Dalteparin in Newborn Thrombosis, Time for a New Starting Dose

BACKGROUND: Neonatal thrombosis is a frequently encountered complication in a neonatal intensive care unit. Dalteparin can be used to treat thrombosis in newborn infants. OBJECTIVES: In this study, we evaluate the current recommended starting dose of 129 ± 43 U/kg/24 h, hypothesizing that this dose is too low to reach therapeutic anti-Xa levels. METHODS: From 2008 until 2017, all infants treated with dalteparin in the University Medical Centre Utrecht were included in this study. In this retrospective cohort study, the correlation between dose and anti-Xa level was observed. RESULTS: Sixty-six infants were included. The most common thrombus types were catheter-related (29 patients, 44%) and venous sinus thrombosis (28 patients, 43%). The mean dalteparin dose needed for the first adequate anti-Xa level (0.5-1.0 IU/mL) was 297.6 U/kg/12 h. Two infants developed a first bleeding episode under dalteparin therapy; they both had anti-Xa levels in the therapeutic range. CONCLUSION: The increase of the starting dose of dalteparin will lead to earlier therapeutic levels of anti-Xa in the studied population and appears to be safe. However, this needs to be evaluated in further study

Precision Medicine in Neonates: A Tailored Approach to Neonatal Brain Injury

Despite advances in neonatal care to prevent neonatal brain injury and neurodevelopmental impairment, predicting long-term outcome in neonates at risk for brain injury remains difficult. Early prognosis is currently based on cranial ultrasound (CUS), MRI, EEG, NIRS, and/or general movements assessed at specific ages, and predicting outcome in an individual (precision medicine) is not yet possible. New algorithms based on large databases and machine learning applied to clinical, neuromonitoring, and neuroimaging data and genetic analysis and assays measuring multiple biomarkers (omics) can fulfill the needs of modern neonatology. A synergy of all these techniques and the use of automatic quantitative analysis might give clinicians the possibility to provide patient-targeted decision-making for individualized diagnosis, therapy, and outcome prediction. This review will first focus on common neonatal neurological diseases, associated risk factors, and most common treatments. After that, we will discuss how precision medicine and machine learning (ML) approaches could change the future of prediction and prognosis in this field

Evaluating the Baby@Home program: Early discharge strategies for (pre)term infants are safe and benefit health outcomes

Aim: Prolonged hospitalisation in the neonatal intensive care unit (NICU) can emotionally tax newborn infants and their families, resulting in developmental adversities and inadequate parent–infant bonding. This study aimed to assess the feasibility and value of the Baby@Home program in reducing prolonged hospital stays. Methods: This is a retrospective cohort study of 26 infants from a tertiary neonatology department, using qualitative data (gathered through interviews with parents (n = 15) and professionals (n = 5)) and quantitative data (retrieved from medical records and the Luscii application). Results: Our study included 26 newborn infants. 76% were premature, born at an average term of 35 weeks and 2 days. During the study period, all infants thrived, and only two adverse events occurred (an allergic reaction and respiratory incident necessitating readmission). Interviews were conducted based on six major themes concerning the feasibility and value of the program. Despite the challenges of application utilisation, the program's overall value was evident. Conclusion: The Baby@Home program effectively facilitated early discharge, promoted family reunification, and yielded favourable safety and health outcomes. Innovative solutions such as Baby@Home have the potential to pave the way for more sustainable and patient-centred care models

Neonatal sepsis and transient immunodeficiency: Potential for novel immunoglobulin therapies?

Neonates, especially preterm neonates, have the highest risk of sepsis of all age groups. Transient immaturity of the neonatal immune system is an important risk factor. Neonates suffer from hypogammaglobulinemia as nor IgA nor IgM is transferred over the placenta and IgG is only transferred over the placenta late in gestation. In addition, neutrophil numbers and complement function are also decreased. This mini-review focuses on strategies to improve neonatal host-defense. Both clinical and preclinical studies have attempted to boost neonatal immunity to lower the incidence of sepsis and improve outcome. Recent advances in the development of (monoclonal) antibodies show promising results in preclinical studies but have yet to be tested in clinical trials. Strategies to increase complement activity seem efficient in vitro but potential disadvantages such as hyperinflammation have held back further clinical development. Increase of neutrophil numbers has been tested extensively in clinical trials but failed to show improvement in mortality. Future research should focus on clinical applicability of promising new prevention strategies for neonatal sepsis

The development and validation of a cerebral ultrasound scoring system for infants with hypoxic-ischaemic encephalopathy

BACKGROUND: Hypoxic-ischaemic encephalopathy (HIE) is an important cause of morbidity and mortality in neonates. When the gold standard MRI is not feasible, cerebral ultrasound (CUS) might offer an alternative. In this study, the association between a novel CUS scoring system and neurodevelopmental outcome in neonates with HIE was assessed. METHODS: (Near-)term infants with HIE and therapeutic hypothermia, a CUS on day 1 and day 3-7 after birth and available outcome data were retrospectively included in cohort I. CUS findings on day 1 and day 3-7 were related to adverse outcome in univariate and the CUS of day 3-7 also in multivariable logistic regression analyses. The resistance index, the sum of deep grey matter and of white matter involvement were included in multivariable logistic regression analyses. A comparable cohort from another hospital was used for validation (cohort II). RESULTS: Eighty-three infants were included in cohort I and 35 in cohort II. The final CUS scoring system contained the sum of white matter (OR = 2.6, 95% CI 1.5-4.7) and deep grey matter involvement (OR = 2.7, 95% CI 1.7-4.4). The CUS scoring system performed well in cohort I (AUC = 0.90) and II (AUC = 0.89). CONCLUSION: This validated CUS scoring system is associated with neurodevelopmental outcome in neonates with HIE

Multi-centre, randomised non-inferiority trial of early treatment versus expectant management of patent ductus arteriosus in preterm infants (the BeNeDuctus trial):statistical analysis plan

Abstract Background Controversy exists about the optimal management of a patent ductus arteriosus (PDA) in preterm infants. A persistent PDA is associated with neonatal mortality and morbidity, but causality remains unproven. Although both pharmacological and/or surgical treatment are effective in PDA closure, this has not resulted in an improved neonatal outcome. In most preterm infants, a PDA will eventually close spontaneously, hence PDA treatment potentially increases the risk of iatrogenic adverse effects. Therefore, expectant management is gaining interest, even in the absence of convincing evidence to support this strategy. Methods/design The BeNeDuctus trial is a multicentre, randomised, non-inferiority trial assessing early pharmacological treatment (24–72 h postnatal age) with ibuprofen versus expectant management of PDA in preterm infants in Europe. Preterm infants with a gestational age of less than 28 weeks and an echocardiographic-confirmed PDA with a transductal diameter of > 1.5 mm are randomly allocated to early pharmacological treatment with ibuprofen or expectant management after parental informed consent. The primary outcome measure is the composite outcome of mortality, and/or necrotizing enterocolitis Bell stage ≥ IIa, and/or bronchopulmonary dysplasia, all established at a postmenstrual age of 36 weeks. Secondary short-term outcomes are comorbidity and adverse events assessed during hospitalization and long-term neurodevelopmental outcome assessed at a corrected age of 2 years. This statistical analysis plan focusses on the short-term outcome and is written and submitted without knowledge of the data. Trial registration ClinicalTrials.gov NTR5479. Registered on October 19, 2015, with the Dutch Trial Registry, sponsored by the United States National Library of Medicine Clinicaltrials.gov NCT02884219 (registered May 2016) and the European Clinical Trials Database EudraCT 2017-001376-28

Risk Factors for Necrotizing Enterocolitis:A Prospective Multicenter Case-Control Study

BACKGROUND: The identification of independent clinical risk factors for necrotizing enterocolitis (NEC) may contribute to early selection of infants at risk, allowing for the development of targeted strategies aimed at the prevention of NEC. OBJECTIVE: The objective of this study was to identify independent risk factors contributing to the development of NEC in a large multicenter cohort. METHODS: This prospective cohort study was performed in 9 neonatal intensive care units. Infants born at a gestational age </=30 weeks were included. Demographic and clinical data were collected daily until day 28 postnatally. Factors predictive of the development of NEC were identified using univariate and multivariable analyses in a 1: 5 matched case-control cohort. RESULTS: In total, 843 infants (56 NEC cases) were included in this study. In the case-control cohort, univariate analysis identified sepsis prior to the onset of NEC and formula feeding to be associated with an increased risk of developing NEC, whereas the administration of antibiotics directly postpartum was inversely associated with NEC. In a multivariable logistic regression model, enteral feeding type and the number of days parenterally fed remained statistically significantly associated with NEC, whereas the administration of antibiotics directly after birth was associated with a lower risk of developing NEC. CONCLUSIONS: Formula feeding and prolonged (duration of) parenteral feeding were associated with an increased risk of NEC. Contrary to expectations, the initiation of treatment with antibiotics within 24 h after birth was inversely associated with NEC

The Sleep Well Baby project: an automated real-time sleep-wake state prediction algorithm in preterm infants

STUDY OBJECTIVES: Sleep is an important driver of early brain development. However, sleep is often disturbed in preterm infants admitted to the neonatal intensive care unit (NICU). We aimed to develop an automated algorithm based on routinely measured vital parameters to classify sleep-wake states of preterm infants in real-time at the bedside. METHODS: In this study, sleep-wake state observations were obtained in 1-minute epochs using a behavioral scale developed in-house while vital signs were recorded simultaneously. Three types of vital parameter data, namely, heart rate, respiratory rate, and oxygen saturation, were collected at a low-frequency sampling rate of 0.4 Hz. A supervised machine learning workflow was used to train a classifier to predict sleep-wake states. Independent training (n = 37) and validation datasets were validation n = 9) datasets were used. Finally, a setup was designed for real-time implementation at the bedside. RESULTS: The macro-averaged area-under-the-receiver-operator-characteristic (AUROC) of the automated sleep staging algorithm ranged between 0.69 and 0.82 for the training data, and 0.61 and 0.78 for the validation data. The algorithm provided the most accurate prediction for wake states (AUROC = 0.80). These findings were well validated on an independent sample (AUROC = 0.77). CONCLUSIONS: With this study, to the best of our knowledge, a reliable, nonobtrusive, and real-time sleep staging algorithm was developed for the first time for preterm infants. Deploying this algorithm in the NICU environment may assist and adapt bedside clinical work based on infants' sleep-wake states, potentially promoting the early brain development and well-being of preterm infants

Isoprostanes as Biomarker for White Matter Injury in Extremely Preterm Infants

Background and Aim: Preterm white matter is vulnerable to lipid peroxidation-mediated injury. F2-isoprostanes (IPs), are a useful biomarker for lipid peroxidation. Aim was to assess the association between early peri-postnatal IPs, white matter injury (WMI) at term equivalent age (TEA), and neurodevelopmental outcome in preterm infants. Methods: Infants with a gestational age (GA) below 28 weeks who had an MRI at TEA were included. IPs were measured in cord blood (cb) at birth and on plasma (pl) between 24 and 48 h after birth. WMI was assessed using Woodward MRI scoring system. Multiple regression analyses were performed to assess the association between IPs with WMI and then with BSITD-III scores at 24 months corrected age (CA). Receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive value of pl-IPs for the development of WMI. Results: Forty-four patients were included. cb-IPs were not correlated with WMI score at TEA, whereas higher pl-IPs and lower GA predicted higher WMI score (p = 0.037 and 0.006, respectively) after controlling for GA, FiO2 at sampling and severity of IVH. The area under the curve was 0.72 (CI 95% = 0.51-0.92). The pl-IPs levels plotted curve indicated that 31.8 pg/ml had the best predictive threshold with a sensitivity of 86% and a specificity of 60%, to discriminate newborns with any WMI from newborns without WMI. IPs were not associated with outcome at 24 months. Conclusion: Early measurement of pl-IPs may help discriminate patients showing abnormal WMI score at TEA, thus representing an early biomarker to identify newborns at risk for brain injury

Role of patent ductus arteriosus in preterms in long-term outcome

Objective: This study aimed to determine long-term neurodevelopmental outcome and cerebral oxygenation in extremely preterm infants, comparing those with a hemodynamic significant patent ductus arteriosus (hsPDA) to those without. Study design: We included infants born before 28 weeks of gestation from 2008 to 2010 with routine echocardiography. Prior to echocardiography, regional cerebral oxygen saturation was measured. At 5 years of age, we evaluated neurodevelopmental outcomes using the Movement Assessment Battery for Children 2nd Dutch edition for motor skills and the Wechsler Preschool and Primary Scale of Intelligence 3rd Dutch edition for cognition. Results: A total of 66 infants (gestational age 26.6 ± 0.9 weeks, birth weight 912 ± 176 g) were included, 34 infants with a hsPDA (including treatment). The group infants with hsPDA showed lower pre-closure cerebral saturation levels (58.2 % ±7.8 % versus 62.8 % ±7.0 %; p = 0.01). At 5 years, impaired motor outcome occurred more often in infants with hsPDA (17 (53 %) vs. 7 (23 %); p = 0.01). In multivariate analysis existence of hsPDA remained unfavourably related to the motor subdomain “aiming and catching”. There were no potential effects of hsPDA on cognitive performance at 5 years of age. Conclusion: Treatment-receiving infants with hsPDA appear to exhibit motor deficits, specifically in “aiming and catching”, by the age 5. Persistent ductal patency could be a contributing factor