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Introduction: Using pre-procedure analgesia with the risk of apnoea may complicate the Less Invasive Surfactant Administration (LISA) procedure or reduce the effect of LISA., Methods: The NONA-LISA trial (ClinicalTrials.gov, NCT05609877) is a multicentre, blinded, randomised controlled trial aiming at including 324 infants born before 30 gestational weeks, meeting the criteria for surfactant treatment by LISA. Infants will be randomised to LISA after administration of fentanyl 0.5-1 mcg/kg intravenously (fentanyl group) or isotonic saline solution intravenously (saline group). All infants will receive standardised non-pharmacological comfort care before and during the LISA procedure. Additional analgesics will be provided at the clinician's discretion. The primary outcome is the need for invasive ventilation, meaning mechanical or manual ventilation via an endotracheal tube, for at least 30 min (cumulated) within 24 h of the procedure. Secondary outcomes include the modified COMFORTneo score during the procedure, bronchopulmonary dysplasia at 36 weeks, and mortality at 36 weeks., Discussion: The NONA-LISA trial has the potential to provide evidence for a standardised approach to relief from discomfort in preterm infants during LISA and to reduce invasive ventilation. The results may affect future clinical practice., Impact: Pre-procedure analgesia is associated with apnoea and may complicate procedures that rely on regular spontaneous breathing, such as Less Invasive Surfactant Administration (LISA). This randomised controlled trial addresses the effect of analgesic premedication in LISA by comparing fentanyl with a placebo (isotonic saline) in infants undergoing the LISA procedure. All infants will receive standardised non-pharmacological comfort. The NONA-LISA trial has the potential to provide evidence for a standardised approach to relief from discomfort or pain in preterm infants during LISA and to reduce invasive ventilation. The results may affect future clinical practice regarding analgesic treatment associated with the LISA procedure., (© 2024. The Author(s).)

Background: Bovine colostrum (BC) contains a range of milk bioactive components, and it is unknown how human milk fortification with BC affects glucose-regulatory hormones in very preterm infants (VPIs). This study aimed to investigate the associations between hormone concentrations and fortification type, birth weight (appropriate/small for gestational age, AGA/SGA), milk intake, postnatal age, and body growth., Methods: 225 VPIs were randomized to fortification with BC or conventional fortifier (CF). Plasma hormones were measured before, one and two weeks after start of fortification. ΔZ-scores from birth to 35 weeks postmenstrual age were calculated., Results: Compared with CF, infants fortified with BC had higher plasma GLP-1, GIP, glucagon, and leptin concentrations after start of fortification. Prior to fortification, leptin concentrations were negatively associated with growth, while IGF-1 concentrations associated positively with growth during fortification. In AGA infants, hormone concentrations generally increased after one week of fortification. Relative to AGA infants, SGA infants showed reduced IGF-1 and leptin concentrations., Conclusion: Fortification with BC increased the plasma concentrations of several glucose-regulatory hormones. Concentrations of IGF-1 were positively, and leptin negatively, associated with growth. Glucose-regulatory hormone levels were affected by birth weight, milk intake and postnatal age, but not closely associated with growth in VPIs., Impact: Little is known about the variation in glucose-regulatory hormones in the early life of very preterm infants (VPIs). This study shows that the levels of glucose-regulatory hormones in plasma of VPIs are highly variable and modified by birth weight (appropriate or small for gestational age, AGA or SGA), the type of fortifier, enteral nutritional intake, and advancing postnatal age. The results confirm that IGF-1 levels are positively associated with early postnatal growth in VPIs, yet the levels of both IGF-1 and other glucose-regulatory hormones appeared to explain only a small part of the overall variation in growth rates., (© 2024. The Author(s).)

Objectives: The safety and feasibility of human milk fortification with bovine colostrum (BC) were investigated in very preterm infants (FortiColos trial, NCT03537365). The BC product contained lower calcium, phosphate, and iron levels compared to the conventional fortifier (CF). We tested whether fortification with BC plus extra phosphate was sufficient to support the infants' mineral status assessed by blood biochemistry., Methods: In a randomised controlled trial (FortiColos, NCT03537365), mineral status was compared after fortification with BC versus CF. Blood calcium, phosphate, and haemoglobin were determined before and up to 3 weeks after the start of fortification (at the mean age of 8-9 days). The maximum supplemental doses of calcium, phosphate, and iron given were retrieved from patient medical records. Results were adjusted for gestational age, birth weight, and enteral nutrition with the mother's own milk and/or donor human milk., Results: Blood values of calcium, phosphate, and haemoglobin were similar between groups. Infants in both groups required supplementation with calcium and phosphate, but infants fed BC required higher maximum doses of phosphate and calcium (p < 0.05) to maintain acceptable blood values. Regardless of fortification groups, the most immature (<29 weeks of gestation) and small for gestational age infants showed a higher risk for requiring additional phosphate (odds ratio [OR]: 3.9, p < 0.001; OR: 2.14, p = 0.07, respectively)., Conclusions: The use of BC as a fortifier for human milk requires additional phosphate and calcium relative to a CF. Regardless of the fortification product, the most immature and small infants require additional mineral supplementation., (© 2024 The Authors. Journal of Pediatric Gastroenterology and Nutrition published by Wiley Periodicals LLC on behalf of European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background: For very preterm infants, human milk is often fortified with formula products based on processed bovine milk. Intact bovine colostrum (BC), rich in anti-inflammatory milk factors, is considered an alternative. We investigated if BC affects anti-inflammatory/T H 2 immunity and infection risk in very preterm infants., Methods: For a secondary analysis of a multicenter, randomized controlled trial (NCT03537365), very preterm infants (26-31 weeks gestation, 23% small for gestational age, SGA) were randomized to receive BC (ColoDan, Biofiber, Denmark, n = 113) or conventional fortifier (PreNAN, Nestlé, Switzerland, n = 116). Infection was defined as antibiotic treatment for five or more consecutive days and 29 cytokines/chemokines were measured in plasma before and after start of fortification., Results: In general, infection risk after start of fortification was associated with low gestational age, SGA status and antibiotics use prior to fortification. Adjusted for confounders, infants fortified with BC showed more infection episodes (20 vs 12%, P < 0.05) and higher cumulative infection risk (hazard ratio, HR 1.9, P = 0.06), particularly for SGA infants (HR 3.6, P < 0.05). Additionally, BC-fortified infants had higher levels of T H 2-related cytokines/chemokines (IL-10, MDC, MCP4) and reduced levels of cytokines related to T H 1/T H 17-responses (IL-15, IL-17, GM-CSF). The differences were most pronounced in SGA infants, displaying higher levels of T H 2-related IL-4, IL-6, and IL-13, and lower interferon-γ and IL-1α levels in the BC group., Conclusion: Infants fortified with BC displayed a delayed shift from T H 2- to T H 1-biased systemic immunity, notably in SGA infants, possibly influenced by multiple confounding factors, alongside elevated antibiotic use, suggesting increased susceptibility to infection., (© 2024. The Author(s).)

Introduction: Simulation-based training (SBT) aids healthcare providers in acquiring the technical skills necessary to improve patient outcomes and safety. However, since SBT may require significant resources, training all skills to a comparable extent is impractical. Hence, a strategic prioritization of technical skills is necessary. While the European Training Requirements in Neonatology provide guidance on necessary skills, they lack prioritization. We aimed to identify and prioritize technical skills for a SBT curriculum in neonatology., Methods: A three-round modified Delphi process of expert neonatologists and neonatal trainees was performed. In round one, the participants listed all the technical skills newly trained neonatologists should master. The content analysis excluded duplicates and non-technical skills. In round two, the Copenhagen Academy for Medical Education and Simulation Needs Assessment Formula (CAMES-NAF) was used to preliminarily prioritize the technical skills according to frequency, importance of competency, SBT impact on patient safety, and feasibility for SBT. In round three, the participants further refined and reprioritized the technical skills. Items achieving consensus (agreement of ≥75%) were included., Results: We included 168 participants from 10 European countries. The response rates in rounds two and three were 80% (135/168) and 87% (117/135), respectively. In round one, the participants suggested 1964 different items. Content analysis revealed 81 unique technical skills prioritized in round two. In round three, 39 technical skills achieved consensus and were included., Conclusion: We reached a European consensus on a prioritized list of 39 technical skills to be included in a SBT curriculum in neonatology., (© 2024 S. Karger AG, Basel.)

Fecal filtrate transfer (FFT) is emerging as a safer alternative to traditional fecal microbiota transplantation (FMT) - particularly in the context of necrotizing enterocolitis (NEC), a severe gastrointestinal condition affecting preterm infants. Using a preterm piglet model, FFT has demonstrated superiority over FMT in safety and NEC prevention. Since FFT is virtually devoid of bacteria, prokaryotic viruses (bacteriophages) are assumed to mediate the beneficial effects. However, this assumption remains unproven. To address this gap, we separated virus-like particles (30 kDa to 0.45 µm) of donor feces from the residual postbiotic fluid. We then compared clinical and gut microbiota responses to these fractions with the parent FFT solution after transferring them to NEC-susceptible preterm piglets. Virome transfer was equally effective as FFT in reducing the severity of NEC-like pathology. The bacterial compositional data corroborated clinical findings as virome transfer reduced the relative abundance of several NEC-associated pathogens e.g. Klebsiella pneumoniae and Clostridium perfringens . Virome transfer diversified gut viral communities with concomitant constraining effects on the bacterial composition. Unexpectedly, virome transfer, but not residual postbiotic fluid, led to earlier diarrhea. While diarrhea may be a minor concern in human infants, future work should identify ways of eliminating this side effect without losing treatment efficacy.

Background: Preterm infants show low blood levels of insulin-like growth factor 1 (IGF-1), known to be negatively correlated with Interleukin-6 (IL-6). We hypothesized that circulating IGF-1 is associated with systemic immune-markers following preterm birth and that exogenous IGF-1 supplementation modulates immune development in preterm pigs, used as model for preterm infants., Methods: Plasma levels of IGF-1 and 29 inflammatory markers were measured in very preterm infants (n = 221). In preterm pigs, systemic immune development, assessed by in vitro challenge, was compared between IGF-1 treated (2.25 mg/kg/day) and control animals., Results: Preterm infants with lowest gestational age and birth weight showed the lowest IGF-1 levels, which were correlated not only with IL-6, but a range of immune-markers. IGF-1 supplementation to preterm pigs reduced plasma IL-10 and Interferon-γ (IFN-γ), IL-2 responses to challenge and reduced expression of genes related to Th1 polarization. In vitro addition of IGF-1 (100 ng/mL) further reduced the IL-2 and IFN-γ responses but increased IL-10 response., Conclusions: In preterm infants, plasma IGF-1 correlated with several immune markers, while supplementing IGF-1 to preterm pigs tended to reduce Th1 immune responses. Future studies should document whether IGF-1 supplementation to preterm infants affects immune development and sensitivity to infection., Impact: Supplementation of insulin-like growth factor 1 (IGF-1) to preterm infants has been proposed to promote postnatal growth, but its impact on the developing immune system is largely unknown. In a cohort of very preterm infants, low gestational age and birth weight were the primary predictors of low plasma levels of IGF-1, which in turn were associated with plasma immune markers. Meanwhile, in immature preterm pigs, experimental supplementation of IGF-1 reduced Th1-related immune responses in early life. Supplementation of IGF-1 to preterm infants may affect the developing immune system, which needs consideration when evaluating overall impact on neonatal health., (© 2023. The Author(s).)

Objective: To evaluate the implementation of switch from intravenous-to-oral antibiotic therapy with amoxicillin in neonates with early-onset infection (EOI)., Design, Setting and Patients: A population-based multicentre cohort study. All term-born neonates with EOI were prospectively included between 1 December 2018 to 30 November 2020., Intervention: Intravenous-to-oral switch antibiotic therapy in clinically stable neonates., Main Outcome Measures: The primary outcome was readmission due to infection. Secondary outcomes were days of hospitalisation and antibiotic use in the pre-implementation versus post implementation period., Results: During 2 years, 835 neonates commenced antibiotics for EOI (1.5% (95% CI 1.4% to 1.6%)) of all term live births). Of those, 554 (66%) underwent a full course of treatment. There were 23 episodes of culture-proven infection (0.42 per 1000 term live births (95% CI 0.27 to 0.63)). A total of 478 of 531 (90%) neonates with probable infection underwent switch therapy. None was readmitted due to infection. The median duration of hospitalisation was 3.0 days (IQR 2.5-3.5) and 7.4 days (IQR 7.0-7.5) in the switch and intravenous therapy groups, respectively. According to antibiotic surveillance data, 1.2% underwent a full course of treatment following implementation of oral switch therapy (2019-2020), compared with 1.2% before (2017-2018)., Conclusion: In clinical practice, switch therapy was safe and used in 9 of 10 neonates with probable EOI. Knowledge of the safety of antibiotic de-escalation is important as home-based oral therapy ameliorates the treatment burden for neonates, caregivers and healthcare systems. Despite the ease of oral administration, implementation of switch therapy did not increase the overall use of antibiotics., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: To determine if trial-related blood sampling increases the risk of later red blood cell (RBC) transfusion in very preterm infants, we compared the volume of clinical- and trial-related blood samples, in a specific trial and correlated to subsequent RBC transfusion., Methods: For 193 very preterm infants, participating in the FortiColos trial (NCT03537365), trial-related blood volume drawn was in accordance with ethical considerations established by the European Commission. Medical records were reviewed to assess the number and accumulated volume (mL/kg) of blood samples (both clinical- and trial-related). Data were compared with the need of RBC transfusions during the first 28 days of life., Results: Mean (SD) gestational age and birth weight was 28 ± 1 weeks and 1168 ± 301 g. In total, 11% of total blood volume was drawn for sampling (8.1 ± 5.1 mL/kg) and trial-related sampling accounted for 1.6 ± 0.6 mL/kg. Trial-related blood sampling had no impact on RBC transfusion (p = 0.9)., Conclusion: Clinical blood sampling in very preterm infants is associated with blood loss and subsequent need for RBC transfusions. In a specific trial requiring blood samples, we found no additional burden of trial-related blood sampling. The study suggests that trial-related sampling is safe if European criteria are followed., (© 2023 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Objective: To identify risk factors associated with methicillin-resistant Staphylococcus aureus (MRSA) colonization in neonatal patients during an MRSA outbreak to minimize future outbreaks., Design: Retrospective case-control study., Setting: Level-IV neonatal intensive care unit (NICU) at Copenhagen University Hospital, Rigshospitalet, Denmark., Patients: Neonates with either MRSA or methicillin-susceptible Staphylococcus aureus (MSSA)., Methods: Methicillin-resistant Staphylococcus aureus -positive neonates were matched with those colonized or infected with MSSA in a 1:1 ratio. The control group was selected from clinical samples, whereas MRSA-positive neonates were identified from clinical samples or from screening. A total of 140 characteristics were investigated to identify risk factors associated with MRSA acquisition. The characteristics were categorized into three categories: patient, unit, and microbiological characteristics., Results: Out of 1,102 neonates screened for MRSA, between December 2019 and January 2022, 33 were MRSA positive. They were all colonized with an MRSA outbreak clone ( spa type t127) and were included in this study. Four patients (12%) had severe infection. Admission due to respiratory diseases, need for intubation, need for peripheral venous catheters, admission to shared rooms with shared toilets and bath facilities in the aisles, and need for readmission were all correlated with later MRSA colonization ( P < 0.05)., Conclusion: We identified clinically relevant diseases, procedures, and facilities that predispose patients to potentially life-threatening MRSA infections. A specific MRSA reservoir remains unidentified; however, these findings have contributed to crucial changes in our NICU to reduce the number of MRSA infections and future outbreaks., Competing Interests: There was no conflict of interest., (© The Author(s) 2023.)

Context: Nonpharmacological strategies are increasingly used in pediatric procedures, but in pediatric MRI, sedation and general anesthesia are still commonly required., Objectives: To evaluate the effectiveness of nonpharmacological interventions in reducing use of sedation and general anesthesia in pediatric patients undergoing MRI, and to investigate effects on scan time, image quality, and anxiety., Data Sources: We searched Ovid Medline, CINAHL, Embase, and CENTRAL from inception through October 10, 2022., Study Selection: We included randomized controlled trials and quasi-experimental designs comparing the effect of a nonpharmacological intervention with standard care on use of sedation or general anesthesia, scan time, image quality, or child and parental anxiety among infants (<2 years), children, and adolescents (2-18 years) undergoing MRI., Data Extraction: Standardized instruments were used to extract data and assess study quality., Results: Forty-six studies were eligible for the systematic review. Limited to studies on children and adolescents, the meta-analysis included 20 studies with 33 873 patients. Intervention versus comparator analysis showed that nonpharmacological interventions were associated with reduced need for sedation and general anesthesia in the randomized control trials (risk ratio, 0.68; 95% confidence interval, 0.48-0.95; l2 = 35%) and nonrandomized studies (risk ratio, 0.58; 95% confidence interval, 0.51-0.66; l2 = 91%). The effect was largest among children aged 3 to 10 years when compared with older children and adolescents aged 11 to 18 years., Limitations: There was substantial heterogeneity among nonrandomized studies., Conclusions: Nonpharmacological interventions must be considered as standard procedure in infants, children, and adolescents undergoing MRI.

Background: Training and assessment of operator competence for the less invasive surfactant administration (LISA) procedure vary. This study aimed to obtain international expert consensus on LISA training (LISA curriculum (LISA-CUR)) and assessment (LISA assessment tool (LISA-AT))., Methods: From February to July 2022, an international three-round Delphi process gathered opinions from LISA experts (researchers, curriculum developers, and clinical educators) on a list of items to be included in a LISA-CUR and LISA-AT (Round 1). The experts rated the importance of each item (Round 2). Items supported by more than 80% consensus were included. All experts were asked to approve or reject the final LISA-CUR and LISA-AT (Round 3)., Results: A total of 153 experts from 14 countries participated in Round 1, and the response rate for Rounds 2 and 3 was >80%. Round 1 identified 44 items for LISA-CUR and 22 for LISA-AT. Round 2 excluded 15 items for the LISA-CUR and 7 items for the LISA-AT. Round 3 resulted in a strong consensus (99-100%) for the final 29 items for the LISA-CUR and 15 items for the LISA-AT., Conclusions: This Delphi process established an international consensus on a training curriculum and content evidence for the assessment of LISA competence., Impact: This international consensus-based expert statement provides content on a curriculum for the less invasive surfactant administration procedure (LISA-CUR) that may be partnered with existing evidence-based strategies to optimize and standardize LISA training in the future. This international consensus-based expert statement also provides content on an assessment tool for the LISA procedure (LISA-AT) that can help to evaluate competence in LISA operators. The proposed LISA-AT enables standardized, continuous feedback and assessment until achieving proficiency., (© 2023. The Author(s).)

Aim: In Denmark, preterm infants are recommended to receive childhood vaccinations without correction for gestational age. This study aimed to describe the timeliness of the Danish Childhood Vaccination Program in preterm infants during the first 13 months of life and to evaluate possible determinants of delay., Methods: This retrospective cohort study included preterm infants admitted to a level III neonatal intensive care unit between October 2019 and October 2020. Clinical data were retrieved from medical records and the Danish Vaccination Register. Timely vaccination was defined corresponding to chronological age of 3-, 5- and 12 months, within a time interval of 30 days before to 29 days after the expected date., Results: Analyses included 365 infants. Timely vaccination occurred in 91%, 83% and 67% of preterm infants for the first, second and third vaccination, respectively, and timeliness was highest if born before gestational age 28 weeks. Gestational age 28-31 + 6 weeks and delayed former vaccinations negatively influenced the timeliness of the following vaccinations., Conclusion: Most preterm infants received the first vaccination timely; however, timeliness decreased with each subsequent vaccination. Efforts to improve timeliness should focus on counselling healthcare personnel and parents to follow the recommendations for the first and the following vaccinations., (© 2023 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Background: Human milk for very preterm infants need fortification for optimal growth and development but the optimal fortification product remains to be identified., Aims: To investigate feasibility, safety and preliminary efficacy on growth and blood biochemistry when using intact bovine colostrum (BC) as a fortifier to human milk in very preterm infants., Methods: In an open-label, multicenter, randomized controlled pilot trial (infants 26-31 weeks' gestation), mother's own milk or donor human milk was fortified with powdered BC (n = 115) or a conventional fortifier (CF, bovine-milk-based, n = 117) until 35 weeks' postmenstrual age. Fortifiers and additional micronutrients were added to human milk according to local guidelines to achieve optimal growth (additional protein up to +1.4 g protein/100 mL human milk). Anthropometry was recorded weekly. Clinical morbidities including necrotizing enterocolitis (NEC) and late-onset sepsis (LOS) were recorded. Clinical biochemistry included plasma amino acid (AA) levels to assess protein metabolic responses to the new fortifier., Results: A total of 232 infants, gestational age (GA) 28.5 ± 1.4 (weeks + days), fulfilled inclusion criteria. Birthweight, GA and delta Z scores from birth to end of intervention on weight, length or head circumference did not differ between groups, nor between the subgroups of small for gestational age infants. Likewise, incidence of NEC (BC: 3/115 vs. CF: 5/117, p = 0.72, unadjusted values), LOS (BC: 23/113 vs. CF: 14/116, p = 0.08) and other morbidities did not differ. BC infants received more protein than CF infants (+10%, p < 0.05) and showed several elevated AA levels (+10-40%, p < 0.05)., Conclusion: Infants fortified with BC showed similar growth but received more protein and showed a moderate increase in plasma AA-levels, compared with CF. Adjustments in protein composition and micronutrients in BC-based fortifiers may be required to fully suit the needs for very preterm infants., Competing Interests: Conflict of interest All authors have no conflicts of interest or financial relationships relevant to this article to disclose. University of Copenhagen holds a patent on the use of bovine colostrum for human infants (PCT/DK2013/050,184) in collaboration with Biofiber Damino that is given a license option. Per T Sangild is listed as sole inventor but has declined any share of potential revenue arising from commercial exploitation of the patent., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

This study aims at understanding the rationale behind performing prefeed gastric aspirations in preterm infants, how nurses and physicians interpret the gastric aspiration and variations between them, and illuminating potential barriers for omitting routine prefeed aspiration. Nurses and physicians from all Danish neonatal intensive care units completed a questionnaire. Of 682 participants, the majority (94%) indicated that they routinely performed prefeed aspiration, primarily to check the feeding tube placement (nurses: 88%, physicians: 46%). Nurses feared necrotizing enterocolitis when observing a large gastric residual (GR) volume (31%) and green-stained GR (63%). Fewer nurses relative to physicians had "no worries" related to large volumes (15% vs 34%) or green-stained GR (14% vs 24%, both P < .01). More nurses than physicians intended to pause enteral feeding when observing green-stained GR (31% vs 16%, P < .01) and more nurses were concerned of completely omitting routine gastric aspirations (90% vs 46%, P < .05). The rationale behind the clinical use of GR volume and color as markers of necrotizing enterocolitis and feeding intolerance differs markedly between nurses and physicians in Denmark. If routine prefeed gastric aspiration should be omitted, special focus on information about early signs of necrotizing enterocolitis and methods to check tube placement is needed., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Human milk does not meet the nutritional needs to support optimal growth of very preterm infants during the first weeks of life. Nutrient fortifiers are therefore added to human milk, though these products are suspected to increase gut dysmotility. The objective was to evaluate whether fortification with bovine colostrum (BC) improves bowel habits compared to a conventional fortifier (CF) in very preterm infants. Methods: In an unblinded, randomized study, 242 preterm infants (26−31 weeks of gestation) were randomized to receive BC (BC, Biofiber Damino, Gesten, Denmark) or CF (FM85 PreNAN, Nestlé, Vevey, Switzerland) as a fortifier. Stools (Amsterdam Stool Scale), bowel gas restlessness, stomach appearance score, volume, and frequency of gastric residuals were recorded before each meal until 35 weeks post-menstrual age. Results: As intake of fortifiers increased, stools became harder in both groups (p < 0.01) though less in BC infants (p < 0.05). The incidence of bowel gas restlessness increased with laxative treatments and days of fortification in both groups (p < 0.01), but laxatives were prescribed later in BC infants (p < 0.01). With advancing age, stomach appearance scores improved, but more so in BC infants (p < 0.01). Conclusions: Although there are limitations, a minimally processed, bioactive milk product such as BC induced similar or slightly improved bowel habits in preterm infants.

Neonatal herpes simplex disease (HSV) is a rare but life-threatening infection associated with high rates of morbidity and mortality. Recent studies indicate that the incidence rate has continued to rise over the past decades, while the mortality remains unchanged. Early clinical suspicion of HSV and parenteral antiviral treatment of acute disease is essential for the prognosis. The subsequent use of suppressive therapy with oral acyclovir has further enhanced the long-term prognosis. This review presents evidence of risk factors, clinical presentation, prevention, and management of HSV in newborns.

Purpose: Paracetamol is recommended as a first-line treatment for pain and fever in paediatric patients. Intravenous (IV) infusions are recommended to be administered as a 15-min infusion to minimize local tissue trauma and related pain. The purpose of this study was to demonstrate that IV paracetamol could be administered during 5 ​min or less in paediatric patients without causing related adverse reactions., Methods: Prospective, observational safety study including children aged <18 years who received IV paracetamol. Pain scores before and after the paracetamol infusions were obtained using VAS, FLACC, COMFORT neo, or COMFORT behaviour scales with scores from 0 to 10 representing no pain to worst pain. Further, objective signs of inflammation at the infusion site were registered., Findings: We included 44 patients (median age 2.8 years, range 0.01-17.0 years) who received paracetamol in a peripheral venous catheter (n ​= ​22) or central venous catheter (n ​= ​22). In total, the 93 paracetamol infusions had a median infusion time of 3:00 ​min, range 0:40 to 5:00 ​min. After infusions, pain scores were lower, compared to before infusions (mean change -0.26, 95% confidence interval -0.45 to -0.07, P  ​= ​0.007), and no objective signs of inflammation were reported., Implications: This safety study indicates that IV paracetamol can be administered in paediatric patients with a shorter infusion time than recommended without causing adverse reactions. The results may contribute to a more efficient workflow at paediatric departments., Competing Interests: None., (© 2021 The Authors.)

Objectives and study: Gut motility in infants mature with increasing post-menstrual age and is affected by numerous hormonal, immunological and nutritional factors. However, it remains unclear how age and diet influence gut motility and its relation to feeding intolerance and gastric residuals in preterm neonates. Using preterm piglets as a model for infants, we investigated if contrast passage rate, as determined by X-ray contrast imaging, is affected by gestational age at birth, advancing postnatal age and different milk diets. Methods: Contrast passage rate was evaluated using serial abdominal X-ray imaging on postnatal day 4 and 18 in preterm and near-term piglets fed infant formula, colostrum or intact bovine milk, with or without added fortifier (total n = 140). Results: Preterm piglets had a faster small intestinal passage rate of contrast solution at day 4 of life than near-term piglets (SIEmpty, hazard ratio (HR): 0.52, 95%CI [0.15, 0.88], p < 0.01). Formula fed piglets at day 4 had a faster passage rate of contrast to caecum (ToCecum, HR: 0.61, 95%CI [0.25,0.96], p = 0.03), and through the colon region (CaecumToRectum, p < 0.05, day 4) than colostrum fed preterm piglets. The time for contrast to leave the stomach, and passage through the colon in day 4 preterm piglets were slower than in older piglets at day 18 (both, p < 0.05). Adding a nutrient fortifier increased body growth, gastric residuals, intestinal length and weight, but did not affect any of the observed passage rates of the contrast solution. Conclusion: Serial X-ray contrast imaging is a feasible method to assess food passage rate in preterm piglets. Contrast passage rate through different gut segments is affected by gestational age at birth, postnatal age, and milk diet. The preterm piglet could be a good model to investigate clinical and dietary factors that support maturation of gut motility and thereby feeding tolerance and gut health in preterm infants., 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 Kappel, Sangild, Scheike, Friborg, Gormsen and Aunsholt.)

Background: Necrotizing enterocolitis (NEC) is a serious intestinal inflammatory disease in preterm infants. High volume of gastric residual (GR) after oral feedings is often used as a predictor of NEC, but evidence is limited. Using NEC-sensitive preterm piglets as models, we hypothesized that GR mass and related plasma biomarkers predict early onset of NEC., Methods: In total, 258 newborn preterm piglets were fed bovine milk-based formulas for 5 days. At euthanasia, the stomach, small intestine, and colon were evaluated for NEC lesions. Mass, acidity, gastrin, and bile acid levels were determined for GR content, together with gastrin, glucagon-like peptide 2 (GLP-2), and gastric inhibitory polypeptide (GIP) levels in plasma., Results: In total, 48% of piglets had NEC lesions in the small intestine and/or colon. These piglets had higher GR mass (+32%, P < 0.001) and lower gastric bile acid concentrations (-22%, P < 0.05) than piglets without NEC lesions. The positive and negative predictive values for these markers were 34%-61%. Gastric acidity, gastrin, GLP-2, and GIP levels were similar for piglets with and without NEC lesions., Conclusion: Elevated GR mass correlates positively with NEC lesions but may be a poor predictor of NEC, even when combined with other biomarkers. More knowledge about gastric emptying and gut transit in preterm neonates is required to understand how GR volume and composition relate to morbidities, such as NEC, in preterm neonates., (© 2020 American Society for Parenteral and Enteral Nutrition.)

Background: Immature gut motility in preterm neonates may be a risk factor for necrotizing enterocolitis (NEC). Using preterm pigs as a model for infants, we hypothesized that intestinal dysmotility precedes NEC development., Methods: Eighty-five preterm pigs were fed increasing amounts of milk diets to induce NEC lesions, as detected at autopsy on day 5. Gut transit time was determined on day 4 by x-ray imaging after oral intake of contrast solution., Results: No clinical or radiological signs of NEC were detected on day 4, but macroscopic NEC lesions were recorded in 59% of pigs (n = 50) on day 5. Relative to pigs without NEC (noNEC, n = 35), pigs with small intestinal lesions (siNEC, n = 18) showed delayed stomach emptying time (StEmpty) and time for contrast to reach cecum (ToCecum) already on day 4. Pigs with lesions only in colon (coNEC, n = 20) showed more diarrhea, shorter ToCecum time, but longer small intestinal emptying time (SiEmpty). ToCecum time predicted siNEC and coNEC lesions with a receiver-operator characteristic area under the curve of 78-81%., Conclusions: Region-dependent changes in gut transit time is associated with early NEC development in preterm pigs. How gut dysmotility is related to NEC in preterm infants requires further investigations., Impact: Using preterm pigs as a model for preterm infants, we show that gut transit time, using serial x-ray contrast imaging, was changed in individuals with NEC-like lesions before they showed the typical radiological signs of NEC. Thus prolonged transit time across the entire gut was recorded when NEC lesions appeared in the small intestine but not when lesions were detected only in the colon. Until now, recordings of food transit have mainly investigated changes in the upper gut. Using serial x-rays, this study describes food transit across the entire gut and documents a region-dependent effect of NEC lesions on gut transit changes in preterm individuals. The findings provide proof of concept for use of x-ray contrast imaging as a tool to monitor gut transit in preterm pigs as models for infants. Delayed passage across the entire gut may be an early sign of small intestinal NEC, at least in pigs. More studies are needed to confirm relations in infants. In the future, it might be possible to use x-ray contrast imaging in preterm infants to better understand gut motility in relation to early NEC progression and need for medical NEC treatment.

Human milk is the optimal diet for infant development, but infant milk formula (IMF) must be available as an alternative. To develop high-quality IMF, bovine milk processing is required to ensure microbial safety and to obtain a protein composition that mimics human milk. However, processing can impact the quality of milk proteins, which can influence gastro-intestinal (GI) tolerance by changing digestion, transit time and/or absorption. The aim of this study was to evaluate the impact of structural changes of proteins due to thermal processing on gastro-intestinal tolerance in the immature GI tract. Preterm and near-term piglets received enteral nutrition based on whey protein concentrate (WPC) either mildly pasteurized (MP-WPC) or extensively heated (EH-WPC). Clinical symptoms, transit time and gastric residuals were evaluated. In addition, protein coagulation and protein composition of coagulates formed during in vitro digestion were analyzed in more detail. Characterization of MP-WPC and EH-WPC revealed that mild pasteurization maintained protein nativity and reduced aggregation of β-lactoglobulin and α-lactalbumin, relative to EH-WPC. Mild pasteurization reduced the formation of coagulates during digestion, resulting in reduced gastric residual volume and increased intestinal tract content. In addition, preterm piglets receiving MP-WPC showed reduced mucosal bacterial adherence in the proximal small intestine. Finally, in vitro digestion studies revealed less protein coagulation and lower levels of β-lactoglobulin and α-lactalbumin in the coagulates of MP-WPC compared with EH-WPC. In conclusion, minimal heat treatment of WPC compared with extensive heating promoted GI tolerance in immature piglets, implying that minimal heated WPC could improve the GI tolerance of milk formulas in infants.

This review summarises the present knowledge of nutrition for infants. Breastfeeding and mother's own milk is recommended for both term and preterm born infants. Much research has been centred on providing optimal nutrition in very preterm infants to improve both their short- and long-term outcomes. Growth charts are very important for all those taking care of and treating both term and preterm born infants. In very preterm infants, the optimal growth velocity remains uncertain. Growth failure is harmful, but rapid weight gain may be harmful as well. Growth can in both term and preterm born infants be evaluated by using WHO growth standards 2006 and 2017.

The incidence of type 1 diabetes (T1D) is increasing, and obesity may be a contributing factor by increasing the risk and accelerating the onset. We investigated the relation between childhood body mass index z-scores (BMIz) and the later risk of T1D, including association with age at onset of T1D. The study included 238 cases and 10 147 controls selected from the Copenhagen School Health Record Register (CSHRR). Cases of T1D were identified in the Danish Registry of Childhood and Adolescent Diabetes and 2 regional studies and linked to CSHRR. Using conditional logistic regression models, the association of childhood prediagnostic BMIz at 7 and 13 years of age and changes between these ages with subsequent risk (odds ratio, OR) of T1D was estimated. A greater BMIz at 7 and 13 years of age was associated with increased risk of T1D with OR of 1.23 (confidence interval, CI 1.09-1.37; P = .0001) and 1.20 (CI 1.04-1.40; P = .016), respectively. The risk was increased by upward changes in z-scores from birth to 7 years (OR=1.21, P = .003) and from 7 to 13 years of age (OR=1.95, P = .023), but in the latter age interval also by a decline in BMIz (OR = 1.91, P = .034). There were no associations between BMIz at 7 and 13 years of age and the age of onset (P = .34 and P = .42, respectively). Increased BMIz is associated with a moderate increase in risk of T1D, but with no relation to age at onset within the analyzed age range. Increased BMIz over time is unlikely to explain the rising incidence of T1D., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Minimal enteral nutrition (MEN) may induce a diet-dependent stimulation of gut adaptation following intestinal resection. Bovine colostrum is rich in growth factors, and we hypothesized that MEN with colostrum would stimulate intestinal adaptation, compared with formula, and would be well tolerated in patients with short bowel syndrome., Methods: In experiment 1, 3-day-old piglets with 50% distal small intestinal resection were fed parenteral nutrition (PN, n = 10) or PN plus MEN given as either colostrum (PN-COL, n = 5) or formula (PN-FORM, n = 9) for 7 days. Intestinal nutrient absorption and histomorphometry were performed. In experiment 2, tolerance and feasibility of colostrum supplementation were tested in a pilot study on 5 infants who had undergone intestinal resection, and they were compared with 5 resected infants who served as controls., Results: In experiment 1, relative wet-weight absorption and intestinal villus height were higher in PN-COL vs PN (53% vs 23% and 362 ± 13 vs 329 ± 7 µm, P < .05). Crypt depth and tissue protein synthesis were higher in PN-COL (233 ± 7 µm, 22%/d) and PN-FORM (262 ± 13 µm, 22%/d) vs PN (190 ± 4 µm, 9%/d, both P < .05). In experiment 2, enteral colostrum supplementation was well tolerated, and no infants developed clinical signs of cow's milk allergy., Conclusion: Minimal enteral nutrition feeding with bovine colostrum and formula induced similar intestinal adaptation after resection in piglets. Colostrum was well tolerated by newly resected infants, but the clinical indication for colostrum supplementation to infants subjected to intestinal resection remains to be determined., (© 2017 American Society for Parenteral and Enteral Nutrition.)

Background: Necrotizing enterocolitis and congenital gastrointestinal malformations in infants often require intestinal resection, with a subsequent risk of short bowel syndrome (SBS). We hypothesized that immediate intestinal adaptation following resection of the distal intestine with placement of a jejunostomy differs between preterm and term neonates., Methods: Preterm or term piglets were born by cesarean section and fed enterally for 2 days. On day 2, piglets were subjected to 50% distal intestinal resection with placement of a jejunostomy. On the following 4-5 days, piglets received parenteral nutrition with gradually increasing doses of enteral nutrition (bovine colostrum). Intestinal tissue samples were collected at delivery and 2 and 6-7 days after birth for histological examination and assessment of digestive enzyme activities., Results: Preterm and term piglets showed similar increases in intestinal weight and digestive enzyme activities from birth to 2 days. On days 6-7 after birth, the remnant intestine showed a similar density (g/cm) and mucosal mass in term and preterm piglets, but villus height, crypt depth, enzyme activities (sucrase, maltase, dipeptidyl peptidase IV [DPPIV]), and hexose uptake capacity were significantly higher in term piglets (P < .05). Preterm piglets were more prone to develop hypoglycemia, respiratory distress syndrome, dehydration, and circulatory instability after surgery compared with term piglets., Conclusion: Studies on intestinal adaptation after resection are feasible in both preterm and term piglets, but intensive clinical support is required when rearing preterm piglets with SBS. Physiological instability and immaturity of the intestine may explain the fact that immediate adaptation after resection is reduced in preterm vs term neonates., (© 2014 American Society for Parenteral and Enteral Nutrition.)

Background: Management of short bowel syndrome (SBS) aims to achieve intestinal autonomy to prevent fluid, electrolyte, and nutrient deficiencies and maintain adequate development. Remnant intestinal adaptation is required to obtain autonomy. In the newborn pig, colostrum has been shown to support intestinal development and hence adaptive processes., Aim: The efficacy of bovine colostrum to improve intestinal function in children with SBS was evaluated by metabolic balance studies., Materials and Methods: Nine children with SBS were included in a randomized, double-blind, crossover study. Twenty percent of enteral fluid intake was replaced with bovine colostrum or a mixed milk diet for 4 weeks, separated by a 4-week washout period. Intestinal absorption of energy and wet weight was used to assess intestinal function and the efficacy of colostrum., Results: Colostrum did not improve energy or wet weight absorption compared with the mixed milk diet (P = 1.00 and P = .93, respectively). Growth as measured by weight and knemometry did not differ between diets (P = .93 and P = .28). In these patients, <150% enteral energy absorption of basal metabolic rate and 50% enteral fluid absorption of basal fluid requirement suggested intestinal failure and a need for parenteral nutrition (PN)., Conclusion: Inclusion of bovine colostrum to the diet did not improve intestinal function. Metabolic nutrient and wet weight balance studies successfully assessed intestinal function, and this method may distinguish between intestinal insufficiency (non-PN-dependent) and intestinal failure (PN-dependent) patients.

Introduction: An educational reform introduced by the National Health Board in 2004 made the Department of Paediatrics, Kolding Sygehus, introduce tuition outpatient clinics. To measure the quality of this initiative after 18 months, an evaluation was performed involving doctors in training positions, the supervising specialists, parents and adolescents., Material and Methods: Residents receiving training as paediatricians or general practitioners staffed outpatient clinics where they were being supervised by consultants and nurses. This initiative was evaluated by an electronic questionnaire which was answered in May 2007 by all participants. The satisfaction of parents and adolescents was continuously monitored on a touch-screen computer between 1 January and 31 June 2007. Data are presented descriptively and differences compared by chi(2)-tests., Results: Eleven of 15 (73%) residents and 5 of 6 (83%) consultants found that participating in outpatient clinics provided a good training opportunity. Residents found that teaching by demonstration was practiced more seldomly than stated by consultants (33% vs. 100%). In general, visitors' satisfaction was high. However, 95% of parents and 90% of adolescents were satisfied by the explanations given by the consultants as compared with only 91% (p < 0.01) and 81% (p = 0.06), respectively, for that given by the residents. Among the parents, 97% had confidence in treatment given by the consultants as compared with 93% in that given by the residents (p = 0.02)., Conclusion: Participation in outpatient clinics has a high training value. It seems that in the future communication should be in focus in the supervision of doctors in training positions.