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In this multicenter, randomized trial involving extremely preterm infants, high-dose erythropoietin administered from 24 hours after birth through 32 weeks of postmenstrual age did not result in a lower risk of severe neurodevelopmental impairment or death at 2 years of age.

ObjectiveTo investigate the association of neonatal hypoglycaemia and hyperglycaemia with outcomes in infants with hypoxic ischaemic encephalopathy (HIE).DesignPost hoc analysis of the CoolCap Study.Setting25 perinatal centres in the UK, the USA and New Zealand during 1999–2002.Patients234 infants at ≥36 weeks’ gestation with moderate-to-severe HIE enrolled in the CoolCap Study. 214 (91%) infants had documented plasma glucose and follow-up outcome data.InterventionInfants were randomised to head cooling for 72 h starting within 6 h of birth, or standard care. Plasma glucose levels were measured at predetermined time intervals after randomisation.Main outcome measureThe unfavourable primary outcome of the study was death and/or severe neurodevelopmental disability at 18 months. Hypoglycaemia (≤40 mg/dL, ≤2.2 mmol/L) and hyperglycaemia (>150 mg/dL, >8.3 mmol/L) during the first 12 h after randomisation were investigated for univariable and multivariable associations with unfavourable primary outcome.Results121 (57%) infants had abnormal plasma glucose values within 12 h of randomisation. Unfavourable outcome was observed in 126 (60%) infants and was more common among subjects with hypoglycaemia (81%, p=0.004), hyperglycaemia (67%, p=0.01) and any glucose derangement within the first 12 h (67%, p=0.002) compared with normoglycaemic infants (48%) in univariable analysis. These associations remained significant after adjusting for birth weight, Apgar score, pH, Sarnat stage and hypothermia therapy.ConclusionsBoth hypoglycaemia and hyperglycaemia in infants with moderate-to-severe HIE were independently associated with unfavourable outcome. Future studies are needed to investigate the prognostic significance of these associations and their role as biomarkers of brain injury.Trial registration number(ClinicalTrials.gov NCT00383305).

Hearing impairment and neurodevelopmental disorders pose a significant global health burden in children. The link between postnatal cytomegalovirus (CMV) infection and these outcomes remains unclear. This study explored the association of postnatal CMV infection with hearing and neurodevelopmental outcomes in term infants aged 3 to 10 months. This was a cohort sub-study within the BabyGel cluster randomised trial in Eastern Uganda. From 1265 term infants screened for CMV, 219 were negative at birth but positive at 3 months, and were age-matched with 219 CMV-negative controls. CMV status was determined by PCR screening of saliva samples, with positive results confirmed using urine samples (Chai Open qPCR, Santa Clara, CA). From the established cohort, 424 infants were successfully followed up between 3 to 10 months of age. Clinical assessments included neurodevelopmental evaluation using the Malawi Developmental Assessment Tool, the Hammersmith Infant Neurological Examination, and hearing screening using Otoacoustic Emission testing (Otoport Lite, Otodynamics Limited). Statistical analyses were performed using descriptive statistics, chi-square tests and log binomial regression models with Stata 18. Of the 424 infants included in the study, 206 were postnatal CMV-infected and 218 were uninfected. Neurodevelopmental assessments indicated no differences between postnatal CMV-infected infants and uninfected groups (ARR 0.88, 95% CI [0.67, 1.15], p = 0.346). Hearing screening revealed a 1.99-fold increased risk of a positive result for postnatal CMV-infected infants compared to uninfected infants (67/106 vs. 39/106, 95% CI [1.27, 3.12], p = 0.003). Postnatal CMV infection was associated with more positive hearing screenings, though no significant differences in neurodevelopmental outcomes were observed in early infancy. Exploration into the feasibility of incorporating hearing and CMV screening into routine care will play a vital role in early identification and intervention, improving the management of both hearing and CMV-related conditions in resource-limited settings.

ObjectiveTo investigate in extremely low birthweight (ELBW; <1000 g) babies the associations between refeeding syndrome (serum phosphate <1.4 mmol·L-1 and serum total calcium>2.8 mmol·L-1) and hypophosphataemia in the first week and death or neurodisability at 2 years’ corrected age (CA).DesignSecondary cohort analysis of the ProVIDe trial participants with serum biochemistry within 7 days of birth. At 2 years’ CA, neurodisability was assessed by Bayley Scales of Infant Development Edition III and neurological examination. Associations between neurodisability and other variables were analysed using t-tests and logistic regression adjusted for sex and smallness-for-gestational age.SettingSix tertiary neonatal intensive care units (NICUs) in New Zealand.Participants352 ELBW babies born between 29 April 2014 and 30 October 2018.Main outcome measureDeath or neurodisability at 2 years’ CA.ResultsFifty-nine babies died, two after discharge from the NICU. Of the 336 babies who survived to 2 years’ CA, 277 had neurodevelopmental assessment and 107 (39%) had a neurodisability. Death or neurodisability was more likely in babies who had refeeding syndrome (aOR 1.96 (95% CI 1.09 to 3.53), p=0.02) and in babies who had hypophosphataemia (aOR 1.74 (95% CI 1.09 to 2.79), p=0.02). Hypophosphataemia was associated with increased risk of death (aOR 2.07 (95% CI 1.09 to 3.95), p=0.03)) and severe hypophosphataemia (<0.9 mmol·L-1) with increased risk of death (aOR 2.67 (95% CI 1.41 to 5.00), p=0.002) and neurodisability (aOR 2.31 (95% CI 1.22 to 4.35), p=0.01).ConclusionsIn ELBW babies, refeeding syndrome and hypophosphataemia in the first week are associated with death or neurodisability. Until optimal phosphate requirements are determined through further research, monitoring for hypophosphataemia and mitigation strategies are indicated.Trial registration numberACTRN12612001084875

Background Perinatal asphyxia and resulting hypoxic-ischemic encephalopathy is a major cause of death and long-term disability in term born neonates. Up to 20,000 infants each year are affected by HIE in Europe and even more in regions with lower level of perinatal care. The only established therapy to improve outcome in these infants is therapeutic hypothermia. Allopurinol is a xanthine oxidase inhibitor that reduces the production of oxygen radicals as superoxide, which contributes to secondary energy failure and apoptosis in neurons and glial cells after reperfusion of hypoxic brain tissue and may further improve outcome if administered in addition to therapeutic hypothermia. Methods This study on the effects of AL lopurinol in addition to hypothermia treatment for hypoxic-ischemic B rain I njury on N eurocognitive O utcome (ALBINO), is a European double-blinded randomized placebo-controlled parallel group multicenter trial (Phase III) to evaluate the effect of postnatal allopurinol administered in addition to standard of care (including therapeutic hypothermia if indicated) on the incidence of death and severe neurodevelopmental impairment at 24 months of age in newborns with perinatal hypoxic-ischemic insult and signs of potentially evolving encephalopathy. Allopurinol or placebo will be given in addition to therapeutic hypothermia (where indicated) to infants with a gestational age ≥ 36 weeks and a birth weight ≥ 2500 g, with severe perinatal asphyxia and potentially evolving encephalopathy. The primary endpoint of this study will be death or severe neurodevelopmental impairment versus survival without severe neurodevelopmental impairment at the age of two years. Effects on brain injury by magnetic resonance imaging and cerebral ultrasound, electric brain activity, concentrations of peroxidation products and S100B, will also be studied along with effects on heart function and pharmacokinetics of allopurinol after iv-infusion. Discussion This trial will provide data to assess the efficacy and safety of early postnatal allopurinol in term infants with evolving hypoxic-ischemic encephalopathy. If proven efficacious and safe, allopurinol could become part of a neuroprotective pharmacological treatment strategy in addition to therapeutic hypothermia in children with perinatal asphyxia. Trial registration NCT03162653, www.ClinicalTrials.gov , May 22, 2017.

Background/Objective The aim of this study was to systematically assess the association of insulin‐manipulation (intentional under‐ and/or overdosing of insulin), psychiatric comorbidity and diabetes complications. Methods Two diagnostic interviews (Diabetes‐Self‐Management‐Patient‐Interview and Children's‐Diagnostic‐Interview for Psychiatric Disorders) were conducted with 241 patients (age 10‐22) with type 1 diabetes (T1D) from 21 randomly selected Austrian diabetes care centers. Medical data was derived from medical records. Results Psychiatric comorbidity was found in nearly half of the patients with insulin‐manipulation (46.3%) compared to a rate of 17.5% in patients, adherent to the prescribed insulin therapy. Depression (18.3% vs 4.9%), specific phobia (21.1% vs 2.9%), social phobia (7.0% vs 0%), and eating disorders (12.7% vs 1.9%) were elevated in patients with insulin‐manipulation. Females (37.7%) were more often diagnosed (P = 0.001) with psychiatric disorders than males (18.4%). In females, the percentage of psychiatric comorbidity significantly increased with the level of non‐adherence to insulin therapy. Insulin‐manipulation had an effect of +0.89% in HbA1c (P = <0.001) compared to patients adherent to insulin therapy, while there was no association of psychiatric comorbidity with metabolic control (HbA1c 8.16% vs 8.12% [65.68 vs 65.25 mmol/mol]). Ketoacidosis, severe hypoglycemia, and frequency of outpatient visits in a diabetes center were highest in patients with insulin‐manipulation. Conclusions This is the first study using a systematic approach to assess the prevalence of psychiatric disorders in patients who do or do not manipulate insulin in terms of intentional under‐ and/or overdosing. Internalizing psychiatric disorders were associated with insulin‐manipulation, especially in female patients and insulin‐manipulation was associated with deteriorated metabolic control and diabetes complications.

Background Fetal growth restriction (FGR) is a serious obstetric condition for which there is currently no treatment. The EVERREST Prospective Study has been designed to characterise the natural history of pregnancies affected by severe early onset FGR and establish a well phenotyped bio-bank. The findings will provide up-to-date information for clinicians and patients and inform the design and conduct of the EVERREST Clinical Trial: a phase I/IIa trial to assess the safety and efficacy of maternal vascular endothelial growth factor (VEGF) gene therapy in severe early onset FGR. Data and samples from the EVERREST Prospective Study will be used to identify ultrasound and/or biochemical markers of prognosis in pregnancies with an estimated fetal weight (EFW) <3rd centile between 20+0 and 26+6 weeks of gestation. Methods This is a 6 year European multicentre prospective cohort study, recruiting women with a singleton pregnancy where the EFW is <3rd centile for gestational age and <600 g at 20+0 to 26+6 weeks of gestation. Detailed data are collected on: maternal history; antenatal, peripartum, and postnatal maternal complications; health economic impact; psychological impact; neonatal condition, progress and complications; and infant growth and neurodevelopment to 2 years of corrected age in surviving infants. Standardised longitudinal ultrasound measurements are performed, including: fetal biometry; uterine artery, umbilical artery, middle cerebral artery, and ductus venosus Doppler velocimetry; and uterine artery and umbilical vein volume blood flow. Samples of maternal blood and urine, amniotic fluid (if amniocentesis performed), placenta, umbilical cord blood, and placental bed (if caesarean delivery performed) are collected for bio-banking. An initial analysis of maternal blood samples at enrolment is planned to identify biochemical markers that are predictors for fetal or neonatal death. Discussion The findings of the EVERREST Prospective Study will support the development of a novel therapy for severe early onset FGR by describing in detail the natural history of the disease and by identifying women whose pregnancies have the poorest outcomes, in whom a therapy might be most advantageous. The findings will also enable better counselling of couples with affected pregnancies, and provide a valuable resource for future research into the causes of FGR. Trial registration NCT02097667 registered 31 st October 2013.

Adequate nutrition is fundamental to neonatal survival and short-term outcomes, but it also has long-term consequences on quality of life and neurologic development of preterm infants. Donkey milk has been suggested as a valid alternative for children allergic to cows’ milk proteins, due to its biochemical similarity to human milk; we, hence, hypothesized that donkey milk could be a suitable basis for developing an innovative human milk fortifier for feeding preterm infants. The aim of the current study was to extend the findings and to evaluate the neurodevelopmental outcomes at 18 months of corrected age of the infants enrolled in the clinical trial named “Fortilat”. Infants born ≤1500 g and <32 weeks of gestational age were randomized to receive either a combination of bovine milk-based multicomponent fortifier and protein supplement or a combination of a novel multicomponent fortifier and protein supplement derived from donkey milk. The followed fortification protocol was the same for the two groups and the two diets were designed to be isoproteic and isocaloric. All infants enrolled were included in a developmental assessment program. The neurodevelopmental assessment was performed at 18 ± 6 months of corrected age. Minor and major neurodevelopmental impairment and General Quotient (GQ) at the Griffiths-II Mental Development Scale were considered. The GQ was considered both in continuous and as two classes: lower than and higher than (or equal to) a defined cutoff (GQcl). The difference in GQ and GQcl between the two arms was estimated using Mann–Whitney–Wilcoxon test or Fischer exact test, respectively, on the assumption of casual loss at follow-up. A further analysis was performed using generalized linear models. There were 103 children (bovine milk-derived fortifier arm = 54, donkey milk-derived fortifier arm = 49) included for the neurodevelopmental follow-up. All observations were included in the interval of 18 ± 6 months of corrected age. No significant difference was observed between the two arms in the incidence of neurologic sequelae and the GQs were similar in the two arms. Our results demonstrated no difference for the donkey milk-derived fortifier compared to standard bovine-derived fortifier regarding long-term neurodevelopmental outcomes.

Nearly three out of ten neurodevelopmental disabilities in the United States have been linked to environmental conditions, prompting emerging lines of research examining the role of the neighborhood on children’s developmental outcomes. Utilizing data from a natural experiment in Denver, this study quantifies the impact of exposure to varied neighborhood contexts on the diagnosis of neurodevelopmental disorders over the course of childhood. Our analysis is based upon retrospective child, caregiver, household and neighborhood data derived from the Denver Child Study for a sample of approximately 590 Latino and African American children and youth whose families were quasi-randomly assigned to subsidized housing operated by the Denver (CO) Housing Authority during part of their childhood. We employed binary response models with endogenous explanatory variables, estimated using instrumental variables (IV) probit and average marginal effects to identify predictors of a neurodevelopmental disorder diagnosis during childhood. We found that multiple dimensions of neighborhood context—especially neighborhood socioeconomic status, older housing stock, residential instability and prevalence of neurological hazards in the ambient air—strongly and robustly predicted the diagnosis of a neurodevelopmental disorder during childhood.

Maternal health during pregnancy plays a major role in shaping health and disease risks in the offspring. The maternal immune activation hypothesis proposes that inflammatory perturbations in utero can affect fetal neurodevelopment, and evidence from human epidemiological studies supports an association between maternal inflammation during pregnancy and offspring neurodevelopmental disorders (NDDs). Diverse maternal inflammatory factors, including obesity, asthma, autoimmune disease, infection and psychosocial stress, are associated with an increased risk of NDDs in the offspring. In addition to inflammation, epigenetic factors are increasingly recognized to operate at the gene–environment interface during NDD pathogenesis. For example, integrated brain transcriptome and epigenetic analyses of individuals with NDDs demonstrate convergent dysregulated immune pathways. In this Review, we focus on the emerging human evidence for an association between maternal immune activation and childhood NDDs, including autism spectrum disorder, attention-deficit/hyperactivity disorder and Tourette syndrome. We refer to established pathophysiological concepts in animal models, including immune signalling across the placenta, epigenetic ‘priming’ of offspring microglia and postnatal immune–brain crosstalk. The increasing incidence of NDDs has created an urgent need to mitigate the risk and severity of these conditions through both preventive strategies in pregnancy and novel postnatal therapies targeting disease mechanisms.The maternal immune activation (MIA) hypothesis proposes that inflammatory perturbations in utero can affect fetal neurodevelopment. This Review examines the emerging human evidence for an association between MIA and childhood neurodevelopmental disorders, including autism spectrum disorder, attention-deficit/hyperactivity disorder and Tourette syndrome.