Neurodevelopmental Sequelae Research Articles

Placental features of fetal vascular malperfusion and infant neurodevelopmental outcomes at 2 years of age in severe fetal growth restriction

Placental pathologic lesions suggesting maternal or fetal vascular malperfusion are common among pregnancies complicated by intrauterine growth restriction. Data on the relationship between pathologic placental lesions and subsequent infant neurodevelopmental outcomes are limited. This study aimed to assess the relationship between placental pathologic lesions and infant neurodevelopmental outcomes at 2 years of age in a cohort of pregnancies complicated by intrauterine growth restriction. An observational cohort study included singleton intrauterine growth restriction pregnancies delivered at ≤34 weeks' gestation and with a birthweight of ≤1500 g at a single institution in the period between 2007 and 2016. Maternal and neonatal data were collected at discharge from the hospital. Infant neurodevelopmental assessment was performed every 3 months during the first year of life and every 6 months in the second year. Penalized logistic regression was used to test the association of maternal vascular malperfusion and fetal vascular malperfusion with infant outcomes adjusting for confounders. Of the 249 pregnancies enrolled, neonatal mortality was 8.8% (22 of 249). Severe and overall maternal vascular malperfusion were 16.1% (40 of 249) and 31.7% (79 of 249), respectively. Severe maternal vascular malperfusion was associated with an increased risk of neonatal mortality (adjusted odds ratio, 3.3; 95% confidence interval, 1.2-9.5). Among the 198 survivors after a 2-year neurodevelopmental follow-up evaluation, the rate of major and minor neurodevelopmental sequelae was 57.1% (4 of 7) among severe fetal vascular malperfusion (adjusted odds ratio, 24.5; 95% confidence interval, 4.1-146), 44.8% (13 of 29) among overall fetal vascular malperfusion (adjusted odds ratio, 5.8; 95% confidence interval, 5.1-16.2), and 7.1% (12 of 169) in pregnancies without fetal vascular malperfusion. Infants born from pregnancies with fetal vascular malperfusion also had lower 2-year general quotient, personal-social, hearing and speech, and performance subscales scores than those without fetal vascular malperfusion. Finally, in the presence of fetal vascular malperfusion, the likelihood of a 2-year infant survival with normal neurodevelopmental outcomes was reduced by more than 70% (adjusted odds ratio, 0.29; 95% confidence interval, 0.14-0.63). Noticeably, 10 of the 20 subjects with a 2-year major neurodevelopmental impairment (3 of 4 with severe fetal vascular malperfusion) had little or no abnormal neurologic findings at discharge from neonatal intensive care unit. In preterm intrauterine growth restriction, placental fetal vascular malperfusion is correlated with an increased risk of abnormal infant neurodevelopmental outcomes at 2 years of age even in the absence of brain lesions or neurologic abnormalities at discharge from the neonatal intensive care unit. In the case of a diagnosis of fetal vascular malperfusion, pediatricians and neurologists should be alerted to an increased risk of subsequent infant neurodevelopmental problems.

Human cytomegalovirus infection is associated with increased expression of the lissencephaly gene PAFAH1B1 encoding LIS1 in neural stem cells and congenitally infected brains.

Congenital infection of the central nervous system by human cytomegalovirus (HCMV) is a leading cause of permanent sequelae, including mental retardation or neurodevelopmental abnormalities. The most severe complications include smooth brain or polymicrogyria, which are both indicative of abnormal migration of neural cells, although the underlying mechanisms remain to be determined. To gain better insight on the pathogenesis of such sequelae, we assessed the expression levels of a set of neurogenesis-related genes, using HCMV-infected human neural stem cells derived from embryonic stem cells (NSCs). Among the 84 genes tested, we found dramatically increased expression of the gene PAFAH1B1, encoding LIS1 (lissencephaly-1), in HCMV-infected versus uninfected NSCs. Consistent with these findings, western blotting and immunofluorescence analyses confirmed the increased levels of LIS1 in HCMV-infected NSCs at the protein level. We next assessed the migratory abilities of HCMV-infected NSCs and observed that infection strongly impaired the migration of NSCs, without detectable effect on their proliferation. Moreover, we observed increased immunostaining for LIS1 in brains of congenitally infected fetuses, but not in control samples, highlighting the clinical relevance of our findings. Of note, PAFAH1B1 mutations (resulting in either haploinsufficiency or gain of function) are primary causes of hereditary neurodevelopmental diseases. Notably, mutations resulting in PAFAH1B1 haploinsufficiency cause classic lissencephaly. Taken together, our findings suggest that PAFAH1B1 is a critical target of HCMV infection. They also shine a new light on the pathophysiological basis of the neurological outcomes of congenital HCMV infection, by suggesting that defective neural cell migration might contribute to the pathogenesis of the neurodevelopmental sequelae of infection. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Human Wharton's Jelly Mesenchymal Stromal Cell-Derived Small Extracellular Vesicles Drive Oligodendroglial Maturation by Restraining MAPK/ERK and Notch Signaling Pathways.

Peripartum cerebral hypoxia and ischemia, and intrauterine infection and inflammation, are detrimental for the precursor cells of the myelin-forming oligodendrocytes in the prematurely newborn, potentially leading to white matter injury (WMI) with long-term neurodevelopmental sequelae. Previous data show that hypomyelination observed in WMI is caused by arrested oligodendroglial maturation rather than oligodendrocyte-specific cell death. In a rat model of premature WMI, we have recently shown that small extracellular vesicles (sEV) derived from Wharton’s jelly mesenchymal stromal cells (WJ-MSC) protect from myelination deficits. Thus, we hypothesized that sEV derived from WJ-MSC directly promote oligodendroglial maturation in oligodendrocyte precursor cells. To test this assumption, sEV were isolated from culture supernatants of human WJ-MSC by ultracentrifugation and co-cultured with the human immortalized oligodendrocyte precursor cell line MO3.13. As many regulatory functions in WMI have been ascribed to microRNA (miR) and as sEV are carriers of functional miR which can be delivered to target cells, we characterized and quantified the miR content of WJ-MSC-derived sEV by next-generation sequencing. We found that WJ-MSC-derived sEV co-localized with MO3.13 cells within 4 h. After 5 days of co-culture, the expression of myelin basic protein (MBP), a marker for mature oligodendrocytes, was significantly increased, while the oligodendrocyte precursor marker platelet-derived growth factor alpha (PDGFRα) was decreased. Notch and MAPK/ERK pathways known to inhibit oligodendrocyte maturation and differentiation were significantly reduced. The pathway enrichment analysis showed that the miR present in WJ-MSC-derived sEV target genes having key roles in the MAPK pathway. Our data strongly suggest that sEV from WJ-MSC directly drive the maturation of oligodendrocyte precursor cells by repressing Notch and MAPK/ERK signaling.

Aromatic l-amino acid decarboxylase deficiency: a patient-derived neuronal model for precision therapies.

Aromatic l-amino acid decarboxylase (AADC) deficiency is a complex inherited neurological disorder of monoamine synthesis which results in dopamine and serotonin deficiency. The majority of affected individuals have variable, though often severe cognitive and motor delay, with a complex movement disorder and high risk of premature mortality. For most, standard pharmacological treatment provides only limited clinical benefit. Promising gene therapy approaches are emerging, though may not be either suitable or easily accessible for all patients. To characterize the underlying disease pathophysiology and guide precision therapies, we generated a patient-derived midbrain dopaminergic neuronal model of AADC deficiency from induced pluripotent stem cells. The neuronal model recapitulates key disease features, including absent AADC enzyme activity and dysregulated dopamine metabolism. We observed developmental defects affecting synaptic maturation and neuronal electrical properties, which were improved by lentiviral gene therapy. Bioinformatic and biochemical analyses on recombinant AADC predicted that the activity of one variant could be improved by l-3,4-dihydroxyphenylalanine (l-DOPA) administration; this hypothesis was corroborated in the patient-derived neuronal model, where l-DOPA treatment leads to amelioration of dopamine metabolites. Our study has shown that patient-derived disease modelling provides further insight into the neurodevelopmental sequelae of AADC deficiency, as well as a robust platform to investigate and develop personalized therapeutic approaches.

Obstetrics, genetics, and litigation.

Claims of medical negligence are universal. Unexpected adverse pregnancy outcome may trigger litigation. Such outcomes, especially with neurodevelopmental sequelae, may be compounded by a genetic disorder, congenital abnormality, or syndrome. This is a report of 297 cases in which a pregnancy complication, error, or incident occurred that was followed by progeny with a genetic disorder, congenital abnormality, or syndrome that spawned litigation. The author assessed, opined, and in many cases, testified about causation. Pregnancies complicated by hypoxic ischemic encephalopathy were not infrequently compounded by offspring with a genetic disorder, congenital abnormality, or syndrome. Multiple cases were brought because of missed ultrasound or laboratory diagnoses, or failures in carrier detection. Teratogenic medication prescribed before or during pregnancy invited legal purview. Failure to refer (or confer) for genetic evaluation or counseling in the face of significant risk, occurred repeatedly. Ethical breaches and hubris promptly led to litigation. Many lessons and recommendations emerge in this report. These include the realization that the vast majority of errors in this series involved at least two caregivers, serial ultrasound studies are important, decreased fetal movements may signal a genetic disorder, congenital abnormality, or syndrome, family history and ethnicity are vital, cognitive biases profoundly affect decision-making. Finally, the simplest of errors have the potential for causing life-long grief.

Toxoplasma Infection Induces Sustained Up-Regulation of Complement Factor B and C5a Receptor in the Mouse Brain via Microglial Activation: Implication for the Alternative Complement Pathway Activation and Anaphylatoxin Signaling in Cerebral Toxoplasmosis.

Toxoplasma gondii is a neurotropic protozoan parasite, which is linked to neurological manifestations in immunocompromised individuals as well as severe neurodevelopmental sequelae in congenital toxoplasmosis. While the complement system is the first line of host defense that plays a significant role in the prevention of parasite dissemination, Toxoplasma artfully evades complement-mediated clearance via recruiting complement regulatory proteins to their surface. On the other hand, the details of Toxoplasma and the complement system interaction in the brain parenchyma remain elusive. In this study, infection-induced changes in the mRNA levels of complement components were analyzed by quantitative PCR using a murine Toxoplasma infection model in vivo and primary glial cells in vitro. In addition to the core components C3 and C1q, anaphylatoxin C3a and C5a receptors (C3aR and C5aR1), as well as alternative complement pathway components properdin (CFP) and factor B (CFB), were significantly upregulated 2 weeks after inoculation. Two months post-infection, CFB, C3, C3aR, and C5aR1 expression remained higher than in controls, while CFP upregulation was transient. Furthermore, Toxoplasma infection induced significant increase in CFP, CFB, C3, and C5aR1 in mixed glial culture, which was abrogated when microglial activation was inhibited by pre-treatment with minocycline. This study sheds new light on the roles for the complement system in the brain parenchyma during Toxoplasma infection, which may lead to the development of novel therapeutic approaches to Toxoplasma infection-induced neurological disorders.

Early Evaluation and the Effect of Socioeconomic Factors on Neurodevelopment in Infants with Tetralogy of Fallot

Neurodevelopmental sequelae are prevalent among patients with congenital heart defects (CHD). In a study of infants and children with repaired tetralogy of Fallot (TOF), we sought to identify those at risk for abnormal neurodevelopment and to test associations between socioeconomic and medical factors with neurodevelopment deficits. Single-center retrospective observational study of patients with repaired TOF that were evaluated at the institution’s Cardiac Kids Developmental Follow-up Program (CKDP) between 2012 and 2018. Main outcomes included neurodevelopmental test scores from the Bayley Infant Neurodevelopmental Screener (BINS), Peabody Developmental Motor Scale (PDMS), and Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III). Mixed effects linear regression and marginal logistic regression models tested relationships between patient characteristics and outcomes. Sub-analyses were conducted to test correlations between initial and later neurodevelopment tests. In total, 49 patients were included, predominantly male (n = 33) and white (n = 28), first evaluated at a median age of 4.5 months. Forty-three percent of patients (n = 16) had deficits in the BINS, the earliest screening test. Several socioeconomic parameters and measures of disease complexity were associated with neurodevelopment, independently of genetic syndrome. Early BINS and PDMS performed in infancy were associated with Bayley-III scores performed after 1 year of age. Early screening identifies TOF patients at risk for abnormal neurodevelopment. Socioeconomic factors and disease complexity are associated with abnormal neurodevelopment and should be taken into account in the risk stratification and follow-up of these patients. Early evaluation with BINS and PDMS is suggested for detection of early deficits.

Oral melatonin as a new tool for neuroprotection in preterm newborns: study protocol for a randomized controlled trial

BackgroundPrevention of neurodevelopmental impairment due to preterm birth is a major health challenge. Despite advanced obstetric and neonatal care, to date there are few neuroprotective molecules available. Melatonin has been shown to have anti-oxidant/anti-inflammatory effects and to reduce brain damage, mainly after hypoxic ischemic encephalopathy. The planned study will be the first aiming to evaluate the capacity of melatonin to mitigate brain impairment due to premature birth.MethodIn our planned prospective, multicenter, double-blind, randomized vs placebo study, we will recruit, within 96 h of birth, 60 preterm newborns with a gestational age ≤ 29 weeks + 6 days; these infants will be randomly allocated to oral melatonin, 3 mg/kg/day, or placebo for 15 days. After the administration period, we will measure plasma levels of malondialdehyde, a lipid peroxidation product considered an early biological marker of melatonin treatment efficacy (primary outcome). At term-equivalent age, we will evaluate neurological status (through cerebral ultrasound, cerebral magnetic resonance imaging, vision and hearing evaluations, clinical neurological assessment, and screening for retinopathy of prematurity) as well as the incidence of bronchodysplasia and sepsis. We will also monitor neurodevelopmental outcome during the first 24 months of corrected age (using the modified Fagan Test of Infant Intelligence at 4–6 months and standardized neurological and developmental assessments at 24 months).DiscussionPreterm birth survivors often present long-term neurodevelopmental sequelae, such as motor, learning, social-behavioral, and communication problems. We aim to assess the role of melatonin as a neuroprotectant during the first weeks of extrauterine life, when preterm infants are unable to produce it spontaneously. This approach is based on the supposition that its anti-oxidant mechanism could be useful in preventing neurodevelopmental impairment. Considering the short- and long-term morbidities related to preterm birth, and the financial and social costs of the care of preterm infants, both at birth and over time, we suggest that melatonin administration could lead to considerable saving of resources. This would be the first study addressing the role of melatonin in very low birth weight preterm newborns, and it could provide a basis for further studies on melatonin as a neuroprotection strategy in this vulnerable population.Trial registrationClinicalTrials.gov NCT04235673. Prospectively registered on 22 January 2020.

Neurodevelopment Outcome of Neonates Treated With Intraventricular Colistin for Ventriculitis Caused by Multiple Drug-Resistant Pathogens-A Case Series.

Background: Multiple-drug-resistant Gram-negative bacteria (MDR-GNB)-associated neonatal ventriculitis is a life-threatening complication that needs timely diagnosis and effective treatment with broad-spectrum antimicrobials in critical-care settings. Inadequate penetration of antibiotics through the blood–brain barrier also demands an intraventricular (IVT) route of administration. This study reports mortality and neurodevelopmental sequelae of neonates till 18 months of age, who received IVT-colistin for treating MDR-GNB associated ventriculitis.Methods: In a case series of seven neonates with ventriculitis due to MDR-GNB at NICU of Aga Khan University Hospital, Pakistan, between June 2015 and 2018, we reviewed IVT-colistin therapy in critically ill neonates. Treatment outcomes were assessed based on clinical sign's resolution and MDR-GNB eradication in subsequent CSF cultures. Neurodevelopmental outcomes were evaluated at 18 months after discharge.Results: The average birth weight was 1.38 kg (range: 1.02–1.5 kg), and the average gestational age was 30.7 weeks (ranged: 26–34 weeks). All neonates reported colistin-sensitive MDR-GNB in CSF, five with Acinetobacter baumannii, and polymicrobial CNS infection was found in two patients (one due to Klebsiella pneumonia and A. baumannii and one due to K. pneumonia and Escherichia coli). All neonates received IVT colistin and concomitant intravenous meropenem, and five of them also received intravenous colistin. One neonate died. At the 18-month assessment, only one neonate had cerebral palsy and hydrocephaly and 50% had seizure disorders.Conclusion: Practicing intraventricular antibiotics in the neonatal population is challenging but may be used successfully, especially to overcome the limitation of poor penetration through the blood–brain barrier.

Perinatal Fentanyl Exposure Leads to Long-Lasting Impairments in Somatosensory Circuit Function and Behavior.

One consequence of the opioid epidemic are lasting neurodevelopmental sequelae afflicting adolescents exposed to opioids in the womb. A translationally relevant and developmentally accurate preclinical model is needed to understand the behavioral, circuit, network, and molecular abnormalities resulting from this exposure. By employing a novel preclinical model of perinatal fentanyl exposure, our data reveal that fentanyl has several dose-dependent, developmental consequences to somatosensory function and behavior. Newborn male and female mice exhibit signs of withdrawal and sensory-related deficits that extend at least to adolescence. As fentanyl exposure does not affect dams' health or maternal behavior, these effects result from the direct actions of perinatal fentanyl on the pups' developing brain. At adolescence, exposed mice exhibit reduced adaptation to sensory stimuli, and a corresponding impairment in primary somatosensory (S1) function. In vitro electrophysiology demonstrates a long-lasting reduction in S1 synaptic excitation, evidenced by decreases in release probability, NMDA receptor-mediated postsynaptic currents, and frequency of miniature excitatory postsynaptic currents (mEPSCs), as well as increased frequency of miniature inhibitory postsynaptic currents (mIPSCs). In contrast, anterior cingulate cortical neurons exhibit an opposite phenotype, with increased synaptic excitation. Consistent with these changes, electrocorticograms (ECoGs) reveal suppressed ketamine-evoked γ oscillations. Morphologic analysis of S1 pyramidal neurons indicate reduced dendritic complexity, dendritic length, and soma size. Further, exposed mice exhibited abnormal cortical mRNA expression of key receptors involved in synaptic transmission and neuronal growth and development, changes that were consistent with the electrophysiological and morphologic changes. These findings demonstrate the lasting sequelae of perinatal fentanyl exposure on sensory processing and function.SIGNIFICANCE STATEMENT This is the first study to show that exposure to fentanyl in the womb results in behavioral, circuitry, and synaptic effects that last at least to adolescence. We also show, for the first time, that this exposure has different, lasting effects on synapses in different cortical areas.

Maternal N-acetyl-cysteine prevents neonatal brain injury associated with necrotizing enterocolitis in a rat model.

Preterm infants with necrotizing enterocolitis (NEC) are at increased risk of cerebral injury and neurodevelopmental dysfunction. N-acetyl-cysteine (NAC) is a known anti-inflammatory and antioxidant agent. Currently, there is no prophylactic treatment in clinical use to prevent NEC and its neurodevelopmental sequelae. We sought to determine whether brain inflammation/apoptosis accompanies NEC systemic inflammation, and whether it can be attenuated by maternal NAC treatment during pregnancy and/or in the neonatal period in a rat model. An established NEC newborn model (hypoxia 5% O2 for 10min and formula feeding thrice daily, beginning on day 1 for 4days) was used in Sprague-Dawley rat pups (n=32). An additional group of pups (n=33) received NAC (300mg/kg intraperitoneal thrice daily) in addition to NEC conditions (NEC-NAC). Control pups (n=33) were nursed and remained with the dam in room air. Two additional groups included pups of dams treated once daily with NAC (300mg/kg intravenous) in the last 3days of pregnancy. After birth, pups were randomized into NAC-NEC (n=33) with NEC conditions and NAC-NEC-NAC (n=36) with additional postnatal NAC treatment. Pups were sacrificed on the fifth day of life. Pup serum interleukin (IL)-6 protein levels, and brain nuclear factor kappa B (NF-κB) p65, neuronal nitric oxide synthase (nNOS), Caspase 3, tumor necrosis factor alpha (TNF-α), IL-6 and IL-1β protein levels were determined by ELISA, western blot and TUNEL staining, and the groups were compared using analysis of variance (ANOVA). NEC pups had significantly increased serum IL-6 levels compared with the control group as well as increased neuronal apoptosis and brain protein levels of NF-κB, nNOS, Caspase 3, TNF-α, IL-6 and IL-1β compared with control. In all NAC treatment groups, levels of serum IL-6, neuronal apoptosis and brain NF-κB, nNOS, Caspase 3, TNF-α, IL-6 and IL-1β protein levels were significantly reduced compared with the NEC group. The most pronounced decrease was demonstrated within the NAC-NEC-NAC group. NAC treatment can attenuate newborn inflammatory response syndrome and decrease offspring brain neuroapoptosis and inflammation in a rat model of NEC by inhibition of NF-κB, nNOS and Caspase 3 pathways.

Fetal Ventriculomegaly and Hydrocephalus - What Shouldn't be Missed on Imaging?

Fetal ventriculomegaly is one of the most frequently diagnosed abnormalities detected prenatally. The finding of additional subtle abnormalities can facilitate accurate prognoses, which may range from normal outcomes to significant neurodevelopmental sequelae. Pathogenesis and imaging patterns of ventriculomegaly and hydrocephalus in the fetus based on the pattern-recognition approach using fetal MRI are reviewed in this paper. This radiological approach may shed light on clinical course prediction and therapeutic efficacy of hydrocephalus in the fetus.

Identifying Clinical Clues in Children With Global Developmental Delay / Intellectual Disability With Abnormal Brain Magnetic Resonance Imaging (MRI).

Global developmental delay / intellectual disability are common pediatric conditions. Brain magnetic resonance imaging (MRI), although an important diagnostic tool in the evaluation of these patients, often requires general anesthesia. Recent literature suggests that unnecessary general anesthesia exposure should be avoided in early years because of possible long-term negative neurodevelopmental sequelae. This study sought to identify clinical clues associated with brain MRI abnormalities in children with global developmental delay / intellectual disability in an attempt to provide guidance to physicians on selecting patients who would benefit from an MRI. Retrospective chart review analysis was conducted for patients presenting to a pediatric neurology tertiary care center between 2014 and 2017 for a first clinic evaluation for global developmental delay / intellectual disability. Detailed clinical history and physical examination findings were analyzed and correlated with brain MRI findings. The majority (218/327, 67%) of children referred for evaluation of global developmental delay / intellectual disability underwent complete clinical and radiologic evaluations. Mean age was 37.9 months (±32.5 standard deviation) and 116 were males (53%). Motor deficits were predominant in most subjects (122/218, 56%). Abnormal MRI findings were observed in 153 children (70%), with the most prevalent abnormalities noted within the white matter (104/153, 68%), corpus callosum (77/153, 50%), and the hippocampus (50/153, 33%). Abnormal MRI findings were prevalent in children with predominant motor delay (84, 69%) and cognitive disability (3, 100%) as well as those with visual and hearing impairment (P < .05). The presence of facial dysmorphisms (57/71, P = .02); cranial nerve abnormalities (79/100; P = .007) and abnormal reflexes (16, P = .01) on examination also correlated significantly with increased MRI abnormalities.

Imaging of fetal ventriculomegaly.

Fetal ventriculomegaly is the most common central nervous system abnormality detected by prenatal imaging. It has a high association with other anomalies. Etiologies and prognoses for fetal ventriculomegaly range from normal outcomes to significant neurodevelopmental sequelae. In this paper, we review the development, terminology, pathogenesis, imaging and prognosis of fetal ventriculomegaly.

Risk Factors for Adverse Neurodevelopment in Transient or Persistent Congenital Hyperinsulinism.

ObjectiveAim was to identify hypotheses why adverse neurodevelopment still occurs in children with transient or persistent hyperinsulinism despite improvements in long-term treatment options during the last decades.Material and MethodsA retrospective review of 87 children with transient (n=37) or persistent congenital hyperinsulinism (CHI) (n=50) was conducted at the University Children’s Hospital Duesseldorf, Germany. Possible risk factors for neurodevelopmental sequelae due to hypoglycemia were analyzed with a focus on the first days after onset of disease.ResultsMedian age at follow-up was 7 years (IQR 8). Adverse neurodevelopmental outcome was seen in 34.5% (n=30) of all CHI patients. Fifteen had mildly abnormal neurodevelopment and 15 had a severe hypoglycemic brain injury. In univariate analysis, mildly abnormal neurodevelopment was associated with the diagnosis of persistent CHI (odds ratio (OR) 8.3; p=0.004) and higher birth weight (mean difference 1049 g; p<0.001). Severe hypoglycemic brain injury was associated with the diagnosis of persistent CHI (OR 5.1; p=0.013), being born abroad (OR 18.3; p<0.001) or in a lower-level maternity hospital (OR 4.8; p=0.039), and of note history of hypoglycemic seizures (OR 13.0; p=<0.001), and a delay between first symptoms of hypoglycemia and first blood glucose measurement/initiation of treatment (OR 10.7; p<0.001). Children with severe hypoglycemic brain injury had lower recorded blood glucose (mean difference -8.34 mg/dl; p=0.022) and higher birth weight than children with normal development (mean difference 829 g; p=0.012). In multivariate binary logistic regression models, lowest blood glucose <20 mg/dl (OR 134.3; p=0.004), a delay between initial symptoms and first blood glucose measurement/initiation of treatment (OR 71.7; p=0.017) and hypoglycemic seizures (OR 12.9; p=0.008) were positively correlated with severe brain injury. Analysis showed that the odds for brain injury decreased by 15% (OR 0.85; p=0.035) if the blood glucose increased by one unit.ConclusionWhile some risk factors for adverse outcome in CHI are not influenceable, others like lowest recorded blood glucose values <20 mg/dl, hypoglycemic seizures, and insufficiently—or even untreated hypoglycemia can be avoided. Future guidelines for management of neonatal hypoglycemia should address this by ensuring early identification and immediate treatment with appropriate escalation steps.

Optimism despite profound uncertainty: school and social relationships in adolescents with single ventricle heart disease.

Survivors of single ventricle heart disease must cope with the physical, neurodevelopmental, and psychosocial sequelae of their cardiac disease, which may also affect academic achievement and social relationships. The purpose of this study was to qualitatively examine the experiences of school and social relationships in adolescents with single ventricle heart disease. A descriptive phenomenological methodology was employed, utilising semi-structured interviews. Demographic and clinical characteristics were obtained via chart review. Fourteen adolescents (aged 14 to 19 years) with single ventricle heart disease participated. Interviews ranged from 25 to 80 minutes in duration. Four themes emerged from the interviews, including "Don't assume": Pervasive ableism; "The elephant in the room": Uncertain future; "Everyone finds something to pick on": Bullying at school; "They know what I have been through": Social support. The overall essence generated from the data was "optimism despite profound uncertainty." Adolescents with single ventricle heart disease identified physical limitations and school challenges in the face of an uncertain health-related future. Despite physical and psychosocial limitations, most remained optimistic for the future and found activities that were congruent with their abilities. These experiences reflect "optimism despite profound uncertainty."

Phenoscreening: a developmental approach to research domain criteria-motivated sampling.

To advance early identification efforts, we must detect and characterize neurodevelopmental sequelae of risk among population-based samples early in development. However, variability across the typical-to-atypical continuum and heterogeneity within and across early emerging psychiatric/neurodevelopmental disorders represent fundamental challenges to overcome. Identifying multidimensionally determined profiles of risk, agnostic to DSM categories, via data-driven computational approaches represents an avenue to improve early identification of risk. Factor mixture modeling (FMM) was used to identify subgroups and characterize phenotypic risk profiles, derived from multiple parent-report measures of typical and atypical behaviors common to autism spectrum disorder, in a community-based sample of 17- to 25-month-old toddlers (n=1,570). To examine the utility of risk profile classification, a subsample of toddlers (n=107) was assessed on a distal, independent outcome examining internalizing, externalizing, and dysregulation at approximately 30 months. FMM results identified five asymmetrically sized subgroups. The putative high- and moderate-risk groups comprised 6% of the sample. Follow-up analyses corroborated the utility of the risk profile classification; the high-, moderate-, and low-risk groups were differentially stratified (i.e., HR>moderate-risk>LR) on outcome measures and comparison of high- and low-risk groups revealed large effect sizes for internalizing (d=0.83), externalizing (d=1.39), and dysregulation (d=1.19). This data-driven approach yielded five subgroups of toddlers, the utility of which was corroborated by later outcomes. Data-driven approaches, leveraging multiple developmentally appropriate dimensional RDoC constructs, hold promise for future efforts aimed toward early identification of at-risk-phenotypes for a variety of early emerging neurodevelopmental disorders.

Evaluation of the immediate outcomes of perinatally asphyxiated newborns in a tertiary care hospital in rural Bangalore: a retrospective study

Background: Perinatal asphyxia is a condition resulting from deprivation of oxygen to a neonate that lasts long enough to cause damage to the brain. Perinatal asphyxia is one of the major causes of early neonatal mortality in India. The goal was to evaluate outcomes of asphyxiated babies. Methods: One hundred consecutive neonates with birth asphyxia (Apgar 0-3 at 5-minute of age) were studied. Data from medical records of all babies with perinatal asphyxia admitted were retrieved and documented for the study.Results: Majority of the neonates are inborn (57%). Male to female ratio was 1.5:1. Spontaneous vaginal delivery constitute 32% and lower segment caesarean section (LSCS) 36%. Mortality was highest in hypoxic ischemic encephalopathy (HIE) stage 3 with 11%. Mean duration of hospitalization is directly related to Sarnat and Sarnat staging of HIE. 22% babies were having neurological sequelae and discharged on anti-convulsant. 21% mortality, majority were outborn.Conclusions: Despite advances in the management of neonates, perinatal asphyxia is still the leading cause of morbidity and mortality. Perinatal asphyxia is still prevalent despite medical advances. Babies with HIE stage III had poor outcome. Appropriate strategies required to minimize the neuro-developmental sequelae.

Cohort protocol: Guangzhou High-Risk Infant Cohort study

IntroductionDespite the increase in the survival rate of high-risk infants (HRIs) worldwide, the prevalence of motor and neurodevelopmental sequelae in such newborns has not shown concomitant improvement. Meanwhile, there are...

The newborn infant parasympathetic evaluation index for acute procedural pain assessment in preterm infants.

Accurate assessments of pain in hospitalized preterm infants present a major challenge in improving the short- and long-term consequences associated with painful experiences. We evaluated the ability of the newborn infant parasympathetic evaluation (NIPE) index to detect acute procedural pain in preterm infants. Different painful and stressful interventions were prospectively observed in preterm infants born at 25 + 0 to 35 + 6 weeks gestation. Pain responses were measured using the composite Premature Infant Pain Profile Revised (PIPP-R) scale, the NIPE index, and skin conductance responses (SCR). Outcome measures were correlations between the NIPE index, the PIPP-R score, and the SCR. Sensitivity/specificity analyses tested the accuracy of the NIPE index and SCR. Two hundred and fifty-four procedures were recorded in 90 preterm infants. No significant correlation was found between PIPP-R and the NIPE index. PIPP-R and SCR were positively correlated (r = 0.27, P < 0.001), with stronger correlations for painful procedures (r = 0.68, P < 0.001) and especially for skin-breaking procedures (r = 0.82, P < 0.001). The NIPE index and SCR had high sensitivity and high negative predictive values to predict PIPP-R > 10, especially for skin-breaking painful procedures. We found no significant correlation between the NIPE index and PIPP-R during routine painful or stressful procedures in preterm infants. Exposure to repetitive pain can lead to neurodevelopmental sequelae. Behavior-based pain scales have limited clinical utility, especially for preterm infants. New devices for monitoring physiological responses to pain have not been validated sufficiently in preterm infants. This study found that the NIPE index was not significantly correlated to the validated PIPP-R scale during acute procedural pain. Secondary analysis of this study showed that NIPE index and SCRs may help to exclude severe pain in preterm infants. In clinical practice, measurements of physiological parameters should be combined with behavior-based scales for multidimensional pain assessments.