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(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.

Objective . To overcome the effects of site differences in EEG-based brain age prediction in preterm infants. Approach . We used a 'bag of features' with a combination function estimated using support vector regression (SVR) and feature selection (filter then wrapper) to predict post-menstrual age (PMA). The SVR was trained on a dataset containing 138 EEG recordings from 37 preterm infants (site 1). A separate set of 36 EEG recordings from 36 preterm infants was used to validate the age predictor (site 2). The feature distributions were compared between sites and a restricted feature set was constructed using only features that were not significantly different between sites. The mean absolute error between predicted age and PMA was used to define the accuracy of prediction and successful validation was defined as no significant differences in error between site 1 (cross-validation) and site 2. Main results . The age predictor based on all features and trained on site 1 was not validated on site 2 ( p < 0.001; MAE site 1 = 1.0 weeks, n = 59 versus MAE site 2 = 2.1 weeks, n = 36). The MAE was improved by training on a restricted features set (MAE site 1 = 1.0 weeks, n = 59 versus MAE site 2 = 1.1 weeks, n = 36), resulting in a validated age predictor when applied to site 2 ( p = 0.68). The features selected from the restricted feature set when training on site 1 closely aligned with features selected when trained on a combination of data from site 1 and site 2. Significance . The ability of EEG classifiers, such as brain age prediction, to maintain accuracy on data collected at other sites may be challenged by unexpected, site-dependent differences in EEG signals. Permitting a small amount of data leakage between sites improves generalization, leading towards universal methods of EEG interpretation in preterm infants., (© 2023 Institute of Physics and Engineering in Medicine.)

The measurement of heart rate variability (HRV) in preterm infants provides important information on function to clinicians. Measuring the underlying electrocardiogram (ECG) in the neonatal intensive care unit is a challenge and there is a trade off between extracting accurate measurements of the HRV and the amount of ECG processed due to contamination. Knowledge on the effects of 1) quantization in the time domain and 2) missing data on the calculation of HRV features will inform clinical implementation. In this paper, we studied multiple 5 minute epochs from 148 ECG recordings on 56 extremely preterm infants. We found that temporal adjustment of NN peaks improves the estimate of the NN interval resulting in HRV features (m = 9) that are better correlated with age (median percentage increase in correlation of individual features: 0.2%, IQR: 0.0 to 5.6%; correlation with age predictor and age from 0.721 to 0.787). Improved (sub-sample) quantization of the NN intervals (via interpolation) reduced the overall value of HRV features (median percentage reduction in feature value: -1.3%, IQR: -18.8 to 0.0; m = 9), primarily through a reduction in the energy of high-frequency oscillations. HRV features were also robust to missing data, with measures such as mean NN, fractal dimension and the smoothed nonlinear energy operator (SNEO) less susceptible to missing data than features such as VLF, LF, and HF. Furthermore, age predictions derived from a combination of HRV measures were more robust to missing data than individual HRV measures.Clinical Relevance-Poor quantization in time when estimating the NN peak and the presence of missing data confound HRV measures, particularly spectral measures.

Background: Preterm birth predisposes infants to adverse outcomes that, without early intervention, impacts their long-term health. To assist bedside monitoring, we developed a tool to track the autonomic maturation of the preterm by assessing heart rate variability (HRV) changes during intensive care., Methods: Electrocardiogram (ECG) recordings were longitudinally recorded in 67 infants (26-38 weeks postmenstrual age (PMA)). Supervised machine learning was used to generate a functional autonomic age (FAA), by combining 50 computed HRV features from successive 5-minute ECG epochs (median of 23 epochs per infant). Performance of the FAA was assessed by correlation to PMA, clinical outcomes and the infant's functional brain age (FBA), an index of maturation derived from the electroencephalogram., Results: The FAA was strongly correlated to PMA (r = 0.86, 95% CI: 0.83-0.93) with a mean absolute error (MAE) of 1.66 weeks and also accurately estimated FBA (MAE = 1.58 weeks, n = 54 infants). The relationship between PMA and FAA was not confounded by neurodevelopmental outcome (p = 0.18, n = 45), sex (p = 0.88, n = 56), patent ductus arteriosus (p = 0.08, n = 56), IVH (p = 0.63, n = 56) or body weight at birth (p = 0.95, n = 56)., Conclusions: The FAA, an index derived from the ubiquitous ECG signal, offers direct avenues towards estimating autonomic maturation at the bedside during intensive care monitoring., Impact: The development of a tool to track functional autonomic age in preterm infants based on heart rate variability features in the electrocardiogram provides a rapid and specialized view of autonomic maturation at the bedside. Functional autonomic age is linked closely to postmenstrual age and central nervous system function response, as determined by its relationship to functional brain age from the electroencephalogram. Tracking functional autonomic age during neonatal intensive care unit monitoring offers a unique insight into cardiovascular health in infants born extremely preterm and their maturational trajectories to term age., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Objective: To investigate whether monitoring of cerebral tissue oxygen saturation using near infrared spectroscopy in addition to routine monitoring combined with defined treatment guidelines during immediate transition and resuscitation increases survival without cerebral injury of premature infants compared with standard care alone., Design: Multicentre, multinational, randomised controlled phase 3 trial., Setting: 11 tertiary neonatal intensive care units in six countries in Europe and in Canada., Participants: 1121 pregnant women (<32 weeks' gestation) were screened prenatally. The primary outcome was analysed in 607 of 655 randomised preterm neonates: 304 neonates in the near infrared spectroscopy group and 303 in the control group., Intervention: Preterm neonates were randomly assigned to either standard care (control group) or standard care plus monitoring of cerebral oxygen saturation with a dedicated treatment guideline (near infrared spectroscopy group) during immediate transition (first 15 minutes after birth) and resuscitation., Main Outcome Measure: The primary outcome, assessed using all cause mortality and serial cerebral ultrasonography, was a composite of survival without cerebral injury. Cerebral injury was defined as any intraventricular haemorrhage or cystic periventricular leukomalacia, or both, at term equivalent age or before discharge., Results: Cerebral tissue oxygen saturation was similar in both groups. 252 (82.9%) out of 304 neonates (median gestational age 28.9 (interquartile range 26.9-30.6) weeks) in the near infrared spectroscopy group survived without cerebral injury compared with 238 (78.5%) out of 303 neonates (28.6 (26.6-30.6) weeks) in the control group (relative risk 1.06, 95% confidence interval 0.98 to 1.14). 28 neonates died (near infrared spectroscopy group 12 (4.0%) v control group 16 (5.3%): relative risk 0.75 (0.33 to 1.70)., Conclusion: Monitoring of cerebral tissue oxygen saturation in combination with dedicated interventions in preterm neonates (<32 weeks' gestation) during immediate transition and resuscitation after birth did not result in substantially higher survival without cerebral injury compared with standard care alone. Survival without cerebral injury increased by 4.3% but was not statistically significant., Trial Registration: ClinicalTrials.gov NCT03166722., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the Austrian Science Fund and the HRB Clinical Research Facility at the University of Cork for the submitted work, and from the Stollery Children’s Hospital Foundation facilitated by the Women and Children’s Health Research Institute; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Preterm infants are at risk for neurodevelopmental deficits. An association between retinopathy of prematurity (ROP) and impaired cognitive outcome has already been described. However, less is known about the impact of ROP on visual motor integration (VMI), which is a prerequisite not only for fine motor abilities but also for further school skills. Therefore, the aim of this study was to retrospectively investigate the impact of ROP on VMI at preschool age., Methods: The study was conducted at the Medical University of Vienna, including patients born between January 2009 and December 2014 with a gestational age of less than 30 weeks and/or a birth weight of less than 1,500 g. VMI was determined by Beery-Buktenica Developmental Test of Visual Motor Integration (Beery VMI) at the age of 5 years., Results: Out of 1,365 patients, 353 met inclusion criteria for this study. Two hundred sixteen of them had no ROP, while 137 had ROP (stage 1: n = 23, stage 2: n = 74, stage 3: n = 40). Mean value of the Beery VMI score was significantly lower in the ROP group compared to the No-ROP group (90 ± 16 vs. 99 ± 14; p < 0.01). By correcting for other important medical conditions, ROP still had a significant impact on Beery VMI score (p < 0.01). Particularly, lower scores were found for stage 2 (p < 0.01) and stage 3 (p < 0.01)., Conclusion: Beery VMI scores were significantly lower in preterm infants with ROP stage 2 and 3 than in infants without ROP. This study shows the negative impact of ROP on VMI skills at preschool age, even after adjustment for key demographic and medical characteristics., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

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., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Respiratory distress syndrome (RDS) care pathways evolve slowly as new evidence emerges. We report the sixth version of "European Guidelines for the Management of RDS" by a panel of experienced European neonatologists and an expert perinatal obstetrician based on available literature up to end of 2022. Optimising outcome for babies with RDS includes prediction of risk of preterm delivery, appropriate maternal transfer to a perinatal centre, and appropriate and timely use of antenatal steroids. Evidence-based lung-protective management includes initiation of non-invasive respiratory support from birth, judicious use of oxygen, early surfactant administration, caffeine therapy, and avoidance of intubation and mechanical ventilation where possible. Methods of ongoing non-invasive respiratory support have been further refined and may help reduce chronic lung disease. As technology for delivering mechanical ventilation improves, the risk of causing lung injury should decrease, although minimising time spent on mechanical ventilation by targeted use of postnatal corticosteroids remains essential. The general care of infants with RDS is also reviewed, including emphasis on appropriate cardiovascular support and judicious use of antibiotics as being important determinants of best outcome. We would like to dedicate this guideline to the memory of Professor Henry Halliday who died on November 12, 2022.These updated guidelines contain evidence from recent Cochrane reviews and medical literature since 2019. Strength of evidence supporting recommendations has been evaluated using the GRADE system. There are changes to some of the previous recommendations as well as some changes to the strength of evidence supporting recommendations that have not changed. This guideline has been endorsed by the European Society for Paediatric Research (ESPR) and the Union of European Neonatal and Perinatal Societies (UENPS)., (© 2023 S. Karger AG, Basel.)

Introduction: This study was set up to investigate if and to what extent non-pharmacological analgesia is able to provide comfort to very preterm infants (VPI) during less invasive surfactant administration (LISA)., Methods: This was a prospective non-randomized multicenter observational study performed in level IV NICUs. Inborn VPI with a gestational age between 220/7 and 316/7 weeks, signs of respiratory distress syndrome, and the need for surfactant replacement were included. Non-pharmacological analgesia was performed in all infants during LISA. In case of failure of the first LISA attempt, additional analgosedation could be administered. COMFORTneo scores during LISA were assessed., Results: 113 VPI with a mean gestational age of 27 weeks (+/- 2.3 weeks) and mean birth weight of 946 g (+/- 33 g) were included. LISA was successful at the first laryngoscopy attempt in 81%. COMFORTneo scores were highest during laryngoscopy. At this time point, non-pharmacological analgesia provided adequate comfort in 61% of the infants. 74.4% of lower gestational aged infants (i.e., 220-266 weeks) were within the comfort zone during laryngoscopy compared to 51.6% of higher gestational aged infants (i.e., 270-320 weeks) (p = 0.016). The time point of surfactant administration did not influence the COMFORTneo scores during the LISA procedure., Conclusion: Non-pharmacological analgesia provided comfort in as much as 61% of the included VPI during LISA. Further research is needed to both develop strategies to identify infants who, despite receiving non-pharmacological analgesia, are at high risk for experiencing discomfort during LISA and define patient-tailored dosage and choice of analgosedative drugs., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: Lung recruitment maneuvers (LRMs) improve lung volume at initiation of high-frequency oscillatory ventilation (HFOV), but it is unclear when to repeat LRMs. We evaluated the efficiency of scheduled LRMs., Methods: In a randomized controlled trial, extremely preterm infants on HFOV received either LRMs at 12-hour intervals and when clinically indicated (intervention) or only when clinically indicated (control). The primary outcome was the cumulative oxygen saturation index (OSI) over HFOV time, limited to 7 days. Additionally, LRMs were analyzed with respect to OSI improvement., Results: Fifteen infants were included in each group. The mean (SD) postmenstrual age and weight at HFOV start were 23 + 6 (0 + 5) weeks and 650 (115) g in the intervention group and 24 + 4 (0 + 6) weeks (p = 0.03) and 615 (95) g (p = 0.38) in the control group. The mean (SD) cumulative OSI amounted to 4.95 (1.72) in the intervention versus 5.30 (2.08) in the control group (p = 0.61). The mean (SD) number of LRMs in 12 h was 1.3 (0.2) in the intervention versus 1.1 (0.5) in the control group (p = 0.13). Performing LRM when FiO2 > 0.6 resulted in a mean OSI reduction of 3.6., Conclusion: Regular versus clinically indicated LRMs were performed with equal frequency in preterm infants during HFOV, and consequently, no difference in lung volume was observed. LRMs seem to be most efficient at high FiO2., Trial Registration: ClinicalTrials.gov ID: NCT04289324 (28/02/2020)., (© 2022. Crown.)

Importance: Intraventricular hemorrhage (IVH) is a major cause of neonatal morbidity and mortality in preterm infants without a specific medical treatment to date., Objective: To assess the safety and short-term outcomes of high-dose erythropoietin in preterm infants with IVH., Design, Setting, and Participants: Between April 1, 2014, and August 3, 2018, a randomized double-blind clinical trial enrolled 121 preterm infants (gestational age <32 weeks or birth weight <1500 g) aged 8 or less days with moderate to severe IVH identified by cerebral ultrasonography from 8 Swiss and Austrian tertiary neonatal units. Statistical analyses were performed between October 1, 2019, and September 12, 2022., Interventions: Infants received intravenous high-dose erythropoietin (2000 units/kg body weight) or placebo at 4 time points between weeks 1 and 4 of life., Main Outcomes and Measures: Secondary outcomes included (1) mortality and morbidity rates and (2) brain magnetic resonance imaging findings at term-equivalent age (TEA). The primary outcome was the composite intelligence quotient at 5 years of age (not available before 2023)., Results: Sixty infants (48% male [n = 29]) were randomly assigned to receive erythropoietin, and 61 infants (61% male [n = 37]) were randomly assigned to receive placebo. The median birth weight was 832 g (IQR, 687-990 g) in the erythropoietin group and 870 g (IQR, 680-1110 g) in the placebo group. Median gestation was 26.1 weeks (IQR, 24.8-27.3 weeks) in the erythropoietin group and 27.0 weeks (24.9-28.1 weeks) in the placebo group. The 2 groups had similar baseline characteristics and morbidities. Up to TEA, 10 newborns died (16.7%) in the erythropoietin group, and 5 newborns (8.2%) died in the placebo group (adjusted odds ratio, 2.24 [95% CI, 0.74-7.66]; P = .15). Infants receiving erythropoietin had higher mean hematocrit levels. Conventional magnetic resonance imaging at TEA for 100 infants showed no significant differences in global or regional brain injury scores., Conclusions and Relevance: This preliminary report of a randomized clinical trial found no evidence that high-dose erythropoietin in preterm infants with IVH affects brain injury scores on conventional magnetic resonance imaging at TEA. Higher mortality in the erythropoietin group was not significant but should be reassessed based on future results from similar trials., Trial Registration: ClinicalTrials.gov Identifier: NCT02076373.

Background and Purpose: Multidynamic multiecho sequence-based imaging enables investigators to reconstruct multiple MR imaging contrasts on the basis of a single scan. This study investigated the feasibility of synthetic MRI-based WM signal suppression (syWMSS), a synthetic inversion recovery approach in which a short TI suppresses myelin-related signals, for the identification of early myelinating brainstem pathways., Materials and Methods: Thirty-one cases of neonatal MR imaging, which included multidynamic multiecho data and conventionally acquired T1- and T2-weighted sequences, were analyzed. The multidynamic multiecho postprocessing software SyMRI was used to generate syWMSS data (TR/TE/TI = 3000/5/410 ms). Two raters discriminated early myelinating brainstem pathways (decussation of the superior cerebellar peduncle, medial lemniscus, central tegmental tract, and medial longitudinal fascicle [the latter 3 assessed at the level of the pons]) on syWMSS data and reference standard contrasts., Results: On the basis of syWMSS data, the decussation of the superior cerebellar peduncle (31/31); left/right medial lemniscus (31/31; 30/31); left/right central tegmental tract (19/31; 20/31); and left/right medial longitudinal fascicle (30/31) were reliably identified by both raters. On the basis of T1-weighted contrasts, the decussation of the superior cerebellar peduncle (14/31); left/right medial lemniscus (22/31; 16/31); left/right central tegmental tract (1/31); and left/right medial longitudinal fascicle (9/31; 8/31) were reliably identified by both raters. On the basis of T2-weighted contrasts, the decussation of the superior cerebellar peduncle (28/31); left/right medial lemniscus (16/31; 12/31); left/right central tegmental tract (23/31; 18/31); and left/right medial longitudinal fascicle (15/31; 14/31) were reliably identified by both raters., Conclusions: syWMSS data provide a feasible imaging technique with which to study early myelinating brainstem pathways. MR imaging approaches that use myelin signal suppression contribute to a more sensitive assessment of myelination patterns at early stages of cerebral development., (© 2022 by American Journal of Neuroradiology.)

Objective: To describe cerebral abnormalities and their risk factors in a contemporary cohort of infants born extremely premature after the introduction of routine cerebral magnetic resonance imaging (cMRI) at term-equivalent age., Study Design: All cMRI examinations performed during November 2017 and November 2020, based on a standardized neonatal cMRI protocol, were included into analysis. Pathologies were retrospectively classified into 3 categories: intraventricular hemorrhage (IVH), white matter disease, and cerebellar injuries., Results: A total of 198 cMRI examinations were available for analyses; 93 (47%) showed abnormalities, most frequently IVH (n = 65, 33%), followed by cerebellar injuries (n = 41, 21%), and white matter disease (n = 28, 14%). Severe abnormalities were found in 18% of patients (n = 36). Significant clinical risk factors for abnormalities on cMRI were lower Apgar scores, lower umbilical artery and first neonatal pH, asphyxia, blood culture-proven sepsis (especially late-onset), and prolonged need of respiratory support and supplemental oxygen., Conclusions: After routine cMRI, without preconfirmed pathology by cranial ultrasonography, low-grade IVH, noncystic white matter disease, and cerebellar injuries were the most frequently found abnormalities. The clinical value and long-term benefit of the detection of these low-grade pathologies have yet to be confirmed., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Premature infants commonly receive adult packed red blood cells (pRBCs) during their hospital stay. As adult erythrocytes differ substantially from those of preterm infants, transfusion of adult pRBCs into preterm infants can be considered inappropriate for the physiology of a preterm infant. An absence of standardisation of transfusion protocols makes it difficult to compare and interpret pertinent clinical data, as reflected by unclear associations between pRBC transfusion and complications related to prematurity, such as bronchopulmonary dysplasia, neurodevelopmental impairment, retinopathy of prematurity, or necrotising enterocolitis. The difficulty in interpreting clinical data is further increased by differences in study designs that either overestimate pRBC-associated complications of prematurity or have not yet been designed to directly link pRBC transfusions to their respective complications. Thus, neonatal transfusion practice has become an ongoing difficulty, in which differences in transfusion guidelines hinder the ability to generate comparable clinical data, and heterogeneity in clinical data prevents the implementation of standardised transfusion protocols. To overcome these issues, novel approaches with biochemical-clinical translational designs could enable clinicians to gather causal evidence instead of circumstantial correlation., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: To assess the reliability, accuracy and precision of distal end-tidal capnography (detCO 2 ) in neonates compared with transcutaneous (tcCO 2 ) carbon dioxide measurements., Design: Observational, prospective clinical study., Setting: Neonatal intensive care unit at Medical University of Vienna., Participants: Conventionally ventilated neonates with a body weight between 1000 g and 3000 g., Intervention: End-tidal partial pressure of CO 2 was measured in distal position using the separate lumen of a double-lumen endotracheal tube connected to an external side-stream capnometer. Three consecutive detCO 2 and tcCO 2 values were recorded simultaneously and compared with simultaneous arterialised partial pressure of CO 2 (paCO 2 ) measurements in each patient., Main Outcome Measures: Reliability, accuracy and precision of detCO 2 and tcCO 2 measurements compared with paCO 2 in neonates., Results: Twenty-five neonates were included with a median (range) weight at enrolment of 1410 (1010-2980) g, from which 81 simultaneous measurements of detCO 2 , tcCO 2 and paCO 2 were obtained. The mean (SD) of paCO 2 , detCO 2 and tcCO 2 was 45.0 (8.6) mmHg, 42.4 (8.4) mmHg and 50.4 (20.4) mmHg, respectively. The intraclass correlation between paCO 2 and detCO 2 and between paCO 2 and tcCO 2 reached 0.80 (95% CI 0.71 to 0.87, p<0.001) and 0.59 (95% CI 0.43 to 0.72, p<0.001), respectively. In the Bland-Altman analysis, bias and precision of detCO 2 with respect to paCO 2 amounted to -2.68 mmHg and 10.62 mmHg (95% CI 8.49 to 14.51), respectively. Bias and precision of tcCO 2 with respect to paCO 2 amounted to 5.39 mmHg and 17.22 mmHg (95% CI 13.21 to 23.34), respectively., Conclusion: DetCO 2 had better reliability, accuracy and precision with paCO 2 than tcCO 2 in ventilated neonates without severe lung diseas., Trial Registration Number: NCT03758313., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (© 2021 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Background and Purpose: Former preterm born males are at higher risk for neurodevelopmental disabilities compared with female infants born at the same gestational age. This retrospective study investigated sex-related differences in the maturity of early myelinating brain regions in infants born <28 weeks' gestational age using diffusion tensor- and relaxometry-based MR imaging., Materials and Methods: Quantitative MR imaging sequence acquisitions were analyzed in a sample of 35 extremely preterm neonates imaged at term-equivalent ages. Quantitative MR imaging metrics (fractional anisotropy; ADC [10 -3 mm 2 /s]; and T1-/T2-relaxation times [ms]) of the medulla oblongata, pontine tegmentum, midbrain, and the right/left posterior limbs of the internal capsule were determined on diffusion tensor- and multidynamic, multiecho sequence-based imaging data. ANCOVA and a paired t test were used to compare female and male infants and to detect hemispheric developmental asymmetries., Results: Seventeen female (mean gestational age at birth: 26 + 0 [SD, 1 + 4] weeks+days) and 18 male (mean gestational age at birth: 26 + 1 [SD, 1 + 3] weeks+days) infants were enrolled in this study. Significant differences were observed in the T2-relaxation time ( P = .014) of the pontine tegmentum, T1-relaxation time ( P = .011)/T2-relaxation time ( P = .024) of the midbrain, and T1-relaxation time ( P = .032) of the left posterior limb of the internal capsule. In both sexes, fractional anisotropy ( P [♀] < .001/ P [♂] < .001) and ADC ( P [♀] = .017/ P [♂] = .028) differed significantly between the right and left posterior limbs of the internal capsule., Conclusions: The combined use of various quantitative MR imaging metrics detects sex-related and interhemispheric differences of WM maturity. The brainstem and the left posterior limb of the internal capsule of male preterm neonates are more immature compared with those of female infants at term-equivalent ages. Sex differences in WM maturation need further attention for the personalization of neonatal brain imaging., (© 2022 by American Journal of Neuroradiology.)

Klebermass-Schrehof Katrin, Thomas Waldhoer, and Lin Yang. The effect of altitude on birthweight/length ratio: a population-based study over 36 years in an altitude range from sea level to 1,700 m. High Alt Med Biol . 23:90-95, 2022. Objective: The negative effect of altitude on fetal growth has been documented, but it is unknown whether this effect changes over time. We investigated the effect of altitude on infant birthweight/length ratio as well as its potential dependence on gestational age and year of birth in the range from sea level up to 1,700 m (Austria). Materials and Methods: Data on maternal characteristics, infant birthweights, and infant lengths were extracted from all Austrian birth certificates between 1984 and 2019. Results: A total of 2,240,439 birth certificates were identified and analyzed. The effect of altitude on birthweight/length ratio was -2.66 g/cm (95% confidence interval [CI]: -2.77 to -2. 54) per 1,000 m increased altitude in 1984-1986, which decreased to -1.96 g/cm (95% CI: -2.09 to -1.82) in 2017-2019. The effect of altitude on birthweight/length ratio remained constant for preterm infants, which fluctuated around -1.5 g/cm. For term infants, the negative effect of altitude on birthweight/length ratio attenuated from -3 to -1.9 g/cm over time with a stronger decrease for infants born between 41 and 42 compared with those between 37 and 40 weeks of gestation. Conclusion: In summary, our data demonstrate a strong effect of altitude on birthweight/length ratio over 36 years with a smaller effect in recent years and a stronger effect in infants born around term age compared with preterm infants.

Objectives: To evaluate a new task-based package-organized (TPO) neonatal emergency backpack and to compare it to the classical (ABC- and material-based) backpack. Methods: Simulation-based assessment of time to retrieve equipment for three different tasks [intraosseous access (IO), intubation and adrenaline administration] using the TPO and the classical emergency backpack was compared. Results: Equipment retrieval times for the three tasks were assessed for 24 nurses (12 intermediate care, 12 intensive care) and were significantly faster in the TPO than in the classical backpack (IO 33 vs. 75 s, p < 0.001; intubation 53 vs. 70 s, p = 0,001; adrenaline 22 vs. 45 s, p < 0.001). The number of missing items was significantly lower using the TPO backpack for IO and adrenaline retrieval (IO 0,9 vs. 2,3 items, p < 00001, adrenaline 0.04 vs. 1, p < 0.001) but not for intubation equipment (0.9 vs. 1, not significant). The subjective rating of overall clearness was significantly higher for the TPO compared with the classical backpack (5,9 vs. 3,5, p < 0.001). Conclusion: Task-based package organization of neonatal emergency backpacks is feasible and might be superior to ABC-/material-oriented storage., Competing Interests: ES is a neonatal consultant at the Medical University Vienna and managing partner/CEO of SIMCharacters Training GmbH (Austria), a company providing medical simulation training in German-speaking countries. However, there is no financial or other related benefit in relation to this manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sommer, Huber-Dangl, Klebermaß-Schrehof, Berger and Schwindt.)

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., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Fish oil is rich in omega-3 fatty acids and essential for neuronal myelination and maturation. The aim of this study was to investigate whether the use of a mixed-lipid emulsion composed of soybean oil, medium-chain triglycerides, olive oil, and fish oil (SMOF-LE) compared to a pure soybean oil-based lipid emulsion (S-LE) for parenteral nutrition had an impact on neuronal conduction in preterm infants. This study is a retrospective matched cohort study comparing preterm infants <1000 g who received SMOF-LE in comparison to S-LE for parenteral nutrition. Visual evoked potentials (VEPs) were assessed longitudinally from birth until discharge. The latencies of the evoked peaks N2 and P2 were analyzed. The analysis included 76 infants (SMOF-LE: n = 41 and S-LE: n = 35) with 344 VEP measurements (SMOF-LE: n = 191 and S-LE n = 153). Values of N2 and P2 were not significantly different between the SMOF-LE and S-LE groups. A possible better treatment effect in the SMOF-LE group was seen as a trend toward a shorter latency, indicating faster neural conduction at around term-equivalent age. Prospective trials and follow-up studies are necessary in order to evaluate the potential positive effect of SMOF-LE on neuronal conduction and visual pathway maturation.

Postnatal growth restriction and deficits in fat-free mass are associated with impaired neurodevelopment. The optimal body composition to support normal brain growth and development remains unclear. This study investigated the association between body composition and brain size in preterm infants. We included 118 infants born <28 weeks of gestation between 2017-2021, who underwent body composition (fat-free mass (FFM) and fat mass (FM)) and cerebral magnetic resonance imaging to quantify brain size (cerebral biparietal diameter (cBPD), bone biparietal diameter (bBPD), interhemispheric distance (IHD), transverse cerebellar diameter (tCD)) at term-equivalent age. FFM Z-Score significantly correlated with higher cBPD Z-Score (rs = 0.69; p < 0.001), bBPD Z-Score (rs = 0.48; p < 0.001) and tCD Z-Score (rs = 0.30; p = 0.002); FM Z-Score significantly correlated with lower brain size (cBPD Z-Score (rs = -0.32; p < 0.001) and bBPD Z-Score (rs = -0.42; p < 0.001). In contrast weight (rs = 0.08), length (rs = -0.01) and head circumference Z-Score (rs = 0.14) did not. Linear regression model adjusted for important neonatal variables revealed that FFM Z-Score was independently and significantly associated with higher cBPD Z-Score (median 0.50, 95% CI: 0.59, 0.43; p < 0.001) and bBPD Z-Score (median 0.31, 95% CI: 0.42, 0.19; p < 0.001); FM Z-Score was independently and significantly associated with lower cBPD Z-Score (median -0.27, 95% CI: -0.42, -0.11; p < 0.001) and bBPD Z-Score (median -0.32, 95% CI: -0.45, -0.18; p < 0.001). Higher FFM Z-Score and lower FM Z-scores were significantly associated with larger brain size at term-equivalent age. These results indicate that early body composition might be a useful tool to evaluate and eventually optimize brain growth and neurodevelopment.

Objective: To establish longitudinal reference values for cerebral ventricular size in the most vulnerable patients at risk for intraventricular hemorrhage (IVH) and posthemorrhagic ventricular dilatation (PHVD)., Study Design: This retrospective study included neurologically healthy preterm neonates born at 23 0/7 -26 6/7  weeks of gestational age between September 2011 and April 2019. Patients were treated at 2 Austrian tertiary centers, Medical University of Vienna and Medical University of Innsbruck. All available cerebral ultrasound scans until 30 weeks corrected age were analyzed. Ventricular measurements included ventricular index, anterior horn width (AHW), and thalamo-occipital distance (TOD) and longitudinal percentiles were created., Results: The study cohort consisted of 244 preterm neonates, with a median gestational age of 25 3/7  weeks (IQR, 24 4/7 -26 0/7  weeks) and a median birth weight of 735 g (IQR, 644-849 g). A total of 993 ultrasound scans were available for analysis, resulting in >1800 measurements of ventricular index, AHW, and TOD. Special attention was given to the 97th percentile as well as 2 mm and 4 mm above the 97th percentile, which are used internationally as cutoffs for intervention in the presence of PHVD., Conclusions: We present percentile charts based on a cohort of extremely premature infants including neonates born at the border of viability suited to follow-up the most vulnerable patients at risk for IVH and PHVD. Furthermore, we provide an extensive literature research and comparison of all available reference values, focusing on ventricular index, AHW, and TOD., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Premature infants are at substantial risk for suffering from perinatal white matter injury. Though the gut microbiota has been implicated in early-life development, a detailed understanding of the gut-microbiota-immune-brain axis in premature neonates is lacking. Here, we profiled the gut microbiota, immunological, and neurophysiological development of 60 extremely premature infants, which received standard hospital care including antibiotics and probiotics. We found that maturation of electrocortical activity is suppressed in infants with severe brain damage. This is accompanied by elevated γδ T cell levels and increased T cell secretion of vascular endothelial growth factor and reduced secretion of neuroprotectants. Notably, Klebsiella overgrowth in the gut is highly predictive for brain damage and is associated with a pro-inflammatory immunological tone. These results suggest that aberrant development of the gut-microbiota-immune-brain axis may drive or exacerbate brain injury in extremely premature neonates and represents a promising target for novel intervention strategies., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Differences in management and outcomes of extremely preterm infants have been reported across European countries. Implementation of standardized guidelines and interventions within existing neonatal care facilities can improve outcomes of extremely preterm infants. This study evaluated whether a multifactorial educational training (MET) course in Vienna focusing on the management of extremely preterm infants had an impact on the management of extremely preterm infants in Central-Eastern European (CEE) countries. Methods: Physicians and nurses from different hospitals in CEE countries participated in a two-day MET in Vienna, Austria with theoretical lectures, bedside teaching, and simulation trainings. In order to evaluate the benefit of the workshops, participants had to complete pre- and post-workshop questionnaires, as well as follow-up questionnaires three and twelve months after the MET. Results: 162 participants from 15 CEE countries completed the two-day MET at our department. Less invasive surfactant administration (LISA) was only used by 39% (63/162) of the participants. After the MET, 80% (122/152) were planning to introduce LISA, and 66% (101/152) were planning to introduce regular simulation training, which was statistically significantly increased three and twelve months after the MET. Thirty-six percent and 57% of the participants self-reported improved outcomes three and twelve months after the MET, respectively. Conclusion: Our standardized training in Vienna promoted the implementation of different perinatal concepts including postnatal respiratory management using LISA as well as regular simulation trainings at the participants' home departments. Moreover, our MET contributed to dissemination of guidelines, promoted best-practice, and improved self-reported outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Steinbauer, Klebermass-Schrehof, Cardona, Bibl, Werther, Olischar, Schmölzer, Berger and Wagner.)

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., (© 2021 Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Background and Purpose: To determine whether neurofilament light chain (NfL), a promising serum and cerebrospinal fluid (CSF) biomarker of neuroaxonal damage, predicts functional outcome in preterm infants with neonatal brain injury., Methods: Our prospective observational study used a sensitive single-molecule array assay to measure serum and CSF NfL concentrations in preterm infants with moderate to severe peri/intraventricular hemorrhage (PIVH). We determined temporal serum and CSF NfL profiles from the initial diagnosis of PIVH until term-equivalent age and their association with clinical and neurodevelopmental outcome until 2 years of age assessed by Bayley Scales of Infant Development (3rd edition). We fitted univariate and multivariate logistic regression models to determine risk factors for poor motor and cognitive development., Results: The study included 48 infants born at < 32 weeks of gestation. Median serum NfL (sNfL) at PIVH diagnosis was 251 pg/mL [interquartile range (IQR) 139-379], decreasing markedly until term-equivalent age to 15.7 pg/mL (IQR 11.1-33.5). CSF NfL was on average 113-fold higher (IQR 40-211) than corresponding sNfL values. Additional cerebral infarction (n = 25)-but not post-hemorrhagic hydrocephalus requiring external ventricular drainage (n = 29) nor any other impairment-was independently associated with sNfL. Multivariate logistic regression models identified sNfL as an independent predictor of poor motor outcome or death at 1 and 2 years., Conclusions: Serum neurofilament light chain dynamics in the first weeks of life predict motor outcome in preterm infants with PIVH.

Purpose: The purpose of this study was to assess the diagnostic accuracy of T1-weighted and T2-weighted contrasts generated by the MR data postprocessing software SyMRI (Synthetic MR AB, Linköping, Sweden) for neonatal brain imaging., Methods: In this study 36 cases of neonatal MRI were retrospectively collected, which included T1-weighted and T2-weighted sequences as well as multi-dynamic multi-echo (MDME) sequences. Of the 36 neonates 32 were included in this study and 4 neuroradiologists independently assessed neonatal brain examinations on the basis of conventional and SyMRI-generated T1-weighted and T2-weighted contrasts, in order to determine the presence or absence of lesions. The sensitivity and specificity of both methods were calculated and compared., Results: Compared to conventionally acquired T1 and T2-weighted images, SyMRI-generated contrasts showed a lower sensitivity but a higher specificity (SyMRI sensitivity 0.88, confidence interval (CI): 0.72-0.95; specificity 1, CI: 0.89-1/conventional MRI: sensitivity: 0.94, CI: 0.80-0.98; specificity: 0.94, CI: 0.80-0.98)., Conclusion: The T1-weighted and T2-weighted images generated by SyMRI showed a diagnostic accuracy comparable to that of conventionally acquired contrasts. In addition to semiquantitative imaging data, SyMRI provides diagnostic images and leads to a more efficient use of available imaging time in neonatal brain MRI.

Background and Purpose: Preterm birth interferes with regular brain development. The aim of this study was to investigate the impact of prematurity on the physical tissue properties of the neonatal brain stem using a quantitative MR imaging approach., Materials and Methods: A total of 55 neonates (extremely preterm [ n  =   30]: <28 + 0 weeks gestational age; preterm [ n  =   10]: 28 + 0-36 + 6 weeks gestational age; term [ n  =   15]: ≥37 + 0 weeks gestational age) were included in this retrospective study. In most cases, imaging was performed at approximately term-equivalent age using a standard MR protocol. MR data postprocessing software SyMRI was used to perform multidynamic multiecho sequence (acquisition time: 5 minutes, 24 seconds)-based MR postprocessing to determine T1 relaxation time, T2 relaxation time, and proton density. Mixed-model ANCOVA (covariate: gestational age at MR imaging) and the post hoc Bonferroni test were used to compare the groups., Results: There were significant differences between premature and term infants for T1 relaxation time (midbrain: P  < .001; pons: P  < .001; basis pontis: P  = .005; tegmentum pontis: P  < .001; medulla oblongata: P  < .001), T2 relaxation time (midbrain: P  < .001; tegmentum pontis: P  < .001), and proton density (tegmentum pontis: P  = .004). The post hoc Bonferroni test revealed that T1 relaxation time/T2 relaxation time in the midbrain differed significantly between extremely preterm and preterm (T1 relaxation time: P  < .001/T2 relaxation time: P  = .02), extremely preterm and term (T1 relaxation time/T2 relaxation time: P  < .001), and preterm and term infants (T1 relaxation time: P  < .001/T2 relaxation time: P  = .006)., Conclusions: Quantitative MR parameters allow preterm and term neonates to be differentiated. T1 and T2 relaxation time metrics of the midbrain allow differentiation between the different stages of prematurity. SyMRI allows for a quantitative assessment of incomplete brain maturation by providing tissue-specific properties while not exceeding a clinically acceptable imaging time., (© 2021 by American Journal of Neuroradiology.)

Background: Previous studies conducted in high altitude regions showed that maternal altitude was associated with low birth weight. The effect size of birth weight reduction is inclusive with unknown effects due to preterm birth. We systematically reviewed the literature and synthesize evidence on associations between altitude elevation from sea level and birth weight., Method: We searched MEDLINE/PubMed, Embase, Scopus, Web of Science, and Cochrane database, from inception to May 5, 2020 for studies that reported maternal altitude and birth weight. Bayesian multilevel effect models were employed to estimate the effect size on birth weight (and gestational age) associated with altitude. Bayesian multilevel effect models were employed to estimate the effect size on birth weight (and gestational age) associated with altitude., Results: The systematic search identified 1020 articles, with 52 articles meeting the inclusion criteria providing 207 estimates for the association of altitude and birth weight (n = 4,428,563), and with 22 articles providing 71 estimates for gestational age (n = 2,149,627). A reduction in mean birth weight of 96.98 g was associated with every 1000 m increase in altitude across 52 studies. A statistically significant but numerically minimal effect of maternal altitude elevation was observed on the gestational age (0.3 days), corresponding to a negligible estimation of 5 g lower birth weight. A relatively high heterogeneity of between-study association (I 2 >84.1%) and small study effect was found., Conclusion: A clinically meaningful birth weight reduction was associated with maternal altitude elevation beginning from sea level. Future longitudinal studies are needed to elucidate the causal association and to understand the late effect of maternal altitude., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To determine the accuracy of, and agreement among, EEG and aEEG readers' estimation of maturity and a novel computational measure of functional brain age (FBA) in preterm infants., Methods: Seven experts estimated the postmenstrual ages (PMA) in a cohort of recordings from preterm infants using cloud-based review software. The FBA was calculated using a machine learning-based algorithm. Error analysis was used to determine the accuracy of PMA assessments and intraclass correlation (ICC) was used to assess agreement between experts., Results: EEG recordings from a PMA range 25 to 38 weeks were successfully interpreted. In 179 recordings from 62 infants interpreted by all human readers, there was moderate agreement between experts (aEEG ICC = 0.724; 95%CI:0.658-0.781 and EEG ICC = 0.517; 95%CI:0.311-0.664). In 149 recordings from 61 infants interpreted by all human readers and the FBA algorithm, random and systematic errors in visual interpretation of PMA were significantly higher than the computational FBA estimate. Tracking of maturation in individual infants showed stable FBA trajectories, but the trajectories of the experts' PMA estimate were more likely to be obscured by random errors. The accuracy of visual interpretation of PMA estimation was compromised by neurodevelopmental outcome for both aEEG and EEG review., Interpretation: Visual assessment of infant maturity is possible from the EEG or aEEG, with an average of human experts providing the highest accuracy. Tracking PMA of individual infants was hampered by errors in experts' estimates. FBA provided the most accurate maturity assessment and has potential as a biomarker of early outcome., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objective: A major challenge in the care of preterm infants is the early identification of compromised neurological development. While several measures are routinely used to track anatomical growth, there is a striking lack of reliable and objective tools for tracking maturation of early brain function; a cornerstone of lifelong neurological health. We present a cot-side method for measuring the functional maturity of the newborn brain based on routinely available neurological monitoring with electroencephalography (EEG)., Methods: We used a dataset of 177 EEG recordings from 65 preterm infants to train a multivariable prediction of functional brain age (FBA) from EEG. The FBA was validated on an independent set of 99 EEG recordings from 42 preterm infants. The difference between FBA and postmenstrual age (PMA) was evaluated as a predictor for neurodevelopmental outcome., Results: The FBA correlated strongly with the PMA of an infant, with a median prediction error of less than 1 week. Moreover, individual babies follow well-defined individual trajectories. The accuracy of the FBA applied to the validation set was statistically equivalent to the training set accuracy. In a subgroup of infants with repeated EEG recordings, a persistently negative predicted age difference was associated with poor neurodevelopmental outcome., Interpretation: The FBA enables the tracking of functional neurodevelopment in preterm infants. This establishes proof of principle for growth charts for brain function, a new tool to assist clinical management and identify infants who will benefit most from early intervention., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

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.

Neonatal seizures are the most prevalent and distinctive sign of neurologic dysfunction in early life and pose an immense challenge for clinicians. Improvements in neonatal care have increased the survival rate of extremely premature infants, considerably changing the spectrum of underlying etiologies, and instigating a gradual shift from mortality to morbidity. Recognizing neonatal seizures can be challenging due to variability in presentation but clinical features can often provide valuable clues about etiology. Yet, the majority of neonatal seizures are subclinical. Even though conventional electroencephalography (EEG) with simultaneous video detection of seizures still represents the diagnostic gold standard, continuous monitoring using a one- to two-channel amplitude-integrated EEG with concurrent unprocessed EEG can be crucial for early recognition and intervention. Furthermore, tremendous progress has been made in neuroimaging, and all infants with seizures should have a magnetic resonance imaging (MRI) to help identify the underlying etiology. While the majority of neonatal seizures are caused by hypoxic-ischemic events, stroke, hemorrhage, or infection, approximately 15% of patients will require more sophisticated algorithms for diagnostic workup, including metabolic and genetic screening. These recent developments have led to renew interest in the classification of neonatal seizures, which aim to help identify etiology and guide appropriate therapeutic and prognostic decisions. In this review, we outline recent progress made in the etiology, diagnosis, and treatment of neonatal seizures and highlight areas that deserve further research., Competing Interests: The authors have no conflict of interest to disclose., (Georg Thieme Verlag KG Stuttgart · New York.)

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., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To assess whether parenteral nutrition for infants of extremely low birth weight using a mixed lipid emulsion that contains fish oil influences electrophysiological brain maturation., Study Design: The study is a prespecified secondary outcome analysis of a randomized controlled trial of 230 infants of extremely low birth weight receiving a mixed (soybean oil, medium-chain triglycerides, olive oil, and fish oil; intervention) or a soybean oil-based lipid emulsion (control). The study was conducted at a single-level IV neonatal care unit (Medical University Vienna; June 2012 to October 2015). Electrophysiological brain maturation (background activity, sleep-wake cycling, and brain maturational scores) was assessed biweekly by amplitude-integrated electroencephalography (birth to discharge)., Results: A total of 317 amplitude-integrated electroencephalography measurements (intervention: n = 165; control: n = 152) from 121 (intervention: n = 63; control: n = 58) of 230 infants of the core study were available for analysis. Demographic characteristics were not significantly different. By 28 weeks of postmenstrual age, infants receiving the intervention displayed significantly greater percentages of continuous background activity. Total maturational scores and individual scores for continuity, cycling, and bandwidth were significantly greater. Maximum maturational scores were reached 2 weeks earlier in the intervention group (36.4 weeks, 35.4-37.5) compared with the control group (38.4 weeks, 37.1-42.4) (median, IQR; P < .001)., Conclusions: Using a mixed parenteral lipid emulsion that contains fish oil, we found that electrophysiological brain maturation was accelerated in infants who were preterm., Trial Registration: ClinicalTrials.gov: NCT01585935., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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.

Objectives: To evaluate the feasibility and reproducibility of superb microvascular imaging (SMI) of the neonatal brain and to describe normal imaging features., Methods: We performed transcranial ultrasound with SMI in 19 healthy term-born neonates. SMI was done according to a structured examination protocol, using two linear 18 MHz and 14 MHz transducers. Superficial and deep scans were acquired in the coronal and sagittal planes, using the left and right superior frontal gyri as anatomical landmarks. All SMI views were imaged by monochrome and colour SMI and evaluated with respect to visibility of extrastriatal (i.e. cortical and medullary) and striatal microvessels., Results: We have described normal morphologic features of intraparenchymal brain microvasculature as "short parallel" cortical vessels, "smoothly curved" medullary vessels, and deep striatal vessels. In general, SMI performance was better on coronal views than on sagittal views. On superficial coronal scans, cortical microvessels were identifiable in 90-100%, medullary microvessels in 95-100%. On deep scans, cortical and medullary microvessels were visible in all cases, while striatal microvessels were identifiable in 71% of cases., Conclusions: Cerebral SMI ultrasound is feasible and well-reproducible and provides a novel non-invasive imaging tool for the assessment of intraparenchymal brain microvasculature (extrastriatal and striatal microvessels) in neonates without the use of contrast., Key Points: • Superb microvascular imaging (SMI) of the neonatal brain is feasible and reproducible. • SMI depicts extrastriatal and striatal microvessels. • SMI detects two types of extrastriatal microvessels: cortical and medullary.

Background: The Bayley Scales of Infant and Toddler Development, third edition (Bayley-III) are widely used to assess the development of children born preterm. However, it is still unclear whether US norms are adequate for use in other populations. In 2014, the German version of the Bayley-III with German norms was published., Objectives: We aimed to compare the performance of very-preterm infants at one, two, and three years of age using the German versus US norms of the Bayley-III., Methods: All children born prior to 32 weeks of gestational age during 2012 and 2015 and taking part in the follow-up program of the Medical University of Vienna were assessed and scored according to both German and US norms by two expert clinical psychologists at the age of one, two, and three years of age., Results: In total, 843 tests were obtained from 450 children. When looking at scaled scores for cognitive, language, and motor outcomes, preterm children achieved significantly lower scores in nearly all subtests with the German as compared to the US norms. In addition, the proportion of impaired children scoring < 1 standard deviation (SD) and < 2 SD below the norm was significantly higher in nearly all subtests when using the German compared to the US norms (p < 0.05)., Conclusions: Applying German and US norms of the Bayley-III leads to different outcomes in very-preterm children, and these differences are statistically significant and clinically relevant. Thus, comparisons of outcomes of very-preterm children using culturally specific norms are problematic, and these findings have to be considered., (© 2019 S. Karger AG, Basel.)

Background: The agreement between invasive and non-invasive blood pressure (BP) readings in the first days of life of preterm infants is contentiously debated., Objective: To compare mean, systolic and diastolic invasive (IBP) and non-invasive BP (NBP) readings obtained during routine care in the first four weeks of life of extremely preterm infants., Methods: We extracted pairs of IBP and NBP readings obtained from preterm infants born below 28 weeks of gestation from the local database. After exclusion of erroneous measurements, we investigated the repeated measures correlation and analyzed the agreement (bias) and precision adjusted for multiple measurements per individual., Results: Among 335 pairs of IBP and NBP readings obtained from 128 patients, we found correlation coefficients >0.65 for mean, systolic and diastolic BP values. The bias for mean BP readings was -0.4 mmHg (SD 6.1), for systolic BP readings 6.2 mmHg (SD 8.1), and for diastolic BP readings -4.3 mmHg (SD 6.5). Overestimation of systolic IBP and underestimation of diastolic IBP by the non-invasive measurement were found both in the group with gestational age from 23 to 25.9 weeks and in the group with gestational age from 26 to 27.9 weeks. Systolic NBP readings tended to exceed invasive readings in the range <50 mmHg (bias 9.9 mmHg) whereas diastolic NBP readings were lower than invasive values particularly in the range >30 mmHg (bias -5.5 mmHg)., Conclusion: The disagreement between invasive and non-invasive BP readings in infants extends to the first four weeks of life. Biases differ for mean, systolic and diastolic BP values. Our observation implies that they may depend on the range of the blood pressure. Awareness of these biases and preemptive concomitant use of IBP and NPB readings may contribute to reducing over- or under-treatment., Competing Interests: The authors have declared that no competing interests exist.

Background: Extrauterine life is an important factor when considering brain maturation. Few studies have investigated the development of visual evoked potentials (VEP) in extremely preterm infants, and only a minority have taken into consideration the impact of extrauterine life. The aim of this study was to assess the normal maturation of VEP in infants born prior to 29 weeks gestational age (GA) and to explore the potential influence of extrauterine life., Methods: VEP were prospectively recorded in extremely preterm infants, and principal peaks (N0, N1, P1, N2, P2, N3) were identified. The mean of peak-time and percentages of peak appearances were assessed for three GA groups (23/24, 25/26, 27/28 weeks) and four subgroups of increasing postnatal age (PNA), up to 8 weeks after birth., Results: A total of 163 VEP recordings in 38 preterm infants were analyzed. With increasing GA at birth, peak-times decreased. When comparing infants with equal GA but longer extrauterine life, those with the highest PNA demonstrated the shortest VEP peak-times. However, this effect was less present in infants born prior to 25 weeks GA., Conclusion: Provided that a certain maturational threshold is reached, extrauterine life appears to accelerate maturation of the visual system in preterm infants.

Aim: Less invasive surfactant administration (LISA) has been shown to decrease the risk of death and bronchopulmonary dysplasia in preterm neonates. The LISAcath is the first catheter to be specifically developed for LISA, and we compared the clinical impressions of neonatologists using the LISAcath and the commonly used Angiocath in a simulated setting., Methods: This was a multinational, multicentre study, conducted in October 2016, which involved 39 neonatologists who were recruited by employees of the sponsor from large, well-recognised neonatal intensive care units across Europe. LISA was not the standard of care in these units in Austria, Belgium, Poland, Spain and the United Kingdom at the time of the study. After training, participants simulated LISA on a neonatal manikin, once with the LISAcath and once with Angiocath, then answered a 10-item questionnaire., Results: The responses to nine of 10 questions showed that 67-95% of the respondents preferred the LISAcath to the Angiocath, with most of the remainder indicating no preference. The only exception was the luer connection question, with two-thirds expressing no preference. The LISAcath was considered potentially safer by 33 of 39 participants, with no votes for the Angiocath., Conclusion: Overall, neonatologists preferred using the LISAcath rather than the Angiocath on a neonatal manikin., (©2018 Chiesi Farmaceutici SpA. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Objective: To develop a method for automated neonatal sleep state classification based on EEG that can be applied over a wide range of age., Methods: We collected 231 EEG recordings from 67 infants between 24 and 45weeks of postmenstrual age. Ten minute epochs of 8 channel polysomnography (N=323) from active and quiet sleep were used as a training dataset. We extracted a set of 57 EEG features from the time, frequency, and spatial domains. A greedy algorithm was used to define a reduced feature set to be used in a support vector machine classifier., Results: Performance tests showed that our algorithm was able to classify quiet and active sleep epochs with 85% accuracy, 83% sensitivity, and 87% specificity. The performance was not substantially lowered by reducing the epoch length or EEG channel number. The classifier output was used to construct a novel trend, the sleep state probability index, that improves the visualisation of brain state fluctuations., Conclusions: A robust EEG-based sleep state classifier was developed. It performs consistently well across a large span of postmenstrual ages., Significance: This method enables the visualisation of sleep state in preterm infants which can assist clinical management in the neonatal intensive care unit., (Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Aim: The World Health Organization recommends regular simulation training to prevent adverse healthcare events. We used specially trained medical students to provide paediatric simulation training to their peers and assessed feasibility, cost and confidence of students who attended the courses., Methods: Students at the Medical University of Vienna, Austria were eligible to participate. Students attended two high-fidelity simulation training sessions, delivered by peers, which were videorecorded for evaluation. The attendees then completed questionnaires before and after the training. Associated costs and potential benefits were analysed., Results: From May 2013 to June 2015, 152 students attended the sessions and 57 (37.5%) completed both questionnaires. Satisfaction was high, with 95% stating their peer tutor was competent and 90% saying that peer tutors were well prepared. The attendees' confidence in treating critically ill children significantly improved after training (p < 0.001). The average costs for a peer tutor were six Euros per working hour, compared to 35 Euros for a physician., Conclusion: Using peer tutors for paediatric simulation training was a feasible and low-cost option that increased the number of medical students who could be trained and increased the self-confidence of the attendees. Satisfaction with the peer tutors was high., (©2017 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Context: Fetal/neonatal thyrotoxicosis is a rare but potentially life-threatening condition. It is most commonly observed in poorly controlled Graves disease during pregnancy., Case Description: Here we describe a fetus/newborn patient with thyrotoxicosis who was born of a woman with Hashimoto thyroiditis and levothyroxine-treated hypothyroidism. Transplacental passage of stimulating thyrotropin (TSH) receptor antibodies, which were measured by a cell-based bioassay, was the underlying mechanism of fetal/neonatal thyrotoxicosis, although the mother had no history of hyperthyroidism., Conclusion: Diagnosis and management of fetal hyperthyroidism can be challenging. TSH receptor antibody testing should be considered in pregnant women with any history of autoimmune thyroid disease and symptoms of fetal hyperthyroidism., (Copyright © 2017 by the Endocrine Society)

Background: Filter and peak detection algorithms implemented in amplitude-integrated electroencephalogram (aEEG) systems are not standardized. New aEEG systems are continuously enriching the market and clinicians are faced with different aEEG devices whose tracings may vary., Objectives: The aim of this work was to determine the role of different aEEG systems on quantitative measurements of the aEEG., Methods: In this observational study, a single-channel aEEG recording (Olympic CFM 6000) with corresponding EEG signal was obtained from 32 infants at a gestational age of 36-44 weeks. The signals were split into 334 episodes of 4 h. New aEEG tracings were generated using the NicoletOne Reader Software and aEEG emulations with varying filter profiles and peak detection settings. The aEEG amplitude margins and automated annotation of continuous normal voltage (CNV) were compared., Results: The output of the Olympic and the NicoletOne systems are very similar but not identical; the Spearman rank correlations of the aEEG amplitude margins exceeded 0.9 and the differences in the lower and upper amplitude margins were 1.55 μV (SD 1.47) and -2.12 μV (SD 1.44) on average (n = 309), respectively. The aEEG emulation showed that the differences between the output of the Olympic and the NicoletOne system could be primarily ascribed to the peak detection algorithm. The differences in output can affect automated analyses with agreement rates in CNV detection of 76% (n = 32, positive) and 92% (n = 32, negative) when comparing the Olympic to the NicoletOne outputs., Conclusions: Commercial aEEG systems have similar but not identical outputs. Care is advised when interpreting automated aEEG classifications across different devices., (© 2017 S. Karger AG, Basel.)

Background: Few data have been published on the combined use of amplitude-integrated electroencephalography (aEEG) and near-infrared spectroscopy (NIRS) for outcome prediction in neonates cooled for hypoxic-ischemic encephalopathy (HIE)., Objective: Our aim was to evaluate the predictive values and the most powerful predictive combinations of single aEEG and NIRS parameters and the respective cut-off values with regard to short-term outcomes in HIE II., Methods: aEEG and NIRS were prospectively studied at the Medical University of Vienna in the first 102 h of life with regard to magnetic resonance imaging (MRI). Thirty-two neonates diagnosed with HIE II treated with hypothermia were investigated. The measurement period was divided into 6-h epochs. According to MRI, 2 outcome groups were defined and predictive values of aEEG parameters, regional cerebral oxygen saturation (rScO2), and the additional value of both methods combined were studied. Receiver operating curves (ROC) were obtained and area under the curve (AUC) values were calculated. ROC were then used to detect the optimal cut-off points, sensitivity, specificity, positive predictive values, and negative predictive values., Results: At all time epochs, combined parameter scores were more predictive than single parameter scores. The highest AUC were observed between 18 and 60 h of cooling for the aEEG summation score (0.72-0.84) and for (background pattern + seizures) × rScO2 (0.79-0.85). At 42-60 h sensitivity was similar between those 2 scores (87.5-90.0%), but the addition of NIRS to aEEG led to an increase in specificity (from 52.4-59.1% to 72.7-90.5%)., Conclusions: In HIE II, aEEG and NIRS are important predictors of short-term outcome. The combination of both methods improves prognostication. The highest predictive abilities were observed between 18 and 60 h of cooling., (© 2017 S. Karger AG, Basel.)