tenotomy, total complications, relapse, adverse events, and additional required major surgery. RESULTS: Eleven randomized controlled trials involving 740 feet were included. According to the SUCRA (surface under the cumulative ranking curve)-based relative ranking, the Ponseti method was associated with the best outcomes in terms of Pirani score changes, maximal ankle dorsiflexion, number of casts, adverse events, and total complications, whereas the accelerated Ponseti method was associated with the best outcomes in terms of time in casts and tenotomy rate. Early TATT ranked best in terms of relapse rate. The Ponseti method with Botox injection was associated with the best outcomes in terms of the need for additional major surgery. CONCLUSIONS: The NMAs suggest that the Ponseti method is the optimal treatment overall, despite potential drawbacks such as longer time in casts and higher rates of tenotomy, relapse, and the need for additional surgery compared with other modified approaches. Therefore, clinicians should consider how treatments can be tailored individually. LEVEL OF EVIDENCE: Therapeutic Level I . See Instructions for Authors for a complete description of levels of evidence.

Predicting early mortality and severe intraventricular hemorrhage in very-low birth weight preterm infants: a nationwide, multicenter study using machine learning.

Our aim was to develop a machine learning-based predictor for early mortality and severe intraventricular hemorrhage (IVH) in very-low birth weight (VLBW) preterm infants in Taiwan. We collected retrospective data from VLBW infants, dividing them into two cohorts: one for model development and internal validation (Cohort 1, 2016-2021), and another for external validation (Cohort 2, 2022). Primary outcomes included early mortality, severe IVH, and early poor outcomes (a combination of both). Data preprocessing involved 23 variables, with the top four predictors identified as gestational age, birth body weight, 5-min Apgar score, and endotracheal tube ventilation. Six machine learning algorithms were employed. Among 7471 infants analyzed, the selected predictors consistently performed well across all outcomes. Logistic regression and neural network models showed the highest predictive performance (AUC 0.81-0.90 in both internal and external validation) and were well-calibrated, confirmed by calibration plots and the lowest two mean Brier scores (0.0685 and 0.0691). We developed a robust machine learning-based outcome predictor using only four accessible variables, offering valuable prognostic information for parents and aiding healthcare providers in decision-making.

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.

The role of glucocorticoid receptors in dexamethasone-induced apoptosis of neuroprogenitor cells in the hippocampus of rat pups.

BACKGROUND: Dexamethasone (Dex) has been used to reduce inflammation in preterm infants with assistive ventilation and to prevent chronic lung diseases. However, Dex treatment results in adverse effects on the brain. Since the hippocampus contains a high density of glucocorticoid receptors (GCRs), we hypothesized that Dex affects neurogenesis in the hippocampus through inflammatory mediators. METHODS: Albino Wistar rat pups first received a single dose of Dex (0.5 mg/kg) on postnatal day 1 (P1) and were sacrificed on P2, P3, P5, and P7. One group of Dex-treated pups (Dex-treated D1D2) was given mifepristone (RU486, a GCR antagonist) on P1 and sacrificed on P2. Hippocampi were isolated for western blot analysis, TUNEL, cleaved-caspase 3 staining for cell counts, and morphological assessment. Control pups received normal saline (NS). RESULTS: Dex reduced the developmental gain in body weight, but had no effect on brain weight. In the Dex-treated D1D2 group, apoptotic cells increased in number based on TUNEL and cleaved-caspase 3 staining. Most of the apoptotic cells expressed the neural progenitor cell marker nestin. Dex-induced apoptosis in P1 pups was markedly reduced (60%) by pretreatment with RU486, indicating the involvement of GCRs. CONCLUSION: Early administration of Dex results in apoptosis of neural progenitor cells in the hippocampus and this is mediated through GCRs.