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.

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.

Neurodevelopment After Neonatal Acute Kidney Injury in Very Preterm-Birth Children.

Introduction: This study aimed to assess head circumference (HC) growth and neurodevelopmental outcomes in very preterm-birth children after neonatal acute kidney injury (AKI). Methods: This longitudinal follow-up cohort included 732 very preterm neonates of gestational age <31 weeks admitted to a tertiary center between 2008 and 2020. AKI was categorized as nonoliguric and oliguric AKI based on the urine output criteria during admission. We compared the differences in death, z scores of HC (zHC) at term-equivalent age (TEA) and at corrected ages of 6, 12, and 24 months, and the neurodevelopmental outcomes at corrected age of 24 months after neonatal nonoliguric and oliguric AKI. Results: Among the 154 neonates who developed AKI, 72 had oliguric AKI and 82 had nonoliguric AKI. At TEA, oliguric AKI, but not nonoliguric AKI, was independently associated with lower zHC than non-AKI (mean differences, -0.49; 95% confidence interval [CI], -0.92 to -0.06). Although the 3 groups were comparable in zHC at corrected ages of 6, 12, and 24 months, the oliguric AKI group, but not the nonoliguric AKI group, had a higher rate of microcephaly by corrected age of 24 months. In addition, the oliguric AKI group, but not the nonoliguric AKI group, was more likely to die (61% vs. 9%) and have neurodevelopmental impairment (41% vs. 14%) compare with the non-AKI group. After adjustment, oliguric (adjusted odds ratio [aOR], 8.97; 95% CI, 2.19-36.76), but not nonoliguric, AKI was associated with neurodevelopmental impairment. Conclusion: Neonatal oliguric AKI is associated with neurodevelopmental impairment in very preterm-birth children. Long-term head-size and neurodevelopmental follow-up after neonatal AKI is warranted.

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.

Association of Cystic Periventricular Leukomalacia and Postnatal Epilepsy in Very Preterm Infants.

INTRODUCTION: Cystic periventricular leukomalacia (PVL) is the most common white matter injury and a common cause of cerebral palsy in preterm infants. Postnatal epilepsy may occur after cystic PVL, but their causal relationship remains uncertain. Our aim was to validate the contribution of cystic PVL to postnatal epilepsy in very preterm infants and demonstrate their seizure characteristics. METHODS: This prospective cohort study enrolled 1,342 preterm infants (birth weight <1,500 g and gestational age <32 weeks) from 2003 to 2015. Cystic PVL was diagnosed by serial cerebral ultrasound, and other comorbidities were recorded during hospitalization. Neurological developments and consequences, including epilepsy, were serially accessed until the age of 5. RESULTS: A total of 976 preterm infants completed a 5-year neurological follow-up; 47 (4.8%) had cystic PVL. Preterm infants with cystic PVL were commonly associated with other comorbidities, including necrotizing enterocolitis stage III, neonatal seizures, and intraventricular hemorrhage during hospitalization. At age 5, 14 of the 47 (29.8%) preterm infants with cystic PVL had postnatal epilepsy. After adjusting for gender, gestational age, and three common comorbidities, cystic PVL was an independent risk factor for postnatal epilepsy (adjust OR: 16.2; 95% CI: 6.8-38.4; p < 0.001). Postnatal epilepsy after cystic PVL was commonly the generalized type (13 of 14, 92.9%), not intractable and most occurred after 1 year of age. DISCUSSION/CONCLUSION: Cystic PVL would independently lead to postnatal epilepsy. Preterm infants with cystic PVL are at risk of postnatal epilepsy after age 1 in addition to cerebral palsy.

The effect of age at onset of type 1 diabetes mellitus on epilepsy vulnerability.

AIMS: To examine whether type 1 diabetes age onset correlates with epilepsy incidence. METHODS: We used type 1 diabetes longitudinal data with onset age ≤ 40 years enrolled in Taiwan National Health Insurance program to examine type 1 diabetes onset age effect on epilepsy occurrence. RESULTS: In 6,165 type 1 diabetes patients, onset age groups included 3,571 patients (58%) ≤ 18 years (childhood-onset) and 2,594 patients (42%) > 18 years (adulthood-onset). After 8.6 years median follow-up following type 1 diabetes onset, epilepsy incidence rate in adulthood-onset group was 2.26-fold higher than that in childhood-onset group. Epilepsy incidence rate ratio was lowest in those with onset age 6-12 years in comparison to that in patients with onset age ≤ 6 years, but was highest in onset age of 30-40 years. Longer follow-up duration correlates with higher epilepsy risk in adulthood-onset group. Multiple logistic regression analysis showed that onset age 30-40 years, male, more than one diabetic ketoacidosis episode, and unprovoked seizure events were independent risk factors for epilepsy following type 1 diabetes onset. CONCLUSIONS: There is age-related vulnerability to epilepsy following type 1 diabetes onset. Adulthood-onset type 1 diabetes is an independent risk factor for epilepsy susceptibility after type 1 diabetes.

Early-Life Slow Enteral Feeding Progression Pattern Is Associated with Longitudinal Head-Size Growth Faltering and Neurodevelopmental Impairment Outcomes in Extremely Preterm Infants.

OBJECTIVE: To determine whether feeding progression patterns in the first eight postnatal weeks, depicted by clustering analysis of daily enteral feeding volume, are associated with longitudinal head-circumference (HC) growth and neurodevelopmental outcomes in extremely preterm (EP) infants. METHODS: 200 infants who were admitted at gestational ages 23-27 weeks between 2011 and 2018; survived to discharge; and underwent longitudinal HC growth measurements at birth, term-equivalent age (TEA), corrected age (CA) 6-month, 12-month, and 24-month; and neurodevelopmental assessment using the Bayley Scales of Infant Development at CA 24 months were included for analysis. RESULTS: kmlShape analysis identified two distinct enteral feeding progression patterns: fast progression in 131 (66%) infants and slow progression in 69 (34%) infants. Compared to the fast progression group, the slow progression group showed significantly lower daily enteral volumes after day 13, was older in postnatal age reaching full feeding, had a higher rate of Delta z scores of HC (zHC) < -1 (p < 0.001) between birth and TEA, and displayed lower longitudinal zHC from TEA to CA 24 months. The slow progression group also showed higher rates of microcephaly [42% vs. 16%, p < 0.001; adjusted odd ratio (aOR): 3.269, p = 0.001] and neurodevelopmental impairment (NDI) (38% vs. 19%, p = 0.007; aOR: 2.095, p = 0.035) at CA 24 months. For NDI, the model including feeding progression patterns showed a lower Akaike information criterion score and a better goodness of fit than the model that did not include feeding patterns. CONCLUSION: Characterizing feeding progression pattern may help identify EP infants at high-risk of head-size growth faltering and NDI at early childhood.

Associations between Early Thyroid-Stimulating Hormone Levels and Morbidities in Extremely Preterm Neonates.

INTRODUCTION: High-end cutoffs of thyroid-stimulating hormone (TSH) have been emphasized for hypothyroidism therapy in extremely preterm infants, but the significance of low TSH levels remains unknown. This study hypothesized that the spectrum of TSH levels by newborn screening after birth signifies specific morbidities in extremely preterm neonates. METHODS: The multicenter population cohort analyzed 434 extremely preterm neonates receiving TSH screening at 24-96 h of age in 2008-2019. Neonates were categorized by blood TSH levels into group 1: TSH <0.5 µU/mL, group 2: 0.5 ≤ TSH <2 µU/mL, group 3: 2 ≤ TSH <4 µU/mL, and group 4: TSH ≥4 µU/mL. Neonatal morbidities were categorized using the modified Neonatal Therapeutic Intervention Scoring System. RESULTS: The four groups differed in gestational age, birth weight, and the postnatal age at blood sampling so did the proportions of mechanical ventilation usage (p = 0.01), hypoxic respiratory failure (p = 0.005), high-grade intraventricular hemorrhage (p = 0.007), and periventricular leukomalacia (p = 0.048). Group 1 had higher severity scores for respiratory distress syndrome (RDS; effect size 0.39 [95% confidence interval [CI]: 0.18-0.59]) and brain injury (0.36 [0.15-0.57]) than group 2, which remained significant after adjusting for gestational age, birth weight, dopamine usage, and the postnatal age at TSH screening (RDS: mean + 0.45 points [95% CI: 0.11-0.79]; brain injury: +0.32 [0.11-0.54]). CONCLUSIONS: Low TSH levels in extremely preterm neonates are associated with severe RDS and brain injuries. Studies recruiting more neonates with complete thyroid function data are necessary to understand central-peripheral interactions of the hypothalamic-pituitary-thyroid axis.

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.

Development of cool and hot executive function deficit in children born very low birth weight with normal early development: A longitudinal cohort from aged 6 to 10.

BACKGROUND: Studies showed preterm children born with very low birth weight (VLBW, <1500 g) are at risk for poorer executive functions (EFs). However, very little research has been reported longitudinally on the development of both cool and hot EFs deficits in preschool to school-age VLBW preterm children with normal early development. AIMS: Present study aimed to investigate the development of cool and hot EFs in VLWB preterm children longitudinally. METHODS: Forty preterm children born VLBW were followed up at ages 6, 8, and 10. Fifty term-born controls were recruited at each age stage. Cool EFs was assessed using backward digit span subtest of WISC-IV, Knox's Cube Test, Comprehensive Non-verbal Attention Test Battery (CNAT), Tower of London (ToL), Wisconsin Card Sorting Test (WCST), and hot EFs was assessed using Theory of Mind (ToM) and Delay of Gratification (GIFT) tasks. RESULTS: The six-year-old VLBW preterm group showed significantly lower scores of planning in ToL, inhibition control in CNAT, and in both ToM and GIFT tasks. There is no significant difference in average cool and hot EFs between the eight and ten-year-old preterm group and the control group. CONCLUSIONS: At six, VLBW preterm infants with normal early development have delayed cool and hot EFs development. Although the average performance of EFs can reach the level of the control group with age increasing to eight and ten years, there are still individual differences. It is recommended that more complete development indicators be established in the future, and early intervention should be made for VLBW premature children with delayed EFs.

Retinopathy of Prematurity Is a Biomarker for Pathological Processes in the Immature Brain.

INTRODUCTION: Retinopathy of prematurity (ROP) is considered a neurovascular disease. We investigated whether ROP, mild or severe, is associated with neurodevelopmental impairment (NDI) in extremely preterm children. METHODS: We conducted a multicenter retrospective cohort study in southern Taiwan. A total of 394 children <28 weeks of gestation who survived to discharge from 2011 to 2018 received neurodevelopmental assessment at corrected age of 24 months. Severe ROP was defined as ROP of stages 2 plus or worse, or recipients of retinal therapy, and mild ROP as stage 1 or 2 in at least one eye. NDI was defined as cognitive or motor impairment using the Bayley Scales of Infant and Toddler Development, moderate to severe cerebral palsy, or profound hearing loss. RESULTS: Among the 374 children validated for analysis, 157 children (42%) had non-ROP, 145 (39%) mild ROP, and 72 (19%) severe ROP. As ROP severity increased progressively from non-ROP, to mild ROP, and to severe ROP, the rates of NDI increased from 25%, to 46%, and to 61%. The multivariable logistic regression showed that the model included three levels of ROP, and neonatal morbidities achieved better overall performance for NDI than the model that included neonatal morbidities alone. Compared with non-ROP, mild ROP and severe ROP had adjusted odds ratios of 1.90 (95% CI: 1.10-3.28) and 2.75 (95% CI: 1.33-5.67) for NDI, respectively. CONCLUSION: Mild ROP and severe ROP are independent neonatal morbidities associated with NDI. Neurodevelopmental follow-up of extremely preterm children with any stage of ROP is needed.

Prognostic factors for functional recovery in children with moderate to severe acute disseminated encephalomyelitis.

BACKGROUND: Acute disseminated encephalomyelitis (ADEM) is an immune-mediated encephalopathy with heterogeneous disease courses. However, clinical characteristics for a prognostication of functional recovery from acute episodes of ADEM remain limited. The study aims to characterize the clinical presentations and neuroimaging findings of children with poor functional recoveries from acute episodes of moderate to severe ADEM. METHODS: The multicenter retrospective cohort study included children under 18 years of age who presented with moderate to severe ADEM (modified Rankin Scale [mRS] ≥ 3 at nadir) from 2002 to 2019. Children were assigned to a good recovery group (mRS ≤ 2) and a poor recovery group (mRS ≥ 3) after mean 4.3 months of follow-up. The clinical presentations and the distribution of brain lesions on magnetic resonance imaging were compared between the two groups by the t-test for numerical variables and Fisher's exact test for categorical variables. Analyses of logistic regression were conducted and significant variables in the multivariate model were examined by the receiver operating characteristic curve for the prediction of functional recovery. RESULTS: Among the 73 children with moderate to severe ADEM, 56 (77%) had good functional recoveries and 17 (23%) showed poor functional recoveries. Children with poor recoveries had a lower rate of prodromal headache (12% vs. 39%, p = 0.04), and presented with higher proportions of dystonia (29% vs. 9%, p = 0.046), myoclonus (24% vs. 2%, p = 0.009), and cerebellar lesions on neuroimages (59% vs. 23%, p = 0.01). The multivariate analyses identified that a lack of prodromal headache (OR 0.1, 95% CI 0.005 - 0.7, p = 0.06) and the presentations of myoclonus (OR 21.6, 95% CI 1.7 - 874, p = 0.04) and cerebellar lesions (OR 4.8, 95% CI 1.3 - 19.9, p = 0.02) were associated with poor functional recoveries. These three factors could prognosticate poor outcomes in children with moderate to severe ADEM (area under the receiver operating characteristic curve 0.80, 95% CI 0.68 - 0.93, p = 0.0002). CONCLUSION: Nearly one-fourth of children with moderate to severe ADEM had a poor functional recovery from acute episodes, who were characterized by a lack of prodromal headache, the presentation of myoclonus, and the neuroimaging finding of cerebellar lesions. The clinical variables associated with poor functional recoveries could assist in the planning of immunotherapies during hospitalization for a better outcome in moderate to severe ADEM.

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.

Gestational Age-Related Associations between Early-Life Feeding Trajectories and Growth Outcomes at Term Equivalent Age in Very Preterm Infants.

Establishing the different feeding trajectories based on daily enteral feeding data in preterm infants at different gestational ages (GAs), may help to identify the risks and extrauterine growth restriction (EUGR) outcomes associated with the adverse feeding pattern. In a single center, we retrospectively included 625 infants born at 23-30 weeks of gestation who survived to term-equivalent age (TEA) from 2009 to 2020. The infants were designated into three GA groups: 23-26, 27-28, and 29-30 weeks. The daily enteral feeding amounts in the first 56 postnatal days were analyzed to determine the feeding trajectories. The primary outcomes were EUGR in body weight and head circumference calculated, respectively, by the changes between birth and TEA. Clustering analysis identified two feeding trajectories, namely the improving and adverse patterns in each GA group. The adverse feeding pattern that occurred in 49%, 20%, and 17% of GA 23-26, 27-28, and 29-30 weeks, respectively, was differentiated from the improving feeding pattern as early as day 7 in infants at GA 23-26 and 27-28 weeks, in contrast to day 21 in infants at GA 29-30 weeks. The adverse feeding patterns were associated with sepsis, respiratory, and gastrointestinal morbidities at GA 23-26 weeks; sepsis, hemodynamic and gastrointestinal morbidities at GA 27-28 weeks; and preeclampsia, respiratory, and gastrointestinal morbidities at GA 29-30 weeks. Using the improving feeding group as a reference, the adverse feeding group showed significantly higher adjusted odds ratios of EUGR in body weight and head circumference in infants at GA 23-26 and 27-28 weeks. Identifying the early-life adverse feeding trajectories may help recognize the related EUGR outcomes of preterm infants in a GA-related manner.

Early Mental Trajectories Predict Different Cognitive Levels at School Age in Very Preterm Children.

INTRODUCTION: Early identification of preterm children at high risk of intellectual disability (intelligence quotient [IQ] <70) or borderline intelligence (IQ = 70-84) is critical for different early intervention. We investigated whether early-life mental trajectories predict intellectual disability and borderline intelligence, respectively, among school-age preterm children. METHODS: A multicenter study recruited preterm infants born at <32 weeks' gestation between 2001 and 2014 in Taiwan who underwent mental assessments (Bayley Scales of Infant Development) at corrected ages 6, 12, and 24 months and IQs at age 5.5 years. Mental trajectories from ages 6 to 24 months determined using group-based trajectory modeling were employed to predict intellectual disability and borderline intelligence, respectively. Model fit was assessed using the area under the receiver operating characteristic curve (AUROC) and Akaike information criterion (AIC). RESULTS: Among the 1,680 children enrolled, three mental trajectories were identified: high-stable (59.7%), high-declining (35.3%), and low-declining (5.0%), in which the borderline-intelligence/intellectual-disability rate was 14.1%/1.5%, 36.1%/13.7%, and 10.7%/82.1%, respectively. Compared with children with normal intelligence, the low-declining trajectory had 37.7-fold higher odds (95% confidence interval [CI], 26.3-48.1) for intellectual disability, and the high-declining trajectory had 4.4-fold higher odds (95% CI, 3.1-6.1) for borderline intelligence. Compared to the models with risk factors alone (AIC 1,791.2), the models that included both risk factors and trajectory groups had better overall performance (AIC 1,419.8) and increased prediction power for intelligence outcomes: low-declining trajectory for intellectual disability (AUROC increased from 0.81 to 0.92) and high-declining trajectory for borderline intelligence (AUROC increased from 0.68 to 0.75). CONCLUSIONS: Early-life mental trajectories help identify preterm children at risk of intellectual disability and borderline intelligence, respectively, at school age for timely intervention.

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.

Lactate Predicts Neurological Outcomes after Perinatal Asphyxia in Post-Hypothermia Era: A Prospective Cohort Study.

BACKGROUND: Neonatal hypoxic-ischemic encephalopathy (HIE) is the most common cause of mortality and neurological disability in infancy after perinatal asphyxia. Reliable biomarkers to predict neurological outcomes of neonates after perinatal asphyxia are still not accessible in clinical practice. METHODS: A prospective cohort study enrolled neonates with perinatal asphyxia. Biochemical blood tests and cerebral Doppler ultrasound were measured within 6 h of age and at the 4th day old. Neurological outcomes were assessed at 1 year old. RESULTS: Sixty-four neonates with perinatal asphyxia were enrolled. Fifty-eight (90%) had hypoxic-ischemic encephalopathy (HIE) including 20 (34%) Stage I, 21 (36%) Stage II, and 17 (29%) Stage III. In the asphyxiated infants without therapeutic hypothermia, HIE stage, PH, and base excess levels within 6 h of age were the predictors of adverse outcomes. In the asphyxiated infants receiving therapeutic hypothermia, HIE stage failed to predict outcomes. Instead, blood lactate levels and pulsatility index (PI) of medial cerebral arteries (MCA) either in 6 h of age or at the 4th day old independently predicted adverse outcomes. CONCLUSIONS: Blood lactate, which is a common accessible test at the hospital and MCA PI on cerebral ultrasound could predict adverse outcomes in asphyxiated infants receiving therapeutic hypothermia.

Temporal Trends of Acute Kidney Injury and Associated Risk Exposures in Extremely Preterm Infants.

BACKGROUND AND OBJECTIVES: Neonatal AKI in the preterm population is an under-recognized morbidity. Detecting AKI in preterm infants is important for their long-term kidney health. We aimed to examine the yearly trends of incidence and the related morbidities and care practices affecting the occurrence of neonatal AKI in extremely preterm (gestational age <29 weeks) and very preterm (gestational age 29-32 weeks) infants. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The trends and the related risk factors and care practices of AKI were examined in the extremely preterm (n=434) and very preterm (n=257) infants who were admitted within 14 days after birth from 2005 to 2018 to the University Hospital and had at least two serum creatinine measurements during hospitalization. We defined AKI as a serum creatinine rise of 0.3 mg/dl or more within 48 hours or a 1.5-fold increase within 7 days. RESULTS: The extremely preterm group had a three-fold higher incidence of AKI (30% versus 10%) than the very preterm group. Among preterm infants with AKI, 92% had one episode of AKI, and 45% experienced stage 2 or 3 AKI; the mean duration of AKI was 12±9 days. Across the 14-year period, the crude incidence of AKI declined markedly from 56% to 17% in the extremely preterm group and from 23% to 6% in the very preterm group. After adjustment, a significant decline of AKI incidence was still observed in the extremely preterm group. The declining AKI in the extremely preterm infants was related to the trends of decreasing incidences of neonatal transfer, prolonged aminoglycoside exposure, prophylactic use of nonsteroidal anti-inflammatory drugs, and sepsis. CONCLUSIONS: We observed a declining trend in the incidence of neonatal AKI among extremely preterm infants from 2005 to 2018, which may be related to improvement of care practices.

Endothelial-specific insulin receptor substrate-1 overexpression worsens neonatal hypoxic-ischemic brain injury via mTOR-mediated tight junction disassembly.

Hypoxic-ischemic (HI) encephalopathy is the major cause of mortality and disability in newborns. The neurovascular unit is a major target of acute and chronic brain injury, and therapies that protect simultaneously both neurons and vascular endothelial cells from neonatal HI injury are in demand. Insulin receptors and its key downstream molecule-insulin receptor substrate -1 (IRS-1) are potential neuroprotective targets and expressed both in neuron and endothelial cells. To investigate whether IRS-1 can act similarly in neurons and vascular endothelial cells in protecting neurovascular units and brain form HI injury, we found that neuron-specific IRS-1 transgenic rats showed reduced neurovascular injury and infarct volumes, whereas endothelial-specific IRS-1 transgenic rats showed increased blood-brain barrier (BBB) disruption and exaggerated neurovascular injury after neonatal HI brain injury. Endothelial-specific IRS-1 overexpression increased vascular permeability and disassembled the tight junction protein (zonula occludens-1) complex. Inhibition of mammalian target of rapamycin (mTOR) by rapamycin preserved tight junction proteins and attenuated BBB leakage and neuronal apoptosis after HI in the endothelial-specific IRS-1 transgenic pups. Together, our findings suggested that neuronal and endothelial IRS-1 had opposite effects on the neurovascular integrity and damage after neonatal HI brain injury and that endothelial IRS-1 worsens neurovascular integrity after HI via mTOR-mediated tight junction protein disassembly.