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Objective: To describe the use and nationwide variation of red blood cell (RBC) transfusions in neonatal intensive care units (NICUs) following the introduction of the revised national transfusion guideline in 2019., Design and Patients: We randomly selected neonates born below 32 weeks' gestation admitted to any NICU in the Netherlands in 2020 to include in our retrospective observational cohort study., Main Outcome Measures: Main outcome measures were the number of neonates receiving at least one transfusion, and the number of transfusions per transfused neonate., Results: Of 762 neonates included, 34% (257/762) received at least one RBC transfusion, varying between centres from 20% (12/61) to 50% (39/77). Median phlebotomy loss during admission was 8.2 mL/kg (IQR 4.5-17.3 mL/kg), equating to 54.3% of the median transfusion volume. Of 770 transfusions, 358 (47%) were administered above the recommended threshold, and the proportion of transfusions given above the threshold varied between centres from 15% to 719%. Median transfusion dosage and mean infusion duration were 15.1 mL/kg (IQR 15.0-16.7 mL/kg) and 3.9 hours (SD 1.1 hour) and varied from 14.8 mL/kg to 18.9 mL/kg and from 2.5 hours to 5.5 hours between centres. Blood transfusion volume was positively correlated with cumulative volume of blood draws (Pearson correlation coefficient 0.84, 95% CI 0.82 to 0.86) and lower gestation., Conclusions: Large variation in transfusion practice remains between Dutch NICUs despite a national guideline. Extreme prematurity and cumulative blood draws were associated with increased use of RBC transfusions. Benchmarking will yield leverage points to understand and potentially prevent unwarranted variation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Introduction: Non-invasive respiratory support strategies have evolved to avoid bronchopulmonary dysplasia (BPD) in preterm infants. However, consensus on the best treatment strategy remains lacking. This study aims to investigate current practices and variations in primary respiratory support for extremely preterm neonates across neonatal intensive care units (NICUs) in the Netherlands., Methods: A web-based questionnaire was distributed to neonatologists in the Netherlands. The survey covered aspects like the choice of respiratory support modalities, criteria for their application, and associated clinical practices., Results: The response rate was 48.5 % (66/136). The majority used continuous positive airway pressure (CPAP) as primary respiratory support; 73.8 % for infants with gestational age (GA) ≤26 wks and 88.9 % for infants with GA 26-28 wks. The most used alternative was non-invasive positive pressure ventilation (NIPPV). Significant variation was particularly found in NIPPV settings. Respiratory support during less invasive surfactant administration (LISA) varied per NICU between CPAP and NIPPV, but overall CPAP was preferred. Caffeine was administered in the delivery room into infants with GA ≤26 weeks (30.2 %) and GA between 26 and 28 weeks (22.2 %). Doxapram was avoided in the first week of life in 81 % of the infants, independent of their GA., Conclusion: The study highlights diverse practices in primary neonatal respiratory support in the Netherlands, with significant variation in NIPPV settings while there is uniformity in CPAP use, underscoring the need for cohesive guidelines and training to standardize care and improve outcomes for extremely preterm neonates., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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., (© 2024 The Author(s). Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Objective: The fecal microbiota and metabolome are hypothesized to be altered before late-onset neonatal meningitis (LOM), in analogy to late-onset sepsis (LOS). The present study aimed to identify fecal microbiota composition and volatile metabolomics preceding LOM., Methods: Cases and gestational age-matched controls were selected from a prospective, longitudinal preterm cohort study (born <30 weeks' gestation) at nine neonatal intensive care units. The microbial composition (16S rRNA sequencing) and volatile metabolome (gas chromatography-ion mobility spectrometry (GC-IMS) and GC-time-of-flight-mass spectrometry (GC-TOF-MS)), were analyzed in fecal samples 1-10 days pre-LOM., Results: Of 1397 included infants, 21 were diagnosed with LOM (1.5%), and 19 with concomitant LOS (90%). Random Forest classification and MaAsLin2 analysis found similar microbiota features contribute to the discrimination of fecal pre-LOM samples versus controls. A Random Forest model based on six microbiota features accurately predicts LOM 1-3 days before diagnosis with an area under the curve (AUC) of 0.88 (n=147). Pattern recognition analysis by GC-IMS revealed an AUC of 0.70-0.76 (P<0.05) in the three days pre-LOM (n=92). No single discriminative metabolites were identified by GC-TOF-MS (n=66)., Conclusion: Infants with LOM could be accurately discriminated from controls based on preclinical microbiota composition, while alterations in the volatile metabolome were moderately associated with preclinical LOM., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

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., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: To characterize bedside 24-h patterns in light exposure in the Neonatal Intensive Care Unit (NICU) and to explore the environmental and individual patient characteristics that influence these patterns in this clinical setting. Methods: We conducted a retrospective cohort study that included 79 very preterm infants who stayed in an incubator with a built-in light sensor. Bedside light exposure was measured continuously (one value per minute). Based on these data, various metrics (including relative amplitude, intradaily variability, and interdaily stability) were calculated to characterize the 24-h patterns of light exposure. Next, we determined the association between these metrics and various environmental and individual patient characteristics. Results: A 24-h light-dark cycle was apparent in the NICU with significant differences in light exposure between the three nurse shifts ( p < 0.001), with the highest values in the morning and the lowest values at night. Light exposure was generally low, with illuminances rarely surpassing 75 lux, and highly variable between patients and across days within a single patient. Furthermore, the season of birth and phototherapy had a significant effect on 24-h light-dark cycles, whereas no effect of bed location and illness severity were observed. Conclusion: Even without an official lighting regime set, a 24-h light-dark cycle was observed in the NICU. Various rhythmicity metrics can be used to characterize 24-h light-dark cycles in a clinical setting and to study the relationship between light patterns and health outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Van der Linden, Hazelhoff, De Groot, Vijlbrief, Schlangen, De Kort, Vermeulen, Van Gilst, Dudink and Kervezee.)

Background: In critically ill (preterm) neonates, catheter-related venous thromboembolism (CVTE) can be a life-threatening complication. Evidence on optimal management in the literature is lacking. In the Netherlands, a consensus-based national management guideline was developed to create uniform CVTE management., Objectives: To evaluate the efficacy and safety of the national guideline., Methods: This prospective, multicenter, observational study included all infants aged ≤6 months with CVTE in the Netherlands between 2014 and 2019. CVTE was divided into thrombosis in veins and that in the right atrium, with their own treatment algorithms. The primary outcomes were recurrent venous thrombotic events (VTEs) and/or death due to CVTE as well as major bleeding., Results: Overall, 115 neonates were included (62% male; 79% preterm). The estimated incidence of CVTE was 4.0 per 1000 neonatal intensive care unit admissions. Recurrent thrombosis occurred in 2 (1.7%) infants and death due to CVTE in 1 (0.9%) infant. Major bleeding developed in 9 (7.8%) infants: 2 of 7 (29%) on recombinant tissue plasminogen activator, which was given for high-risk right-atrium thrombosis, and 7 of 63 (11%) on low-molecular-weight heparin (LMWH). Five of the 7 bleedings because of LMWH were complications of subcutaneous catheter use for LMWH administration., Conclusion: The management of neonatal CVTE according to the Dutch CVTE management guideline led to a low incidence of recurrent VTEs and death due to VTEs. Major bleeding occurred in 7.8% of the infants. Specific guideline adjustments may improve efficacy and, especially, safety of CVTE management in neonates., Competing Interests: Declaration of competing interests C.H.v.O. reports consulting fees paid to the department from Bayer BV, Boehringer Ingelheim, and Daiichi Sankyo; lecture honoraria paid to the department from Boehringer Ingelheim; and an unrestricted grant paid to the department from Octapharma, all outside the submitted work., (Copyright © 2022 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background: Cyclooxygenase inhibitors are commonly used in infants with patent ductus arteriosus (PDA), but the benefit of these drugs is uncertain., Methods: In this multicenter, noninferiority trial, we randomly assigned infants with echocardiographically confirmed PDA (diameter, >1.5 mm, with left-to-right shunting) who were extremely preterm (<28 weeks' gestational age) to receive either expectant management or early ibuprofen treatment. The composite primary outcome included necrotizing enterocolitis (Bell's stage IIa or higher), moderate to severe bronchopulmonary dysplasia, or death at 36 weeks' postmenstrual age. The noninferiority of expectant management as compared with early ibuprofen treatment was defined as an absolute risk difference with an upper boundary of the one-sided 95% confidence interval of less than 10 percentage points., Results: A total of 273 infants underwent randomization. The median gestational age was 26 weeks, and the median birth weight was 845 g. A primary-outcome event occurred in 63 of 136 infants (46.3%) in the expectant-management group and in 87 of 137 (63.5%) in the early-ibuprofen group (absolute risk difference, -17.2 percentage points; upper boundary of the one-sided 95% confidence interval [CI], -7.4; P<0.001 for noninferiority). Necrotizing enterocolitis occurred in 24 of 136 infants (17.6%) in the expectant-management group and in 21 of 137 (15.3%) in the early-ibuprofen group (absolute risk difference, 2.3 percentage points; two-sided 95% CI, -6.5 to 11.1); bronchopulmonary dysplasia occurred in 39 of 117 infants (33.3%) and in 57 of 112 (50.9%), respectively (absolute risk difference, -17.6 percentage points; two-sided 95% CI, -30.2 to -5.0). Death occurred in 19 of 136 infants (14.0%) and in 25 of 137 (18.2%), respectively (absolute risk difference, -4.3 percentage points; two-sided 95% CI, -13.0 to 4.4). Rates of other adverse outcomes were similar in the two groups., Conclusions: Expectant management for PDA in extremely premature infants was noninferior to early ibuprofen treatment with respect to necrotizing enterocolitis, bronchopulmonary dysplasia, or death at 36 weeks' postmenstrual age. (Funded by the Netherlands Organization for Health Research and Development and the Belgian Health Care Knowledge Center; BeNeDuctus ClinicalTrials.gov number, NCT02884219; EudraCT number, 2017-001376-28.)., (Copyright © 2022 Massachusetts Medical Society.)

Early detection of late-onset sepsis (LOS) in preterm infants is crucial since timely treatment initiation is a key prognostic factor. We hypothesized that fecal volatile organic compounds (VOCs), reflecting microbiota composition and function, could serve as a non-invasive biomarker for preclinical pathogen-specific LOS detection. Fecal samples and clinical data of all preterm infants (≤30 weeks' gestation) admitted at nine neonatal intensive care units in the Netherlands and Belgium were collected daily. Samples from one to three days before LOS onset were analyzed by gas chromatography-ion mobility spectrometry (GC-IMS), a technique based on pattern recognition, and gas chromatography-time of flight-mass spectrometry (GC-TOF-MS), to identify unique metabolites. Fecal VOC profiles and metabolites from infants with LOS were compared with matched controls. Samples from 121 LOS infants and 121 matched controls were analyzed using GC-IMS, and from 34 LOS infants and 34 matched controls using GC-TOF-MS. Differences in fecal VOCs were most profound one and two days preceding Escherichia coli LOS (Area Under Curve; p -value: 0.73; p = 0.02, 0.83; p < 0.002, respectively) and two and three days before gram-negative LOS (0.81; p < 0.001, 0.85; p < 0.001, respectively). GC-TOF-MS identified pathogen-specific discriminative metabolites for LOS. This study underlines the potential for VOCs as a non-invasive preclinical diagnostic LOS biomarker.

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Beudeker, Vijlbrief, van Montfrans, Rooijakkers and Flier.)

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., (© Sleep Research Society 2022. Published by Oxford University Press on behalf of the Sleep Research Society.)

The threshold to initiate empiric antibiotics for suspicion of early-onset sepsis (EOS) is low in preterm infants. Antibiotics' effects on short-term outcomes have recently been debated. We aimed at exploring the extent of early empiric antibiotic exposure (EEAE) in preterm infants and the association between the duration of EEAE with necrotizing enterocolitis (NEC) and late-onset sepsis (LOS) within different EEAE groups. EEAE practice for suspicion of EOS was evaluated in all included infants (gestational age < 30 weeks) born in 9 centers in the Netherlands and Belgium between Oct. 2014 and Jan. 2019. EEAE association with NEC and LOS development was analyzed by multivariate regression. After excluding 56 EOS cases, 1259 infants were included. A total of 1122 infants (89.1%) were exposed to empirical antibiotics for the suspicion of EOS of whom 802 (63.7%) had short (≤ 72 h) and 320 (25.4%) prolonged EEAE (> 72 h). Infants with EEAE ≤ 72 h had a lower incidence of NEC compared to both infants without EEAE (adjusted odds ratio (aOR) 0.39; 95% confidence interval (CI) [0.19-0.80]; p = 0.01) and with prolonged EEAE (> 72 h) (aOR [95%CI]: 0.58 [0.35-0.96]; p = 0.03). With every additional day of EEAE, LOS incidence decreased (aOR [95%CI]: 0.90 [0.85-0.97]; p = 0.003)., Conclusion: Almost 90% of preterm infants who have negative blood culture results in the first 72 h of life are exposed to EEAE under suspicion of EOS. One-fourth has prolonged EEAE. Duration of EEAE was differently associated with NEC and LOS incidence. The effects of antibiotics, and potentially induced microbial dysbiosis related to development of NEC and LOS, should further be explored., What Is Known: • Preterm infants often receive antibiotics empirically directly after birth for suspicion of early-onset sepsis. • The effects of the duration of early empirical antibiotic exposure on the risk for necrotizing enterocolitis and late-onset sepsis are debated., What Is New: • Almost 90% of preterm infants with a gestational age below 30 weeks are exposed to antibiotics empirically after birth despite negative culture results. In a quarter of these culture-negative infants, empirical antibiotics are prolonged. • A short course of empirical antibiotics (≤72h) is associated with decreased odds for necrotizing enterocolitis compared to both prolonged (>72h) or no empirical antibiotics after birth. Furthermore, every additional day of empirical antibiotic exposure is associated with decreased risk for late-onset sepsis in the first month of life., (© 2022. The Author(s).)

Early brain activity, measured using amplitude-integrated EEG (aEEG), is correlated with neurodevelopmental outcome in preterm newborns. F 2 -isoprostanes (IPs) are early biomarkers predictive for brain damage. We aimed to investigate the relationship between perinatal IPs concentrations and quantitative aEEG measures in preterm newborns. Thirty-nine infants (gestational age (GA) 24-27 ± 6 weeks) who underwent neuromonitoring using aEEG during the first two days after birth were enrolled. The rate of spontaneous activity transients per minute (SAT rate) and inter-SAT interval (ISI) in seconds were computed. Two postnatal time-points were examined: within 12 h (day 1) and between 24 and 48 h (day 2). IPs were measured in plasma from cord blood (cb-IPs) and between 24 and 48 h (pl-IPs). Multivariable regression analyses were performed to assess the correlation between IPs and brain activity. Cb-IPs were not associated with SAT rate and ISI at day 1. Higher pl-IPs were followed by longer ISI (R = 0.68; p = 0.034) and decreased SAT rate (R = 0.58; p = 0.007) at day 2 after adjusting for GA, FiO 2 and IVH. Higher pl-IPs levels are associated with decreased functional brain activity. Thus, pl-IPs may represent a useful biomarker of brain vulnerability in high-risk infants.

Central line associated bloodstream infections (CLABSI) with Staphylococcus epidermidis are a major cause of morbidity in neonates, who have an increased risk of infection because of their immature immune system. As especially preterm neonates suffer from antibody deficiency, clinical studies into preventive therapies have thus far focused on antibody supplementation with pooled intravenous immunoglobulins from healthy donors (IVIG) but with little success. Here we study the potential of monoclonal antibodies (mAbs) against S. epidermidis to induce phagocytic killing by human neutrophils. Nine different mAbs recognizing Staphylococcal surface components were cloned and expressed as human IgG1s. In binding assays, clones rF1, CR5133 and CR6453 showed the strongest binding to S. epidermidis ATCC14990 and CR5133 and CR6453 bound the majority of clinical isolates from neonatal sepsis (19 out of 20). To study the immune-activating potential of rF1, CR5133 and CR6453, bacteria were opsonized with mAbs in the presence or absence of complement. We observed that activation of the complement system is essential to induce efficient phagocytosis of S. epidermidis . Complement activation and phagocytic killing could be enhanced by Fc-mutations that improve IgG1 hexamerization on cellular surfaces. Finally, we studied the ability of the mAbs to activate complement in r-Hirudin neonatal plasma conditions. We show that classical pathway complement activity in plasma isolated from neonatal cord blood is comparable to adult levels. Furthermore, mAbs could greatly enhance phagocytosis of S. epidermidis in neonatal plasma. Altogether, our findings provide insights that are crucial for optimizing anti- S. epidermidis mAbs as prophylactic agents for neonatal CLABSI., Competing Interests: FB is affiliated with Genmab. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 de Vor, Beudeker, Flier, Scheepmaker, Aerts, Vijlbrief, Bekker, Beurskens, van Kessel, de Haas, Rooijakkers and van der Flier.)

Infants developing necrotizing enterocolitis (NEC) have a different metabolomic profile compared to controls. The potential of specific metabolomics, i.e. amino acids and amino alcohols (AAA), as early diagnostic biomarkers for NEC is largely unexplored. In this multicenter prospective case-control study, longitudinally collected fecal samples from preterm infants (born <30 weeks of gestation) from 1-3 days before diagnosis of severe NEC (Bell's stage IIIA/IIIB), were analyzed by targeted high-performance liquid chromatography (HPLC). Control samples were collected from gestational and postnatal age-matched infants. Thirty-one NEC cases (15 NEC IIIA;16 NEC IIIB) with 1:1 matched controls were included. Preclinical samples of infants with NEC were characterized by five increased essential amino acids-isoleucine, leucine, methionine, phenylalanine and valine. Lysine and ethanolamine ratios were lower prior to NEC, compared to control samples. A multivariate model was rendered based on isoleucine, lysine, ethanolamine, tryptophan and ornithine, modestly discriminating cases from controls (AUC 0.67; p < 0.001). Targeted HPLC pointed to several specific AAA alterations in samples collected 1-3 days before NEC onset, compared to controls. Whether this reflects metabolic alterations and has a role in early biomarker development for NEC, has yet to be elucidated., (© 2022. The Author(s).)

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., (© 2021. The Author(s).)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tataranno, Vijlbrief, Dudink and Benders.)

Necrotizing enterocolitis (NEC) is one of the most common and lethal gastrointestinal diseases in preterm infants. Early recognition of infants in need for surgical intervention might enable early intervention. In this multicenter case-control study, performed in nine neonatal intensive care units, preterm born infants (< 30 weeks of gestation) diagnosed with NEC (stage ≥ IIA) between October 2014 and August 2017 were divided into two groups: (1) medical (conservative treatment) and (2) surgical NEC (sNEC). Perinatal, clinical, and laboratory parameters were collected daily up to clinical onset of NEC. Univariate and multivariate logistic regression analyses were applied to identify potential predictors for sNEC. In total, 73 preterm infants with NEC (41 surgical and 32 medical NEC) were included. A low gestational age (p value, adjusted odds ratio [95%CI]; 0.001, 0.91 [0.86-0.96]), no maternal corticosteroid administration (0.025, 0.19 [0.04-0.82]), early onset of NEC (0.003, 0.85 [0.77-0.95]), low serum bicarbonate (0.009, 0.85 [0.76-0.96]), and a hemodynamically significant patent ductus arteriosus for which ibuprofen was administered (0.003, 7.60 [2.03-28.47]) were identified as independent risk factors for sNEC.Conclusions: Our findings may support the clinician to identify infants with increased risk for sNEC, which may facilitate early decisive management and consequently could result in improved prognosis. What is Known: • In 27-52% of the infants with NEC, a surgical intervention is indicated during its disease course. • Absolute indication for surgical intervention is bowel perforation, whereas fixed bowel loop or clinical deterioration highly suggestive of bowel perforation or necrosi, is a relative indication. What is New: • Lower gestational age, early clinical onset, and no maternal corticosteroids administration are predictors for surgical NEC. • Low serum bicarbonate in the 3 days prior clinical onset and patent ductus arteriosus for which ibuprofen was administered predict surgical NEC.

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Coviello, Perrone, Buonocore, Negro, Longini, Dani, de Vries, Groenendaal, Vijlbrief, Benders and Tataranno.)

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., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

Background: Late onset sepsis (LOS) in preterm infants is preceded by fecal volatile organic compound (VOC) alterations, suggesting an etiologic role of gut microbiota in LOS rather than being primarily caused by central venous catheters (CVC). To increase our knowledge about the involvement of the gut microbiota in LOS, we analyzed fecal samples from septic infants without a CVC., Methods: In this prospective multicenter study, fecal samples were collected daily from all infants born at ≤30 weeks gestation. Fecal VOC profiles up to 3 days prior to sepsis onset from infants with non-catheter-related LOS were compared with profiles from non-septic controls by means of High-Field Asymmetric Waveform Ion Mobility Spectrometry., Results: In total, 104 fecal samples were analyzed. Fecal VOC profiles allowed for discrimination between non-catheter-related LOS cases (n = 24) and matched controls (n = 25). Discriminative accuracy increased after focusing on center of origin (area under the curve, sensitivity, specificity; 0.95, 100%, 83%) and after focusing on LOS cases caused by Staphylococcus epidermidis (0.95, 100%, 78%), the most cultured pathogen (n = 11)., Conclusions: Fecal VOC profiles of preterm LOS infants without a CVC differed from matched controls underlining the increasing notion that aberrations in gut microbiota composition and activity may play a role in LOS etiology.

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.

Over 75% of severely thrombocytopenic neonates receive platelet transfusions, though little evidence supports this practice, and only 10% develop major bleeding. In a recent randomized trial, giving platelet transfusions at a threshold platelet count of 50x10 9 /L compared to a threshold of 25x10 9 /L was associated with an increased risk of major bleeding or mortality. This finding highlights the need for improved and individualized guidelines on neonatal platelet transfusion, which require accurate prediction of bleeding risk. Therefore, the objective of this study was to develop a dynamic prediction model for major bleeding in thrombocytopenic preterm neonates. This model allows for calculation of bleeding risk at any time-point during the first week after the onset of severe thrombocytopenia. In this multicenter cohort study, we included neonates with a gestational age <34 weeks, admitted to a neonatal intensive care unit, who developed severe thrombocytopenia (platelet count <50x10 9 /L). The study endpoint was major bleeding. We obtained predictions of bleeding risk using a proportional baselines landmark supermodel. Of 640 included neonates, 71 (11%) had a major bleed. We included the variables gestational age, postnatal age, intrauterine growth retardation, necrotizing enterocolitis, sepsis, platelet count and mechanical ventilation in the model. The median cross-validated c-index was 0.74 (interquartile range, 0.69-0.82). This is a promising dynamic prediction model for bleeding in this population that should be explored further in clinical studies as a potential instrument for supporting clinical decisions. The study was registered at www.clinicaltrials.gov (NCT03110887)., (Copyright© 2019 Ferrata Storti Foundation.)

Background: Late-onset sepsis (LOS) in preterm infants is a leading cause of mortality and morbidity. Timely recognition and initiation of antibiotics are important factors for improved outcomes. Identification of risk factors could allow selection of infants at an increased risk for LOS., Objectives: The aim was to identify risk factors for LOS., Methods: In this multicenter case-control study, preterm infants born at ≤30 weeks of gestation were included at 9 neonatal intensive care units. Detailed demographical and clinical data were collected daily up to day 28 postnatally. Clinical and demographic risk factors were identified using univariate and multivariate regression analyses in a 1: 1 matched case-control cohort., Results: In total, 755 infants were included, including 194 LOS cases (41 gram-negative cases, 152 gram-positive cases, and 1 fungus). In the case-control cohort, every additional day of parenteral feeding increased the risk for LOS (adjusted OR = 1.29; 95% CI 1.07-1.55; p = 0.006), whereas antibiotics administration decreased this risk (OR = 0.08; 95% CI 0.01-0.88; p = 0.039). These findings could largely be attributed to specific LOS-causative pathogens, since these predictive factors could be identified for gram-positive, but not for gram-negative, LOS cases. Specifically cephalosporins administration prior to clinical onset was inversely related to coagulase-negative staphylococcus LOS (CoNS-LOS) development. Formula feeding was an independent risk factor for development of CoNS-LOS (OR = 3.779; 95% CI 1.257-11.363; p = 0.018)., Conclusion: The length of parenteral feeding was associated with LOS, whereas breastmilk administration was protective against CoNS-LOS. A rapid advancement of enteral feeding, preferably with breastmilk, may proportionally reduce the number of parenteral feeding days and consequently the risk for LOS., (© 2019 The Author(s) Published by S. Karger AG, Basel.)

Background: The intestinal microbiota has increasingly been considered to play a role in the etiology of late-onset sepsis (LOS). We hypothesize that early alterations in fecal volatile organic compounds (VOCs), reflecting intestinal microbiota composition and function, allow for discrimination between infants developing LOS and controls in a preclinical stage., Methods: In 9 neonatal intensive care units in the Netherlands and Belgium, fecal samples of preterm infants born at a gestational age ≤30 weeks were collected daily, up to the postnatal age of 28 days. Fecal VOC were measured by high-field asymmetric waveform ion mobility spectrometry (FAIMS). VOC profiles of LOS infants, up to 3 days prior to clinical LOS onset, were compared with profiles from matched controls., Results: In total, 843 preterm born infants (gestational age ≤30 weeks) were included. From 127 LOS cases and 127 matched controls, fecal samples were analyzed by means of FAIMS. Fecal VOCs allowed for preclinical discrimination between LOS and control infants. Focusing on individual pathogens, fecal VOCs differed significantly between LOS cases and controls at all predefined time points. Highest accuracy rates were obtained for sepsis caused by Escherichia coli, followed by sepsis caused by Staphylococcus aureus and Staphylococcus epidermidis., Conclusions: Fecal VOC analysis allowed for preclinical discrimination between infants developing LOS and matched controls. Early detection of LOS may provide clinicians a window of opportunity for timely initiation of individualized therapeutic strategies aimed at prevention of sepsis, possibly improving LOS-related morbidity and mortality.

Background: Fetal growth restriction (FGR) is associated with an increased risk for kidney disease in later life. Studies reporting on early signs of renal disturbances in FGR are sparse and mostly include invasive measurements, which limit the possibility for early identification and prevention. We aim to investigate whether renal tissue oxygen saturation (rSO2) measured with near-infrared spectroscopy (NIRS) and the derived value fractional tissue oxygen extraction (FTOE) differ between premature FGR and control neonates in the first three days after birth., Methods: Nine FGR and seven control neonates born <32 weeks of gestation were included. FGR was defined as biometry

Background: Much controversy exists about the optimal management of a patent ductus arteriosus (PDA) in preterm infants, especially in those born at a gestational age (GA) less than 28 weeks. No causal relationship has been proven between a (haemodynamically significant) PDA and neonatal complications related to pulmonary hyperperfusion and/or systemic hypoperfusion. Although studies show conflicting results, a common understanding is that medical or surgical treatment of a PDA does not seem to reduce the risk of major neonatal morbidities and mortality. As the PDA might have closed spontaneously, treated children are potentially exposed to iatrogenic adverse effects. A conservative approach is gaining interest worldwide, although convincing evidence to support its use is lacking., Methods: This multicentre, randomised, non-inferiority trial is conducted in neonatal intensive care units. The study population consists of preterm infants (GA < 28 weeks) with an echocardiographic-confirmed PDA with a transductal diameter > 1.5 mm. Early treatment (between 24 and 72 h postnatal age) with the cyclooxygenase inhibitor (COXi) ibuprofen (IBU) is compared with an expectative management (no intervention intended to close a PDA). The primary outcome is the composite of mortality, and/or necrotising enterocolitis (NEC) Bell stage ≥ IIa, and/or bronchopulmonary dysplasia (BPD) defined as the need for supplemental oxygen, all at a postmenstrual age (PMA) of 36 weeks. Secondary outcome parameters are short term sequelae of cardiovascular failure, comorbidity and adverse events assessed during hospitalization and long-term neurodevelopmental outcome assessed at a corrected age of 2 years. Consequences regarding health economics are evaluated by cost effectiveness analysis and budget impact analysis., Discussion: As a conservative approach is gaining interest, we investigate whether in preterm infants, born at a GA less than 28 weeks, with a PDA an expectative management is non-inferior to early treatment with IBU regarding to the composite outcome of mortality and/or NEC and/or BPD at a PMA of 36 weeks., Trial Registration: This trial is registered with the Dutch Trial Register NTR5479 (registered on 19 October 2015), the 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 .

Background: Surgical treatment of critical aortic coarctation (CoA) is difficult in very low birth weight (VLBW) infants ≤1500 g and preferably postponed until 3 kg with prostaglandins (PGE)., Objectives: To investigate the procedure and outcome of primary coronary stent implantation as bridging therapy to surgery in VLBW infants with CoA., Methods: Retrospective evaluation of primary CoA stenting in VLBW infants from 2010 to 2015., Results: Five VLBW infants with a median gestational age of 29 weeks (27-32) underwent primary CoA stenting. Indication was cardiac failure in 4 and severe hypertension in 1 patient. Age and weight at intervention were 14 days (range 12-16) and 1200 g (680-1380), respectively. Stent diameter ranged 3-5 mm. The femoral artery used for intervention was occluded in all infants without clinical compromise. Severe restenosis and aneurysm occurred in 1 VLBW infant and was successfully treated with covered coronary stents. Median age at surgical correction was 200 days (111-804) and weight 5500 g (4500-11,400). No reinterventions were required during a median postoperative follow-up of 2.8 years (0.1-5.0). Neurodevelopmental outcomes were normal and comparable between patients and siblings (4/5 gemelli)., Conclusions: Primary coronary stent implantation in VLBW infants with critical CoA is a feasible bridging therapy to surgery., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: Brain injury in neonates born prematurely is associated strongly with poor neurodevelopmental outcome. The aim of this study was to evaluate whether tocolysis with nifedipine or atosiban in women with threatened preterm birth can reduce the incidence of overall brain injury in neonates born prematurely., Methods: This was a secondary analysis of the APOSTEL-III trial (Dutch Clinical Trial Registry, no. NTR2947), a randomized clinical trial in which women with threatened preterm labor between 25 and 34 weeks of gestation were allocated to treatment with nifedipine or atosiban. In this secondary analysis, women delivered at ≤ 32 weeks of gestational age in the two main contributing centers were included. Primary outcome was the presence of neonatal brain injury, which was defined as presence of abnormalities on ultrasound investigation and classified into mild and severe. To evaluate type and severity of brain injury, all neonatal ultrasounds performed during neonatal intensive and medium care admission were analyzed. To test the robustness of our results, a sensitivity analysis was performed assessing differences in baseline or known risk factors for brain injury., Results: A total of 117 neonates (from 102 women) were studied, of which 51 had been exposed to nifedipine and 66 to atosiban. Brain injury was observed in 22 (43.1%) neonates in the nifedipine group compared with 37 (56.1%) in the atosiban group (OR, 0.60; 95% CI, 0.29-1.24). Presence of mild brain injury was comparable between the nifedipine (33.3%) and atosiban (48.5%) groups (OR, 0.53; 95% CI, 0.25-1.13). Severe brain injury was also comparable between the groups, observed in 9.8% of neonates in the nifedipine vs 7.6% of those in the atosiban group (OR, 1.33; 95% CI, 0.36-4.85). Intraventricular hemorrhage (≥ Grade I) was the most frequently seen ultrasound abnormality, observed in 18 (35.3%) neonates in the nifedipine group vs 25 (37.9%) in the atosiban group (OR, 0.90; 95% CI, 0.42-1.91). The sensitivity analysis, with adjustment for maternal age and gestational age at randomization, showed no statistical difference between the groups for presence of brain injury (OR, 0.58; 95% CI, 0.27-1.27)., Conclusion: In children born before 32 weeks of gestation after the use of tocolytics, the prevalence of brain injury was high. No significant differences were found with respect to overall brain injury between neonates exposed to nifedipine and those exposed to atosiban. However, as this study was a secondary analysis of the APOSTEL III trial, it was underpowered for brain injury. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.)

Background: In critically ill (preterm) neonates, central venous catheters (CVCs) are increasingly used for administration of medication or parenteral nutrition. A serious complication, however, is the development of catheter-related thrombosis (CVC-thrombosis), which may resolve by itself or cause severe complications. Due to lack of evidence, management of neonatal CVC-thrombosis varies among neonatal intensive care units (NICUs). In the Netherlands an expert-based national management guideline has been developed which is implemented in all 10 NICUs in 2014., Methods: The NEOCLOT study is a multicentre prospective observational cohort study, including 150 preterm and term infants (0-6 months) admitted to one of the 10 NICUs, developing CVC-thrombosis. Patient characteristics, thrombosis characteristics, risk factors, treatment strategies and outcome measures will be collected in a web-based database. Management of CVC-thrombosis will be performed as recommended in the protocol. Violations of the protocol will be noted. Primary outcome measures are a composite efficacy outcome consisting of death due to CVC-thrombosis and recurrent thrombosis, and a safety outcome consisting of the incidence of major bleedings during therapy. Secondary outcomes include individual components of primary efficacy outcome, clinically relevant non-major and minor bleedings and the frequency of risk factors, protocol variations, residual thrombosis and post thrombotic syndrome., Discussion: The NEOCLOT study will evaluate the efficacy and safety of the new, national, neonatal CVC-thrombosis guideline. Furthermore, risk factors as well as long-term consequences of CVC-thrombosis will be analysed., Trial Registration: Trial registration: Nederlands Trial Register NTR4336 . Registered 24 December 2013.

This systematic review investigated the effectiveness of vaccinating healthcare workers against pertussis on the occurrence of nosocomial pertussis outbreaks or infections among unprotected infants. We focused on eight studies, with five different study designs, that involved 39,129 healthy adolescents and adults, 115 healthcare workers, 2000 simulated healthcare workers and a simulated population of 200,000 people., Conclusion: There was moderate evidence that tetanus-diphtheria acellular pertussis vaccinations for healthcare workers were effective in preventing pertussis in all age groups and specifically in infants. The results must be interpreted with caution due to the low quality and heterogeneity of the studies., (©2017 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

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., (© 2018 The Author(s) Published by S. Karger AG, Basel.)

Objective: The aim of this study was to identify inter-centre differences in persistent ductus arteriosus treatment and their related outcomes. Materials and methods We carried out a retrospective, multicentre study including infants between 24+0 and 27+6 weeks of gestation in the period between 2010 and 2011. In all centres, echocardiography was used as the standard procedure to diagnose a patent ductus arteriosus and to document ductal closure., Results: In total, 367 preterm infants were included. All four participating neonatal ICU had a comparable number of preterm infants; however, differences were observed in the incidence of treatment (33-63%), choice and dosing of medication (ibuprofen or indomethacin), number of pharmacological courses (1-4), and the need for surgical ligation after failure of pharmacological treatment (8-52%). Despite the differences in treatment, we found no difference in short-term morbidity between the centres. Adjusted mortality showed independent risk contribution of gestational age, birth weight, ductal ligation, and perinatal centre., Conclusions: Using benchmarking as a tool identified inter-centre differences. In these four perinatal centres, the factors that explained the differences in patent ductus arteriosus treatment are quite complex. Timing, choice of medication, and dosing are probably important determinants for successful patent ductus arteriosus closure.

Background: Impairment of gas and substrate exchange through the placenta leads to fetal hypoxia and growth restriction. Oxygenation of vital organs is maintained with preferential perfusion at the expense of less vital organs, challenging the fetal cardiovascular system., Objectives: To identify cardiovascular compromise in preterm small for gestational age (SGA) infants using the cardiac biomarker B-type natriuretic peptide (BNP), which indicates the workload of the myocardium., Methods: In this retrospective case-control study, 26 SGA infants born at less than 32 weeks of gestation from October 2009 to October 2010 were matched for gestational age and month of birth with 26 appropriate for gestational age (AGA) infants. Antenatal Doppler ultrasound was used to identify fetal hemodynamic changes by determination of the pulsatility index (PI) of the middle cerebral artery (MCA-PI), umbilical artery (UA-PI) and veins of the ductus venosus (DV-PIV). These indices were compared with BNP levels obtained within 6 h after birth., Results: Antenatal PIs of MCA, UA and DV were significantly related to elevated BNP levels after birth in SGA infants, but not in AGA infants (SGA: MCA-PI = r(2) 0.23, p < 0.05; UA-PI = r(2) 0.46, p < 0.01; DV-PIV = r(2) 0.31, p < 0.05). Furthermore, signs of perinatal (chronic) asphyxia coincided with elevated levels of BNP. SGA was related to more postnatal cardiocirculatory complications. No significant relations between postnatal cardiac ultrasound measurements, placenta size and BNP were found., Conclusion: BNP levels were elevated early after birth in SGA infants and corresponded positively with Doppler indices of circulatory compromise. This suggests an increased workload of the myocardium.

Cardiac biomarkers are used to identify cardiac disease in term and preterm infants. This review discusses the roles of natriuretic peptides and cardiac troponins. Natriuretic peptide levels are elevated during atrial strain (atrial natriuretic peptide (ANP)) or ventricular strain (B-type natriuretic peptide (BNP)). These markers correspond well with cardiac function and can be used to identify cardiac disease. Cardiac troponins are used to assess cardiomyocyte compromise. Affected cardiomyocytes release troponin into the bloodstream, resulting in elevated levels of cardiac troponin. Cardiac biomarkers are being increasingly incorporated into clinical trials as indicators of myocardial strain. Furthermore, cardiac biomarkers can possibly be used to guide therapy and improve outcome. Natriuretic peptides and cardiac troponins are potential tools in the diagnosis and treatment of neonatal disease that is complicated by circulatory compromise. However, clear reference ranges need to be set and validation needs to be carried out in a population of interest.

Background: Little is known about the effects of hypothermia on the cardiovascular system in term newborns with neonatal encephalopathy., Objectives: To evaluate whether mild hypothermia for neonatal encephalopathy is cardioprotective as indicated by the cardiac biomarkers cardiac troponin I (cTnI) and B-type natriuretic peptide (BNP)., Methods: This was an observational cohort study of infants treated for perinatal asphyxia. In infants, mild total body hypothermia treatment of 33.5°C during 72 h was initiated (n = 20). Samples of cTnI and BNP were collected before the start of hypothermia, at 24 and 48 h after birth, and after rewarming (84 h). BNP and cTnI values were then compared with BNP and cTnI values of asphyxiated infants not treated with hypothermia (n = 28)., Results: No differences were found between the groups in clinical patient characteristics or inotropic support. The hypothermia-treated patients seemed to be clinically more affected (5-min Apgar score, p < 0.05; umbilical artery pH, p = 0.08), but showed similar encephalopathy scores. Significantly lower values for BNP were found in hypothermia- compared to nonhypothermia-treated infants at 48 h and at normothermia after rewarming [144 pmol/l (95-286) vs. 75 pmol/l (45-143), 182 pmol/l (73-341) vs. 43 pmol/l (24-163)]. No differences were found for cTnI concentrations between both groups., Conclusions: The raised, but similar, cTnI values between hypothermia- and nonhypothermia-treated infants indicate similar myocardial damage in both groups. The lower BNP levels during hypothermia treatment suggest that hypothermia after perinatal asphyxia exerts a beneficial effect on cardiac function., (Copyright © 2012 S. Karger AG, Basel.)

Aim: The incidence of necrotizing enterocolitis (NEC) strongly increased in an neonatal intensive care unit (NICU) in 1997 and 1998 compared with previous years, which coincided with increased incidence of nosocomial sepsis. Specific risk factors related to this NICU and a possible relationship between NEC and nosocomial sepsis were studied retrospectively, including all patients with NEC since 1990 and matched controls., Methods: Clinical and bacteriological data from the period before the development of NEC and a similar period for the controls were collected retrospectively and corrected for birthweight and gestational age. Statistical analysis was performed by a stepwise regression model., Results: Data of 104 neonates with NEC and matched controls were analysed. The median day of onset of NEC was 12 d (range 1-63 d). Significant risk factors for NEC were: insertion of a peripheral artery catheter [odds ratio (OR) 2.3, 95% confidence interval (95% CI) 1.3-3.9] and a central venous catheter (OR 5.6, 95% CI 3.1-10.1), colonization with Klebsiella sp. (OR 3.4, 95% CI 1.5-7.5) and Escherichia coli (OR 2.1, 95% CI 1.0-4.5), and the occurrence of sepsis, in particular due to coagulase-negative staphylococci (OR 2.6, 95% CI 1.4-5.1). The risk for NEC was decreased after the early use (< 48 h after birth) of amoxicillin-clavulanate and gentamicin (OR 0.3, 95% CI 0.2-0.6)., Conclusion: Insertion of central venous and peripheral arterial catheters is positively associated with NEC, as is colonization with the Gram-negative bacilli Klebsiella and E. coli and the occurrence of sepsis, particularly due to coagulase-negative staphylococci. Early treatment with amoxicillin-clavulanate and gentamicin is negatively associated with NEC and may be protective against NEC.