Search

(1) Background: Lower birth weight among newborns in higher altitudes has been well documented in previous literature. Several possible causes for this phenomenon have been investigated, including biophysiological adaptation, epigenetic or genetic mechanisms or lifestyle changes. This is the first study to show the effect modification of altitude and parity on the birth weight length ratio (BWLR) in women resident in moderate altitudes compared to a low sea level.; (2) Methods: This population-based study obtained data on altitude (0–300, 300–500, 500–700,700–900, >900 m), parity (1, 2, ..., 7, 8/9), birth weight and length on all births in Austria between 1984 and 2020 from birth certificates provided by Statistics Austria. The BWLR was calculated, and the effect of moderate altitude and parity was estimated using multivariable linear mixed models adjusting for predefined variables. Sub-group regression analyses were conducted by altitude group. (3) Results: Data on 2,057,702 newborns from 1,280,272 mothers were analyzed. The effect of parity on BWLR, as indicated by the difference of BWLR between the first- and second-born infants, ranged between 1.87 to 2.09 g per centimeter across all altitude groups. Our analyses found that the effect of parity on BWLR diminished from parity three onwards at altitude 0–300, whilst the effect of parity on BWLR continued to increase at higher than 300 m and was most notable in the highest altitude group >900 m. (4) Conclusions: Findings from our study indicated that the negative effect of increasing altitude on BWLR was deprived for newborns of higher parity. It shows that the residential altitude can modify the effect of parity on BWLR. [ABSTRACT FROM AUTHOR]

Introduction: Preterm birth and cerebral hemorrhage have adverse effects on brain development. Alterations in regional brain size on magnetic resonance imaging (MRI) can be assessed using 2D biometrical analysis, an easily applicable technique showing good correlation with 3D brain volumes. Methods: This retrospective study included 74 preterm neonates with intraventricular hemorrhage (IVH) born <32+0 weeks of gestation between 2011 and 2019. Cerebral MRI was performed at term-equivalent age, and 2D measurement techniques were used for biometrical analysis and compared to normative data of two control groups. Finally, the correlation and association of brain parameters and patterns of impaired brain growth and outcome at 2 and 3 years of age were evaluated. Results: Interhemispheric distance (IHD), the 3rd ventricle, and lateral ventricles presented larger, in contrast, cerebral biparietal width (cBPW), fronto-occipital diameter (FOD), and the length of the corpus callosum were smaller in IVH patients compared to respective controls. The strongest correlations with outcome were observed for the parameters FOD, anteroposterior diameter of the vermis, transverse cerebellar diameter (tCD), corpus callosum, 3rd ventricle, and left ventricular index. Patients with the small FOD, small BPW, and increased IHD pattern reached overall lower outcome scores at follow-up. Discussion: Preterm neonates with IVH showed reduced total brain sizes and enlarged pericerebral spaces compared to neurologically healthy controls. Biometric analysis revealed that several 2D brain parameters as well as different patterns of impaired brain growth were associated with neurodevelopmental impairment in early childhood. These findings may support prediction of long-term outcome and parental counseling in patients with IVH. [ABSTRACT FROM AUTHOR]

Background and Objective: Previously, we developed a pharmacokinetic-pharmacodynamic model of allopurinol, oxypurinol, and biomarkers, hypoxanthine, xanthine, and uric acid, in neonates with hypoxic-ischemic encephalopathy, in which high initial biomarker levels were observed suggesting an impact of hypoxia. However, the full pharmacodynamics could not be elucidated in our previous study. The current study included additional data from the ALBINO study (NCT03162653) placebo group, aiming to characterize the dynamics of hypoxanthine, xanthine, and uric acid in neonates with hypoxic-ischemic encephalopathy. Methods: Neonates from the ALBINO study who received allopurinol or placebo mannitol were included. An extended population pharmacokinetic-pharmacodynamic model was developed based on the mechanism of purine metabolism, where synthesis, salvage, and degradation via xanthine oxidoreductase pathways were described. The initial level of the biomarkers was a combination of endogenous turnover and high disease-related amounts. Model development was accomplished by nonlinear mixed-effects modeling (NONMEM®, version 7.5). Results: In total, 20 neonates treated with allopurinol and 17 neonates treated with mannitol were included in this analysis. Endogenous synthesis of the biomarkers reduced with 0.43% per hour because of precursor exhaustion. Hypoxanthine was readily salvaged or degraded to xanthine with rate constants of 0.5 1/h (95% confidence interval 0.33–0.77) and 0.2 1/h (95% confidence interval 0.09–0.31), respectively. A greater salvage was found in the allopurinol treatment group consistent with its mechanism of action. High hypoxia-induced initial levels of biomarkers were quantified, and were 1.2-fold to 2.9-fold higher in neonates with moderate-to-severe hypoxic-ischemic encephalopathy compared with those with mild hypoxic-ischemic encephalopathy. Half-maximal xanthine oxidoreductase inhibition was achieved with a combined allopurinol and oxypurinol concentration of 0.68 mg/L (95% confidence interval 0.48–0.92), suggesting full xanthine oxidoreductase inhibition during the period studied. Conclusions: This extended pharmacokinetic-pharmacodynamic model provided an adequate description of the complex hypoxanthine, xanthine, and uric acid metabolism in neonates with hypoxic-ischemic encephalopathy, suggesting a positive allopurinol effect on these biomarkers. The impact of hypoxia on their dynamics was characterized, underlining higher hypoxia-related initial exposure with a more severe hypoxic-ischemic encephalopathy status. [ABSTRACT FROM AUTHOR]

Aim: To create a magnetic resonance imaging (MRI)‐based scoring system specific to neonates born preterm with intraventricular haemorrhage (IVH), which could serve as a reliable prognostic indicator for later development and might allow for improved outcome prediction, individually‐tailored parental counselling, and clinical decision‐making. Method: This retrospective, two‐center observational cohort study included 103 infants born preterm with IVH (61 males, 42 females; median gestational age 26wks 6d), born between 2000 and 2016. Term‐equivalent MRI was evaluated using a novel scoring system consisting of 11 items. A total MRI score was calculated and correlated with neurodevelopment between 2 years and 3 years of age. Prediction models for outcome were defined. Results: The proposed MRI scoring system showed high correlation and strong predictive ability with regard to later cognitive and motor outcome. The prediction models were translated into easy‐to‐use tables, allowing developmental risk assessment. Interpretation: The proposed MRI‐based scoring system was created especially for infants born preterm with IVH and enables a comprehensive assessment of important brain areas as well as potential additional abnormalities commonly associated with IVH. Thus, it better represents the severity of brain damage when compared with the conventional IVH classification. Our scoring system should provide clinicians with valuable information, to optimize parental counselling and clinical decision‐making. [ABSTRACT FROM AUTHOR]

Background: Allopurinol, an xanthine oxidase (XO) inhibitor, is a promising intervention that may provide neuroprotection for neonates with hypoxic-ischemic encephalopathy (HIE). Currently, a double-blind, placebo-controlled study (ALBINO, NCT03162653) is investigating the neuroprotective effect of allopurinol in HIE neonates. Objective: The aim of the current study was to establish the pharmacokinetics (PK) of allopurinol and oxypurinol, and the pharmacodynamics (PD) of both compounds on hypoxanthine, xanthine, and uric acid in HIE neonates. The dosage used and the effect of allopurinol in this population, either or not undergoing therapeutic hypothermia (TH), were evaluated. Methods: Forty-six neonates from the ALBINO study and two historical clinical studies were included. All doses were administered on the first day of life. In the ALBINO study (n = 20), neonates received a first dose of allopurinol 20 mg/kg, and, in the case of TH (n = 13), a second dose of allopurinol 10 mg/kg. In the historical cohorts (n = 26), neonates (all without TH) received two doses of allopurinol 20 mg/kg in total. Allopurinol and oxypurinol population PK, and their effects on inhibiting conversions of hypoxanthine and xanthine to uric acid, were assessed using nonlinear mixed-effects modelling. Results: Allopurinol and oxypurinol PK were described by two sequential one-compartment models with an autoinhibition effect on allopurinol metabolism by oxypurinol. For allopurinol, clearance (CL) was 0.83 L/h (95% confidence interval [CI] 0.62–1.09) and volume of distribution (Vd) was 2.43 L (95% CI 2.25–2.63). For metabolite oxypurinol, CL and Vd relative to a formation fraction (fm) were 0.26 L/h (95% CI 0.23–0.3) and 11 L (95% CI 9.9–12.2), respectively. No difference in allopurinol and oxypurinol CL was found between TH and non-TH patients. The effect of allopurinol and oxypurinol on XO inhibition was described by a turnover model of hypoxanthine with sequential metabolites xanthine and uric acid. The combined allopurinol and oxypurinol concentration at the half-maximal XO inhibition was 0.36 mg/L (95% CI 0.31–0.42). Conclusion: The PK and PD of allopurinol, oxypurinol, hypoxanthine, xanthine, and uric acid in neonates with HIE were described. The dosing regimen applied in the ALBINO trial leads to the targeted XO inhibition in neonates treated with or without TH. [ABSTRACT FROM AUTHOR]

Data evaluating mortality and morbidity in infants born ≤500 g are scarce and show wide variability. To support counselling and decision‐making, we analysed neurodevelopmental outcome in all neonates ≤500 g birth weight. Retrospective analysis including preterm infants with a birth weight ≤500 g and a gestational age >22 weeks born at a single tertiary perinatal centre between 2010 and 2017. Of 59 live births, 88% received standard care. Birth weight ranged from 318 to 500 g and gestational age from 23 to 29 weeks. 56% of neonates were born ≤3rd percentile and 42% of treated infants survived. Neurodevelopmental outcome was available in 91% of patients and was evaluated using Bayley Scales of Infant Development at two years. 50% showed a favourable mental development (normal or mild impairment), 75% a favourable motor development and 45% a favourable outcome in both outcome subcategories. When additionally considering visual and hearing disability and, or, cerebral palsy level ≥2 according to the Gross Motor Function Classification System 35% had a good neurodevelopmental outcome. Survival rate was 37% for all live births and 42% for infants with standard care. More than one‐third of survivors showed no significant neurodevelopmental impairment at two years. [ABSTRACT FROM AUTHOR]

Objectives: The software "SyMRI" generates different MR contrasts and characterizes tissue properties based on a single acquisition of a multi-dynamic multi-echo (MDME)-FLAIR sequence. The aim of this study was to assess the applicability of "SyMRI" in the assessment of myelination in preterm and term-born neonates. Furthermore, "SyMRI" was compared with conventional MRI.Methods: A total of 30 preterm and term-born neonates were examined at term-equivalent age using a standardized MRI protocol. MDME sequence (acquisition time, 5 min, 24 s)-based post-processing was performed using "SyMRI". Myelination was assessed by scoring seven brain regions on quantitative T1-/T2-maps, generated by "SyMRI" and on standard T1-/T2-weighted images, acquired separately. Analysis of covariance (ANCOVA) (covariate, gestational age (GA) at MRI (GAMRI)) was used for group comparison.Results: In 25/30 patients (83.3%) (18 preterm and seven term-born neonates), "SyMRI" acquisitions were successfully performed. "SyMRI"-based myelination scores were significantly lower in preterm compared with term-born neonates (ANCOVA: T1: F(1, 22) = 7.420, p = 0.012; T2: F(1, 22) = 5.658, p = 0.026). "SyMRI"-based myelination scores positively correlated with GAMRI (T1: r = 0.662, n = 25, p ≤ 0.001; T2: r = 0.676, n = 25, p ≤ 0.001). The myelination scores based on standard MRI did not correlate with the GAMRI. No significant differences between preterm and term-born neonates were detectable.Conclusions: "SyMRI" is a highly promising MR technique for neonatal brain imaging. "SyMRI" is superior to conventional MR sequences in the visual detection of delayed myelination in preterm neonates.Key Points: • By providing multiple MR contrasts, "SyMRI" is a time-saving method in neonatal brain imaging. • Differences concerning the myelination in term-born and preterm infants are visually detectable on T1-/T2-weighted maps generated by "SyMRI". • "SyMRI" allows a faster and more sensitive assessment of myelination compared with standard MR sequences. [ABSTRACT FROM AUTHOR]

Children born preterm are at higher risk to develop language deficits. Auditory speech discrimination deficits may be early signs for language developmental problems. The present study used functional near-infrared spectroscopy to investigate neural speech discrimination in 15 preterm infants at term-equivalent age compared to 15 full term neonates. The full term group revealed a significantly greater hemodynamic response to forward compared to backward speech within the left hemisphere extending from superior temporal to inferior parietal and middle and inferior frontal areas. In contrast, the preterm group did not show differences in their hemodynamic responses during forward versus backward speech, thus, they did not discriminate speech from non-speech. Groups differed significantly in their responses to forward speech, whereas they did not differ in their responses to backward speech. The significant differences between groups point to an altered development of the functional network underlying language acquisition in preterm infants as early as in term-equivalent age. [ABSTRACT FROM AUTHOR]

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 ALlopurinol in addition to hypothermia treatment for hypoxic-ischemic Brain Injury on Neurocognitive Outcome (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. [ABSTRACT FROM AUTHOR]

Humans are biologically endowed with the faculty of language. However, the way neonates can crack this complex communicative code is yet not totally understood. While phonetic discrimination has been widely investigated in neonates, less is known about the role of supra-segments patterns in the recognition of native language. Therefore, the aim of this study was to evaluate accent discrimination abilities in newborns in a sentential prosody paradigm. We used near-infared spectroscopy to investigate accent discrimination in 21 full-term born infants within the first days of life. Sentential prosody was used to investigate: (a) native accent, (b) foreign accent, and (c) flattened accent. Neonates revealed a significantly smaller hemodynamic response to native accent compared to flattened accent and foreign accent, respectively. Cluster-based permutation analysis revealed two clusters with a significant difference between the two conditions native accent and foreign accent. The first cluster covered the middle and superior frontal, middle and superior temporal, central, and parietal areas within the left hemisphere. The second cluster, located in the right hemisphere, covered inferior, middle, and superior frontal, central, middle and superior temporal areas. We therefore conclude that neonates can differentiate prosodic features like accents within the same language a few days after birth. [ABSTRACT FROM AUTHOR]