Identifying effect modifiers of systemic hydrocortisone treatment initiated 7-14 days after birth in ventilated very preterm infants on long-term outcome: secondary analysis of a randomised controlled trial.

OBJECTIVE: To explore clinical effect modifiers of systemic hydrocortisone in ventilated very preterm infants for survival and neurodevelopmental outcome at 2 years' corrected age (CA). DESIGN: Secondary analysis of a randomised placebo-controlled trial. SETTING: Dutch and Belgian neonatal intensive care units. PATIENTS: Infants born <30 weeks' gestational age (GA), ventilator-dependent in the second week of postnatal life. INTERVENTION: Infants were randomly assigned to systemic hydrocortisone (cumulative dose 72.5 mg/kg; n=182) or placebo (n=190). MAIN OUTCOME MEASURES: The composite of death or neurodevelopmental impairment (NDI) at 2 years' CA and its components. Candidate effect modifiers (GA, small for GA, respiratory index, sex, multiple births, risk of moderate/severe bronchopulmonary dysplasia or death) were analysed using regression models with interaction terms and subpopulation treatment effect pattern plots. RESULTS: The composite outcome was available in 356 (96.0%) of 371 patients (one consent withdrawn). For this outcome, treatment effect heterogeneity was seen across GA subgroups (<27 weeks: hydrocortisone (n=141) vs placebo (n=156), 54.6% vs 66.2%; OR 0.61 (95% CI 0.38 to 0.98); ≥27 weeks: hydrocortisone (n=30) vs placebo (n=31), 66.7% vs 45.2%; OR 2.43 (95% CI 0.86 to 6.85); p=0.02 for interaction). This effect was also found for the component death (<27 weeks: 20.1% vs 32.1%; OR 0.53 (95% CI 0.32 to 0.90); ≥27 weeks: 28.1% vs 16.1%; OR 2.04 (95% CI 0.60 to 6.95); p=0.049 for interaction) but not for the component NDI. No differential treatment effects were observed across other subgroups. CONCLUSION: This secondary analysis suggests that in infants <27 weeks' GA, systemic hydrocortisone may improve the outcome death or NDI, mainly driven by its component death. There was insufficient evidence for other selected candidate effect modifiers.

Adsorption of insulin onto neonatal infusion sets: should intravenous administration of insulin to treat hyperglycemia in preterm babies on the NICU be proceeded by priming of the intravenous system, adding of albumin, or non-priming to get to a stable insulin dose?

Insulin is used to treat neonatal hyperglycaemia when blood glucose concentrations are consistently high, and to treat neonatal diabetes. Within this brief report, a review of the existing literature is conducted to determine if intravenous administration of insulin should be proceeded by priming of the intravenous system, adding of albumin, or non-priming to get a stable insulin dose. Within this literature search, we focused on experimental insulin adsorption data (in vitro studies).

Implementation of Nationwide Evidence- and Consensus-Based Guidelines to Harmonize Neonatal Care in The Netherlands.

BACKGROUND: A Dutch committee for National Guidelines in Neonatology developed nineteen evidence- and consensus-based guidelines to be used in all Dutch neonatal intensive care units (NICUs). The primary goal was to make clinical practices more uniform and consistent. OBJECTIVE: This study investigated to what extent the guidelines were implemented and which factors played a role in implementation. STUDY DESIGN: A mixed method study design was used to investigate both the level and the process of implementation. A nationwide, multicenter, cross-sectional survey was performed using a validated instrument for measuring the level of implementation (Normalization MeAsure Development questionnaire, NoMAD). The number of implemented guidelines per NICU and the frequency and content of the amendments that NICUs made to the original consensus guidelines were analyzed. Through semi-structured interviews, perceived barriers and facilitators for implementation were explored. PARTICIPANTS: Fellows and neonatologists working at all ten Dutch level 3-4 NICUs were eligible. RESULTS: On an average, NICUs implemented 12.6 (of 19) guidelines (range 6-17). The Normalization Process Scale was 54 (of 65). Main influencing factors impeding implementation were guideline-related (e.g., unpractical, lengthy guidelines) and personal (e.g., an active representative responsible for local implementation). CONCLUSION: The implementation of our guidelines appears to be successful. Ways for improvement can be distinguished in personal, guideline-related and external factors. Empowerment of local representatives was considered most essential.

Migration of Umbilical Venous Catheters.

OBJECTIVE: Migration of umbilical venous catheters (UVCs) after initial correct position has been described. The aim of this study was to assess the incidence of malposition of the tip of the UVCs at 24 to 36 hours postinsertion. STUDY DESIGN: Retrospective analysis of all neonates who had UVC placement in a 14-month period. The primary outcome was the rate of UVCs incorrectly positioned 24 to 36 hours after initial correct placement, defined as the UVC tip below or more than 5 mm above the level of the right diaphragm on a thoracoabdominal X-ray. RESULTS: We included 86 neonates with a median (range) birth weight of 1,617 (535-5,000) grams, and gestational age of 31 (24-42) weeks. Of the 80 UVCs that were further analyzed, only in 38 (48%) of 80 patients, the tip of the UVC still had a correct position 24 to 36 hours after initial placement. In 22 (28%) of 80 patients, the UVCs had a position that was too high and in 20 (25%) that was too low. CONCLUSION: More than half of UVCs migrated at 24 to 36 hours postinsertion to positions known to have higher complication rates. We, therefore, recommend follow-up evaluation at 24 to 36 hours postinsertion, to prevent complications from malposition.

Maternal use of prednisolone is unlikely to be associated with neonatal adrenal suppression-a single-center study of 16 cases.

The use of supra-physiological, exogenous corticosteroids in pregnancy may lead to neonatal adrenal suppression. We report on a single-center, case series study carried out between 2006 and 2014, which included all newborns (n = 16) of mothers using prednisolone ≥10 mg/day during pregnancy. Newborns were routinely assessed according to hospital protocol, with follow-up until 6 weeks after birth. We investigated the clinical symptoms and biochemical findings of adrenal suppression occurring in the newborns. Mean dose of maternal prednisolone was 29.7 ± 16.1 mg/day with a mean duration of 18.4 ± 15.4 weeks. Five newborns showed hypoglycemia with normal serum cortisol concentrations and urinary steroid profiles. Two newborns had abnormal urinary steroid profiles, probably the result of prematurity, but with adequate adrenal stress response during clinical sepsis. CONCLUSION: In this retrospective case series, we found no evidence of prolonged effects of maternal prednisolone use during pregnancy on the neonatal hypothalamic-pituitary-adrenal axis. What is known: • The use of prednisolone during pregnancy may cause increased steroid levels in the fetus by partially passing through the placenta. • So far, there was very limited data available on the occurrence of adrenal suppression in the newborn of mothers using prednisolone during pregnancy. What is new: • The use of high-dosage prednisolone during pregnancy for ≥1 week (mean duration of 18.4 ± 15.4 weeks), prior to delivery, appears to have little influence on the neonatal hypothalamic-pituitary-adrenal axis.

Biallelic Truncating Mutations in ALPK3 Cause Severe Pediatric Cardiomyopathy.

BACKGROUND: Cardiomyopathies are usually inherited and predominantly affect adults, but they can also present in childhood. Although our understanding of the molecular basis of pediatric cardiomyopathy has improved, the underlying mechanism remains elusive in a substantial proportion of cases. OBJECTIVES: This study aimed to identify new genes involved in pediatric cardiomyopathy. METHODS: The authors performed homozygosity mapping and whole-exome sequencing in 2 consanguineous families with idiopathic pediatric cardiomyopathy. Sixty unrelated patients with pediatric cardiomyopathy were subsequently screened for mutations in a candidate gene. First-degree relatives were submitted to cardiac screening and cascade genetic testing. Myocardial samples from 2 patients were processed for histological and immunohistochemical studies. RESULTS: We identified 5 patients from 3 unrelated families with pediatric cardiomyopathy caused by homozygous truncating mutations in ALPK3, a gene encoding a nuclear kinase that plays an essential role in early differentiation of cardiomyocytes. All patients with biallelic mutations presented with severe hypertrophic and/or dilated cardiomyopathy in utero, at birth, or in early childhood. Three patients died from heart failure within the first week of life. Moreover, 2 of 10 (20%) heterozygous family members showed hypertrophic cardiomyopathy with an atypical distribution of hypertrophy. Deficiency of alpha-kinase 3 has previously been associated with features of both hypertrophic and dilated cardiomyopathy in mice. Consistent with studies in knockout mice, we provide microscopic evidence for intercalated disc remodeling. CONCLUSIONS: Biallelic truncating mutations in the newly identified gene ALPK3 give rise to severe, early-onset cardiomyopathy in humans. Our findings highlight the importance of transcription factor pathways in the molecular mechanisms underlying human cardiomyopathies.

Vein of Galen Aneurysmal Malformation in Neonates Presenting With Congestive Heart Failure.

The authors report the case of a neonate presenting with signs of a congenital cardiac disease. Echocardiography showed a structural normal heart, right-to-left ductal flow, a dilated superior caval vein, and reversed diastolic flow in the proximal descending aorta. Brain magnetic resonance imaging showed a vein of Galen arteriovenous malformation. This highlights the importance of considering an intracranial cause in the differential diagnosis of neonatal congestive heart failure.

Similar Occurrence of Febrile Episodes Reported in Non-Atopic Children at Three to Five Years of Age after Prebiotics Supplemented Infant Formula.

This is a follow up study of a multicenter randomised placebo-controlled trial in seven centres in five West European countries. The RCT assessed the effect of infant formula supplemented with a mixture of prebiotics (with neutral short-chain and long-chain oligosaccharides and pectin-derived acidic oligosaccharides) during infancy in term-born children (n=1130). In the follow-up study 672 children (60% of the study population) participated: 232 (56%) from the prebiotics group (PG), 243 (58%) from the control group (CG), and 197 (66%) from the non-randomised breast-fed group (BG). The primary outcome was the occurrence of febrile episodes at three to five years of age prospectively documented by the parents: in the PG 1.17 (interquartile range 0.50-2.08) episodes per year versus 1.20 (0.52-2.57) in the CG; and 1.48 (0.65-2.60) in the BG. This specific prebiotics mixture given during infancy in healthy non-atopic subjects does not decrease febrile episodes and therefore seems not to prevent infection between their third and fifth birthday.

Jejunoileal atresia and cystic fibrosis: don't miss it.

BACKGROUND: While an increased prevalence of cystic fibrosis (CF) in patients with jejunal atresia and ileal atresia (JIA) has been described previously, it still may not be a practice routine to indicate a sweat test or DNA test for CFTR mutations in newborns presenting with JIA. Leading textbooks do not mention JIA as a possible presenting clinical feature of CF. We describe two cases of JIA with a delayed diagnosis of CF (4 months [post mortem] and 19 months). This led to a retrospective review of all patients with JIA in our hospital. We hypothesised that also in the past although indicated further testing for CF had not always been performed. METHODS: Over an 18-year period from January 1991 until December 2008, all cases of JIA in our centre were reviewed (n=50). We compared patients who have been tested for CF (n=18) with patients who have not been tested for CF (n=32), with respect to their patient characteristics, either by logistic regression analysis or a nonparametric test (p<0.05). RESULTS: Of all 50 patients the proportion of infants actually tested for CF was 18 (36%). A statistical significant difference between the group of patients who were tested for CF versus the group of those who were not tested was found in a higher occurrence of postoperative bilious retention after 7 days (56% versus 25%, respectively), and postoperative complications (78% versus 34%, respectively). CF was confirmed in 4 (8%). CONCLUSION: Testing for CF in newborns presenting with JIA does not appear to be common practice. A timely diagnosis of CF leads to presymptomatic treatment and has beneficial effects on morbidity and mortality. CF should be tested for in all children with JIA. We recommend a sweat test for term children and CFTR DNA testing as a first step for preterm infants. Medical professional awareness may be increased if future editions of leading text books in the relevant fields should include JIA as an indication to follow an appropriate CF-diagnostic algorithm. TRIAL REGISTRATION: Statement on reporting of a clinical trial: This article is not based on a clinical trial.

Antibiotic use in infants in the first year of life in five European countries.

AIM: To assess in infants the number of illness episodes treated with antibiotics and prescription rates in five European countries. METHODS: This study was embedded in a multicenter nutritional intervention study and was conducted in five European countries. Infants were followed until 1 year of age. Illness episodes and prescriptions of systemic antibiotics were recorded by the parents. RESULTS: Illness episodes were caused by upper respiratory tract infections (URTIs) in 55-64% and by otitis media (OM) in 2-6.8%. URTIs were statistically significant and more frequently treated with antibiotics in Italy (18.8%), and less frequently in Switzerland (1.4%). OM was statistically significant and less frequently treated with antibiotics in the Netherlands (55%) when compared to Italy (82%). The antibiotic prescription rate varied between countries, ranging from 0.2 to 1.3 prescriptions per infant per year. CONCLUSIONS: As the frequency of illness episodes did not differ between countries, other factors, such as physician's attitude, parental pressure or other socio-economic determinants, most likely play a role in antibiotic prescribing habits in the first year of life.

Tolerance and safety evaluation in a large cohort of healthy infants fed an innovative prebiotic formula: a randomized controlled trial.

BACKGROUND: the addition of oligosaccharides to infant formula has been shown to mimic some of the beneficial effects of human milk. The aim of the study was to assess the tolerance and safety of a formula containing an innovative mixture of oligosaccharides in early infancy. METHODOLOGY/PRINCIPAL FINDINGS: this study was performed as a multi-center, randomized, double-blind, placebo-controlled trial including healthy term infants. Infants were recruited before the age of 8 weeks, either having started with formula feeding or being fully breast-fed (breastfeeding group). Formula-fed infants were randomized to feeding with a regular formula containing a mixture of neutral oligosaccharides and pectin-derived acidic oligosaccharides (prebiotic formula group) or regular formula without oligosaccharides (control formula group). Growth, tolerance and adverse events were assessed at 8, 16, 24 and 52 weeks of age. The prebiotic and control groups showed similar mean weight, length and head circumference, skin fold thicknesses, arm circumference gains and stool frequency at each study point. As far as the anthropometric parameters are concerned, the prebiotic group and the control group did not attain the values shown by the breastfeeding group at any study point. The skin fold thicknesses assessed in the breastfeeding group at 8 weeks were strikingly larger than those in formula fed infants, whereas at 52 weeks were strikingly smaller. The stool consistency in the prebiotic group was softer than in the control group at 8, 16 and 24 weeks (p<0.001) and closer to that of the breastfeeding group. There was no difference in the incidence of adverse events between the two formula groups. CONCLUSIONS: our findings demonstrate the tolerability and the long term safety of a formula containing an innovative mixture of oligosaccharides in a large cohort of healthy infants. TRIAL REGISTRATION: drks-neu.uniklinik-freiburg.de DRKS 00000201.

Fluorescent cell barcoding as a tool to assess the age-related development of intracellular cytokine production in small amounts of blood from infants.

Fluorescent Cell Barcoding (FCB) is a flow cytometric technique which has been used for assessing signaling proteins. This FCB technique has the potential to be applied in other multiparameter analyses. Since data on antigen (Ag)-specific T-cell immune responses, like intracellular cytokine production, are still lacking in infants because limited blood volumes can be obtained for analysis, the FCB technique could be very useful for this purpose. The objectives of this study were to modify the FCB method to be able to measure multiple Ag-specific cytokine reponses in T-cells upon simultaneous stimulation by various antigens and mitogens in small amounts of blood and to investigate the cytokine pattern of T-cell subsets in healthy infants aged six and twelve months. Blood samples, collected from 20 healthy infants aged six and twelve months, were stimulated in vitro with the antigens: phorbol-myristate-acetate (PMA), purified-protein-derivative (PPD), Tetanus-toxoid (TT), Staphylococcal-enterotoxin-B (SEB), and phytohemagglutinin (PHA). Each stimulus was barcoded by labelling with different intensities of fluorescent cell barcoding (FCB) markers. Intracellular production of interleukin-2, interferon-gamma, and tumor necrosis factor-alpha was measured simultaneously in just one blood sample of 600 µl whole blood. Significant age-related differences in cytokine production were shown for PMA, PHA, and TT in CD4(+) T-cells, and for PMA, PHA, SEB, and TT in CD8(+) T-cells. The intracellular cytokine production by CD4(+) and CD8(+) T-cells was higher at twelve months compared to six months of age for all antigens, except for PMA, which was lower at the age of twelve months. Based on the consistency in both T-cell subsets, we conclude that the new FCB method is a promising tool to investigate the age-related development of intracellular cytokine production in infants.

Do prebiotics reduce the number of fever episodes in healthy children in their first year of life: a randomised controlled trial.

The objective of the present study was to assess the effect of adding specific prebiotics to standard formula feeding on the number of fever episodes in the first year of life. In the present randomised, double-blind, placebo-controlled trial in seven centres in five West European countries, 830 healthy term infants, without a first-degree family history of allergic disease, of mothers who indicated to give only formula feeding were randomised either to receive a standard non-hydrolysed cows' milk-based formula to which a mixture of specific oligosaccharides was added (prebiotics group (PG)), or to receive a similar formula without oligosaccharides (control group (CG)). A separate reference group consisted of 300 breast-fed infants. The primary outcome was the number of fever episodes prospectively documented by the parents. There was no difference in the number of fever episodes between the PG (median value 1·19; 25th-75th percentile 0·09-2·34) and CG (1·16; 25th-75th percentile 0·06-2·38). The median number of fever episodes in the separate breast-feeding reference group was 1·24 (25th-75th percentile 0·51-3·45). There was no effect of adding specific prebiotics to standard formula feeding in reducing the number of fever episodes in the present study.

A mixture of three prebiotics does not affect vaccine specific antibody responses in healthy term infants in the first year of life.

BACKGROUND: Previous studies have shown, that prebiotics can modulate the immune response in infants at risk for allergy, leading to a lower incidence of atopic dermatitis. Few studies have evaluated the effect of prebiotic carbohydrates alone on the vaccine-specific antibody response as a marker for the development of the immune system in healthy infants not at risk for allergy. AIM: This study evaluates the effect of adding a specific prebiotic mixture of short chain galacto-oligosaccharides (scGOS)/long chain fructo-oligosaccharides (lcFOS) ratio 9:1 and pectin-derived acidic oligosaccharides (pAOS) to formula feeding on the specific immunoglobulin responses to Haemophilus influenza type b (Hib) and tetanus immunization in healthy non-atopic infants during the first year of life. METHODS: This substudy has been embedded in a multinational multicenter RCT (n=1130 children) to evaluate the effect of study prebiotics on the incidence of fever episodes during the first year of life. The study prebiotics were administered throughout the first year of life. This is a substudy on the vaccine-specific immunoglobulin responses to Hib and tetanus immunizations. Only data of the Dutch children, 80 in the prebiotics group and 84 in the control group, were used for this substudy. They all followed the national vaccination schedule leading to a homogeneous group. Blood was sampled at 6 and 12 months of age. RESULTS: Hib immunizations: median values did not differ between groups at the age of 6 and 12 months. At the age of 12 months, 34 out of 37 (91.9%) infants in the prebiotics group and 31 out of 34 infants (91.2%) in the control group had Hib antibody levels >1.0 µg/ml. Tetanus immunizations: median values did not differ between groups at the age of 6 and 12 months and were above the cut-off value of 0.1 IU/ml in all infants in both the prebiotics and the control group. CONCLUSION: No effect of prebiotics supplementation on vaccination specific antibody levels was found in children up to the age of 12 months; the vaccine specific antibody levels in infants fed the study prebiotics or a control diet were similar during the first year of life. We hypothesize that this specific prebiotic mixture, which resembles the composition of oligosaccharides in human milk, mainly promotes Th1 and Treg dependent immune responses and induces a down regulation of IgE-mediated allergic responses, while the desired vaccine-specific serum antibody responses remain intact.

Reduced occurrence of early atopic dermatitis because of immunoactive prebiotics among low-atopy-risk infants.

BACKGROUND: Most infants developing atopic dermatitis have a low risk for atopy. Primary prevention of atopic dermatitis is difficult. OBJECTIVE: To assess the effect of supplementation of an infant and follow-on formula with prebiotic and immunoactive oligosaccharides on the occurrence of atopic dermatitis in the first year of life. METHODS: Healthy term infants from 5 European countries with low atopy risk were recruited before the age of 8 weeks, either having started with formula feeding or being on full breast-feeding (breast-feeding group). Formula-fed infants were randomized to feeding with a regular formula containing a specific mixture of neutral oligosaccharides and pectin-derived acidic oligosaccharides (prebiotic formula group) or regular formula without oligosaccharides (control formula group). RESULTS: A total of 414 infants were randomized to the prebiotic group and 416 infants to the control group. A total of 300 infants were followed in the breast-feeding group. Up to the first birthday, atopic dermatitis occurred in significantly fewer infants from the prebiotic group (5.7%) than from the control group (9.7%; P = .04). The cumulative incidence of atopic dermatitis in the prebiotic group was in the low range of the breast-feeding group (7.3%). In a Cox regression model, the rate of atopic dermatitis was significantly lower by 44% in the prebiotic group versus the control group (P = .04). The number needed to prevent 1 case of atopic dermatitis by supplementation of prebiotics was 25 infants. CONCLUSION: Formula supplementation with a specific mixture of oligosaccharides was effective as primary prevention of atopic dermatitis in low atopy risk infants.

Pharmacological treatment of young children with permanent junctional reciprocating tachycardia.

Our objective was to assess the efficacy of pharmacological treatment in reducing the incidence of permanent junctional reciprocating tachycardia in young children, or to bring the mean heart rate over 24 h to a normal level. We included 21 children with a median age of 0.05 year seen with permanent junctional reciprocating tachycardia over the period 1990 through 2001. Of these children, two had abnormal left ventricular function. Follow-up visits were made at least every 6 months. We registered the presence of the tachycardia over 24 h, the mean heart rate over 24 h, and cardiac function. Treatment was started with propafenone alone, or in combination with digoxin as the first choice. Treatment was effective in 14 cases (67%), with either complete disappearance of the tachycardia after discontinuation of medication, or continuation in sinus rhythm with medication; partially effective in 4 cases (20%) when the mean heart rate over 24 h on the last Holter recording was less than 1 standard deviation above the normal for age; but was not effective in the remaining 3 cases (14%). In 3 patients treated with propafenone, or 13 given propafenone and digoxin, treatment was effective in 12 (75%), partially effective in 2 (13%), and ineffective in the other 2 (13%). All 21 children had a normal left ventricular function at the end of follow-up. The median duration of follow-up was 2.4 years. Permanent junctional reciprocating tachycardia had disappeared spontaneously in one-third of the children, 5 being less than 1 year old. Adverse effects, seen in 5 cases, were mild or asymptomatic. No signs of proarrhythmia were registered. Pharmacological treatment, either with propafenone alone, or in combination with digoxin, is safe and effective in young children with permanent junctional reciprocating tachycardia. The mean heart rate is normalized, and cardiac function is restored and preserved. Radiofrequency ablation may be delayed to a safer age, with the arrhythmia disappearing spontaneously in one-third.

Unilateral CHARGE association.

UNLABELLED: A case with a predominantly unilateral CHARGE association is reported. The CHARGE association refers to a combination of congenital malformations. This boy had left-sided anomalies consisting of choanal atresia, coloboma and peripheral facial palsy. The infant had a frontal encephalocele, an anomaly not included in the definitions of CHARGE association. CONCLUSION: even when anomalies are predominantly unilateral, the CHARGE association should be considered in the differential diagnosis.