Deep Learning Based Prediction of Pulmonary Hypertension in Newborns Using Echocardiograms.

Pulmonary hypertension (PH) in newborns and infants is a complex condition associated with several pulmonary, cardiac, and systemic diseases contributing to morbidity and mortality. Thus, accurate and early detection of PH and the classification of its severity is crucial for appropriate and successful management. Using echocardiography, the primary diagnostic tool in pediatrics, human assessment is both time-consuming and expertise-demanding, raising the need for an automated approach. Little effort has been directed towards automatic assessment of PH using echocardiography, and the few proposed methods only focus on binary PH classification on the adult population. In this work, we present an explainable multi-view video-based deep learning approach to predict and classify the severity of PH for a cohort of 270 newborns using echocardiograms. We use spatio-temporal convolutional architectures for the prediction of PH from each view, and aggregate the predictions of the different views using majority voting. Our results show a mean F1-score of 0.84 for severity prediction and 0.92 for binary detection using 10-fold cross-validation and 0.63 for severity prediction and 0.78 for binary detection on the held-out test set. We complement our predictions with saliency maps and show that the learned model focuses on clinically relevant cardiac structures, motivating its usage in clinical practice. To the best of our knowledge, this is the first work for an automated assessment of PH in newborns using echocardiograms.

Parental knowledge and attitudes to infant immunization in the context of RSV: All about confidence?

BACKGROUND: Recently, the first RSV vaccines have been approved, but vaccine hesitancy still poses great challenges to immunization programs. OBJECTIVE: To investigate this phenomenon in the context of the new RSV vaccines and an increased virus activity in 2022/23, we assessed parental knowledge and attitudes towards general childhood and RSV vaccines. METHODS: Parents of infants from 0-36 months completed an online questionnaire on demographics, socio-economic status, mental well-being, knowledge on RSV and perceptions of disease, attitudes to general childhood and RSV vaccines. The survey was conducted from February-June 2023 in the region of Regensburg, Germany. We compared continuous or categorical data with two-sided t-tests or Chi-square tests, respectively. Linear and logistic regression models were used to adjust for confounders. RESULTS: From 191 survey participants, 84 % had never refused any recommended vaccination and 91 % trusted their paediatrician's information. 11 % felt that children should have fewer vaccinations or rather get over the illness. Parents who were supportive or undecided about RSV vaccination were less likely to be vaccine hesitant in general (OR 0.03, p < 0.001; OR 0.13, p = 0.003). 58 % reported to have basic or good knowledge on RSV, correlating with a higher socioeconomic index (p = 0.049). 24 % were undecided about RSV immunization, while all parents rated its benefit high in the child's first year of life. Parents who refused RSV vaccination were less concerned about the infection compared to vaccine supporters (OR 0.44, p < 0.001). Parents with previously hospitalized (OR 3.88, p = 0.017) or preterm born children (OR 5.12, p = 0.026) were generally more concerned. CONCLUSION: Many factors influence parental decision-making leading to three main groups of attitudes: vaccine acceptors, refusers and hesitant but accessible parents. They (24%) represent the "target group" to increase vaccine uptake. Information on the vaccine-preventable disease reduces vaccine hesitancy, underlining the importance of healthcare professionals who remain an important source of trust.

Europe-wide comparison regarding the first medical examination of the newborn after birth: Absence of uniform standards.

INTRODUCTION: The first medical examination of the newborn after birth plays an essential role in identifying congenital malformations and life-threatening conditions. Currently, no Europe-wide guidelines or standards for performing the first neonatal examination exist. It is unclear which professional group carries out this examination in different European countries. Additionally, there are no requirements for an examination accepted throughout Europe. The objective of this cross-sectional study was to identify the status quo of medical guidelines and legal requirements in place as well as to determine which profession carries out the first neonatal examination in European countries. METHODS: By means of a structured questionnaire, one expert survey at two international medical specialist conferences in Europe in 2019 were carried out. Participants were asked whether medical guidelines or legal requirements exist in their home country and which medical profession is recommended to perform the neonatal examination. Survey participants were delegates of national neonatal or perinatal societies. To verify statements, further neonatal experts at European level were contacted. RESULTS: A total of 51 participants from 35 countries in Europe were interviewed. Overall, 28 of 35 participating countries (80%) have published medical guidelines and 24 (69%) have legal requirements in place for the first neonatal examination. A wide range of professional groups (midwives, neonatologists, pediatricians, obstetricians, general practitioners, nurse practitioners and advanced neonatal nurse practitioners) performs the first neonatal exam. In 27 (77%) countries, midwives are the main group of examiners. CONCLUSIONS: Currently a European patchwork of different medical guidelines and legal requirements in regard to the first medical examination of the newborn after birth exists. In addition, a variety of professional groups perform the first neonatal examination. There is great potential for standardization and an expert committee could establish common European guidelines in order to ensure the best possible neonatal care throughout Europe.

Meeting the need for effective and standardized neonatology training: a pan-European Master's Curriculum.

Neonatology is a pediatric sub-discipline focused on providing care for newborn infants, including healthy newborns, those born prematurely, and those who present with illnesses or malformations requiring medical care. The European Training Requirements (ETR) in Neonatology provide a framework for standardized quality and recognition of equality of training throughout Europe. The latest ETR version was approved by the Union of European Medical Specialists (UEMS) in April 2021. Here, we present the curriculum of the European School of Neonatology Master of Advanced Studies (ESN MAS), which is based on the ETR in Neonatology and aims to provide a model for effective and standardized training and education in neonatal medicine. We review the history and theory that form the foundation of contemporary medical education and training, provide a literature review on best practices for medical training, pediatric training, and neonatology training specifically, including educational frameworks and evidence-based systems of evaluation. The ESN MAS Curriculum is then evaluated in light of these best practices to define its role in meeting the need for a standardized empirically supported neonatology training curriculum for physicians, and in the future for nurses, to improve the quality of neonatal care for all infants. IMPACT STATEMENT: A review of the neonatology training literature was conducted, which concluded that there is a need for standardized neonatology training across international contexts to keep pace with growth in the field and rapidly advancing technology. This article presents the European School of Neonatology Master of Advanced Studies in Neonatology, which is intended to provide a standardized training curriculum for pediatricians and nurses seeking sub-specialization in neonatology. The curriculum is evaluated in light of best practices in medical education, neonatology training, and adult learning theory.

Neurofilament Light Chain Concentration in Cerebrospinal Fluid in Children with Acute Nontraumatic Neurological Disorders.

(1) Introduction: This pilot study aimed to analyze neurofilament light chain levels in cerebrospinal fluid (cNfL) in a cohort of children with different acute nontraumatic neurological conditions. (2) Methods: This prospective observational cohort study consisted of 35 children aged 3 months to 17 years and was performed from November 2017 to December 2019. Patients' clinical data were reviewed, and patients were assigned to the following groups: n = 10 (28.6%) meningitis, 5 (14.3%) Bell's palsy, 7 (20.0%) febrile non-CNS infection, 3 (8.6%) complex febrile seizure, 4 (11.4%) idiopathic intracranial hypertension, and 6 (17.1%) others. cNfL levels were measured using a sensitive single-molecule array assay. (3) Results: The cNfL levels [median (range)] in children with meningitis were 120.5 pg/mL (58.1-205.4), in Bell's palsy 88.6 pg/mL (48.8-144.5), in febrile non-CNS infection 103.9 pg/mL (60.1-210.8), in complex febrile seizure 56 pg/mL (53.2-58.3), and in idiopathic intracranial hypertension 97.1 pg/mL (60.1-124.6). Within the meningitis group, children with Lyme neuroborreliosis (LNB) had significantly higher cNfL concentrations (median 147.9 pg/mL; range 87.8-205.4 pg/mL) than children with enterovirus meningitis (72.5 pg/mL; 58.1-95.6 pg/mL; p = 0.048) and non-significantly higher cNfL levels when compared to Bell's palsy (88.6 pg/mL; 48.8-144.5 pg/mL; p = 0.082). There was no correlation between cNfL levels and age. (4) Conclusions: Although the number of patients in this pilot study cohort is limited, higher cNfL levels in children with LNB compared to those with viral meningitis (significant) and Bell's palsy (trend) may indicate the potential of cNfL as a biomarker in the differential diagnosis of pediatric meningitis and facial palsy.

European Training Requirements in Neonatology 2021: The ESPR, EAP, and UEMS Accredited European Syllabus for Neonatal Training.

INTRODUCTION: The European Union stipulates transnational recognition of professional qualifications for several sectoral professions, including medical doctors. The Union of European Medical Specialists (UEMS), in its "Charter on Training of Medical Specialists," defines the principles for high-level medical training. These principles are manifested in the framework for European Training Requirements (ETR), ensuring medical training reflects modern medical practice and current scientific findings. In 1998, the European Society for Paediatric Research developed the first ETR for Neonatology. We present the ETR Neonatology in its third iteration (ETR III), ratified by the European Academy of Paediatrics (EAP), and approved by UEMS in 2021. METHODS: In generating the ETR III, existing European policy documents on training requirements, including national syllabi and the European Standards of Care for Newborn Health were considered. To ensure the ETR III meets a pan-European standard of expertise in Neonatology, input from representatives from 27 European national paediatric/neonatal societies, and a European parent organisation, was sought. RESULTS: The ETR III summarises the requirements of contemporary training programs in Neonatology and offers a system for accrediting trainers and training centres. We describe the content of the ETR III training syllabus and means of gaining and assessing competency as a medical care provider in Neonatology. CONCLUSION: Graduates of courses following the ETR III Neonatology will obtain a certificate of satisfactory training completion which should be accepted by all European member states as a baseline qualification to practice as a specialist in neonatal medicine, enabling mutual recognition of status throughout Europe.

Vasoactive peptides as biomarkers for the prediction of retinopathy of prematurity.

BACKGROUND: Retinopathy of prematurity (ROP) is a major complication in preterm infants. We assessed if plasma levels of midregional pro-atrial natriuretic peptide (MR-proANP) and C-terminal pro-endothelin-1 (CT-proET1) serve as early markers for subsequent ROP development in preterm infants <32 weeks gestation. METHODS: Prospective, two-centre, observational cohort study. MR-proANP and CT-proET1 were measured on day seven of life. Associations with ROP ≥ stage II were investigated by univariable and multivariable logistic regression models. RESULTS: We included 224 infants born at median (IQR) 29.6 (27.1-30.8) weeks gestation and birth weight of 1160 (860-1435) g. Nineteen patients developed ROP ≥ stage II. MR-proANP and CT-proET1 levels were higher in these infants (median (IQR) 864 (659-1564) pmol/L and 348 (300-382) pmol/L, respectively) compared to infants without ROP (median (IQR) 299 (210-502) pmol/L and 196 (156-268) pmol/L, respectively; both P < 0.001). MR-proANP and CT-proET1 levels were significantly associated with ROP ≥ stage II in univariable logistic regression models and after adjusting for co-factors, including gestational age and birth weight z-score. CONCLUSIONS: MR-proANP and CT-proET1 measured on day seven of life are strongly associated with ROP ≥ stage II in very preterm infants and might improve early prediction of ROP in the future. IMPACT: Plasma levels of midregional pro-atrial natriuretic peptide and C-terminal pro-endothelin-1 measured on day seven of life in very preterm infants show a strong association with development of retinopathy of prematurity ≥ stage II. Both biomarkers have the potential to improve early prediction of retinopathy of prematurity. Vasoactive peptides might allow to reduce the proportion of screened infants substantially.

Pancreatic Insufficiency, Digestive Enzyme Supplementation, and Postnatal Growth in Preterm Babies.

BACKGROUND: Optimising postnatal growth facilitates better long-term neonatal neurodevelopmental outcomes. Early postnatal growth is often hindered by a variety of factors unique to the extrauterine environment and digestive immaturity both contributing to reduced enteral feed tolerance during the first few days and weeks after birth. Preterm infants display varying levels of pancreatic insufficiency that are related to gestational age and providing digestive enzyme supplementation, may be one way in which to improve postnatal growth in enterally fed preterm babies. SUMMARY: In this review, we explore which exocrine pancreatic enzymes are deficient in preterm babies, the methods by which exocrine pancreatic function is measured, potential avenues by which digestive enzyme replacement might improve postnatal growth failure, and which babies might benefit most from this intervention. KEY MESSAGES: Pancreatic exocrine function exhibits developmental immaturity in extremely preterm infants and may contribute to postnatal growth failure. Stool elastase is a simple, non-invasive method of assessing pancreatic function in preterm infants. Available evidence does not currently support routine use of digestive enzyme supplementation in preterm infants.

Directed acyclic graph for epidemiological studies in childhood food allergy: Construction, user's guide, and application.

Understanding modifiable prenatal and early life causal determinants of food allergy is important for the prevention of the disease. Randomized clinical trials studying environmental and dietary determinants of food allergy may not always be feasible. Identifying risk/protective factors for early-life food allergy often relies on observational studies, which may be affected by confounding bias. The directed acyclic graph (DAG) is a causal diagram useful to guide causal inference from observational epidemiological research. To date, research on food allergy has made little use of this promising method. We performed a literature review of existing evidence with a systematic search, synthesized 32 known risk/protective factors, and constructed a comprehensive DAG for early-life food allergy development. We present an easy-to-use online tool for researchers to re-construct, amend, and modify the DAG along with a user's guide to minimize confounding bias. We estimated that adjustment strategies in 57% of previous observational studies on modifiable factors of childhood food allergy could be improved if the researchers determined their adjustment sets by DAG. Future researchers who are interested in the causal inference of food allergy development in early life can apply the DAG to identify covariates that should and should not be controlled in observational studies.

Interpretable and intervenable ultrasonography-based machine learning models for pediatric appendicitis.

Appendicitis is among the most frequent reasons for pediatric abdominal surgeries. Previous decision support systems for appendicitis have focused on clinical, laboratory, scoring, and computed tomography data and have ignored abdominal ultrasound, despite its noninvasive nature and widespread availability. In this work, we present interpretable machine learning models for predicting the diagnosis, management and severity of suspected appendicitis using ultrasound images. Our approach utilizes concept bottleneck models (CBM) that facilitate interpretation and interaction with high-level concepts understandable to clinicians. Furthermore, we extend CBMs to prediction problems with multiple views and incomplete concept sets. Our models were trained on a dataset comprising 579 pediatric patients with 1709 ultrasound images accompanied by clinical and laboratory data. Results show that our proposed method enables clinicians to utilize a human-understandable and intervenable predictive model without compromising performance or requiring time-consuming image annotation when deployed. For predicting the diagnosis, the extended multiview CBM attained an AUROC of 0.80 and an AUPR of 0.92, performing comparably to similar black-box neural networks trained and tested on the same dataset.

Management of preterm labor: Clinical practice guideline and recommendation by the WAPM-World Association of Perinatal Medicine and the PMF-Perinatal Medicine Foundation.

This practice guideline follows the mission of the World Association of Perinatal Medicine in collaboration with the Perinatal Medicine Foundation, bringing together groups and individuals throughout the world, with the goal of improving the management of preterm labor. In fact, this document provides further guidance for healthcare practitioners on the appropriate use of examinations with the aim to improve the accuracy in diagnosing preterm labor and allow timely and appropriate administration of tocolytics, antenatal corticosteroids and magnesium sulphate and avoid unnecessary or excessive interventions. Therefore, it is not intended to establish a legal standard of care. This document is based on consensus among perinatal experts throughout the world in the light of scientific literature and serves as a guideline for use in clinical practice.

Validating the early phototherapy prediction tool across cohorts.

Background: Hyperbilirubinemia of the newborn infant is a common disease worldwide. However, recognized early and treated appropriately, it typically remains innocuous. We recently developed an early phototherapy prediction tool (EPPT) by means of machine learning (ML) utilizing just one bilirubin measurement and few clinical variables. The aim of this study is to test applicability and performance of the EPPT on a new patient cohort from a different population. Materials and methods: This work is a retrospective study of prospectively recorded neonatal data from infants born in 2018 in an academic hospital, Regensburg, Germany, meeting the following inclusion criteria: born with 34 completed weeks of gestation or more, at least two total serum bilirubin (TSB) measurement prior to phototherapy. First, the original EPPT-an ensemble of a logistic regression and a random forest-was used in its freely accessible version and evaluated in terms of the area under the receiver operating characteristic curve (AUROC). Second, a new version of the EPPT model was re-trained on the data from the new cohort. Third, the predictive performance, variable importance, sensitivity and specificity were analyzed and compared across the original and re-trained models. Results: In total, 1,109 neonates were included with a median (IQR) gestational age of 38.4 (36.6-39.9) and a total of 3,940 bilirubin measurements prior to any phototherapy treatment, which was required in 154 neonates (13.9%). For the phototherapy treatment prediction, the original EPPT achieved a predictive performance of 84.6% AUROC on the new cohort. After re-training the model on a subset of the new dataset, 88.8% AUROC was achieved as evaluated by cross validation. The same five variables as for the original model were found to be most important for the prediction on the new cohort, namely gestational age at birth, birth weight, bilirubin to weight ratio, hours since birth, bilirubin value. Discussion: The individual risk for treatment requirement in neonatal hyperbilirubinemia is robustly predictable in different patient cohorts with a previously developed ML tool (EPPT) demanding just one TSB value and only four clinical parameters. Further prospective validation studies are needed to develop an effective and safe clinical decision support system.

Effect of QT interval-prolonging drugs taken in pregnancy on the neonatal QT interval.

Introduction: Acquired QT interval prolongations due to drug side effects can result in detrimental arrhythmia. Maternal use of placenta-permeable drugs may lead to fetal exposure, thus leading to an increased risk of neonatal QT prolongation and arrhythmia. Objectives: This study aimed to evaluate the influence of maternal QT-prolonging medication on the neonatal QT interval. Methods: In the prospective KUNO-Kids health study, an ongoing population-based birth cohort, we classified maternal medications according to the known risk of QT interval prolongation. Effects on the neonatal QT interval were tested by linear regression analyses, correcting for perinatal confounders (birth weight, gestational age, birth mode, and age at ECG recording). Subgroup analyses were performed for selective serotonin reuptake inhibitors, proton pump inhibitors, and antihistamine dimenhydrinate. Logistic regression analysis was performed using a QTc of 450 ms as the cut-off value. Results: A total of 2,550 pregnant women received a total of 3,990 medications, of which 315 were known to increase the risk of QT prolongation, resulting in 105 (4.1%) neonates exposed in the last month of pregnancy. Overall, the mean age of the neonates at ECG was 1.9 days and the mean QTc (Bazett) was 414 ms. Univariate (regression coefficient -2.62, p = 0.288) and multivariate (regression coefficient -3.55, p = 0.146) regression analyses showed no significant effect of fetal medication exposure on the neonatal QT interval, neither in the overall nor in the subgroup analysis. Logistic regression analysis showed no association of exposure to maternal medication with an increased risk of neonatal QT interval prolongation (OR (odds ratio) 0.34, p = 0.14). Conclusion: The currently used maternal medication results in a relevant number of fetuses exposed to QT interval-prolonging drugs. In our cohort, exposure was found to have no effect on the neonatal QT interval.

[Operating models and organizational structures: opportunities and challenges for human milk banking in Germany]. / Versorgungsstrukturen und Betreibermodelle: Chancen und Herausforderungen des Frauenmilchbankwesens in Deutschland.

BACKGROUND: Donor human milk is the recommended alternative for feeding preterm infants if mother's own milk is unavailable. Human milk banks collect, screen, store and distribute donated human milk according to pre-specified standard operating procedures to premature infants without mothers own milk. AIM: Herein we characterize current operating models and the structural organisation of German milk bank institutions. The analysis of current and future opportunities and challenges may support the development of a comprehensive donor milk service within Germany. MATERIAL AND METHODS: Summary of the panel discussion entitled "Operating models and organizational structures: opportunities and risks for donor human milk bank in Germany" during the 3rd Scientific Symposium of the German Human Milk Bank Initiative (FMBI), November 25th to 26th 2022, in Nuremberg, Germany. RESULTS AND DISCUSSION: Differing operator models may facilitate the use of donor human milk by incorporating unique site-specific factors, pre-existing infrastructure, and individual needs. In addition to the establishment of milk banks serving single neonatal units, high-capacity milk banks should be enabled to provide donor human milk using several hub-and-spoke systems. This may create a nationwide network for a sustainable human milk supply for preterm infants that is based on qualified breastfeeding and lactation support.

Serum neurofilament light chain reference database for individual application in paediatric care: a retrospective modelling and validation study.

BACKGROUND: Neurological conditions represent an important driver of paediatric disability burden worldwide. Measurement of serum neurofilament light chain (sNfL) concentrations, a specific marker of neuroaxonal injury, has the potential to contribute to the management of children with such conditions. In this context, the European Medicines Agency recently declared age-adjusted reference values for sNfL a top research priority. We aimed to establish an age-adjusted sNfL reference range database in a population of healthy children and adolescents, and to validate this database in paediatric patients with neurological conditions to affirm its clinical applicability. METHODS: To generate a paediatric sNfL reference dataset, sNfL values were measured in a population of healthy children and adolescents (aged 0-22 years) from two large cohorts in Europe (the Coronavirus Antibodies in Kids from Bavaria study, Germany) and North America (a US Network of Paediatric Multiple Sclerosis Centers paediatric case-control cohort). Children with active or previous COVID-19 infection or SARS-CoV-2 antibody positivity at the time of sampling, or a history of primary systemic or neurological conditions were excluded. Linear models were used to restrospectively study the effect of age and weight on sNfL concentrations. We modelled the distribution of sNfL concentrations as a function of age-related physiological changes to derive reference percentile and Z score values via a generalised additive model for location, scale, and shape. The clinical utility of the new reference dataset was assessed in children and adolescents (aged 1-19 years) with neurological diseases (epilepsy, traumatic brain injury, bacterial CNS infections, paediatric-onset multiple sclerosis, and myelin oligodendrocyte glycoprotein antibody-associated disease) from the paediatric neuroimmunology clinic at the University of California San Francisco (San Francisco, CA, USA) and the Children's Hospital of the University of Regensburg (Regensburg, Germany). FINDINGS: Samples from 2667 healthy children and adolescents (1336 [50·1%] girls and 1331 [49·9%] boys; median age 8·0 years [IQR 4·0-12·0]) were used to generate the reference database covering neonatal age to adolescence (target age range 0-20 years). In the healthy population, sNfL concentrations decreased with age by an estimated 6·8% per year until age 10·3 years (estimated multiplicative effect per 1 year increase 0·93 [95% CI 0·93-0·94], p<0·0001) and was mostly stable thereafter up to age 22 years (1·00 [0·52-1·94], p>0·99). Independent of age, the magnitude of the effect of weight on sNfL concentrations was marginal. Samples from 220 children with neurological conditions (134 [60·9%] girls and 86 [39·1%] boys; median age 14·7 years [IQR 10·8-16·5]) were used to validate the clinical utility of the reference Z scores. In this population, age-adjusted sNfL Z scores were higher than in the reference population of healthy children and adolescents (p<0·0001) with higher effect size metrics (Cohen's d=1·56) compared with the application of raw sNfL concentrations (d=1·28). INTERPRETATION: The established normative sNfL values in children and adolescents provide a foundation for the clinical application of sNfL in the paediatric population. Compared with absolute sNfL values, the use of sNfL Z score was associated with higher effect size metrics and allowed for more accurate estimation of the extent of ongoing neuroaxonal damage in individual patients. FUNDING: Swiss National Science Foundation, US National Institutes of Health, and the National Multiple Sclerosis Society.

Serum Neurofilament light chain (NfL) levels in children with and without neurologic diseases.

BACKGROUND/OBJECTIVE: Serum neurofilament light chain (sNfL) is a specific biomarker of neuronal damage. Elevated sNfL levels have been reported in numerous neurologic diseases in adults, whereas data on sNfL in the pediatric population are incomplete. The aim of this study was to investigate sNfL levels in children with various acute and chronic neurologic disorders and describe the age dependence of sNfL from infancy to adolescence. METHODS: The total study cohort of this prospective cross-sectional study consisted of 222 children aged from 0 to 17 years. Patients' clinical data were reviewed and patients were assigned to the following groups: 101 (45.5%) controls, 34 (15.3%) febrile controls, 23 (10.4%) acute neurologic conditions (meningitis, facial nerve palsy, traumatic brain injury, or shunt dysfunction in hydrocephalus), 37 (16.7%) febrile seizures, 6 (2.7%) epileptic seizures, 18 (8.1%) chronic neurologic conditions (autism, cerebral palsy, inborn mitochondrial disorder, intracranial hypertension, spina bifida, or chromosomal abnormalities), and 3 (1.4%) severe systemic disease. sNfL levels were measured using a sensitive single-molecule array assay. RESULTS: There were no significant differences in sNfL levels between controls, febrile controls, febrile seizures, epileptic seizures, acute neurologic conditions, and chronic neurologic conditions. In children with severe systemic disorders, by far the highest NfL levels were found with an sNfL of 429 pg/ml in a patient with neuroblastoma, 126 pg/ml in a patient with cranial nerve palsy and pharyngeal Burkitt's lymphoma, and 42 pg/ml in a child with renal transplant rejection. The relationship between sNfL and age could be described by a second order polynomial with an R2 of 0.153 with a decrease of sNfL by 3.2% per year from birth to age 12 years and thereafter an increase by 2.7% per year until age 18 years. CONCLUSIONS: In this study cohort, sNfL levels were not elevated in children with febrile or epileptic seizures, or various other neurologic diseases. Strikingly high sNfL levels were detected in children with oncologic disease or transplant rejection. A biphasic sNfL age-dependency was documented, with highest levels in infancy and late adolescence and the lowest levels in middle school age.

Stem-cell therapy in neonates - an option?

Within the fast-growing field of regenerative medicine stem-cell therapy is well established in various hematologic and immunologic diseases and has received a recent substantial boost from the introduction of gene editing and gene transfer technologies. In neonates, for example, regenerative medicine may benefit those with congenital or acquired disease due to prematurity or perinatal hypoxia-ischemia. We compare and contrast the two main approaches - autologous vs. allogeneic - and summarize the recent advances and applications of interventional stem-cell research in perinatally acquired disorders such as intraventricular hemorrhage, hypoxia-ischemia and stroke. After discussing stem-cell sources and routes of administration, we conclude by highlighting the key opportunities and obstacles in this exciting field.

Safety and Short-term Outcomes of High-Dose Erythropoietin in Preterm Infants With Intraventricular Hemorrhage: The EpoRepair Randomized Clinical Trial.

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.

Vaginal Delivery Is Associated with Neurochemical Evidence of Increased Neuroaxonal Remodelling in Infants from the KUNO-Kids Health Study: Cross-Sectional Analysis.

AIM: Little is known about neonatal brain plasticity or the impact of birth mode on neurointegrity. As a reflection of neuroaxonal damage, the neuronal structural protein neurofilament light chain (NfL) has emerged as a highly specific biomarker. Our purpose was to test the hypothesis that vaginal delivery is associated with increased NfL in neonates. METHODS: NfL concentrations were measured using single-molecule array immunoassay in umbilical cord serum from healthy term neonates enrolled in the prospective KUNO-Kids Health Study. NfL values were investigated for independent influencing factors using linear and logistic models, followed by post hoc propensity score-matching. RESULTS: Of 665 neonates, n = 470 (70.7%) were delivered vaginally and n = 195 (29.3%) by cesarean section. Median serum NfL was significantly higher after vaginal delivery 14.4 pg/mL (11.6-18.5) compared to primary 7.5 pg/mL (6.1-8.9) and secondary cesarean delivery 9.3 pg/mL (7.5-12.0). Multivariable logistic regression models showed delivery mode and gestational age to be independently associated with NfL. Propensity score-matching analysis confirmed that assisted vaginal delivery generated higher NfL compared to vaginal (non-assisted), while lowest levels were associated with cesarean section. INTERPRETATION: Our data confirm the significant impact of birth mode on neonatal NfL levels. The persistence of these differences and their potential long-term impact have yet to be investigated.