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AimNeurofilament light Chain (NfL) is a promising brain injury biomarker which may assist diagnosis and prognostication in hypoxic-ischemic encephalopathy (HIE). The aim of this study was to investigate serum NfL levels after hypoxia-ischemia (HI) in a newborn piglet model. Second, to characterize the influence of sex, weight, and treatment with remote ischemic postconditioning (RIPC) on NfL and the correlation between NfL, brain imaging and histologic brain injury.MethodsWe used serum from 48 newborn piglets of both sexes subjected to 45 min of global HI, and 4 sham piglets. Blood was collected pre-HI, 2 h post-HI and 72 h post-HI. NfL was measured by single-molecule array (Simoa™). We analysed the temporal profile of NfL after HI, and correlations between NfL, magnetic resonance spectroscopy brain Lac/NAA ratios and histologic brain injury 72 h after HI.ResultsMedian (IQR) NfL levels were: pre-HI: 66 pg/ml (45–87), 2 h post-HI: 105 pg/ml (77–140), and 72 h post-HI: 380 pg/ml (202–552). The increase in NfL after HI was statistically significant (p p = 0.11, paired t-test). Neither sex, nor treatment with RIPC influenced NfL levels. Weight had a small, not biologically important, influence. NfL levels at 72 h were moderately correlated with histologic brain injury and brain Lac/NAA ratios. NfL 72 h post-HI > 330 pg/ml had a sensitivity of 89% (95% CI, 57%–99%) and a specificity of 52% (95% CI, 34%–69%) for predicting basal ganglia Lac/NAA ratio in the highest quartile. NfL 72 h post-HI > 445 pg/ml had a sensitivity of 90% (95% CI, 60%–99%) and a specificity of 74% (95% CI, 58%–86%) for predicting cortical brain histopathology injury in the highest quartile.ConclusionNfL increased after HI, with the largest values at 72 h post-HI. Early NfL was sensitive but not very specific, whereas NfL at 72 h was both highly sensitive and specific for exposure to moderate-severe HI in this model of HI-induced brain injury. This was supported by a moderate correlation of NfL at 72 h with brain Lac/NAA ratio and histopathology.

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.

Background Perinatal arterial ischemic stroke (PAIS) is a neurologic disorder leading to long-term complications. Mesenchymal stem cells (MSCs) have emerged as a novel therapeutic agent. This systematic review aims to determine the effects of stem cell-based interventions for the treatment of PAIS in preclinical studies. Methods We included all controlled studies on MSCs in neonatal animals with PAIS. Functional outcome was the primary outcome. The literature search was performed in February 2021. Results In the 20 included studies, MSCs were most frequently delivered via intracerebral injection (n = 9), 3 days after the induction of PAIS (n = 8), at a dose ranging from 5 × 104 to 5 × 106 cells. The meta-analysis showed an improvement on the cylinder rearing test (MD: −10.62; 95% CI: −14.38 to −6.86) and on the water maze test (MD: 1.31 MD; 95% CI: 0.80 to 1.81) in animals treated with MSCs compared to the control group animals. Conclusion MSCs appear to improve sensorimotor and cognitive performance in PAIS-injured animals; however, the certainty of the evidence is low. Registration of the protocol of preclinical studies, appropriate sample size calculation, rigorous randomization, and reporting of the data on animal sex and survival are warranted. PROSPERO registration number: CRD42021239642. Impact This is the first systematic review and meta-analysis of preclinical studies investigating the effects of MSCs in an experimental model of PAIS. MSCs appear to improve sensorimotor and cognitive performance in PAIS-injured neonatal animals. The certainty of the evidence is low due to high or unclear risk of bias in most domains.

Background: Newborns delivered by elective cesarean section (CS) are at higher respiratory risk than those delivered vaginally or by CS proceeded by labor (secondary CS). The oxytocin challenge test (OCT) induces uterine contractions that trigger the release of fetal hormones regulating lung fluid clearance during transition from the uterine to an air-breathing environment. Objectives: The aim is to summarize current evidence and outline the Lacarus trial protocol. Methods: Literature review informed the design of a randomized placebo-controlled multicenter trial of OCT preceding elective CS in 1,450 women with a singleton pregnancy due for CS at >35 weeks gestation, without preceding contractions, rupture of the membranes, or antenatal steroids. OCT comprises the infusion of oxytocin 5 IU/500 mL Ringer lactate at a rate of 12 mL/h, doubling every 10 min until inducing 5 uterine contractions per 15-min interval. The primary endpoint is the occurrence of neonatal respiratory morbidity within 24 h after birth. Secondary endpoints include biochemical and physiological parameters of fetal and maternal well-being, such as breastfeeding rate and fetal plasma copeptin concentrations. Conclusion: This is the first trial to test the hypothesis that oxytocin-induced contractions before elective CS is a promising application of physiologic principles gleaned from natural birth to improve neonatal and maternal outcomes.

The coronavirus disease 2019 (COVID‐19) caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) appears milder in children but little is known about neonates and about the chains of infections after delivery.1‐3 When in early March 2020 a midwife in our large maternity and perinatal center returned from vacation in Ischgl, Austria, she triggered a COVID‐19 outbreak affecting 36 midwives, nurses and doctors. We reported previously on the successful containment of this outbreak and characterized the clinical symptoms and immunoglobulin development in staff members exposed to SARS‐CoV‐2.4‐5

With increasing number of SARS‐CoV‐2 infections and COVID‐19 patients to be taken care of by the health system, more and more health workers become affected by the disease. It has been reported that right from the beginning of the outbreak in Lombardy up to 20% of the doctors and nurses became infected. Under these circumstances, the regular operation of health institutions already suffering from a shortage of staff becomes difficult. This has led to complete or partial shutdowns of hospitals, either due to a lack of uninfected personnel or because of uncontrollable chains of infection endangering patients. In one of the largest university perinatal center in Bavaria with more than 3000 births per year, an outbreak of COVID‐19 occurred in March 2020, affecting 36 staff members, including doctors, nurses, and midwives. Here, we describe the outbreak and present the measures contributing to the successful containment of the outbreak within three weeks. At the same time, clinical services could be maintained, however, not without deployment of personnel exposed to employees infected with SARS‐CoV‐2. Apart from massive testing of personnel in pre‐defined phases and increased hygiene measures, including a general obligation to wear surgical face masks, we identified the need to monitor cases of illness across all groups of employees, to ensure social distancing within personnel and to evaluate contacts of clinical personnel outside of the hospital environment, in order to be able to interpret chains of infections and to disrupt them. Overall, only a bundle of measures is needed to contain such an outbreak.

Background: Current strategies for risk stratification and prediction of neonatal early-onset sepsis (EOS) are inefficient and lack diagnostic performance. The aim of this study was to use machine learning to analyze the diagnostic accuracy of risk factors (RFs), clinical signs and biomarkers and to develop a prediction model for culture-proven EOS. We hypothesized that the contribution to diagnostic accuracy of biomarkers is higher than of RFs or clinical signs.Study Design: Secondary analysis of the prospective international multicenter NeoPInS study. Neonates born after completed 34 weeks of gestation with antibiotic therapy due to suspected EOS within the first 72 hours of life participated. Primary outcome was defined as predictive performance for culture-proven EOS with variables known at the start of antibiotic therapy. Machine learning was used in form of a random forest classifier.Results: One thousand six hundred eighty-five neonates treated for suspected infection were analyzed. Biomarkers were superior to clinical signs and RFs for prediction of culture-proven EOS. C-reactive protein and white blood cells were most important for the prediction of the culture result. Our full model achieved an area-under-the-receiver-operating-characteristic-curve of 83.41% (±8.8%) and an area-under-the-precision-recall-curve of 28.42% (±11.5%). The predictive performance of the model with RFs alone was comparable with random.Conclusions: Biomarkers have to be considered in algorithms for the management of neonates suspected of EOS. A 2-step approach with a screening tool for all neonates in combination with our model in the preselected population with an increased risk for EOS may have the potential to reduce the start of unnecessary antibiotics.

Observational studies demonstrating reduced rates of infections, necrotizing enterocolitis (NEC), and mortality in preterm infants fed their own mother's milk, as opposed to formula, have prompted endeavors to achieve similar effects with the right choice of food and food additives. In a systematic review of meta-analyses and randomized controlled trials (RCTs), we considered nutritional interventions aimed at reducing the rates of infections, NEC, or mortality in very preterm infants. The overall effects of particular interventions were presented as risk ratios with 95% confidence intervals. In RCTs, pasteurized human donor milk, as opposed to formula, reduced NEC but not infections or mortality. No differences emerged between infants receiving human or bovine milk-based fortifiers. Pooled data of small trials and a recent large RCT suggested that bovine lactoferrin reduced rates of fungal sepsis without impact on other infections, NEC, or mortality. Pooled data of RCTs assessing the use of prebiotic oligosaccharides found reduced infection but not mortality. Enteral L-glutamine (six RCTs) lowered infection rates, and enteral L-arginine (three RCTs) reduced NEC. A meta-analysis sensitivity approach found multiple-strain (but not single-strain) probiotics to be highly effective in reducing NEC and mortality. Thus, selected food components may help to improve outcomes in preterm infants.

Background: Given the absence of consolidated and standardized international guidelines for managing pediatric appendicitis and the few strictly data-driven studies in this specific, we investigated the use of machine learning (ML) classifiers for predicting the diagnosis, management and severity of appendicitis in children. Materials and Methods: Predictive models were developed and validated on a dataset acquired from 430 children and adolescents aged 0-18 years, based on a range of information encompassing history, clinical examination, laboratory parameters, and abdominal ultrasonography. Logistic regression, random forests, and gradient boosting machines were used for predicting the three target variables. Results: A random forest classifier achieved areas under the precision-recall curve of 0.94, 0.92, and 0.70, respectively, for the diagnosis, management, and severity of appendicitis. We identified smaller subsets of 6, 17, and 18 predictors for each of targets that sufficed to achieve the same performance as the model based on the full set of 38 variables. We used these findings to develop the user-friendly online Appendicitis Prediction Tool for children with suspected appendicitis. Discussion: This pilot study considered the most extensive set of predictor and target variables to date and is the first to simultaneously predict all three targets in children: diagnosis, management, and severity. Moreover, this study presents the first ML model for appendicitis that was deployed as an open access easy-to-use online tool. Conclusion: ML algorithms help to overcome the diagnostic and management challenges posed by appendicitis in children and pave the way toward a more personalized approach to medical decision-making. Further validation studies are needed to develop a finished clinical decision support system., Frontiers in Pediatrics, 9, ISSN:2296-2360

There is a lack of diagnostic tools for early risk stratification of cognitive outcome in infants born preterm and infants with asphyxia. Using auditory event-related potentials and mismatch response, we aimed to assess possible differences in early attention and learning, as a marker for brain maturation to subsequently improve the allocation of early neurodevelopmental support.This cross-sectional study included 22 very preterm infants (gestational age (GA)32 weeks), eight term infants with asphyxia and 35 healthy term infants. An auditory oddball-paradigm with three consecutive stimulation blocks, separated by a two-minute break, was used as a cognitive discrimination task to assess attention and habituation.The peak-to-peak analysis in the group comparisons showed no significant differences for the first stimulation block. In term healthy infants and term infants after asphyxia, no significant differences were found in amplitudes between block one and three. Preterm infants showed significantly (We found no differences in the auditory attention paradigm between preterm or term asphyxic and control infants when they were evaluated at term corrected age. Most infants did not show any electrophysiologically measurable learning effect indicating habituation or dishabituation. The small sample size of this study is a clear limitation. Therefore, the results must be evaluated with caution, especially regarding their potential predictive value for future cognitive development of infants with a developmental risk. However, our study underlines the possibility of an electrophysiological evaluation as a feasible tool to assess very early cognition in infants.

Background Bronchopulmonary dysplasia (BPD) is a major complication in preterm infants Methods This was a prospective, two-center, observational cohort study. MR-proANP and CT-proET-1 were measured at day 7 (±2) of life. Associations with duration of supplemental oxygen and the composite outcome of moderate or severe BPD or death (BPD/death) were investigated. Results Two hundred and twenty-nine infants p p p = 0.015) compared to infants without BPD/death. Levels of both biomarkers were significantly associated with BPD/death in univariable models but not after adjusting for co-factors. Conclusions MR-proANP and CT-proET-1 are associated with the duration of supplemental oxygen and the composite outcome BPD/death, but their prognostic value does not complement that of clinical risk factors. Impact Plasma levels of MR-proANP and CT-proET-1, measured on day 7 of life (±2 days) are associated in univariable analyses with duration of supplemental oxygen and the combined outcome of BPD or death in VLGA infants. Associations between both biomarkers and respiratory morbidity do not persist in multivariable models, in particular when gestational age is included. MR-proANP and CT-proET-1 have limited additional value to predict respiratory morbidity in VLGA infants compared to clinical parameters.

Machine learning models may enhance the early detection of clinically relevant hyperbilirubinemia based on patient information available in every hospital. We conducted a longitudinal study on preterm and term born neonates with serial measurements of total serum bilirubin in the first two weeks of life. An ensemble, that combines a logistic regression with a random forest classifier, was trained to discriminate between the two classes phototherapy treatment vs. no treatment. Of 362 neonates included in this study, 98 had a phototherapy treatment, which our model was able to predict up to 48 h in advance with an area under the ROC-curve of 95.20%. From a set of 44 variables, including potential laboratory and clinical confounders, a subset of just four (bilirubin, weight, gestational age, hours since birth) suffices for a strong predictive performance. The resulting early phototherapy prediction tool (EPPT) is provided as an open web application. Early detection of clinically relevant hyperbilirubinemia can be enhanced by the application of machine learning. Existing guidelines can be further improved to optimize timing of bilirubin measurements to avoid toxic hyperbilirubinemia in high-risk patients while minimizing unneeded measurements in neonates who are at low risk.

BACKGROUND Therapeutic hypothermia following hypoxic ischaemic encephalopathy in term infants was introduced into Switzerland in 2005. Initial documentation of perinatal and resuscitation details was poor and neuromonitoring insufficient. In 2011, a National Asphyxia and Cooling Register was introduced. AIMS To compare management of cooled infants before and after introduction of the register concerning documentation, neuromonitoring, cooling methods and evaluation of temperature variability between cooling methods. STUDY DESIGN Data of cooled infants before the register was in place (first time period: 2005-2010) and afterwards (second time period: 2011-2012) was collected with a case report form. RESULTS 150 infants were cooled during the first time period and 97 during the second time period. Most infants were cooled passively or passively with gel packs during both time periods (82% in 2005-2010 vs 70% in 2011-2012), however more infants were cooled actively during the second time period (18% versus 30%). Overall there was a significant reduction in temperature variability (p < 0.001) comparing the two time periods. A significantly higher proportion of temperature measurements within target temperature range (72% versus 77%, p < 0.001), fewer temperature measurements above (24% versus 7%, p < 0.001) and more temperatures below target range (4% versus 16%, p < 0.001) were recorded during the second time period. Neuromonitoring improved after introduction of the cooling register. CONCLUSION Management of infants with HIE improved since introducing the register. Temperature variability was reduced, more temperature measurements in the target range and fewer temperature measurements above target range were observed. Neuromonitoring has improved, however imaging should be performed more often.

Background: Preterm infants suffering from intraventricular hemorrhage (IVH) are at increased risk for neurodevelopmental impairment. Observational data suggest that recombinant human erythropoietin (rEPO) improves long-term cognitive outcome in infants with IVH. Recent studies revealed a beneficial effect of early high-dose rEPO on white matter development in preterm infants determined by magnetic resonance imaging (MRI). Objectives: To summarize the current evidence and to delineate the study protocol of the EpoRepair trial (Erythropoietin for the Repair of Cerebral Injury in Very Preterm Infants). Methods: The study involves a review of the literature and the design of a double-blind, placebo-controlled, multicenter trial of repetitive high-dose rEPO administration, enrolling 120 very preterm infants with moderate-to-severe IVH diagnosed by cranial ultrasound in the first days of life, qualitative and quantitative MRI at term-equivalent age and long-term neurodevelopmental follow-up until 5 years of age. Results and Conclusions: The hypothesis generated by observational data that rEPO may improve long-term cognitive outcomes of preterm infants suffering from IVH are to be confirmed or refuted by the randomized controlled trial, EpoRepair.

Background and PurposeSerum neurofilament light chain (sNfL) has recently emerged as a promising biomarker reflecting structural neuro-axonal damage in different neurological diseases. Our study aimed at assessing whether sNfL can predict the functional outcome in preterm infants who suffered from neonatal haemorrhagic brain injury.MethodsIn this prospective observational study, we used an ultrasensitive single-molecule array assay to measure serum and cerebrospinal fluid (CSF) concentrations of NfL in preterm infants diagnosed with intraventricular haemorrhage (IVH) in the first few days of life. We determined the temporal profile of serum and CSF NfL levels from first diagnosis of IVH until term equivalent age, their association with cerebral imaging markers, and with clinical and functional outcome until 2 years of age assessed by Bayley Scales of Infant Development. We fitted univariable and multivariable logistic regression models to determine risk factors for low motor and cognitive development. Longitudinal mixed effects models modelled NfL levels using cubic spline smoothers to track the trajectory over time.ResultsThe study included 48 infants born with less than 32 weeks of gestation. At the time point of IVH diagnosis, NfL median levels were 271.9 pg/mL (IQR 151.2–389.7), and strongly decreased until term equivalent age to 15.7 pg/mL (IQR 11.1–32.2). CSF values were 113-fold higher (IQR 40–211) than corresponding serum values. Additional cerebral infarction (n=23) but not post-haemorrhagic hydrocephalus with permanent external ventricular drainage (n=29) or other diseases independently determined sNfL levels. In multivariate logistic regression models, the only significant predictor of poor motor outcome at 2 years or death was sNfL level (p=0.02).There was a clear difference between the NfL trajectory for those with poor motor outcome at 1 year.ConclusionsThis study shows that early sNfL is an independent prognostic biomarker for motor functional outcome in preterm infants after IVH.Disclosure(s)Nothing to disclose

Arginine vasopressin (AVP) plays a major role in the homeostasis of fluid balance, vascular tonus, and the regulation of the endocrine stress response. The measurement of AVP levels is difficult due to its short half-life and laborious method of detection. Copeptin is a more stable peptide derived from the same precursor molecule, is released in an equimolar ratio to AVP, and has a very similar response to osmotic, hemodynamic, and stress-related stimuli. In fact, copeptin has been propagated as surrogate marker to indirectly determine circulating AVP concentrations in various conditions. Here, we present an overview of the current knowledge on AVP and copeptin in perinatology with a particular focus on the baby’s transition from placenta to lung breathing. We performed a systematic review of the literature on fetal stress hormone levels, including norepinephrine, cortisol, AVP, and copeptin, in regard to birth stress. Finally, diagnostic and therapeutic options for copeptin measurement and AVP functions are discussed.

Adrenomedullin (ADM) is one of the strongest endogenous vasodilating hormones. Its stable by-product midregional-proADM (MR-proADM) is an established indicator of systemic infection and cardiovascular compromise in adult patients.A prospective cross-sectional study was performed to investigate the perinatal factors affecting MR-proADM plasma concentrations in 328 newborn infants with a gestational age (GA) between 24 and 41 wk.Blood samples were obtained in 270 infants from umbilical veins (with additional 108 paired samples from umbilical arteries), and at 2-3 d of life in 183 infants. Paired venous and arterial umbilical cord MR-proADM concentrations were closely related (Spearman's rank order correlation coefficient (R(s)) = 0.825, P0.001). MR-proADM concentrations at birth and at 2-3 d were inversely related to GA (R(s) = -0.403 and R(s) = -0.541, respectively) and birth weight (BW; R(s) = -0.421 and R(s) = -0.530, respectively; all P0.001). On stepwise regression analysis, clinical chorioamnionitis and umbilical arterial blood base excess retained a significant impact on MR-proADM cord venous blood concentrations. At 2-3 d of life, histologic chorioamnionitis and GA at delivery were significantly associated with MR-proADM levels.As compared with adults, MR-proADM concentrations are elevated in neonates, especially those born very preterm. Immaturity and infection, which both feature low systemic vascular resistance, are related to increased MR-proADM concentrations.

Hypoxia and other adverse conditions are commonly encountered by rapidly growing cells. The RNA-binding protein RBM3 (RNA-binding motif protein 3), which is transcriptionally induced by low temperature and hypoxia, has recently been implicated in survival of colon cancer cells by mechanisms involving cyclooxygenase-2 (COX-2) signaling. Immunohistochemically, we found strong RBM3 expression in a variety of malignant and proliferating tissues but low expression in resting and terminally differentiated cells. RBM3 expression in fibroblasts and human embryonal kidney (HEK293) cells subjected to serum deprivation or contact inhibition closely paralleled proliferation rates, assessed by real-time RT-PCR and immunoblotting. siRNA-mediated RBM3 knockdown reduced cell viability and finally led to cell death, which did not involve caspase-3-mediated apoptosis, cell cycle arrest, or COX-2 regulation. In contrast, RBM3 over-expression rescued cells from death under serum starvation. This was associated with increased translation rates, as measured by C serine and H phenylalanine incorporation. Together, RBM3 is a critical factor providing cellular survival advantages in an adverse microenvironment presumably by restoring translation efficacy.

White matter disease in preterm infants comes along with focal destructions or with diffuse myelination disturbance. Recent experimental work with transgenic mice paves the way for a unifying molecular model for both types of brain injury, placing oxygen sensing by oligodendrocyte precursor cells at the center stage. Mice genetically altered to mimic high local oxygen tension in oligodendroglia lineage cells (via deletion of hypoxia-inducible factor, HIF) develop white matter disease resembling cystic periventricular leukomalacia (cPVL) within the first 7 days of life. Mice in which local hypoxia is mimicked in oligodendroglial cells (via genetic inhibition of HIF decay) display arrested oligodendrocyte precursor cell maturation and subsequent hypomyelination, reminiscent of the diffuse white matter disease (dWMD) observed in preterm infants and infants with congenital heart disease. These recent experimental findings on oxygen sensing and myelination are awaiting integration into a clinical framework. Gene regulation in response to hyperoxia or hypoxia, rather than oxidative stress, may be an important mechanism underlying neonatal white matter disease.

Background: Bronchopulmonary dysplasia (BPD) is a common complication in preterm infants. Clinical prediction of BPD at an early stage in life is difficult. Plasma proendothelin-1 (CT-proET-1) is a lung injury biomarker in pulmonary hypertension and respiratory distress. Objective: To assess the prognostic ability of CT-proET-1 in BPD. Methods: In 227 prospectively enrolled preterm infants born at Results: The predictive ability of CT-proET-1 for any BPD was poor at birth [area under the ROC curve (AUC) 0.654, 95% CI 0.494-0.814], moderate at DOL 2 and 3 (AUC 0.769, 95% CI 0.666-0.872) and excellent at DOL 6 (AUC 0.918, 95% CI 0.840-0.995). Multivariable regression analysis revealed that CT-proET-1 levels at DOL 2, 3, 6 and 28 were strongly related to the duration of oxygen supplementation, independently of GA and the duration of respiratory support. Conclusions: CT-proET-1 is a novel promising biomarker for predicting the development of BPD in preterm infants when measured at the end of the first week of life.

Introduction: To investigate the ability of cardiovascular plasma biomarkers to identify imminent preeclampsia (PE) among pregnant women at triage. Material and Methods: C-terminal pro-arginine vasopressin (copeptin), C-terminal pro-endothelin-1 (CT-proET-1), mid-regional pro-adrenomedullin (MR-proADM), and mid-regional pro-atrial natriuretic peptide (MR-proANP) were prospectively measured in pregnant women presenting at the obstetrical triage units of the University Hospitals of Basel and Zurich, Switzerland. Logistic regression and receiver operating characteristics (ROC) analysis was used to assess and quantify the predictive ability of cardiovascular biomarkers. Results: Of the 147 included women, 27 (18.4%) were diagnosed at admission with PE. All biomarker levels were significantly higher in participants with PE as compared to controls. However, only MR-proANP, MR-proADM and CT-proET-1 were significant and independent predictors of PE, after taking into account the effect of various clinical confounders. The area under the ROC curve (AUC) was 0.62 (95% confidence interval 0.50-0.73) for copeptin, 0.64 (0.52-0.76) for MR-proADM, 0.71 (0.61-0.82) for CT-proET-1, and 0.83 (0.73-0.92) for MR-proANP. The combination of MR-proANP and MR-proADM resulted in the highest diagnostic performance (AUC 0.88; 0.79-0.96). Discussion: Assessment of the cardiovascular plasma biomarkers MR-proANP and MR-proADM holds promise to support diagnosis of PE at triage.

Background The diagnostic and prognostic appraisal of patent ductus arteriosus (PDA) in preterm infants is still debatable. Aims To compare plasma cardiovascular biomarkers with echocardiographic indices alongside ductus arteriosus (DA) evolution in very preterm infants within the first week of life. Methods Mid-regional pro-atrial natriuretic peptide (MR-proANP) and C-terminal pro-endothelin-1 (CT-proET-1) levels were prospectively measured on the second and sixth days of life (DOL) in 52 preterm infants born before 32weeks of gestation. Echocardiographic indices to define DA patency and significance were simultaneously obtained. Logistic regression and receiver operating characteristics (ROC) analyses were used to assess and quantify the biomarkers' diagnostic capacities. Results Thirty infants exhibited PDA on DOL 2; in 21 of these infants, DA was characterized as hemodynamically significant. Treatment failure after a first course of indomethacin was noted in 8 infants (DOL 6), whereas 7 participants underwent later surgical ligation. The diagnostic accuracy of cardiovascular biomarkers was moderate on DOL 2 but high on DOL 6. PDA was the only significant predictor of MR-proANP levels on DOL 6, independent of the effect of clinical confounders (regression coefficient 0.426, R 2 0.60). Infants with MR-proANP ≥850pmol/l on DOL 2 had 3.9-fold higher risk (95% CI 1.01 to 14.5) of being diagnosed with significant DA, whereas infants with MR-proANP ≥700pmol/l on DOL 6 had 7.1-fold higher risk (1.9 to 27.2) for pharmaceutical treatment failure. Conclusion The cardiovascular plasma biomarker MR-proANP is a promising candidate for monitoring PDA evolution in very preterm infants.

Plasma concentrations of the stable endothelin-1 precursor, C-terminal portion of the endothelin-1 precursor, determined prospectively in 293 newborn infants (gestational age, 24-41 weeks) at birth and on day 3 of life were unrelated to gestational age at birth, but strongly associated with respiratory distress when measured on day 3 of life.

Background: In very preterm infants, clinical decision-making, such as closing a patent ductus arteriosus (PDA), may be aided by measuring circulating natriuretic and endothelial pro-peptides. Objectives: To investigate the association between perinatal characteristics, PDA echocardiography and plasma concentrations of stable pro-peptides of B-type natriuretic peptide (NT-proBNP), atrial natriuretic peptide (MR-proANP) and endothelin-1 (CT-proET-1). Methods: A prospective, cross-sectional, single-center study was performed in 66 infants who were less than 32 weeks of gestational age. Pro-peptide concentrations were determined at birth and at day 2–3 of life. Results: Plasma concentrations of all 3 pro-peptides increased on average 2- to 5-fold from birth to day 2–3 of life. NT-proBNP and MR-proANP were closely related at birth and at day 2–3 (Rs 0.902 and 0.897, respectively, p < 0.001), whereas CT-proET-1 was related to NT-proBNP and MR-proANP at birth (Rs 0.478 and 0.460, respectively, p < 0.001) but not at day 2–3. Birth weight was negatively related to all 3 pro-peptides at birth (p < 0.01); however, preeclampsia and compromised placental perfusion were associated with elevated NT-proBNP and MR-proANP concentrations at birth. At day 2–3, MR-proANP and NT-proBNP correlated significantly with the ductal diameter (Rs 0.416 and 0.415, respectively, both p = 0.011), whereas CT-proET-1 correlated with the left atrium/aorta ratio (Rs 0.506, p = 0.027). CT-proET-1 was elevated in infants with treated compared to untreated PDA [median (5–95% range) 388 (272–723) vs. 303 (152–422) pmol/l, p = 0.011], but not NT-proBNP or MR-proANP. Conclusion: CT-proET-1 is a promising predictor in determining the need for PDA intervention.

Objective To investigate the safety and short term outcome of high dose recombinant human erythropoietin (rhEpo) given shortly after birth and subsequently over the first 2 days for neuroprotection to very preterm infants. Study design Randomized, double masked phase II trial. Preterm infants (gestational age 26 0/7-31 6/7 weeks) were given rhEpo (n t = 229; 3000 U/kg body weight) or NaCl 0.9% (n c = 214) intravenously at 3, 12-18, and 36-42 hours after birth. Results There were no relevant differences between the groups for short-term outcomes such as mortality, retinopathy of prematurity, intraventricular hemorrhage, sepsis, necrotizing enterocolitis, and bronchopulmonary dysplasia. At day 7-10, we found significantly higher hematocrit values, reticulocyte, and white blood cell counts, and a lower platelet count in the rhEpo group. Conclusions Early high-dose rhEpo administration to very premature infants is safe and causes no excess in mortality or major adverse events. Trial registration ClinicalTrials.gov: NCT00413946.

Background Endothelin-1 (ET-1) is a potent pulmonary vasoconstrictor, involved in lung injury and remodelling. ET-1 can be estimated by measuring its stable by-product, C-terminal pro-ET-1 (CT-proET-1), in plasma. Aims To investigate CT-proET-1 values in very preterm infants (gestational age Methods Prospective cross-sectional study of 391 CT-proET-1 measurements (fully automated immunoflorescent assay) from 267 very preterm infants. Measurements were performed at birth (n = 72 infants), on day of life (DOL) 2 (n = 89), on DOL 6 (n = 49), on DOL 28 (n = 106), and at PMA 36 (n = 75). Trial registration: ClinicalTrials.gov NCT01644981. Results CT-proET-1 values were (median) 151 pmol/L (IQR 118–186) at birth, peaked on DOL 2 (319 pmol/L (235–382)), and declined thereafter to 214 pmol/L (148–293) on DOL 6, 184 pmol/L (149–233) on DOL 28, and 150 pmol/L (118–188) at PMA 36. Infants with BPD had higher CT-proET-1 values on DOL 2 (p = 0.001), DOL 6 (p Conclusions The levels and the pattern of CT-proET-1 increase during the first week of life might serve as an early marker of BPD.

Background Preterm infants suffering from intraventricular haemorrhage (IVH) are at increased risk for neurodevelopmental impairment. Observational data suggest that recombinant human erythropoietin (EPO) aimed at preventing anaemia also improves long-term cognitive outcome in infants with IVH (Neubauer AP et al ., Annals Neurology, 2010). The recently completed first early high-dose EPO trial in very preterm infants did not raise any significant safety concerns (Fauchere J-C. et al ., ESPR Annual Meeting, 2012). Hypothesis : High-dose EPO improves long-term neurodevelopmental outcome in preterm infants with IVH. Methods Design: Double blind, 1:1 randomised clinical study in 11 perinatal centres (Germany and Switzerland). Patients : 120 very preterm (gestational age I°) diagnosed by cranial ultrasound during the first 4 days of life. Intervention : 5 intravenous applications of EPO (2000 U/kg) or placebo spread over 3 weeks. Primary objective : Neurodevelopmental outcome at 5 years of age (Kaufmann-ABC or Son-R). Secondary objectives : (1) safety; (2) MRI at term equivalent age to quantitatively analyse brain injury and growth; (3) psychomotor development at 2 years of age (BSID-III). Recruitment : March 2014 to February 2016. Results and conclusions Given the fact that long-term neurodevelopmental outcome cannot be reliably assessed until preschool age, the primary outcome of this study providing evidence as to whether high-dose EPO improves restitution of brain damage in preterm infants will not be reported before 2021. However, MRI data can be reported much earlier. (Funded by the Swiss National Science Foundation; Clinical Trials Registry: NCT02076373).

95 High Copeptin (Arginine-Vasopressin) Concentrations in Umbilical Cord Blood After Vaginal Delivery and Birth Acidosis

Background and aims Plasma concentrations of endothelin-1 (ET-1), a potent pulmonary vasoconstrictor with a short serum half-life, can be estimated by measuring its stable by-product, C-terminal pro-Endothelin-1 (CT-proET-1). To investigate the association between CT-proET-1, gestational age, and pulmonary morbidity in newborn infants. Methods A prospective cross-sectional study at two tertiary university hospitals was conducted. CT-proET-1 concentrations (pmol/L) were determined in plasma samples of 293 newborn infants (gestational age 24–41 weeks) at birth and on day 3 of life with BRAHMS KRYPTOR automated immunoflorescent assay. Results At birth, CT-proET-1 concentrations were unrelated to birth weight and gestational age. Venous umbilical cord CT-proET-1 concentrations were consistently higher than matched arterial ones (M 148 vs. 134 pmol/L, p S =0.745, p S 0.566, 0.658, and 0.819, respectively, for all p Conclusions In term and preterm newborn infants, pulmonary compromise is associated with increased concentrations of circulating CT-proET-1.

Background: Induced hypothermia is the only therapy with proven efficacy to reduce brain damage after perinatal asphyxia. While hypothermia downregulates global protein synthesis and cell metabolism, low temperature induces a small subset of proteins that includes the RNA-binding protein RBM3, which is transcriptionally induced also in response to hypoxia and has recently been implicated in cell survival. Methods/results: We studied RBM3 expression in the developing murine brain by immunohistochemistry and found RBM3 widely expressed in neurons of the hippocampus, the subventricular zone, and the cerebellum during the first postnatal days. In adult brains, RBM3 was present only in neuronal precursor and stem cells, characterized by the presence of doublecortin. Hypothermia profoundly promoted RBM3 expression in juvenile as well as in mature neurons, and hypothermia-induced RBM3 expression was associated with protection of primary neurons and neuronal cell lines from forced apoptosis. Blocking RBM3 expression by siRNAs in neuronal cells significantly diminished the neuroprotective effect of hypothermia while vector-driven RBM3 overexpression prevented activation of caspase-3. Conclusion: Together, the RNA-binding protein RBM3 protects neuronal cells from apoptosis. RBM3 upregulation apparently accounts for a substantial proportion of hypothermia-induced neuroprotection.

Objective: Pontosubicular neuron necrosis (PSN) represents an age-specific response to severe hypoxic-ischemic injury (HII) occurring in human neonates but not in older children or adults. Histologically, PSN is characterised by acute neuronal death in the pontine nuclei and the hippocampal subiculum bearing the hallmarks of apoptosis. The expression of Rbm3, a glycine-rich RNA-binding protein, is enhanced under hypoxic conditions and independent of HIF (hypoxia inducible factor). It is well known, that proteins which are dependant on HIF, e.g. Erythropoetin play an important role in HII. This study aims to determine whether the HIF-independent activation of Rbm3 is also a significant factor in the pathogenesis of PSN. Methods: We have investigated the expression of Rbm3 in human autopsy material consisting of 12 PSN cases and 10 age-matched controls without PSN. Immunohistochemistry and double labeling for Rbm3 and the astrocyte marker glial fibrillary acid protein (GFAP), the microglia/macrophage specific marker KiM1P and the neuronal marker NeuN was performed on formalin-fixed, paraffin-embedded brain specimens. Results: In PSN cases and controls, mainly neuronal cells expressed Rbm3. The number of immunopositive cells was significantly increased (p=0.001) in PSN cases. Predominantly degenerating cells with signs of later apoptotic stages showed Rbm3 expression. In earlier stages of apoptosis immunopositivity for Rbm3 was increased compared to contols, but less prominent. Conclusion: In addition to HIF-dependant proteins, the induction of the HIF-independent protein RMB3 is observed in response to human hypoxic-ischemic injury.