"Every breath you take": evaluating sound levels and acoustic characteristics of various neonatal respiratory support and ventilation modalities.

Background: Early sensory experiences have a significant impact on the later life of preterm infants. The NICU soundscape is profoundly influenced by various modalities of respiratory support or ventilation, which are often mandatory early in the care. The incubator, believed to shield from external noise, is less effective against noise originating inside. The objective of this study was to evaluate the sound levels and characteristics of frequently used respiratory support and ventilation modalities, taking into consideration the developing auditory system of premature infants. Methods: To evaluate sound dynamics inside and outside an incubator during respiratory support/ventilation, experimental recordings were conducted at the Center for Pediatric Simulation Training of the Medical University Vienna. The ventilator used was a FABIAN HFOI®. Results: Jet CPAP (Continuous positive airway pressure), whether administered via mask or prongs, generates significantly higher sound levels compared to High-flow nasal cannula (HFNC) and to High-frequency oscillatory ventilation (HFOV) delivered through an endotracheal tube. Upon evaluating the sound spectrum of jet CPAP support, a spectral peak is observed within the frequency range of 4 to 8 kHz. Notably, this frequency band aligns with the range where the hearing threshold of preterm infants is at its most sensitive. Conclusion: Non-invasive HFNC and invasive HFOV generate lower sound levels compared to those produced by jet CPAP systems delivered via masks or prongs. Moreover, HFNC and HFOV show a reduced acoustic presence within the frequency range where the preterm infant's hearing is highly sensitive. Therefore, it is reasonable to speculate that the potential for auditory impairment might be more pronounced in preterm infants who require prolonged use of jet CPAP therapy during their time in the incubator.

Neuroactive metabolites and bile acids are altered in extremely premature infants with brain injury.

The gut microbiome is associated with pathological neurophysiological evolvement in extremely premature infants suffering from brain injury. The exact underlying mechanism and its associated metabolic signatures in infants are not fully understood. To decipher metabolite profiles linked to neonatal brain injury, we investigate the fecal and plasma metabolome of samples obtained from a cohort of 51 extremely premature infants at several time points, using liquid chromatography (LC)-high-resolution mass spectrometry (MS)-based untargeted metabolomics and LC-MS/MS-based targeted analysis for investigating bile acids and amidated bile acid conjugates. The data are integrated with 16S rRNA gene amplicon gut microbiome profiles as well as patient cytokine, growth factor, and T cell profiles. We find an early onset of differentiation in neuroactive metabolites between infants with and without brain injury. We detect several bacterially derived bile acid amino acid conjugates in plasma and feces. These results provide insights into the early-life metabolome of extremely premature infants.

Detailed statistical analysis plan for ALBINO: effect of Allopurinol in addition to hypothermia for hypoxic-ischemic Brain Injury on Neurocognitive Outcome - a blinded randomized placebo-controlled parallel group multicenter trial for superiority (phase III).

BACKGROUND: Despite therapeutic hypothermia (TH) and neonatal intensive care, 45-50% of children affected by moderate-to-severe neonatal hypoxic-ischemic encephalopathy (HIE) die or suffer from long-term neurodevelopmental impairment. Additional neuroprotective therapies are sought, besides TH, to further improve the outcome of affected infants. Allopurinol - a xanthine oxidase inhibitor - reduced the production of oxygen radicals and subsequent brain damage in pre-clinical and preliminary human studies of cerebral ischemia and reperfusion, if administered before or early after the insult. This ALBINO trial aims to evaluate the efficacy and safety of allopurinol administered immediately after birth to (near-)term infants with early signs of HIE. METHODS/DESIGN: The ALBINO trial is an investigator-initiated, randomized, placebo-controlled, double-blinded, multi-national parallel group comparison for superiority investigating the effect of allopurinol in (near-)term infants with neonatal HIE. Primary endpoint is long-term outcome determined as survival with neurodevelopmental impairment versus death versus non-impaired survival at 2 years. RESULTS: The primary analysis with three mutually exclusive responses (healthy, death, composite outcome for impairment) will be on the intention-to-treat (ITT) population by a generalized logits model according to Bishop, Fienberg, Holland (Bishop YF, Discrete Multivariate Analysis: Therory and Practice, 1975) and ."will be stratified for the two treatment groups. DISCUSSION: The statistical analysis for the ALBINO study was defined in detail in the study protocol and implemented in this statistical analysis plan published prior to any data analysis. This is in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. TRIAL REGISTRATION: ClinicalTrials.gov NCT03162653. Registered on 22 May 2017.

Quantitative Magnetic Resonance Imaging for Neurodevelopmental Outcome Prediction in Neonates Born Extremely Premature-An Exploratory Study.

PURPOSE: Neonates born at < 28 weeks of gestation are at risk for neurodevelopmental delay. The aim of this study was to identify quantitative MR-based metrics for the prediction of neurodevelopmental outcomes in extremely preterm neonates. METHODS: T1-/T2-relaxation times (T1R/T2R), ADC, and fractional anisotropy (FA) of the left/right posterior limb of the internal capsule (PLIC) and the brainstem were determined at term-equivalent ages in a sample of extremely preterm infants (n = 33). Scores for cognitive, language, and motor outcomes were collected at one year corrected-age. Pearson's correlation analyses detected relationships between quantitative measures and outcome data. Stepwise regression procedures identified imaging metrics to estimate neurodevelopmental outcomes. RESULTS: Cognitive outcomes correlated significantly with T2R (r = 0.412; p = 0.017) and ADC (r = -0.401; p = 0.021) (medulla oblongata). Furthermore, there were significant correlations between motor outcomes and T1R (pontine tegmentum (r = 0.346; p = 0.049), midbrain (r = 0.415; p = 0.016), right PLIC (r = 0.513; p = 0.002), and left PLIC (r = 0.504; p = 0.003)); T2R (right PLIC (r = 0.405; p = 0.019)); ADC (medulla oblongata (r = -0.408; p = 0.018) and pontine tegmentum (r = -0.414; p = 0.017)); and FA (pontine tegmentum (r = -0.352; p = 0.045)). T2R/ADC (medulla oblongata) (cognitive outcomes (R2 = 0.296; p = 0.037)) and T1R (right PLIC)/ADC (medulla oblongata) (motor outcomes (R2 = 0.405; p = 0.009)) revealed predictive potential for neurodevelopmental outcomes. CONCLUSION: There are relationships between relaxometry­/DTI-based metrics determined by neuroimaging near term and neurodevelopmental outcomes collected at one year of age. Both modalities bear prognostic potential for the prediction of cognitive and motor outcomes. Thus, quantitative MRI at term-equivalent ages represents a promising approach with which to estimate neurologic development in extremely preterm infants.

Magnetic Resonance Imaging-Based Reference Values for Two-Dimensional Quantitative Brain Metrics in a Cohort of Extremely Preterm Infants.

INTRODUCTION: Cerebral magnetic resonance imaging (cMRI) is an important diagnostic tool in neonatology. In addition to qualitative analysis, quantitative measurements may help identify infants with impaired brain growth. This study aimed to create reference values for brain metrics of various brain areas in neonates without major brain injuries born before 28 weeks of gestation. METHODS: This retrospective study analyzes cMRI imaging data of high-risk patients without severe brain pathologies at term-equivalent age, collected over 4 years since November 2017. Nineteen brain areas were measured, reference values created, and compared to published values from fetal and postnatal MRI. Furthermore, correlations between brain metrics and gestational age at birth were evaluated. RESULTS: A total of 174 cMRI examinations were available for analysis. Reference values including cut-offs for impaired brain growth were established for different gestational age groups. There was a significant correlation between gestational age at birth and larger "tissue" parameters, as well as smaller "fluid" parameters, including intracerebral and extracerebral spaces. DISCUSSION: With quantitative brain metrics infants with impaired brain growth might be detected earlier. Compared to preexisting reference values, these are the first of a contemporary collective of extremely preterm neonates without severe brain injuries. Measurements can be easily performed by radiologists as well as neonatologists without specialized equipment or computational expertise. CONCLUSION: Two-dimensional cMRI brain measurements at term-equivalent age represent an easy and reliable approach for the evaluation of brain size and growth in infants at high risk for neurodevelopmental impairment.

Analysing heart rate variability in preterm infants: the effect of temporal adjustment of NN peaks and missing data.

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.

Perceived stress of mothers and fathers on two NICUs before and during the SARS-CoV-2 pandemic.

Parents of very low birth weight (VLBW) infants in a neonatal intensive care unit experienced additional stress during the SARS-CoV-2 pandemic due to the related restrictions in hospital visiting policies. Our study aimed to compare parents' burdens before and during the pandemic. This survey included 121 parents of 76 VLBW infants in two European Level IV perinatal centers before and during the pandemic. We performed standardized parent questionnaires with mothers and fathers separately to evaluate their emotional stress and well-being. The pandemic worsened the emotional well-being of parents of VLBW infants, particularly of mothers. During the pandemic, mothers reported significantly higher state anxiety levels (48.9 vs. 42.9, p = 0.026) and hampered bonding with the child (6.3 vs. 5.2, 0 = 0.003) than before. In addition, mothers felt more personally restricted than fathers (6.1 vs. 5.2, p = 0.003). Fathers experienced lower levels of stress than mothers; they were equally burdened before and during the pandemic. Restrictions in visiting policies for families of VLBW infants during the SARS-CoV-2 pandemic have a significant negative impact on parental stress and should therefore be applied cautiously.

Successful delayed interval delivery of a triplet pregnancy using conservative management.

Preterm birth is a significant cause of perinatal morbidity and mortality, especially in multiple pregnancies. Delayed interval delivery can prolong pregnancy for the remaining fetus(es) in an imminent stillbirth or extremely preterm birth of the first fetus, improving the lastborn's outcomes. We present a case of delayed interval delivery of a triplet pregnancy following preterm prelabour rupture of membranes and progressive cervical insufficiency. Following vaginal delivery of the first fetus at 24+1 gestational weeks, the patient received antibiotics and tocolysis. Cerclage was not conducted as the mother had a vaginal infection. A 15-day delivery interval for the second and third fetuses was achieved. The firstborn required mechanical ventilation and inotropic support, while the others only required continuous positive airway pressure. There is no consensus on the best way to perform delayed interval delivery. We achieved a complications-free interval of 15 days with conservative management in a triplet pregnancy.

Altitude Modifies the Effect of Parity on Birth Weight/Length Ratio: A Study Comprising 2,057,702 Newborns between 1984 and 2020 in Austria.

(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.

Inter-site generalizability of EEG based age prediction algorithms in the preterm infant.

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.

Assessment of Comfort during Less Invasive Surfactant Administration in Very Preterm Infants: A Multicenter Study.

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.

European Consensus Guidelines on the Management of Respiratory Distress Syndrome: 2022 Update.

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).

Impact of Retinopathy of Prematurity on Visual Motor Integration.

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.

The impact of pandemic restrictive visiting policies on infant wellbeing in a NICU.

BACKGROUND: Given the countrywide lockdown in the first pandemic period and the respective Hospital restrictive policies, we aimed to investigate if the SARS-COV-2 pandemic was associated to a reduced parental presence in the NICU and in which form this had an impact on infant wellbeing. METHODS: Retrospective cohort study about altered NICUs parental presence (measured by number of visits and kangaroo care time) due to pandemic restrictive policies and its impact on infant wellbeing (measured through The Neonatal Pain Agitation and Sedation scale and nurses' descriptive documentation). RESULTS: Presence of both parents at the same time was significantly lower during pandemic. Contrary, maternal presence only and total kangaroo-care time were higher within the pandemic (163.36 ± 94.07 vs 122.71 ± 64.03; p = 0.000). Lower NPASS values were documented during the lookdown (1.28 ± 1.7 vs 1.78 ± 2.2; p = 0.000). CONCLUSION: Data collected through the pandemic confirm the importance of parental presence for infants' wellbeing in a NICU setting. IMPACT: Parental support is an extremely important aspect for infants hospitalized in an intensive care unit. Their presence was limited in many NICUs worldwide during the SARS-COV-2 pandemic. This study confirm the importance of parental presence for infants' wellbeing also in a pandemic situation. Our results support a family-centered newborn individualized developmental care approach in the NICU.

Brain Biometry Reveals Impaired Brain Growth in Preterm Neonates with Intraventricular Hemorrhage.

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.

Cerebral regional tissue Oxygen Saturation to Guide Oxygen Delivery in preterm neonates during immediate transition after birth (COSGOD III): multicentre randomised phase 3 clinical trial.

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.

Bedside tracking of functional autonomic age in preterm infants.

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.

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.