Abnormal Neurodevelopmental Outcome Research Articles

Association of fluoride exposure with disease burden and neurodevelopment outcomes in children in South Korea.

Community water fluoridation is an effective public health strategy for preventing dental caries, yet. Concerns exist about potential health problems. This study explores associations between tap water fluoride levels and pediatric disease burden, as well as neurodevelopmental outcomes at 6years of age. This nationwide population-based cohort study included children born in Korean cities with and without tap water fluoridation projects, between 2006 and 2012, aiming for a fluoride concentration of 0.8 ± 0.2mg/L in treated tap water. Data from the National Health Insurance Service were used, spanning from birth to 2018. The relationship between exposure to fluoridated tap water and incidence of 16 childhood diseases that were previously identified as potentially linked to fluoride exposure were examined. Additionally, we evaluated the neurodevelopmental outcomes across various domains, including gross motor, fine motor, cognition, language, social skills, and self-help functions. These assessments were performed using data from a comprehensive national health screening program for children aged six years. A fluoride-unexposed group included 22,881 children, whereas a fluoride-exposed group comprised 29,991 children (52% males). Children in the fluoride-exposed group had a decreased risk of dental caries and bone fractures [hazard ratio (95% confidence interval, CI), 0.76 (0.63-0.93) and 0.89 (0.82-0.93), respectively] and increased risk of hepatic failures [1.85, (1.14-2.98)] compared to those in the unexposed group. Additionally, the risk ratio of abnormal neurodevelopmental screening outcomes increased by 9%, but this was statistically uncertain (95% CI, 0.95-1.26). Fluoridated tap water was associated with an increased risk of hepatic failure but a decreased risk of bone fractures in children. The association between fluoridated tap water and neurodevelopmental screening outcomes at 6years remains unclear, highlighting the need for further studies to clarify this association.

Prognostic value of quantitative EEG in early hours of life for neonatal encephalopathy and neurodevelopmental outcomes

BackgroundThe ability to determine severity of encephalopathy is crucial for early neuroprotective therapies and for predicting neurodevelopmental outcome. The objective of this study was to assess a novel brain state of newborn (BSN) trend to distinguish newborns with presence of hypoxic ischemic encephalopathy (HIE) within hours after birth and predict neurodevelopmental outcomes at 2 years of age.MethodThis is a prospective cohort study of newborns at 36 weeks’ gestation or later with and without HIE at birth. The Total Sanart Score (TSS) was calculated based on a modified Sarnat exam within 6 h of life. BSN was calculated from electroencephalogram (EEG) measurements initiated after birth. The primary outcome at 2 year of age was a diagnosis of death or disability using the Bayley Scales of Infant Development III.ResultsBSN differentiated between normal and abnormal neurodevelopmental outcomes throughout the entire recording period from 6 h of life. Additionally, infants with lower BSN values had higher odds of neurodevelopmental impairment and HIE. BSN distinguished between normal (n = 86) and HIE (n = 46) and showed a significant correlation with the concomitant TSS.ConclusionBSN is a sensitive real-time marker for monitoring dynamic progression of encephalopathy and predicting neurodevelopmental impairment.ImpactThis is a prospective cohort study to investigate the ability of brain state of newborn (BSN) trend to predict neurodevelopmental outcome within the first day of life and identify severity of encephalopathy.BSN predicts neurodevelopmental outcomes at 2 years of age and the severity of encephalopathy severity. It also correlates with the Total Sarnat Score from the modified Sarnat exam.BSN could serve as a promising bedside trend aiding in accurate assessment and identification of newborns who may benefit from additional neuroprotection therapies.

Continuous Electroencephalogram (cEEG) Findings and Neurodevelopmental Outcomes in Neonates with Congenital Heart Disease (CHD) at 12-24 Months of Age.

This study aims to assess the role of continuous EEG (cEEG) background patterns and duration of cross-clamp time and cardiopulmonary bypass (CPB) in children with congenital heart disease (CHD) undergoing cardiac surgery and its correlation with abnormal neurodevelopmental outcomes at 12-24 months on Bayley Scales of Infant and Toddler Development (BSID-III). This retrospective cohort study included infants with CHD and cEEG monitoring, who underwent surgery by 44 weeks gestational age. 34 patients were included, who were operated at median age - 7 days. Longer duration of cross- camp time was associated with poor language composite scores (LCS) (p value = 0.036). A significant association existed between severity of encephalopathy in 24-hour post-operative period and poor LCS (p value = 0.026). Majority of neonates with CHD have below average cognitive, language and motor composite scores on BSID-III. Longer duration of cross-clamp time and severity of encephalopathy during 24-hour post-operative EEG monitoring are associated with poor LCS.

Resting state electroencephalographic brain activity in neonates can predict age and is indicative of neurodevelopmental outcome

ObjectiveElectroencephalography (EEG) can be used to estimate neonates’ biological brain age. Discrepancies between postmenstrual age and brain age, termed the brain age gap, can potentially quantify maturational deviation. Existing brain age EEG models are not well suited to clinical cot-side use for estimating neonates’ brain age gap due to their dependency on relatively large data and pre-processing requirements. MethodsWe trained a deep learning model on resting state EEG data from preterm neonates with normal neurodevelopmental Bayley Scale of Infant and Toddler Development (BSID) outcomes, using substantially reduced data requirements. We subsequently tested this model in two independent datasets from two clinical sites. ResultsIn both test datasets, using only 20 min of resting-state EEG activity from a single channel, the model generated accurate age predictions: mean absolute error = 1.03 weeks (p-value = 0.0001) and 0.98 weeks (p-value = 0.0001). In one test dataset, where 9-month follow-up BSID outcomes were available, the average neonatal brain age gap in the severe abnormal outcome group was significantly larger than that of the normal outcome group: difference in mean brain age gap = 0.50 weeks (p-value = 0.04). ConclusionsThese findings demonstrate that the deep learning model generalises to independent datasets from two clinical sites, and that the model’s brain age gap magnitudes differ between neonates with normal and severe abnormal follow-up neurodevelopmental outcomes. SignificanceThe magnitude of neonates’ brain age gap, estimated using only 20 min of resting state EEG data from a single channel, can encode information of clinical neurodevelopmental value.

Assessment of brain structure and volume reveals neurodevelopmental abnormalities in preterm infants with low-grade intraventricular hemorrhage

There is increasing evidence of abnormal neurodevelopmental outcomes in preterm infants with low-grade intraventricular hemorrhage (IVH). The purpose of the study was to explore whether brain microstructure and volume are associated with neuro-behavioral outcomes at 40 weeks corrected gestational age in preterm infants with low-grade IVH. MR imaging at term-equivalent age (TEA) was performed in 25 preterm infants with mild IVH (Papile grading I/II) and 40 control subjects without IVH. These subjects all had neonatal behavioral neurological assessment (NBNA) at 40 weeks’ corrected age. Microstructure and volume evaluation of the brain were performed by using diffusion kurtosis imaging (DKI) and Synthetic MRI. Correlations among microstructure parameters, volume, and developmental outcomes were explored by using Spearman's correlation. In preterm infants with low-grade IVH, the volume of brain parenchymal fraction (BPF) was reduced. In addition, mean kurtosis (MK), fractional anisotropy (FA), radial kurtosis (RK), axial kurtosis (AK) in several major brain regions were reduced, while mean diffusivity (MD) was increased (P < 0.05). BPF, RK in the cerebellum, MK in the genu of the corpus callosum, and MK in the thalamus of preterm infants with low-grade IVH were associated with lower NBNA scores (r = 0.831, 0.836, 0.728, 0.772, P < 0.05). DKI and Synthetic MRI can quantitatively evaluate the microstructure alterations and brain volumes in preterm infants with low-grade IVH, which provides clinicians with a more comprehensive and accurate neurobehavioral assessment of preterm infants with low-grade IVH.

PCO2 values in asphyxiated infants under therapeutic hypothermia after tailored respiratory management: a retrospective cohort study.

Hypoxic-ischemic encephalopathy (HIE) represents one of the major causes of neonatal death and long-term neurological disability. Both hypoxic-ischemic insults and therapeutic hypothermia (TH) can affect respiratory function. Currently, there is no evidence regarding optimal respiratory management in these infants. This is a retrospective cohort study examining newborns with HIE treated with TH between January 2015 and September 2020. The study population was divided into two groups based on different respiratory assistance during TH: spontaneous breathing (Group A) or mechanical ventilation (Group B). The primary outcome of the study was the mean pCO2 ± SD evaluation during TH in ventilated and non-ventilated asphyxiated infants. The secondary outcome was the correlation between ventilation strategy and short-term neurologic outcome according to Rutherford et al.'s MRI scoring system. A total of 126 newborns were enrolled, 75 in Group A and 51 in Group B. Respiratory management was individualized, and volume guarantee (VG) ventilation was the first choice for ventilated infants. Group B infants showed more severe conditions at birth. During TH, ventilated infants showed optimal mean pCO2 comparable with those breathing spontaneously (40.6 mmHg vs. 42.3 mmHg, respectively, p 0.091), with no significant difference in pCO2 standard deviation between (7.7 mmHg vs. 8.1 mmHg, respectively, p 0.522). Mean pH, pH standard deviation, mean pO2, pO2 standard deviation, and mean respiratory rate also did not differ between groups. MRI patterns of brain injury predictive of abnormal neurodevelopmental outcomes were similar in both groups. Logistic regression analysis demonstrated that only umbilical cord arterial blood pH-affected MRI lesions were associated with poor neurodevelopmental outcomes (OR 1.505; CI 95% 1.069-2.117). Infants cooled after HIE should receive individualized respiratory management, not necessarily involving intubation. In those infants requiring mechanical ventilation, a volume-targeted strategy appeared to be effective in maintaining stable blood gas levels. Short-term neurological outcomes appeared comparable in ventilated and non-ventilated infants.

Assessment of the Prognostic Factors for Abnormal Neurodevelopmental Outcomes in Children with Acute Bacterial Meningitis by Using RNDA Tool

This observational follow up study was carried in the Department of Paediatrics, Institute of Child and Mother Health (ICMH), Matuail, Dhaka, during November 2016 to December 2017, to determine the prognostic factors for assessment of the prognostic factors for abnormal neurodevelopmental outcomes in children with acute bacterial meningitis by using RNDA tool. A total of 56 children with acute bacterial meningitis of age &gt; 1month - 15 years admitted in the inpatient department were enrolled in this study. Most 34 (60.7%) of the children belonged to age &lt;12 months and male to female ratio was almost 2:1. More than half (58.9%) children admitted &gt;48hrs after onset of illness, 11(19.6%) children received previous treatment with antibiotics and most (85.7%) of the children had occurrence of seizures prior to admission. More than one third (39.3%) children had &gt;100 cell count in their CSF. CSF glucose/ serum glucose ratio was found &lt;0.2 in case of 8(14.3%) children. More than three fourth (78.6%) children had high protein in their CSF. Abnormal developmental outcome assessed by RNDA on follow ups. It was observed that gross motor development was mildly impaired in 6(12.0%), 8(16.3%) and 5 (11.6%) cases on 1st, 2nd and 3rd follow up respectively. Gross motor was moderately impaired in 4 (8.0%), 3 (6.1%) and 3 (7.0%) cases on 1st, 2nd and 3rd follow up respectively. Accordingly, fine motor was mild impaired in 5 (10.0%), 4 (8.2%) and 5 (11.6%) cases and moderately impaired in 2 (4.0%), 3 (6.1%) and 2 (4.7%) cases on 1st, 2nd and 3rd follow up respectively. Cognition was mild impaired in 11 (22.0%), 12 (24.5%) and 11 (25.6%) cases and moderately impaired in 4 (8.0%), 4 (8.2%) and 3 (7.0%) cases on 1st, 2nd and 3rd follow up respectively. Children found with any selective neurological complication or abnormal developmental outcome in at least one follow up was considered to be abnormal. Hypertonic muscle tone and exaggerated jerk was found in 2(3.8%) children. 5(9.6%) children had developmental regression on follow up. 3(5.8%) children had squint, 2 (3.8%) children had subdural effusion, 2 (3.8%) children had visual deficit, 6 (11.5%) children had hearing deficit and 4 (7.7%) children had afebrile seizures on follow up. One (11.1%) child with focal seizure and 6 (60.0%) children with hazy CSF colour had significantly (p&lt;0.05) developed abnormal developmental outcome. Children under 12 months of age, children who received previous treatment with antibiotics, seizures prior to admission, high WBC count, hazy CSF colour and CSF glucose/ serum glucose ratio below 0.2 were significantly (p&lt;0.05) associated with acute complications during hospital stay. Children with focal seizure and children with hazy CSF colour were significantly (p&lt;0.05) associated to abnormal developmental outcome. Multivariate regression analysis showed no significant (p&gt;0.05) association between acute complications and prognostic factors. Age under 12 months in adjusted OR 0.970 with 95.0% C.I 0.943 to 0.997, CSF leukocytosis in adjusted OR 0.99 with 95.0% C.I. 0.99 to 1.00) and CSF glucose/serum glucose ratio&lt;0.2 in adjusted OR 15.23 with 95.0% C.I. 1.28 to 100.0 were significantly associated with abnormal developmental outcome in multivariate regression analysis.

Volumetric changes in brain MRI of infants with hypoxic-ischemic encephalopathy and abnormal neurodevelopment who underwent therapeutic hypothermia

BackgroundHypoxic-ischemic encephalopathy (HIE) is a severe neonatal complication that can result in 40–60 % of long-term morbidity. Magnetic Resonance Imaging (MRI) is a noninvasive method which is usually performed before discharge to visually assess acquired cerebral lesions associated with HIE and severity of lesions possibly providing a guide for detecting adverse outcomes. This study aims to evaluate the impact of HIE on brain volume changes observed in MRI scans performed at a mean 10 days of life, which can serve as a prognostic indicator for abnormal neurodevelopmental (ND) outcomes at 18–24 months among HIE infants. MethodsWe retrospectively identified a cohort of HIE patients between June 2013 and March 2017. The inclusion criteria for therapeutic hypothermia (TH) were a gestational age ≥35 weeks, a birth weight ≥1800 g, and the presence of ≥ moderate HIE. Brain MRI was performed at a mean 10 days of life and brain volumes (total brain volume, cerebral volume, cerebellar volume, brain stem volume, and ventricle volume) were measured for quantitative assessment. At 18–24 months, the infants returned for follow-up evaluations, during which their cognitive, language, and motor skills were assessed using the Bayley Scales of Infant and Toddler Development III. ResultsThe study recruited a total of 240 infants between 2013 and 2017 for volumetric brain MRI evaluation. Among these, 83 were normal control infants, 107 were TH-treated HIE infants and 37 were HIE infants who did not receive TH due to contraindications. Clinical evaluation was further proceeded. We compared the brain volumes between the normal control infants (n = 83) with normal ND but TH-treated HIE infants (n = 76), abnormal ND TH-treated HIE infants (n = 31), and the severe HIE MRI group with no TH (n = 37). The abnormal ND TH-treated HIE infants demonstrated a significant decrease in brainstem volume and an increase in ventricle size (p < 0.001) (Table 4). Lastly, the severe brain MRI group who did not receive TH showed significantly smaller brain stem (p = 0.006), cerebellar (p = 0.006) and cerebrum volumes (p = 0.027), accompanied by larger ventricular size (p = 0.013) compared to the normal control group (Table 5). ConclusionIn addition to assessing the location of brain injuries in MRI scans, the reduction in brain stem volume coupled with an increase in ventricular volume in HIE infants may serve as a biomarker indicating severe HIE and adverse long-term ND outcomes among HIE infants who either received therapeutic hypothermia (TH) treatment or not.

Microstate Analysis Reflects Maturation of the Preterm Brain.

Preterm neonates are at risk of long-term neurodevelopmental impairments due to disruption of natural brain development. Electroencephalography (EEG) analysis can provide insights into brain development of preterm neonates. This study aims to explore the use of microstate (MS) analysis to evaluate global brain dynamics changes during maturation in preterm neonates with normal neurodevelopmental outcome.The dataset included 135 EEGs obtained from 48 neonates at varying postmenstrual ages (26.4 to 47.7 weeks), divided into four age groups. For each recording we extracted a 5-minute epoch during quiet sleep (QS) and during non-quiet sleep (NQS), resulting in eight groups (4 age group x 2 sleep states). We compared MS maps and corresponding (map-specific) MS metrics across groups using group-level maps. Additionally, we investigated individual map metrics.Four group-level MS maps accounted for approximately 70% of the global variance and showed non-random syntax. MS topographies and transitions changed significantly when neonates reached 37 weeks. For both sleep states and all MS maps, MS duration decreased and occurrence increased with age. The same relationships were found using individual maps, showing strong correlations (Pearson coefficients up to 0.74) between individual map metrics and post-menstrual age. Moreover, the Hurst exponent of the individual MS sequence decreased with age.The observed changes in MS metrics with age might reflect the development of the preterm brain, which is characterized by formation of neural networks. Therefore, MS analysis is a promising tool for monitoring preterm neonatal brain maturation, while our study can serve as a valuable reference for investigating EEGs of neonates with abnormal neurodevelopmental outcomes.

Glial fibrillary acidic protein as a serum neuromarker of brain injury in pediatric patients with congenital heart defects undergoing cardiac surgery

Abstract Objective: The aim of this study was to assess glial fibrillary acidic protein (GFAP) as a marker of short-term neurodevelopmental delay in pediatric patients with congenital defects (CHD) after cardiovascular surgical intervention. Methods: Included patients were screened by Denver Developmental Screening Test II scale a few days before and then at 4 to 6 months after the surgical intervention. Blood samples were collected preoperatory and at 24 hours after surgery; GFAP levels were assessed by enzyme-linked immunosorbent assay using commercial kit form BioVendor. Results: Forty children were enrolled and dichotomized into two groups based on peripheric oxygen saturation: cyanotic (&lt;95%) and non-cyanotic (&gt;=95%) group. 63% from our population had an abnormal neurodevelopmental outcome. Significant differences between groups were found in language domain scores preoperatory (p=0.03) and in fine motor domain postoperatory (p=0.03). In the postoperatory period, GFAP had significantly higher values (p=0.0248) in the cyanotic CHD group. Association between GFAP and NIRS were analyzed and significant differences were found in both groups with a good predicting model in the non-cyanotic CHD group (aria under curve of 0.7 for receiver operative characteristic). Higher GFAP levels from the postoperatory period correlated with neurodevelopmental impairment (mean value of: 0.66 ± 0.02ng/ml in those with good neurodevelopmental score, 0.69 ± 0.02ng/ml in those with low neurodevelopmental score, p=0.01). Conclusions: GFAP could be a reliable neuromarker in identifying early acute brain injury documented by NIRS monitorization during perioperatory period and it also could identify short term neurodevelopmental impairment documented by lower neurodevelopmental scores.

Insights into Neonatal Cerebral Autoregulation by Blood Pressure Monitoring and Cerebral Tissue Oxygenation: A Qualitative Systematic Review.

The aim of this qualitative systematic review was to identify publications on blood pressure monitoring in combination with cerebral tissue oxygenation monitoring during the first week after birth focusing on cerebral autoregulation. A systematic search was performed on PubMed. The following search terms were used: infants/newborn/neonates, blood pressure/systolic/diastolic/mean/MAP/SAP/DAP, near-infrared spectroscopy, oxygenation/saturation/oxygen, and brain/cerebral. Additional studies were identified by a manual search of references in the retrieved studies and reviews. Only human studies were included. Thirty-one studies focused on preterm neonates, while five included preterm and term neonates. In stable term neonates, intact cerebral autoregulation was shown by combining cerebral tissue oxygenation and blood pressure during immediate transition, while impaired autoregulation was observed in preterm neonates with respiratory support. Within the first 24 h, stable preterm neonates had reduced cerebral tissue oxygenation with intact cerebral autoregulation, while sick neonates showed a higher prevalence of impaired autoregulation. Further cardio-circulatory treatment had a limited effect on cerebral autoregulation. Impaired autoregulation, with dependency on blood pressure and cerebral tissue oxygenation, increased the risk of intraventricular hemorrhage and abnormal neurodevelopmental outcomes. Integrating blood pressure monitoring with cerebral tissue oxygenation measurements has the potential to improve treatment decisions and optimizes neurodevelopmental outcomes in high-risk neonates.

Effects of prenatal exposure to (es)citalopram and maternal depression during pregnancy on DNA methylation and child neurodevelopment

Studies assessing associations between prenatal exposure to antidepressants, maternal depression, and offspring DNA methylation (DNAm) have been inconsistent. Here, we investigated whether prenatal exposure to citalopram or escitalopram ((es)citalopram) and maternal depression is associated with differences in DNAm. Then, we examined if there is an interaction effect of (es)citalopram exposure and DNAm on offspring neurodevelopmental outcomes. Finally, we investigated whether DNAm at birth correlates with neurodevelopmental trajectories in childhood. We analyzed DNAm in cord blood from the Norwegian Mother, Father and Child Cohort Study (MoBa) biobank. MoBa contains questionnaire data on maternal (es)citalopram use and depression during pregnancy and information about child neurodevelopmental outcomes assessed by internationally recognized psychometric tests. In addition, we retrieved ADHD diagnoses from the Norwegian Patient Registry and information on pregnancies from the Medical Birth Registry of Norway. In total, 958 newborn cord blood samples were divided into three groups: (1) prenatal (es)citalopram exposed (n = 306), (2) prenatal maternal depression exposed (n = 308), and (3) propensity score-selected controls (n = 344). Among children exposed to (es)citalopram, there were more ADHD diagnoses and symptoms and delayed communication and psychomotor development. We did not identify differential DNAm associated with (es)citalopram or depression, nor any interaction effects on neurodevelopmental outcomes throughout childhood. Trajectory modeling identified subgroups of children following similar developmental patterns. Some of these subgroups were enriched for children exposed to maternal depression, and some subgroups were associated with differences in DNAm at birth. Interestingly, several of the differentially methylated genes are involved in neuronal processes and development. These results suggest DNAm as a potential predictive molecular marker of later abnormal neurodevelopmental outcomes, but we cannot conclude whether DNAm links prenatal (es)citalopram exposure or maternal depression with child neurodevelopmental outcomes.

Growth and Neurodevelopmental Outcomes of Very Low Birth Weight Infants upto Six Months of Age at a Tertiary Level NICU in Central India: A Prospective Cohort Study

Introduction: The long-term outcomes of Very Low Birth Weight (VLBW) infants are influenced by prematurity, as well as the occurrence of various short-term morbidities, such as Respiratory Distress Syndrome (RDS), sepsis, Necrotising Enterocolitis (NEC), Patent Ductus Arteriosus (PDA), Intraventricular Haemorrhage (IVH), Periventricular Leukomalacia (PVL), Retinopathy Of Prematurity (ROP), and Chronic Lung Disease (CLD). It has been estimated that approximately half of all VLBW infants develop cognitive and behavioural deficits in the future. Therefore, studying VLBW infants and providing longitudinal follow-up after their hospital discharge is increasingly important. This helps in the early diagnosis of neurodevelopmental abnormalities and enables timely intervention for a better quality of life in the future. Aim: To assess the growth and neurodevelopmental outcomes of VLBW infants discharged from the NICU until six months of age. Materials and Methods: A prospective cohort study was conducted in the Neonatal In tensive Crae Unit (NICU) at NSCB Medical College, Jabalpur, Madhya Pradesh, India. The duration of the study was one year and six months, from March 2018 to September 2019. A total of 40 VLBW infants were enrolled and followed-up for six months. The infants were divided into two groups: Group 1 (&lt;32 weeks) and group 2 (&gt;32 weeks). Physical parameters such as weight, length, and head circumference were recorded on admission and at one, three and six months of corrected gestational age. Developmental assessment was performed using the Denver Developmental Screening Test-II (DDST-II) method. The association of risk factors with neurodevelopmental outcomes was also assessed. Data were analysed using Statistical Package for Social Sciences (SPSS) version 20.0, and the Chi-square test, Fisher’s-exact test, and Student’s t-test were used. A p-value less than 0.05 was considered significant. Results: Among the 40 subjects, 12 (30%) were &lt;32 weeks, and 28 (70%) were ≥32 weeks. Overall, parameters were higher in infants ≥32 weeks. Weight and head circumference gain velocity were greater in infants ≥32 weeks during the first three months of life (p&lt;0.05). From three to six months, &lt;32 weeks infants showed a significant increase (p&lt;0.001) in weight and head circumference gain velocity. The length gain velocity in both groups was comparable since birth, and &lt;32 weeks VLBW infants demonstrated good catch-up growth, which was statistically significant (p&lt;0.05). At six months of corrected age, 16 (40%) infants out of the total 40 infants had abnormal neurodevelopmental outcomes. A total of 7 (58.33%) of the &lt;32 weeks VLBW infants and 9 (32.14%) of the ≥32 weeks VLBW infants had Neurodevelopmental Delay (NDD). Hypoglycaemia, shock, hyaline membrane disease, and mechanical ventilation were significantly associated with an increased risk of NDD. Conclusion: The incidence of NDD was significantly higher in infants with lower gestational age, lower birth weight and the presence of associated factors such as hyaline membrane disease, hypoglycaemia, shock, ventilation, and hyperbilirubinaemia. Improved perinatal care, early assessment of development using appropriate tools, and early intervention are necessary to improve the outcomes of these infants.

Prenatal tobacco smoke exposure and risk of brain abnormalities on magnetic resonance imaging at term in infants born very preterm

Prenatal tobacco smoke exposure and preterm birth are associated with abnormal brain and neurodevelopmental outcomes in infants. Studies that can disentangle indirect mediating effects from direct effects of prenatal tobacco smoke exposure on sensitive early brain magnetic resonance imaging biomarkers in very preterm infants are needed. This study aimed to determine whether prenatal tobacco smoke exposure in preterm infants posed any direct effects on magnetic resonance imaging-determined global brain abnormality score and secondary measures of brain abnormalities after removing any indirect mediating effects of preterm birth on neurostructural outcomes. We examined brain magnetic resonance imaging findings collected at 39 to 44 weeks postmenstrual age from a prospective cohort of 395 infants born very preterm (gestational age of ≤32 weeks). The primary outcome was global brain abnormality score, and the secondary outcomes were global efficiency of structural connectome, diffuse white matter abnormality volume, total brain tissue volume, total gray and white matter volumes, and cerebellar volume. Maternal reports of smoking during pregnancy were obtained. We performed multivariable linear regression analyses to examine the association between prenatal tobacco smoke exposure and our magnetic resonance imaging outcomes, controlling for prospectively collected confounders. Moreover, we performed a mediation analysis to estimate the direct effects of prenatal tobacco smoke exposure on brain abnormalities and any indirect effects through preterm birth. Overall, 12.6% of infants had prenatal tobacco smoke exposure. Infants with prenatal tobacco smoke exposure had a higher median global brain abnormality score than nonexposed infants (7 [interquartile range, 0-41] vs 5 [interquartile range, 0-34]; P≤.001); the findings remained significant (P<.001) after controlling for antenatal confounders. Global efficiency (P<.001), diffuse white matter volume (P=.037), and total brain tissue volume (P=.047) were significantly different between TSE groups in multivariable analyses. On mediation analysis, preterm birth mediated between 0% and 29% of the indirect effect of prenatal tobacco smoke exposure on several measures of brain abnormality outcomes. Thus, prenatal tobacco smoke exposure had a direct adverse effect between 71% and 100% on brain injury or abnormal development. Our study has identified multiple adverse effects of prenatal tobacco smoke exposure on sensitive and objective measures of neonatal brain injury and abnormal development; most cases seemed to be a direct effect of prenatal tobacco smoke exposure on fetal brain development. The results underscored the significant adverse neurostructural effects of prenatal tobacco smoke exposure to tobacco smoke pollutants.

Emergency arterial switch: Rescue therapy for life-threatening hypoxemia in infants with transposition of great arteries with intact intraventricular septum

ObjectiveA small percentage of infants with d-loop transposition of the great arteries with intact intraventricular septum have life-threatening refractory hypoxemia often due to coexistent persistent pulmonary hypertension of the newborn. In this case series we describe the outcomes of a “rescue” emergency arterial switch operation (ASO). MethodsWe undertook a retrospective medical record analysis of infants with d-loop transposition of the great arteries with intact intraventricular septum who underwent an ASO in New Zealand from January 1, 1996, to April 30, 2017. Data were compared for those who received an emergency ASO and those with a nonemergency ASO for descriptive purposes. An emergency ASO was defined as one that was undertaken for life-threatening refractory hypoxemia when the only alternative stabilization strategy was preoperative extracorporeal life support. Primary outcome measures were 30-day postoperative mortality and abnormal neurodevelopmental outcome in the survivors. Secondary outcomes were low cardiac output, arrhythmia, renal dysfunction, postoperative seizures, and length of stay. Other known risk factors for morbidity and mortality were also assessed. ResultsTwo hundred seventy-two infants underwent an ASO with 25 (9%) who received an emergency ASO. No infants received preoperative extracorporeal life support. The emergency group had greater 30-day postoperative mortality (8.0% vs 0.4%; P = .01) with no difference in abnormal neurodevelopmental outcome among the survivors (17.4% vs 13.8%; P = .35). The emergency group had more therapies for low cardiac output syndrome, more postoperative seizures, and a longer length of stay. ConclusionsAn emergency ASO is a definitive rescue therapy that can be undertaken with acceptable mortality and neurodevelopmental outcome with consideration of the preoperative clinical state.

Neonatal hyperoxia in mice triggers long-term cognitive deficits via impairments in cerebrovascular function and neurogenesis.

Preterm birth is the leading cause of death in children under 5 years of age. Premature infants who receive life-saving oxygen therapy often develop bronchopulmonary dysplasia (BPD), a chronic lung disease. Infants with BPD are at a high risk of abnormal neurodevelopment, including motor and cognitive difficulties. While neural progenitor cells (NPCs) are crucial for proper brain development, it is unclear whether they play a role in BPD-associated neurodevelopmental deficits. Here, we show that hyperoxia-induced experimental BPD in newborn mice led to lifelong impairments in cerebrovascular structure and function as well as impairments in NPC self-renewal and neurogenesis. A neurosphere assay utilizing nonhuman primate preterm baboon NPCs confirmed impairment in NPC function. Moreover, gene expression profiling revealed that genes involved in cell proliferation, angiogenesis, vascular autoregulation, neuronal formation, and neurotransmission were dysregulated following neonatal hyperoxia. These impairments were associated with motor and cognitive decline in aging hyperoxia-exposed mice, reminiscent of deficits observed in patients with BPD. Together, our findings establish a relationship between BPD and abnormal neurodevelopmental outcomes and identify molecular and cellular players of neonatal brain injury that persist throughout adulthood that may be targeted for early intervention to aid this vulnerable patient population.

Decreased cerebrospinal fluid kynurenic acid in epileptic spasms: A biomarker of response to corticosteroids.

SummaryBackgroundEpileptic (previously infantile) spasms is the most common epileptic encephalopathy occurring during infancy and is frequently associated with abnormal neurodevelopmental outcomes. Epileptic spasms have a diverse range of known (genetic, structural) and unknown aetiologies. High dose corticosteroid treatment for 4 weeks often induces remission of spasms, although the mechanism of action of corticosteroid is unclear. Animal models of epileptic spasms have shown decreased brain kynurenic acid, which is increased after treatment with the ketogenic diet. We quantified kynurenine pathway metabolites in the cerebrospinal fluid (CSF) of infants with epileptic spasms and explored clinical correlations.MethodsA panel of nine metabolites in the kynurenine pathway (tryptophan, kynurenine, kynurenic acid, 3-hydroxykynurenine, xanthurenic acid, anthranilic acid, 3-hydroxyanthranilic acid, quinolinic acid, and picolinic acid) were measured using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). CSF collected from paediatric patients less than 3 years of age with epileptic spasms (n=34, 19 males, mean age 0.85, median 0.6, range 0.3–3 yrs) were compared with other epilepsy syndromes (n=26, 9 males, mean age 1.44, median 1.45, range 0.3–3 yrs), other non-inflammatory neurological diseases (OND) (n=29, 18 males, mean age 1.47, median 1.6, range 0.1–2.9 yrs) and inflammatory neurological controls (n=12, 4 males, mean age 1.80, median 1.80, range 0.8–2.5 yrs).FindingsThere was a statistically significant decrease of CSF kynurenic acid in patients with epileptic spasms compared to OND (p<0.0001). In addition, the kynurenic acid/kynurenine (KYNA/KYN) ratio was lower in the epileptic spasms subgroup compared to OND (p<0.0001). Epileptic spasms patients who were steroid responders or partial steroid responders had lower KYNA/KYN ratio compared to patients who were refractory to steroids (p<0.005, p<0.05 respectively).InterpretationThis study demonstrates decreased CSF kynurenic acid and KYNA/KYN in epileptic spasms, which may also represent a biomarker for steroid responsiveness. Given the anti-inflammatory and neuroprotective properties of kynurenic acid, further therapeutics able to increase kynurenic acid should be explored.FundingFinancial support for the study was granted by Dale NHMRC Investigator grant APP1193648, Petre Foundation, Cerebral Palsy Alliance and Department of Biochemistry at the Children's Hospital at Westmead. Prof Guillemin is funded by NHMRC Investigator grant APP1176660 and Macquarie University.

EBNEO commentary: Association between seizures during rewarming after hypothermia therapy for neonatal hypoxic-ischemic encephalopathy and abnormal neurodevelopmental outcomes.

EBNEO commentary: Association between seizures during rewarming after hypothermia therapy for neonatal hypoxic-ischemic encephalopathy and abnormal neurodevelopmental outcomes.

Fetal periventricular pseudocysts: is MRI evaluation needed? What is the long-term neurodevelopmental outcome? Systematic review and meta-analysis.

To explore the value of magnetic resonance imaging (MRI) in fetuses with periventricular pseudocysts (PVPC) and the neurodevelopmental outcomes of these fetuses via meta-analysis. MEDLINE and EMBASE database were searched for studies reporting on the MRI assessment of fetuses diagnosed with PVPC on neurosonography. The neurosonography was conducted according to the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) guidelines or standard axial, coronal and sagittal planes for advanced central nervous system (CNS) assessment. Single-shot fast spin-echo T2-weighted sequences of MRI technique in three orthogonal planes were necessarily performed. The pooled proportion of CNS anomalies missed on neurosonography and detected only at prenatal MRI was calculated. Subanalysis was performed according to the types of intracranial anomalies. The pregnancy outcomes (including normal, abnormal, termination of pregnancy, and perinatal death) of PVPC fetuses were also analyzed. Five studies comprising 136 fetuses were included in this meta-analysis. Mean gestational age was 29.8weeks (16-38weeks) at ultrasonography and 31.5weeks (25-37weeks) at MRI. Overall, MRI detected exclusively CNS anomalies in 25.2% (95% CI 15.9-35.8%) of cases. Among them, the highest incidence was white matter abnormalities with the pooled proportion of 16.3% (95% CI 9.7-24.2%). When getting rid of whitematter abnormalities, the risk of associated CNS anomalies only detected on MRI was reduced to 9.1% (95% CI 1.8-21.4%). Meanwhile, 130 cases were studied to assess the pregnancy outcomes with the scope of 1month to 10years. The pooled proportion of normal outcomes in isolated PVPC fetuses was as high as 95.0% (95% CI 83.9-99.8%). When analyzing the neurodevelopmental outcomes in non-isolated PVPC fetuses, the incidence of normal neurodevelopmental outcomes was about 22.1% (95% CI 5.6-45.5%) with mild and single additional abnormalities, the rate of abnormal neurodevelopmental outcomes was 19.5% (95% CI 11.0-29.7%) with apparent and/or multiple abnormalities. Besides, 53.6% (95% CI 35.4-71.3%) of non-isolated PVPC cases were terminated mainly due to infections, genetic anomalies, metabolic disorders and hemorrhage. MRI assessment of PVPC fetuses is recommended to detect associated intracranial anomalies that may be missed on dedicated neurosonography. White matter abnormalities on MRI account for the majority of additional anomalies, which might to be the clue of CMV infection, aminoacidopathy or white matter disease. Moreover, the neurodevelopmental outcome of isolated PVPC fetuses remains favorable, while the neurodevelopmental outcomes of non-isolated PVPC fetuses depend on the accompanying anomaly.

Neurodevelopmental Outcomes of Neonatal Rotavirus-Associated Leukoencephalopathy.

Rotavirus infection has been reported to be associated with neonatal seizures with a diffuse and symmetrical diffusion restriction of periventricular white matter, namely, neonatal rotavirus-associated leukoencephalopathy. The extensive white matter injury seen in this cohort raises concerns about the long-term neurodevelopmental outcomes. In the present study, we prospectively assessed the neurodevelopmental outcomes of 13 patients with neonatal rotavirus-associated leukoencephalopathy at a median age of 26 months (range, 23-68 months). Neurodevelopmental outcomes were evaluated using a neurological examination, developmental evaluations, and magnetic resonance imaging (MRI) of the brain. Overall, 6 of the 13 patients (46%) had abnormal neurodevelopmental outcomes: 1 patient had mental retardation, visual-motor integration (VMI) dysfunction, cerebral palsy, and epilepsy; 1 patient had cerebral palsy and VMI dysfunction; remaining 4 patients had VMI dysfunction. Follow-up MRI in 12 of 13 patients showed an increased signal intensity on periventricular white matter in all patients. These findings suggested that neonatal rotavirus-associated leukoencephalopathy could not be assumed to be benign in long-term neurodevelopment, particularly in VMI function. Early intervention and long-term follow-up are necessary for these patients. Our findings raise caution for rotavirus infection in this vulnerable population for infants.